Cannabis in Form Information on Cannabis

Dennis Cruise

Abstract: Cannabis is a federally controlled substance, it’s very familiar to many but its neurobiological substrates are not well-characterized. In the brain, most areas prevalently having cannabinoid receptors have been associated with behavioral control and cognitive effects due to cannabinoids. Study over the last several decades suggested cannabinoids (CBs) exert copious oftentimes opposite effects on countless neuronal receptors and processes. In fact, owing to this plethora of effects, it’s still cryptic how CBs trigger neuronal circuits. Cannabis use has been revealed to cause cognitive deficits from basic motor coordination to more complex executive functions, for example, the aptitude to plan, organize, make choices, solve glitches, remember, and control emotions as well as behavior. Numerous factors like age of onset and duration of cannabis use regulate the severity of the difficulties. People with the cannabis-linked deficiency in executive functions have been found to have trouble learning and applying the skills requisite for fruitful recovery, setting them at amplified risk for deterioration to cannabis use. Exploring the impacts of cannabis on the brain is imperative. Therefore the intention of this study was to analyze the neuropsychological effects and the impact of CBs on the dynamics of neural circuits, and its potential as the drug of addiction.

The present study focused on the use of medicinal cannabis and its derivatives for the treatment of epileptic seizures in children, as well as, adults. " Epilepsy " defined as a chronic non-communicable disorder of the brain had shown to affect people of all age groups. There were many conventional treatments discovered up till date to minimize and alleviate the symptoms produced as a result of epilepsy, yet none among them could provide the long term safety and efficacy of the interventional drug. On the other hand, increased resistance to conventional drug therapy is another issue which has made researchers to think for the alternative treatment for the long run. On an average, it had been estimated that approximately, 50 million people worldwide were suffering from epilepsy, which thus made it one of the most common neurological diseases globally. Epilepsy accounted for 0. 75%, of the global burden of disease due to premature mortality, lost work productivity, health care needs and unhealthy quality of life. In 2012, epilepsy was responsible for approximately 20. 6 million disability-adjusted life years (DALYs) lost. According to WHO survey, it was estimated that about 80% of the people suffering from epilepsy resided in low-and middle-income countries in which three fourths of people could not access the treatment due to cost-effective or non-availability of the treatment in comparison to the people who availed the conventional treatment responded to only approximately 70% of the time. Besides, in many parts of the world, people with epilepsy and their families suffered a lot from stigma and discrimination therefore, making it a social economic burden for hampering the quality of life of the patient as well as, that of the patient caregivers. Several countries (including Canada, Netherlands, and Israel) and 23 of 50 states in the United States had permitted the use of cannabis for medicinal purposes, with or without undergoing a systematic medicines approval process. Epilepsy-related deaths are a significant public health problem, yet are poorly understood and often overlooked. Hence, people with epilepsy are two to three times more likely to die prematurely than people without the disease which is surely a matter of concern to both the health providers and the patient. Abbreviations DALYs = disability-adjusted life years CBD = Cannabinoid SUDEP = Sudden unexpected death in epilepsy GNP = Gross national Product THC = Tetrahydrocannabinol EEG = Electroencephalogram HIPAA = Health Insurance Portability and Accountability Act of 1996 WHO = World Health Organization PAME = Partners against Mortality in Epilepsy

Cannabis is an interesting domesticated crop with a long history of cultivation and use. Strains have been selected through informal breeding programs with undisclosed parentage and criteria. The term "strain" refers to minor morphological differences and grower branding rather than distinct cultivated varieties. We hypothesized that strains sold by different licensed producers are chemotaxonomically indistinguishable and that the commercial practice of identifying strains by the ratio of total THC and CBD is insufficient to account for the reported human health outcomes. We used targeted metabolomics to analyze 11 known cannabinoids and an untargeted metabolomics approach to identify 21 unknown cannabinoids. Five clusters of chemotaxonomically indistinguishable strains were identified from the 33 commercial products. Only 3 of the clusters produce CBDA in significant quantities while the other 2 clusters redirect metabolic resources toward the THCA production pathways. Six unknown metabolites were unique to CBD-rich strains and/or correlated to CBDA and 3 unknowns were found only in THC-rich strains. Together, these data indicate the domestication of the cannabis germplasm has resulted in a loss of the CBDA pathway in some strains and reallocation of resources between CBDA and THCA pathways in others. The impact of domestication is a lack of chemical diversity and loss of biodiversity in modern cannabis strains. Cannabis sativa L. (marijuana) is a dioecious, annual plant from Central Asia that has been used medicinally and recreationally for thousands of years 1. The domestication of cannabis has included human selection, inbreeding and cross breeding as well as natural outcrossing and genome mixing 1. Strains are not easily delineated by genotype and only moderate correlations have been observed between C. indica and C. sativa ancestry. In addition, large genetic variance has been observed within identically named strains 2,3. Standardized, highly controlled programs to breed elite varieties or cultivars by selection of phytochemical profile have been limited 4,5. It is estimated that there are several hundred or perhaps thousands of strains of cannabis currently being cultivated in legal and illegal markets 4. It is possible that chemically identical or very closely related plant material is being sold under several different names by different producers and there is no clear definition of the concept of a "strain". Cannabis producers market their products based on the amounts of total Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) with the assumption that the overall phytochemical composition of the material can be extrapolated from these values, but there is considerable anecdotal evidence suggesting that strains with similar THC/CBD content have different effects on human physiology 6,7. More than 120 different cannabinoids have been described in cannabis 8,9 with the most interesting phytochemistry found in the glandular trichomes on the flowers of the female inflorescences 10. THC is the most researched cannabinoid and there are ten additional classes of cannabinoids with varying chemical structures 8. Cannabinoids are synthesized in acidic forms through the condensation of geranyl diphosphate (GPP) and most commonly olivetolic acid, products of the methyleryth-ritol phosphate (MEP) and polyketide pathways 11,12. There are several other polyketides that can be used in place of olivetolic acid, which contribute to the wide variation within this chemical class 13,14. Neutral cannabinoids are products of decarboxylation from processing and handling harvested flowers. Chemometric models are used to evaluate metabolite datasets to delineate relationships and identify potential influences on phytochemical diversity 15-17. These approaches can be classified as targeted analysis, untar-geted phytochemical discovery, metabolomic profiling or fingerprinting 15. Targeted metabolomics determines

Cannabis in Form Information on Cannabis Chapter 1 Cannabis 1.1 Cannabis (drug) of cannabis preparations containing psychoactive cannabinoids illegal in most countries of the world.* [21]* [22] Medical cannabis refers to the physician-recommended use of cannabis, which is taking place in Canada, Belgium, Australia, the Netherlands, Spain, and 23 U.S. states.* [23] Cannabis use started to become popular in the US in the 1970s.* [24] Support for legalization has increased in the United States and several US states have legalized recreational or medical use.* [25] “Marijuana”redirects here. For other uses, see Marijuana (disambiguation). Cannabis, also known as marijuana among other names,* a[›] is a preparation of the Cannabis plant intended for use as a psychoactive drug or medicine.* [7]* [8]* [9] The main psychoactive part of cannabis is tetrahydrocannabinol (THC); one of 483 known compounds in the plant,* [10] including at least 65 other cannabinoids.* [11] Cannabis can 1.1.1 be used by smoking, vaporization, within food, or as an extract.* [12] Uses Bodily effects of Cannabis is often used for its mental and physical e ects, such as a “high”or “stoned”feeling, a general change in perception, euphoria (heightened mood), and an increase in appetite.* [12]* [13] Short term side e ects may include a decrease in short-term memory, dry mouth, impaired motor skills, red eyes, and feelings of paranoia or anxiety.* [12]* [14]* [15] Long term side e ects may include addiction, decreased mental ability in those who started as teenagers, and behavioral problems in children whose mothers used cannabis during pregnancy.* [12] Onset of effects is within minutes when smoked and about 30 to 60 minutes when cooked and eaten.* [12]* [16] They last for between two and six hours.* [16] Cannabis Eyes: - Reddening - Decreased intra-ocular pressure Mouth: - Dryness Skin: - Sensation of heat or cold Cannabis is mostly used recreationally or as a medicinal drug. It may also be used for religious or spiritual purposes. In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65).* [17] In 2015, 43% of Americans had used cannabis which increased to 51% in 2016.* [18] About 12% have used it in the past year, and 7.3% have used it in the past month.* [19] This makes it the most commonly used illegal drug both in the world and the United States.* [12]* [17] Heart: - Increased heart rate Muscles: - Relaxation The earliest recorded uses date from the 3rd millennium BC.* [20] Since the early 20th century, cannabis has been Main short-term physical e ects of cannabis subject to legal restrictions, with the having, use, and sale 2 1.1. CANNABIS (DRUG) Medical Main article: Medical cannabis 3 pseudohallucinations and ataxia from selective impairment of polysynaptic re exes. In some cases, cannabis can lead to dissociative states such as depersonalization* [34]* [35] and derealization.* [36] Cannabis is used to reduce nausea and vomiting during chemotherapy, to improve appetite in people with HIV/AIDS, to treat chronic pain, and help with muscle spasms.* [26]* [27] Its use for other medical applications is insu cient for conclusions about safety or e cacy. Shortterm use increases minor adverse e ects, but does not appear to increase major adverse e ects.* [28] Long-term effects of cannabis are not clear,* [28]* [29] and there are concerns including memory and cognition problems, risk for addiction, risk of schizophrenia among young people, and the risk of children taking it by accident.* [26] Some immediate undesired side e ects include a decrease in short-term memory, dry mouth, impaired motor skills and reddening of the eyes.* [37] Aside from a subjective change in perception and mood, the most common short-term physical and neurological e ects include increased heart rate, increased appetite and consumption of food, lowered blood pressure, impairment of short-term and working memory,* [38]* [39] psychomotor coordination, and concentration. Some users may experience an episode of acute psychosis, which usually abates after 6 hours, but in rare instances heavy users may nd the symp* The medicinal value of cannabis is disputed. The American toms continuing for many days. [40] Society of Addiction Medicine dismisses medical use because of concerns about dependence and adverse health ef- Spiritual fects.* [30] The US Food and Drug Administration (FDA) states that cannabis is associated with numerous harmful Main article: Entheogenic use of cannabis health e ects, and that signi cant aspects such as content, Cannabis has held sacred status in several religions. It has production, and supply are unregulated. The FDA approves of the prescription of two products (not for smoking) that have pure THC in a small controlled dose as the active substance.* [31] Recreational Main article: E ects of cannabis Cannabis has psychoactive and physiological e ects when Process of making bhang in a Sikh village in Punjab, India. Hindu saints have used bhang for centuries. A woman smoking a marijuana “joint”. consumed.* [32] The immediate desired e ects from consuming cannabis include relaxation and euphoria (the “high”or “stoned”feeling), a general alteration of conscious perception, increased awareness of sensation, increased libido* [33] and distortions in the perception of time and space. At higher doses, e ects can include altered body image, auditory and/or visual illusions, been used in an entheogenic context – a chemical substance used in a religious, shamanic, or spiritual context* [41] in India and Nepal since the Vedic period dating back to approximately 1500 BCE, but perhaps as far back as 2000 BCE. There are several references in Greek mythology to a powerful drug that eliminated anguish and sorrow. Herodotus wrote about early ceremonial practices by the Scythians, thought to have occurred from the 5th to 2nd century BCE. Itinerant Hindu saints have used it in Nepal 4 CHAPTER 1. CANNABIS and India for centuries.* [42] In modern culture the spiri- 1.1.2 Adverse e ects tual use of cannabis has been spread by the disciples of the Rastafari movement who use cannabis as a sacrament and as Main article: Long-term e ects of cannabis an aid to meditation. The earliest known reports regarding Further information: Cannabis in pregnancy the sacred status of cannabis in India and Nepal come from According to the United States Department of Health and the Atharva Veda estimated to have been written sometime around 2000–1400 BCE.* [43] 2.9 Heroin Alcohol 2.7 Crack cocaine Main article: Cannabis consumption Cannabis is consumed in many di erent ways:* [44] Crystal meth 2.5 Social harm score Available forms Cocaine 2.3 Benzodiazepines Nicotine Inhaled solvents 2.1 Methadone 1.9 Dihydrocodeine/Codeine/Tramadol Buprenorphine Ketamine Barbiturates LSD Amphetamine Ecstasy/MDMA 1.7 Methylphenidate/Ritalin Cannabis Magic mushrooms 1.5 1.5 1.7 1.9 2.1 2.3 2.5 2.7 2.9 Personal harm score In a 2011 survey of 292 clinical experts in Scotland, Cannabis ranked last in personal harm and 18th in social harm out of 19 common recreational drugs.* [50] Human Services, there were 455,000 emergency room visits associated with cannabis use in 2011. These statistics include visits in which the patient was treated for a condition induced by or related to recent cannabis use. The drug use A joint prior to rolling, with a paper handmade lter on the left must be “implicated”in the emergency department visit, but does not need to be the direct cause of the visit. Most of the illicit drug emergency room visits involved multiple * • smoking, which typically involves burning and inhal- drugs. [51] In 129,000 cases, cannabis was the only impli* * ing vaporized cannabinoids (“smoke”) from small cated drug. [52] [53] pipes, bongs (portable versions of hookahs with a wa- Heavy, long term exposure to marijuana may have ter chamber), paper-wrapped joints or tobacco-leaf- biologically-based physical, mental, behavioral and social wrapped blunts, and other items.* [45] health consequences and may be “associated with diseases of the liver (particularly with co-existing hepatitis C), * • vaporizer, which heats any form of cannabis to 165– lungs, heart, and vasculature”. [54] It is recommended that 190 °C (329–374 °F),* [46] causing the active ingredi- cannabis use be stopped before and during pregnancy as ents to evaporate into a vapor without burning the plant it can result in negative outcomes for both the mother and * * material (the boiling point of THC is 157 °C (315 °F) baby. [55] [56] A 2014 review found that while cannabis use may be less harmful than alcohol use, the recommenat 760 mmHg pressure).* [47] dation to substitute it for problematic drinking is premature without further study.* [57] • cannabis tea, which contains relatively small concentrations of THC because THC is an oil (lipophilic) and is only slightly water-soluble (with a solubility of 2.8 Toxicity mg per liter).* [48] Cannabis tea is made by rst adding a saturated fat to hot water (e.g. cream or any milk ex- THC, the principal psychoactive constituent of the cannabis cept skim) with a small amount of cannabis.* [49] plant, has low toxicity. The dose of THC needed to kill 50% of tested rodents is extremely high. Acute e ects may in• edibles, where cannabis is added as an ingredient to clude anxiety and panic, impaired attention, and memory one of a variety of foods, including butter and baked (while intoxicated), an increased risk of psychotic sympgoods. toms, and possibly an increased risk of accidents if a per- 5 1.1. CANNABIS (DRUG) not believed to increase risk of lung or upper airway cancer. Evidence for causing these cancers is mixed concerning heavy, long-term use. In general there are far lower risks of pulmonary complications for regular cannabis smokers when compared with those of tobacco.* [66] A 2015 review found an association between cannabis use and the development of testicular germ cell tumors (TGCTs), particularly non-seminoma TGCTs.* [73] Combustion products are not present when using a vaporizer, consuming THC in pill form, or consuming cannabis foods. Cardiovascular A 2015 study found that marijuana's margin of exposure (MOE) values were in a low-risk range, whereas alcohol's MOE was in the “high risk”range. Shown above is the MOE for daily drug use from the study.* [58] son drives a motor vehicle while intoxicated.* [59] Shortterm Cannabis intoxication can hinder the mental processes of organizing and collecting thoughts. This condition is known as temporal disintegration.* [60] Psychotic episodes are well-documented and typically resolve within minutes or hours. There have been few reports of symptoms lasting longer.* [61]* [62] Cannabis has not been reported to cause fatal overdose.* [63] Studies have found that cannabis use during adolescence is associated with impairments in memory that persist beyond short-term intoxication.* [64] Lungs There has been a limited amount of studies that have looked at the e ects of smoking cannabis on the respiratory system.* [65] Chronic heavy marijuana smoking is associated with coughing, production of sputum, wheezing, and other symptoms of chronic bronchitis.* [59] Regular cannabis use has not been shown to cause signi cant abnormalities in lung function.* [66] Short-term use of cannabis is associated with bronchodilation.* [67] Cancer Cannabis smoke contains thousands of organic and inorganic chemical compounds. This tar is chemically similar to that found in tobacco smoke,* [68] and over fty known carcinogens have been identi ed in cannabis smoke,* [69] including; nitrosamines, reactive aldehydes, and polycylic hydrocarbons, including benz[a]pyrene.* [70] Cannabis smoke is also inhaled more deeply than is tobacco smoke.* [71] As of 2015, there is no consensus regarding whether cannabis smoking is associated with an increased risk of cancer.* [72] Light and moderate use of cannabis is There is serious suspicion among cardiologists, spurring research but falling short of de nitive proof, that cannabis use has the potential to contribute to cardiovascular disease.* [74] Cannabis is believed to be an aggravating factor in rare cases of arteritis, a serious condition that in some cases leads to amputation. Because 97% of casereports also smoked tobacco, a formal association with cannabis could not be made. If cannabis arteritis turns out to be a distinct clinical entity, it might be the consequence of vasoconstrictor activity observed from delta-8THC and delta-9-THC.* [75] Other serious cardiovascular events including myocardial infarction, stroke, sudden cardiac death, and cardiomyopathy have been reported to be temporally associated with cannabis use. Research in these events is complicated because cannabis is often used in conjunction with tobacco, and drugs such as alcohol and cocaine.* [76] These putative e ects can be taken in context of a wide range of cardiovascular phenomena regulated by the endocannabinoid system and an overall role of cannabis in causing decreased peripheral resistance and increased cardiac output, which potentially could pose a threat to those with cardiovascular disease.* [77] There is some evidence from case reports that cannabis use may provoke fatal cardiovascular events in young people who have not been diagnosed with cardiovascular disease.* [78] Smoking cannabis has also been shown to increase the risk of myocardial infarction by 4.8 times for the 60 minutes after consumption.* [79] Neurological A 2013 review comparing di erent structural and functional imaging studies showed morphological brain alterations in long-term cannabis users which were found to possibly correlate to cannabis exposure.* [80] A 2010 review found resting blood ow to be lower globally and in prefrontal areas of the brain in cannabis users, when compared to non-users. It was also shown that giving THC or cannabis correlated with increased blood ow in these areas, and facilitated activation of the anterior cingu- 6 late cortex and frontal cortex when participants were presented with assignments demanding use of cognitive capacity.* [81] Both reviews noted that some of the studies that they examined had methodological limitations, for example small sample sizes or not distinguishing adequately between cannabis and alcohol consumption.* [80]* [81] A 2011 review found that cannabis use impaired cognitive functions on several levels, ranging from basic coordination to executive function tasks.* [82] A 2013 review found that cannabis users consistently had smaller hippocampi than nonusers, but noted limitations in the studies analyzed such as small sample sizes and heterogeneity across studies.* [83] A 2012 meta-analysis found that the e ects of cannabis use on neurocognitive functions were “limited to the rst 25 days of abstinence”and that there was no evidence that such use had long-lasting e ects.* [84] A 2015 review found that cannabis use was associated with neuroanatomic alterations in brain regions rich in cannabinoid receptors, such as the hippocampus, prefrontal cortex, amygdala, and cerebellum. The same review found that greater dose of marijuana and earlier age at onset of use were also associated with such alterations.* [85] There is limited evidence that chronic cannabis use can reduce levels of glutamate metabolites in the human brain.* [86] CHAPTER 1. CANNABIS who experiment with marijuana eventually become dependent. The rate goes up to 1 in 6 among those who begin use as adolescents, and one quarter to one-half of those who use it daily according to a NIDA review.* [53] A 2013 review estimates daily use is associated with a 10-20% rate of dependence.* [26] The highest risk of cannabis dependence is found in those with a history of poor academic achievement, deviant behavior in childhood and adolescence, rebelliousness, poor parental relationships, or a parental history of drug and alcohol problems.* [90] Cannabis withdrawal is less severe than withdrawal from alcohol.* [91] Motor vehicle crashes A 2012 meta-analysis found that cannabis use was associated with an increased risk of being involved in a motor vehicle crash.* [92] A 2016 review also found a statistically signi cant increase in crash risk associated with marijuana use, but noted that this risk was“of low to medium magnitude.”* [93] The increase in risk of motor vehicle crash for cannabis use is between 2 and 3 times relative to baseline, whereas that for comparable doses of alcohol is between 6 and 15 times.* [78] It is not clear whether cannabis use a ects the rate of suicide.* [63]* [87] 1.1.3 Chronic use E ects of chronic use may include bronchitis, a cannabis dependence syndrome, and subtle impairments of attention and memory. These de cits persist while chronically intoxicated.* [59] There is little evidence that cognitive impairments persist in adult abstinent cannabis users.* [88] Compared to non-smokers, people who smoked cannabis regularly in adolescence exhibit reduced connectivity in speci c brain regions associated with memory, learning, alertness, and executive function.* [53] A study has suggested that sustained heavy, daily, adolescent onset cannabis use over decades is associated with a decline in IQ by age 38. No e ects were found in those who initiated cannabis use later, or in those who ceased use earlier in adulthood.* [78] Tolerance and withdrawal Main article: Cannabis dependence Cannabis usually causes no tolerance or withdrawal symptoms except in heavy users. In a survey of heavy users 42.4% experienced withdrawal symptoms when they tried to quit marijuana such as craving, irritability, boredom, anxiety and sleep disturbances.* [89] About 9% of those Pharmacology Mechanism of action See also: E ects of cannabis α Biochemical mechanisms in the brain The high lipid-solubility of cannabinoids results in their persisting in the body for long periods of time.* [94] Even after a single administration of THC, detectable levels of THC can be found in the body for weeks or longer (depending on the amount administered and the sensitivity of the assessment method).* [94] A number of investigators have suggested that this is an important factor in marijuana's e ects, perhaps because cannabinoids may accumulate in the body, particularly in the lipid membranes of neurons.* [95] Not until the end of the 20th century was the speci c mechanism of action of THC at the neuronal level studied. Researchers have subsequently con rmed that THC exerts its most prominent e ects via its actions on two types of cannabinoid receptors, the CB1 receptor and the CB2 receptor, both of which are G-protein coupled receptors.* [96] The CB1 receptor is found primarily in the brain as well as in some peripheral tissues, and the CB2 receptor is found primarily in peripheral tissues, but is also expressed in neuroglial cells.* [97] THC appears to alter mood and cognition through its agonist actions on the CB1 receptors, which inhibit a secondary messenger system (adeny- 7 1.1. CANNABIS (DRUG) late cyclase) in a dose dependent manner. These actions self-administered zinc producing false-negative urine drug can be blocked by the selective CB1 receptor antagonist tests.* [107] SR141716A (rimonabant), which has been shown in clinical trials to be an e ective treatment for smoking cessation, weight loss, and as a means of controlling or reducing 1.1.5 Varieties and strains metabolic syndrome risk factors.* [98] However, due to the dysphoric e ect of CB1 antagonists, this drug is often discontinued due to these side e ects.* [99] Via CB1 activation, THC indirectly increases dopamine release and produces psychotropic e ects. Cannabidiol also acts as an allosteric modulator of the mu and delta opioid receptors.* [100] THC also potentiates the e ects of the glycine receptors.* [101] The role of these interactions in the “marijuana high”remains elusive. 1.1.4 Physical and chemical properties Detection in body uids Main article: Cannabis drug testing THC and its major (inactive) metabolite, THC-COOH, can be measured in blood, urine, hair, oral uid or sweat using chromatographic techniques as part of a drug use testing program or a forensic investigation of a tra c or other criminal o ense.* [102] The concentrations obtained from such analyses can often be helpful in distinguishing active use from passive exposure, elapsed time since use, and extent or duration of use. These tests cannot, however, distinguish authorized cannabis smoking for medical purposes from unauthorized recreational smoking.* [103] Commercial cannabinoid immunoassays, often employed as the initial screening method when testing physiological specimens for marijuana presence, have di erent degrees of crossreactivity with THC and its metabolites.* [104] Urine contains predominantly THC-COOH, while hair, oral uid and sweat contain primarily THC.* [102] Blood may contain both substances, with the relative amounts dependent on the recency and extent of usage.* [102] Types of cannabis CBD is a 5-HT1A receptor agonist, which may also contribute to an anxiolytic e ect.* [108] This likely means the high concentrations of CBD found in Cannabis indica mitigate the anxiogenic e ect of THC signi cantly.* [108] The e ects of sativa are well known for their cerebral high, hence its daytime use as medical cannabis, while indica is The Duquenois–Levine test is commonly used as a well known for its sedative e ects and preferred night time screening test in the eld, but it cannot de nitively con- use as medical cannabis.* [108] rm the presence of cannabis, as a large range of substances have been shown to give false positives. Despite this, it is common in the United States for prosecutors to seek plea Psychoactive ingredients bargains on the basis of positive D–L tests, claiming them de nitive, or even to seek conviction without the use of gas According to the United Nations O ce on Drugs and chromatography con rmation, which can only be done in Crime (UNODC), “the amount of THC present in a the lab.* [105] In 2011, researchers at John Jay College of cannabis sample is generally used as a measure of cannabis Criminal Justice reported that dietary zinc supplements can potency.”* [109] The three main forms of cannabis prodmask the presence of THC and other drugs in urine.* [106] ucts are the ower, resin (hashish), and oil (hash oil). The However, a 2013 study conducted by researchers at the Uni- UNODC states that cannabis often contains 5% THC conversity of Utah School of Medicine refute the possibility of tent, resin“can contain up to 20% THC content”, and that 8 CHAPTER 1. CANNABIS “Cannabis oil may contain more than 60% THC content.” is the most widely consumed form,* [121] containing 3% to * 20% THC,* [122] with reports of up-to 33% THC.* [123] In [109] A 2012 review found that the THC content in marijuana contrast, cannabis varieties used to produce industrial hemp had increased worldwide from 1970 to 2009.* [110] It is un- contain less*than 1% THC and are thus not valued for recreclear, however, whether the increase in THC content has ational use. [124] caused people to consume more THC or if users adjust based on the potency of the cannabis. It is likely that the higher THC content allows people to ingest less tar. At the same time Cannabidiol (CBD) levels in seized samples have lowered, in part because of the desire to produce higher THC levels and because more illegal growers cultivate indoors using arti cial lights. This helps avoid detection but reduces the CBD production of the plant.* [111] Australia's National Cannabis Prevention and Information Centre (NCPIC) states that the buds ( owers) of the female cannabis plant contain the highest concentration of THC, followed by the leaves. The stalks and seeds have “much lower THC levels”.* [112] The UN states that leaves can contain ten times less THC than the buds, and the stalks one hundred times less THC.* [109] This is the stock material from which all other preparations are derived. It is noted that cannabis or its extracts must be su ciently heated or dehydrated to cause decarboxylation of its most abundant cannabinoid, tetrahydrocannabinolic acid (THCA), into psychoactive THC.* [125] Kief Main article: Kief Kief is a powder, rich in trichomes,* [126] which can be sifted from the leaves and owers of cannabis plants and either consumed in powder form or compressed to produce cakes of hashish.* [127] The word“kif”derives from After revisions to cannabis rescheduling in the UK, the gov* ernment moved cannabis back from a class C to a class B colloquial Arabic ࡛࠯࣎ kēf/kīf, meaning pleasure. [128] drug. A purported reason was the appearance of high potency cannabis. They believe skunk accounts for between 70 and 80% of samples seized by police* [113] (despite the fact that skunk can sometimes be incorrectly mistaken for Hashish all types of herbal cannabis).* [114]* [115] Extracts such as hashish and hash oil typically contain more THC than high Main article: Hashish potency cannabis owers.* [116] 1.1.6 Preparations • Dried ower buds • Kief • Hashish • Tincture • Hash oil Hashish (also spelled hasheesh, hashisha, or simply hash) is a concentrated resin cake or ball produced from pressed kief, the detached trichomes and ne material that falls o cannabis owers and leaves.* [129] or from scraping the resin from the surface of the plants and rolling it into balls. It varies in color from black to golden brown depending upon purity and variety of cultivar it was obtained from.* [130] It can be consumed orally or smoked, and is also vaporised, or 'vaped'.* [131] The term “Rosin Hash” refers to a high quality solventless product obtained through heat and pressure.* [132] • Infusion (dairy butter) • Pipe resin Tincture • A forced-air vaporizer. The detachable balloon lls with vapors Main article: Tincture of cannabis Cannabinoids can be extracted from cannabis plant matter using high-proof spirits (often grain alcohol) to create Marijuana or marihuana (herbal cannabis),* [117] consists a tincture, often referred to as “green dragon”.* [133] of the dried owers and subtending leaves and stems of Nabiximols is a branded product name from a tincture manthe female Cannabis plant.* [118]* [119]* [120]* [121] This ufacturing pharmaceutical company.* [134] Marijuana 9 1.1. CANNABIS (DRUG) Hash oil Medical use Main article: Hash oil Further information: Medical cannabis Hash oil is a resinous matrix of cannabinoids obtained from Medical marijuana refers to the use of the Cannabis plant the Cannabis plant by solvent extraction,* [135] formed into as a physician-recommended herbal therapy as well as synthetic* [149] THC and cannabinoids. So far, the meda hardened or viscous mass.* [136] ical use of cannabis is legal only in a limited number Hash oil can be the most potent of the main cannabis prodof territories, including Canada, Belgium, Australia, the ucts because of its high level of psychoactive compound per Netherlands, Spain, and several U.S. states. This usage its volume, which can vary depending on the plant's mix of generally requires a prescription, and distribution is usually essential oils and psychoactive compounds.* [137] Butane done within a framework de ned by local laws. There is and supercritical carbon dioxide hash oil have become popevidence supporting the use of cannabis or its derivatives in * ular in recent years. [138] the treatment of chemotherapy-induced nausea and vomiting, neuropathic pain, and multiple sclerosis. Lower levels of evidence support its use for AIDS wasting syndrome, Infusions epilepsy, rheumatoid arthritis, and glaucoma.* [53] There are many varieties of cannabis infusions owing to the variety of non-volatile solvents used.* [139] The plant material is mixed with the solvent and then pressed and ltered 1.1.7 History to express the oils of the plant into the solvent. Examples of solvents used in this process are cocoa butter, dairy butter, See also: War on Drugs, Legal history of cannabis in the cooking oil, glycerine, and skin moisturizers. Depending on United States, and History of medical cannabis * the solvent, these may be used in cannabis foods or applied Cannabis is indigenous to Central and South Asia. [152] topically.* [140] Adulterated cannabis Contaminants or adulterants may be found in marijuana or hashish. Other substances may be added to cannabis to add weight to the product (lead has been used in some cases), to increase its psychoactive e ects (e.g., Phencyclidine), or as part of the cultivation and processing of the cannabis (e.g., fertilizer). Hashish obtained from “soap bar"-type sources.* [141] The dried owers of the plant may be contaminated by the plant taking up heavy metals and other toxins from its growing environment,* [142] or by the addition of glass.* [143] In the Netherlands, chalk has been used to make cannabis appear to be of a higher quality.* [144] Increasing the weight of hashish products in Germany with lead caused lead intoxication in at least 29 users.* [145] Despite cannabis being generally perceived as a natural product,* [146] in a recent Australian survey* [147] one in four Australians consider cannabis grown indoors under hydroponic conditions to be a greater health risk due to increased contamination, added to the plant during cultivation to enhance the plant growth and quality. Drug dealers may “spike”or lace marijuana with other chemicals such as PCP, creating a product known as “wet marijuana"; this enhances the e ects of smoking it* [148] and it can be used to make low-grade, low-potency marijuana seem more e ective. The Chinese character for hemp (⿇ or má) depicts two plants under a shelter.* [150] Cannabis cultivation dates back at least 3000 years in Taiwan.* [151] There is evidence of inhalation of cannabis smoke from the 3rd millennium BCE, namely charred cannabis seeds found in a ritual brazier at an ancient burial site in present-day Romania.* [153] In 2003, a leather basket lled with cannabis leaf fragments and seeds was found next to a 2,500- to 2,800-year-old mummi ed shaman 10 in the northwestern Xinjiang Uygur Autonomous Region of China.* [154]* [155] Evidence of cannabis consumption was also found in Egyptian mummies dated about 950 BC.* [156]* [157] CHAPTER 1. CANNABIS A study published in the South African Journal of Science showed that “pipes dug up from the garden of Shakespeare's home in Stratford-upon-Avon contain traces of cannabis.”* [166] The chemical analysis was carried out after researchers hypothesized that the “noted weed” mentioned in Sonnet 76 and the “journey in my head” from Sonnet 27 could be references to cannabis and the use thereof.* [167] Examples of classic literature featuring cannabis include Les paradis arti ciels by Charles Baudelaire and The Hasheesh Eater by Fitz Hugh Ludlow. Cannabis was also used by the ancient Hindus of India and Nepal thousands of years ago. The herb is called ganja (Sanskrit: गजा, IAST: gañjā) or ganjika in Sanskrit and other modern Indo-Aryan languages.* [158]* [159] Some scholars suggest that the ancient drug soma, mentioned in the Vedas, was cannabis, although this theory is disJohn Gregory Bourke described use of“mariguan”, which puted.* [160] he identi es as Cannabis indica or Indian hemp, by MexiCannabis was also known to the ancient Assyrians, can residents of the Rio Grande region of Texas in 1894. He who discovered its psychoactive properties through the described its uses for treatment of asthma, to expedite de* Aryans. [161] Using it in some religious ceremonies, they livery, to keep away witches, and as a love-philtre. He also called it qunubu (meaning “way to produce smoke”), a wrote that many Mexicans added the herb to their cigar* probable origin of the modern word“cannabis”. [162] The mescal, often taking a bite of sugar afterward to ritos or Aryans also introduced cannabis to the Scythians, Thracians intensify the e ect. Bourke wrote that because it was often and Dacians, whose shamans (the kapnobatai̶"those who used in a mixture with toloachi (which he inaccurately dewalk on smoke/clouds”) burned cannabis owers to induce scribes as Datura stramonium), mariguan was one of several * trance. [163] plants known as "loco weed". Bourke compared mariguan to hasheesh, which he called“one of the greatest curses of the East”, citing reports that users “become maniacs and are apt to commit all sorts of acts of violence and murder”, causing degeneration of the body and an idiotic appearance, and mentioned laws against sale of hasheesh“in most Eastern countries”.* [168]* [169]* [170] Cannabis sativa from Vienna Dioscurides, 512 AD Cannabis has an ancient history of ritual use and is found in pharmacological cults around the world. Hemp seeds discovered by archaeologists at Pazyryk suggest early ceremonial practices like eating by the Scythians occurred during the 5th to 2nd century BCE, con rming previous historical reports by Herodotus.* [164] It was used by Muslims in various Su orders as early as the Mamluk period, for example by the Qalandars.* [165] Cannabis was criminalized in various countries beginning in the early 20th century. In the United States, the rst restrictions for sale of cannabis came in 1906 (in District of Columbia).* [171] It was outlawed in South Africa in 1911, in Jamaica (then a British colony) in 1913, and in the United Kingdom and New Zealand in the 1920s.* [172] Canada criminalized cannabis in the Opium and Drug Act of 1923, before any reports of use of the drug in Canada. In 1925 a compromise was made at an international conference in The Hague about the International Opium Convention that banned exportation of“Indian hemp”to countries that had prohibited its use, and requiring importing countries to issue certi cates approving the importation and stating that the shipment was required “exclusively for medical or scienti c purposes”. It also required parties to “exercise an e ective control of such a nature as to prevent the illicit international tra c in Indian hemp and especially in the resin”.* [173]* [174] In the United States in 1937, the Marihuana Tax Act was passed, and prohibited the production of hemp in addition to cannabis. The reasons that hemp was also included in this law are disputed̶several scholars have claimed that the act was passed in order to destroy the US hemp industry,* [175]* [176]* [177] with the primary involvement of businessmen Andrew Mellon, Randolph Hearst, and the Du Pont family.* [175]* [177] But the improvements of the 11 1.1. CANNABIS (DRUG) In New York City, there were more than 19,000 kg (41,000 lb) of marijuana growing like weeds throughout the boroughs until 1951, when the“White Wing Squad”, headed by the Sanitation Department General Inspector John E. Gleason, was charged with destroying the many pot farms that had sprouted up across the city. The Brooklyn Public Library reports: this group was held to a high moral standard and was prohibited from“entering saloons, using foul language, and neglecting horses.”The Squad found the most weed in Queens but even in Brooklyn dug up “millions of dollars”worth of the plants, many as “tall as Christmas trees”. Gleason oversaw incineration of the plants in Woodside, Queens.* [184] The United Nations' 2012 Global Drug Report stated that cannabis“was the world's most widely produced, tra cked, and consumed drug in the world in 2010”, identifying that between 119 million and 224 million users existed in the world's adult (18 or older) population.* [185] 1.1.8 Society and culture See also: Cannabis culture Legal status Main article: Legality of cannabis See also: Prohibition of drugs and Drug liberalization Since the beginning of the 20th century, most coun- Cannabis indica uid extract, American Druggists Syndicate, pre1937 decorticators, machines that separate the bers from the hemp stem, could not make hemp ber a very cheap substitute for bers from other sources because it could not change that basic fact that strong bers are only found in the bast, the outer part of the stem. Only about 1/3 of the stem are long and strong bers.* [175]* [178]* [179]* [180] The company DuPont and many industrial historians dispute a link between nylon and hemp. They argue that the purpose of developing the nylon was to produce a ber that could be used in thin stockings for females and compete with silk.* [181]* [182]* [183] Cannabis propaganda sheet from 1935 tries have enacted laws against the cultivation, possession or transfer of cannabis.* [187] These laws have impacted adversely on the cannabis plant's cultivation for nonrecreational purposes, but there are many regions where, under certain circumstances, handling of cannabis is legal or licensed. Many jurisdictions have lessened the penalties 12 CHAPTER 1. CANNABIS for possession of small quantities of cannabis, so that it is Usage punished by con scation and sometimes a ne, rather than imprisonment, focusing more on those who tra c the drug In 2013, between 128 and 232 million people used cannabis on the black market. (2.7% to 4.9% of the global population between the ages of * In some areas where cannabis use has been historically tol- 15 and 65). [17] erated, some new restrictions have been put in place, such as the closing of cannabis co ee shops near the borders of the Netherlands,* [188] closing of co ee shops near secondary United States In 2015, almost half of the people in the schools in the Netherlands and crackdowns on “Pusher United States have tried marijuana, 12% have used *it in the Street”in Christiania, Copenhagen in 2004.* [189]* [190] past year, and 7.3% have used it in the past month. [19] In 2014, daily marijuana use amongst US college students had Some jurisdictions use free voluntary treatment programs reached its highest level since records began in 1980, rising and/or mandatory treatment programs for frequent known from 3.5% in 2007 to 5.9% in 2014 and had surpassed daily users. Simple possession can carry long prison terms in cigarette use.* [202] some countries, particularly in East Asia, where the sale of cannabis may lead to a sentence of life in prison or even In the US, men are over twice as likely to use marijuana as are six times more likely to use execution. More recently however, many political parties, women and 18-29 year-olds * [24] In 2015, a record 44% of the US as over 65-year-olds. non-pro t organizations and causes based on the legalizapopulation has tried marijuana in their lifetime, an increase tion of medical cannabis and/or legalizing the plant entirely from 38% in 2013 and 33% in 1985.* [24] (with some restrictions) have emerged. In December 2012, the U.S. state of Washington became the rst state to o cially legalize cannabis in a state law Economics (Washington Initiative 502) (but still illegal by federal law),* [191] with the state of Colorado following close behind (Colorado Amendment 64).* [192] On January 1, 2013, the rst marijuana “club”for private marijuana smoking (no buying or selling, however) was allowed for the rst time in Colorado.* [193] The California Supreme Court decided in May 2013 that local governments can ban medical marijuana dispensaries despite a state law in California that permits the use of cannabis for medical purposes. At least 180 cities across California have enacted bans in recent years.* [194] In December 2013, Uruguay became the rst country to legalize growing, sale and use of cannabis.* [195] However, as of August 2014, no cannabis has yet been sold legally in Uruguay. According to the law, the only cannabis that can Woman selling cannabis and bhang in Guwahati, Assam, India be sold legally must be grown in the country by no more than ve licensed growers, and these have yet to be selected; in fact the call for applications did not go out until August 1, 2014.* [196] In the elections of October 2014, there is a sig- Production Main article: Cannabis cultivation ni cant chance that lawmakers opposed to legal cannabis will come to control the legislature, and the law will be reIt is often claimed by growers and breeders of herbal pealed before it has fully taken e ect.* [197]* [198]* [199] cannabis that advances in breeding and cultivation techOn October 17, 2015, Australian health minister Sus- niques have increased the potency of cannabis since the san Ley presented a new law that will allow the cultiva- late 1960s and early '70s, when THC was rst discovered tion of cannabis for scienti c research and medical trails and understood. However, potent seedless cannabis such as on patients.* [200] In December 2015, it was reported "Thai sticks" were already available at that time. Sinsemilla that the Canadian government had committed to legalizing (Spanish for“without seed”) is the dried, seedless in orescannabis, but at that time no timeline for the legalization cences of female cannabis plants. Because THC production was set out.* [201] drops o once pollination occurs, the male plants (which produce little THC themselves) are eliminated before they shed pollen to prevent pollination. Advanced cultivation 13 1.1. CANNABIS (DRUG) techniques such as hydroponics, cloning, high-intensity arti cial lighting, and the sea of green method are frequently employed as a response (in part) to prohibition enforcement e orts that make outdoor cultivation more risky. It is often cited that the average levels of THC in cannabis sold in United States rose dramatically between the 1970s and 2000, but such statements are likely skewed because of undue weight given to much more expensive and potent, but less prevalent samples.* [203] “Skunk”refers to several named strains of potent cannabis, grown through selective breeding and sometimes hydroponics. It is a cross-breed of Cannabis sativa and C. indica (although other strains of this mix exist in abundance). Skunk cannabis potency ranges usually from 6% to 15% and rarely as high as 20%. The average THC level in co ee shops in the Netherlands is about 18–19%.* [204] Price The price or street value of cannabis varies widely depending on geographic area and potency.* [205] In the United States, cannabis is overall the number four value crop, and is number one or two in many states including California, New York and Florida, averaging $3,000/lb.* [206]* [207] It is believed to generate an estimated $36 billion market.* [208] The United Nations O ce on Drugs and Crime claims in its 2008 World Drug Report that typical U.S. retail prices are $10–15 per gram (approximately $280–420 per ounce). Street prices in North America are known to range from about $40 to $400 per ounce, depending on quality.* [209] Some studies state that while there is no proof for the gateway hypothesis,* [215] young cannabis users should still be considered as a risk group for intervention programs.* [216] Other ndings indicate that hard drug users are likely to be poly-drug users, and that interventions must address the use of multiple drugs instead of a single hard drug.* [217] Almost two-thirds of the poly drug users in the “2009/10 Scottish Crime and Justice Survey”used cannabis.* [218] The gateway e ect may appear due to social factors involved in using any illegal drug. Because of the illegal status of cannabis, its consumers are likely to nd themselves in situations allowing them to acquaint with individuals using or selling other illegal drugs.* [219]* [220] Utilizing this argument some studies have shown that alcohol and tobacco may additionally be regarded as gateway drugs;* [221] however, a more parsimonious explanation could be that cannabis is simply more readily available (and at an earlier age) than illegal hard drugs. In turn alcohol and tobacco are easier to obtain at an earlier point than is cannabis (though the reverse may be true in some areas), thus leading to the “gateway sequence”in those individuals since they are most likely to experiment with any drug o ered.* [212] An alternative to the gateway hypothesis is the common liability to addiction (CLA) theory. It states that some individuals are, for various reasons, willing to try multiple recreational substances. The “gateway”drugs are merely those that are (usually) available at an earlier age than the harder drugs. Researchers have noted in an extensive review, Vanyukov et al., that it is dangerous to present the seThe European Monitoring Centre for Drugs and Drug quence of events described in gateway“theory”in causative Addiction reports that typical retail prices in Europe for terms as this hinders both research and intervention.* [222] cannabis varies from €2 to €20 per gram, with a majority of European countries reporting prices in the range €4– 10.* [210] 1.1.9 Research Distribution Marijuana vending machines for selling or Further information: Medical cannabis#Research dispensing cannabis are in use in the United States and are planned to be used in Canada.* [211] Cannabis research is challenging since the plant is illegal in most countries.* [223]* [224]* [225]* [226]* [227] Researchgrade samples of the drug are di cult to obtain for research Gateway drug purposes, unless granted under authority of national governMain article: Gateway drug theory ments. The Gateway Hypothesis states that cannabis use increases the probability of trying “harder”drugs. The hypothesis has been hotly debated as it is regarded by some as the primary rationale for the United States prohibition on cannabis use.* [212]* [213] A Pew Research Center poll found that political opposition to marijuana use was signi cantly associated with concerns about health e ects and whether legalization would increase marijuana use by children.* [214] There are also other di culties in researching the e ects of cannabis. Many people who smoke cannabis also smoke tobacco.* [228] This causes confounding factors, where questions arise as to whether the tobacco, the cannabis, or both that have caused a cancer. Another di culty researchers have is in recruiting people who smoke cannabis into studies. Because cannabis is an illegal drug in many countries, people may be reluctant to take part in research, and if they do agree to take part, they may not say how much cannabis 14 they actually smoke.* [229] 1.1.10 Footnotes ^ a: Weed,* [230] pot,* [231] grass,* [232] and herb* [233] are among the many other nicknames for cannabis as a drug.* [234]* [235] ^ b: Sources for this section and more information can be found in the Medical cannabis article 1.1.11 See also • Cannabinoid hyperemesis syndrome • Nederwiet • Hemp 1.1.12 References [1] Mahmoud A. ElSohly (2007). Marijuana and the Cannabinoids. Springer. p. 8. ISBN 978-1-59259-947-9. [2] United Nations. “World Drug Report 2013” (PDF). The united Nations. Retrieved 13 December 2014. [3] “Medical Use of Marijuana”. Health Canada. Retrieved 12 January 2015. [4] “New Colombia Resources Inc Subsidiary, Sannabis, Produces First Batch of Medical Marijuana Based Products in Colombia to Fill Back Orders.”. prnewswire.com. PR Newswire. 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Recreational use of cannabis is illegal in most parts of the world, but the medical use of cannabis is legal in certain countries, including Austria, Canada, Czech Republic, Finland, Germany, Israel, Italy, the Netherlands, Portugal and Spain. Australia is currently in the process of passing a law which would allow the use of marijuana for medical and scienti c purposes.* [14]* [15] In the United States, federal law outlaws all cannabis use, while 25 states and the District of Columbia no longer prosecute individuals for the possession or sale of medical marijuana, as long as the individuals are in compliance with the state's medical marijuana sale regulations. However, an appeals court ruled in January 2014 that a 2007 Ninth Circuit ruling remains binding in relation to the ongoing illegality, in federal legislative terms, of Californian cannabis dispensaries, rea rming the impact of the federal Controlled Substances Act.* [16] Medical cannabis, or medical marijuana can refer to the use of cannabis and its cannabinoids to treat disease or improve symptoms; however, there is no single agreed upon de nition.* [1]* [2] The use of cannabis as a medicine 1.2.1 has not been rigorously scienti cally tested, often due to production restrictions and other federal regulations.* [3] There is limited evidence suggesting cannabis can be used to reduce nausea and vomiting during chemotherapy, to improve appetite in people with HIV/AIDS, and to treat chronic pain and muscle spasms.* [4]* [5]* [6] Its use for other medical applications is insu cient for conclusions about safety or e cacy. Medical uses Short-term use increases the risk of both minor and major adverse e ects.* [5] Common side e ects include dizziness, feeling tired, vomiting, and hallucinations.* [5] Longterm e ects of cannabis are not clear.* [7] Concerns include memory and cognition problems, risk of addiction, schizophrenia in young people, and the risk of children taking it by accident.* [4] The Cannabis plant has a history of medicinal use dating back thousands of years across many cultures.* [8] Its current use is controversial. The American Medical Association, the Minnesota Medical Association, the American Society of Addiction Medicine, and other medical organizations have issued statements opposing its use for medicinal purposes.* [9]* [10]* [11] The American Academy of Pediatrics states that while cannabinoids may have potential as therapy for a number of medical conditions, they do not recommend it until more research is done. They, along with the American Medical Association and the Minnesota Medical Association, call for moving cannabis out of DEA Schedule I to facilitate this research.* [11]* [12]* [13] Cannabis as illustrated in Köhler's book of medicinal plants from 1897 Medical cannabis has several potential bene cial effects.* [5] Evidence is moderate that it helps in chronic pain Medical cannabis can be administered using a variety of and muscle spasms.* [5] Lesser evidence supports its use methods, including liquid tinctures, vaporizing or smoking for reducing nausea during chemotherapy, improving apdried buds, eating cannabis edibles, taking capsules, using petite in HIV/AIDS, improving sleep, and improving tics 23 1.2. MEDICAL CANNABIS in Tourettes syndrome.* [5] The National Institute on Drug Abuse (NIDA) states that cannabis is unlikely to be useful as medicine as "(1) it is an unpuri ed plant containing numerous chemicals with unknown health e ects; (2) it is typically consumed by smoking further contributing to potential adverse e ects; and (3) its cognitive impairing e ects may limit its utility.” * [17] Due to risks and little evidence supporting its use the American Society of Addiction Medicine in March 2011 recommending a halt on use of marijuana as medication in the United States, even in states where it had been declared legal.* [18] It is recommended that cannabis use be stopped in pregnancy.* [19] Nausea and vomiting liative care the use appears safer than that of opioids.* [28] A 2014 review found limited and weak evidence that smoked cannabis was e ective for chronic non-cancer pain. The review recommended that it be used for people for whom cannabinoids and other analgesics were not e ective.* [29] A 2015 review found moderate quality evidence that cannabinoids were e ective for chronic pain.* [5] A 2015 meta-analysis found that inhaled medical cannabis was e ective in reducing neuropathic pain in the short term for one in ve to six patients.* [30] Another 2015 systematic review and meta-analysis found limited evidence that medical cannabis was e ective for neuropathic pain when combined with traditional analgesics.* [31] Neurological problems The e cacy of cannabis in treating neurological problems, including multiple sclerosis, epilepsy, and movement problems, is not clear.* [32] Studies of the e cacy of cannabis for treating multiple sclerosis have produced varying results. The combination of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) extracts give subjective relief of spasticity, though objective post-treatment assessments do not reveal signi cant changes.* [33] Evidence also suggests that oral cannabis extract is e ective for reducing patientcentered measures of spasticity.* [34] A trial of cannabis is deemed to be a reasonable option if other treatments have not been e ective.* [4] Its use for MS is approved in ten A 2010 Cochrane review said that cannabinoids were countries.* [4]* [35] A 2012 review found no problems with “probably e ective”in treating chemotherapy-induced nau- tolerance, abuse or addiction.* [36] sea in children, but with a high side e ect pro le (mainly drowsiness, dizziness, altered moods, and increased appetite). Less common side e ects were“occular problems, Posttraumatic stress disorder orthostatic hypotension, muscle twitching, pruritis, vagueness, hallucinations, lightheadedness and dry mouth”.* [24] There is some suggestive evidence that medical cannabis is e ective at reducing posttraumatic stress disorder symptoms, but, as of 2016, there is insu cient evidence to conrm its e ectiveness for this condition due to a lack of HIV/AIDS large-scale trials.* [37] Evidence is lacking for both e cacy and safety of cannabis and cannabinoids in treating patients with HIV/AIDS or for anorexia associated with AIDS. As of 2013, current studies 1.2.2 Adverse e ects su er from e ects of bias, small sample size, and lack of Medical use long-term data.* [25] Medical cannabis is somewhat e ective in chemotherapyinduced nausea and vomiting (CINV)* [4] and may be a reasonable option in those who do not improve following preferential treatment.* [20] Comparative studies have found cannabinoids to be more e ective than some conventional antiemetics such as prochlorperazine, promethazine, and metoclopramide in controlling CINV,* [21] but these are used less frequently because of side e ects including dizziness, dysphoria, and hallucinations.* [7]* [22] Longterm cannabis use may cause nausea and vomiting, a condition known as cannabinoid hyperemesis syndrome.* [23] Pain Cannabis appears to be somewhat e ective for the treatment of chronic pain, including pain caused by neuropathy and possibly that due to bromyalgia and rheumatoid arthritis.* [26]* [27] A 2009 review states it was unclear if the bene ts were greater than the risks,* [26] while a 2011 review considered it generally safe for this use.* [27] In pal- There is insu cient data to draw strong conclusions about the safety of medical cannabis.* [38] Typically, adverse effects of medical cannabis use are not serious.* [4] These include: tiredness, dizziness, cardiovascular and psychoactive e ects. Tolerance to these e ects develops over a period of days or weeks. The amount of cannabis normally used for medicinal purposes is not believed to cause any permanent cognitive impairment in adults, though long-term treatment in adolescents should be weighed carefully as they are more 24 CHAPTER 1. CANNABIS drugs.* [43] In 129,000 cases, cannabis was the only implicated drug.* [44]* [45] E ects of chronic use may include bronchitis, a cannabis dependence syndrome, and subtle impairments of attention and memory. These de cits persist while chronically intoxicated.* [40] There is little evidence that cognitive impairments persist in adult abstinent cannabis users.* [46] Compared to non-smokers, people who smoked cannabis regularly in adolescence exhibit reduced connectivity in speci c brain regions associated with memory, learning, alertness, and executive function.* [45] One study suggested that sustained heavy, daily, adolescent onset cannabis use over decades is associated with a decline in IQ by age 38, with no e ects found in those who initiated cannabis use later, or in those who ceased use earlier in adulthood.* [47] American medical hashish susceptible to these impairments. Withdrawal symptoms are rarely a problem with controlled medical administration of cannabinoids. The ability to drive vehicle or operating machinery may be impaired until a tolerance is developed.* [20] Although supporters of medical cannabis say that it is safe,* [38] further research is required to assess the long-term safety of its use.* [7]* [39] There has been a limited amount of studies that have looked at the e ects of smoking cannabis on the respiratory system.* [48] Chronic heavy marijuana smoking is associated with coughing, production of sputum, wheezing, coughing, and other symptoms of chronic bronchitis.* [40] Regular cannabis use has not been shown to cause signi cant abnormalities in lung function.* [49] Cannabis smoke contains thousands of organic and inorganic chemical compounds. This tar is chemically similar to that found in tobacco smoke,* [50] and over fty known carcinogens have been identi ed in cannabis smoke,* [51] including; nitrosamines, reactive aldehydes, and polycylic hydrocarbons, including benz[a]pyrene.* [52] Light and moderate use of cannabis is not believed to increase risk of lung or upper airway cancer. Evidence for causing these cancers is mixed concerning heavy, long-term use. In genRecreational use eral there are far lower risks of pulmonary complications for regular cannabis smokers when compared with those of See also: Long-term e ects of cannabis tobacco.* [49] Combustion products are not present when using a vaporizer, consuming THC in pill form, or consumTHC, the principal psychoactive constituent of the cannabis ing cannabis foods. plant, has low toxicity while the LD50 (dose of THC needed to kill 50% of tested rodents) is high. Acute e ects may in- There is serious suspicion among cardiologists, spurring reclude anxiety and panic, impaired attention, and memory search but falling short of de nitive proof, that cannabis the potential to contribute to cardiovascular dis(while intoxicated), an increased risk of psychotic symp- use has * toms, and possibly increased risk of accidents if a person ease. [53] Cannabis is believed to be an aggravating facdrives a motor vehicle while intoxicated.* [40] Psychotic tor in rare cases of arteritis, a serious condition that in episodes are well-documented and typically resolve within some cases leads to amputation. Because 97% of caseminutes or hours. There have been few reports of symp- reports also smoked tobacco, a formal association with cannabis could not be made. If cannabis arteritis turns toms lasting longer.* [41]* [42] out to be a distinct clinical entity, it might be the conseAccording to the United States Department of Health and quence of vasoconstrictor activity observed from delta-8Human Services, there were 455,000 emergency room vis- THC and delta-9-THC.* [54] Other serious cardiovascular its associated with cannabis use in 2011. These statistics in- events including myocardial infarction, stroke, sudden carclude visits in which the patient was treated for a condition diac death, and cardiomyopathy have been reported to be induced by or related to recent cannabis use. The drug use temporally associated with cannabis use. Research in these must be “implicated”in the emergency department visit, events is complicated because cannabis is often used in conbut does not need to be the direct cause of the visit. Most junction with tobacco, and drugs such as alcohol and coof the illicit drug emergency room visits involved multiple 25 1.2. MEDICAL CANNABIS caine.* [55] These putative e ects can be taken in context of a wide range of cardiovascular phenomena regulated by the endocannabinoid system and an overall role of cannabis in causing decreased peripheral resistance and increased cardiac output, which potentially could pose a threat to those with cardiovascular disease.* [56] Cannabis usually causes no tolerance or withdrawal symptoms except in heavy users. In a survey of heavy users 42.4% experienced withdrawal symptoms when they tried to quit marijuana such as craving, irritability, boredom, anxiety and sleep disturbances.* [57] About 9% of those who experiment with marijuana eventually become dependent. The rate goes up to 1 in 6 among those who begin use as adolescents, and one quarter to one-half of those who use it daily according to a NIDA review.* [45] A 2013 review estimates daily use is associated with a 10-20% rate of dependence.* [4] The highest risk of cannabis dependence is found in those with a history of poor academic achievement, deviant behavior in childhood and adolescence, rebelliousness, poor parental relationships, or a parental history of drug and alcohol problems.* [58] Impact on psychosis A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use.* [63] A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related.* [64] A 2004 literature review on the subject concluded that cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is “neither necessary nor su cient” to cause psychosis.* [65] A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.* [66] Some studies have suggested that cannabis users have a greater risk of developing psychosis than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder.* [67]* [68] A 2005 paper from the Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene.* [69] However, a more recent study cast doubt on the proposed the e ects of cannabis on A 2013 literature review found that exposure to marijuana connection between this gene and * the development of psychosis. [70] had biologically-based physical, mental, behavioral and social health consequences and was“associated with diseases A 2008 German review reported that cannabis was a causal of the liver (particularly with co-existing hepatitis C), lungs, factor in some cases of schizophrenia and stressed the need heart, and vasculature”.* [59] for better education among the public due to increasingly relaxed access to cannabis.* [71] Cognitive e ects A 2011 systematic review evaluated published studies of the acute and long-term cognitive e ects of cannabis. THC intoxication is well established to impair cognitive functioning on an acute basis, including e ects on the ability to plan, organize, solve problems, make decisions, and control impulses. The extent of this impact may be greater in novice users, and paradoxically, those habituated to high level ingestion may have reduced cognition during withdrawal. Studies of long-term e ects on cognition have provided con icting results, with some studies nding no difference between long-term abstainers and never-users and others nding long-term de cits. The discrepancies between studies may re ect greater long-term e ects among heavier users relative to occasional users, and greater duration of e ect among those with heavy use as adolescents compared to later in life.* [60] A second systematic review focused on neuroimaging studies found little evidence supporting an e ect of cannabis use on brain structure and function.* [61] A 2003 meta analysis concluded that any long-term cognitive e ects were relatively modest in magnitude and limited to certain aspects of learning and memory.* [62] Other potential long-term e ects A 2008 National Institutes of Health study of 19 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 28 g to 272 g (1 to 9+ oz) weekly) and 24 controls found elevated levels of apolipoprotein C-III (apoC-III) in the chronic smokers.* [72] An increase in apoC-III levels induces the development of hypertriglyceridemia. 1.2.3 Pharmacology The genus Cannabis contains two species which produce useful amounts of psychoactive cannabinoids: Cannabis indica and Cannabis sativa, which are listed as Schedule I medicinal plants in the US;* [4] a third species, Cannabis ruderalis, has few psychogenic properties.* [4] Cannabis contains more than 460 compounds;* [8] at least 80 of these are cannabinoids* [73]* [74] – chemical compounds that interact with cannabinoid receptors in the brain.* [4] As of 2012, more than 20 cannabinoids were being studied by the U.S. FDA.* [75] The most psychoactive cannabinoid found in the 26 cannabis plant is tetrahydrocannabinol (or delta-9tetrahydrocannabinol, commonly known as THC).* [8] Other cannabinoids include delta-8-tetrahydrocannabinol, cannabidiol (CBD), cannabinol (CBN), cannabicyclol (CBL), cannabichromene (CBC) and cannabigerol (CBG); they have less psychotropic e ects than THC, but may play a role in the overall e ect of cannabis.* [8] The most studied are THC, CBD and CBN.* [59] 1.2.4 Physical and chemical properties CHAPTER 1. CANNABIS cepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision.”* [77] 1.2.5 History Main article: History of medical cannabis Ancient Cannabis, called má ⿇ (meaning“hemp; cannabis; numbness”) or dàmá ⼤⿇ (with “big; great”) in Chinese, was used in Taiwan for ber starting about 10,000 years ago.* [78] The botanist Li Hui-Lin wrote that in China, “The use of Cannabis in medicine was probably a very early development. Since ancient humans used hemp seed as food, it was quite natural for them to also discover the medicinal properties of the plant.”* [79] Emperor ShenNung, who was also a pharmacologist, wrote a book on treatment methods in 2737 BCE that included the medical Some forms of medicinal cannabis. bene ts of cannabis. He recommended the substance for Smoking is the means of administration of cannabis for many ailments, including constipation, gout, rheumatism, * many consumers,* [76] and the most common method of and absent-mindedness. [80] Cannabis is one of the 50 * medical cannabis consumption in the US as of 2013.* [4] “fundamental”herbs in traditional Chinese medicine. [81] It is di cult to predict the pharmacological response The Ebers Papyrus (ca. 1550 BCE) from Ancient Egypt deto cannabis because concentration of cannabinoids varies scribes medical cannabis.* [82] The ancient Egyptians used widely as there are di erent ways of preparing cannabis hemp (cannabis) in suppositories for relieving the pain of for consumption (smoked, applied as oils, eaten, infused hemorrhoids.* [83] into other foods, or drunk) and a lack of production conSurviving texts from ancient India con rm that cannabis' trols.* [4] The potential for adverse e ects from smoke inpsychoactive properties were recognized, and doctors used halation makes smoking a less viable option than oral prepait for treating a variety of illnesses and ailments, including * rations. [76] insomnia, headaches, gastrointestinal disorders, and pain, Cannabis vaporizers have gained popularity because of the including during childbirth.* [84] perception among users that less harmful chemicals are inThe Ancient Greeks used cannabis to dress wounds and gested when components are inhaled via aerosol rather than sores on their horses,* [85] and in humans, dried leaves of * smoke. [4] cannabis were used to treat nose bleeds, and cannabis seeds Cannabinoid medicines are available in pill form were used to expel tapeworms.* [85] (dronabinol and nabilone) and liquid extracts formuIn the medieval Islamic world, Arabic physicians made use lated into an oromucosal spray (nabiximols).* [4] Oral of the diuretic, antiemetic, antiepileptic, anti-in ammatory, preparations are “problematic due to the uptake of analgesic and antipyretic properties of Cannabis sativa, and cannabinoids into fatty tissue, from which they are released used it extensively as medication from the 8th to 18th censlowly, and the signi cant rst-pass liver metabolism, turies.* [86] which breaks down Δ9THC and contributes further to the variability of plasma concentrations”.* [76] The U.S. Food and Drug Administration (FDA) has not approved smoked cannabis for any condition or disease as it deems evidence is lacking concerning safety and e cacy of cannabis for medical use.* [77] The FDA issued a 2006 advisory against smoked medical cannabis stating: “marijuana has a high potential for abuse, has no currently ac- Modern An Irish physician, William Brooke O'Shaughnessy, is credited with introducing the therapeutic use of cannabis to Western medicine, to help treat muscle spasms, stomach cramps and general pain.* [87] 27 1.2. MEDICAL CANNABIS Albert Lockhart and Manley West began studying in 1964 the health e ects of traditional cannabis use in Jamaican communities. They developed, and in 1987 gained permission to market, the pharmaceutical “Canasol”, one of the rst cannabis extracts.* [88] In the 1970s, a synthetic version of THC was produced and approved for use in the United States as the drug Marinol.* [89] Voters in eight US states showed their support for cannabis prescriptions or recommendations given by physicians between 1996 and 1999, going against policies of the federal government.* [90] As of mid-2014, 23 states plus the District of Columbia have passed medical marijuana laws,* [91] and in the November elections three more states (total 26) joined the burgeoning group, many of which are as yet in con ict with conditions set forth by the federal government. On 15 June 2015, the Colorado Supreme Court ruled that even though medical marijuana is legal in Colorado, employers can re workers who use marijuana for medical reasons because it violates federal law. The case involved a quadriplegic who had a doctorʼs authorization to smoke medical marijuana, but who was red by Dish Network in 2010 after failing a company drug test.* [92] Worldwide laws on cannabis possession for medical purposes as of 2014 Cannabis is in Schedule IV of the United Nations' Single Convention on Narcotic Drugs, making it subject to special restrictions. Article 2 provides for the following, in reference to Schedule IV drugs:* [93] A Party shall, if in its opinion the prevailing conditions in its country render it the most appropriate means of protecting the public health and welfare, prohibit the production, manufacture, export and import of, trade in, possession or use of any such drug except for amounts which may be necessary for medical and scienti c research only, including clinical trials therewith to be conducted under or subject to the direct supervision and control of the Party. • The use of cannabis, at least as ber, has been shown to go back at least 10,000 years in Taiwan. “Dà má" (Pinyin pronunciation) is the Chinese expression for cannabis, the rst character meaning “big”and the The convention thus allows countries to outlaw cannabis for second character meaning “hemp”. all non-research purposes but lets nations choose to allow medical and scienti c purposes if they believe total prohi• Cannabis indica uid extract, American Druggists bition is not the most appropriate means of protecting health Syndicate, pre-1937. and welfare. The convention requires that states that permit • An advertisement for cannabis americana distributed the production or use of medical cannabis must operate a licensing system for all cultivators, manufacturers and disby a pharmacist in New York in 1917 tributors and ensure that the total cannabis market of the • The Ebers Papyrus (ca. 1550 BCE) from Ancient state shall not exceed that required “for medical and sciEgypt has a prescription for medical marijuana ap- enti c purposes.”* [93] plied directly for in ammation. 1.2.6 Society and culture Legal status Programs As of 2014, 23 states plus the District of Columbia have passed medical cannabis laws,* [91] but its use remains illegal by federal law.* [35] In 1978 the US government created a program called the Compassionate Investigational New Drug program which dispenses cannabis cigarettes to 20 people with debilitating conditions* [8] including glaucoma and a rare bone disease. The program was“closed to new candidates in 1991”,* [8] but as of 2013, allowed four people previously in the program to continue receiving medical cannabis. See also: Legal and medical status of cannabis, Cannabis in the United Kingdom, and Medical cannabis in the United States Medical use of cannabis or preparation containing THC as the active substance is legalized in Austria, Belgium, Canada, Chile, Colombia Czech Republic, Finland, Israel, Netherlands, Spain, the UK and some states in the US, alEconomics though it is illegal under US federal law. 28 CHAPTER 1. CANNABIS Brand names In the U.S., the FDA has approved two oral cannabinoids for use as medicine: dronabinol and nabilone.* [4] Dronabinol, synthetic THC, is listed as Schedule III, meaning it has some potential for dependence, and nabilone, a synthetic cannabinoid, is Schedule II, indicating high potential for side e ects and addiction.* [75] Nabiximols, an oromucosal spray derived from two strains of Cannabis sativa and containing THC and CBD,* [75] is not approved in the U.S., but is approved in several European countries, Canada, and New Zealand as of 2013.* [4] Medical marijuana dispensary As an antiemetic, these medications are usually used when conventional treatment for nausea and vomiting associated with cancer chemotherapy fail to work.* [4] Nabiximols is used for treatment of spasticity associated with MS when other therapies have not worked, and when an initial trial demonstrates “meaningful improvement” .* [4] Trials for FDA approval in the U.S. are underway.* [4] It is also approved in several European countries for overactive bladder and vomiting.* [75] When sold under the trade name Sativex as a mouth spray, the prescribed daily dose in Sweden delivers a maximum of 32.4 mg of THC and 30 mg of CBD; mild to moderate dizziness is common during the rst few weeks.* [100] Distribution The method of obtaining medical cannabis varies by region and by legislation. In the US, most consumers grow their own or buy it from marijuana dispensaries in the 23 states and the District of Columbia that permit the use of medical cannabis.* [4]* [94] Marijuana vending machines for selling or dispensing cannabis are in use in the United States and are planned to be used in Canada.* [95] In 2014, the startup Meadow began o ering on-demand delivery of medical marijuana in the San FranRelative to inhaled consumption, peak concentration of oral cisco Bay Area, through their mobile app.* [96] THC is delayed, and it may be di cult to determine optimal dosage because of variability in patient absorption.* [4] Insurance In the United States, health insurance companies may not pay for a medical marijuana prescription as the Food and Drug Administration must approve any sub- 1.2.7 Research stance for medicinal purposes. Before this can happen, the FDA must rst permit the study of the medical bene ts and drawbacks of the substance, which it has not done since it was placed on Schedule I of the Controlled Substances Act in 1970. Therefore, all expenses incurred ful lling a medical marijuana prescription will possibly be incurred as outof-pocket.* [97] However, the New Mexico Court of Appeals has ruled that workers' compensation insurance must pay for marijuana prescribed as part of the state's Medical Cannabis Program.* [98] Recreational use The authors of a report on a 2011 survey of medical cannabis users say that critics have suggested that some users“game the system”to obtain medical cannabis ostensibly for treatment of a condition, but then use it for nonmedical purposes – though the truth of this claim is hard to measure.* [99] The report authors suggested rather that medical cannabis users occupied a “continuum”between medical and nonmedical use.* [99] “Victoria”, the United States' rst legal medical marijuana plant grown by The Wo/Men's Alliance for Medical Marijuana. United States The Schedule I classi cation of cannabis in the US makes the study of medical cannabis di cult there.* [4] 29 1.2. MEDICAL CANNABIS Cancer Epilepsy A 2012 Cochrane review said there is not enough evidence to draw conclusions about the safety or e cacy of cannabinoids in the treatment of epilepsy.* [113] As of 2012, there have been few studies of the anticonvulsive properties of CBD and epileptic disorders. The major reasons for the lack of clinical research have been the introduction of new synthetic and more stable pharmaceutical anticonvulsants, the recognition of important adverse effects and the legal restriction to the use of cannabis-derived medicines.* [114] Epidiolex, a cannabis-based product developed by GW Pharmaceuticals for experimental treatment of epilepsy, underwent stage-two trials in the US in 2014.* [115] Pairs of phase 3 trials for Dravet syndrome and Lennox-Gastaut syndrome have begun and should be completed in 2015.* [116]* [117] They are also running a phase 2 study of non-psychoactive cannabidivarin.* [118] As of Although there is ongoing research, claims that cannabis 2016, the mechanisms by which cannabis may be e ective has been proved to cure cancer are, according to Cancer in the treatment of epilepsy remain unclear, and further reResearch UK, both prevalent on the internet and “highly search is needed.* [119] misleading”.* [106] Cannabinoids have been shown to exhibit some anti-cancer e ects in laboratory experiments, although there has been little research into their use as a cancer treatment in people.* [101] Laboratory experiments have suggested that cannabis and cannabinoids have anticarcinogenic and antitumor e ects,* [102] including a potential e ect on breastand lung-cancer cells.* [103] The National Cancer Institute reports that as of November 2013 there have been no clinical trials on the use of cannabis to treat cancer in people, and only one small study using delta-9-THC that reported potential antitumoral activity.* [104] While cannabis may have potential for refractory cancer pain, use as an antiemetic, and as an antitumor agent, much of the evidence comes from outdated or small studies, or animal experiments.* [105] There is no rm evidence that cannabis helps reduce the risk of getting cancer; whether it increases the risk is di cult to Glaucoma establish, since most users smoke it mixed with tobacco, In 2009, the American Glaucoma Society noted that while and this complicates research.* [106] cannabis can help lower intraocular pressure, it recommended against its use because of“its side e ects and short duration of action, coupled with a lack of evidence that its Dementia use alters the course of glaucoma”.* [120] As of 2008 relatively little research had been done concerning therapeutic * Cannabinoids have been proposed to have the potential for e ects of cannabinoids on the eyes. [121] * lessening the e ects of Alzheimer's disease. [107] A 2012 review of the e ect of cannabinoids on brain ageing found that “clinical evidence regarding their e cacy as thera- Tourette syndrome peutic tools is either inconclusive or still missing”.* [108] A 2009 Cochrane review said that the“one small randomized A 2007 review of the history of medical cannabis said controlled trial [that] assessed the e cacy of cannabinoids cannabinoids showed potential therapeutic value in treat* in the treatment of dementia ... [had] ... poorly presented ing Tourette syndrome (TS). [122] A 2005 review said that controlled research on treating TS with dronabinol showed results and did not provide su cient data to draw any useful * the patients taking the pill had a bene cial response withconclusions”. [109] out serious adverse e ects;* [123] a 2000 review said other studies had shown that cannabis“has no e ects on tics and increases the individuals inner tension”.* [124] Diabetes A 2009 Cochrane review examined the two controlled trials to date using cannabinoids of any preparation type for There is emerging evidence that cannabidiol may help slow the treatment of tics or TS (Muller-Vahl 2002, and Mullercell damage in diabetes mellitus type 1.* [110] There is Vahl 2003). Both trials compared delta-9-THC; 28 patients a lack of meaningful evidence of the e ects of medical were included in the two studies (8 individuals participated cannabis use on people with diabetes; a 2010 review con- in both studies).* [76] Both studies reported a positive e ect cluded that “the potential risks and bene ts for diabetic on tics, but“the improvements in tic frequency and severity patients remain unquanti ed at the present time”.* [111] were small and were only detected by some of the outcome GW is studying tetrahydrocannabivarin for type 2 dia- measures”.* [76] The sample size was small and a high numbetes.* [112] ber of individuals either dropped out of the study or were 30 CHAPTER 1. CANNABIS sea, and to inhibit cancer cell growth.* [132] Preliminary studies have also shown potential over psychiatric conditions such as anxiety, depression, and psychosis.* [133] Because cannabidiol relieves the aforementioned symptoms, cannabis strains with a high amount of CBD may benet people with multiple sclerosis or frequent anxiety atCannabinoid medication might be useful in the treatment * tacks. [33]* [132] * of the symptoms in patients with TS, [76] but the 2009 review found that the two relevant studies of cannibinoids in treating tics had attrition bias, and that there was “not 1.2.8 See also enough evidence to support the use of cannabinoids in treating tics and obsessive compulsive behaviour in people with • Charlotte's Web cannabis strain Tourette's syndrome”.* [76] excluded.* [76] The original Muller-Vahl studies reported individuals who remained in the study; patients may drop out when adverse e ects are too high or e cacy is not evident.* [76] The authors of the original studies acknowledged few signi cant results after Bonferroni correction.* [76] • Chinese herbology Other conditions • Medical cannabis in the United States Anecdotal evidence and pre-clinical research has suggested • Tilden's Extract that cannabis or cannabinoids may be bene cial for treating Huntington's disease or Parkinson's disease, but follow-up studies of people with these conditions have not produced 1.2.9 References good evidence of therapeutic potential.* [125] A 2001 paper “Medicinal argued that cannabis had properties that made it potentially [1] Murnion, B (December 2015). Australian prescriber 38 (6): 212–5. cannabis.”. applicable to the treatment of amyotrophic lateral sclerosis, doi:10.18773/austprescr.2015.072. PMC 4674028. PMID and on that basis research on this topic should be permitted, 26843715. * despite the legal di culties of the time. [126] A 2005 review and meta-analysis said that bipolar disorder was not well-controlled by existing medications and that there were “good pharmacological reasons”for thinking cannabis had therapeutic potential, making it a good candidate for further study.* [127] Cannabinoids have been proposed for the treatment of primary anorexia nervosa, but have no measurable benecial e ect.* [128] The authors of a 2003 paper argued that cannabinoids might have useful future clinical applications in treating digestive diseases.* [129] Laboratory experiments have shown that cannabinoids found in marijuana may have analgesic and anti-in ammatory e ects.* [103] In 2014, the American Academy of Neurology reviewed all available ndings levering the use of marijuana to treat brain diseases. The result was that the scienti c evidence is weak that cannabis in any form serves as medicinal for curing or alleviating neurological disorders. To ease multiple sclerosis patients' sti ness, which may be accomplished by their taking cannabis extract by mouth or as a spray, there is support. The academy has published new guidelines on the use of marijuana pills and sprays in the treatment of MS.* [130] Cannabis is being investigated for its possible use in in ammatory bowel disease but as of 2014 there is only weak evidence for its bene ts as a treatment.* [131] A 2007 review said cannabidiol had shown potential to relieve convulsion, in ammation, cough, congestion and nau- [2] “What is medical marijuana?". National Institute of Drug Abuse. July 2015. Retrieved 19 April 2016. The term medical marijuana refers to using the whole unprocessed marijuana plant or its basic extracts to treat a disease or symptom. [3] “Release the strains”. Nature Medicine 21: 963. 4 September 2015. doi:10.1038/nm.3946. Retrieved 8 September 2015. 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MEDICAL CANNABIS 35 [107] Campbell VA, Gowran A (2007). “Alzheimer's dis- [118] “GW Pharmaceuticals Initiates Phase 2 Clinical Study of ease; taking the edge o with cannabinoids?". British Cannabidivarin (CBDV) in Epilepsy (NASDAQ:GWPH)". Journal of Pharmacology (Review) 152 (5): 655–62. ir.gwpharm.com. Retrieved 19 September 2015. doi:10.1038/sj.bjp.0707446. PMC 2190031. PMID [119] Reddy, DS; Golub, V (19 January 2016). “The Pharmaco17828287. logical Basis of Cannabis Therapy for Epilepsy.”. The Journal of Pharmacology and Experimental Therapeutics 357: [108] Bilkei-Gorzo A (2012). “The endocannabinoid system 45–55. doi:10.1124/jpet.115.230151. PMID 26787773. in normal and pathological brain ageing”. Philosophical transactions of the Royal Society of London. Series B, Biological sciences (Review) 367 (1607): 3326– [120] Jampel, Henry (10 August 2009). “Position statement on marijuana and the treatment of glaucoma”. American Glau41. doi:10.1098/rstb.2011.0388. PMC 3481530. 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Retrieved 19 selected neurologic disorders”. Neurology 82 (17): 1556– September 2015. 1563. doi:10.1212/wnl.0000000000000363. 36 CHAPTER 1. CANNABIS [131] Naftali T, Mechulam R, Lev LB, Koniko FM (2014). “Cannabis for in ammatory bowel disease”. Dig Dis (Review) 32 (4): 468–74. doi:10.1159/000358155. PMID 24969296. 1.3 Legal history of cannabis in the United States The legal history of cannabis in the United States relates to the regulation of cannabis (legal term marijuana) use for medical, recreational or industrial purposes in the United States. Increased restrictions and labeling of cannabis as a poison began in many states from 1906 onward, and outright prohibitions began in the 1920s. By the mid-1930s [133] Campos AC, Moreira FA, Gomes FV, Del Bel EA, marijuana was regulated as a drug in every state, includGuimarães FS (December 2012). “Multiple mechanisms ing 35 states that adopted the Uniform State Narcotic Drug involved in the large-spectrum therapeutic potential of Act.* [1] The rst national regulation was the Marihuana cannabidiol in psychiatric disorders”. Philos. Trans. R. Tax Act of 1937. Soc. Lond., B, Biol. Sci. (Review) 367 (1607): 3364– [132] Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (August 2007). “Cannabidiol--recent advances” . Chem. Biodivers. (Review) 4 (8): 1678–92. doi:10.1002/cbdv.200790147. PMID 17712814. 78. doi:10.1098/rstb.2011.0389. PMC 3481531. PMID 23108553. 1.2.10 Further reading • Iversen, Leslie L. (2000). The Science of Marijuana. Oxford University Press. ISBN 0-19-513123-1. Multiple e orts to reschedule cannabis under the Act have failed, and the United States Supreme Court has ruled in United States v. Oakland Cannabis Buyers' Cooperative and Gonzales v. Raich that the federal government has a right to regulate and criminalize cannabis, even for medical purposes. 1.3.1 Early history (pre-1850s) • 2009 Conference on Cannabinoids in Medicine, International Association for Cannabis as Medicine The Virgnia Company, by decree of King James I in 1619, ordered every colonist to grow 100 plants speci cally for • “References on Multiple Sclerosis and Marijuana” export for ber. Thus, England's only colony in America . Scha er Library of Drug Policy. Retrieved 18 De- began to grow hemp in order to meet this obligation and, soon, to serve a growing demand in other colonies.* [2]* [3] cember 2013. George Washington grew hemp at Mount Vernon as one of • Wujastyk, Dominik (12 September 2001).“Cannabis his three primary crops. The use of hemp for rope and fabin Traditional Indian Herbal Medicine” (PDF). ric was ubiquitous throughout the 18th and 19th centuries Archived from the original (PDF) on 10 November in the United States. Medicinal preparations of cannabis became available in American pharmacies in the 1850s fol2005. Retrieved 23 September 2009. lowing an introduction to its use in Western medicine by William O'Shaughnessy a decade earlier in 1839.* [4] 1.2.11 External links • Medical cannabis at DMOZ, links to websites about medical cannabis • Information on Cannabis and Cannabinoids from the U.S. National Cancer Institute • Information on cannabis (marihuana, marijuana) and the cannabinoids from Health Canada • The Center for Medicinal Cannabis Research of the University of California • “Medical Marijuana” – a 2014-2015 3 part CNN documentary produced by Sanjay Gupta Around the same time, e orts to regulate the sale of pharmaceuticals began, and laws were introduced on a state-to-state basis that created penalties for mislabeling drugs, adulterating them with undisclosed narcotics, and improper sale of those considered "poisons". Poison laws generally either required labels on the packaging indicating the harmful e ects of the drugs or prohibited sale outside of licensed pharmacies and without a doctor's prescription. Those that required labeling often required the word“poison”if the drug was not issued by a pharmacy. Other regulations were prohibitions on the sale to minors, as well as restrictions on re lls. Some pharmaceutical laws speci cally enumerated the drugs that came under the e ect of the regulations, while others didn't ̶leaving the matter to medical experts. Those that did generally included references to cannabis, either under the category of “cannabis and its preparations”or“hemp and its preparations.”* [5] 1.3. LEGAL HISTORY OF CANNABIS IN THE UNITED STATES 37 In New York, the original law did enumerate cannabis, and was passed in 1860 following a string of suicides allegedly involving the substances later categorized as poisons. The rst draft of the bill 'An act to regulate the sale of poisons' prohibited the sale of cannabis ̶as with the other substances ̶without the written order of a physician.* [7] The nal bill as passed allowed the sale without a prescription so long as the purpose to which it was issued and name and address of the buyer was recorded, and in addition, all packaging of such substances ̶whether sold with a prescription or not ̶had to have the label “poison”on them in uppercase red letters. In 1862, the section which enumerated the substances was repealed with an amendatory act, though cannabis was still required to be labeled.* [8] In some states where poison laws excluded cannabis, there were nonetheless attempts to include it. A bill introduced in 1880 in the California state legislature was titled 'An act to regulate the sale of opium and other narcotic poisons' and would have prohibited anyone to keep, sell, furnish, or give away any“preparations or mixtures made or prepared from opium, hemp, or other narcotic drugs”without a doctor's prescription at a licensed store. That bill was withdrawn in favor of one speci cally aimed at opium, though further bills including hemp-based drugs were introduced in 1885 and in 1889.* [4] Cannabis uid extract medicine bottle from 1906 A 1905 Bulletin from the US Department of Agriculture lists twenty-nine states with laws mentioning cannabis. Eight are listed with “sale of poisons”laws that speci cally mention cannabis: North Carolina, Ohio, Wisconsin, Louisiana, Vermont, Maine, Montana, and the District of Columbia. Among those that required a prescription for sale were Wisconsin and Louisiana. Several “sale of poison”laws did not specify restricted drugs, including in Indiana, Rhode Island, Hawaii, Nebraska, Kentucky, Mississippi, and New York. Many states did not consider cannabis a “poison”but required it be labeled.* [6] Excerpt from the New York Times, March 7, 1884 Background to later restrictions As early as 1853, recreational cannabis was listed as a“fashionable narcotic”.* [9] By the 1880s, oriental-style hashish parlors were ourishing alongside opium dens, to the point that one could be found in every major city on the east coast. It was estimated there were around 500 such establishments in New York City alone.* [10] An article in Harperʼs Magazine (1883), attributed to Harry Hubbell Kane, describes a hashish-house in New York frequented by a large clientele, including males and females of “the better classes,” 38 and further talks about parlors in Boston, Philadelphia and Chicago.* [4] Hemp cigarettes were reported to be used by Mexican soldiers early as 1874.* [11] 1.3.2 Criminalization (1900s) Strengthening of poison laws (1906–1938) The Pure Food and Drug Act was then passed by the United States Congress in 1906 and required that certain special drugs, including cannabis, be accurately labeled with contents. Previously, many drugs had been sold as patent medicines with secret ingredients or misleading labels.* [12] Even after the passage of regulations, there continued to be criticisms about the availability of narcotics and around 1910 there was a wave of legislation aimed to strengthen requirements for their sale and remove what were commonly referred to as “loopholes”in poison laws. The new revisions aimed to restrict all narcotics, including cannabis, as poisons, limit their sale to pharmacies, and require doctor's prescriptions. The rst instance was in the District of Columbia in 1906, under 'An act to regulate the practice of pharmacy and the sale of poisons in the District of Columbia, and for other purposes'. This act was updated in 1938 to the Federal Pure Food, Drug, and Cosmetics Act of 1938 which remains in e ect even today, creating a legal paradox for federal sentencing. Under this act, the framework for prescription and non-prescription drugs and foods are set, along with standards as well as the enforcing agency, the FDA. “Goods found in violation of the law were subject to seizure and destruction at the expense of the manufacturer. That, combined with a legal requirement that all convictions be published (Notices of Judgment), proved to be important tools in the enforcement of the statute and had a deterrent e ect upon would-be violators. " Marijuana remains under this law de ned as a“dangerous drug”.* [13] CHAPTER 1. CANNABIS to increase as other narcotics become harder to obtain.* [16] In the West, the rst state to include cannabis as a poison was California. The Poison Act was passed in 1907 and amended in 1909 and 1911, and in 1913 an amendatory act (Stats. 1913, Ch. 342, p. 697) was made to make possession of “extracts, tinctures, or other narcotic preparations of hemp, or loco-weed, their preparations and compounds” a misdemeanor.* [4] There's no evidence that the law was ever used or intended to restrict pharmaceutical cannabis; instead it was a legislative mistake, and in 1915 another revision placed cannabis under the same restriction as other poisons.* [4] Other states followed with marijuana laws including: Wyoming (1915); Texas (1919);* [17] Iowa (1923); Nevada (1923); Oregon (1923); Washington (1923); Arkansas (1923); Nebraska (1927);* [18] Louisiana (1927); and Colorado (1929).* [19] One source of tensions in the western and southwestern states was the in ux of Mexicans to the US following the 1910 Mexican Revolution.* [20] Many Mexicans also smoked marijuana to relax after working in the elds.* [21] It was also seen as a cheaper alternative to alcohol, due to Prohibition (which went into e ect nationally in 1920).* [22] Later in the 1920s, negative tensions grew between the small farms and the large farms that used cheaper Mexican labor. Shortly afterwards, the Great Depression came which increased tensions as jobs and resources became more scarce. Because of that, the passage of the initial laws is often described as a product of racism, yet use of hashish by near eastern immigrants were also cited, as well as the misuse of pharmaceutical hemp, and the laws conformed with other legislation that was being passed around the country. Mexico itself had passed prohibition in 1925, following the International Opium Convention (see * Further regulation of cannabis followed in Massachusetts below). [23] (1911), New York (1914), and Maine (1914). In New York, reform legislation began under the Towns-Boylan International Opium Convention (1925) Act, which targeted all “habit-forming drugs”, restricted their sale, prohibited re lls in order to prevent habitua- In 1925 the United States supported regulation of Indian tion, prohibited sale to people with a habit, and prohib- hemp, also known as hashish, in the International Opium ited doctors who were themselves habituated from sell- Convention.* [24] The convention banned exportation of ing them.* [14] Shortly after, several amendments were “Indian hemp”, and the preparations derived therefrom, to passed by the New York Board of Health, including adding countries that had prohibited its use and required importcannabis to the list of habit-forming drugs.* [15] ing countries to issue certi cates approving the importation A New York Times article noted on the cannabis amend- and stating that the shipment was required“exclusively for medical or scienti c purposes”. The convention did not ment: ban trade in bers and other similar products from EuroThe inclusion of Cannabis indica among the pean hemp, and traditionally grown in the United States, drugs to be sold only on prescription is common According to the 1912 edition of a Swedish encyclopedia sense. Devotees of hashish are now hardly nuthe European hemp grown for its bers lacks the THC conmerous here enough to count, but they are likely tent that characterizes Indian hemp.* [25] 39 1.3. LEGAL HISTORY OF CANNABIS IN THE UNITED STATES Uniform State Narcotic Act (1925–1932) nine nations had registered their rati cation of the limitation treaty. On Jan. 1, 1935, only nine States had adopted the uniform State statute. As 1933 witnessed rati cation of the treaty by thirty-one additional nations, so may 1935 witness the adoption of the uniform drug act by at least thirty-one more states, thereby placing interstate accord abreast of international accord, to the honor of the legislative bodies of our States and for the promotion of the welfare of our people and the peoples of other lands.” ̶Franklin D. Roosevelt, March 1935 in a radio message read by United States Attorney General, Homer Stille Cummings, * [31] The Uniform State Narcotic Act, rst tentative draft in 1925 and fth nal version in 1932, was a result of work by the National Conference of Commissioners on Uniform State Laws. It was argued that the tra c in narcotic drugs should have the same safeguards and the same regulation in all of the states. The committee took into consideration the fact that the federal government had already passed The Harrison Act in 1914 and The Federal Import and Export Act in 1922. Many people assumed that the Harrison Act was all that was necessary. The Harrison Act, however, was a revenue-producing act and, while it provided penalties for violation, it did not give the states themselves authority to exercise police power in regard to seizure of drugs used in illicit trade, or in regard to punishment of those responsible. The act was recommended to the states for that purpose.* [26] As a result of the Uniform State Narcotic Act, the Federal Bureau of Narcotics encouraged state governments to adopt the act. By the middle of the 1930s all member states had some regulation of cannabis.* [27]* [28]* [29] Anslinger claimed cannabis caused people to commit violent crimes and act irrationally and overly sexual. The FBN produced propaganda lms promoting Anslinger's views and Anslinger often commented to the press regarding his views on marijuana.* [32] Federal Bureau of Narcotics (1930) The 1936 Geneva Tra cking Conventions FBN public service announcement used in the late 1930s and 1940s In 1936 the Convention for the Suppression of the Illicit Tra c in Dangerous Drugs (1936 Tra cking Convention) was concluded in Geneva. The US, led by Anslinger, had attempted to include the criminalization of all activities in the treaty – cultivation, production, manufacture and distribution – related to the use of opium, coca (and its derivatives) and cannabis for non-medical and non-scienti c purposes. Many countries opposed this and the focus remained on illicit tra cking. Article 2 of the Convention called upon signatory countries to use their national criminal law systems to“severely”punish,“particularly by imprisonment or other penalties of deprivation of liberty”acts directly related to drug tra cking.* [33] The US refused to sign the nal version because it considered the convention too weak, especially in relation to extradition, extraterritoriality and the con scation of tra cking pro ts.* [34] The use of cannabis and other drugs came under increasing scrutiny after the formation of the Federal Bureau of Nar- Marijuana Tax Act (1937) cotics (FBN) in 1930,* [30] headed by Harry J. Anslinger as part of the government's broader push to outlaw all recre- Main articles: Marijuana Tax Act of 1937 and Hemp ational drugs. The American Medical Association (AMA) opposed the act because the tax was imposed on physicians prescribing cannabis, retail pharmacists selling cannabis, and medical “When the present administration took o ce cannabis cultivation and manufacturing; instead of enactten countries had rati ed the Geneva Narcotic ing the Marijuana Tax Act the AMA proposed cannabis Limitation Convention. The United States was be added to the Harrison Narcotics Tax Act.* [36] This apone of these ten.... It was my privilege, as Presproach was unappealing to some legislators who feared that ident, to proclaim, on that day, that this treaty adding a new substance to the Harrison Act would subject had become e ective throughout the jurisdiction that act to new legal scrutiny. Since the federal government of the United States....On Jan. 1, 1933, only 40 CHAPTER 1. CANNABIS reau drafted a legislative plan for Congress seeking a new law, and the head of the FBN, Harry J. Anslinger, ran a campaign against marijuana.* [41]* [42] Newspaper mogul William Randolph Hearst's empire of newspapers used the "yellow journalism" pioneered by Hearst to demonize the cannabis plant and spread a public perception that there were connections between cannabis and violent crime.* [43] Several scholars argue that the goal was to destroy the hemp industry,* [44]* [45]* [46] largely as an e ort of Hearst, Andrew Mellon and the Du Pont family.* [44]* [46] They argue that with the invention of the decorticator hemp became a very cheap substitute for the wood pulp that was Tax stamp for a producer of hemp used in the newspaper industry.* [44]* [47] However, Hearst newspapers owed large debts to Canadian suppliers of pahad no authority under the 10th Amendment to regulate per, who used wood as raw material. If an alternative raw medicines, that power being reserved by individual states in material for paper had emerged, it would have lowered the 1937, a tax was the only viable way to legislate marijuana. price of the paper needed to print Hearst's many newspapers̶a positive thing for Hearst.* [48]* [49] Mellon was Secretary of the Treasury, as well as the wealthiest man in America, and had invested heavily in nylon, DuPont's new synthetic ber. He considered nylon's success to depend on its replacement of the traditional resource, hemp.* [44]* [50]* [51]* [52]* [53]* [54]* [55]* [56] Hemp for Victory, a short documentary produced by the United States Department of Agriculture during World War 2 to inform and encourage farmers to grow hemp. After the Philippines fell to Japanese forces in 1942, the Department of Agriculture and the U.S. Army urged farmers to grow hemp ber and tax stamps for cultivation were issued to farmers. Without any change in the Marijuana Tax Act, over 400,000 acres of hemp were cultivated between 1942 and 1945. The last commercial hemp elds were planted in Wisconsin in 1957.* [37] New York Mayor Fiorello LaGuardia, who was a strong opponent of the 1937 Marijuana Tax Act, started the LaGuardia Commission that in 1944 contradicted the earlier reports of addiction, madness, and overt sexuality.* [38] The decision of the United States Congress to pass the Marijuana Tax Act of 1937 was based on poorly attended hearings and reports based on questionable studies.* [39]* [40] In 1936 the Federal Bureau of Narcotics (FBN) noticed an increase of reports of people smoking marijuana, which further increased in 1937. The Bu- The company DuPont and many industrial historians dispute a link between nylon and hemp. They argue that the purpose of developing the nylon was to produce a ber that could compete with silk and rayon in for example thin stockings for women. Silk was much more expensive than hemp and imported largely from Japan. There was more money in substitute for silk. DuPont focused early on thin stockings for women. As a commercial product was nylon a revolution in textiles. Strong, water-resistant, it was possible to make very thin bers and made from cheap raw materials. The rst sales in 1938 in New York of nylon stockings created a line with 4000 middle class women. Due to the nylon properties become demand for nylon a number of years to come much bigger than that DuPont could produce. And the DuPont Group was very big, it could move on if nylon had not become a success.* [57]* [58]* [59] In 1916 United States Department of Agriculture (USDA) chief scientists Jason L. Merrill and Lyster H. Dewey created a paper, USDA Bulletin No. 404 “Hemp Hurds as Paper-Making Material”,* [60] in which they stated that paper from the woody inner portion of the hemp stem broken into pieces, so called hemp hurds, was “favorable in comparison with those used with pulp wood”. Merrill and Dewey's ndings was not repeated in a later book by Dewey* [61] and have not been con rmed by experts on paper production. The consistency of long bers is too low in hemp hurds for commercial papermaking. In 1937 were hemp hurds still a waste material. Numerous machines had been devised for breaking and scutching hemp bers but non had been found to be fully satisfactory in 41 1.3. LEGAL HISTORY OF CANNABIS IN THE UNITED STATES Reorganization (1968, 1973) United States Cannabis Arrests (Data:FBI UCR) 900 800 Arrests (Thousands) 700 600 500 400 300 200 100 2010 2005 2000 1995 Year 1990 1985 1980 1975 1970 0 1965 Hemp, bast with bers. The stem in the middle. actual commercial work* [49]* [61]* [62] To produce ber U.S. cannabis arrests by year. from hemp was a labor-intensive process if you include harvest, transport and processing. Technological developments decreased the labor but not su cient to eliminate this dis- In 1968 the United States Department of the Treasury subadvantage.* [63] sidiary the Bureau of Narcotics and the United States Department of Health, Education, and Welfare subsidiary the There was also a misconception about the intoxicating efBureau of Drug Abuse Control merged to create the Bureau fects of hemp because it has the same active substance, of Narcotics and Dangerous Drugs as a United States DeTHC, which is in all cannabis strains. Hemp normally has subsidiary.* [69] partment of Justice a minimal amount of THC when compared to recreational cannabis strains but, in the 1930s, THC was not yet fully identi ed.* [64] The methods FBN used for predicting the psychoactive e ect of di erent samples of cannabis and hemp therefore gave confusing results.* [65]* [66] In 1973 President Richard Nixon's “Reorganization Plan Number Two”proposed the creation of a single federal agency to enforce federal drug laws and Congress accepted the proposal, as there was concern regarding the growing availability of drugs.* [70] As a result, on July 1, 1973, the Bureau of Narcotics and Dangerous Drugs (BNDD) and the O ce of Drug Abuse Law Enforcement (ODALE) Mandatory sentencing (1952, 1956) merged to create the Drug Enforcement Administration (DEA).* [38] On December 1, 1975, the Supreme Court Mandatory sentencing and increased punishment were en- ruled that it was “not cruel or unusual for Ohio to senacted when the United States Congress passed the Boggs tence someone to 20 years for having or selling cannabis.” Act of 1952 and the Narcotics Control Act of 1956. The * [71] acts made a rst-time cannabis possession o ense a minimum of two to ten years with a ne up to $20,000; however in 1970 the United States Congress repealed mandatory penalties for cannabis o enses.* [38] State O ce of Narcotics and Drug Abuse (1977) The Controlled Substances Act (1970) In its 1969 Leary v. United States decision the Supreme Court held the Marijuana Tax Act to be unconstitutional, since it violated the Fifth Amendment privilege against self-incrimination.* [67] In response, Congress passed the Controlled Substances Act as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970, which repealed the Marijuana Tax Act.* [68] In January 1976, California's study of the economic impact of its law repealing prohibitions of use went into e ect. The law reduced the penalty for personal possession of an ounce or less of marijuana from a felony to a citable misdemeanor with a maximum ne of $100. Possession of more than an ounce was made a misdemeanor, making the maximum ne $500 and/or six months in jail. After the law went into e ect, the state's annual spending towards marijuana laws went down 74%. Prior to the law, the state had been spending from $35 million to $100 million.* [72] 42 Mandatory sentencing and three-strikes (1984, 1986) CHAPTER 1. CANNABIS In Gonzales the respondents (criminal defendants) argued because the cannabis in question had been grown, transported, and consumed entirely within the state of California, in compliance with California medical cannabis laws, the defendants' activity did not implicate interstate commerce. Therefore, the defendants argued, their activity could not be regulated, and eventually prosecuted, by the federal government through the Commerce Clause. During the Reagan Administration the Sentencing Reform Act provisions of the Comprehensive Crime Control Act of 1984 created the Sentencing Commission, which established mandatory sentencing guidelines.* [73] The AntiDrug Abuse Act of 1986 reinstated mandatory prison sentences, including large scale cannabis distribution.* [74] Later an amendment created a three-strikes law, which creThe U.S. Supreme Court disagreed, nding that cannabis ated mandatory 25-years imprisonment for repeated serious grown within California for medical purposes is indistincrimes – including certain drug o enses- and allowed the guishable from illicit marijuana. Moreover, because the indeath penalty to be used against “drug kingpins.”* [38] trastate medical cannabis market contributes to the interstate illicit marijuana market, the Commerce Clause apUnited States v. Oakland Cannabis Buyers' Cooperative plies. Even where California citizens are using medical cannabis in compliance with state law, those individuals and (2001) businesses can still be prosecuted by federal authorities for * Main article: United States v. Oakland Cannabis Buyers' violating federal law. [77] Cooperative To combat state-approved medical cannabis legislation, the In 1996 California voters passed Proposition 215, which legalized medical cannabis. The Oakland Cannabis Buyers' Cooperative was created to “provide seriously ill patients with a safe and reliable source of medical cannabis, information and patient support”in accordance with Proposition 215.* [75] In January 1998 the U.S. Government sued Oakland Cannabis Buyers' Cooperative for violating federal laws created as a result of Controlled Substances Act of 1970. On May 14, 2001, the United States Supreme Court ruled in United States v. Oakland Cannabis Buyers' Coop that federal anti-drug laws do not permit an exception for medical cannabis and rejected the common-law medical necessity defense to crimes enacted under the Controlled Substances Act because Congress concluded cannabis has “no currently accepted medical use”when the act was passed in 1970.* [76] Gonzales v. Raich (2005) Main article: Gonzales v. Raich Drug Enforcement Administration (DEA) routinely targets and arrests medical cannabis patients as well as seizing medical cannabis and the business assets of growers and medical dispensaries. However, the Obama administration has indicated that this practice may potentially be curtailed.* [78] 1.3.3 E orts to decriminalize (1970s–) Main article: Decriminalization of non-medical cannabis in the United States Medical use Main article: Medical cannabis In 1978 Robert Randall sued the federal government for arresting him for using cannabis to treat his glaucoma. The judge ruled Randall needed cannabis for medical purposes and required the Food and Drug Administration set up a program to grow cannabis on a farm at the University of Mississippi and to distribute 300 cannabis cigarettes a month to Randall. In 1992 George H. W. Bush discontinued the program after Randall tried to make HIV/AIDS patients eligible for the program. Thirteen people were already enrolled and were allowed to continue receiving cannabis cigarettes; today the government still ships cannabis cigarettes to four people. Irvin Rosenfeld, who became eligible to receive cannabis from the program in 1982 to treat rare bone tumors, urged the George W. Bush administration to reopen the program; however, he was unsuccessful.* [79] Gonzales v. Raich 545 U.S. 1 (2005) was a decision in which the U.S. Supreme Court ruled (6–3) that even where individuals or businesses in accordance with state-approved medical cannabis programs are lawfully cultivating, possessing, or distributing medical cannabis, such persons or businesses are violating federal marijuana laws. Therefore, under federal law violators are prosecuted because the Commerce Clause of the United States Constitution grants the federal government jurisdiction to prosecute marijuana o enses, here defendants violation of the U.S. Controlled Substances Act. Alaska, Colorado, Washington, Oregon, and the District 1.3. LEGAL HISTORY OF CANNABIS IN THE UNITED STATES of Columbia are the only states where possession of up to one ounce is legal.* [80] “Citing the dangers of marijuana and the lack of clinical research supporting its medicinal value”the American Society of Addiction Medicine in March 2011 issued a white paper recommending a halt to using marijuana as a medicine in US states where it has been declared legal.* [81]* [82] Advocacy Several U.S.-based advocate groups seek to modify the drug policy of the United States to decriminalize cannabis. These groups include Law Enforcement Against Prohibition, Students for Sensible Drug Policy, The Drug Policy Alliance, the Marijuana Policy Project, NORML, Coalition for Rescheduling Cannabis, and Americans for Safe Access. In June 2005, libertarian economist Je rey Alan Miron and over 530 other economists, including Nobel Prize winner Milton Friedman, called for the legalization of cannabis in an open letter to President George W. Bush, the United States Congress, Governors of the United States, and State Legislatures of the United States. The open letter contained Miron's“Budgetary Implications of Marijuana Prohibition in the United States”report (view report).* [83] In 1997, the Connecticut Law Revision Commission recommended that Connecticut reduce cannabis possession of one ounce or less for adults aged 21 years and over to a civil ne although driving privileges maybe suspended for up to 60 days.* [84] In 2001, the New Mexico statecommissioned Drug Policy Advisory Group stated that decriminalizing cannabis “will result in greater availability of resources to respond to more serious crimes without any increased risks to public safety.”* [85] On November 3, 2004, Oakland, California passed Proposition Z, which makes “adult recreational marijuana use, cultivation and sales the lowest [city] law enforcement priority.”* [86] 43 Non-medical use Further information: Decriminalization of non-medical cannabis in the United States and Legality of cannabis by U.S. jurisdiction In 1970 the United States Congress repealed mandatory penalties for cannabis o enses and The Comprehensive Drug Abuse Prevention and Control Act separated cannabis from other illicit narcotics and removed mandatory sentences for possession of small amounts of cannabis.* [38] In 1972 President Richard Nixon commissioned a comprehensive study from the National Commission on Marijuana and Drug Abuse. The Commission found that the constitutionality of cannabis prohibition was suspect and that the executive and legislative branches had a responsibility to obey the Constitution, even in the absence of a court ruling to do so. The Richard Nixon administration did not implement the study's recommendations.* [89] In 1973 Oregon decriminalized cannabis.* [90] Laws changed again in 1995 that reduced penalties. Possession of one ounce or less became legally de ned as a “violation” (a crime that is considered a lesser o ence than a misdemeanor) and now is punishable by a $500 to $1,000 ne and up to 6 months of jail time,* [91] in some jurisdictions, paid o by means of community service. Possession of multiple containers of any weight, or possession of more than one ounce can sometimes add the additional crime “Intent to Sell”. In some cases people who have no marijuana, but are caught at the scene of a drug bust, are charged with “Frequenting”. Stricter punishments exist for sale, cultivation, and proximity to schools.* [92] Colorado, Alaska, Ohio, and California followed suit in 1975. By 1978 Mississippi, North Carolina,* [93] New York, and Nebraska had some form of cannabis decriminalization.* [94]* [95] In 2001 Nevada reduced cannabis possession from a felony o ense to a misdemeanor, but only for adults age 21 and older, with other restrictions.* [96] Starting in the 1970s multiple states, counties, and cities decriminalized cannabis for non-medical purposes. While many states, counties, and cities have partially decriminalized cannabis, on November 3, 2004, Oakland passed Proposition Z, and became the rst place to fully decriminalize cannabis to allow the licensing, taxing, and regulation of cannabis sales if California law is amended to allow so.* [97] In 2008 Massachusetts passed a voter initiative that decriminalized simple possession of up to one ounce of marijuana, instead making it a civil infraction punishable by a $100 ne. Criminal penalties for cultivation and distribution remain in place.* [98] In June 2011, Connecticut decriminalized possession of small amounts of marijuana. Ron Paul, a Texas Congressman and 2008 and 2012 Presidential Candidate, stated at a rally in response to a question by a medical cannabis patient that he would“never use the federal government to force the law against anybody using marijuana.”* [87] Based on the collective perspective of its Editorial Board, The New York Times commenced a series examining the legalization of cannabis in July 2014 titled “High Time: An Editorial Series on Marijuana Legalization”. The introductory article concludes with the statement: “We recognize that this Congress is as unlikely to take action on marijuana as it has been on other big issues. But it is long past time to repeal this version of Prohibition.” * On November 6, 2012, Colorado Amendment 64 (2012) [88] 44 CHAPTER 1. CANNABIS was passed by initiative, thereby legalizing the recreational ing it the rst city on the east coast to do so. The citizens use of cannabis. Colorado Governor John Hickenlooper voted in the law with 67% in favor of legalization. The signed two bills on May 28, 2013 that made Colorado the law does not allow the sale of marijuana and city police world's rst fully regulated recreational cannabis market for still intend to enforce state law, under which possession is adults. Hickenlooper explained to the media: “Certainly, a civil o ense and only medical marijuana is legal. Supthis industry will create jobs. Whether itʼs good for the porters of marijuana legalization believe, “this is just the brand of our state is still up in the air. But the voters passed next domino,”said Marijuana Policy Project Maine PolitiAmendment 64 by a clear majority. Thatʼs why weʼre go- cal Director, David Boyer, “I think there's national impliing to implement it as e ectively as we possibly can.”In its cations, keeping the momentum that Washington and Colindependent analysis, the Colorado Center on Law & Policy orado started last November in ending marijuana prohibifound that the state could expect a to see "$60 million in to- tion.”There are hopes that the vote will be a push to legalize tal combined savings and additional revenue for Coloradoʼ it statewide within the next few years.* [107]* [108] s budget with a potential for this number to double after The same day, voters in the cities of Ferndale, Jackson and 2017.”* [99] On September 9, 2013, the Colorado Depart- Lansing, Michigan also voted on and approved similar meament of Revenue adopted nal regulations for recreational sures to legalize possession and transfer of less than one marijuana establishments, implementing the Colorado Re- ounce of marijuana. The votes were 69%, 61% and 63% tail Marijuana Code (HB 13-1317).* [100] On September in favor respectively. Similar to Portland, state law (where 16, 2013, the Denver City Council adopted an ordinance for only medical marijuana is legal) will likely be enforced, as retail marijuana establishments.* [101] The rst stores o - indicated by the Governor's statement that“no city charter cially opened on January 1, 2014.* [102] The state prepared provision 'shall con ict with or contravene the provisions of for an in ux of tourists with extra police o cers posted in any general law of the state.'"* [109] Denver. Safety fears led to o cials seeking to limit use of On November 4, 2014, the states of Alaska and Oregon the drug in popular ski resorts.* [103] along with Washington D.C. (Initiative 71) legalized the recreational usage of marijuana, with laws similar to those of Colorado and Washington. However, by a rider of the State-level legalization 2014“Cromnibus”bill (Consolidated Appropriations Act, Ravin v. State was a 1975 decision by the Alaska Supreme 2014), Washington DC was prevented from making adCourt that held the Alaska Constitution's right to privacy ditional changes to its marijuana laws for the scal year, home use and cultivation, but not commercial protects an adult's ability to use and possess a small amount allowing * * * * sales. [110] [111] of marijuana in the home for personal use. [104] [105] The Alaska Supreme Court thereby became the rst̶and only ̶state or federal court to announce a constitutional privacy right that protects some level of marijuana use and possession.* [104] Various e orts to legalize recreational marijuana have been attempted by ballot measure, including California Proposition 19 (2010) and Oregon Measure 80 (2012). On November 6, 2012, Colorado and Washington became the rst states to legalize the sale and possession of cannabis for recreational use since the Marijuana Tax Act of 1937 when they passed Colorado Amendment 64 and Washington Initiative 502.* [106] Each regulated marijuana in a way similar to alcohol, allowing possession of up to an ounce for adults ages 21 and older, with "DUID" provisions similar to those against drunk driving. Unlike Initiative 502, Amendment 64 allows personal cultivation (of up to 6 plants). Both provide for commercial cultivation and sales, subject to regulation and taxes. It remains to be seen how the con icts of these laws with federal law will be resolved. As of November 2014, 28 states have enacted medical marijuana laws, removed jail time for possession of small amounts of marijuana, and/or have legalized the possession, distribution, and sale of marijuana outright.* [112] The factors which have led to this change are many, but some of them could include increased support from the medical community for legalization,* [113] viable regulatory systems modeled o of alcohol regulation,* [114] and the potential for state nancial gains from decreased criminal justice costs and increased tax revenues.* [115] Although outright legalization for nonmedical use of marijuana has only occurred in four states in the Union, in view of the movements in many states, it is possible that those states will not be alone for long.* [112] Territorial-level legalization In November 2014, Guam became the rst US territory to legalize cannabis for medical use. In December 2014, the US Virgin Islands passed a bill that decriminalized possesThe city of Portland, Maine legalized the possession of up sion of cannabis up to an ounce.* [116] In Puerto Rico, medto 2.5 ounces of marijuana on November 5, 2013 mak- ical cannabis was legalized on May 3, 2015 by an executive 1.3. LEGAL HISTORY OF CANNABIS IN THE UNITED STATES order from its governor.* [117] 45 The Compassionate Access, Research Expansion and Respect States (CARERS) Act of 2015 Indian Reservation-level legalization March 10, 2015 – Senators Rand Paul (R-KY), Cory Booker (D-NJ), and Kirsten Gillibrand (D-NY) proposed a In December 2014, the US Justice Department allowed new bipartisan medical marijuana bill for patients and vetrecognized Indian Reservations to regulate cannabis laws erans to access medical marijuana. within their reservation. The laws in the reservations are allowed to be di erent from state and federal laws. As with The act: State and Territories, the Federal government will not intervene as long as the reservations regulate strict control over Would reschedule marijuana from a Schedmarijuana. Some domestic nations such as the Yakama Naule I to Schedule II drug to recognize it has action and the Oglala Sioux Tribal Council rejected the apcepted medical use, and would amend federal law proval to allow marijuana on their reservation.* [118] to allow states to set their own medical marijuana policies. The bill would also permit VA doctors In 2015, the Flandreau Santee Sioux Tribe (South to prescribe veterans medical marijuana to treat Dakota) voted to legalize recreational cannabis on its terserious injuries and chronic conditions. The leg* ritory. [119] islation would not legalize medical marijuana in all 50 states, rather it would respect the states that set their own medical marijuana programs 1.3.4 Federal reform e orts (2013– ) and prevents federal law enforcement from prosecuting patients, doctors and caregivers in those Ending Federal Marijuana Prohibition Act states.* [125] On February 5, 2013 Colorado representative Jared Polis introduced Ending Federal Marijuana Prohibition Act of Ending Federal Marijuana Prohibition Act of 2015 2013 (H.R. 499; 113th Congress), a bill that would decriminalize marijuana on the federal level, instead treating it as November 4, 2015 -Senator Bernie Sanders introduced the a substance to be regulated in a similar manner to alcohol. bill into Senate. It was read twice and referred to the ComThe act has not yet been approved by the Congress.* [120] mittee on the Judiciary. The intentions of the bill are to limit the application of Federal laws to the distribution and consumption of marijuana, and for other purposes.* [126] Respect State Marijuana Laws Act On April 12, 2013 Rep. Dana Rohrabacher [R-CA48] introduced H.R.1523 “Respect State Marijuana Laws.” * [121] Eleven cosponsors, representing both major political parties, have joined Rohrbacher in a federalist approach to drug policy reformation. It passed the House of Representatives on May 30, 2014 and still awaits approval from the Senate.* [122] No Welfare for Weed Act of 2014 The bill would prevent the use of welfare credit cards to purchase marijuana in states where it has been legalized. The bill was approved by the House in September 2014.* [123] Regulate Marijuana Like Alcohol Act and Marijuana Tax Revenue Act of 2015 In February 2015, two national-level legalization acts were proposed in Congress, the Regulate Marijuana Like Alcohol Act by Jared Polis (D-Colorado) and the Marijuana Tax Revenue Act by Earl Blumenauer (D-Oregon).* [124] 1.3.5 Drug courts Main article: Drug court Drug courts rst started in 1989 and have spread since. 2140 drug courts were in operation May 2008, with another 284 being planned or developed.* [127] They o er o enders charged with less-serious crimes of being under the in uence, possession of a controlled substance, or even drug-using o enders charged with a non-drug-related crime the option of entering the drug court system instead of a conventional criminal court with the possibility of serving a jail sentence. To take advantage of this program, o enders have to plead guilty to the charge, agree to take part in treatment, regular drug screenings, and regular reporting to the drug court judge for a minimum of one year, as well as pay heavy nes and monthly drug court fees. Drug court systems in some areas utilize a color code system, whereas each o ender is assigned a designated color, one of which is selected daily by the drug court for drug screening. O enders must call the“color code”o ce each morning to see if 46 CHAPTER 1. CANNABIS their color has been selected for screening. Should the of- [10] Jones, Nick (2004). Spli s: A Celebration of Cannabis Culture. New York: Black Dock Publishing. fender fail to comply with one or more of the requirements they may be removed from the drug court and incarcerated [11] “THE USE OF TOBACCO.; INCREASE IN THE CONat the judge's discretion. If they complete the drug court SUMPTION OF NARCOTIC STIMULANTS. THE PERprogram the charges brought against them are dropped or NICIOUS PRACTICE SPREADING AMONG AMERreduced.* [128] ICAN WOMEN ̶SNUFF-DIPPING IN THE UNITED 1.3.6 See also • Adult lifetime cannabis use by country • Annual cannabis use by country • Cannabis in the United States • Colorado Amendment 64 • E ects of cannabis • Illegal drug trade • Legal and medical status of cannabis • Legality of cannabis by country • Single Convention on Narcotic Drugs • Timeline of cannabis legalization in the United States 1.3.7 References [1] “Richard J. Bonnie & Charles H. Whitebread, II: PASSAGE OF THE UNIFORM NARCOTIC DRUG ACT”. Druglibrary.org. Retrieved March 9, 2011. [2] Deitch, Robert (2003). Hemp – American History Revisited. New York City: Algora Publishing. p. 16. ISBN 0-87586206-3. [3] Frontline, PBS. “Busted – america's war on marijuana”. pbs.org. Retrieved September 4, 2014. [4] Gieringer, Dale H. (1999). “The Forgotten Origins of Cannabis Prohibition in California” (PDF). 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[62] Hayo M.G. van der Werf : Hemp facts and hemp ction CHAPTER 1. CANNABIS [79] Koch, Wendy (June 7, 2005). “Court's pot ruling won't apply to patients in federal program”. USA Today. Retrieved May 2, 2007. [63] T. Randall Fortenbery and Michael Bennett: Is Industrial Hemp Worth Further Study in the US? A Survey of the Literature, Department of Agricultural and Applied Economics, University of Wisconsin – Ma7dison. July 2001 [80] Volz, Matt (July 11, 2006). “Judge rules against Alaska marijuana law”. The Seattle Times (Frank A. Blethen). Retrieved May 22, 2008. [64] “Interview with the winner of the rst ECNP Lifetime Achievement Award: Raphael Mechoulam, Israel” (February 2007). Matters.ecnp.nl. [81] “American Society of Addiction Medicine Rejects Use of 'Medical Marijuana,' Citing Dangers and Failure To Meet Standards of Patient Care, March 23, 2011”. Maryland: Prnewswire.com. Retrieved April 20, 2011. [65] “David P. West: Fiber Wars: The Extinction of Kentucky Hemp chapter 8”. Gametec.com. Retrieved March 9, 2011. [66] “Marihuana Conference HELD DECEMBER 5, 1938, in the UNITED STATES Bureau of Internal Revenue”. Gametec.com. Retrieved March 9, 2011. [67] “Timothy Leary v. US, Supreme Court of the United States, 1969”. Druglibrary.org. Retrieved March 9, 2011. [68] Pub. L. No. 91-513, 84 Stat. 1236. October 27, 1973. [69] Illinois General Assembly; Legislative Investigating Commission (1971). The Drug Crisis: Report on Drug Abuse in Illinois to the Illinois General Assembly. Chicago, Illinois: Illinois Legislative Investigating Commission. p. 184. [70] “History of the DEA: 1970 – 1975”. www.deamuseum. org. Archived from the original on September 28, 2007. Retrieved April 30, 2007. External link in |publisher= (help) [71] “Supreme Court / Marijuana / Busing / Speedy Trial NBC News broadcast from the Vanderbilt Television News Archive”. Tvnews.vanderbilt.edu. December 1, 1975. Retrieved March 9, 2011. [82] “Medical Marijuana, American Society of Addiction Medicine, 2010”. Asam.org. April 1, 2010. Retrieved April 20, 2011. [83] An Open Letter to the President, Congress, Governors, and State Legislatures Prohibition Costs [84] “The American Society of Addiction Medicine views marijuana as non-medicinal”. . May 12, 2016. Retrieved March 26, 2007. External link in |publisher= (help) [85] “Report and Recommendations: Governor's Drug Policy Advisory Group”. Drug Policy Alliance. January 2001. Retrieved March 20, 2007. [86] “Election 2004: Oakland Marijuana Measure in the Bag”. journalism.berkeley.edu. Retrieved July 7, 2008. [87] “Ron Paul on marijuana laws”. YouTube. Retrieved January 2, 2008. [88] Editorial Board (July 2014). “Our Position: Repeal Prohibition, Again”. The New York Times. Retrieved July 28, 2014. [72] Analysis of marijuana policy. General Books. 2010. ISBN 978-1-154-43725-6. [89] “Marihuana, A Signal of Misunderstanding – Table of Contents”. Druglibrary.org. Retrieved May 26, 2011. [73] “An Overview of the United States Sentencing Commission”(PDF). United States Department of State. Retrieved April 30, 2007. [90] McVeigh, Frank J. Brief History of Social Problems: a critical thinking approach, 2004. Page 62. [74] “1985–1990”. Drug Enforcement Administration. Retrieved April 30, 2007. [75] Hanson, Glen; Venturelli, Peter; Fleckenstein, Annette (2008). Student Study Guide to Accompany Drugs and Society. Sudbury, Massachusetts: Jones & Bartlett Learning. p. 355. ISBN 978-0-7637-5932-2. [76] UNITED STATES v. OAKLAND CANNABIS BUYERSʼCOOPERATIVE. Cornell Law School. Retrieved May 26, 2011 [77] Supreme Court. GONZALES V. RAICH (2008). Cornell Law School. [78] Memorandum for selected United States Attorneys, Department of Justice, October 19, 2009, http://www.justice.gov/ opa/documents/medical-marijuana.pdf [91] “Marijuana Laws Oregon”. [92] “51 F.3d 269”. Ftp.resource.org. Retrieved May 26, 2011. [93] “North Carolina State Legislature”. (NC § 90‑94) / (NC § 90‑95 subs 4). Retrieved June 8, 2011. [94] “New York Marijuana Penalties”. NORML. January 1, 1970. Retrieved May 26, 2011. [95] "http://norml.org/pdf_files/state_penalties/NORML_NE_ State_Penalties.pdf". NORML. November 3, 2010. [96] Harrison, Ann (June 5, 2001). “Capitol Hill's cannabis catch-up? Medical marijuana ruling puts spotlight on pending legislation”. San Francisco Bay Guardian. Archived from the original on May 3, 2005. Retrieved April 24, 2007. 1.3. LEGAL HISTORY OF CANNABIS IN THE UNITED STATES 49 [97] Thakker, Jo; Durrant, Russil (2003). Substance Use and [114] “An Error Occurred Setting Your User Cookie”. Abuse: Cultural and Historical Perspectives. Thousand Oaks, California: Sage Publishing. p. 243. ISBN 978-0-7619- [115] http://www.justice.gov/archive/ndic/pubs44/44849/ 44849p.pdf 2342-8. [116] “U.S. Virgin Islands decriminalized marijuana”. United [98]“States decide on gay rights, abortion - Politics - Decision '08 States: Marijuana.com. December 23, 2014. - Decision ʼ08 – ballot initiatives - msnbc.com”. MSNBC. November 5, 2008. Retrieved May 26, 2011. [117] “Gobernador ordena viabilizar uso medicinal de productos derivados del cannabis (Governor orders medicinal use of [99] David Knowles (May 28, 2013).“Colorado becomes worldʼ cannabis products)". O cina Del Gobernador La Fortaleza s rst legal, fully regulated market for recreational marijuana (Governor of Puerto Rico). May 3, 2015. Retrieved August as it anticipates millions in tax revenues”. New York Daily 2015. News. Retrieved May 29, 2013. [118] the D.O.J. allows indian reservations to grow and sell mar[100] Ingold, John (September 10, 2013). “Colorado rst state in ijuana, nwherald.com, December 12, 2014, retrieved Decountry to nalize rules for recreational pot”. The Denver cember 24, 2014 Post. [119] “Tribe Bets on Legal Pot”. US News. June 16, 2015. [101] Meyer, Jeremy P. (September 17, 2013). “Denver council Retrieved July 12, 2015. passes historic retail marijuana rules and regulations”. The [120] “H.R. 499 – Summary”. United States Congress. Retrieved Denver Post. September 20, 2013. [102] Healy, Jack (January 1, 2014). “Colorado Stores Throw Open Their Doors to Pot Buyers”. The New York Times. [121] Rep. Dana Rohrabacher [R-CA48]. “Respect State Marijuana Laws Act of 2013 (H.R. 1523)". GovTrack.us. Retrieved June 23, 2013. [103] Nick Allen (December 31, 2013). “Colorado becomes rst US state to sell cannabis”. London: telegraph.co.uk. Re[122] “House Blocks DEA From Targeting Medical Marijuana” trieved January 2, 2014. . The Hu ngton Post. May 30, 2014. [104] Brandeis 2012, p. 175. [123] Ohlemacher, Stephen. “House Passes 'No Welfare For Weed' Bill”. Retrieved September 19, 2014. [105] Brandeis, Jason (2012). “The Continuing Vitality of Ravin v. State: Alaskans Still Have a Constitutional Right to Pos- [124] With Little Fanfare, Two Federal Marijuana Legalization sess Marijuana in the Privacy of Their Homes”. Alaska Law Bills Were Introduced in Congress Last Week (February Review 29 (2): 175–236. 22, 2015). Inquisitr http://www.inquisitr.com/1865579/ with-little-fanfare-two-federal-marijuana-legalization-bills-were-introduced-in [106] Archived November 10, 2012, at the Wayback Machine. #R5TXfFydzyivPTBr.99. Retrieved February 27, 2015. Missing or empty |title= (help) [107] name="Hu ngton Post">Wilkey, Rob (November 5, 2013). “Portland, Maine, Legalizes Recreational Mar[125] “Sens. Paul, Booker, & Gillibrand Announce CARERS ijuana”. Hu ngton Post. Retrieved November 6, Act”. Rand Paul (paul.senate.gov). 10 March 2015. Re2013. trieved 17 March 2015. [108] name="Portland Press Herald">Billings, Randy. “Portland [126] “S. 2237”. 114th Congress. November 28, 2015. voters legalize marijuana”. Maine Today Media. Retrieved [127] “Drug courts”. Whitehousedrugpolicy.gov. Retrieved November 16, 2013. March 9, 2011. [109] name="Hu ngton Post">Abbey-Lambertz, Kate (November 5, 2013). “Michigan Makes Big Strides Toward Mari- [128] “Drug Courts: The Second Decade | National Institute of Justice”. Nij.gov. Retrieved May 26, 2011. juana Reform”. Hu ngton Post. Retrieved November 16, 2013. [110] “Washington DC legalises marijuana possession and use” . BBC News. February 26, 2015. Retrieved February 26, 2015. [111] Cummings, William (February 26, 2015).“Pot now legal in D.C. despite threats from Congress”. USA Today. Retrieved February 26, 2015. [112] Marijuana Policy Project. “State Policy - MPP”. MPP. [113] “MMS: Error”. 1.3.8 Further reading • Deitch, Robert (2003), Hemp: American history revisited: the plant with a divided history, Algora Pub, ISBN 0-87586-206-3 • Holland, Julie M.D. (2010), The pot book : a complete guide to cannabis : its role in medicine, politics, science, and culture, Park Street Press, ISBN 978-159477-368-6 50 CHAPTER 1. CANNABIS • United States. Congress. Senate. (2013). Con icts between State and Federal Marijuana Laws: Hearing before the Committee on the Judiciary, United States Senate, One Hundred Thirteenth Congress, First Session, Tuesday, September 10, 2013. Washington, DC: U.S. Government Publishing O ce, 2015. 1.4 Controlled Substances Act The Controlled Substances Act (CSA) is the statute prescribing federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain substances is regulated. It was passed by the 91st United States Congress as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970 and signed into law by President Richard Nixon.* [1] The Act also served as the national implementing legislation for the Single Convention on Narcotic Drugs. Part F of the Comprehensive Drug Abuse Prevention and Control Act of 1970 established the National Commission on Marijuana and Drug Abuse̶known as the Shafer Commission after its chairman, Raymond P. Shafer̶to study cannabis abuse in the United States.* [8] During his presentation of the commission's First Report to Congress, Shafer recommended the decriminalization of marijuana in small amounts, saying, [T]he criminal law is too harsh a tool to apply to personal possession even in the e ort to discourage use. It implies an overwhelming indictment of the behavior which we believe is not appropriate. The actual and potential harm of use of the drug is not great enough to justify intrusion by the criminal law into private behavior, a step which our society takes only with the greatest reluctance. Rufus King notes that this stratagem was similar to that used by Harry Anslinger when he consolidated the previous antidrug treaties into the Single Convention and took the opportunity to add new provisions that otherwise might have been unpalatable to the international community.* [9] According to David T. Courtwright, “the Act was part of an omnibus reform package designed to rationalize, and in some respects to liberalize, American drug policy.”(Courtwright noted that the Act became, not libertarian, but instead repressionistic to the point of tyrannical, in its intent.) It eliminated mandatory minimum sentences and provided support for drug treatment and research.* [10] King notes that the rehabilitation clauses were added as a compromise to Senator Jim Hughes, who favored a moderate approach. The bill, as introduced by Senator Everett Dirksen, ran to 91 pages. While it was being drafted, the Uniform Controlled Substances Act, to be passed by state legislatures, was also 1.4.1 History being drafted by the Department of Justice; its wording closely mirrored the Controlled Substances Act.* [9] The nation rst outlawed addictive drugs in the early 1900s and the International Opium Convention helped lead inter- Since its enactment in 1970, the Act has been amended sevnational agreements regulating trade.* [4]* [5]* [6] The Food eral times:* [11] and Drugs Act of 1906 was the beginning of over 200 laws concerning public health and consumer protections. Others • The Medical Device Amendments of 1976. were the Federal Food, Drug, and Cosmetic Act (1938), and the Kefauver Harris Amendment of 1962.* [7] • The Psychotropic Substances Act of 1978 added provisions implementing the Convention on Psychotropic In 1969, President Richard Nixon announced that the Substances. Attorney General, John N. Mitchell, was preparing a comThe legislation created ve Schedules (classi cations), with varying quali cations for a substance to be included in each. Two federal agencies, the Drug Enforcement Administration and the Food and Drug Administration, determine which substances are added to or removed from the various schedules, although the statute passed by Congress created the initial listing. Congress has sometimes scheduled other substances through legislation such as the Hillory J. Farias and Samantha Reid Date-Rape Prevention Act of 2000, which placed gamma hydroxybutyrate in Schedule I. Classi cation decisions are required to be made on criteria including potential for abuse (an unde ned term),* [2]* [3] currently accepted medical use in treatment in the United States, and international treaties. prehensive new measure to more e ectively meet the narcotic and dangerous drug problems at the federal level by combining all existing federal laws into a single new statute. The CSA not only combined existing federal drug laws and expanded their scope but it also changed the nature of federal drug law policies, and expanded Federal law enforcement pertaining to controlled substances. • The Controlled Substances Penalties Amendments Act of 1984. • The Chemical Diversion and Tra cking Act of 1988 (implemented August 1, 1989 as Article 12) added provisions implementing the United Nations Convention Against Illicit Tra c in Narcotic Drugs and Psy- 1.4. CONTROLLED SUBSTANCES ACT 51 chotropic Substances that went into force on Novem- should be controlled or removed from control. This reber 11, 1990. quest is sent to the Assistant Secretary of Health of HHS. Then, HHS solicits information from the Commissioner of • The Anabolic Steroids Act, passed as part of the Crime the Food and Drug Administration and evaluations and recControl Act of 1990, which placed anabolic steroids ommendations from the National Institute on Drug Abuse into Schedule III* [12]* :30 and, on occasion, from the scienti c and medical community at large. The Assistant Secretary, by authority of the • The Domestic Chemical Diversion and Control Act of Secretary, compiles the information and transmits back to 1993 (e ective on April 16, 1994) in response to the the DEA a medical and scienti c evaluation regarding the methamphetamine tra cking. drug or other substance, a recommendation as to whether the drug should be controlled, and in what schedule it should • The Federal Analog Act. be placed. • The Ryan Haight Online Pharmacy Consumer Protec- The HHS recommendation on scheduling is binding to the tion Act of 2008* [13] extent that if HHS recommends, based on its medical and scienti c evaluation, that the substance not be controlled, • The Electronic Prescriptions for Controlled Sub- then the DEA may not control the substance. Once the stances (EPCS) 2010. DEA has received the scienti c and medical evaluation from HHS, the DEA Administrator evaluates all available data and makes a nal decision whether to propose that a 1.4.2 Content drug or other substance be controlled and into which schedule it should be placed. Under certain circumstances, the The Controlled Substances Act consists of 2 subchapters. Government may temporarily schedule* [17] a drug withSubchapter I de nes Schedules I-V, lists chemicals used in out following the normal procedure. An example is when the manufacture of controlled substances, and di erentiinternational treaties require control of a substance. In adates lawful and unlawful manufacturing, distribution, and dition, 21 U.S.C. α 811(h) allows the Attorney General to possession of controlled substances, including possession temporarily place a substance in Schedule I “to avoid an of Schedule I drugs for personal use; this subchapter also imminent hazard to the public safety”. Thirty days' nospeci es the dollar amounts of nes and durations of prison tice is required before the order can be issued, and the terms for violations. Subchapter II describes the laws for scheduling expires after a year; however, the period may exportation and importation of controlled substances, again be extended six months if rulemaking proceedings to perspecifying nes and prison terms for violations.* [14] manently schedule the drug are in progress. In any case, once these proceedings are complete, the temporary order is automatically vacated. Unlike ordinary scheduling pro1.4.3 Enforcement authority ceedings, such temporary orders are not subject to judicial review. The Drug Enforcement Administration was established in * 1973, combining the Bureau of Narcotics and Dangerous The CSA also creates a closed system of distribution [18] Drugs (BNDD) and Customsʼdrug agents.* [15] Proceed- for those authorized to handle controlled substances. The ings to add, delete, or change the schedule of a drug or other cornerstone of this system is the registration of all those substance may be initiated by the DEA, the Department of authorized by the DEA to handle controlled substances. Health and Human Services (HHS), or by petition from any All individuals and rms that are registered are required to interested party, including the manufacturer of a drug, a maintain complete and accurate inventories and records of medical society or association, a pharmacy association, a all transactions involving controlled substances, as well as public interest group concerned with drug abuse, a state or security for the storage of controlled substances. local government agency, or an individual citizen. When a petition is received by the DEA, the agency begins its own investigation of the drug. 1.4.4 Treaty obligations The DEA also may begin an investigation of a drug at any time based upon information received from laboratories, state and local law enforcement and regulatory agencies, or other sources of information. Once the DEA has collected the necessary data, the Deputy Administrator of DEA,* [16] requests from HHS a scienti c and medical evaluation and recommendation as to whether the drug or other substance The Congressional ndings in 21 USC αα 801(7), 801a(2), and 801a(3) state that a major purpose of the CSA is to“enable the United States to meet all of its obligations”under international treaties. The CSA bears many resemblances to these Conventions. Both the CSA and the treaties set out a system for classifying controlled substances in sev- 52 CHAPTER 1. CANNABIS eral Schedules in accordance with the binding scienti c and medical ndings of a public health authority. Under 21 U.S.C. α 811 of the CSA, that authority is the Secretary of Health and Human Services (HHS). Under Article 3 of the Single Convention and Article 2 of the Convention on Psychotropic Substances, the World Health Organization is that authority. The domestic and international legal nature of these treaty obligations must be considered in light of the supremacy of the United States Constitution over treaties or acts and the equality of treaties and Congressional acts. In Reid v. Covert the Supreme Court of the United States addressed both these issues directly and clearly holding: [N]o agreement with a foreign nation can confer power on the Congress, or on any other branch of Government, which is free from the restraints of the Constitution. Article VI, the Supremacy Clause of the Constitution, declares: “This Constitution, and the Laws of the United States which shall be made in Pursuance thereof, and all Treaties made, or which shall be made, under the Authority of the United States, shall be the supreme Law of the Land; . . .” There is nothing in this language which intimates that treaties and laws enacted pursuant to them do not have to comply with the provisions of the Constitution. Nor is there anything in the debates which accompanied the drafting and rati cation of the Constitution which even suggests such a result. These debates, as well as the history that surrounds the adoption of the treaty provision in Article VI, make it clear that the reason treaties were not limited to those made in “pursuance”of the Constitution was so that agreements made by the United States under the Articles of Confederation, including the important peace treaties which concluded the Revolutionary War, would remain in effect. It would be manifestly contrary to the objectives of those who created the Constitution, as well as those who were responsible for the Bill of Rights̶let alone alien to our entire constitutional history and tradition̶to construe Article VI as permitting the United States to exercise power under an international agreement without observing constitutional prohibitions. In e ect, such construction would permit amendment of that document in a manner not sanctioned by Article V. The prohibitions of the Constitution were designed to apply to all branches of the National Government, and they cannot be nulli ed by the Executive or by the Executive and the Senate combined. There is nothing new or unique about what we say here. This Court has regularly and uniformly recognized the supremacy of the Constitution over a treaty. For example, in Geofroy v. Riggs, 133 U. S. 258, 133 U. S. 267, it declared: “The treaty power, as expressed in the Constitution, is in terms unlimited except by those restraints which are found in that instrument against the action of the government or of its departments, and those arising from the nature of the government itself and of that of the States. It would not be contended that it extends so far as to authorize what the Constitution forbids, or a change in the character of the government, or in that of one of the States, or a cession of any portion of the territory of the latter, without its consent.” This Court has repeatedly taken the position that an Act of Congress, which must comply with the Constitution, is on a full parity with a treaty, and that, when a statute which is subsequent in time is inconsistent with a treaty, the statute to the extent of conict renders the treaty null. It would be completely anomalous to say that a treaty need not comply with the Constitution when such an agreement can be overridden by a statute that must conform to that instrument.* [19] 53 1.4. CONTROLLED SUBSTANCES ACT According to the Cato Institute, these treaties only bind (legally obligate) the United States to comply with them as long as that nation agrees to remain a state party to these treaties. The U.S. Congress and the President of the United States have the absolute sovereign right to withdraw from or abrogate at any time these two instruments, in accordance with said nation's Constitution, at which point these treaties will cease to bind that nation in any way, shape, or form.* [20] Rohypnol is not approved or available for medical use in the United States, but it is temporarily controlled in Schedule IV pursuant to a treaty obligation under the 1971 Convention on Psychotropic Substances. At the time unitrazepam was placed temporarily in Schedule IV (November 5, 1984), there was no evidence of abuse or tra cking of the drug in the United States.* [21] A provision for automatic compliance with treaty obligations is found at 21 U.S.C. α 811(d), which also establishes The Cato Institute's Handbook for Congress calls for repealmechanisms for amending international drug control regu- ing the CSA, an action that would likely bring the United lations to correspond with HHS ndings on scienti c and States into con ict with international law, were the United medical issues. If control of a substance is mandated by States not to exercise its sovereign right to withdraw from the Single Convention, the Attorney General is required to and/or abrogate the Single Convention on Narcotic Drugs “issue an order controlling such drug under the schedule and/or the 1971 Convention on Psychotropic Substances he deems most appropriate to carry out such obligations,” prior to repealing the Controlled Substances Act.* [20] The without regard to the normal scheduling procedure or the exception would be if the U.S. were to claim that the treaty ndings of the HHS Secretary. However, the Secretary has obligations violate the United States Constitution. Many argreat in uence over any drug scheduling proposal under the ticles in these treaties̶such as Article 35 and Article 36 of Single Convention, because 21 U.S.C. α 811(d)(2)(B) re- the Single Convention̶are prefaced with phrases such as quires the Secretary the power to“evaluate the proposal and “Having due regard to their constitutional, legal and adminfurnish a recommendation to the Secretary of State which istrative systems, the Parties shall . . .”or “Subject to its shall be binding on the representative of the United States constitutional limitations, each Party shall . . .”According in discussions and negotiations relating to the proposal.” to former United Nations Drug Control Programme Chief of Demand Reduction Cindy Fazey, “This has been used Similarly, if the United Nations Commission on Narcotic by the USA not to implement part of article 3 of the 1988 Drugs adds or transfers a substance to a Schedule estabConvention, which prevents inciting others to use narcotic lished by the Convention on Psychotropic Substances, so or psychotropic drugs, on the basis that this would be in conthat current U.S. regulations on the drug do not meet the travention of their constitutional amendment guaranteeing treaty's requirements, the Secretary is required to issue a freedom of speech".* [22] recommendation on how the substance should be scheduled under the CSA. If the Secretary agrees with the Commission's scheduling decision, he can recommend that the Attorney General initiate proceedings to reschedule the drug 1.4.5 Schedules of controlled substances accordingly. If the HHS Secretary disagrees with the UN controls, however, the Attorney General must temporar- Placing a drug or other substance in a certain Schedule or ily place the drug in Schedule IV or V (whichever meets removing it from a certain Schedule is primarily based on the minimum requirements of the treaty) and exclude the 21 USC αα 801, 801a, 802, 811, 812, 813, and 814. Evsubstance from any regulations not mandated by the treaty, ery schedule otherwise requires nding and specifying the while the Secretary is required to request that the Secretary “potential for *abuse”before a substance can be placed in of State take action, through the Commission or the UN that schedule. [23] The speci c classi cation of any given Economic and Social Council, to remove the drug from in- drug or other substance is usually a source of controversy, ternational control or transfer it to a di erent Schedule un- as is the purpose and e ectiveness of the entire regulatory der the Convention. The temporary scheduling expires as scheme. soon as control is no longer needed to meet international treaty obligations. The term “controlled substance”means a drug or other substance, or immediate precursor, This provision was invoked in 1984 to place Rohypnol included in schedule I, II, III, IV, or V of part ( unitrazepam) in Schedule IV. The drug did not then B of this subchapter. The term does not include meet the Controlled Substances Act's criteria for scheduldistilled spirits, wine, malt beverages, or tobacco, ing; however, control was required by the Convention on as those terms are de ned or used in subtitle E of Psychotropic Substances. In 1999, an FDA o cial exthe Internal Revenue Code of 1986. plained to Congress: ̶21 U.S.C. α 802(6)* [24] 54 CHAPTER 1. CANNABIS Some have argued that this is an important exemption, since proceeding.* [29] Sentences for violent o enders are much alcohol and tobacco are two of the most widely used drugs higher . in the United States.* [25]* [26] Also of signi cance, the Drugs in this schedule include: exclusion of alcohol includes wine which is sacramentally used by many major religious denominations in the United • MT (alpha-methyltryptamine), a psychedelic, States. stimulant, and entactogen drug of the tryptamine class that was originally developed as an antidepressant by workers at Upjohn in the 1960s. 1.4.6 Schedule I controlled substances Main article: List of Schedule I drugs (US) Schedule I substances are those that have the following ndings: 1. The drug or other substance has a high potential for abuse. 2. The drug or other substance has no currently accepted medical use in treatment in the United States. 3. There is a lack of accepted safety for use of the drug or other substance under medical supervision.* [27] No prescriptions may be written for Schedule I substances, and such substances are subject to production quotas which the DEA imposes. Under the DEA's interpretation of the CSA, a drug does not necessarily have to have the same“high potential for abuse” as heroin, for example, to merit placement in Schedule I: [W]hen it comes to a drug that is currently listed in schedule I, if it is undisputed that such drug has no currently accepted medical use in treatment in the United States and a lack of accepted safety for use under medical supervision, and it is further undisputed that the drug has at least some potential for abuse su cient to warrant control under the CSA, the drug must remain in schedule I. In such circumstances, placement of the drug in schedules II through V would con ict with the CSA since such drug would not meet the criterion of “a currently accepted medical use in treatment in the United States.”21 USC 812(b). (emphasis added)* [28] ̶Drug Enforcement Administration, Notice of denial of petition to reschedule marijuana (2001) Sentences for rst-time, non-violent o enders convicted of tra cking in Schedule I drugs can easily turn into de facto life sentences when multiple sales are prosecuted in one • BZP (benzylpiperazine), a synthetic stimulant once sold as a designer drug. It has been shown to be associated with an increase in seizures if taken alone.* [30] Although the e ects of BZP are not as potent as MDMA, it can produce neuroadaptations that can cause an increase in the potential for abuse of this drug.* [31] • Cathinone, an amphetamine-like stimulant found in the shrub Catha edulis (khat). • DMT (dimethyltryptamine), a naturally-occurring psychedelic drug that is widespread throughout the plant kingdom and endogenous to the human body. DMT is the main psychoactive constituent in the psychedelic South American brew, ayahuasca, for which the UDV are granted exemption from DMT's schedule I status on the grounds of religious freedom. • Etorphine, a semi-synthetic opioid possessing an analgesic potency approximately 1,000–3,000 times that of morphine. • GHB, a general anesthetic and treatment for narcolepsy-cataplexy and alcohol withdrawal with a limited safe dosage range and poor ability to control pain when used as an anesthetic (severely limiting its usefulness).* [32] It was placed in Schedule I in March 2000 after widespread recreational use led to increased emergency room visits, hospitalizations, and deaths.* [33] A speci c formulation of this drug is also listed in Schedule III for limited uses, under the trademark Xyrem. • Heroin (diacetylmorphine), which is used in some European countries as a potent pain reliever in terminal cancer patients, and as second option, after morphine (it is about twice as potent, by weight, as morphine). • LSD (lysergic acid diethylamide), a semi-synthetic psychedelic drug famous for its involvement in the counterculture of the 1960s. • Marijuana and its cannabinoids. Pure (–)-transΔ9-tetrahydrocannabinol is also listed in Schedule III for limited uses, under the trademark Marinol. Ballot measures in several states such as Colorado, 55 1.4. CONTROLLED SUBSTANCES ACT • • • • • • Washington, Oregon and others have made allowances 2. The drug or other substances have currently for recreational and medical use of marijuana and/or accepted medical use in treatment in the have decriminalized possession of small amounts of United States, or currently accepted medmarijuana – such measures operate only on state ical use with severe restrictions laws, and have no e ect on Federal law. Despite 3. Abuse of the drug or other substances may such ballot measures, and multiple studies showing lead to severe psychological or physical demedicinal bene ts, marijuana nevertheless remains on pendence.* [27] Schedule I, e ective across all U.S. states and territories.* [28]* [29] Except when dispensed directly by a practitioner, other than a pharmacist, to an ultimate user, no controlled substance MDMA (“ecstasy”), a stimulant, psychedelic, and in Schedule II, which is a prescription drug as determined entactogenic drug which initially garnered attention in under the Federal Food, Drug, and Cosmetic Act (21 USC psychedelic therapy as a treatment for post-traumatic 301 et seq.), may be dispensed without the written prescripstress disorder (PTSD). The medical community orig- tion of a practitioner, except that in emergency situations, inally agreed upon placing it as a Schedule III sub- as prescribed by the Secretary by regulation after consultastance, but the government denied this suggestion, de- tion with the Attorney General, such drug may be dispensed spite two court rulings by the DEA's administrative upon oral prescription in accordance with section 503(b) law judge that placing MDMA in Schedule I was ille- of that Act (21 USC 353 (b)). With exceptions, an origgal. It was temporarily unscheduled after the rst ad- inal prescription is always required even though faxing in ministrative hearing from December 22, 1987 – July a prescription in advance to a pharmacy by a prescriber is 1, 1988.* [34] allowed.* [35] Prescriptions shall be retained in conformity with the requirements of section 827 of this title. No preMescaline, a naturally-occurring psychedelic drug scription for a controlled substance in schedule II may be and the main psychoactive constituent of peyote re lled.* [36] Notably no emergency situation provisions ex(Lophophora williamsii), San Pedro cactus (Echinopist outside the Controlled Substances Act's“closed system” sis pachanoi), and Peruvian torch cactus (Echinopsis although this closed system may be unavailable or nonfuncperuviana). tioning in the event of accidents in remote areas or disasMethaqualone (Quaalude, Sopor, Mandrax), a seda- ters such as hurricanes and earthquakes. Acts which would tive that was previously used for similar purposes as widely be considered morally imperative remain o enses subject to heavy penalties.* [37] barbiturates, until it was rescheduled. These drugs vary in potency: for example fentanyl is about Peyote (Lophophora williamsii), a cactus growing in 80 times as potent as morphine (heroin is roughly four times nature primarily in northeastern Mexico; one of the as potent). More signi cantly, they vary in nature. Pharfew plants speci cally scheduled, with a narrow exmacology and CSA scheduling have a weak relationship. ception to its legal status for religious use by members Because re lls of prescriptions for Schedule II substances of the Native American Church. are not allowed, it can be burdensome to both the practiPsilocybin and psilocin, naturally-occurring tioner and the patient if the substances are to be used on psychedelic drugs and the main psychoactive a long-term basis. To provide relief, in 2007, 21 C.F.R. constituents of psilocybin mushrooms. 1306.12 was amended (at 72 FR 64921) to allow practitioners to write up to three prescriptions at once, to provide Controlled substance analogs intended for human con- up to a 90-day supply, specifying on each the earliest date sumption (as de ned by the Federal Analog Act) on which it may be lled.* [38] 1.4.7 Schedule II controlled substances Main article: List of Schedule II drugs (US) Schedule II substances are those that have the following ndings: 1. The drug or other substances have a high potential for abuse Drugs in this schedule include: • Cocaine: used as a topical anesthetic • Amphetamine (originally placed in Schedule III, but moved to Schedule II in 1971), Adderall, Dextroamphetamine (Dexedrine), Lisdexamfetamine (Vyvanse): treatment of ADHD, narcolepsy • Methylphenidate (Ritalin, Concerta), Dexmethylphenidate (Focalin): treatment of ADHD, narcolepsy 56 • Methamphetamine: obesity CHAPTER 1. CANNABIS treatment of ADHD, severe • Opium tincture (Laudanum): a potent antidiarrheal • Fentanyl and most other strong pure opioid agonists, i.e. levorphanol, opium 2. The drug or other substance has a currently accepted medical use in treatment in the United States. 3. Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence.* [27] • Methadone: treatment of heroin addiction, extreme Except when dispensed directly by a practitioner, other than a pharmacist, to an ultimate user, no controlled substance chronic pain in schedule III or IV, which is a prescription drug as deter• Oxycodone (semi-synthetic opioid; active ingredient mined under the Federal Food, Drug, and Cosmetic Act (21 in Percocet, OxyContin, and Percodan) USC 301 et seq.), may be dispensed without a written or oral prescription in conformity with section 503(b) of that Act • Oxymorphone (semi-synthetic opioid; active ingredi(21 USC 353 (b)). Such prescriptions may not be lled or ent in Opana) re lled more than six months after the date thereof or be relled more than ve times after the date of the prescription • Morphine unless renewed by the practitioner.* [36] A prescription for • Hydromorphone (semi-synthetic opioid; active ingre- controlled substances in Schedules III, IV, and V issued by dient in Dilaudid, Palladone) a practitioner, may be communicated either orally, in writ• Pure codeine and any drug for non-parenteral admin- ing, or by facsimile to the pharmacist, and may be re lled * istration containing the equivalent of more than 90 mg if so authorized on the prescription or by call-in. [35] Control of wholesale distribution is somewhat less stringent than of codeine per dosage unit; Schedule II drugs. Provisions for emergency situations are • Hydrocodone in any formulation as of October less restrictive within the“closed system”of the Controlled 2014 (Examples include Vicodin, Norco, Tussionex). Substances Act than for Schedule II though no schedule has Prior to October 2014, formulations containing hy- provisions to address circumstances where the closed sysdrocodone and over-the-counter NSAIDs such as Ac- tem is unavailable, nonfunctioning or otherwise inadequate. etaminophen and Ibuprofen were Schedule III. Drugs in this schedule include: • Secobarbital (Seconal) • Anabolic steroids (including prohormones such • Pethidine (USAN: Meperidine; Demerol) as androstenedione); the speci c end molecule testosterone in many of its forms (Androderm, • Pure diphenoxylate AndroGel, Testosterone Cypionate, and Testosterone • Phencyclidine (PCP) Enanthate) are labeled as scheduled III while lowdose testosterone when compounded with estrogen • Short-acting barbiturates, such as pentobarbital derivatives have been exempted (from scheduling) by the FDA* [39] • Nabilone (Cesamet) - A synthetic cannabinoid. An analogue to dronabinol (Marinol) which is a Schedule • Intermediate-acting barbiturates, such as talbutal or III drug. butalbital • Tapentadol (Nucynta) - A drug with mixed opioid ag• Buprenorphine (semi-synthetic opioid; active in onist and norepinephrine re-uptake inhibitor activity. Suboxone, Subutex) 1.4.8 Schedule III controlled substances Main article: List of Schedule III drugs (US) Schedule III substances are those that have the following ndings: 1. The drug or other substance has a potential for abuse less than the drugs or other substances in schedules I and II. • Dihydrocodeine when compounded with other substances, to a certain dosage and concentration. • Ketamine, a drug originally developed as a safer, shorter-acting replacement for PCP (mainly for use as a human anesthetic) but has since become popular as a veterinary and pediatric anesthetic; • Xyrem, a preparation of GHB used to treat narcolepsy. Xyrem is in Schedule III but with a restricted distribution system. All other forms of GHB are in Schedule I. 57 1.4. CONTROLLED SUBSTANCES ACT • Marinol, synthetically prepared tetrahydrocannabinol Drugs in this schedule include: (o cially referred to by its INN, dronabinol) used to treat nausea and vomiting caused by chemotherapy, as • Benzodiazepines, such as alprazolam (Xanax), well as appetite loss caused by AIDS. chlordiazepoxide (Librium), clonazepam (Klonopin), diazepam (Valium), and Lorazepam (Ativan), as well • Paregoric, an antidiarrheal and anti-tussive, which as: contains opium combined with camphor (which makes it less addiction-prone than laudanum, which is in Schedule II). • Phendimetrazine Tartrate, a stimulant synthesized for use as an anorexiant. • Benzphetamine HCl (Didrex), a stimulant designed for use as an anorexiant. • Fast-acting barbiturates such as secobarbital (Seconal) and pentobarbital (Nembutal), when combined with one or more additional active ingredient(s) not in Schedule II (e.g., Carbrital (no longer marketed), a combination of pentobarbital and carbromal). • Ergine (lysergic acid amide), listed as a sedative but considered by some to be psychedelic.* [40]* [41] An ine cient precursor to its N,N-diethyl analogue, LSD, ergine occurs naturally in the seeds of the common garden owers Turbina corymbosa, Ipomoea tricolor, and Argyreia nervosa. 1.4.9 Schedule IV controlled substances Main article: List of Schedule IV drugs (US) “Placement on schedules; ndings required Schedule IV substances are those that have the following ndings: 1. The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III 2. The drug or other substance has a currently accepted medical use in treatment in the United States 3. Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III* [27] Control measures are similar to Schedule III. Prescriptions for Schedule IV drugs may be re lled up to ve times within a six-month period. A prescription for controlled substances in Schedules III, IV, and V issued by a practitioner, may be communicated either orally, in writing, or by facsimile to the pharmacist, and may be re lled if so authorized on the prescription or by call-in.* [35] • temazepam (Restoril) (note that some states require specially coded prescriptions for temazepam) • unitrazepam (Rohypnol) (note that unitrazepam is not used medically in the United States) • The benzodiazepine-like Z-drugs: zolpidem (Ambien), zopiclone (Imovane), eszopiclone (Lunesta), and zaleplon (Sonata) (zopiclone is not commercially available in the U.S.) • Chloral hydrate, a sedative-hypnotic • Long-acting barbiturates such as phenobarbital • Some partial agonist opioid analgesics, such as pentazocine (Talwin) • The stimulant-like drug moda nil (sold in the U.S. as Provigil) as well as its (R)-enantiomer armoda nil (sold in the U.S. as Nuvigil) • Difenoxin, an antidiarrheal drug, such as when combined with atropine (Motofen) (difenoxin is 2–3 times more potent than diphenoxylate, the active ingredient in Lomotil, which is in Schedule V) • Tramadol (Ultram) • Carisoprodol (Soma) has become a Schedule IV medication as of 11 January 2012* [42] 1.4.10 Schedule V controlled substances Main article: List of Schedule V drugs (US) Schedule V substances are those that have the following ndings: 1. The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule IV 2. The drug or other substance has a currently accepted medical use in treatment in the United States 58 CHAPTER 1. CANNABIS 3. Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule IV.* [27] Additionally, the law restricts an individual to the retail purchase of no more than three packages or 3.6 grams of such product per day per purchase – and no more than 9 grams in a single month. A violation of this statute constitutes a misdemeanor. Retailers now commonly require PSE-containing products to be sold behind the pharmacy or service counter. This a ects many preparations which were previously available over-the-counter without restriction, such as Actifed and its generic equivalents. No controlled substance in schedule V which is a drug may be distributed or dispensed other than for a medical purpose.* [36] A prescription for controlled substances in Schedules III, IV, and V issued by a practitioner, may be communicated either orally, in writing, or by facsimile to the pharmacist, and may be re lled if so authorized on the 1.4.12 prescription or by call-in.* [35] Drugs in this schedule include: • Cough suppressants containing small amounts of codeine (e.g., promethazine+codeine); • Preparations containing small amounts of opium or diphenoxylate (used to treat diarrhea); Alternatives to scheduling The UK Science and Technology Select Committee published a 2006 report which suggested that the current system of recreational drug classi cation in the UK was arbitrary and unscienti c and that a more scienti c measure of harm should be used for classifying drugs. The new classi cation system suggested that heroin, cocaine, alcohol, benzodiazepines, methamphetamine, and tobacco have a high or a very high risk of harm or abuse potential, whilst cannabis, LSD, and Ecstasy were all below the two legal drugs in harm or abuse potential.* [45] • Some anticonvulsants, such as pregabalin (Lyrica), lacosamide (Vimpat) and retigabine (ezogabine) (Potiga/Trobalt); In 2007, The Lancet published a journal about researchers having introduced an alternative method for drug classi ca• Pyrovalerone (used to treat chronic fatigue and as an tion.* [46] This new system uses a “nine category matrix appetite suppressant for weight loss); of harm, with an expert Delphic procedure, to assess the harms of a range of illicit drugs in an evidence-based fash• Some centrally-acting antidiarrheals, such as ion.”The new classi cation system suggested that alcohol diphenoxylate (Lomotil) when mixed with atropine and tobacco were in the mid-range of harm, while cannabis, (to make it unpleasant for people to grind up, cook, LSD, and MDMA were all less harmful than the two legal and inject). Difenoxin with atropine (Motofen) has drugs.* [47] been moved to Schedule IV. Without atropine, these drugs are in Schedule II. 1.4.13 Criticism 1.4.11 Federal regulation of doephedrine and ephedrine pseu- There has been criticism against the schedule classi cations See also: Pseudoephedrine → National Legislation → United States of the listed drugs and substances in the CSA, citing unde ned terms.* [2]* [3] Some criticism has arisen due to research that has found several substances on the list of Schedule I substances to have actual accepted medical uses and low abuse potential, despite the requirement for a Schedule I listing mandating that any substance so scheduled have both a high potential for abuse and no accepted medical use.* [48]* [49] One such example is the legalization of marijuana in some capacity in over 23 states. Due to pseudoephedrine (PSE) and ephedrine being widely used in the manufacture of methamphetamine, the U.S. Congress passed the Methamphetamine Precursor Control Act which places restrictions on the sale of any medicine containing pseudoephedrine. That bill was then superseded by the Combat Methamphetamine Epidemic Act of 2005, which was passed as an amendment to the Patriot 1.4.14 See also Act renewal and included wider and more comprehensive • Convention on Psychotropic Substances restrictions on the sale of PSE-containing products. This law requires* [43] customer signature of a“log-book”and • Drug-Free Workplace Act of 1988 presentation of valid photo ID in order to purchase PSEcontaining products from all retailers.* [44] • Fair Sentencing Act 59 1.4. CONTROLLED SUBSTANCES ACT • Gonzales v. Raich • Legality of the War on Drugs • List of pharmaceutical companies • Medical amnesty policy • Regulation of therapeutic goods [9] The 1970 Act: Don't Sit There, Amend Something [10] Courtwright, David T. (2004-10-05).“The Controlled Substances Act: how a“big tent”reform became a punitive drug law”. doi:10.1016/j.drugalcdep.2004.04.012. Retrieved 2008-02-12. [11] Legislation reform- Retrieved 2012-12-30 • Removal of cannabis from Schedule I of the Controlled Substances Act [12] Steven B. Karch. Pathology, Toxicogenetics, and Criminalistics of Drug Abuse. CRC Press, 2007 ISBN 9781420054569 • Single Convention on Narcotic Drugs (1961) [13] Ryan Haight Act- Retrieved 2012-12-30 • Treaty Clause and Head Money Cases [14] http://www.deadiversion.usdoj.gov/21cfr/21usc/ • United States v. Oakland Cannabis Buyers' Cooperative [15] .DEA- Retrieved 2012-12-30 Similar legislation outside of the United States: • Controlled Drugs and Substances Act (Canada) • Misuse of Drugs Act 1971 (United Kingdom) 1.4.15 Notes [1] Pub.L. 91–513, 84 Stat. 1236, enacted October 27, 1970, codi ed at 21 U.S.C. α 801 et. seq. [2] Docket ID: DEA-2009-0013 in DEA-2009-0013-0003 HHS recommendation document. Enclosure: BASIS FOR THE RECOMMENDATION TO CONTROL 5METHOXY-DIMETHYLTRYPTAMINE (5-MeO-DMT) IN SCHEDULE I OF THE CONTROLLED SUBSTANCES ACT, (B.) (1.) The term“abuse”is not de ned in the CSA. [3] "[D]rug abuse may refer to any type of drug or chemical without regard to its pharmacologic actions. It is an eclectic concept having only one uniform connotation: societal disapproval. ... The Commission believes that the term drug abuse must be deleted from o cial pronouncements and public policy dialogue. The term has no functional utility and has become no more than an arbitrary codeword for that drug use which is presently considered wrong.”– Second Report of the National Commission on Marihuana and Drug Abuse; Drug Use In America: Problem In Perspective (March 1973), p.13 [4] Illegal Drugs in America: A Modern History [5] The 1912 Hague International Opium Convention [6] History of Legislative Control Over Opium, Cocaine, and Their Derivatives [7] - Retrieved 2012-12-30 [8] Part F is printed on the inside cover of Drug Use In America: Problem In Perspective, Second Report of the National Commission on Marihuana and Drug Abuse, March 1973 [16] Federal Register: August 21, 2009 (Volume 74, Number 161), Page 42220 “Under the authority vested in the Attorney General by section 201(a) of the CSA (21 USC 811(a)), and delegated to the Administrator of DEA by Department of Justice regulations (28 CFR 0.100), and redelegated to the Deputy Administrator pursuant to 28 CFR 0.104...” [17] Temporary drug scheduling-Retrieved 2012-12-30 [18] Pharmacy Practice and the Law(Book, p 184); By Richard R. Abood -Retrieved 2012-12-30 [19] “Reid v. Covert, 354 U. S. 1 at pp 17–19”. Justia Law. Retrieved 30 October 2014. [20] “The War on Drugs”(PDF). Cato Handbook for Congress: Policy Recommendations for the 108th Congress (PDF). Cato Institute. 2003. pp. 171–178. Retrieved 2012-10-20. [21] “Date Rape”Drugs [22] |url=http://www.fuoriluogo.it/arretrati/2003/apr_17_en. htm |date=20150423160616 fuoriluogo.it – aprile 2003 Archive copy at the Wayback Machine [23] 21 USC Chapter 13 – DRUG ABUSE PREVENTION AND CONTROL | LII / Legal Information Institute [24] 21 USC α 802 – De nitions | LII / Legal Information Institute [25] “Appendix C: Measurement of Dependence, Abuse, Treatment, and Treatment Need – 2000 NHSDA – Substance Dependence, Abuse, and Treatment”. National Household Survey on Drug Abuse. SAMHSA, O ce of Applied Studies. 2000. [26] “InfoFacts – Cigarettes and Other Tobacco Products”. Retrieved 30 October 2014. [27] 21 U.S.C. α 812 – Schedules of controlled substances [28] Marshall, Donnie (20 March 2001). “Notice of denial of petition to reschedule marijuana”. Federal Register (Drug Enforcement Administration) 66 (75): 20038–20076. Retrieved 13 June 2013. 60 CHAPTER 1. CANNABIS [29] See United States v. Angelos, 433 F.3d 738 (10th Cir. 2006) (55 years for three sales of marijuana). [44] “General Information Regarding the Combat Methamphetamine Epidemic Act 2005”. Drug Enforcement Administration, O ce of Diversion Control. Retrieved October 20, 2012. [30] Gee, Paul; Gilbert, Mark; Richardson, Sandra; Moore, Grant; Paterson, Sharon; Graham, Patrick (2008). “Toxicity from the Recreational Use of 1benzylpiperazine”. Clinical Toxicology 46 (9): 802–07. doi:10.1080/15563650802307602. PMID 18821145. [45] Science and Technology committee 2006, p. 176. [46] “Development of a rational scale to assess the harm of drugs of potential misuse”, The Lancet, doi:10.1016/S01406736(07)60464-4, PMID 17382831(subscription required) [31] Brennan, K.; Johnstone, A.; Fitzmaurice, P.; Lea, R.; Schenk, S. (2007). “Chronic Benzylpiperazine (BZP) Exposure Produces Behavioral Sensitization and Cross-sensitization to Methamphetamine (MA)". Drug and Alcohol Dependence 88 (2–3): 204–13. doi:10.1016/j.drugalcdep.2006.10.016. PMID 17125936. [47] Nutt, David; King, Leslie A.; Saulsbury, William; Blakemore, Colin (24 March 2007), The Lancet Missing or empty |title= (help) [32] Tunnicli , G. (1997). “Sites of action of gamma hydroxybutyrate (GHB)--A neuroactive drug with abuse potential”. Clinical Toxicology 35 (6): 581–590. doi:10.3109/15563659709001236. [48] Nutt, David J, King, Leslie A, & Phillips, Lawrence D. (2010). Drug harms in the UK: A multicriteria decision analysis. The Lancet, 376(9752), 1558-1565. [33] Okun, M. S.; Boothy, L. A.; Bart eld, R. B.; Doering, P. L. (2001). “GHB: An important pharmacologic and clinical update”. Journal of Pharmacy and Pharmacological Science 4 (=2): 167–175. [49] http://www.drugabuse.gov/publications/drugfacts/ marijuana-medicine [34] “MAPS Legal History of MDMA”. Retrieved 30 October 2014. 1.4.16 External links [35] “Manuals - Practitioner's Manual - SECTION V”. Retrieved 2014-01-07 • Full text of Controlled Substances Act [36] 21 USC α 829 – Prescriptions | LII / Legal Information Institute [37] 21 USC Part D – O enses and Penalties | LII / Legal Information Institute 1.5 Cannabinoid “Cannabinoid receptor agonist”redirects here, although [38] “Issuance of Multiple Prescriptions for Schedule II Con- “cannabinoid”is not a perfect synonym for this term. trolled Substances”. U.S. DEA, U.S. DOJ. November 2007. Retrieved 3 September 2014. [39] Exempt Anabolic Steroids (21 CFR α 1308.33 and 21 CFR α 1308.34) 05 February 2015 Drug Enforcement Administration O ce of Diversion Control Drug and Chemical Evaluation Section [40] Halpern, J.H. (2004). “Hallucinogens and dissociative agents naturally growing in the United States” . Pharmacology & Therapeutics 102: 131–138. doi:10.1016/j.pharmthera.2004.03.003. [41] Schultes, R.E. and Hofmann, A., 1980. The botany and chemistry of hallucinogens, Charles C. Thomas, Spring eld, IL. [42] [Federal Register Volume 76, Number 238 (Monday, December 12, 2011)] [Rules and Regulations] [Pages 7733077360] Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors in cells that repress neurotransmitter release in the brain. Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals),* [1] the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured articially). The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis.* [2]* [3] Cannabidiol (CBD) is another major constituent of the plant.* [4] There are at least 113 di erent cannabinoids isolated from cannabis, exhibiting varied e ects.* [5] Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids [43] “Federal Pseudoephedrine Law” (PDF). doh.state. .us. (cannabimimetics) including the aminoalkylindoles, 1,5Florida Department of Health, Division of Medical Quality diarylpyrazoles, quinolines, and arylsulfonamides, as well as eicosanoids related to the endocannabinoids.* [2] Assurance. October 5, 2006. Retrieved 2012-10-20. 61 1.5. CANNABINOID 1.5.1 Cannabinoid receptors Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral e ects via nonspeci c interaction with cell membranes, instead of interacting with speci c membrane-bound receptors. The discovery of the rst cannabinoid receptors in the 1980s helped to resolve this debate.* [6] These receptors are common in animals, and have been found in mammals, birds, sh, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2 ,* [1] with mounting evidence of more.* [7] The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.* [8] Cannabinoid receptor type 1 Main article: Cannabinoid receptor type 1 The bracts surrounding a cluster of Cannabis sativa owers are coated with cannabinoid-laden trichomes CB1 receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus.* [1] They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Cannabinoid receptor type 2 Main article: Cannabinoid receptor type 2 CB2 receptors are predominantly found in the immune system, or immune-derived cells* [9] with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.* [10] CB2 receptors appear to be responsible for the anti-in ammatory and possibly other therapeutic effects of cannabis seen in animal models.* [9] 1.5.2 Phytocannabinoids Cannabis indica plant Types All classes derive from cannabigerol-type compounds and di er mainly in the way this precursor Cannabis-derived cannabinoids is cyclized.* [11] The classical cannabinoids are derived The classical cannabinoids are concentrated in a viscous from their respective 2-carboxylic acids (2-COOH) by (catalyzed by heat, light, or alkaline conresin produced in structures known as glandular trichomes. decarboxylation * ditions). [12] At least 113 di erent cannabinoids have been isolated from the Cannabis plant* [5] To the right, the main classes of cannabinoids from Cannabis are shown. The best • CBG (Cannabigerol) studied cannabinoids include tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN). • CBC (Cannabichromene) 62 CHAPTER 1. CANNABIS • CBL (Cannabicyclol) Cannabinol • CBV (Cannabivarin) • THCV (Tetrahydrocannabivarin) • CBDV (Cannabidivarin) • CBCV (Cannabichromevarin) • CBGV (Cannabigerovarin) • CBGM (Cannabigerol Monomethyl Ether) Main article: Cannabinol Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its a nity to the CB2 receptor is higher than for the CB1 receptor.* [20] Cannabigerol Main article: Cannabigerol article: Cannabigerol (CBG) is non-psychoactive but still a ects the overall e ects of Cannabis. CBG has been shown to promote apoptosis in cancer cells and inhibit tumor growth in mice.* [21] It acts as an 2 -adrenergic receptor agoTetrahydrocannabinol (THC) is the primary psychoacnist, 5-HT1A receptor antagonist, and CB1 receptor antagtive component of the Cannabis plant. Delta−9* onist. [22] It also binds to the CB2 receptor.* [22] tetrahydrocannabinol (Δ9 -THC, THC) and delta−8tetrahydrocannabinol (Δ8 -THC), mimic the action of anandamide, a neurotransmitter produced naturally in the Tetrahydrocannabivarin Main article: body. These two cannabinoids produce the e ects asso- Tetrahydrocannabivarin ciated with cannabis by binding to the CB1 cannabinoid receptors in the brain. Tetrahydrocannabivarin (THCV) is prevalent in certain central Asian and southern African strains of Cannabis.* [23]* [24] It is an antagonist of THC at CB1 Cannabidiol Main article: Cannabidiol receptors and attenuates the psychoactive e ects of THC.* [25] Cannabidiol (CBD) is non-psychotropic. Recent evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.* [13] Cannabidiol has Cannabidivarin Main article: Cannabidivarin little a nity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists.* [14] It was found Although cannabidivarin (CBDV) is usually a minor conto be an antagonist at the putative new cannabinoid recepstituent of the cannabinoid pro le, enhanced levels of tor, GPR55, a GPCR expressed in the caudate nucleus and CBDV have been reported in feral cannabis plants from the * putamen. [15] Cannabidiol has also been shown to act as a northwest Himalayas, and in hashish from Nepal.* [24]* [26] * 5-HT1A receptor agonist. [16] Tetrahydrocannabinol Tetrahydrocannabinol Main It appears to relieve convulsion, in ammation, anxiety, and nausea in animal studies.* [14] CBD has shown antitumor activity on human breast carcinoma by inhibiting cancer cell growth. At slightly higher concentrations it is cytotoxic to normal cells* [17] CBD has a greater a nity for the CB2 receptor than for the CB1 receptor.* [14] Cannabichromene Main article: Cannabichromene Cannabichromene (CBC) is non-psychoactive and does not a ect the psychoactivity of THC.* [27] CBC has shown antitumor e ects in breast cancer xenoplants in mice.* [28] CBD shares a precursor with THC and is the main cannabi- More common in tropical cannabis varieties. noid in low-THC Cannabis strains. CBD has been shown to play a role in preventing the short-term memory loss as- Biosynthesis Cannabinoid production starts when an sociated with THC.* [18] enzyme causes geranyl pyrophosphate and olivetolic acid A 2014 Cochrane review concluded that there was insufcient evidence to conclude that cannabidiol has an antipsychotic e ect.* [19] A 2015 systematic review found CBD to be e ective as an antipsychotic compound, and may lower the risk for developing cannabis-related psychosis. Trials indicated it was safe and well tolerated.* [13] to combine and form CBGA. Next, CBGA is independently converted to either CBG, THCA, CBDA or CBCA by four separate synthase, FAD-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the propyl homologues (THCVA, CBDVA and CBCVA), there is an anal- 63 1.5. CANNABINOID ogous pathway that is based on CBGVA from divarinolic Cannabis plant pro le acid instead of olivetolic acid. Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of Double bond position In addition, each of the com- cannabinoids produced by a plant is known as the plant's pounds above may be in di erent forms depending on the cannabinoid pro le. Selective breeding has been used to position of the double bond in the alicyclic carbon ring. control the genetics of plants and modify the cannabinoid There is potential for confusion because there are di er- pro le. For example, strains that are used as ber (coment numbering systems used to describe the position of this monly called hemp) are bred such that they are low in psydouble bond. Under the dibenzopyran numbering system choactive chemicals like THC. Strains used in medicine widely used today, the major form of THC is called Δ9 - are often bred for high CBD content, and strains used for THC, while the minor form is called Δ8 -THC. Under the al- recreational purposes are usually bred for high THC content ternate terpene numbering system, these same compounds or for a speci c chemical balance. are called Δ1 -THC and Δ6 -THC, respectively. Quantitative analysis of a plant's cannabinoid pro le is often determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible and, unlike GC methods, can di erentiate between the acid and neutral forms of the cannabinoids. There have been systematic attempts to monitor the cannabinoid pro le of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries. Length Most classical cannabinoids are 21-carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain attached to the aromatic ring. In THC, CBD, and CBN, this sidechain is a pentyl (5-carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3carbon) chain. Cannabinoids with the propyl side-chain are named using the su x varin, and are designated, for examPharmacology ple, THCV, CBDV, or CBNV. Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injecCannabinoids in other plants tion, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, Phytocannabinoids are known to occur in several plant especially by cytochrome P450 mixed-function oxidases, species besides cannabis. These include Echinacea mainly CYP 2C9.* [38] Thus supplementing with CYP 2C9 purpurea, Echinacea angustifolia, Acmella oleracea, inhibitors leads to extended intoxication.* [38] Helichrysum umbraculigerum, and Radula marginata.* [29] The best-known cannabinoids that are not derived Some is also stored9 in fat in addition to being metaboin the liver. Δ -THC is metabolized to 11-hydroxyfrom Cannabis are the lipophilic alkamides (alky- lized 9 which is then metabolized to 9-carboxy-THC. Δ -THC, lamides) from Echinacea species, most notably the Some cannabis metabolites can be detected in the body sevcis/trans isomers dodeca-2E,4E,8Z,10E/Z-tetraenoic-acideral weeks after administration. These metabolites are the isobutylamide.* [29] At least 25 di erent alkylamides have chemicals recognized by common antibody-based “drug been identi ed, and some of them have shown a nities to tests"; in the case of THC or others, these loads do not * * the CB2 -receptor. [30] [31] In some Echinacea species, represent intoxication (compare to ethanol breath tests that cannabinoids are found throughout the plant structure, but measure instantaneous blood alcohol levels), but an inte* * are most concentrated in the roots and owers. [32] [33] gration of past consumption over an approximately monthYangonin found in the Kava plant has signi cant a nity to lipophilic long window. This is because they are fat-soluble, * the CB1 receptor. [34] Tea (Camellia sinensis) catechins * have an a nity for human cannabinoid receptors.* [35] molecules that accumulate in fatty tissues. [39] A widespread dietary terpene, beta-caryophyllene, a component from the essential oil of cannabis and other Separation medicinal plants, has also been identi ed as a selective agonist of peripheral CB2 -receptors, in vivo.* [36] Black Cannabinoids can be separated from the plant by extraction tru es contain anandamide.* [37] with organic solvents. Hydrocarbons and alcohols are often Most of the phytocannabinoids are nearly insoluble in wa- used as solvents. However, these solvents are ammable ter but are soluble in lipids, alcohols, and other non-polar and many are toxic. Butane may be used, which evaporganic solvents. orates extremely quickly. Supercritical solvent extraction 64 CHAPTER 1. CANNABIS with carbon dioxide is an alternative technique. Once ex- although its chemical structure is di erent. Anandamide tracted, isolated components can be separated using wiped binds to the central (CB1 ) and, to a lesser extent, periphlm vacuum distillation or other distillation techniques. eral (CB2 ) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB1 receptor.* [41] Anandamide is found in nearly all tissues in History a wide range of animals.* [42] Anandamide has also been found in plants, including small amounts in chocolate.* [43] Cannabinoids were rst discovered in the 1940s, when CBD analogs of anandamide, 7,10,13,16and CBN were identi ed. The structure of THC was rst Two docosatetraenoylethanolamide and homo- determined in 1964. linolenoylethanolamine, have similar pharmacology. Due to molecular similarity and ease of synthetic conver- All of these are members of a family of signalling sion, CBD was originally believed to be a natural precursor lipids called N-acylethanolamines, which also includes to THC. However, it is now known that CBD and THC are the noncannabimimetic palmitoylethanolamide and produced independently in the cannabis plant from the pre- oleoylethanolamide, which possess anti-in ammatory cursor CBG. and orexigenic e ects, respectively. Many Nacylethanolamines have also been identi ed in plant seeds* [44] and in molluscs.* [45] 1.5.3 Endocannabinoids For more details on the roles and regulation of the endo- 2-Arachidonoylglycerol (2-AG) cannabinoids, see Endocannabinoid system. Arachidonoylglycerol Endocannabinoids are substances produced from within Main article: 2- Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB1 and CB2 receptors with similar a nity, acting as a full agonist at both.* [41] 2-AG is present at signi cantly higher concentrations in the brain than anandamide,* [46] and there is some controversy over whether 2AG rather than anandamide is chie y responsible for endocannabinoid signalling in vivo.* [1] In particular, one in vitro study suggests that 2-AG is capable of stimulating higher G-protein activation than anandamide, although the physiological implications of this nding are not yet known.* [47] Anandamide, an endogenous ligand of CB1 and CB2 2-Arachidonyl glyceryl ether (noladin ether) article: 2-Arachidonyl glyceryl ether Main In 2001, a third, ether-type endocannabinoid, 2-arachidonyl the body that activate cannabinoid receptors. After the disglyceryl ether (noladin ether), was isolated from porcine covery of the rst cannabinoid receptor in 1988, scientists brain.* [48] Prior to this discovery, it had been synthesized began searching for an endogenous ligand for the recepas a stable analog of 2-AG; indeed, some controversy retor.* [6]* [40] mains over its classi cation as an endocannabinoid, as another group failed to detect the substance at“any appreciable amount”in the brains of several di erent mammalian Types of endocannabinoid ligands species.* [49] It binds to the CB1 cannabinoid receptor (Kᵢ = 21.2 nmol/L) and causes sedation, hypothermia, intestiArachidonoylethanolamine (Anandamide or AEA) nal immobility, and mild antinociception in mice. It binds Main article: Arachidonoylethanolamine primarily to the CB1 receptor, and only weakly to the CB2 receptor.* [41] In 1992, in Raphael Mechoulam's lab, the rst such compound was identi ed as arachidonoyl ethanolamine and named anandamide, a name derived from the Sanskrit N-Arachidonoyl dopamine (NADA) Main article: word for bliss and -amide. Anandamide is derived from N-Arachidonoyl dopamine arachidonic acid. It has a pharmacology similar to THC, 65 1.5. CANNABINOID Discovered in 2000, NADA preferentially binds to the CB1 receptor.* [50] Like anandamide, NADA is also an agonist for the vanilloid receptor subtype 1 (TRPV1), a member of the vanilloid receptor family.* [51]* [52] Virodhamine (OAE) Main article: Virodhamine A fth endocannabinoid, virodhamine, or O-arachidonoylethanolamine (OAE), was discovered in June 2002. Although it is a full agonist at CB2 and a partial agonist at CB1 , it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than anandamide in the brain, but 2to 9-fold higher concentrations peripherally.* [53] Lysophosphatidylinositol (LPI) Recent evidence has highlighted lysophosphatidylinositol as the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth endocannabinoid.* [54] Function Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activating the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons. Furthermore, endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research. in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic trafc. The ultimate e ect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net e ect is an increase in the excitability of the endocannabinoidreleasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoidreleasing cell. Range Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating di usely from their source cells, they have much more restricted spheres of in uence than do hormones, which can a ect cells throughout the body. 1.5.4 Synthetic cannabinoids Main article: Synthetic cannabinoid Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids, and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.* [56] Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modi cations of cannabinoid The endocannabinoid 2-AG has been found in bovine and molecules.* [57] human maternal milk.* [55] When synthetic cannabinoids are used recreationally, they present signi cant health dangers to users.* [58] In the peRetrograde signal Conventional neurotransmitters are riod of 2012 through 2014, over 10,000 contacts to poison released from a ʻpresynapticʼcell and activate appropri- control centers in the United States were related to use of ate receptors on a ʻpostsynapticʼcell, where presynaptic synthetic cannabinoids.* [58] and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids, on the other Medications containing natural or synthetic cannabinoids or hand, are described as retrograde transmitters because they cannabinoid analogs: most commonly travelʻbackwardʼ against the usual synaptic transmitter ow. They are, in e ect, released from the post• Dronabinol (Marinol), is Δ9 -tetrahydrocannabinol synaptic cell and act on the presynaptic cell, where the tar(THC), used as an appetite stimulant, anti-emetic, and get receptors are densely concentrated on axonal terminals analgesic 66 CHAPTER 1. CANNABIS • Nabilone (Cesamet, Canemes), a synthetic cannabi- 1.5.7 References noid and an analog of Marinol. It is Schedule II unlike [1] Pacher, P.; Bátkai, S; Kunos, G (2006). “The EndoMarinol, which is Schedule III • Rimonabant (SR141716), a selective cannabinoid (CB1 ) receptor inverse agonist once used as an antiobesity drug under the proprietary name Acomplia. It was also used for smoking cessation Other notable synthetic cannabinoids include: cannabinoid System as an Emerging Target of Pharmacotherapy”. Pharmacological Reviews 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947. [2] Lambert, Didier M.; Fowler, Christopher J. (2005). “The Endocannabinoid System: Drug Targets, Lead Compounds, and Potential Therapeutic Applications”. Journal of Medicinal Chemistry 48 (16): 5059–87. doi:10.1021/jm058183t. PMID 16078824. • JWH-018, a potent synthetic cannabinoid agonist discovered by John W. Hu man at Clemson University. It is being increasingly sold in legal smoke blends collectively known as “spice”. Several countries and states have moved to ban it legally. [3] Pertwee, Roger, ed. (2005). Cannabinoids. SpringerVerlag. p. 2. ISBN 3-540-22565-X. • JWH-073 [5] Aizpurua-Olaizola, Oier; Soydaner, Umut; Öztürk, Ekin; Schibano, Daniele; Simsir, Yilmaz; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, Aresatz (2016-02-02). “Evolution of the Cannabinoid and Terpene Content during the Growth ofCannabis sativaPlants from Di erent Chemotypes”. Journal of Natural Products 79 (2): 324–331. doi:10.1021/acs.jnatprod.5b00949. • CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC. • Dimethylheptylpyran * • HU-210, about 100 times as potent as THC [59] • HU-331 a potential anti-cancer drug derived from cannabidiol that speci cally inhibits topoisomerase II. • SR144528, a CB2 receptor antagonist • WIN 55,212-2, a potent cannabinoid receptor agonist • JWH-133, a potent selective CB2 receptor agonist • Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine • AM-2201, a potent cannabinoid receptor agonist 1.5.5 Table of plant cannabinoids 1.5.6 See also • Cannabinoid receptor antagonist • Endocannabinoid enhancer • Endocannabinoid reuptake inhibitor • Cancer and nausea α Cannabinoids [4] “Bulletin on Narcotics – 1962 Issue 3 – 004”. UNODC (United Nations O ce of Drugs and Crime). 1962-01-01. Retrieved 2014-01-15. 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[43] Di Tomaso, Emmanuelle; Beltramo, Massimiliano; Piomelli, Daniele (1996).“Brain cannabinoids in chocolate”. Nature 382 (6593): 677–8. doi:10.1038/382677a0. PMID 8751435. [52] Ralevic, Vera (2003). “Cannabinoid modulation of peripheral autonomic and sensory neurotransmission”. European Journal of Pharmacology 472 (1–2): 1–21. doi:10.1016/S0014-2999(03)01813-2. PMID 12860468. [44] Chapman, K. D.; Venables, B; Markovic, R; Blair Jr, RW; Bettinger, C (1999). “N-Acylethanolamines in Seeds. [53] Porter, A. C.; Sauer, JM; Knierman, MD; Becker, GW; Berna, MJ; Bao, J; Nomikos, GG; Carter, P; Bymaster, 1.5. CANNABINOID FP; Leese, AB; Felder, CC (2002). “Characterization of a Novel Endocannabinoid, Virodhamine, with Antagonist Activity at the CB1 Receptor”. Journal of Pharmacology and Experimental Therapeutics 301 (3): 1020–4. doi:10.1124/jpet.301.3.1020. PMID 12023533. [54] Piñeiro, Roberto; Falasca, Marco (2012). “Lysophosphatidylinositol signalling: New wine from an old bottle”. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1821 (4): 694–705. doi:10.1016/j.bbalip.2012.01.009. PMID 22285325. [55] Fride, E; Bregman, T; Kirkham, TC (2005).“Endocannabinoids and food intake: Newborn suckling and appetite regulation in adulthood”. Experimental biology and medicine 230 (4): 225–34. PMID 15792943. [56] ElSohly, Mahmoud A.; Gul, Waseem; Wanas, Amira S.; Radwan, Mohamed M. (2014-02-27). “Synthetic cannabinoids: Analysis and metabolites”. Life Sciences. Special Issue: Emerging Trends in the Abuse of Designer Drugs and Their Catastrophic Health E ects: Update on Chemistry, Pharmacology, Toxicology and Addiction Potential 97 (1): 78–90. doi:10.1016/j.lfs.2013.12.212. [57] Lauritsen, Kirstin J.; Rosenberg, Harold (2016-02-24). “Comparison of outcome expectancies for synthetic cannabinoids and botanical marijuana”. The American Journal of Drug and Alcohol Abuse 0 (0): 1–8. doi:10.3109/00952990.2015.1135158. ISSN 0095-2990. PMID 26910181. [58] “N-(1-amino-3-methyl-1-oxobutan-2-yl)−1(cyclohexylmethyl)−1H-indazole-3-carboxamide(ABCHMINACA), N-(1-amino-3-methyl-1-oxobutan-2-yl)−1pentyl-1H-indazole-3-carboxamide (AB-PINACA)and[1(5- uoropentyl)−1H-indazol-3-yl](naphthalen-1yl)methanone(THJ-2201)" (PDF). Drug and Chemical Evaluation Section, O ce of Diversion Control, Drug Enforcement Administration. December 2014. [59] “More medicinal uses for marijuana”. Marijuana.org. October 18, 2005. Archived from the original on 2005-12-21. Retrieved 2014-01-15. 1.5.8 Further reading • De Meijer, EP; Bagatta, M; Carboni, A; Crucitti, P; Moliterni, VM; Ranalli, P; et al. (2003). “The inheritance of chemical phenotype in Cannabis sativa L” . Genetics 163 (1): 335–46. PMC 1462421. PMID 12586720. • Devane, W.; Hanus, L; Breuer, A; Pertwee, R.; Stevenson, L.; Gri n, G; et al. (1992). “Isolation and structure of a brain constituent that binds to the cannabinoid receptor”. Science 258 (5090): 1946–9. Bibcode:1992Sci...258.1946D. doi:10.1126/science.1470919. PMID 1470919. 69 • Elsohly, Mahmoud A.; Slade, Desmond (2005). “Chemical constituents of marijuana: The complex mixture of natural cannabinoids”. Life Sciences 78 (5): 539–48. doi:10.1016/j.lfs.2005.09.011. PMID 16199061. • Hanus, Lumir; Gopher, Asher; Almog, Shlomo; Mechoulam, Raphael (1993). “Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor”. Journal of Medicinal Chemistry 36 (20): 3032–4. doi:10.1021/jm00072a026. PMID 8411021. • Hanus, L (1987). “Biogenesis of cannabinoid substances in the plant”. Acta Universitatis Palackianae Olomucensis Facultatis Medicae 116: 47–53. PMID 2962461. • Hanuš, L.; Krej‫م‬í, Z. (1975). “Isolation of two new cannabinoid acids from Cannabis sativa L. of Czechoslovak origin”. Acta Univ. Olomuc., Fac. Med 74: 161–166. • Hanuš, L.; Krej‫م‬í, Z.; Hruban, L. (1975). “Isolation of cannabidiolic acid from Turkish variety of cannabis cultivated for bre”. Acta Univ. Olomuc., Fac. Med 74: 167–172. • Kﬁfalvi, Attila, ed. (2008). “Cannabinoids and the Brain”. doi:10.1007/978-0-387-74349-3. ISBN 9780-387-74348-6. • Mechoulam, Raphael; Ben-Shabat, Shimon; Hanus, Lumir; Ligumsky, Moshe; Kaminski, Norbert E.; Schatz, Anthony R.; et al. (1995). “Identi cation of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors”. Biochemical Pharmacology 50 (1): 83–90. doi:10.1016/00062952(95)00109-D. PMID 7605349. • Nicoll, Roger A.; Alger, Bradley E. (2004). “The Brain's Own Marijuana”. Scienti c American 291 (6): 68–75. doi:10.1038/scienti camerican1204-68. PMID 15597982. • Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.; Rehnelt, J.; Martín, M.; et al. (2008).“Interferon- is a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain”. Journal of Neuroscience 28 (46): 12136–45. doi:10.1523/JNEUROSCI.340208.2008. PMC 3844840. PMID 19005078. • Racz, I.; Nadal, X.; Alferink, J.; Baños, J. E.; Rehnelt, J.; Martín, M.; et al. (2008). “Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic 70 CHAPTER 1. CANNABIS Pain”. Journal of Neuroscience 28 (46): 12125– in the CNS. In 2007, the binding of several cannabinoids 35. doi:10.1523/JNEUROSCI.3400-08.2008. PMC to the G protein-coupled receptor GPR55 in the brain was 3844839. PMID 19005077. described.* [9] • Turner, C. E.; Mole, M. L.; Hanus, L.; Elsohly, H. N. (1981). “Constituents of Cannabis sativa. XIX. Isolation and Structure Elucidation of Cannabiglendol, A Novel Cannabinoid from an Indian Variant”. Journal of Natural Products 44 (1): 27–33. doi:10.1021/np50013a005. 1.6 Cannabinoid receptor The protein sequences of CB1 and CB2 receptors are about 44% similar.* [10]* [11] When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%.* [4] In addition, minor variations in each receptor have been identi ed. Cannabinoids bind reversibly and stereo-selectively to the cannabinoid receptors. Subtype selective cannabinoids have been developed which theoretically may have advantages for treatment of certain diseases such as obesity.* [12] 1.6.1 CB1 Main article: Cannabinoid receptor type 1 CB1 and CB2 structures. Cannabinoid receptors, located throughout the body, are part of the Endocannabinoid system which is involved in a variety of physiological processes including appetite, painsensation, mood, and memory. Cannabinoid receptors are of a class of cell membrane receptors under the G protein-coupled receptor superfamily.* [1]* [2]* [3] As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains.* [4] Cannabinoid receptors are activated by three major groups of ligands: endocannabinoids, produced by the mammillary body; plant cannabinoids (such as Cannabidiol, produced by the cannabis plant); and synthetic cannabinoids (such as HU-210). All of the endocannabinoids and plant cannabinoids are lipophilic, such as fat soluble compounds. There are currently two known subtypes of cannabinoid receptors, termed CB1 and CB2 .* [5]* [6] The CB1 receptor is expressed mainly in the brain (central nervous system or “CNS”), but also in the lungs, liver and kidneys. The CB2 receptor is expressed mainly in the immune system and in hematopoietic cells.* [7] Mounting evidence suggests that there are novel cannabinoid receptors* [8] that is, non-CB1 and non-CB2 , which are expressed in endothelial cells and Cannabinoid receptor type 1 (CB1 ) receptors are thought to be one of the most widely expressed G protein-coupled receptors in the brain. This is due to endocannabinoidmediated depolarization-induced suppression of inhibition, a very common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Endocannabinoids released from the depolarized post-synaptic neuron bind to CB1 receptors in the pre-synaptic neuron and cause a reduction in GABA release. They are also found in other parts of the body. For instance, in the liver, activation of the CB1 receptor is known to increase de novo lipogenesis.* [13] A 2004 study suggested that the endocannabinoids and their cannabinoid receptors play a major role during pre- and postnatal development.* [14]* [15] In another recent study a group of researchers combined stochastic optical reconstruction microscopy (STORM) and patch clamp in order to see CB1 distribution on a nano scale with incredible resolution.* [16]* [17] 1.6.2 CB2 Main article: Cannabinoid receptor type 2 CB2 receptors are mainly expressed on T cells of the immune system, on macrophages and B cells, and in hematopoietic cells. They also have a function in keratinocytes. They are also expressed on peripheral nerve terminals. These receptors play a role in antinociception, or the relief of pain. In the brain, they are mainly expressed by microglial cells, where their role remains unclear. While 71 1.6. CANNABINOID RECEPTOR the most likely cellular targets and executors of the CB2 receptor-mediated e ects of endocannabinoids or synthetic agonists are the immune and immune-derived cells (e.g. leukocytes, various populations of T and B lymphocytes, monocytes/macrophages, dendritic cells, mast cells, microglia in the brain, Kup er cells in the liver, etc.), the number of other potential cellular targets is expanding, now including endothelial and smooth muscle cells, broblasts of various origins, cardiomyocytes, and certain neuronal elements of the peripheral or central nervous systems.* [7] messenger molecule cyclic AMP), and positively in uenced inwardly rectifying potassium channels (=Kir or IRK).* [25] However, a much more complex picture has appeared in di erent cell types, implicating other potassium ion channels, calcium channels, protein kinase A and C, Raf-1, ERK, JNK, p38, c-fos, c-jun and many more.* [25] Separation between the therapeutically undesirable psychotropic e ects, and the clinically desirable ones, however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identi ed so far that bind to the cannabinoid receptors ̶anandamide and 2-arachidonylglycerol (2-AG) 1.6.3 Other cannabinoid receptors ̶produce most of their e ects by binding to both the CB1 and CB2 cannabinoid receptors. While the e ects mediThe existence of additional cannabinoid receptors has long ated by CB1 , mostly in the central nervous system, have been suspected, due to the actions of compounds such been thoroughly investigated, those mediated by CB2 are as abnormal cannabidiol that produce cannabinoid-like efnot equally well de ned. fects on blood pressure and in ammation, yet do not activate either CB1 or CB2 .* [18]* [19] Recent research strongly supports the hypothesis that the N-arachidonoyl 1.6.5 Physiology glycine (NAGly) receptor GPR18 is the molecular identity of the abnormal cannabidiol receptor and additionally Gastrointestinal activity suggests that NAGly, the endogenous lipid metabolite of anandamide (also known as arachidonoylethanolamide or Inhibition of gastrointestinal activity has been observed afAEA), initiates directed microglial migration in the CNS ter administration of Δ9 -THC, or of anandamide. This efthrough activation of GPR18.* [20] Other molecular biolfect has been assumed to be CB1 -mediated since the speogy studies have suggested that the orphan receptor GPR55 ci c CB1 antagonist SR 141716A (Rimonabant) blocks the should in fact be characterised as a cannabinoid receptor, e ect. on the basis of sequence homology at the binding site. Subsequent studies showed that GPR55 does indeed respond to cannabinoid ligands.* [9]* [21] This pro le as a distinct Cardiovascular activity non-CB1 /CB2 receptor that responds to a variety of both endogenous and exogenous cannabinoid ligands, has led Recent studies have also suggested that activation some groups to suggest GPR55 should be categorized as of CB1 receptors in human and rodent cardiomythe CB3 receptor, and this re-classi cation may follow in ocytes,* [26]* [27] coronary artery endothelial and intime.* [22] However this is complicated by the fact that anammatory cells* [28]* [29]* [30] promotes activation other possible cannabinoid receptor has been discovered of mitogen-activated protein (MAP) kinases p38 and in the hippocampus, although its gene has not yet been JNK, reactive oxygen species generation, cell death, and cloned,* [23] suggesting that there may be at least two more cardiovascular in ammatory response both in vitro, as well cannabinoid receptors to be discovered, in addition to the as in models of heart failure, atherosclerosis and vascular two that are already known. GPR119 has been suggested as in ammation.* [26]* [27]* [29]* [30] a fth possible cannabinoid receptor.* [24] 1.6.4 Signaling Cannabinoid receptors are activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.* [10] After the receptor is engaged, multiple intracellular signal transduction pathways are activated. At rst, it was thought that cannabinoid receptors mainly inhibited the enzyme adenylate cyclase (and thereby the production of the second Bone The endocannabinoid system through CB2 signaling plays a key role in the maintenance of bone mass. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. CB2 agonists enhance endocortical osteoblast number and activity while restraining trabecular osteoclastogenesis. Another important e ect is that CB2 agonists attenuates ovariectomy-induced bone loss while increasing cortical thickness. These ndings suggest CB2 o ers a potential molecular target for the diagnosis and treatment of osteoporosis.* [31] 72 CHAPTER 1. CANNABIS 1.6.6 Cannabinoid treatments Main article: Medical cannabis Cannabis preparations have been known as therapeutic agents against various diseases for millennia.* [32] The psychoactive compound tetrahydrocannabinol (THC) was found to be the principal mediator of the e ects of cannabis.* [33] Synthetic THC is prescribed today, under the INN dronabinol or the brand name Marinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients. Several synthetic cannabinoids have been shown to bind to the CB2 receptor with a higher a nity than to the CB1 receptor.* [34] Most of these compounds exhibit only modest selectivity. One of the described compounds, a classical THC-type cannabinoid, L-759,656, in which the phenolic group is blocked as a methyl ether, has a CB1 /CB2 binding ratio > 1000.* [35] The pharmacology of these agonists has yet to be described. Certain tumors, especially gliomas, express CB2 receptors. CB2 selective agonists are e ective in the treatment of pain, in ammatory diseases (in animal models),* [31]* [36] osteoporosis* [31] and atherosclerosis.* [37] CB1 selective antagonists have previously been used for weight reduction and smoking cessation (see Rimonabant). Activation of CB1 provides neuroprotection after brain injury.* [38] 1.6.7 Ligands See also: cannabinoid receptor type 1 ligands, cannabinoid receptor type 2 ligands Binding a nity and selectivity of cannabinoid ligands 1.6.8 See also • Cannabinoid receptor antagonist • Endocannabinoid enhancer • Endocannabinoid reuptake inhibitor • Cannabidiol • E ects of cannabis 1.6.9 References [1] Howlett AC (August 2002). “The cannabinoid receptors”. Prostaglandins Other Lipid Mediat. 68-69: 619–31. doi:10.1016/S0090-6980(02)00060-6. PMID 12432948. [2] Mackie K (May 2008). “Cannabinoid receptors: where they are and what they do”. J. Neuroendocrinol. 20 Suppl 1: 10–4. doi:10.1111/j.1365-2826.2008.01671.x. PMID 18426493. [3] Graham ES, Ashton JC, Glass M (2009). “Cannabinoid receptors: a brief history and “what's hot"". Front. Biosci. 14 (14): 944–57. doi:10.2741/3288. PMID 19273110. 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Chem. 14 (8): 917–36. doi:10.2174/092986707780363023. PMID 17430144. chain variations on CB(2) cannabinoid receptor activity”. J. Med. Chem. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781. [44] Aung MM, Gri n G, Hu man JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (August 2000). “In uence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding”. Drug Alcohol Depend 60 (2): 133–40. doi:10.1016/S03768716(99)00152-0. PMID 10940540. 1.6.10 External links • Cannabinoid Receptors at the US National Library of Medicine Medical Subject Headings (MeSH) • The Endocannabinoid System Network (ECSN) - CB1 receptor • “Cannabinoid Receptors”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 1.7 Cannabidiol Not to be confused with cannabinol or cannabinodiol. [37] Ste ens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F (2005). “Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice”. Nature 434 (7034): 782–6. doi:10.1038/nature03389. PMID 15815632. Cannabidiol (CBD) is one of at least 113 active cannabinoids identi ed in cannabis.* [5]* [6] It is a major phytocannabinoid, accounting for up to 40% of the plant's extract.* [7] CBD is considered to have a wide scope of potential medical applications - due to clinical reports show[38] Panikashvili D, Simeonidou C, Ben-Shabat S, Hanuš L, ing the lack of side e ects, particularly a lack of psyBreuer A, Mechoulam R, Shohami E (2001). “An endogechoactivity (as is typically associated with ∆9-THC), and nous cannabinoid (2-AG) is neuroprotective after brain innon-interference with several Psychomotor learning and jury”. Nature 413 (6855): 527–31. doi:10.1038/35097089. psychological functions. PMID 11586361. [39] “PDSP Database - UNC”. Retrieved 11 June 2013. [40] Ligresti, A.; Villano, R.; Allarà, M.; Ujváry, I. N.; Di Marzo, V. (2012). “Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB1 receptor ligand”. Pharmacological Research 66 (2): 163–169. doi:10.1016/j.phrs.2012.04.003. PMID 22525682. [41] WO patent 200128557, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 2001-06-07 [42] US patent 7241799, Makriyannis A, Deng H, “Cannabimimetic indole derivatives”, granted 200707-10 1.7.1 Research Epilepsy Although anecdotally, cannabidiol has been claimed to be of bene t in helping people with epilepsy, there is no established mechanism of action, and the lack of high-quality evidence in this area precludes conclusions being drawn.* [8] Dravet syndrome is a rare form of epilepsy that is difcult to treat. It is a catastrophic form of intractable epilepsy that begins in infancy. Initial seizures are most of[43] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, ten prolonged events and in the second year of life other * Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu seizure types begin to emerge. [9] A number of high prole and anecdotal reports have sparked interest in treatCZ, Chandran P, Meyer MD (January 2010). “Indol-3ylcycloalkyl ketones: e ects of N1 substituted indole side ment of Dravet syndrome with CBD.* [10] GW Pharma- 75 1.7. CANNABIDIOL agonists.* [20]* [21] While one would assume that this would cause cannabidiol to reduce the e ects of THC, it may potentiate THC's e ects by increasing CB1 receptor density or through another CB1 -related mechanism.* [22] It may also extend the duration of the e ects of THC via inhibition of the cytochrome P-450-3A and 2C enzymes.* [23] Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.* [24] Cannabidiol has also been shown to act as a 5-HT1A receptor partial agonist,* [25] an action which may be involved in its antidepressant,* [26]* [27] anxiolytic,* [27]* [28] and neuroprotective* [29]* [30] e ects. Cannabidiol is an allosteric modulator of μ and -opioid receptors.* [31] Cannabidiol's pharmacological e ects have also been attributed to PPAR- receptor agonism and intracellular calcium release.* [7] The bud of a Cannabis sativa ower coated with trichomes bearing cannabidiol and other cannabinoids Research suggests that CBD may exert some of its pharmacological action through its inhibition of FAAH, which may in turn increase the levels of endocannabinoids, such anandamide, produced by the body.* [7] as ceuticals is seeking FDA approval to market a formulation of CBD, under the tradename Epidiolex, as a treatment for Dravet syndrome. Epidiolex was granted fast1.7.3 Pharmacokinetic interactions track status and is in late stage trials following positive early results from the drug.* [10]* [11]* [12]* [13]* [14] Some There is some preclinical evidence to suggest that cannabidcannabis extract preparations containing CBD are marketed iol may reduce THC clearance, modestly increasing THC's as dietary supplements and claim e cacy against Dravet plasma concentrations resulting in a greater amount of THC Syndrome. One such preparation is marketed under the available to receptors, increasing the e ect of THC in a tradename Charlotte's web.* [15]* [16] dose-dependent manner.* [32]* [33] Despite this, the available evidence in humans suggests no signi cant e ect of CBD on THC plasma levels.* [34] Schizophrenia As of 2016 data on the antipsychotic e ects of cannabidiol in schizophrenia is still limited, but with promising initial 1.7.4 Pharmaceutical preparations results and a lack of side-e ects. With current trials limited to 6 weeks of treatment at maximum, information on long- Nabiximols (USAN, trade name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of term e cacy and tolerability is not available yet.* [17] CBD and THC. The drug was approved by Canadian auA 2014 Cochrane Review concluded that the evidence is thorities in 2005 to alleviate pain associated with multiple insu cient to conclude that CBD has anti-psychotic ef- sclerosis.* [35]* [36]* [37] Epidiolex, a drug with cannabidfects.* [18] iol as its active pharmaceutical ingredient, received orphan drug status in the United States for treatment of Dravet synin July 2015.* [38] drome Safety Epidiolex is an oil formulation of CBD extracted from CBD safety in humans has been studied in multiple small the cannabis plant undergoing clinical trials for refractory studies, suggesting that it is well tolerated at doses of up to epilepsy syndromes.* [39] 1500 mg/day (p.o.) or 30 mg (i.v.).* [19] 1.7.2 Pharmacodynamics 1.7.5 Chemistry Cannabidiol is insoluble in water but soluble in organic solCannabidiol has a very low a nity for CB1 and CB2 vents such as pentane. At room temperature, it is a colreceptors but acts as an indirect antagonist of their orless crystalline solid.* [40] In strongly basic media and 76 CHAPTER 1. CANNABIS the presence of air, it is oxidized to a quinone.* [41] Under acidic conditions it cyclizes to THC.* [42] The synthesis of cannabidiol has been accomplished by several research groups.* [43]* [44]* [45] Biosynthesis Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the last step, where CBDA synthase performs catalysis instead of THCA syn- Cannabidiol numbering thase.* [46] Natural sources Selective breeding by growers in the USA dramatically lowered the CBD content of cannabis; their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.* [47] To meet the demands of medical cannabis patients, growers are currently developing more CBD-rich strains.* [48] Several industrial hemp varieties can be legally cultivated in western Europe. A variety such as “Fedora 17”has a cannabinoid pro le consistently around 1% cannabidiol (CBD) with THC less than 0.1%.* [49] Legal status Taura, F., Sirikantaramas, S., Shoyama, Y., Yoshikai, K., Shoyama, Y., Morimoto, S. (2007). “Cannabidiolic-acid synthase, the chemotype-determining enzyme in the ber-type Cannabis sativa”. FEBS Letters 581 (16): 2929–2934. doi:10.1016/j.febslet.2007.05.043 Isomerism Cannabidiol is not scheduled by the Convention on Psychotropic Substances. CBD does not cause the “high”associated with the ∆9-THC in marijuana. As the legal landscape and understanding about the di erences in medical cannabinoids unfolds, it will be increasingly important to distinguish “medical marijuana”(with noted varying degrees of psychotropic e ects and de cits in executive function) - from “medical CBD”(in which the high CBD and low THC content may mitigate psychosis).* [50]* [51]* [52] Various breeds/strains of “medical marijuana”are found to have a signi cant variety in the ratios of CBD-to-THC and are known to contain other non-psychotropic cannabinoids.* [53]* [54] However it is only the amount of ∆9-THC that chemically gives a legal determination as to whether the plant material(s) used for the purposes of extracting CBD are considered hemp, or considered marijuana. Based on: Nagaraja, Kodihalli Nanjappa, Synthesis of delta3-cannabidiol and the derived rigid analogs, Arizona UniAny psychoactive marijuana, regardless of it's CBD conversity 1987. tent, is derived from the ower (or bud) of the genus See also: Tetrahydrocannabinol#Isomerism, Abnormal cannabis. Non-psychoactive hemp (also commonly-termed cannabidiol. industrial hemp), regardless of it's CBD content, is any part of the genus cannabis plant, whether growing or not, containing a ∆−9 tetrahydrocannabinol concentration of no more than three-tenths of one percent (0.3%) on a dry 1.7.6 Society and culture weight basis. Certain standards are required for the legal 1.7. CANNABIDIOL 77 growth and production of hemp. The Colorado Industrial Hemp Program registers growers of industrial hemp and samples crops to verify that the THC concentration does not exceed 0.3% on dry weight basis.* [55] [4] McPartland JM, Russo EB (2001). “Cannabis and cannabis extracts: greater than the sum of their parts?" (PDF). Journal of Cannabis Therapeutics 1 (3/4): 103–132. doi:10.1300/J175v01n03_08. The United States Drug Enforcement Administration, the DEA, recently eased some of the regulatory requirements for those who are conducting FDA-approved clinical trials on cannabidiol (CBD).* [56] [5] Borgelt LM, Franson KL, Nussbaum AM, Wang GS (February 2013).“The pharmacologic and clinical e ects of medical cannabis”. Pharmacotherapy (Review) 33 (2): 195–209. doi:10.1002/phar.1187. PMID 23386598. Australia Prescription Medicine (Schedule 4) for therapeutic use containing 2 per cent (2.0%) or less of other cannabinoids commonly found in cannabis (such as ∆9THC).* [57] [6] Aizpurua-Olaizola, Oier; Soydaner, Umut; Öztürk, Ekin; Schibano, Daniele; Simsir, Yilmaz; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, Aresatz (2016-02-02). “Evolution of the Cannabinoid and Terpene Content during the Growth ofCannabis sativaPlants from Di erent Chemotypes”. Journal of Natural Products 79 (2): 324–331. doi:10.1021/acs.jnatprod.5b00949. Canada Cannabidiol is a Schedule II drug in Canada. Prescription medication.* [58] UK Cannabidiol, in an oral-mucosal spray formulation combined with delta-9-tetrahydrocannabinol, is a prescription product available for relief of severe spasticity due to multiple sclerosis (where other anti-spasmodics have not been e ective).* [59] EU Cannabidiol is listed in EU Cosmetics Ingredient Database.* [60] 1.7.7 References [1] DEA News Release, DEA Eases Requirements for FDA Approved Clinical Trials on Cannabidiol (Dec. 23, 2015) (“CBD is a Schedule I controlled substance as de ned under the CSA.”), http://www.dea.gov/divisions/hq/2015/ hq122315.shtml; Joseph T. Rannazzisi Deputy Assistant Administrator Drug Enforcement Administration Before the Caucus on International Narcotics Control, United States Senate, at 2 (June 24, 2015) (CBD is a Schedule I drug.); see also Frank Robison, Elvira Strehle-Henson, Cannabis Laws and Research at Colorado Institutions of Higher Education, COLO. LAW., OCTOBER 2015, AT 73, 76 ( “[T]the DEA's position on CBD is clear--it is a Schedule I substance.”). [2] Mechoulam R, Parker LA, Gallily R (November 2002). “Cannabidiol: an overview of some pharmacological aspects”. J Clin Pharmacol (Review) 42 (11 Suppl): 11S–19S. doi:10.1177/0091270002238789. PMID 12412831. [3] Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G (May 2009).“Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders”. Phytother Res (Review) 23 (5): 597–602. doi:10.1002/ptr.2625. PMID 18844286. [7] Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (December 2012). “Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders”. Philos. Trans. R. Soc. Lond., B, Biol. Sci. (Review) 367 (1607): 3364– 78. doi:10.1098/rstb.2011.0389. PMC 3481531. PMID 23108553. [8] Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D (2014). “Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders”. Epilepsia (Review) 55 (6): 791–802. doi:10.1111/epi.12631. PMC 4707667. PMID 24854329. [9] http://www.dravetfoundation.org/dravet-syndrome/ what-is-dravet-syndrome#sthash.jAC0bZ89.dpuf What is Dravet Syndrome? [10] Melville, Nancy A. (14 Aug 2013), Seizure Disorders Enter Medical Marijuana Debate, Medscape Medical News., retrieved 2014-01-14 [11] Throckmorton, Douglas (24 June 2015). “Cannabidiol: Barriers to Research and Potential Medical Bene ts”. FDA. FDA. Retrieved 15 December 2015. [12] Gloss D, Vickrey B (13 June 2012). “Cannabinoids for epilepsy”. Cochrane Database Syst Rev (Review) 6: CD009270. doi:10.1002/14651858.CD009270.pub2. PMID 22696383. [13] Devinsky, Orrin (2015). “E cacy and Safety of Epidiolex (Cannabidiol) in Children and Young Adults with Treatment-Resistant Epilepsy”. Annual Meeting Abstracts (American Epilepsy Society). Retrieved 13 December 2015. [14] Angus, Chen (8 December 2015). “Marijuana's Main Ingredient, Cannabidiol, May Be An E ective Way To Treat Epilepsy”. Medical Daily. Retrieved 14 December 2015. 78 CHAPTER 1. CANNABIS [27] Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS (January 2009). “5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in [16] Young, Saundra. “Marijuana stops child's severe seizures” rats”. British Journal of Pharmacology 156 (1): 181–8. (PDF). CNN. CNN. Retrieved 7 January 2016. doi:10.1111/j.1476-5381.2008.00046.x. PMC 2697769. PMID 19133999. [17] Leweke FM, Mueller JK, Lange B, Rohleder C “Therapeutic Potential of Cannabinoids [28] Campos AC, Guimarães FS (August 2008). “Involve(2016). Biol. Psychiatry 79 (7): 604–12. in Psychosis”. ment of 5HT1A receptors in the anxiolytic-like e ects of doi:10.1016/j.biopsych.2015.11.018. PMID 26852073. cannabidiol injected into the dorsolateral periaqueductal [15] Maa, Edward; Figi, Paige (2014). “The case for medical marijuana in epilepsy”. Epilepsia 55 (6): 783–786. doi:10.1111/epi.12610. ISSN 0013-9580. [18] McLoughlin BC, Pushpa-Rajah JA, Gillies D, Rathbone J, Variend H, Kalakouti E, Kyprianou K (2014). “Cannabis and schizophrenia”. Cochrane Database Syst Rev 10: CD004837. doi:10.1002/14651858.CD004837.pub3. PMID 25314586. [19] Devinsky O et al Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014 Jun;55(6):791-802. PMID 24854329 Free full text gray of rats”. Psychopharmacology 199 (2): 223–30. doi:10.1007/s00213-008-1168-x. PMID 18446323. [29] Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M (May 2005). “Cannabidiol prevents cerebral infarction via a serotonergic 5hydroxytryptamine1A receptor-dependent mechanism”. Stroke; a Journal of Cerebral Circulation 36 (5): 1077– 82. doi:10.1161/01.STR.0000163083.59201.34. PMID 15845890. [20] Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus [30] Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu AX, Fujioka M, Abe K, Hasebe N, Egashira N, LO (August 2007). “Cannabidiol--recent advances” Iwasaki K, Fujiwara M (March 2007). “Repeated treat. Chem. Biodivers. (Review) 4 (8): 1678–92. ment with cannabidiol but not Delta9-tetrahydrocannabinol doi:10.1002/cbdv.200790147. PMID 17712814. has a neuroprotective e ect without the development [21] Pertwee RG (2008). “The diverse CB1 and CB2 of tolerance”. Neuropharmacology 52 (4): 1079–87. receptor pharmacology of three plant cannabidoi:10.1016/j.neuropharm.2006.11.005. PMID 17320118. noids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9tetrahydrocannabivarin”. British Journal of Pharmacology [31] Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (2006). “Cannabidiol is an allosteric modulator at mu- and 153 (2): 199–215. doi:10.1038/sj.bjp.0707442. PMC delta-opioid receptors”. Naunyn-Schmiedeberg's Archives 2219532. 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British Journal of Pharmacology 152 (7): 1092– 101. doi:10.1038/sj.bjp.0707460. PMC 2095107. PMID 17876302. [25] Russo EB, Burnett A, Hall B, Parker KK (August 2005). “Agonistic properties of cannabidiol at 5-HT1a receptors”. Neurochemical Research 30 (8): 1037–43. doi:10.1007/s11064-005-6978-1. PMID 16258853. [26] Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR (January 2010). “Antidepressant-like e ects of cannabidiol in mice: possible involvement of 5-HT1A receptors”. British Journal of Pharmacology 159 (1): 122–8. doi:10.1111/j.1476-5381.2009.00521.x. PMC 2823358. PMID 20002102. [33] Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl T, Long LE, Huang XF, Liu K, Arnold JC, McGregor IS (November 2011). “Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural e ects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats”. Psychopharmacology 218 (2): 443–457. doi:10.1007/s00213-011-2342-0. PMID 21667074. 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[55] https://www.colorado.gov/pacific/agplants/ industrial-hemp [56] http://www.dea.gov/divisions/hq/2015/hq122315.shtml [57] https://www.legislation.gov.au/Details/F2016L00174 [58] Controlled Drugs and Substances Act – Schedule II [59] https://www.medicines.org.uk/emc/medicine/23262 [60] http://ec.europa.eu/growth/tools-databases/cosing/index. cfm?fuseaction=search.details_v2&id=93486 1.7.8 External links • Project CBD Non-pro t educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol. [46] Marks MD, Tian L, Wenger JP, Omburo SN, SotoFuentes W, He J, Gang DR, Weiblen GD, Dixon RA (2009). “Identi cation of candidate genes a ecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa” . Journal of Experimental Botany 60 (13): 3715–3726. doi:10.1093/jxb/erp210. PMC 2736886. PMID 19581347. 1.8 [47] Romney, Lee (13 September 2012). “On the frontier of medical pot to treat boy's epilepsy”. Los Angeles Times. Not to be confused with cannabidiol or cannabinodiol. Cannabinol [48] Good, Alastair (26 October 2010). “Growing marijuana that won't get you high”. The Daily Telegraph (London). Cannabinol (CBN) is a weak psychoactive cannabinoid found only in trace amounts in Cannabis sativa and [49] Fournier, G.; Beherec, O.; Bertucelli, S. (2003). “Intérêt Cannabis indica.* [5] It is mostly a metabolite of du rapport Δ−9-THC / CBD dans le contrôle des cultures tetrahydrocannabinol (THC).* [6] CBN acts as a weak de chanvre industriel”. Annales de Toxicologie Analytique agonist of CB receptors, but has a higher a nity 1 15 (4): 250–259. doi:10.1051/ata/2003003. to CB2 receptors, with lower a nities in comparison to * * [50] Sachs J et al Safety and Toxicology of Cannabinoids. Neu- THC. [7] [8] Cannabinol has been shown to have analgesic * rotherapeutics. 2015 Oct; 12(4): 735–746. PMC4604177 properties. [9] [51] Iseger TA, Bossong MG (2015). “A systematic review of the antipsychotic properties of cannabidiol in humans”. Schizophr. Res. 162 (1-3): 153–61. doi:10.1016/j.schres.2015.01.033. PMID 25667194. Unlike other cannabinoids, CBN does not stem from CBG, but is the degraded product of THC. If cannabis is exposed to air or ultraviolet light for a prolonged period of time, THCA will convert to CBNA. CBN is then formed by decarboxylation of CBNA.* [10] 80 CHAPTER 1. CANNABIS 1.8.1 Chemistry In contrast to THC, CBN has no double bond isomers nor stereoisomers. 1.8.2 Legal status CBN is not scheduled by the United Nations' Convention on Psychotropic Substances. United States CBN is not scheduled at the federal level in the United States,* [11] but it could legally be considered an analog of THC and sales or possession could be prosecuted under the Federal Analogue Act. [6] McCallum ND, Yagen B, Levy S, Mechoulam R (May 1975). “Cannabinol: a rapidly formed metabolite of delta1- and delta-6-tetrahydrocannabinol”. Experientia 31 (5): 520–1. doi:10.1007/bf01932433. PMID 1140243. [7] Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK (October 2000). “Novel cannabinol probes for CB1 and CB2 cannabinoid receptors”. Journal of Medicinal Chemistry 43 (20): 3778–85. doi:10.1021/jm0001572. PMID 11020293. [8] Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998). “Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors”. Life Sciences 63 (1): PL1–6. doi:10.1016/S0024-3205(98)00238-0. PMID 9667767. [9] http://link.springer.com/article/10.1007%2FBF00421466 [10] Medical Jane, Cannabinol CBN [11] α1308.11 Schedule I. 1.8.4 External links • Erowid Compounds found in Cannabis sativa 1.9 Cannabinol 10 mg transdermal patches sold at marijuana dispensaries in Colorado, USA 1.8.3 References [3] [4] [5] Cannabis sativa is an annual herbaceous plant in the Cannabis genus, a species of the Cannabaceae family. People have cultivated Cannabis sativa throughout recorded history as a source of industrial bre, seed oil, food, recreation, religious and spiritual moods, and medicine. Each part of the plant is harvested di erently, depending on the purpose of its use. The species was rst classi ed by Carl Linnaeus in 1753.* [1] 1.9.1 Common uses Main articles: Industrial and personal uses of Cannabis, Cannabis (drug) and Hemp David R. Lide (2012). CRC Handbook of Chemistry and Its seeds are chie y used to make hempseed oil which can be used for cooking, lamps, lacquers, or paints. They can Physics. CRC Press. pp. 3–90. ISBN 1-43988049-2. also be used as caged-bird feed, as they provide a moderSigma-Aldrich Co., Cannabinol solution, 1.0 mg/mL in ate source of nutrients for most birds. The owers (and methanol, analytical standard, for drug analysis. to a lesser extent the leaves, stems, and seeds) contain psychoactive chemical compounds known as cannabinoids Biotrend: Cannabinol (PDF: 21 kB) that are consumed for recreational, medicinal, and spirKarniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty itual purposes. When so used, preparations of owRE (1975). “E ects of delta9-tetrahydrocannabinol and ers (marijuana) and leaves and preparations derived from cannabinol in man”. Pharmacology 13 (6): 502–12. resinous extract (e.g.hashish) are consumed by smoking, vadoi:10.1159/000136944. PMID 1221432. porizing and oral ingestion. Historically, tinctures, teas, [1] Cannabinol in the ChemIDplus database. [2] Cannabis sativa 81 1.9. CANNABIS SATIVA need of seeds for the growing process. A Cannabis plant in the vegetative growth phase of its life requires more than 12–13 hours of light per day to stay vegetative. Flowering usually occurs when darkness equals at least 12 hours per day. The owering cycle can last anywhere between nine to fteen weeks, depending on the strain and environmental conditions. In soil, the optimum pH for the plant is 6.3 to 6.8. In hydroponic growing, the nutrient solution is best at 5.2 to 5.8, making Cannabis well-suited to hydroponics because this pH range is hostile to most bacteria and fungi. 1.9.3 Cultivars Broadly, there are three main cultivar groups of cannabis that are cultivated today: • Cultivars primarily cultivated for their bre, characterised by long stems and little branching. • Cultivars grown for seed which can be eaten entirely raw or from which hemp oil is extracted. A sack made from hemp ber and ointments have also been common preparations. In traditional medicine of India in particular C. sativa has been used as hallucinogenic, hypnotic, sedative, analgesic, and anti-in ammatory agent.* [2] 1.9.2 Plant physiology • Cultivars grown for medicinal or recreational purposes. A nominal if not legal distinction is often made between industrial hemp, with concentrations of psychoactive compounds far too low to be useful for that purpose, and marijuana. 1.9.4 Pharmacology Main article: Cannabis (drug) Although the main psychoactive constituent of Cannabis Main articles: Cannabis and Cannabis cultivation The owers of the female plant are arranged in racemes and can produce hundreds of seeds. Male plants shed their pollen and die several weeks prior to seed ripening on the female plants. Although genetic factors dispose a plant to become male or female, environmental factors including the diurnal light cycle can alter sexual expression.* [3] Naturally occurring monoecious plants, with both male and female parts, are either sterile or fertile but arti cially induced "hermaphrodites" (a commonly used misnomer) can have fully functional reproductive organs. “Feminized” seed sold by many commercial seed suppliers are derived from arti cially “hermaphrodytic”females that lack the male gene, or by treating the plants with hormones or silver thiosulfate. In the case of production related to recreational use of Cannabis, the process of “cloning”provides the grower with DNA identical female plants eliminating the Δ9 -tetrahydrocannabinol (THC) is tetrahydrocannabinol (THC), the plant is known to contain more than 500 compounds, among them at least 113 cannabinoids; however, most of these “minor”cannabinoids are only produced in trace amounts.* [4] Besides THC, another cannabinoid produced in high concentrations 82 CHAPTER 1. CANNABIS does not contain CBD, CBN, or other cannabinoids, which is one reason why its pharmacological e ects may di er signi cantly from those of natural Cannabis preparations. 1.9.5 Chemical constituents Beside cannabinoids, Cannabis chemical constituents include about 120 compounds responsible for its characteristic aroma. These are mainly volatile terpenes and sesquiterpenes. • -Pinene* [6] • Myrcene* [6] • Linalool* [6] • Limonene* [6] • Trans- -ocimene* [6] • The ower of a hybrid Cannabis indica plant -Terpinolene* [6] • Trans-caryophyllene* [6] • -Humulene,* [6] contributes to the characteristic aroma of Cannabis sativa • Caryophyllene-oxide,* [6] with which some hashish detection dogs are trained* [7] Di erence between C. sativa and C. indica On average, some studies indicated that Cannabis indica has higher levels of THC to CBD, whereas Cannabis sativa has higher levels of CBD compared to THC.* [8] However, huge variability exists within either species, and there is an increasing discussion whether the existing paradigm of the di erence between species adequately represents the variability found within the Cannabis genus.* [9]* [10]* [11] There are ve chemotaxonomic types of Cannabis: one with high levels of THC, one which is more brous and has higher levels of CBD, one that is an intermediate between the two, another one with high levels of cannabigerol (CBG), and the last one almost without cannabinoids.* [12] Cannabis sativa, scienti c drawing from c1900 by some plants is cannabidiol (CBD), which is not psychoactive but has recently been shown to block the e ect of THC in the nervous system.* [5] Di erences in the chemical composition of Cannabis varieties may produce di erent e ects in humans. Synthetic THC, called dronabinol, Cannabis strains with relatively high CBD:THC ratios are less likely to induce anxiety than vice versa. This may be due to CBD's antagonistic e ects at the cannabinoid receptors, compared to THC's partial agonist e ect.* [13] CBD is also a 5-HT1A receptor (serotonin) agonist, which may also contribute to an anxiolytic-content e ect.* [14] The effects of sativa are well known for its cerebral high, while indica is well known for its sedative e ects which some prefer for night time use.* [14] Both types are used as medical cannabis. Indica plants are normally shorter and stockier 83 1.10. CANNABIS INDICA than sativas.* [15] They have broader, deeply serrated leaves and a compact and dense ower cluster. The e ects of indicas are predominantly physical and sedative. 1.9.6 See also • Coca • Cannabis indica • Cannabis ruderalis • Cannabis strains • Opium • Kava 1.9.7 References [1] Greg Green, The Cannabis Breeder's Bible, Green Candy Press, 2005, pp. 15-16 ISBN 9781931160278 [2] Wang, L; Waltenberger, B; Pferschy-Wenzig, EM; Blunder, M; Liu, X; Malainer, C; Blazevic, T; Schwaiger, S; Rollinger, JM; Heiss, EH; Schuster, D; Kopp, B; Bauer, R; Stuppner, H; Dirsch, VM; Atanasov, AG (2014). “Natural product agonists of peroxisome proliferator-activated receptor gamma (PPAR ): a review”. Biochem Pharmacol 92 (1): 73–89. doi:10.1016/j.bcp.2014.07.018. PMC 4212005. PMID 25083916. [3] Scha ner, John H. (1921-01-01). “In uence of Environment on Sexual Expression in Hemp”. Botanical Gazette 71 (3): 197–219. [4] Aizpurua-Olaizola, Oier; Soydaner, Umut; Öztürk, Ekin; Schibano, Daniele; Simsir, Yilmaz; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, Aresatz (2016-02-02). “Evolution of the Cannabinoid and Terpene Content during the Growth ofCannabis sativaPlants from Di erent Chemotypes”. Journal of Natural Products 79 (2): 324–331. doi:10.1021/acs.jnatprod.5b00949. [8] Hillig, K. W.; Mahlberg, P. G. (1 June 2004). “A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae)". American Journal of Botany 91 (6): 966– 975. doi:10.3732/ajb.91.6.966. PMID 21653452. Retrieved 28 May 2015. [9] Piomelli, Daniele; Russo, Ethan B. (2016-01-14). “The Cannabis sativa Versus Cannabis indica Debate: An Interview with Ethan Russo, MD”. Cannabis and Cannabinoid Research 1 (1): 44–46. doi:10.1089/can.2015.29003.ebr. [10] Aizpurua-Olaizola, Oier; Omar, Jone; Navarro, Patricia; Olivares, Maitane; Etxebarria, Nestor; Usobiaga, Aresatz (2014-10-23). “Identi cation and quanti cation of cannabinoids in Cannabis sativa L. plants by high performance liquid chromatography-mass spectrometry”. Analytical and Bioanalytical Chemistry 406 (29): 7549–7560. doi:10.1007/s00216-014-8177-x. ISSN 1618-2642. [11] Hazekamp, A.; Fischedick, J. T. (2012-07-01). “Cannabis - from cultivar to chemovar”. Drug Testing and Analysis 4 (7-8): 660–667. doi:10.1002/dta.407. ISSN 1942-7611. [12] Mandolino, Giuseppe; Bagatta, Manuela; Carboni, Andrea; Ranalli, Paolo; Meijer, Etienne de (2003-03-01). “Qualitative and Quantitative Aspects of the Inheritance of Chemical Phenotype in Cannabis”. Journal of Industrial Hemp 8 (2): 51–72. doi:10.1300/J237v08n02_04. ISSN 1537-7881. [13] 2015. “Marijuana Chemicals Cannabinoids, Terpenes, Flavonoids (THC and CBD).”Howtogrowmarijuana.com. Retrieved from http://howtogrowmarijuana. com/cannabinoids-terpenes-flavonoids-cbd-thc/. [14] J.E. Joy, S. J. Watson, Jr., and J.A. Benson, Jr, (1999). Marijuana and Medicine: Assessing The Science Base. Washington D.C: National Academy of Sciences Press. ISBN 0585-05800-8. [15] Fischedick, Justin Thomas; Hazekamp, Arno; Erkelens, Tjalling; Choi, Young Hae; Verpoorte, Rob (December 2010). “Metabolic ngerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes”. Phytochemistry 71 (1718): 2058–2073. doi:10.1016/j.phytochem.2010.10.001. PMID 21040939. Retrieved 28 May 2015. [5] Russo, Ethan B (2011-08-01). “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage e ects”. British Journal of Pharmacology 163 (7): 1344–1364. doi:10.1111/j.1476-5381.2011.01238.x. ISSN 1476-5381. PMC 3165946. PMID 21749363. 1.9.8 External links [6] Novak J, Zitterl-Eglseer K, Deans SG, Franz CM (2001). “Essential oils of di erent cultivars of Cannabis sativa L. and their antimicrobial activity”. Flavour and Fragrance Journal 16 (4): 259–262. doi:10.1002/ j.993. 1.10 [7] Essential Oils • Data related to Cannabis sativa at Wikispecies Cannabis indica Cannabis indica, formally known as Cannabis sativa forma indica, is an annual plant in the Cannabaceae family. A putative species of the genus Cannabis. 84 1.10.1 Taxonomy In 1785, Jean-Baptiste Lamarck published a description of a second species of Cannabis, which he named Cannabis indica. Lamarck based his description of the newly named species on plant specimens collected in India. Richard Evans Schultes described C. indica as relatively short, conical, and densely branched, whereas C. sativa was described as tall and laxly branched.* [1] Loran C. Anderson described C. indica plants as having short, broad lea ets whereas those of C. sativa were characterized as relatively long and narrow.* [2]* [3] Cannabis indica plants conforming to Schultes's and Anderson's descriptions may have originated from the Hindu Kush mountain range. Because of the often harsh and variable (extremely cold winters, and warm summers) climate of those parts, C. indica is well-suited for cultivation in temperate climates. 1.10.2 Cultivation Broad-leafed Cannabis indica plants in India, Afghanistan, Bangladesh and Pakistan are traditionally cultivated for the production of charas. Pharmacologically, C. indica landraces tend to have a higher cannabidiol (CBD) content than C. sativa strains* [4]* [5] Some commercially available indica strains have been selected for high levels of CBD, with some users reporting more of a “stoned”feeling and less of a “high”from C. indica when compared to C. sativa.* [6] The Cannabis indica high is often referred to as a “body buzz”and has bene cial properties such as pain relief in addition to being an e ective treatment for insomnia and an anxiolytic, as opposed to sativa's more common reports of a “spacey”and mental inebriation, and even, albeit rarely, comprising hallucinations.* [7] Di erences in the terpenoid content of the essential oil may account for some of these di erences in e ect.* [8]* [9] Common indica strains for recreational or medicinal use include Kush and Northern Lights. CHAPTER 1. CANNABIS ternodal length, leaf size and structure, buds size and density, owering time, odour, smoke and e ects.* [11] Indica plants tend to grow shorter and bushier than the sativa plants. Indica strains tend to have wide, short leaves with short wide blades, whereas sativa strains have long leaves with thin long blades. The buds of indica strains tend to be wide, dense and bulk, while sativa strains are likely to be long, sausage shaped owers.* [12] On average, Cannabis indica has higher levels of THC compared to CBD, whereas Cannabis sativa has lower levels of THC to CBD.* [5] However, huge variability exists within either species. A note about the relative CBD to THC ratios mentioned here. These are merely comparative values, we must not interpret that the CBD is higher than THC in a typical strain of indica developed over the last 50 years. The reverse is generally true with a ratio of 20:1 (THC:CBD) being average in most cannabis strains. In the recent era of cannabis breeding high CBD strains are being developed from Indica origins that will test out as 1:1 or even as high as a 22:1 ratio. The medical interests in Cannabis are taking this further and we will see more strains developed with a reverse CBD:THC ratio. Low anxiety and hallucinogenic properties make these “CBD strains”very desirable for chronic treatment programs. There are three chemotaxonomic types of Cannabis: one with high levels of THC, one which is more brous and has higher levels of CBD, and one that is an intermediate between the two.* [5]* [13] Cannabis strains with relatively high CBD:THC ratios are less likely to induce anxiety than vice versa. This may be due to CBD's antagonistic e ects at the cannabinoid receptors, compared to THC's partial agonist e ect. CBD is also a 5-HT1A receptor (serotonin) agonist, which may also contribute to an anxiolytic-content e ect.* [14] The e ects of sativa are well known for its cerebral high. Users can expect a more vivid and uplifting high, while indica is well A recent genetic analysis included both the narrow-lea et known for its sedative e ects which some prefer for night and wide-lea et drug “biotypes”under C. indica, as well time use. Indica possesses a more calming, soothing, and as southern and eastern Asian hemp ( ber/seed) landraces numbing experience in which can be used to relax or relieve pain. This is mainly because of the higher CBD:THC and wild Himalayan populations.* [10] ratio.* [14] Both types are used as medical cannabis. • Broad leaf of a C. indica plant • Cannabis • Cannabis indica owering During the 1970s, Cannabis indica strains from Afghanistan and Hindu Kush were brought to the United States, where the rst hybrids with Cannabis sativa plants from equatorial areas were developed, widely spreading marijuana cultivation throughout the States.* [15] The name indica originally referred to the geographical area in which the plant was grown.* [16] Whether C. sativa and C. indica are separate species is still a matter of debate.* [17] There are several key di erences between Cannabis indica However, investigation into chemotaxonomic di erences and Cannabis sativa. These include height and stature, inDi erence between C. indica and C. sativa 85 1.11. CANNABIS RUDERALIS support a two-species hypothesis.* [5] [11] “Indica vs Sativa – Di erences”. Freedom Seeds. 1.10.3 Genome [12] Ed, Rosenthal (2010). Marijuana Grower's Handbook (Ask ed.). Oakland, California: Quick American Publishing. p. 40. ISBN 978-0-932551-46-7. In 2011, a team of Canadian researchers announced that [13] Fischedick, Justin Thomas; Hazekamp, Arno; Erkelens, they had sequenced a draft genome of the Purple Kush vaTjalling; Choi, Young Hae; Verpoorte, Rob (December riety of C. indica.* [18] 2010). “Metabolic ngerprinting of Cannabis indica 1.10.4 See also • Cannabis sativa 1.10.5 References [1] Richard Evans Schultes, William M. Klein, Timothy Plowman & Tom E. Lockwood (1974). "Cannabis: an example of taxonomic neglect”(PDF). Harvard University Botanical Museum Lea ets 23: 337–367. [2] Loran C. Anderson (1980). “Leaf variation among Cannabis species from a controlled garden”. Harvard University Botanical Museum Lea ets 28 (1): 61–69. [3] Dr. Loran C. Anderson - FSU Biological Science Faculty Emeritus [4] Fischedick, Justin Thomas; Hazekamp, Arno; Erkelens, Tjalling; Choi, Young Hae; Verpoorte, Rob (December 2010). “Metabolic ngerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes”. Phytochemistry 71 (1718): 2058–2073. doi:10.1016/j.phytochem.2010.10.001. PMID 21040939. Retrieved 30 May 2015. [5] Karl W. Hillig & Paul G. Mahlberg (2004). “A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae)". American Journal of Botany 91 (6): 966– 975. doi:10.3732/ajb.91.6.966. PMID 21653452. [6]“Sativa vs Indica.”AMSTERDAM – THE CHANNELS. Web. 05 Dec. 2010. <http://www.channels.nl/knowledge/ 25700.html>. [7] “Di erence Marijuana Cannabis Sativa and Indica, Sativa or Indica Marijuana Seed Strains.”. Amsterdam Marijuana Seeds Seed Bank. L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes”. Phytochemistry 71 (1718): 2058–2073. doi:10.1016/j.phytochem.2010.10.001. PMID 21040939. Retrieved 28 May 2015. [14] J.E. Joy, S. J. Watson, Jr., and J.A. Benson, Jr, (1999). Marijuana and Medicine: Assessing The Science Base. Washington D.C: National Academy of Sciences Press. ISBN 0585-05800-8. [15] Tom Flowers, Marijuana ower forcing, Quick American Archives, 1997, p.48 [16] George Nakamura, FORENSIC IDENTIFICATION OF MARIJUANA: SOME QUESTIONS AND ANSWERES, Journal of Police Science and Administration, 1973, p.102-112 [17] Russo, EB (August 2007). “History of cannabis and its preparations in saga, science, and sobriquet.”. Chemistry & Biodiversity 4 (8): 1614–48. doi:10.1002/cbdv.200790144. PMID 17712811. Retrieved 30 May 2015. [18] Van Bakel, H.; Stout, J. M.; Cote, A. G.; Tallon, C. M.; Sharpe, A. G.; Hughes, T. R.; Page, J. E. (2011).“The draft genome and transcriptome of Cannabis sativa”. Genome Biology 12 (10): R102. doi:10.1186/gb-2011-12-10-r102. PMC 3359589. PMID 22014239. 1.10.6 External links • Four full pages of photos of cannabis cultivation in Morocco (Rif) on geopium.org 1.11 Cannabis ruderalis Cannabis ruderalis is a species of Cannabis originating in central Russia. It is less common than the other species of [8] McPartland, J. M.; Russo, E. B. (2001). "Cannabis Cannabis.* [1] and Cannabis extracts: greater than the sum of their parts?". Journal of Cannabis Therapeutics 1 (3/4): 103–132. doi:10.1300/J175v01n03_08. [9] Karl W. Hillig (2004).“A chemotaxonomic analysis of terpenoid variation in Cannabis". Biochemical Systematics and Ecology 32 (10): 875–891. doi:10.1016/j.bse.2004.04.004. 1.11.1 Etymology The term ruderalis is derived from the Latin rūdera, which is the plural form of rūdus, a Latin word meaning rub* * [10] Karl W. Hillig (2005). “Genetic evidence for speciation ble, [2] lump, or rough piece of bronze. [3] A ruderal in Cannabis (Cannabaceae)". Genetic Resources and Crop species refers to any plant that is the rst to colonize land Evolution 52: 161–180. doi:10.1007/s10722-003-4452-y. after a disturbance removing competition. 86 1.11.2 Morphology C. ruderalis rarely grows over two feet in height, and matures in approximately seven weeks.* [4] The plants have a “thin, slightly brous stem”with little branching.* [5] Foliage is open with large leaves.* [5] Cannabis ruderalis will produce owers based on its age, rather than light cycle, unlike owering in C. sativa and C. indica varieties.* [6] This kind of owering is also known as "auto owering".* [7] CHAPTER 1. CANNABIS attractive to plant breeders.* [11] C. indica strains are frequently cross-bred with C. ruderalis to produce auto owering plants with high THC content, improved hardiness and reduced height.* [12] One strain, identi ed in 1960, is Cannabis x intersita Sojak which is a cross between C. sativa and C. ruderalis.* [5] Attempts to produce a Cannabis strain with a shorter growing season are another application of cultivating C. ruderalis.* [8] C. ruderalis when crossed with sativa and indica strains produces a plant which owers automatically and is fully mature in 10 weeks.* [13] It has less THC in its resin compared to other Cannabis species.* [4] However, it is often high in cannabidiol 1.11.5 Uses (CBD).* [8] C. ruderalis is traditionally used in Russian and Mongolian folk medicine, especially for uses in treating depression.* [5] It is not advised to use pure C. ruderalis as a recreational 1.11.3 Origin and range drug because of the low THC content.* [10] C. ruderalis was rst scienti cally identi ed in 1942 in In modern use, C. ruderalis is crossed with Bedrocan strains southern Siberia, although it also grows wild in other ar- to produce Bediol for medical prescriptions.* [14] eas of Russia.* [4] The Russian botanist, Janischewski, was studying wild Cannabis in the Volga River system and realized he had come upon a third species.* [9] C. ruderalis is a 1.11.6 See also hardier variety grown in the northern Himalayas and south• Cannabis indica ern states of the former Soviet Union, characterized by a * more sparse, “weedy”growth. [8] • Cannabis sativa Similar C. ruderalis populations can be found in most of the • Cannabis strains areas where hemp cultivation was once prevalent. The most notable region in North America is the midwestern United • Cannabaceae States, though populations occur sporadically throughout • Auto owering cannabis the United States and Canada.* [10] Large wild C. ruderalis populations are also found in central and eastern Europe, most of them in Lithuania, Belarus, Latvia, Estonia and adjacent countries. Without human selection, these plants 1.11.7 References have lost many of the traits they were originally selected for, [1] Resin, Harry (9 May 2014). “5 Di erences Between Sativa and have acclimated to their environment.* [8] and Indica”. High Times. Retrieved 15 July 2015. [2] “De nition for ruderal”. 1.11.4 Cultivation [3] “Latin etymology of ruderalis”. Seeds of C. ruderalis were brought to Amsterdam in the early 1980s in order to enhance the breeding program of the Seed Bank.* [10] [4] Sta ord, Peter (1992). Psychedelics Encyclopedia. Berkeley, California: Ronin Publishing, Inc. p. 159. ISBN 9781579511692. Cannabis ruderalis has a lower THC content than either C. sativa or C. indica, so it is rarely grown for recreational use and the shorter stature of C. ruderalis limits its application for hemp production. Cannabis ruderalis strains are high in the cannabіnoid cannabidiol, so they are grown by some medical marijuana users. [5] Ratsch, Christian (1998). Marijuana Medicine: A World Tour of the Healing and Visionary Powers of Cannabis. translated by John Baker. Switzerland: AT Verlag Aarau. pp. 59–60. ISBN 9780892819331. [6] Rosenthal, Ed. “Flowering Ruderalis”. Cannabis Culture Magazine. Retrieved 16 February 2012. However, C. ruderalis' early, plant-age triggered“auto owering”characteristic (which o ers some agricultural advantages over the day-length owering varieties) as well as its reputed resistance to insect and disease pressures makes it [7] Green, Greg (2005). The Cannabis Breeder's Bible: The De nitive Guide to Marijuana Genetics, Cannabis Botany and Creating Strains for the Seed Market. Green Candy Press. p. 14. ISBN 978-1931160278. 87 1.12. HASHISH [8] Clarke, Robert Connell (1981). Marijuana Botany: An Advanced Study. Berkeley, California: Ronin Publishing, Inc. pp. 115, 157. ISBN 9780914171782. [9] Booth, Martin (2005). Cannabis: A History. Picador. pp. 2–3. ISBN 9781250082190. [10] Cervantes, Jorge (2006). Marijuana Horticulture: The Indoor/Outdoor Medical Grower's Bible (5th ed.). Van Patten Publishing. p. 12. ISBN 9781878823236. [11] “Euro Grow”. High Times. 12 February 2010. Retrieved 15 July 2015. [12] DMT.“The Return of Ruderalis”. Cannabis Culture Magazine. Retrieved 16 February 2012. [13] “Cannabis Ruderalis”. Dutch Passion Seed Company. Retrieved 15 July 2015. “Prescription [14] Bienenstock, David (1 March 2011). Strength”. High Times. Retrieved 15 July 2015. 1.11.8 External links 1.5 grams pressed hashish • Media related to Cannabis ruderalis at Wikimedia Commons • Data related to Cannabis ruderalis at Wikispecies 1.12 Hashish For the village in Iran, see Hashish, Iran. Hashish, or hash, is an extracted product composed of compressed or puri ed preparations of stalked resin glands, called trichomes, from the cannabis plant. It contains the same active ingredients as marijuana ̶such as tetrahydrocannabinol (THC) and other cannabinoids̶but often in higher concentrations than the unsifted buds or leaves from which the marijuana is made of.* [2] Hashish may be solid or resinous depending on the preparation; pressed hashish is usually solid, whereas water-puri ed hashish̶often called“bubble melt hash”̶is often a paste- One gram “bubble melt”Cannabis indica hashish like substance with varying hardness and pliability; its color, most commonly light to dark brown, can vary from transparent to yellow, tan, black or red. This all depends on the Hashish Trail, only small pieces of Lebanese hashish were process and amount of solvent left over.* [3] found in Morocco.* [4] However, hemp has been reported from a cultural setting on Taiwan as long ago as 10,000 BC., and "[t]he earliest human use of Cannabis appears to have 1.12.1 History occurred in the steppe regions of Central Asia or in China.” * The name hashish comes from the Arabic word ( ‫[ ) حشيش‬5] which means grass. It is believed that massive hashish production for international trade originated in Morocco during the 1960s, where the cannabis plant was widely available. Before the coming of the rst hippies from the Hippie Northern India has a long social tradition in the production of hashish, known locally as charas, which is believed to be the same plant resin as was burned in the ceremonial booz rooz of Ancient Persia.* [6] Cannabis indica grows wild 88 CHAPTER 1. CANNABIS almost everywhere on the Indian sub-continent, and special strains have been particularly cultivated for production of ganja and hashish particularly in West Bengal, Rajasthan and the Himalayas. In 1596, Dutchman Jan Huyghen van Linschoten spent three pages on“Bangue”(bhang) in his historic work documenting his journeys in the East. He particularly mentioned the Egyptian Hashish.* [7] He said, “Bangue is likewise much used in Turkie and Egypt, and is made in three sorts, having also three names. The rst by the Egyptians is called Assis (Hashish (Arab.)), which is the poulder of Hemp, or of Hemp leaves, which is water made in paste or dough, they would eat ve peeces, (each) as big as a Chestnut (or larger); This is used by the common people, because it is of a small price, and it is no wonder, that such vertue proceedeth from the Hempe, for that according to Galens opinion, Hempe excessively lleth the head.” In the 1800s, hashish was embraced in some European literary circles. Most famously, the Club des Hashischins was a Parisian club dedicated to the consumption of hashish and other drugs; its members included literary luminaries such as Victor Hugo, Alexandre Dumas, Charles Baudelaire and Honoré de Balzac.* [8] Baudelaire later wrote the 1860 book Les paradis arti ciels, about the state of being under the in uence of opium and hashish. At around the same time, American author Fitz Hugh Ludlow wrote the 1857 book The Hasheesh Eater about his youthful experiences, both positive and negative, with the drug. 1.12.2 Use Hashish is consumed only by smoking; typically in a pipe, Making cannabis resin, Uttarakhand, India vaporizer or joints, where it is normally mixed with tobacco, as pure hashish will not ignite in joints. a screen by hand or in motorized tumblers. This technique is known as“drysifting”. The resulting powder, referred to 1.12.3 Manufacturing processes as“kief”or“drysift”, is compressed with the aid of heat into blocks of hashish; if pure, the kief will become gooey Hashish is made from cannabinoid-rich glandular hairs and pliable. When a high level of pure THC is present, the known as trichomes, as well as varying amounts of cannabis end product will be almost transparent and will start to melt ower and leaf fragments. The owers of a mature fe- at the point of human contact. Ice-water separation is anmale plant contain the most trichomes, though trichomes other mechanical method of isolating trichomes. The clarare also found on other parts of the plant. Certain strains of ity of the nal product determines quality of the nal prodcannabis are cultivated speci cally for their ability to pro- uct. Nowadays, new techniques have been developed, such duce large amounts of trichomes. The resin reservoirs of as heat and pressure separations, static-electricity sieving or the trichomes, sometimes erroneously called pollen (ven- acoustical dry sieving.* [9] dors often use the euphemism“pollen catchers”to describe Chemical separation methods generally use a solvent such screened kief-grinders in order to skirt paraphernalia selling as ethanol, butane or hexane to dissolve the lipophilic delaws), are separated from the plant through various meth- sirable resin. Remaining plant materials are ltered out of ods. the solution and sent to the compost. The solvent is then Mechanical separation methods use physical action to re- evaporated, or boiled o (purged) leaving behind the demove the trichomes from the plant, such as sieving through sirable resins, called honey oil, "hash oil", or just “oil”. 89 1.13. TRICHOME Honey oil still contains waxes and essential oils and can be further puri ed by vacuum distillation to yield “red oil”. The product of chemical separations is more commonly referred to as“honey oil.”This oil is not really hashish, as the latter name covers trichomes that are extracted by sieving. This leaves most of the glands intact. [7] Burnell, Arthur Coke & Tiele, P.A (1885). The voyage of John Huyghen van Linschoten to the East Indies. from the old English translation of 1598: the rst book, containing his description of the East. London: The Hakluyt Society. pp. 115–117. Full text at Internet Archive. Chapter on Bangue. [8] Levinthal, C. F. (2012). Drugs, behavior, and modern soci- ety. (6th ed.). Boston: Pearson College Div. In a study conducted in 2014 by Jean-Jaques Filippi, Marie Marchini, Céline Charvoz, Laurence Du[9] Skunk Pharma Search, Acoustical dry sieving jourdy and Nicolas Baldovini (Multidimensional analysis of cannabis volatile constituents: Identi cation of 5,5- [10] Alchimia Blog, Hashishene, the new terpene of cannabis dimethyl-1-vinylbicyclo[2.1.1]hexane as a volatile marker of hashish, the resin of Cannabis sativa L.) the researchers [11] Inciardi, James A. (1992). The War on Drugs II. Mountain View, CA: May eld Publishing Company. p. 19. ISBN 1linked the characteristic avour of hashish with a rearrange55934-016-9. ment of myrcene caused during the process of manufac* ture. [10] 1.12.4 Quality Tiny pieces of leaf matter may be accidentally or even purposefully added; adulterants introduced when the hash is being produced will reduce the purity of the material and often resulting in green nished product. The tetrahydrocannabinol (THC) content of hashish comes in wide ranges from almost none to 65% and that of hash oil from 30% to 90%.* [11] 1.12.5 See also • Hemp oil 1.12.6 References [1] Mahmoud A. ElSohly (2007). Marijuana and the Cannabinoids. Springer. p. 8. ISBN 978-1-59259-947-9. [2] Russo, Ethan. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential, p. 34 (Routledge 2013). 1.12.7 Further reading • Hashish! by Robert Connell Clarke, ISBN 0-92934905-9 • The Hasheesh Eater by Fitz Hugh Ludlow; rst edition 1857 • Starkes, Michael. Marijuana Potency. Berkeley, California: And/Or Press, 1977. Chapter 6 “Extraction of THC and Preparation of Hash Oil”pp. 111–122. ISBN 0-915904-27-6. 1.12.8 External links • Bibliography of scholarly histories on cannabis and hashish • Hashish Making and Varieties 1.13 Trichome Trichomes (/ˈtraɪkoʊmz/ or /ˈtrɪkoʊmz/), from the Greek τρίχωμ (trikhōma) meaning "hair", are ne outgrowths [3] Guide To The Di erent Types Of Hash From Around The or appendages on plants, algae, lichens, and certain protists. World They are of diverse structure and function. Examples are hairs, glandular hairs, scales, and papillae. A covering of [4] Hashish! by Robert Connell Clarke, ISBN 0-929349-05-9 any kind of hair on a plant is an indumentum, and the sur[5] Merlin, M. D. 2003 "Archaeological evidence face bearing them is said to be pubescent. for the tradition of psychoactive plant use in the Old World,”Economic Botany 57 (3): 295-323. Table 1 (re Taiwan) and p. 312 (quotation). http://link.springer.com/article/10.1663/0013-0001% 282003%29057%5B0295:AEFTTO%5D2.0.CO%3B2. Rtvd 2014.02.22. [6] Usaybia, Abu; Notes on Uyunu al-Anba Tabaquat alAtibba, Berkeley: University of California Press, 1965. 1.13.1 Algal trichomes Certain, usually lamentous, algae have the terminal cell produced into an elongate hair-like structure called a trichome. The same term is applied to such structures in some cyanobacteria, such as Spirulina and Oscillatoria. 90 CHAPTER 1. CANNABIS Flower bud of a Capsicum pubescens plant, with many trichomes Cyanobacteria trichomes may be unsheathed, as in Oscillatoria, or sheathed, as in Calothrix.* [1] These structures play an important role in preventing soil erosion, particularly in cold desert climates. The lamentous sheaths form a persistent sticky network that helps maintain soil structure. 1.13.2 Plant trichomes Sticky trichomes of a carnivorous plant, Drosera capensis with a trapped insect, contain proteolytic enzymes. Aerial surface hairs Trichomes on plants are epidermal outgrowths of various kinds. The terms emergences or prickles refer to outgrowths that involve more than the epidermis. This distinction is not always easily applied (see Wait-a-minute tree). Also, there are nontrichomatous epidermal cells that protrude from the surface. A common type of trichome is a hair. Plant hairs may be unicellular or multicellular, branched or unbranched. Multicellular hairs may have one or several layers of cells. Branched hairs can be dendritic (tree-like) as in kangaroo paw (Anigozanthos), tufted, or stellate (star-shaped), as in Arabidopsis thaliana. Another common type of trichome is the scale or peltate hair, that has a plate or shield-shaped cluster of cells attached directly to the surface or borne on a stalk of some kind. Common examples are the leaf scales of bromeliads such as the pineapple, Rhododendron and sea buckthorn Trichomes on Cannabis, rich in cannabinoids. (Hippophae rhamnoides). Any of the various types of hairs may be glandular, producing some kind of secretion, such as the essential oils produced by mints and many other members of the family Lamiaceae. In describing the surface appearance of plant organs, such as stems and leaves, many terms are used in reference to the presence, form, and appearance of trichomes. The most basic terms used are glabrous̶lacking hairs̶and pubescent 91 1.13. TRICHOME face smooth • hirsute – coarsely hairy • hispid – having bristly hairs • articulate – simple pluricellular-uniseriate hairs • downy – having an almost wool-like covering of long hairs • pilose – pubescent with long, straight, soft, spreading or erect hairs • puberulent – minutely pubescent; having ne, short, usually curly, hairs Trichomes on the surface of a Solanum scabrum leaf • pubescent – bearing hairs or trichomes of any type • strigillose – minutely strigose • strigose – having straight hairs all pointing in more or less the same direction as along a margin or midrib • tomentellous – minutely tomentose • tomentose – covered with dense, matted, woolly hairs • villosulous – minutely villous • villous – having long, soft hairs, often curved, but not matted Trichomes on the petiole of a Solanum quitoense leaf Hairs on plants are extremely variable in their presence across species and even within a species, such as their location on plant organs, size, density, and therefore functionality. However, several basic functions or advantages of having surface hairs can be listed. It is likely that in many cases, hairs interfere with the feeding of at least some small herbivores, and, depending upon sti ness and irritability to the palate, large herbivores as well. Hairs on plants growing in areas subject to frost keep the frost away from the living surface cells. In windy locations, hairs break up the ow of air across the plant surface, reducing transpiration. Dense coatings of hairs re ect sunlight, protecting the more delicate tissues underneath in hot, dry, open habitats. In addition, in locations where much of the available moisture comes from fog drip, hairs appear to enhance this process. Root hairs Root hairs, the rhizoids of many vascular plants, are tubular outgrowths of trichoblasts, the hair-forming cells on the epidermis of a plant root. That is, root hairs are lateral extensions of a single cell and only rarely branched. Just prior ̶having hairs. Details are provided by: to the root hair development, there is a point of elevated phosphorylase activity. Root hairs vary between 5 and 17 • glabrous, glabrate – lacking hairs or trichomes; sur- micrometres in diameter, and 80 to 1,500 micrometres in Epidermis of Arabidopsis thaliana with a trichome. 92 length (Dittmar, cited in Esau, 1965). Root hairs can survive for two to three weeks and then die o . At the same time new root hairs are continually being formed at the top of the root. This way, the root hair coverage stays the same. It is therefore understandable that repotting must be done with care, because the root hairs are being pulled o for the most part. This is why planting out may cause plants to wilt. 1.13.3 Signi cance for taxonomy CHAPTER 1. CANNABIS 1.13.5 Defense Plants may use trichomes in order to deter herbivore attack via physical and/or chemical means, e.g. in specialized, stinging hairs of Urtica (Nettle) species that deliver in ammatory chemicals such as histamine. However, some organisms have developed mechanisms to resist the e ects of trichomes. The larvae of Heliconius charithonia, for example, are able to physically free themselves from trichomes, are able to bite o trichomes, and are able to form silk blankets in order to navigate the leaves better.* [7] The type, presence and absence and location of trichomes 1.13.6 See also are important diagnostic characters in plant identi cation and plant taxonomy.* [2] In forensic examination, plants • Colleter (botany) such as Cannabis sativa can be identi ed by microscopic examination of the trichomes.* [3]* [4] Although trichomes • Seta are rarely found preserved in fossils, trichome bases are reg• Kief ularly found and, in some cases, their cellular structure is important for identi cation. 1.13.7 References [1] “Identify That Alga”. Retrieved September 20, 2013. [2] Davis, P.H.; Heywood, V.H. (1963). Principles of angiosperm taxonomy. Princeton, New Jersey: Van Nostrandpage. p. 154. [3] Bhatia, R.Y.P.; Raghavan, S.; Rao, K.V.S.; Prasad, V.N. (1973). “Forensic examination of leaf and leaf fragments in fresh and dried conditions.”. Journal of the Forensic Science Society 13 (3): 183–190. doi:10.1016/S00157368(73)70794-5. Bud and scape of a Stylidium species, displaying the trichomes that can trap and kill insects 1.13.4 Uses [4] United Nations O ce on Drugs and Crime (2009). Recommended Methods for the Identi cation and Analysis of Cannabis and Cannabis Products (Revised and updated). New York: United Nations. pp. 30–32. ISBN 9789211482423. [5] Szyndler, M.W.; Haynes, K.F.; Potter, M.F.; Corn, R.M.; Loudon, C. (2013). “Entrapment of bed bugs by leaf trichomes inspires microfabrication of biomimetic surfaces” (PDF). Journal of The Royal Society Interface 10 (83). doi:10.1098/rsif.2013.0174. ISSN 1742-5662. Bean leaves have been used historically to trap bedbugs in houses in Eastern Europe. The trichomes on the bean leaves capture the insects by impaling their feet (tarsi). The leaves would then be destroyed.* [5] [6] Eltz, Thomas; Küttner, Jennifer; Lunau, Klaus; Tollrian, Ralph (6 January 2015). “Plant secretions prevent wasp parasitism in nests of wool-carder bees, with implications for the diversi cation of nesting materials in Megachilidae”. Frontiers in Ecology and Evolution 2. doi:10.3389/fevo.2014.00086. Trichomes are an essential part of nest building for the European wool carder bee (Anthidium manicatum). This bee species incorporates trichomes into their nests by scraping them o of plants and using them as a lining for their nest cavities.* [6] [7] Cardoso, Márcio Z.“Ecology, Behavior and Binomics: Herbivore Handling of a Plant's Trichome: The Case of Heliconius Charithonia (L.) (Lepidoptera:Nymphalidae) and Passi ora Lobata (Kilip) Hutch. (Passi oraceae).”Neotropical Entomology 37.3 (2008): 247-52. Web. 93 1.14. HEMP • Esau, K. 1965. Plant Anatomy, 2nd Edition. John Wiley & Sons. 767 pp. 1.14 Hemp This article is about industrial uses of Cannabis. For recreational marijuana, see Cannabis (drug). For other uses, see Hemp (disambiguation). Hemp or industrial hemp (from Old English hænep),* [1] Hemp grown for animal feed legality of industrial hemp varies widely between countries. Some governments regulate the concentration of THC and permit hemp that's bred with an especially low THC content.* [7]* [8] 1.14.1 Etymology Hemp eld in Côtes-d'Armor, Brittany, France typically found in the northern hemisphere, is a variety of the Cannabis sativa plant species that is grown speci cally for the industrial uses of its derived products.* [2] It is one of the fastest growing plants* [3] and was one of the rst plants to be spun into usable ber 10,000 years ago.* [4] It can be re ned into a variety of commercial items including paper, textiles, clothing, biodegradable plastics, paint, insulation, biofuel, food, and animal feed.* [5] Although recreational marijuana and industrial hemp are both members of the species Cannabis sativa and contain the psychoactive component tetrahydrocannabinol (THC), they are distinct strains with unique biochemical compositions and uses.* [6] Hemp has lower concentrations of THC and higher concentrations of cannabidiol (CBD), which decreases or eliminates its psychoactive e ects.* [6] The Further information: Etymology of cannabis The etymology is uncertain but there appears to be no common Proto-indoeuropean source for the various forms of the word, which is likely due to the fact that wild hemp originally grew sparsely across a large geographic area from Central Asia to Germany. The Greek term kánnabis is the oldest attested form, which may have been borrowed from an earlier Scythian or Thracian word. Then it appears to have been borrowed into Latin, and separately into Slavic and from there into Baltic, Finnish, and Germanic languages. Following Grimm's law, the “k”would have changed to“h”with the rst Germanic sound shift,* [9]* [10] after which it may have been adapted into the Old English form, hænep. However, this theory assumes that hemp wasn't widely spread among di erent societies until after it was already being used as a psychoactive drug, which Adams and Mallory (1997) believe to be unlikely based on 94 CHAPTER 1. CANNABIS archaeological evidence.* [10] Cognates of hemp in other Germanic languages, include Danish and Norwegian, hamp; German, hanf; and Swedish, hampa.* [10] 1.14.2 Uses Hemp seed Hemp seed Hemp is used to make a variety of commercial and industrial products including rope, clothes, food, paper, textiles, plastics, insulation and biofuel.* [5] The bast bers can be used to make textiles that are 100% hemp, but they are commonly blended with other organic bers such as ax, cotton or silk, to make woven fabrics for apparel and furnishings. The inner two bers of the plant are more woody and typically have industrial applications, such as mulch, animal bedding and litter. When oxidized (commonly referred to as “drying”), hemp oil from the seeds becomes solid and can be used in the manufacture of oil-based paints, in creams as a moisturizing agent, for cooking, and in plastics. Hemp seeds have been used in bird feed mix as well.* [11] A survey in 2003 showed that more than 95% of hemp seed sold in the European Union was used in animal and bird feed.* [12] hemp seed and hemp oil for use as ingredients in foods such as granola.* [15] In the UK, the Department for Environment, Food and Rural A airs (Defra) treats hemp as a purely non-food crop, but with proper licensing and proof of less than 0.2% THC concentration, hemp seeds can be imported for sowing or for sale as a food or food ingredient.* [16] In the U.S., imported hemp can be used legally in food products and as of 2000, was typically sold in health food stores or through mail order.* [14] Nutrition Further information: Hemp protein 100 grams of hulled hemp seeds supply 586 calories. They are 5% water, 5% carbohydrates, 49% total fat and 31% protein. Hemp seeds are notable in providing 64% of the Daily Value (DV) of protein per 100 gram serving.* [17] Hempseed amino acid pro le is comparable to other sources of protein such as meat, milk, eggs and soy.* [18] Protein Digestibility Corrected Amino Acid Score values Food (PDCAAS), which measure the degree to which a food for humans is a“complete protein”, were 0.49-0.53 for whole Hemp seeds can be eaten raw, ground into a meal, sprouted, hemp seed, 0.46-0.51 for hemp seed meal, and 0.63-0.66 or made into dried sprout powder. The leaves of the hemp for dehulled hemp seed.* [19] plant can be consumed raw in salads. Hemp can also be made into a liquid and used for baking or for beverages such Hemp seeds are a rich source of B vitamins, the dietary as hemp milk, hemp juice, and tea.* [13] Hempseed oil is minerals, manganese (362% DV), phosphorus (236% DV), cold-pressed from the seed and is high in unsaturated fatty magnesium (197% DV), zinc (104% DV), iron (61% DV) acids.* [14] In 2011, the U.S. imported $11.5 million worth and dietary ber (20% DV) (table). of hemp products, mostly driven by growth in demand for Approximately 73% of the energy in hemp seeds is in 95 1.14. HEMP the form of fats and essential fatty acids,* [17] mainly frame.* [24] However hemp bres are extremely strong and polyunsaturated fatty acids, linoleic, oleic and alpha- durable, and have been shown to be usable as a replacement for wood for many jobs including creating very durable and linolenic acids.* [18] breathable homes. Storage Hemp oil oxidizes and turns rancid within a short period of time if not stored properly;* [14] its shelf life is extended when stored in a dark airtight container and refrigerated. Fiber Hemp stem showing bers. The rst example of the use of hempcrete was in 1986 in France with the renovation of the Maison de la Turque in Nogent-sur-Seine by the innovator Charles Rasetti.* [25] In the UK hemp lime was rst used in 2000 for the construction of two test dwellings in Haverhill.* [26] Designed by Modece Architects,* [27] who pioneered hemp's use in UK construction, the hemp houses were monitored in comparison with other standard dwellings by BRE. Completed in 2009, The Renewable House is one of the most technologically advanced made from hemp-based materials.* [28] The rst US home made of hemp-based materials was completed in August 2010 in Asheville, North Carolina.* [29] A panellized system of hemp-lime panels for use in building construction is currently under test in a European Union funded research collaboration led by the University of Bath. The panels are being designed to assure high quality construction, rapid on-site erection, optimal hygrothermal performance from day one and energy and resource e cient buildings. The 36-month-long work programme aims to rene product and manufacturing protocols, produce data for certi cation and marketing, warranty, insurance cover and availability of nance. It also includes the development of markets in Britain, France and Spain.* [30] Hemp is used as an internal plaster and is a mixture of hemp Hemp ber has been used extensively throughout history, hurd (shive) mixed with larger proportions of a lime based with production climaxing soon after being introduced to binder. Hemp plaster has insulative qualities.* [31] the New World. Items ranging from rope, to fabrics, to industrial materials were made from hemp ber. Hemp was • Hemp ber board often used to make sail canvas, and the word canvas derives • Hemp thermal insulation from cannabis.* [20]* [21] Today, a modest hemp fabric industry exists, and hemp bers can be used in clothing.* [22] • Hemp interior thermal insulation blocks Pure hemp has a texture similar to linen.* [23] • Hemp dress • Hemp dress • 100% hemp fabric • Hemp sack (Japan) Building material Main article: hempcrete Concrete-like blocks made with hemp and lime have been used as an insulating material for construction. Such blocks are not strong enough to be used for structural elements; they must be supported by a brick, wood, or steel • Hemp acoustic ceiling insulation • Concrete block made with hemp in France Plastic and composite materials Main article: Bioplastic A mixture of berglass, hemp ber, kenaf, and ax has been used since 2002 to make composite panels for automobiles.* [32] The choice of which bast ber to use is primarily based on cost and availability. Various car makers are beginning to use hemp in their cars, including Audi, BMW, Ford, GM, Chrysler, Honda, Iveco, Lotus, Mercedes, Mitsubishi, Porsche, Saturn, Volkswagen* [33] and Volvo. For example, the Lotus Eco Elise* [34] and the 96 CHAPTER 1. CANNABIS Mercedes C-Class both contain hemp (up to 20 kg in each hurds is similar to that of wood,* [40] making hemp a good choice as a raw material for manufacturing paper. Modern car in the case of the latter).* [35] research has not con rmed the positive nding about hemp hurds from 1916. A later book about hemp and other bers • Hemp plastic interior of a car door by the same L.H. Dewey(1943) have no words about hemp as a raw material for production of paper.* [41] Dried hemp • Hemp plastic automobile glove box has about 57% cellulose (the principal ingredient in paper), • Hemp plastic column, automobile compared to about 40-50% in wood.* [42]* [43]* [44] Hemp also has the advantage of a lower lignin content: hemp con• Hemp composite sink basin tains only 5-24% lignin* [45] against the 20-35% found in wood.* [46] This lignin must be removed chemically and wood requires more use of chemicals in the process.* [47] Paper The actual production of hemp ber in the U.S continued to decline until 1933 to around 500 tons/year. Between 193435, the cultivation of hemp began to increase but still at a very low level and with no signi cant increase of paper from hemp.* [48]* [49] Wrapping paper with hemp ber excavated from the Han Tomb of Wu Di (140-87 BC) at Baqiao, Xi'An. History and development The rst identi ed coarse paper, made from hemp, dates to the early Western Han Dynasty, two hundred years before the nominal invention of papermaking by Cai Lun, who improved and standardized paper production using a range of inexpensive materials, including hemp ends, approximately 2000 years ago.* [36] Recycled hemp clothing, rags and shing nets were used as inputs for paper production. Contemporary Currently there is a small niche market for hemp pulp, for example as cigarette paper.* [50] Hemp ber is mixed with ber from other sources than hemp. In 1994 there was no signi cant production of 100% true hemp paper.* [51] World hemp pulp production was believed to be around 120,000 tons per year in 1991 which was about 0.05% of the world's annual pulp production volume.* [52] The total world production of hemp ber had in 2003 declined to about 60,000 from 80,000 tons.* [50] This can be compared to a typical pulp mill for wood ber, which is never smaller than 250,000 tons per annum.* [51]* [53] The cost of hemp pulp is approximately six times that of wood pulp,* [52] mostly because of the small size and outdated equipment of the few hemp processing plants in the Western world, and because hemp is harvested once a year (during August) and needs to be stored to feed the mill the whole year through. This storage requires a lot of (mostly manual) handling of the bulky stalk bundles. Another issue is that the entire hemp plant cannot be economically prepared for paper production. While the wood products industry uses nearly 100% of the ber from harvested trees, only about 25% of the dried hemp stem ̶the bark, called bast ̶contains the long, strong bers desirable for paper production.* [54] All this accounts for a high raw material cost. Hemp pulp is bleached with hydrogen peroxide, a process today also commonly used for wood pulp. The Saint Petersburg, Russia, paper mill of Goznak opened in 1818. It used hemp as its main input material. Paper from the mill was used in the printing of "bank notes, Market share Around the year 2000, the production stamped paper, credit bills, postal stamps, bonds, stocks, quantity of ax and hemp pulp total 25000-30000 tons per and other watermarked paper.”* [37] year, having been produced from approximately 37000In 1916, U.S. Department of Agriculture chief scientists 45000 tonnes bers. Up to 80% of the produced pulp is Lyster Hoxie Dewey and Jason L. Merrill created paper used for specialty papers (including 95% of cigarette pamade from hemp pulp and concluded that paper from hemp per). Only about 20% hemp ber input goes into the stanhurds was “favorable in comparison with those used with dard pulp area and are here mostly in lower quality (unpulp wood.”* [38]* [39] The chemical composition of hemp treated oakum high shive content added) wood pulps. With 97 1.14. HEMP hemp pulp alone, the proportion of specialty papers probably at about 99%. The market is considered saturated with little or no growth in this area.* [55]* [56] Jewelry Main article: Hemp jewelry Hemp jewelry is the product of knotting hemp twine Hemp rope. Hemp and bead Jewelry. through the practice of macramé. Hemp jewellery includes bracelets, necklaces, anklets, rings, watches and other adornments. Some jewellery features beads made from glass, stone, wood and bones. The hemp twine varies in thickness and comes in a variety of colors. There are many di erent stitches used to create hemp jewellery, however, the half knot and full knot stitches are most common. Cordage Hemp rope was used in the age of sailing ships, though the rope had to be protected by tarring, since hemp rope has a propensity for breaking from rot, as the capillary e ect of the rope-woven bers tended to hold liquid at the interior, while seeming dry from the outside.* [57] Tarring was a labor-intensive process, and earned sailors the nickname "Jack Tar". Hemp rope was phased out when Manila, which does not require tarring, became widely available. Manila is sometimes referred to as Manila hemp, but is not related to hemp; it is abacá, a species of banana. Animal bedding Hemp straw animal bedding. animal bedding (horses, for instance), or for horticultural mulch.* [58] Industrial hemp is much more pro table if both bers and shives (or even seeds) can be used. Water and soil puri cation Hemp shives are the core of the stem, hemp hurds are Hemp can be used as a “mop crop”to clear impurities broken parts of the core. In the EU, they are used for out of wastewater, such as sewage e uent, excessive phos- 98 CHAPTER 1. CANNABIS phorus from chicken litter, or other unwanted substances or chemicals. Additionally Hemp is being used to clean contaminants at the Chernobyl nuclear disaster site. By way of a process which is known as phytoremediation - the process of clearing radioisotopes as well as a variety of other toxins from the soil, water, and air.* [59] Weed control Main article: Weed control α Organic methods Hemp, because of its height, dense foliage and its high Biodiesel sample. garbage, wastewater, dead plant and animal material, animal feces and kitchen waste.* [65] The dense growth of hemp helps kill weeds, even thistle. planting density as a crop, is a very e ective and long used method of killing tough weeds in farming by minimizing the pool of weed seeds of the soil.* [60] Using hemp this way can help farmers avoid the use of herbicides, to help gain organic certi cation and to gain the bene ts of crop rotation. Due to its rapid, dense growth characteristics, in some jurisdictions hemp is considered a prohibited noxious weed, much like Scotch Broom. 1.14.3 Cultivation Biofuels Biodiesel can be made from the oils in hemp seeds and stalks and alcohol fuel (ethanol or, less commonly, methanol) from the fermentation of the whole plant. Biodiesel produced from hemp is sometimes known as “hempoline”.* [61] Hemp being harvested Filtered hemp oil can be used directly to power diesel engines. In 1892, Rudolf Diesel invented the diesel engine, Hemp is usually planted between March and May in the which he intended to power “by a variety of fuels, espe- northern hemisphere, between September and November cially vegetable and seed oils, which earlier were used for in the southern hemisphere.* [66] It matures in about three oil lamps, i.e. the Argand lamp.”* [62]* [63]* [64] to four months. Production of vehicle fuel from hemp is very small. Com- Millennia of selective breeding have resulted in varieties mercial biodiesel and biogas is typically produced from ce- that look quite di erent. Also, breeding since circa 1930 reals, coconuts, palmseeds and cheaper raw materials like has focused quite speci cally on producing strains which 1.14. HEMP 99 would perform very poorly as sources of drug material. Hemp grown for ber is planted closely, resulting in tall, slender plants with long bers. “Until the early 1900s industrial hemp was a valuable crop used all over the world for its strong bers and oil seeds. Today, however, the common perception of the industrial hemp plant is generally negative and associated with the drug marijuana. This perception is the legacy of a century of powerful in uences construing hemp as a dangerous drug, even though it is not a drug and it has the potential to be a pro table alternative crop. In the United States, the public's perception of hemp as marijuana has blocked hemp from becoming a useful crop and product,”* [67] in spite of its vital importance prior to World War II.* [68] Ideally, according to Britain's Department for Environment, Food and Rural A airs, the herb should be desiccated and harvested towards the end of owering. This early cropping reduces the seed yield but improves the ber yield and quality.* [69] In these strains of industrial hemp the tetrahydrocannabinol (THC) content would have been very low.* [67] The seeds are sown from mid-April to mid-May with grain drills to 4–6 cm sowing depth. Hemp needs less fertilizer than corn does. A total of 60–150 kg of nitrogen, 40–140 kg phosphorus (P2 O5 ) and 75–200 kg of potassium [5] per acre for hemp ber made before sowing and again later, maybe three to four weeks. When practiced, especially in Cannabis sativa stem France double use of ber and seed fertilization with nitrogen doses up to 100 kg / ha rather low. Organic fertilizers such as manure can utilize industrial hemp well. Neither weeds nor crop protection measures are necessary.* [67] Cultivars A total of 26 varieties of hemp with low levels of tetrahydrocannabinol (THC) are certi ed by the European Union (EU).* [70] They have, unlike other types, a very high ber content of 30-40%. In contrast to cannabis for medical use, varieties grown for ber and seed have less than 0.2% THC and they are unsuitable for producing hashish and mari- Hemp strains USO-xx and Zolotoniski-xx juana.* [71] The most important cannabinoid in industrial hemp is cannabidiol (CBD) with a proportion of 1 to 5%. ical or psychological e ects. Typically, hemp contains Cannabis sativa L. subsp. sativa var. sativa is the vari- below 0.3% THC, while cultivars of Cannabis grown for ety grown for industrial use, while C. sativa subsp. in- recreational use can contain anywhere from 2% to over dica generally has poor ber quality and is primarily used 20%.* [73] for recreational and medicinal purposes. The major differences between the two types of plants are the appearance, and the amount of Δ9 -tetrahydrocannabinol (THC) Harvesting secreted in a resinous mixture by epidermal hairs called glandular trichomes, although they can also be distinguished Smallholder plots are usually harvested by hand. The plants genetically.* [72] Oilseed and ber varieties of Cannabis ap- are cut at 2 to 3 cm above the soil and left on the ground to proved for industrial hemp production produce only minute dry. Mechanical harvesting is now common, using specially amounts of this psychoactive drug, not enough for any phys- adapted cutter-binders or simpler cutters. 100 CHAPTER 1. CANNABIS • • • Location and crop rotation Hemp maze in France The variety of appearances for cannabis. Only C. sativa (left) is suited for industrial hemp, but it also has medicinal varieties. For pro table hemp farming, particularly deep, humusrich, nutrient-rich soil with controlled water ow is preferable. Water logged acidic, compressed or extremely light (sandy) soils primarily a ect the early development of plants. Steep and high altitudes of more than 400 m above sea level are best avoided. Hemp is relatively insensitive to cold temperatures and can withstand frost down to −5 degrees C. Seeds can germinate down to 1-3 degrees. Hemp needs a lot of heat, so earlier varieties come to maturation. The water requirement is 300-500 l / kg dry matter. Up to 3 feet growing roots into the soil can also use water supplies from deeper soil layers. Worth noting is that the water requirement of hemp is at least 14 times lower than that of cotton which takes between 7 000-29 000 l/kg, according to WWF. Hemp bene ts crops grown after it. For this reason, it is generally grown before winter cereals. Advantageous changes are high weed suppression, soil loosening by the Industrial hempseed harvesting machine in France. large hemp root system and the positive e ect on soil tilth. Since hemp is very self-compatible, it can also be grown The cut hemp is laid in swathes to dry for up to four days. several years in a row in the same elds (monoculture). This was traditionally followed by retting, either water retting (the bundled hemp oats in water) or dew retting (the hemp remains on the ground and is a ected by the mois- Diseases ture in dew, and by molds and bacterial action). Modern processes use steam and machinery to separate the ber, a Main article: List of hemp diseases process known as thermomechanical pulping. • Hemp plants can be vulnerable to various pathogens, including bacteria, fungi, nematodes, viruses and other mis- 1.14. HEMP 101 cellaneous pathogens. Such diseases often lead to reduced ber quality, stunted growth, and death of the plant. These diseases rarely a ect the yield of a hemp eld, so hemp production is not traditionally dependent on the use of pesticides. Environmental impact Hemp is considered by a 1998 study in Environmental Economics to be environmentally friendly due to a decrease of land use and other environmental impacts, indicating a possible decrease of ecological footprint in a US context compared to typical benchmarks.* [74] A 2010 study, however, that compared the production of paper speci cally from hemp and eucalyptus concluded that“industrial hemp presents higher environmental impacts than eucalyptus paper"; however, the article also highlights that “there is scope for improving industrial hemp paper production” .* [75] Hemp is also claimed to require few pesticides and no herbicides, and it has been called a carbon negative raw material.* [76]* [77] Results indicate that high yield of hemp may require high total nutrient levels ( eld plus fertilizer nutrients) similar to a high yielding wheat crop.* [78] 1.14.4 Producers Dried hemp stalks displayed at the International Hemp Fair in Vienna. The world-leading producer of hemp is France, which produces more than 70% of the world output. China ranks second with approximately a quarter of the world production. There is smaller production in Europe, Chile and North Korea. Over thirty countries produce industrial hemp, including Australia, Austria, Canada, Chile, China, Denmark, Egypt, Finland, Germany, Great Britain, Hungary, India, Italy, Japan, Korea, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, Slovenia, Spain, Sweden, Switzerland, Thailand, Turkey and Ukraine.* [79]* [80] ber and 2-3 tonnes of core material can be decorticated from 3-4 tonnes of good quality, dry retted straw. For an annual yield of this level is it in Ontario recommended to add nitrogen (N):70–110 kg/ha, phosphate (P2 O5 ): up to 80 kg/ha and potash (K2 O): 40–90 kg/ha.* [82] The average yield of dry hemp stalks in Europe was 6 ton/ha (2.4 ton/ac) in 2001 and 2002.* [12] FAO argue that an optimum yield of hemp ber is more than 2 tonnes per ha, while average yields are around 650 The United Kingdom and Germany resumed commercial kg/ha.* [83] production in the 1990s. British production is mostly used as bedding for horses; other uses are under development. Companies in Canada, the UK, the United States and Ger- Australia many, among many others, process hemp seed into a growing range of food products and cosmetics; many traditional In the Australian states of Tasmania, Victoria, Queensland growing countries still continue to produce textile-grade - and, most recently, New South Wales, the state governbre. ments have issued licences to grow hemp for industrial use. Air dry stem yields in Ontario have from 1998 and onward The rst to initiate modern research into the potential of ranged from 2.6-14.0 tonnes of dry, retted stalks per hectare cannabis was the state of Tasmania pioneered the licensing (1-5.5 t/ac) at 12% moisture. Yields in Kent County, have of hemp during the early 1990s. The state of Victoria was adopter in 1998, and has reissued the regulation in averaged 8.75 t/ha (3.5 t/ac). Northern Ontario crops aver- an early * [84] 2008. aged 6.1 t/ha (2.5 t/ac) in 1998. Statistic for the European Union for 2008 to 2010 say that the average yield of hemp Queensland has allowed industrial production under licence straw has varied between 6.3 and 7.3 ton per ha.* [81] Only since 2002,* [85] where the issuance is controlled under the a part of that is bast ber. Approximately one tonne of bast Drugs Misuse Act 1986.* [86] Most recently, New South 102 CHAPTER 1. CANNABIS Wales now issues licences* [87] under a law, the Hemp Industry Regulations Act 2008 (No 58), that came into e ect as of 6 November 2008.* [88] Canada Commercial production (including cultivation) of industrial hemp has been permitted in Canada since 1998 under licenses and authorization issued by Health Canada (9,725 ha in 2004, 5450 ha in 2009).* [89] In the early 1990s, industrial hemp agriculture in North America began with the Hemp Awareness Committee at the University of Manitoba. The Committee worked with the provincial government to get research and development assistance, and was able to obtain test plot permits from the Canadian government. Their e orts led to the legalization of industrial hemp (hemp with only minute amounts of tetrahydrocannabinol) in Canada and the rst harvest in 1998.* [90]* [91] The cultivated area for hemp in the Prairie provinces of Canada is stable at about 90,000 acres (36,000 ha) over 2013-15.* [92] Harvesting hemp in the USSR, 1956 France Russia and Ukraine From the 1950s to the 1980s, the Soviet Union was the world's largest producer of hemp (3,000 km² in 1970). The main production areas were in Ukraine,* [94] the Kursk and Orel regions of Russia, and near the Polish border. Since its inception in 1931, the Hemp Breeding Department at the Institute of Bast Crops in Hlukhiv (Glukhov), Ukraine, has been one of the world's largest centers for developing new hemp varieties, focusing on improving ber quality, perhectare yields, and low THC content.* [95]* [96] After the collapse of the Soviet Union, the commercial cultivation of hemp declined sharply. However, it is estimated that at least 2.5 million acres of hemp grows wild in the Russian Far East and Black Sea regions.* [97] Industrial hemp production in France France is the world's biggest producer with 8,000 hectares cultivated. 70-80% of the hemp bre produced in Europe in 2003 was used for specialty pulp for cigarette papers and technical applications. About 15% is used in the automotive sector and 5-6% were used for insulation mats. Approximately 95% of hurds were used as animal bedding, while almost 5% were used in the building sector.* [12] In 2010/2011, a total of 11 000 ha was cultivated with hemp in the EU, a decline compared with previous year.* [81]* [93] United Kingdom In the United Kingdom, cultivation licences are issued by the Home O ce under the Misuse of Drugs Act 1971. When grown for non-drug purposes, hemp is referred to as industrial hemp, and a common product is bre for use in a wide variety of products, as well as the seed for nutritional aspects and for the oil. Feral hemp or ditch weed is usually a naturalized bre or oilseed strain of Cannabis that has escaped from cultivation and is self-seeding.* [98] 1.14. HEMP 103 United States Hemp was made illegal to grow without a permit in the U.S. under the Controlled Substances Act passed in 1970 because of its relation to cannabis,* [15] and any imported hemp products must meet a zero tolerance level.* [99] Some states have made the cultivation of industrial hemp legal, but farmers in many states have not yet begun to grow it because of resistance from the federal Drug Enforcement Administration.* [100] In 2013, after the legalization of cannabis in the state, several farmers in Colorado planted and harvested several acres of hemp, bringing in the rst hemp crop in the United States in over half a century.* [101] Colorado,* [102] Vermont, California, and North Dakota have passed laws enabling hemp licensure. All four states are waiting for permission to grow hemp from the DEA. Currently,* [103] North Dakota representatives are pursuing legal measures to force DEA approval.* [104] Oregon has licensed industrial hemp as of August 2009.* [105] Congress included a provision in the Agricultural Act of 2014 that allowed colleges and state agencies to grow and conduct research on hemp in states where it is legal.* [15] 1.14.5 History Radical 200 (⿇ or má), the Chinese character for hemp, depicts two plants under a shelter. The use of hemp in Taiwan dates back at least 10,000 years.* [106] Hemp is one of the earliest domesticated plants known.* [107] It has been cultivated by many civilizations for over 12,000 years.* [108] Hemp use archaeologically dates back to the Neolithic Age in China, with hemp ber imprints found on Yangshao culture pottery dating from the 5th millennium BC.* [106]* [109] The Chinese later used hemp to make clothes, shoes, ropes, and an early form of paper.* [106] The classical Greek historian Herodotus (ca. 480 BC) reported that the inhabitants of Scythia would often inhale the vapors of hemp-seed smoke, both as ritual and for their own pleasurable recreation.* [110] Textile expert Elizabeth Wayland Barber summarizes the historical evidence that Cannabis sativa, “grew and was known in the Neolithic period all across the northern latitudes, from Europe (Germany, Switzerland, Austria, Romania, Ukraine) to East Asia (Tibet and China),”but,“textile use of Cannabis sativa does not surface for certain in the West until relatively late, namely the Iron Age.”* [111] “I strongly suspect, however, that what catapulted hemp to sudden fame and fortune as a cultigen and caused it to spread rapidly westwards in the rst millennium B.C. was the spread of the habit of pot-smoking from somewhere in south-central Asia, where the drug-bearing variety of the plant originally occurred. The linguistic evidence strongly supports this theory, both as to time and direction of spread and as to cause.”* [112] Jews living in Palestine in the 2nd century were familiar with the cultivation of hemp, as witnessed by a reference to it in the Mishna (Kil'ayim 2:5) as a variety of plant, along with Arum, that sometimes takes as many as three years to grow from a seedling. In late medieval Germany and Italy, hemp was employed in cooked dishes, as lling in pies and tortes, or boiled in a soup.* [113] Hemp in later Europe was Yangshao culture mainly cultivated for its bers, and was used for ropes on (ca. 4800 BCE) amphora with impressed hemp cord many ships, including those of Christopher Columbus. The use of hemp as a cloth was centered largely in the coundesign 104 CHAPTER 1. CANNABIS tryside, with higher quality textiles being available in the towns. United States“Marihuana”production permit. In the United States, hemp cultivation is legally prohibited, but during World War II farmers were encouraged to grow hemp for cordage, to replace Manila hemp previously obtained from Japanese-controlled areas. The U.S. government produced a lm explaining the uses of hemp, called Hemp for Victory. ary, which reads“Began to seperate [sic] the Male from the Female hemp at Do.&̶rather too late”is evidence that he was trying to grow female plants for the THC found in the owers. However, the editorial remark accompanying the diary states that“This may arise from their [the male] being coarser, and the stalks larger”* [117] In subsequent days, he describes soaking the hemp* [118] (to make the bers Cannabis sativa from Vienna Dioscurides, 512 AD. usable) and harvesting the seeds,* [119] suggesting that he The Spaniards brought hemp to the Western Hemisphere was growing hemp for industrial purposes, not recreational. and cultivated it in Chile starting about 1545.* [114] How- George Washington also imported the Indian Hemp plant ever, in May 1607,“hempe”was among the crops Gabriel from Asia, which was used for ber and, by some growArcher observed being cultivated by the natives at the main ers, for intoxicating resin production. In a letter to William Powhatan village, where Richmond, Virginia is now sit- Pearce who managed the plants for him Washington says, uated;* [115] and in 1613, Samuell Argall reported wild “What was done with the Indian Hemp plant from last sumhemp“better than that in England”growing along the shores mer? It ought, all of it, to be sown again; that not only a of the upper Potomac. As early as 1619, the rst Virginia stock of seed su cient for my own purposes might have House of Burgesses passed an Act requiring all planters in been raised, but to have disseminated seed to others; as it Virginia to sow “both English and Indian”hemp on their is more valuable than common hemp.” plantations.* [116] The Puritans are rst known to have culAdditional presidents known to have farmed hemp include tivated hemp in New England in 1645.* [114] Thomas Je erson,* [120] James Madison, James Monroe, George Washington pushed for the growth of hemp and Andrew Jackson, Zachary Taylor, and Franklin Pierce. even grew hemp himself, as it was a cash crop commonly * [121] used to make rope and fabric. In May 1765 he noted in his diary about the sowing of seeds each day until mid-April. Historically, hemp production had made up a signi cant Then he recounts the harvest in October which he grew 27 portion of antebellum Kentucky's economy. Before the American Civil War, many slaves worked on plantations bushels that year. producing hemp.* [122] There is some speculation that George Washington smoked the ower of the cannabis plant in order to achieve a recre- In 1937, the Marihuana Tax Act of 1937 was passed in the ational high (“Like all farmers, Washington probably sam- United States. levying a tax on anyone who dealt commerpled the quality and potency of what he grew, and he may cially in cannabis, hemp, or marijuana. The passing of the have used this hemp to treat his chronic tooth aches”),* [68] Act to destroy the US hemp industry has been disputed to Mellon, Randolph Hearst and but there is no evidence in any of his writings that he grew involve businessmen* Andrew * * the Du Pont family. [123] [124] [125] hemp for anything other than industrial purposes. It is sometimes supposed that an excerpt from Washington's di- One claim is that Hearst believed that his extensive tim- 105 1.14. HEMP ber holdings were threatened by the invention of the decorticator which he feared would allow hemp to become a cheap substitute for the paper pulp used for newspaper.* [123]* [126] Historical research indicates this fear was unfounded because improvements of the decorticators in the 1930s – machines that separated the bers from the hemp stem – could not make hemp ber a cheaper substitute for bers from other sources. Further, decorticators did not perform satisfactorily in commercial production.* [41]* [123] Another claim is that Mellon, Secretary of the Treasury and the wealthiest man in America at that time, had invested heavily in DuPont's new synthetic ber, nylon, and believed that the replacement of the traditional resource, hemp, was integral to the new product's success.* [123]* [127]* [128]* [129]* [130]* [131]* [132]* [133] The company DuPont and many industrial historians dispute a link between nylon and hemp, nylon became immediately a scarce commodity. Nylon had characteristics that could be used for toothbrushes (sold from 1938) and very thin nylon ber could compete with silk and rayon in various textiles normally not produced from hemp ber, such as very thin stockings for women.* [41]* [134]* [135]* [136]* [137] West took o in the eighteenth century, but was grown in the sixteenth century in eastern England.* [139] Because of colonial and naval expansion of the era, economies needed large quantities of hemp for rope and oakum. In the early 1940s, world production of hemp ber ranged from 250 000 to 350 000 metric tonnes, Russia was the biggest producer.* [41] In Western Europe, the cultivation of hemp was not legally banned by the 1930s, but the commercial cultivation stopped by then, due to decreased demand compared to increasingly popular arti cial bers.* [140] Speculation about the potential for commercial cultivation of hemp in large quantities has been criticized due to successful competition from other bers for many products. The world production of hemp ber fell from over 300,000 metric tons 1961 to about 75,000 metric tons in the early 1990s and has after that been stable at that level.* [141] Japanese Shinto shrine with rope made of hemp Hemp for Victory, a short documentary produced by the United States Department of Agriculture during World War 2 Hemp was used extensively by the United States during World War II to make uniforms, canvas, and rope.* [138] Much of the hemp used was cultivated in Kentucky and the Midwest. During World War II, the U.S. produced a short 1942 lm, Hemp for Victory, promoting hemp as a necessary crop to win the war. Historical cultivation Japan In Japan, hemp was historically used as paper and a ber crop. There is archaeological evidence cannabis was used for clothing and the seeds were eaten in Japan back to the Jōmon period (10,000 to 300 BCE). Many Kimono designs portray hemp, or asa (Japanese: ⿇), as a beautiful plant. In 1948, marijuana was restricted as a narcotic drug. The ban on marijuana imposed by the United States authorities was alien to Japanese culture, as the drug had never been widely used in Japan before. Though these laws against marijuana are some of the world's strictest, allowing ve years imprisonment for possession of the drug, they exempt hemp growers, whose crop is used to make robes for Buddhist monks and loincloths for Sumo wrestlers. Because marijuana use in Japan has doubled in the past decade, these exemptions have recently been called into question.* [142] Hemp has been grown for millennia in Asia and the Middle Portugal The cultivation of hemp in Portuguese lands East for its bre. Commercial production of hemp in the began around the fourteenth century onwards, it was raw 106 material for the preparation of rope and plugs for the Portuguese ships. Colonies for factories for the production of ax hemp, such as the Royal Flax Hemp Factory in Brazil. After the Restoration of Independence in 1640, in order to recover the ailing Portuguese naval eet, were encouraged its cultivation as the Royal Decree of D. John IV in 1656. At that time its cultivation was carried out in Trás-os-Montes, Zone Tower Moncorvo, more precisely in Vilariça Valley, fertile land for any crop irrigation, and a very large area, at and very fertile culture still wide until the last century grew up tobacco, a plant that needs a large space to expand and grow, the area lies in the valley of Serra de Bornes. CHAPTER 1. CANNABIS [6] Swanson 2015, p. 602. [7] Talbot, Geo (2015). Specialty Oils and Fats in Food and Nutrition: Properties, Processing and Applications. Elsevier Science. p. 39. ISBN 978-1-78242-397-3. [8] Crime, United Nations O ce on Drugs and (2009). Recommended Methods for the Identi cation and Analysis of Cannabis and Cannabis Products: Manual for Use by National Drug Testing Laboratories. United Nations Publications. p. 12. ISBN 978-92-1-148242-3. [9] McConvell, Patrick; Smith, Michael (2003), “Millers and Mullers: The archaeo-linguisitic stratigraphy of technological change in holocene Australia”, in Henning Andersen, Language Contacts in Prehistory: Studies in Stratigraphy, John Benjamins Publishing, p. 181, ISBN 9781588113795 In 1971, the cultivation of hemp became illegal, and the production was substantially reduced. Because of EU regulations 1308/70, 619/71 and 1164/89, this law was revoked [10] Adams, DQ (1997), JP Mallory and DQ Adams, eds., (for some certi ed seed varieties).* [143] 1.14.6 See also • Cannabis ower essential oil • Fiber rope • Hemp Industries Association • Industrial Hemp Farming Act of 2009 • International Year of Natural Fibres • Natural bre • Plant textiles • The Emperor Wears No Clothes (book) 1.14.7 References [1] http://tfd.com/hemp [2] Swanson, TE (2015), “Controlled Substances Chaos: The Department of Justiceʼs New Policy Position on Marijuana and What It Means for Industrial Hemp Farming in North Dakota” (PDF), North Dakota Law Review 90 (3): 613 [3] Robert Deitch (2003). Hemp: American History Revisited: The Plant with a Divided History. Algora Publishing. p. 219. ISBN 978-0-87586-226-2. [4] Tourangeau, Wesley (2015), “Re-de ning Environmental Harms: Green Criminology and the State of Canada's Hemp Industry”, Canadian Journal of Criminology & Criminal Justice 57 (4): 528–554, doi:10.3138/cjccj.2014.E11 [5] Keller, NM (2013), “The Legalization of Industrial Hemp and What it Could Mean for Indiana's Biofuel Industry” (PDF), Indiana International & Comparative Law Review 23 (3): 555, doi:10.18060/17887 Encyclopedia of Indo-European Culture (Illustrated ed.), London, UK: Taylor & Francis, p. 266, ISBN 9781884964985 [11] “Erowid Cannabis Vault : Culture #2”. erowid.org. Retrieved 2008-06-20. [12] “Michael Karus: European Hemp Industry 2002 Cultivation, Processing and Product Lines. Journal of Industrial Hemp Volume 9 Issue 2 2004, Taylor & Francis, London” . Informaworld.com. Retrieved 2011-04-20. [13] “America's First Hemp Drink - Chronic Ice - Making a Splash in the Natural Beverage Market”. San Francisco Chronicle (Los Angeles). Vocus. 8 June 2011. Archived from the original on 2011-12-27. Retrieved 19 June 2011. [14] “USDA ERS - Industrial Hemp in the United States: Status and Market Potential” (PDF). Ers.usda.gov. Retrieved 2013-11-09. [15] “Farm bill promotes hemp as legal crop”. Leg.state.or.us. Retrieved 2014-02-05. [16] “Industrial bre crops: business opportunities for farmers” , gov.uk (Department for Environment, Food & Rural Affairs), 13 Jun 2013, retrieved 18 May 2016 [17] “Nutrition Facts for Hemp Seeds (shelled) per 100 g serving”. Conde Nast, Custom Analysis. 2014. Retrieved 19 February 2015. [18] Callaway, J. C. (2004-01-01). “Hempseed as a nutritional resource: An overview” (PDF). Euphytica (Kluwer Academic Publishers) 140 (1–2): 65–72. doi:10.1007/s10681004-4811-6. Retrieved 2013-03-13. [19] House JD, Neufeld J, Leson G; Neufeld; Leson (November 2010). “Evaluating the quality of protein from hemp seed (Cannabis sativa L.) products through the use of the protein digestibility-corrected amino acid score method”. 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Etat,acteurs privés et innovation dans le domaine des matériaux de construction écologiques : Le développement du béton de chanvre depuis 1986 (PDF) (MASTER - Politiques publiques et gouvernements comparés thesis) (in French). 'Institut d'Etudes Politiques de Lyon. [26] “The Haverhill Hemp Houses”. bre.co.uk. Retrieved 201302-08. [27] “Modece Architects”. modece.com. Retrieved 2013-0208. [40] Stevulova, Nadezda (December 2014).“Properties Characterization of Chemically Modi ed Hemp Hurds”. Materials 7: 8131–8150. doi:10.3390/ma7128131. [41] Dewey LH (1943). “Fiber production in the western hemisphere”. United States Printing O ce, Washington. p. 67. Retrieved 25 February 2015. [42] Cellulose. (2008). In Encyclopædia Britannica. Retrieved January 11, 2008, from Encyclopædia Britannica Online. [43] Chemical Composition of Wood. ipst.gatech.edu. [44] Piotrowski, Stephan and Carus, Michael (May 2011) Multicriteria evaluation of lignocellulosic niche crops for use in biore nery processes. nova-Institut GmbH, Hürth, Germany. [45] Multi-criteria evaluation of lignocellulosic niche crops for use in biore nery processes. nova-Institut GmbH, Hürth, Germany. [46] Li Jingjing (2011) Isolation of Lignin from Wood. SAIMAA UNIVERSITY OF APPLIED SCIENCES. [28]“The NNFCC Renewable House”. Renewable-house.co.uk. Retrieved 2011-04-20. [47] “Papper”. Hampa.net. Retrieved 2013-11-09. [29] “Hemp homes are cutting edge of green building”. USA Today. 2010-09-12. [48] “David P. West: Fiber Wars: The Extinction of Kentucky Hemp”. Gametec.com. Retrieved 2011-04-20. [30] “HEMPSEC project website”. European Union research. Retrieved 8 July 2014. [49] “Additional Statement of H.J. Anslinger, Commissioner of Narcotics”. Retrieved 2006-03-25. [31] Allin, Steve. Building with Hemp, Seed Press, 2012, ISBN 978-0-9551109-1-7. (p. 95, 2nd Edition). [50] “Michael Karus:European hemp industry 2001 till 2004: Cultivation, raw materials, products and trends, 2005” (PDF). Retrieved 2011-04-20. [32] “Thermoformable Composite Panels”(PDF). Composites World. 2006. [33] “Plastics”. hemp.com. 2013-05-14. Retrieved 2013-1109. [34] “Lotus announces hemp-based Eco Elise: a new type of 'green' car”. transport20.com. Retrieved 2013-11-09. [35] “Green Cars, Fuel E ciency and the Environment | Mercedes-Benz”. Mbusa.com. Retrieved 2013-11-09. [36] “Cai Lun Improved the Papermaking Technology”. chinaculture.org. [37] A brief history of the St. Petersburg Paper Mill of Goznak (www.goznak.spb.ru) Archived May 28, 2006, at the Wayback Machine. [38] Dewey and Merrill, U.S.D.A. Bulletin No. 404, Hemp Hurds as Paper-Making Material, Washington, D.C., October 14, 1916. Page 25 [51] “Steam energy:Hemp Pulp & Paper Production, January 1st 1994”. Hempline.com. Retrieved 2011-04-20. [52] Van Roekel, Gerjan J. (1994). “Hemp Pulp and Paper Production”. Journal of the International Hemp Association (Wageningen, The Netherlands). [53] “Anatomy of a Modern Paper Mill, Faculty of Natural Resources Management, Lakehead University”. Borealforest.org. Retrieved 2013-11-09. [54] “Boise: Nonwood Alternatives to Wood Fiber in Paper”. bc.com. 2007-07-08. Archived from the original on July 8, 2007. Retrieved 2013-11-09. [55] Ivan Bócsa, Michael Karus, Daike Lohmeyer: The cultivation of hemp. Botany, varieties, cultivation and harvesting, markets and product lines. 2 support, agricultural Verlag GmbH, Münster 2000th 108 [56] Michael Carus et al. Study of market and competition for natural bers and natural ber materials (Germany and EU) trade talks Gülzower 26, ed. of the Agency of Renewable Resources, Gülzow 2008 Download nova-Institut (ed.): The small hemp-Lexikon Verlag The Workshop, Gﬁttingen, 2. Edition, 2003, page 79 ISBN 3-89533-271-2 [57] Schubert, Pit. “Our ropes are much stronger than we believe”. Union Internationale Des Associations D'Alpinisme. Archived from the original on September 27, 2009. [58] NNFCC. In the US, pet manufacturers use hemp in dog and cat bedding.“Crop Factsheet: Hemp”, National Non-Food Crops Centre, 2008-06-09. Retrieved on 2009-05-06 [59] “Phytoremediation: Using Plants to Clean Soil”. Mhhe.com. Retrieved 2011-04-20. [60] “Hemp As Weed Control”. gametec.com. Retrieved 200807-09. [61] “COOLFUEL Episode: Sugarcane and Hempoline”. Retrieved 2009-10-16. [62] “Clean Energy Solutions”. Hemp 4 Fuel. Retrieved 201104-20. [63] “Pollution: Petrol vs. Hemp”. Hempcar.org. Retrieved 2011-04-20. CHAPTER 1. CANNABIS [70] “Bundesanstalt für Landwirtschaft und Ernährung: ''FÜR DIREKTZAHLUNGEN IN BETRACHT KOMMENDE HANFSORTEN''" (PDF) (in German). Retrieved 2015-0306. [71] Frank Waskow (1995), Katalyse-Institut für Angewandte Umweltforschung, ed. (in German), Hanf & Co.: die Renaissance der heimischen Faserp anzen, Gﬁttingen: Verlag Die Werkstatt, pp. 45, ISBN 3-89533-138-4 [72] Datwyler, SL; Weiblen, GD (2006). “Genetic Variation in Hemp and marijuana (Cannabis sativa L.) sativa plants are taller and less dense. Indica plants are shorter but a lot more dense than sativas. According to Ampli ed Fragment Length Polymorphisms”. Journal of Forensic Sciences 51 (2): 371–375. doi:10.1111/j.1556-4029.2006.00061.x. [73] Hemp and Marijuana: Myths & Realities written by David P. West, Ph.D. for the North American Industrial Hemp Council [74] “Industrial hemp's double dividend: a study for the USA” . Ecological Economics 25: 291–301. 1998-06-30. doi:10.1016/S0921-8009(97)00040-2. Retrieved 2013-1109. [64] “Biofuels Facts”. Hempcar.org. Retrieved 2011-04-20. [75] “Industrial hemp or eucalyptus paper?". The International Journal of Life Cycle Assessment 15: 368–375. doi:10.1007/s11367-010-0152-y. Retrieved 2013-11-09. [65] “Increased biogas production at the Henriksdals Waste Water plant, Cajsa Hellstedt et. all, June 2010” (PDF). [76] “FAQs & Facts: Facts”. Resources: Education. The HIA. Retrieved 2008-07-05. [66] Hemp Cultivation (www.green.net.au) Archived April 10, 2012, at the Wayback Machine. [67] This paper begins with a history of hemp use and then describes how hemp was constructed as a dangerous crop in the U.S. The paper then discusses the potential of hemp as an alternative crop. Luginbuhl, April M. (2001). “Industrial hemp (Cannabis sativa L): The geography of a controversial plant”. The California Geographer (PDF) 41. California Geographical Society. pp. 1–14. Retrieved 2013-03-28. Hemp contains less than 1% THC, or tetrahydrocannabinols, the psychoactive property in marijuana. In other words, smoking hemp cannot create a 'high.' ... The dense growth of hemp eliminates other weeds.... The best growing technique for hemp, planting 300 to 500 plants per square meter, also helps authorities easily tell the hemp from marijuana, which is a plant that is less densely cultivated. (Roulac 1997; 149). [68] Deitch, Robert (2003). Hemp: American History Revisited: The Plant with a Divided History. Algora Publishing. pp. 4–26. ISBN 9780875862262. Retrieved 2013-11-16. Cannabis is ... a plant that played an important role in colonial America's prosperous economy and remained a valuable commercial commodity up until the Second World War. [69] http://archive.defra.gov.uk/foodfarm/growing/crops/ industrial/pdf/flaxhemp-report.pdf [77] “HIA: Resources: Education: FAQs & Facts: FAQs: Answers”. thehia.org. Retrieved 2008-07-05. [78] “D. Risula, and others, Saskatchewan Ministry of Agriculture, October 2009”. Retrieved 2011-04-20. [79] “Hemp vs. Marijuana”. azhemp.org. Retrieved 2008-0618. [80] “Hemp Facts”. thehia.org. Retrieved 2013-11-09. [81] “Agriculture in the European Union, Statistical and Economic Information 2011, European Union DirectorateGeneral for Agriculture and Rural Development, page 283” (PDF). Retrieved 2013-11-09. [82] “Growing Industrial Hemp in Ontario, Ministry of Agriculture, Food and Rural A airs, Canada, 2008”. ON, CA: Omafra. Retrieved 2011-04-20. [83] Graeme Thomas. “Natural Fibers: Hemp Food and Agriculture Organization of the United Nations, 2009”. Natural bres2009.org. Retrieved 2011-04-20. [84] “Drugs, Poisons and Controlled Substances (Industrial Hemp) Regulations 2008”(PDF). dms.dpc.vic.gov.au. Retrieved 2008-11-24. 109 1.14. HEMP [85] “Guidelines for engaging in the commercial production of [103] “North Dakota”. hemp.org. industrial hemp in Queensland”. dpi.qld.gov.au. Archived from the original on December 20, 2008. Retrieved 2008- [104] “North Dakota Case”. Votehemp.com. Retrieved 201104-20. 11-24. [86] “Drugs Misuse Act 1986” (PDF). legislation.qld.gov.au. [105] “75th Oregon Legislative Assembly ̶2009 Regular Session Senate Bill 676”. Leg.state.or.us. Retrieved 2011-04-20. Retrieved 2008-11-24. [87] “Opportunities to engage in commercial low THC hemp [106] Sta ord, Peter (1992). Psychedelics Encyclopedia. Berkeley, CA, USA: Ronin Publishing. ISBN 0-914171-51-8. bre and seed production in NSW”. dpi.nsw.gov.au. Retrieved 2008-11-24. [107] “Information paper on industrial hemp (industrial cannabis)". 2.dpi.qld.gov.au. Archived from the original on [88] “Hemp Industry Regulation 2008”. legislation.nsw.gov.a. 2008-07-23. Retrieved 2008-07-05. Retrieved 2008-11-24. [89] “Government of Alberta: Industrial Hemp Production in Canada, February 2, 2010”. .agric.gov.ab.ca. Retrieved 2011-04-20. [90]“Where the heck is hemp?, The Alberta Express, April 18th, 2007”. www.hempline.com. [108] Amar K. Mohanty; Manjusri Misra; Lawrence T. Drzal (2005). Natural Fibers, Biopolymers, and Biocomposites. CRC Press. p. 74. ISBN 978-0-203-50820-6. [109] Barber, E. J. W. (1992). Prehistoric Textiles: The Development of Cloth in the Neolithic and Bronze Ages with Special Reference to the Aegean. Princeton University Press. p. 17. [91] “Manitoba Harvest 2007 Peoples Choice, Eco Libris, Oct [110] 8th, 2007”. ecolibris.blogspot.ca/. [111] [92] Arnason R (29 January 2015). “Interest high in hemp, but acres stable”. The Western Producer. Retrieved 30 March 2015. [112] [93] Jordbruksverket: 2.1–2.3, 2.5 Marknadssituationen fﬁr spannmål, oljeväxter, proteingrﬁdor, ris,2011-03-10, [113] (Swedish Board of Agriculture, Report from an expert group in the European Union about the market situation for a number of agricultural products. Published only in Swedish) Archived January 18, 2012, at the Wayback [114] Machine. [94] “Hemp research and growing in Ukraine”. inukraine.com. 2002-01-06. Retrieved 2011-04-20. [95] Hemp will help Ukraine to grow wealthy (Russian) Ag- Herodotus. Histories IV. 73–75. Barber, E. J. W. (1992). Prehistoric Textiles: The Development of Cloth in the Neolithic and Bronze Ages with Special Reference to the Aegean. Princeton University Press. p. 18. Barber (1992). p. 19. Regional Cuisines of Medieval Europe: A Book of Essays (2002), edited by Melitta Weiss Adamson, ISBN 0-41592994-6, pg. 98, 166 Daryl T. Ehrensing (May 1998). “Feasibility of Industrial Hemp Production in the United States Paci c Northwest, SB681”. Oregon State University. Retrieved May 15, 2016. [115] Gabriel Archer, A Relatyon of the Discoverie of Our River..., printed in Archaeologia Americana 1860, p. 44. William Strachey (1612) records a native (Powhatan) name for hemp (weihkippeis). [96] Interview with Dr. V. G. Virovets, the head of the Hemp Breeding Department at the Institute of Bast Crops (1998) [116] Proceedings of the Virginia Assembly, 1619, cf. the 1633 Act: Hening's Statutes at Large, p. 218 (English) [97] "(Website/ Products)". Retrieved Sep 28, 2011. [117] “Diary of George Washington, entry 7 August 1765”. founders.archives.gov. Retrieved 2014-06-03. [98] Jon Merrills; Jonathan Fisher (2013). Pharmacy Law and Practice. Academic Press. p. 227. ISBN 978-0-12-394618- [118] “Diary of George Washington, entry 22 August 1765”. founders.archives.gov. Retrieved 2014-06-03. 8. [99] Frank J. House (2006). Agricultural Programs, Terms and [119] “Diary of George Washington, entry September 1765”. founders.archives.gov. Retrieved 2014-06-03. Laws. Nova Publishers. p. 146. ISBN 978-1-59454-892-5. [100] http://www.ncsl.org/research/ agriculture-and-rural-development/ state-industrial-hemp-statutes.aspx [120] Bear, James A. Jr., and Lucia C. Stanton, eds. Je erson's Memorandum Books: Accounts, with Legal Records and Miscellany, 1767-1826. Princeton, NJ: Princeton University Press, 1997, 1:383. [101] “Hemp, hemp, hooray: Bill aims to aid farmers with new but controversial crop”. Minnesotaindependent.com. Retrieved [121] Robinson, Rowan. The Great Book of Hemp: The Complete Guide to the Environmental, Commercial, and Medicinal 2011-04-20. Uses of the World's Most Extraordinary Plant. Rochester, [102] Colorado Amendment 64 VT. Park Street Press, 2010. Chapter 5:129-135. Print 110 CHAPTER 1. CANNABIS [122] James F. Hopkins, “Slavery in the Hemp Industry”, Drug [139] New Fossil Evidence for the Past Cultivation and Processing Library of Hemp (Cannabis sativa L.) in Eastern England Author(s): R. H. W. Bradshaw, P. Coxon, J. R. A. Greig, A. R. Hall [123] French, Laurence; Manzanárez, Magdaleno (2004). NAFTA Source: New Phytologist, Vol. 89, No. 3 (Nov., 1981), pp. & neocolonialism: comparative criminal, human & social 503-510 Published by: Blackwell Publishing on behalf of justice. University Press of America. p. 129. ISBN 978the New Phytologist Trust Accessed: 06/07/2009 0-7618-2890-7. [140] “Dr. Ivan BÛcsa, GATE Agricultural Research Institute, Kompolt - Hungary, Book Review Re-discovery of [124] Earlywine, 2005: p. 24 the Crop Plant Cannabis Marihuana Hemp (Die Wiederentdeckung der Nutzplanze Cannabis Marihuana Hanf)". [125] Peet, 2004: p. 55 Hempfood.com. Retrieved 2011-04-20. [126] Sterling Evans (2007). Bound in twine: the history and ecology of the henequen-wheat complex for Mexico and the [141] Lynn Robins; et al. (July 2013).“Economic Considerations for Growing Industrial Hemp:Implications for Kentucky's American and Canadian Plains, 1880–1950. Texas A&M Farmers and Agricultural Economy” (PDF). Department University Press. p. 27. ISBN 978-1-58544-596-7. of Agricultural Economics, University of Kentucky. [127] Evans, Sterling, ed. (2006). The borderlands of the Amer[142] Yuka Hayashi (2009-03-04).“In Drug-Leery Japan, Arrests ican and Canadian Wests: essays on regional history of the for Marijuana Are on the Rise”. Wall Street Journal. forty-ninth parallel. University of Nebraska Press. p. 199. ISBN 978-0-8032-1826-0. [143] “Commission Regulation (EC) No 605/98 of 17 March 1998 amending Regulation (EEC) No 1164/89 laying down [128] Gerber, Rudolph Joseph (2004). Legalizing marijuana: drug detailed rules concerning the aid for bre ax and hemp”. policy reform and prohibition politics. Greenwood PublishOctober 2015. ing Group. p. 7. ISBN 978-0-275-97448-0. [129] Earleywine, Mitchell (2005). Understanding marijuana: a new look at the scienti c evidence. Oxford University Press. p. 231. ISBN 978-0-19-518295-8. [130] Robinson, Matthew B & Scherlen, Renee G (2007). Lies, damned lies, and drug war statistics: a critical analysis of claims made by the o ce of National Drug Control Policy. SUNY Press. p. 12. ISBN 978-0-7914-6975-0. [131] Rowe, Thomas C (2006). Federal narcotics laws and the war on drugs: money down a rat hole. Psychology Press. p. 26. ISBN 978-0-7890-2808-2. [132] Sullivan, Larry E et al., eds. (2005). Encyclopedia of Law Enforcement: Federal. SAGE. p. 747. ISBN 978-0-76192649-8. [133] Lusane, Clarence (1991). Pipe dream blues: racism and the war on drugs. South End Press. pp. 37–8. ISBN 978-089608-410-0. [134] “the history of nylon”. caimateriali.org. [135] “Nylon: A Revolution in Textiles”. chemheritage.org. 1.14.8 External links • Hemp as an Agricultural Commodity Congressional Research Service (PDF) • Industrial Hemp in the United States: Status and Market Potential (www.ers.usda.gov) • "Hemp". New International Encyclopedia. 1905. 1.15 Cannabis This article is about the plant genus. For use as a psychoactive drug, see Cannabis (drug). For other uses, see Cannabis (disambiguation). Cannabis (/ˈkænəbɪs/) is a genus of owering plant that includes three species (and seven taxa)* [2] or subspecies,* [3] sativa, indica, and ruderalis. The plant is indigenous to central Asia and the Indian subcontinent.* [4] Cannabis has long been used for hemp bre, for hemp oils, for medicinal purposes, and as a recreational drug. Industrial hemp products are made from cannabis plants selected to produce an abundance of ber. To satisfy the [137] “Who invented the toothbrush and when was it? (EvUN Narcotics Convention, some cannabis strains have been eryday Mysteries: Fun Science Facts from the Library of bred to produce minimal levels of tetrahydrocannabinol Congress)". loc.gov. (THC), the principal psychoactive constituent. Many plants [138] Armagnac, Alden P. (1943).“Plant Wizards Fight Wartime have been selectively bred to produce a maximum of THC Drug Peril”(September): 62–63. (cannabinoids), which is obtained by curing the owers. [136] “American Chemical Society: THE FIRST NYLON PLANT. 1995” (PDF). acs.org. 111 1.15. CANNABIS Various compounds, including hashish and hash oil, are ex- similar leaves without di culty and without special equiptracted from the plant.* [5] ment. Tiny samples of Cannabis plants also can be identied with precision by microscopic examination of leaf cells Globally, in 2013, 60,400 kilograms of cannabis were proand similar features, but that requires special expertise and * duced legally. [6] In 2013 between 128 and 232 million * equipment. [9] people are thought to have used cannabis as a recreational drug (2.7% to 4.9% of the global population between the The plant is believed to have originated in the mountainages of 15 and 65).* [7] ous regions northwest of the Himalayas. It is also known as hemp, although this term is often used to refer only to varieties of Cannabis cultivated for non-drug use. 1.15.1 Description Reproduction Cannabis growing as weeds at the foot of Dhaulagiri. Cannabis is an annual, dioecious, owering herb. The leaves are palmately compound or digitate, with serrate lea ets.* [8] The rst pair of leaves usually have a single lea et, the number gradually increasing up to a maximum of about thirteen lea ets per leaf (usually seven or nine), depending on variety and growing conditions. At the top of a owering plant, this number again diminishes to a single lea et per leaf. The lower leaf pairs usually occur in an opposite leaf arrangement and the upper leaf pairs in an alternate arrangement on the main stem of a mature plant. The leaves have a peculiar and diagnostic venation pattern that enables persons poorly familiar with the plant to distinguish a cannabis leaf from unrelated species that have confusingly similar leaves (see illustration). As is common in serrated leaves, each serration has a central vein extending to its tip. However, the serration vein originates from lower down the central vein of the lea et, typically opposite to the position of, not the rst notch down, but the next notch. This means that on its way from the midrib of the lea et to the point of the serration, the vein serving the tip of the serration passes close by the intervening notch. Sometimes the vein will actually pass tangent to the notch, but often it will pass by at a small distance, and when that happens a spur vein (occasionally a pair of such spur veins) branches o and joins the leaf margin at the deepest point of the notch. This venation pattern varies slightly among varieties, but in general it enables one to tell Cannabis leaves from super cially Cannabis normally has imperfect owers, with staminate “male”and pistillate“female” owers occurring on separate plants.* [10] It is not unusual, however, for individual plants to bear both male and female owers.* [11] Although monoecious plants are often referred to as “hermaphrodites” , true hermaphrodites (which are less common) bear staminate and pistillate structures on individual owers, whereas monoecious plants bear male and female owers at di erent locations on the same plant. Male owers are normally borne on loose panicles, and female owers are borne on racemes.* [12] “At a very early period the Chinese recognized the Cannabis plant as dioecious”,* [13] and the (c. 3rd century BCE) Erya dictionary de ned xi 枲 “male Cannabis" and fu 莩 (or ju 苴) “female Cannabis".* [14] All known strains of Cannabis are wind-pollinated* [15] and the fruit is an achene.* [16] Most strains of Cannabis are short day plants,* [15] with the possible exception of C. sativa subsp. sativa var. spontanea (= C. ruderalis), which is commonly described as “auto- owering”and may be day-neutral. Biochemistry and drugs Cannabis plants produce a group of chemicals called cannabinoids, which produce mental and physical e ects when consumed. Cannabinoids, terpenoids, and other compounds are secreted by glandular trichomes that occur most abundantly on the oral calyxes and bracts of female plants.* [17] As a drug it usually comes in the form of dried ower buds (marijuana), resin (hashish), or various extracts collectively known as hashish oil.* [5] In the early 20th century, it became illegal in most of the world to cultivate or possess Cannabis for sale or personal use. • Root system side view • Root system top view • Micrograph C. sativa (left), C. indica (right) 112 Chromosomes and genome Cannabis, like many organisms, is diploid, having a chromosome complement of 2n=20, although polyploid individuals have been arti cially produced.* [18] The rst genome sequence of Cannabis, which is estimated to be 820 Mb in size, was published in 2011 by a team of Canadian scientists.* [19] Taxonomy CHAPTER 1. CANNABIS the “high”one experiences from consuming marijuana. There are 483 identi able chemical constituents known to exist in the cannabis plant,* [24] and at least 85 di erent cannabinoids have been isolated from the plant.* [25] The two cannabinoids usually produced in greatest abundance are cannabidiol (CBD) and/or Δ9 -tetrahydrocannabinol (THC), but only THC is psychoactive.* [26] Since the early 1970s, Cannabis plants have been categorized by their chemical phenotype or “chemotype”, based on the overall amount of THC produced, and on the ratio of THC to CBD.* [27] Although overall cannabinoid production is inuenced by environmental factors, the THC/CBD ratio is genetically determined and remains xed throughout the life of a plant.* [28] Non-drug plants produce relatively low levels of THC and high levels of CBD, while drug plants produce high levels of THC and low levels of CBD. When plants of these two chemotypes cross-pollinate, the plants in the rst lial (F1 ) generation have an intermediate chemotype and produce similar amounts of CBD and THC. Female plants of this chemotype may produce enough THC to be utilized for drug production.* [27]* [29] Underside of Cannabis sativa leaf, showing diagnostic venation The genus Cannabis was formerly placed in the Nettle (Urticaceae) or Mulberry (Moraceae) family, and later, along with the Humulus genus (hops), in a separate family, the Hemp family (Cannabaceae sensu stricto).* [20] Recent phylogenetic studies based on cpDNA restriction site analysis and gene sequencing strongly suggest that the Cannabaceae sensu stricto arose from within the former Celtidaceae family, and that the two families should Top of Cannabis plant in vegetative growth stage be merged to form a single monophyletic family, the Whether the drug and non-drug, cultivated and wild types Cannabaceae sensu lato.* [21]* [22] of Cannabis constitute a single, highly variable species, or Various types of Cannabis have been described, and vari- the genus is polytypic with more than one species, has been ously classi ed as species, subspecies, or varieties:* [23] a subject of debate for well over two centuries. This is a contentious issue because there is no universally accepted * • plants cultivated for ber and seed production, de- de nition of a species. [30] One widely applied criterion for species recognition is that species are “groups of actuscribed as low-intoxicant, non-drug, or ber types. ally or potentially interbreeding natural populations which • plants cultivated for drug production, described as are reproductively isolated from other such groups.”* [31] high-intoxicant or drug types. Populations that are physiologically capable of interbreeding, but morphologically or genetically divergent and iso• escaped, hybridised, or wild forms of either of the lated by geography or ecology, are sometimes considered above types. to be separate species.* [31] Physiological barriers to reproduction are not known to occur within Cannabis, and Cannabis plants produce a unique family of terpeno- plants from widely divergent sources are interfertile.* [18] phenolic compounds called cannabinoids, which produce However, physical barriers to gene exchange (such as the 1.15. CANNABIS 113 Himalayan mountain range) might have enabled Cannabis gene pools to diverge before the onset of human intervention, resulting in speciation.* [32] It remains controversial whether su cient morphological and genetic divergence occurs within the genus as a result of geographical or ecological isolation to justify recognition of more than one species.* [33]* [34]* [35] History of cannabis Cannabis sativa appears naturally in many tropical and humid parts of the world. Its use as a mind-altering drug has been documented by archaeological nds in prehistoric societies in Euro-Asia and Africa.* [36] The oldest written record of cannabis usage is the Greek historian Herodotus's reference to the central Eurasian Scythians taking cannabis steam baths.* [37] His (c. 440 BCE) Histories records,“The Scythians, as I said, take some of this hemp-seed [presumably, owers], and, creeping under the felt coverings, throw it upon the red-hot stones; immediately it smokes, and gives out such a vapour as no Grecian vapour-bath can exceed; the Scyths, delighted, shout for joy.”* [38] Classical Greeks and Romans were using cannabis, while in the Middle East, use spread throughout the Islamic empire to North Africa. In 1545 cannabis spread to the western hemisphere where Spaniards im- Relative size of varieties of Cannabis ported it to Chile for its use as ber. In North America cannabis, in the form of hemp, was grown for use in rope, century, the single-species concept was still widely acclothing and paper.* [39]* [40]* [41]* [42] cepted, except in the Soviet Union where Cannabis continued to be the subject of active taxonomic study. The name Cannabis indica was listed in various Pharmacopoeias, and Early classi cations was widely used to designate Cannabis suitable for the manThe Cannabis genus was rst classi ed using the “mod- ufacture of medicinal preparations.* [46] ern”system of taxonomic nomenclature by Carl Linnaeus in 1753, who devised the system still in use for the naming of species.* [43] He considered the genus to be mono- 20th century typic, having just a single species that he named Cannabis sativa L. (L. stands for Linnaeus, and indicates the author- In 1924, Russian botanist D.E. Janichevsky concluded that ity who rst named the species). Linnaeus was familiar ruderal Cannabis in central Russia is either a variety of with European hemp, which was widely cultivated at the C. sativa or a separate species, and proposed C. sativa L. time. In 1785, noted evolutionary biologist Jean-Baptiste var. ruderalis Janisch. and Cannabis ruderalis Janisch. de Lamarck published a description of a second species as alternative names.* [23] In 1929, renowned plant exof Cannabis, which he named Cannabis indica Lam.* [44] plorer Nikolai Vavilov assigned wild or feral populations of Lamarck based his description of the newly named species Cannabis in Afghanistan to C. indica Lam. var. ka ristanon plant specimens collected in India. He described C. in- ica Vav., and ruderal populations in Europe to C. sativa L. dica as having poorer ber quality than C. sativa, but greater var. spontanea Vav.* [29]* [45] In 1940, Russian botanists utility as an inebriant. Additional Cannabis species were Serebriakova and Sizov proposed a complex classi cation proposed in the 19th century, including strains from China in which they also recognized C. sativa and C. indica as and Vietnam (Indo-China) assigned the names Cannabis separate species. Within C. sativa they recognized two subchinensis Delile, and Cannabis gigantea Delile ex Vil- species: C. sativa L. subsp. culta Serebr. (consisting of morin.* [45] However, many taxonomists found these pu- cultivated plants), and C. sativa L. subsp. spontanea (Vav.) tative species di cult to distinguish. In the early 20th Serebr. (consisting of wild or feral plants). Serebriakova 114 CHAPTER 1. CANNABIS formity, chemotype, and numerical analysis of phenotypic characters.* [27]* [45]* [50] Professors William Emboden, Loran Anderson, and Harvard botanist Richard E. Schultes and coworkers also conducted taxonomic studies of Cannabis in the 1970s, and concluded that stable morphological di erences exist that support recognition of at least three species, C. sativa, C. indica, and C. ruderalis.* [51]* [52]* [53]* [54] For Schultes, this was a reversal of his previous interpretation that Cannabis is monotypic, with only a single species.* [55] According to Schultes' and Anderson's descriptions, C. sativa is tall and laxly branched with relatively narrow lea ets, C. indica is shorter, conical in shape, and has relatively wide lea ets, and C. ruderalis is short, branchless, and grows wild in central Asia. This taxonomic interpretation was emCannabis ruderalis braced by Cannabis a cionados who commonly distinguish narrow-leafed“sativa”drug strains from wide-leafed“in* and Sizov split the two C. sativa subspecies into 13 varieties, dica”drug strains. [56] including four distinct groups within subspecies culta. However, they did not divide C. indica into subspecies or varieties.* [23]* [47] This excessive splitting of C. sativa proved Continuing research too unwieldy, and never gained many adherents. In the 1970s, the taxonomic classi cation of Cannabis took on added signi cance in North America. Laws prohibiting Cannabis in the United States and Canada speci cally named products of C. sativa as prohibited materials. Enterprising attorneys for the defense in a few drug busts argued that the seized Cannabis material may not have been C. sativa, and was therefore not prohibited by law. Attorneys on both sides recruited botanists to provide expert testimony. Among those testifying for the prosecution was Dr. Ernest Small, while Dr. Richard E. Schultes and others testi ed for the defense. The botanists engaged in heated debate (outside of court), and both camps impugned the other's integrity.* [33]* [34] The defense attorneys were not often successful in winning their case, because the intent of the law was clear.* [48] Molecular analytical techniques developed in the late 20th century are being applied to questions of taxonomic classication. This has resulted in many reclassi cations based on evolutionary systematics. Several studies of Random Ampli ed Polymorphic DNA (RAPD) and other types of genetic markers have been conducted on drug and ber strains of Cannabis, primarily for plant breeding and forensic purposes.* [57]* [58]* [59]* [60]* [61] Dutch Cannabis researcher E.P.M. de Meijer and coworkers described some of their RAPD studies as showing an“extremely high”degree of genetic polymorphism between and within populations, suggesting a high degree of potential variation for selection, even in heavily selected hemp cultivars.* [28] They also commented that these analyses con rm the continuity of the Cannabis gene pool throughout the studied accesIn 1976, Canadian botanist Ernest Small* [49] and Amer- sions, and provide further con rmation that the genus comican taxonomist Arthur Cronquist published a taxonomic prises a single species, although theirs was not a systematic revision that recognizes a single species of Cannabis with study per se. two subspecies: C. sativa L. subsp. sativa, and C. sativa L. Karl W. Hillig, a graduate student in the laboratory of subsp. indica (Lam.) Small & Cronq.* [45] The authors hy- long-time Cannabis researcher Paul G. Mahlberg* [62] at pothesized that the two subspecies diverged primarily as a Indiana University, conducted a systematic investigation result of human selection; C. sativa subsp. sativa was pre- of genetic, morphological, and chemotaxonomic variation sumably selected for traits that enhance ber or seed pro- among 157 Cannabis accessions of known geographic oriduction, whereas C. sativa subsp. indica was primarily se- gin, including ber, drug, and feral populations. In 2004, lected for drug production. Within these two subspecies, Hillig and Mahlberg published a chemotaxomic analysis of Small and Cronquist described C. sativa L. subsp. sativa cannabinoid variation in their Cannabis germplasm collecvar. spontanea Vav. as a wild or escaped variety of low- tion. They used gas chromatography to determine cannabiintoxicant Cannabis, and C. sativa subsp. indica var. ka ris- noid content and to infer allele frequencies of the gene that tanica (Vav.) Small & Cronq. as a wild or escaped variety controls CBD and THC production within the studied popof the high-intoxicant type. This classi cation was based ulations, and concluded that the patterns of cannabinoid on several factors including interfertility, chromosome uni- variation support recognition of C. sativa and C. indica as 115 1.15. CANNABIS indica”, “mostly indica”, “indica/sativa”, “mostly sativa”, or “pure sativa”. 1.15.2 Uses Cannabis is used for a wide variety of purposes. Recreational use Main article: Cannabis (drug) Cannabis is a popular recreational drug around the world, Active/Lethal Dose Ratio and Dependence Potential of Psychoactive Drugs Heroin Very high High Dependence Potential separate species, but not C. ruderalis.* [29] The authors assigned ber/seed landraces and feral populations from Europe, central Asia, and Asia Minor to C. sativa. Narrowlea et and wide-lea et drug accessions, southern and eastern Asian hemp accessions, and feral Himalayan populations were assigned to C. indica. In 2005, Hillig published a genetic analysis of the same set of accessions (this paper was the rst in the series, but was delayed in publication), and proposed a three-species classi cation, recognizing C. sativa, C. indica, and (tentatively) C. ruderalis.* [32] In his doctoral dissertation published the same year, Hillig stated that principal components analysis of phenotypic (morphological) traits failed to di erentiate the putative species, but that canonical variates analysis resulted in a high degree of discrimination of the putative species and infraspeci c taxa.* [63] Another paper in the series on chemotaxonomic variation in the terpenoid content of the essential oil of Cannabis revealed that several wide-lea et drug strains in the collection had relatively high levels of certain sesquiterpene alcohols, including guaiol and isomers of eudesmol, that set them apart from the other putative taxa.* [64] Hillig concluded that the patterns of genetic, morphological, and chemotaxonomic variation support recognition of C. sativa and C. indica as separate species. He also concluded there is little support to treat C. ruderalis as a separate species from C. sativa at this time, but more research on wild and weedy populations is needed because they were underrepresented in their collection. Moderate / High Morphine Pentobarbital Cocaine Ephedra Moderate Moderate / Low Nicotine Marijuana Nitrous oxide Rohypnol Caﬀeine Alcohol MDMA Legend Narcotics Depressants Stimulants Anesthetics Hallucinogens Cannabis Ketamine Low Very low LSD Mescaline Psilocybin 0.001 0.002 0.01 0.02 0.1 0.2 Active Dose / Lethal Dose Comparison of physical harm and dependence regarding various drugs* [67] In September 2005, New Scientist reported that researchers at the Canberra Institute of Technology had identi ed a new type of Cannabis based on analysis of mitochondrial and chloroplast DNA.* [65] The New Scientist story, which was picked up by many news agencies and web sites, indicated that the research was to be published in the journal Forensic Science International.* [66] Popular usage The scienti c debate regarding taxonomy has had little effect on the terminology in widespread use among cultivators and users of drug-type Cannabis. Cannabis a cionados recognize three distinct types based on such factors as morphology, native range, aroma, and subjective psychoactive characteristics. Sativa is the most widespread variety, which is usually tall, laxly branched, and found in warm lowland regions. Indica designates shorter, bushier plants adapted to cooler climates and highland environments. Ruderalis is the informal name for the short plants that grow wild in Europe and central Asia. A dried bud, typical of what is sold for drug use only behind alcohol, ca eine and tobacco. In the United States alone, it is believed that over 100 million Americans have tried cannabis, with 25 million Americans having used it within the past year.* [68] The psychoactive e ects of cannabis are known to have a biphasic nature. Primary psychoactive e ects include a state of relaxation, and to a lesser degree, euphoria from its main psychoactive compound, tetrahydrocannabinol. SecBreeders, seed companies, and cultivators of drug type ondary psychoactive e ects, such as a facility for philosophCannabis often describe the ancestry or gross phenotypic ical thinking, introspection and metacognition have been recharacteristics of cultivars by categorizing them as “pure ported amongst cases of anxiety and paranoia.* [69] Finally, 116 CHAPTER 1. CANNABIS the tertiary psychoactive e ects of the drug cannabis, can Industrial use (Hemp) include an increase in heart rate and hunger, believed to be caused by 11-OH-THC, a psychoactive metabolite of THC Main article: Cannabis (industrial uses) produced in the liver. The term hemp is used to name the durable soft ber from Normal cognition is restored after approximately three hours for larger doses via a smoking pipe, bong or vaporizer.* [69] However, if a large amount is taken orally the e ects may last much longer. After 24 hours to a few days, minuscule psychoactive e ects may be felt, depending on dosage, frequency and tolerance to the drug. Various forms of the drug cannabis exist, including extracts such as hashish and hash oil* [5] which, because of appearance, are more susceptible to adulterants when left unregulated. Cannabidiol (CBD), which has no psychotropic e ects by itself* [26] (although sometimes showing a small stimulant e ect, similar to ca eine),* [70] attenuates, or reduces* [71] the higher anxiety levels caused by THC alone.* [72] According to Delphic analysis by British researchers in 2007, cannabis has a lower risk factor for dependence compared to both nicotine and alcohol.* [73] However, everyday use of Cannabis can in some cases be correlated with psychological withdrawal symptoms such as irritability and insomnia,* [69] and evidence could suggest that if a user experiences stress, the likeliness of getting a panic attack increases because of an increase of THC metabolites.* [74]* [75] However, cannabis withdrawal symptoms are typically mild and are never life-threatening.* [76] Medical use Main article: Medical cannabis Medical cannabis (or medical marijuana) refers to the use of cannabis and its constituent cannabinoids, to treat disease or improve symptoms. Cannabis is used to reduce nausea and vomiting during chemotherapy, to improve appetite in people with HIV/AIDS, and to treat chronic pain and muscle spasms.* [77]* [78] Cannabis sativa stem longitudinal section the Cannabis plant stem (stalk). Cannabis sativa cultivars are used for bers due to their long stems; Sativa varieties may grow more than six metres tall. However, hemp can refer to any industrial or foodstu product that is not intended for use as a drug. Many countries regulate limits for psychoactive compound (THC) concentrations in products labeled as hemp. Cannabis for industrial uses is valuable in tens of thousands of commercial products, especially as bre* [82] ranging from paper, cordage, construction material and textiles in general, to clothing. Hemp is stronger and longer-lasting than cotton. It also is a useful source of foodstu s (hemp milk, hemp seed, hemp oil) and biofuels. Hemp has been used by many civilizations, from China to Europe (and later North America) during the last 12,000 years.* [82]* [83] In Cannabinoids are under preliminary research for their po- modern times novel applications and improvements have tential to a ect stroke* [80] or children's epilepsy.* [81] been explored with modest commercial success.* [84]* [85] Short-term use increases both minor and major adverse effects.* [78] Common side e ects include dizziness, feeling tired, vomiting, and hallucinations.* [78] Long-term e ects of cannabis are not clear.* [79] Concerns including memory and cognition problems, risk of addiction, schizophrenia in young people, and the risk of children taking it by accident.* [77] 117 1.15. CANNABIS Ancient and religious uses Main articles: Religious and spiritual use of cannabis and History of medical cannabis The Cannabis plant has a history of medicinal use dat- “While we have no evidence of the use of ephedra among the steppe tribes, we have already seen that they did share in the cultic use of hemp, a practice that ranged from Romania east to the Yenisei River from at least the 3rd millennium BC onwards where its use was later encountered in the apparatus for smoking hemp found at Pazyryk.”* [90] Cannabis is rst referred to in Hindu Vedas between 2000 and 1400 BCE, in the Atharvaveda. By the 10th century CE, it has been suggested that it was referred to by some in India as“food of the gods”.* [91] Cannabis use eventually became a ritual part of the Hindu festival of Holi. In Buddhism, cannabis is generally regarded as an intoxicant and may be a hindrance to development of meditation and clear awareness. In ancient Germanic culture, Cannabis was associated with the Norse love goddess, Freya.* [92]* [93] An anointing oil mentioned in Exodus is, by some translators, said to contain Cannabis.* [94] Su s have used Cannabis in a spiritual context since the 13th century CE.* [95] Cannabis Museum in Amsterdam ing back thousands of years across many cultures.* [86] The Yanghai Tombs, a vast ancient cemetery (54 000 m2 ) situated in the Turfan district of the Xinjiang Uyghur Autonomous Region of the People's Republic of China, have revealed the 2700-year-old grave of a shaman. He is thought to have belonged to the Jushi culture recorded in the area centuries later in the Hanshu, Chap 96B.* [87] Near the head and foot of the shaman was a large leather basket and wooden bowl lled with 789g of cannabis, superbly preserved by climatic and burial conditions. An international team demonstrated that this material contained tetrahydrocannabinol, the psychoactive component of cannabis. The cannabis was presumably employed by this culture as a medicinal or psychoactive agent, or an aid to divination. This is the oldest documentation of cannabis as a pharmacologically active agent.* [88] In modern times the Rastafari movement has embraced Cannabis as a sacrament.* [96] Elders of the Ethiopian Zion Coptic Church, a religious movement founded in the United States in 1975 with no ties to either Ethiopia or the Coptic Church, consider Cannabis to be the Eucharist, claiming it as an oral tradition from Ethiopia dating back to the time of Christ.* [97] Like the Rastafari, some modern Gnostic Christian sects have asserted that Cannabis is the Tree of Life.* [98]* [99] Other organized religions founded in the 20th century that treat Cannabis as a sacrament are the THC Ministry,* [100] Cantheism,* [101] the Cannabis Assembly* [102] and the Church of Cognizance. Rastafarians tend to be among the biggest consumers of modern Cannabis use. Clay pipes at William Shakespeare's Stratfordupon-Avon garden may contain cannabis, indicating that Shakespeare may have been a cannabis smoker.* [103]* [104]* [105]* [106]* [107] 1.15.3 Reproduction Breeding systems Cannabis is predominantly dioecious,* [15]* [108] although many monoecious varieties have been described.* [109] Subdioecy (the occurrence of monoecious individuals and dioecious individuals within the same population) is widespread.* [110]* [111]* [112] Many populations have been described as sexually labile.* [59]* [113]* [114] Settlements which date from c. 2200–1700 BCE in the Bactria and Margiana contained elaborate ritual structures with rooms containing everything needed for making drinks containing extracts from poppy (opium), hemp (cannabis), and ephedra (which contains ephedrine).* [89] As a result of intensive selection in cultivation, Cannabis 118 CHAPTER 1. CANNABIS Cannabis sativa fruits (achenes) that contain the seeds Male Cannabis ower buds Sex determination Cannabis has been described as having one of the most complicated mechanisms of sex determination among the dioecious plants.* [115] Many models have been proposed to explain sex determination in Cannabis. Cannabis ower with visible trichomes exhibits many sexual phenotypes that can be described in terms of the ratio of female to male owers occurring in the individual, or typical in the cultivar.* [115] Dioecious varieties are preferred for drug production, where the female owers are used. Dioecious varieties are also preferred for textile ber production, whereas monoecious varieties are preferred for pulp and paper production. It has been suggested that the presence of monoecy can be used to differentiate licit crops of monoecious hemp from illicit drug crops.* [110] However, sativa strains often produce monoecious individuals, probably as a result of inbreeding. Based on studies of sex reversal in hemp, it was rst reported by K. Hirata in 1924 that an XY sex-determination system is present.* [113] At the time, the XY system was the only known system of sex determination. The X:A system was rst described in Drosophila spp in 1925.* [116] Soon thereafter, Scha ner disputed Hirata's interpretation,* [117] and published results from his own studies of sex reversal in hemp, concluding that an X:A system was in use and that furthermore sex was strongly in uenced by environmental conditions.* [114] Since then, many di erent types of sex determination systems have been discovered, particularly in plants.* [108] Dioecy is relatively uncommon in the plant kingdom, and a very low percentage of dioecious plant species have been determined to use the XY system. In most cases where the XY system is found it is believed to have evolved recently and independently.* [118] Since the 1920s, a number of sex determination models have been proposed for Cannabis. Ainsworth describes sex determination in the genus as using“an X/autosome dosage type”.* [108] 119 1.15. CANNABIS chromosomes were clearly visible in a karyotype. Cannabis was one of the rst plant species to be karyotyped; however, this was in a period when karyotype preparation was primitive by modern standards (see History of Cytogenetics). Heteromorphic sex chromosomes were reported to occur in staminate individuals of dioecious “Kentucky”hemp, but were not found in pistillate individuals of the same variety. Dioecious “Kentucky”hemp was assumed to use an XY mechanism. Heterosomes were not observed in analyzed individuals of monoecious “Kentucky”hemp, nor in an unidenti ed German cultivar. These varieties were assumed to have sex chromosome composition XX.* [119] According to other researchers, no modern karyotype of Cannabis had been published as of 1996.* [120] Proponents of the XY system state that Y chromosome is slightly larger than the X, but di cult to di erentiate cytologically.* [121] A male hemp plant More recently, Sakamoto and various coauthors* [122]* [123] have used RAPD to isolate several genetic marker sequences that they name MaleAssociated DNA in Cannabis (MADC), and which they interpret as indirect evidence of a male chromosome. Several other research groups have reported identi cation of male-associated markers using RAPD and AFLP.* [28]* [59]* [124] Ainsworth commented on these ndings, stating, “It is not surprising that male-associated markers are relatively abundant. In dioecious plants where sex chromosomes have not been identi ed, markers for maleness indicate either the presence of sex chromosomes which have not been distinguished by cytological methods or that the marker is tightly linked to a gene involved in sex determination.* [108] " Environmental sex determination is known to occur in a variety of species.* [125] Many researchers have suggested that sex in Cannabis is determined or strongly in uenced by environmental factors.* [114] Ainsworth reviews that treatment with auxin and ethylene have feminizing effects, and that treatment with cytokinins and gibberellins have masculinizing e ects.* [108] It has been reported that sex can be reversed in Cannabis using chemical treatment.* [126] A PCR-based method for the detection of female-associated DNA polymorphisms by genotyping has been developed.* [127] Dense raceme of carpellate owers typical of drug-type varieties of Cannabis 1.15.4 Etymology Main article: Cannabis (etymology) The question of whether heteromorphic sex chromosomes The word cannabis is from Greek κάνν ις (kánnabis) are indeed present is most conveniently answered if such (see Latin cannabis),* [128] which was originally Scythian 120 CHAPTER 1. CANNABIS or Thracian.* [129] It is related to the Persian kanab, the [10] Lebel-Hardenack, Sabine; Grant, Sarah R. (1997).“Genetics of sex determination in owering plants”. Trends in Plant English canvas and possibly even to the English hemp (Old Science 2 (4): 130–6. doi:10.1016/S1360-1385(97)01012English hænep).* [129] In modern Hebrew, ‫ ַ ַּנּבֹוס‬qannabōs 1. (modern pronunciation: [kanaˈbos]) is used but there are those who have theorized that it was referred to in an- [11] Moliterni, V. M. Cristiana; Cattivelli, Luigi; Ranalli, P.; tiquity as ‫ ני בו ם‬q'nei bosem, a component of the bibMandolino, Giuseppe (2004).“The sexual di erentiation of lical anointing oil.* [130]* [131] Old Akkadian qunnabtu, Cannabis sativa L.: A morphological and molecular study”. Neo-Assyrian and Neo-Babylonian qunnabu were used to Euphytica 140: 95–106. doi:10.1007/s10681-004-4758-7. refer to the plant meaning “a way to produce smoke.” * [12] Bouquet, R. J. 1950. Cannabis. United Nations O ce on [132]* [133]* [134] Drugs and Crime. Retrieved on 23 February 2007 1.15.5 See also • Cannabis cultivation • Cannabis drug testing • Cannabis Social Club • Hash, Marihuana & Hemp Museum • Indian Hemp Drugs Commission 1.15.6 References [1] Geo rey William Guy; Brian Anthony Whittle; Philip Robson (2004). The Medicinal Uses of Cannabis and Cannabinoids. Pharmaceutical Press. pp. 74–. ISBN 978-0-85369517-2. [2] Karl Hillig (January 2005). “Genetic evidence for speciation in Cannabis (Cannabaceae)" (PDF). Researchgate. Retrieved 24 October 2015. [3] “Cannabis sativa information from NPGS/GRIN”. www. ars-grin.gov. Retrieved 13 July 2008. [4] A. ElSohly, Mahmoud (2007). Marijuana and the Cannabinoids. Humana Press. p. 8. ISBN 1-58829-456-0. Retrieved 2 May 2011. [5] Erowid. 2006. Cannabis Basics. Retrieved on 25 February 2007 [6] Narcotic Drugs 2014 (pdf). INTERNATIONAL NARCOTICS CONTROL BOARD. 2015. p. 21. ISBN 9789210481571. [13] Li Hui-Lin (1973). “The Origin and Use of Cannabis in Eastern Asia: Linguistic-Cultural Implications”, Economic Botany 28.3: 293–301, p. 294. [14] 13/99 and 13/133. In addition, 13/98 de ned fen 蕡 "Cannabis in orescence”and 13/159 bo 薜“wild Cannabis". [15] Clarke, Robert C. 1991. Marijuana Botany, 2nd ed. Ron Publishing, California. ISBN 0-914171-78-X [16] Small, Ernest (1975). “Morphological variation of achenes of Cannabis". Canadian Journal of Botany 53 (10): 978–87. doi:10.1139/b75-117. [17] Mahlberg Paul G., Soo Kim Eun (2001). “THC (tetrahyrdocannabinol) accumulation in glands of Cannabis (Cannabaceae)". The Hemp Report 3 (17). [18] Small, Ernest (1972). “Interfertility and chromosomal uniformity in Cannabis". Canadian Journal of Botany 50 (9): 1947–9. doi:10.1139/b72-248. [19] Van Bakel, Harm; Stout, Jake M; Cote, Atina G; Tallon, Carling M; Sharpe, Andrew G; Hughes, Timothy R; Page, Jonathan E (2011). “The draft genome and transcriptome of Cannabis sativa”. 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[123] Sakamoto, Koichi; Abe, Tomoko; Matsuyama, Tomoki; Yoshida, Shigeo; Ohmido, Nobuko; Fukui, Kiichi; Satoh, Shinobu (2005). “RAPD markers encoding retrotransposable elements are linked to the male sex inCannabis sativaL”. Genome 48 (5): 931–6. doi:10.1139/g05-056. PMID 16391699. [124] Tﬁrjék, Ottó; Bucherna, Nándor; Kiss, Erzsébet; Homoki, Hajnalka; Finta-Korpelová, Zsuzsanna; Bócsa, Iván; Nagy, István; Heszky, László E. (2002). Euphytica 127 (2): 209– 218. doi:10.1023/A:1020204729122. Missing or empty |title= (help) [125] Tanurdzic, M.; Banks, JA (2004).“Sex-Determining Mechanisms in Land Plants”. The Plant Cell Online 16 (Suppl): S61–71. doi:10.1105/tpc.016667 (inactive 2015-01-01). PMC 2643385. PMID 15084718. [126] Mohan Ram, HY; Sett, R (1982). “Induction of fertile male owers in genetically female Cannabis sativa plants by silver nitrate and silver thiosulphate anionic complex”. Theoretical and Applied Genetics 62 (4): 369–75. doi:10.1007/BF00275107 (inactive 2015-01-01). PMID 24270659. [127] Shao, Hong; Song, Shu-Juan; Clarke, Robert C. (2003). “Female-Associated DNA Polymorphisms of Hemp (Cannabis sativaL.)". Journal of Industrial Hemp 8: 5–9. doi:10.1300/J237v08n01_02. visited: The Plant with a Divided History. Algora Pub. ISBN 0-87586-206-3. • Earleywine, Mitchell (2005). Understanding Marijuana: A New Look at the Scienti c Evidence. Oxford University Press. ISBN 0-19-513893-7. • Emmett, David; Graeme Nice (2009). What you need to know about cannabis: understanding the facts. Jessica Kingsley Publishers. ISBN 1-84310-697-3. • Hulsewé, A. F. P. (1979). China in Central Asia: The Early Stage 125 BC – AD 23: an annotated translation of chapters 61 and 96 of the History of the Former Han Dynasty. E. J. Brill, Leiden. ISBN 90-04-05884-2. • Geo rey William, Guy; Brian Anthony Whittle; Philip Robson (2004). The medicinal uses of cannabis and cannabinoids. Pharmaceutical Press. ISBN 085369-517-2. • Holland, Julie M.D. (2010). The Pot Book: A Complete Guide to Cannabis: Its Role in Medicine, Politics, science, and culture. Park Street Press. ISBN 978-159477-368-6. • Iversen, Leslie L (2008). The science of marijuana (2nd ed.). Oxford University Press. ISBN 978-0-19532824-0. • Jenkins, Richard (2006). Cannabis and Young People: Reviewing the Evidence. Jessica Kingsley. ISBN 184310-398-2. 1.15. CANNABIS • Lambert, Didier M (2008). Cannabinoids in Nature and Medicine. Wiley-VCH. ISBN 3-906390-56-X. • Mallory, J. P. and Victor H. Mair (2000). The Tarim Mummies: Ancient China and the Mystery of the Earliest Peoples from the West. Thames & Hudson, London. ISBN 0-500-05101-1. • Ro man, Roger A; Robert S. Stephens (2006). Cannabis Dependence: Its Nature, Consequences, and Treatment. Cambridge University Press. ISBN 0-52181447-2. • Russo, Ethan; Melanie Creagan Dreher; Mary Lynn Mathre (2004). Women and Cannabis: Medicine, Science, and Sociology. Haworth Press. ISBN 0-78902101-3. • Solowij, Nadia (1998). Cannabis and Cognitive Functioning. Cambridge University Press. ISBN 0-52159114-7. 1.15.8 External links • International Plant Names Index (IPNI) 125 Chapter 2 Text and image sources, contributors, and licenses 2.1 Text • Cannabis (drug) Source: https://en.wikipedia.org/wiki/Cannabis_(drug)?oldid=720820761 Contributors: AxelBoldt, Bryan Derksen, Novalis, Fubar Obfusco, Heron, Leandrod, Stevertigo, D, Bewildebeast, Fred Bauder, Fuzzie, Ronincyberpunk, Gabbe, Ixfd64, 172, AlexR, Qaz, GTBacchus, Ahoerstemeier, Docu, Angela, JWSchmidt, LittleDan, Julesd, Ugen64, Glenn, Bogdangiusca, Cratbro, Deisenbe, Evercat, Beck, Eszett, Nohat, Andrevan, Dino, Random832, Ike9898, Geary, Steinsky, Tpbradbury, Hyacinth, Grendelkhan, Bhuston, LMB, Ed g2s, Floydian, Moros~enwiki, Samsara, Mackensen, Dbabbitt, Bloodshedder, Pakaran, Jerzy, Aenar, Catskul, Sander123, Gak, Moondyne, Goethean, Altenmann, JosephBarillari, Calmypal, Samrolken, Merovingian, Aaron Pannell, Academic Challenger, Markewilliams, Premeditated Chaos, Auric, Rhombus, Rebrane, Catbar, Roozbeh, Mushroom, SoLando, Dina, Vacuum, Nagelfar, Alan Liefting, Dave6, Cedars, Matt Gies, Alerante, Decrypt3, Centrx, Waliy sherpa, DocWatson42, Christopher Parham, Nat Krause, Nunh-huh, BenFrantzDale, Tom harrison, Meursault2004, Ferkelparade, Orangemike, Peoplesyak, Ich, Peruvianllama, Everyking, Bkonrad, Lode Runner, Alison, Henry Flower, Jfdwol , Guanaco, FrYGuY, LockeShocke, Iota, AlistairMcMillan, Falcon Kirtaran, Tweenk, Boothinator, SWAdair, AdamJacobMuller, Bobblewik, Wmahan, JE, Barneyboo, Thewikipedian, Chowbok, Kukuman, Utcursch, Pgan002, Uranographer, Calm, CryptoDerk, Sonjaaa, Gzuckier, Antandrus, Alteripse, Lockeownzj00, Drue, Beland, Elembis, Kaldari, Kiteinthewind, Jossi, MacGyverMagic, Rdsmith4, Kesac, Dragon ySixtyseven, Sharavanabhava, Cihan, Kevin B12, Daniel11, Gscshoyru, Commodore Sloat, Creidieki, Mrdectol, Neutrality, Joyous!, Jcw69, Imjustmatthew, Goobergunch, Buickid, Tromatic, Neale Monks, Aknorals, Sonett72, Karl Dickman, Picapica, JavaTenor, ScrollMaker, Laguna72, Adashiel, Trevor MacInnis, TheObtuseAngleOfDoom, Acsenray, Moxfyre, Shotwell, Il hamster, Mike Rosoft, Alkivar, Reason~enwiki, Mormegil, Dramenbejs, Freakofnurture, AliveFreeHappy, Monkeyman, Primary0, Jiy, Mindspillage, Kathar, Discospinster, Brianhe, Rich Farmbrough, Rhobite, Avriette, Inkypaws, Silverweed, Insertwackynamehere, David Schaich, Nuview, Xezbeth, Paul August, Horsten, Bender235, ESkog, Cyclopia, Jambalaya~enwiki, Mashford, JoeSmack, Violetriga, Pedant, PsychoDave, Mr. Billion, Livajo, Ben Webber, Mwanner, Chairboy, Aude, Shanes, Tom, Spearhead, RoyBoy, Dennis Brown, Triona, Bookofjude, Nrbelex, Amerika, Aaronbrick, Mschoel, Jpgordon, Causa sui, Alxndr, PatrikR, Bobo192, Utopian at, Martey, NetBot, Hurricane111, Smalljim, Clawson, K0hlrabi, Viriditas, Jbrader, Hismattness, Foobaz, Scapermoya, I9Q79oL78KiL0QTFHgyc, Wolfrider~enwiki, Irrawaddy, La goutte de pluie, Pgsa, Rje, Zetawoof, James Foster, Krellis, Stephen Bain, NickCatal, Danski14, Alansohn, Gary, Eric Kvaalen, Theaterfreak64, The RedBurn, Atlant, Philip Cross, Rd232, Keenan Pepper, Jeltz, PatrickFisher, Andrewpmk, Cjthellama, Howrealisreal, El stiko, Riana, AzaToth, Yamla, Thoric, Lectonar, Calton, Axl, Hinotori, SlimVirgin, Zekklen, Ciaran H, Apoc2400, Ransack, Kz9dsr0t387346, Mailer diablo, InShaneee, Phocks, Dark Shikari, Theodore Kloba, Muugokszhiion, Hu, Malo, Yummifruitbat, Katefan0, Bart133, Caesura, NTK, Bootstoots, Snowolf, Miltonhowe, Schaefer, Benna, Wtmitchell, Sudasana, Gdavidp, Keepsleeping, Cburnett, Jakek101, Stephan Leeds, Garzo, Leoadec, Docboat, Evil Monkey, Canar, Omphaloscope, Anthony Ivano , Ilse@, Harej, Amorymeltzer, Jon Cates, Costoa, Danthemankhan, Wadems, Scott Gall, W7KyzmJt, Computerjoe, BDD, Gene Nygaard, Drbreznjev, Axeman89, Memenen, NuVanDibe, Bookandco ee, Ceyockey, Galaxiaad, RyanGerbil10, Kenyon, Dismas, Squiquifox, Tariqabjotu, Mahanga, Mhazard9, DarTar, Dr Gangrene, Gmaxwell, BadLeprechaun, Louisgag, MickWest, FrancisTyers, Joelpt, Angr, Kelly Martin, Alvis, Je rey O. 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TEXT 127 Haldrik, Celebere, Zath42, Nagytibi, Bornhj, Rikoshi, Mhking, JesseGarrett, Gdrbot, Random user 39849958, VolatileChemical, Voodoom, Bgwhite, Hall Monitor, Digitalme, GarconDansLeNoir, NSR, Scuzzi, WriterHound, Gwernol, Tone, Ivesfreak, Myeager, Quid~enwiki, Raelx, The Rambling Man, YurikBot, ThunderPeel2001, Radishes, Crotalus horridus, Eraserhead1, Sceptre, Stan2525, Jachin, Dnik, Peter G Werner, Brandmeister (old), Je theji , RussBot, FrenchIsAwesome, AcrophobicEagle, Jtkiefer, Backburner001, Severa, Anonymous editor, Garglebutt, Splash, Pigman, Anache, Generalleo , StarkRG, SpuriousQ, Skidoo, Fabricationary, Tsch81, Matt Fitzpatrick, Akamad, Stephenb, Manop, Shell Kinney, Gaius Cornelius, Ksyrie, Shaddack, Megastar, Theelf29, Rockyhorror42, Kimchi.sg, Varnav, Wimt, Bullzeye, The Hokkaido Crow, Gustavb, Daveswagon, Alynna Kasmira, Shanel, NawlinWiki, IAMTHEEGGMAN, SEWilcoBot, Wiki alf, Ytcracker, Bachrach44, Kremmy, Jaxl, D-Katana, Clam0p, Twin Bird, Poison girl, Dilaudid~enwiki, Howcheng, Robchurch, Joelr31, JTBurman, Lexicon, JDoorjam, Irishguy, Nick, Aaron Brenneman, Anetode, Banes, Trollderella, Dmoss, Dennis!, Matticus78, Esqg, Blu Aardvark, Yoasif, Raven4x4x, Ezeu, Lachie, Furtim, Tony1, Alex43223, SameerKhan, Syrthiss, DGJM, M2k41, Todfox, DeadEyeArrow, BigRedBall, Asarelah, Klutzy, Cardsplayer4life, Derek.cashman, Hosterweis, Spark.1.4, Tullie, Thereverendeg, Elkman, Du DudeX1, Ochiwar, Mjsabby, Black Falcon, Louieduvall, Nlu, User27091, Smaines, Wknight94, MagicOgre, Volantares, Ms2ger, Searchme, Amigan, BazookaJoe, FF2010, Veatch, Jczerwinski, Calcwatch, Johndburger, Djramone, Ali K, Gtdp, Imaninjapirate, Ankles, TheMadBaron, Saranghae honey, Theda, Closedmouth, Spondoolicks, Ketsuekigata, Arthur Rubin, Pb30, Adpas, Sean Whitton, BorgQueen, Black-Velvet, GraemeL, Haddock420, JoanneB, Vicarious, Alias Flood, Scoutersig, Jolb, JLaTondre, ArielGold, Tsiaojian lee, Curpsbot-unicodify, Channels, Johnpseudo, Tall Midget, ASchmoo, Nsevs, Allens, Internaciulo~enwiki, Katieh5584, Kungfuadam, Junglecat, RG2, PietrzakL, DearPrudence, John Broughton, The Way, BigaZon, AssistantX, Drunkmule, Jdufresne, Babij, DVD R W, Kf4bdy, Bibliomaniac15, SaulPerdomo, That Guy, From That Show!, Quadpus, Sambauers, Luk, Sycthos, Hiddekel, SpLoT, Drippingmintleaves, Vanka5, Crystallina, Sarah, Fightindaman, Anth a narchy, SmackBot, Amcbride, Bluelip, Ashenai, RedHouse18, Avengerx, Sticky Parkin, Moeron, Bobet, Urania3, Tarret, Benzo, KnowledgeOfSelf, Royalguard11, McGeddon, Skeezix1000, Shoy, Pgk, C.Fred, Od Mishehu, AndyZ, Blue520, Bomac, Edakin, Davewild, Chairman S., KVDP, Jrockley, Delldot, Jongpil Yun, Jihiro, Antrophica, Arny, Hardyplants, RamsayHank, Athaler, PJM, Timeshifter, Frymaster, Vilerage, SampsonSimpson, Apartmento, Nil Einne, Swerdnaneb, Nsche ey, Edgar181, HalfShadow, Alex earlier account, LonglivetheDee, Preeeemo, Ga , Flannel, Xaos ux, DarkIye, Aksi great, Peter Isotalo, Gilliam, Portillo, Ohnoitsjamie, Hmains, Betacommand, Oscarthecat, Skizzik, Msignor, Chromo SDR, NickGarvey, SourceLimit, OldsVistaCruiser, Tennekis, Andy M. 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Packham, Abeg92, Future Perfect at Sunrise, Supposed, A D 13, Fnoriegac, Bpg542, Steel, Zeppelin462, Michaelas10, MissMetalmouth, Gogo Dodo, Jkokavec, AtTheAbyss, Albert0, Anthonyhcole, JFreeman, Fastolfe00, JosephO75, Llort, Rajveers2001, Thirstyferret, Amchamp, Beefnut, Torvik, Sappy2yah, Wikipediarules2221, Elyse420, Luckyherb, Sa.vakilian, Caliga10, Kara as, Tawkerbot4, Gspence, Msnicki, M a s, Flatninthbird, DumbBOT, B oSabres09, Asenine, Crana, Nickleus, Javsav, Dinnerbone, Gojukebox, Viridae, CanadianConservative, Zer0faults, Skanking, The Lizard Wizard, Superbeatles, Omicronpersei8, JodyB, G0t rap3, Tedbundy777, Mindrearranger, Lo2u, Hex01A4, Grant M, Bellpepper, Krylonblue83, Christopher Isar, Independent Journalist, EvocativeIntrigue, Lightabyss, Barnaldo, Rjm656s, Crazyeddy17, Johnblock1988, Barticus88, 123mehe, DaemonLee, Erich Schmidt, Do-nutz@hotmail.com, Djluminus89, Sv23, Mongoosedogg, PetePassword, Wwoody123, LeeG, Sm0key321, Tsmartman123, Free fool, Dasani, Blowski, Tommybtennis2, CL8~enwiki, Loudsox, Ucanlookitup, Craggyisland, Bendroz, N5iln, Elementjunky, Mojo Hand, Anupam, D digidy dod, Subvertc, Ri- 128 CHAPTER 2. 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(MasterPiece), Hunenmensch, CAPTAIN RAJU, Barbara (WVS), Sprisacaru, Potguru and Anonymous: 3605 • Medical cannabis Source: https://en.wikipedia.org/wiki/Medical_cannabis?oldid=719051260 Contributors: AxelBoldt, Eloquence, Bryan Derksen, William Avery, Mbecker, Edward, Patrick, Gabbe, Delirium, Mkweise, Snoyes, TUF-KAT, TUF-KAT, JWSchmidt, Bueller 007, Julesd, Jll, Lukobe, Dino, DJ Clayworth, Saltine, Phoebe, Pakaran, Finlay McWalter, Pollinator, Calieber, Dale Arnett, Benwing, Yelyos, Postdlf, Ktotam, Arm, Alan Liefting, Inter, Plautus satire, Idril, Sunny256, Jfdwol , Guanaco, Ezhiki, Mboverload, Pascal666, Jackol, Bobblewik, Neilc, Ferre, Beland, OverlordQ, JoJan, Vanished user 1234567890, PDH, Jossi, Mzajac, Sharavanabhava, NoPetrol, Creidieki, Neutrality, Goobergunch, Vsb, Liberlogos, Lostchicken, Trevor MacInnis, O'Dea, Haiduc, Jiy, Discospinster, Rich Farmbrough, Rhobite, Bender235, JJJJust, Cyclopia, Zaslav, Mashford, JoeSmack, Petersam, Sgeo, RoyBoy, LordRM, Aaronbrick, Adambro, Renice, Bobo192, Smalljim, Clawson, BrokenSegue, Viriditas, Cmdrjameson, Gira edata, Acjelen, VBGFscJUn3, Towel401, Nsaa, DrDeke, Alansohn, Rocketfairy, Polarscribe, Eric Kvaalen, Hydriotaphia, Rd232, Mr Adequate, Arthur Livermore, Danheac, Sade, Lugevas, Snowolf, Benna, Velella, Rafti Institute, Knowledge Seeker, Wadems, Soldadito de Plomo, Galaxiaad, Richwales, Squiquifox, Lemworld, Fredricktoo, Jgwest, Angr, TigerShark, Guy M, Kosher Fan, Je 3000, Ropcat, Rickjpelleg, Miss Madeline, Tabletop, CryptoStorm, Scootey, Triddle, Laurel Bush, Hughcharlesparker, Sev- 130 CHAPTER 2. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES entyThree, Sundaypinball, Thc420, Rad Racer, Allen3, Dysepsion, RichardWeiss, BD2412, Dan Ros, Dilvie, FreplySpang, Rjwilmsi, TitaniumDreads, Harro5, Nneonneo, Moorlock, Bhadani, Opiax, DickClarkMises, Yamamoto Ichiro, FayssalF, RobertG, Ground Zero, AED, Weel, JdforresterBot, RexNL, Gurch, Jrtayloriv, Ahunt, BMF81, Aspro, Theshibboleth, Kazuba, Zath42, DVdm, Voodoom, Bgwhite, NSR, WriterHound, Gwernol, Wavelength, Dannycas, RussBot, Pigman, Chris Capoccia, OldRight, DarkEvil, Chaser, Stephenb, Gaius Cornelius, CambridgeBayWeather, Shaddack, Pseudomonas, Cryptic, Tanzeel, NawlinWiki, Wiki alf, Daemon8666, JTBurman, Thsgrn, Aaron Brenneman, Thesuperpower, Rmky87, Ezeu, TDogg310, Tony1, Bucketsofg, JPMcGrath, Todfox, DeadEyeArrow, Wujastyk, Asarelah, Mistercow, Ochiwar, Smaines, Wknight94, BlueZenith, WAS 4.250, Sandstein, American2, Chase me ladies, I'm the Cavalry, Kris33, ProdigySportsman, Saudade7, Ladysway1985, CWenger, ArielGold, Rathfelder, Argos'Dad, Allens, John Broughton, BiH, Trevorlo in, SmackBot, Daksya, Zanter, Anarchist42, VigilancePrime, David.Mestel, Poldavo, Davidkevin, Alejocrux, Jagged 85, Jab843, Timeshifter, Edgar181, Gilliam, Brianski, Portillo, Ohnoitsjamie, Wlmg, Rmosler2100, Vechs, Chris the speller, Master Jay, Jprg1966, Maxinater, Deli nk, StrangerInParadise, Adun12, CSWarren, Jfsamper, Quackslikeaduck, Darth Panda, John Reaves, Yow2002, Veggies, Zsinj, Dethme0w, Muboshgu, Can't sleep, clown will eat me, Jahiegel, Mulder416, Gatherton, Adamantios, PetterBudt, MrRadioGuy, Fuhghettaboutit, BullRangifer, James084, Ladlergo, Altogether, Rock nj, Kukini, BlackTerror, Ohconfucius, Alakey2010, John, Dade ciku, BurnDownBabylon, SilkTork, Loodog, Gobonobo, Evenios, Jo elo , IronGargoyle, Jballentine, Ckatz, Collect, Astuishin, Slakr, Notwist, Beetstra, Optimale, Nathansands, SandyGeorgia, AdultSwim, Truthmissile, Ryulong, Kvng, M eld, Keahapana, Levineps, Iridescent, 293.xx.xxx.xx, Dakart, Shoeofdeath, J Di, Joao.caprivi, TurabianNights, Tony Fox, Jaybo33, Freelance Intellectual, Adambiswanger1, Courcelles, FairuseBot, Tawkerbot2, Dave Runger, Runderwo, Danger123, AbsolutDan, ChrisCork, Fvasconcellos, Flora68, JForget, CmdrObot, Mattbr, FunPika, Dycedarg, BeenAroundAWhile, Mrlego9, Kylu, Dgw, Wooyi, Argon233, Aventinus, Lentower, Neelix, Meodipt, KevinScott, Haridan, Jehfes, Chq, Maxxicum, Cydebot, Cahk, Samuell, Gogo Dodo, Chasingsol, Torvik, Daniel J. 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), Lunaintern, J04n, YoungTesla, Alumnum, Aaronisa amer, Pooley1234, DaveScoundrel, Zefr, Crabjuicer, JhanCRUSH, The Interior, Lenitha, Et bravo, Savecharlie, 78.26, Grantmidnight, Psychonaught, Falastine fee Qalby, Litebrite1919, Jsorr, A.amitkumar, Conductivedan, Sir towlie, Captain-n00dle, Sko1221, FrescoBot, Anonymoussell, Zombie president, Maxpowers4040, Reverendmary, Paine Ellsworth, Agent Agent, Hiram408, Kpstewart, Roswellmack, Moin.max, Sbblakey777, Allen750, HJ Mitchell, Vishnu2011, Daherb, House4556, Budtrader, Crusher7, Cpu420, Redondomax, Ddorian4004, Citation bot 1, Dare7878, Javert, Dammax07, Jcheckler, Biker Biker, Pinethicket, Jim Klahr, Jonesey95, A8UDI, Pikiwyn, Meaghan, Herbal Hi, Tea with toast, Cjsklions13, FoxBot, Mic 24, CannabisNetwork, Trappist the monk, Zklink, Aamcoregon, Vrenator, Nulibrary, Iowawindow, David Hedlund, Charcolgirl, Je rd10, Gtziavelis, Awesomeo34, Tpipos, Nnstonervibes, RjwilmsiBot, Mungox, Ufukers, Xcannabis, Darwinerasmus, Balph Eubank, Skamecrazy123, Kaitlint, 14schltr, Coinpeice, Fjstewart1, PopularMax, John of Reading, Iowa.gybo, Look2See1, Dadaist6174, Jkodadek, Mmsright21, Da Best Editz, Zero Diggity, Amorrison08, Will.a.may, Jmils1994, Robgl00, Stewart52ab, Wikipelli, K6ka, Stevenmoseley, AllstonTMitchell, Hoygan!!, Basrblog, Devonmerryman, Checkingfax, Misty MH, Traxs7, Crazydeadbread, Escabared, Maryjanemedicine, Everard Proudfoot, DigitalMeta01, H3llBot, Cimmerian praetor, GgrV, Dylan Inquisitor, Mindovermatter77, Artofscience, Timetraveler3.14, Lilleybusiness, Tolly4bolly, Bradylord, L Kensington, Dante8, Michaellatulippe, Ego White Tray, BobM3, Kdorlich, AndyTheGrump, EvanAmos, NTox, Limxzero, Wardrubrecht, TheBabyman, Spacechickengrrl, ClueBot NG, Gdaviau32, Jack Greenmaven, Galilsnap, Blaxeep, Green Tanner, MelbourneStar, Kalqaatri, Fazzme, AveVeritas, Snotbot, Johnt7731, Dro420, ScottSteiner, Widr, Antiqueight, Vrdwebservices, Asluby, Yoyokiller, Helpful Pixie Bot, Bibcode Bot, Iamtheman69, Lowercase sigmabot, BG19bot, Bigo2013, Wcallaway4, Rastamees, Thebugman18, Petrarchan47, WikiTryHardDieHard, Humphreyking, AragonCandu, Shelbowelbow, Userwhosit, Carl Wagneer, Northamerica1000, 2.1. TEXT 131 Mike.gambol, Smcg8374, Dan653, Botticcelli420, Exercisephys, Asutt81215, BoDiddly99, Msruzicka, Damyon13, Blazin123, Viridis Veritas, Doggiedayz, Epicurus B., COice6, Neuroscientist28, Glacialfox, Highlandsguy, Shirudo, Midnight toboggan, Achowat, Shaun, EdwardH, Wineland at central college, Kyle Van Rees, BattyBot, TheBaur, Jeremy112233, Chrisgedwards, Gartenspinnen, ChrisGualtieri, MMCWS, LHcheM, TylerDurden8823, Soulparadox, Gumbygreen89, Jackpots777, Trinitresque, Baklarab, Mogism, Mspu nstu 420, Cerabot~enwiki, Delysid126, Little9a9, Lugia2453, BLZebubba, SFK2, EntroDipintaGabbia, TreezySamedi, Pregnantembryo, 069952497a, CSorBb, SexyVanillaFreshness, Vanished user svoinsr8wiraek u3rhnsfvr4sb, Godot13, Diana1991, Ruby Murray, Muppet Apocalypse, Michipedian, Everymorning, Seminshooter, Ebanaian, Medische-wiet, Alderman20, Clr324, Jballan623, Jadewhit, Leif Stenberg, JETmanBanshee, BruceBlaus, Dymethylated, Sam Sailor, Mrmikecaruso, OCC JCS, Mentalmoney, Wasserm, Jodan333, ȸ, DudeWithAFeud, Meteor sandwich yum, Ktownnative, SaraMetz, Njol, Mmikhaie, Lali6038, GrahamJones1212, Talkin56, Parabolooidal, Monkbot, Renamed user 51g7z61hz5af2azs6k6, Scottyman2003, VivamusAmemus, Medgirl131, Aethyta, Poiuytrewqvtaatv123321, Handpolk, SStephens13, Steal the Kosher Bacon, LordHello1, Fhebynes, Beren98, ComicsAreJustAllRight, Sizeo nt, Antiv31, Listenforgood, Piano Concerto in F Minor, Charlotte135, C.bluth and Anonymous: 1298 • Legal history of cannabis in the United States Source: https://en.wikipedia.org/wiki/Legal_history_of_cannabis_in_the_United_States? oldid=720984019 Contributors: Ahoerstemeier, Feedmecereal, Dale Arnett, Chrism, Rfc1394, Brianshapiro, Andrew Levine, Alan Liefting, Sharavanabhava, Neutrality, Ukexpat, Discospinster, Rich Farmbrough, Deatonjr, Surachit, Rosenzweig, Hipocrite, Wikidea, Preferstobenameless, Coolgamer, Stemonitis, Richard Arthur Norton (1958- ), Pchov, Edgewise, Jaymo, RichardWeiss, BenJonson, BD2412, Rjwilmsi, Mfwills, G Clark, El Cid, RickAguirre, Buekerc1, Voodoom, Bgwhite, WriterHound, FrankTobia, Wasted Time R, Pigman, Cplbeaudoin, Rsrikanth05, Grafen, Twin Bird, Phgao, Closedmouth, KGasso, Johnpseudo, Katieh5584, SGMidence, Sardanaphalus, SmackBot, InverseHypercube, Wehwalt, AlexNordeen, Timeshifter, Peter.mottola, Hmains, NickGarvey, OldsVistaCruiser, Jprg1966, Rorybowman, Victorgrigas, Muboshgu, Zone46, JDiPierro, Captain Zyrain, Kendrick7, Salamurai, Harryboyles, Khazar, Loodog, Gobonobo, Killerlula, Normalityrelief, Goodnightmush, Nagle, Ckatz, Stwalkerster, SQGibbon, SandyGeorgia, DavidOaks, Pithecanthropus, Devourer09, CmdrObot, Kevin j, Donaldpugh, Wooyi, Lokal Pro l, Cydebot, Breedimm, Dusty relic, Shirulashem, Mattisse, Epbr123, N5iln, Marek69, Seaphoto, Dubhagan, SteveSims, Jaysweet, VoABot II, Nyttend, Avicennasis, KConWiki, Mkdw, Allstarecho, DerHexer, WLU, Tracer9999, Racepacket, CommonsDelinker, J.delanoy, Captain panda, Badmilk, DMCer, Ja 62, Steinberger, Christopher Mann McKay, Je G., Philip Trueman, Martinevans123, Id4abel, Zenswashbuckler, From-cary, Azoetrope, Demize, CMBJ, CWPappas, MilFlyboy, Breawycker, Perspicacite, Aperseghin, Oxymoron83, Tombomp, Int21h, Blacksonicus, Alive and living, StaticGull, Alatari, Dala11a, Mygerardromance, Flodadolf, LeeUSA, Elassint, ClueBot, The Thing That Should Not Be, Jdb00, Frmorrison, Excirial, Getmorehigh, Razor ame, Romatt, Another Believer, Chaosdruid, Yonskii, Callinus, NJGW, Vybr8, Classicrockfan42, DumZiBoT, Zenwhat, XLinkBot, JS747, Ost316, ESO Fan, Bobokapi, Loki racer, Shawisland, Tcncv, Noozgroop, Ashanda, Chin Chill-A Eat Mor Rodents, Simeon24601, Debresser, West.andrew.g, Lightbot, Yobot, Legobot II, Librsh, Guy1890, SwisterTwister, AnomieBOT, Jim1138, CasperBraske, Wandering Courier, Carlsotr, Eumolpo, LilHelpa, Simultaneous movement, Zad68, Zerim, Jsharpminor, AbigailAbernathy, J04n, Shirik, Back2reality07, Locobot, Brutaldeluxe, Moxy, White whirlwind, Ajax151, FrescoBot, Lothar von Richthofen, Knosisophile, DrilBot, Pinethicket, MJ94, CrowzRSA, Spazzychalk, DARTH SIDIOUS 2, RjwilmsiBot, Aircorn, Skamecrazy123, GA bot, STATicVapor, Dewritech, Immortal Glory, GoingBatty, Gimmetoo, Tommy2010, CaliFamouss, Evanh2008, Cybermud, EdEColbert, Chazzyb31, Hazard-SJ, H3llBot, AmyPentagon, AutoGeek, Jay-Sebastos, GeorgeBarnick, Wordsforthewise, Carmichael, ClueBot NG, Elperformer, Thirdagestime, Wdchk, Marechal Ney, Widr, Helpful Pixie Bot, Brambentein, Thesmuck, BG19bot, Cheywoodward2, The Banner Turbo, WikiTryHardDieHard, Northamerica1000, ZombieRamen, AliceMira, Piguy101, Mark Arsten, Jcrusin, 9711CA, BattyBot, Ziggypowe, Cyberbot II, Mikerrr, The Illusive Man, Khazar2, Soulparadox, Vichwiv, Dan12345654321, Reverend Mick man34, Mxheil, HistoricMN44, Uve bianche, Aawrodriguez, Seqqis, Stephanie515, Ebanaian, Clr324, Cidkid~enwiki, Megamondo, Kennethaw88, Robhunt99, Munchkin2013, Mr. Smart LION, Amortias, Sharilewis121, Goonsquad LCpl Mulvaney, Melodeewiki, Dbtucky, Civil society80, Noitdoesntmakeitfact, Ajackson4370, Datbubblegumdoe, Readingit, Harmon758, Potguru, Finddankweed, Coolfactperson and Anonymous: 378 • Controlled Substances Act Source: https://en.wikipedia.org/wiki/Controlled_Substances_Act?oldid=719036865 Contributors: Damian Yerrick, Grouse, Deb, Azhyd, Edward, Bewildebeast, Isomorphic, Shoaler, Tregoweth, Mkweise, JWSchmidt, Samw, Ilyanep, Charles Matthews, WhisperToMe, Katana0182, Raul654, Jamesday, Aenar, Dale Arnett, Josh Cherry, Donreed, Mirv, Postdlf, Blainster, Hadal, Seth Ilys, Cybersavior, Davidcannon, DocWatson42, TOttenville8, Lethe, Karn, Eequor, Allstar86, Wmahan, MSTCrow, Cyanoacry, Quadell, Beland, Jaguara, Bk0, Sam Hocevar, Kmweber, Mrrhum, Creidieki, Neutrality, Controlled Substance, Daevatgl, MattKingston, Archer3, Discospinster, Rich Farmbrough, Cacycle, Moki80, Exabyte, Paul August, Bender235, Mpnolan, Remember, Triona, Bdoserror, Coolcaesar, Feitclub, Bcholmes, Orbst, Cmdrjameson, Arcadian, Kjkolb, RussBlau, Mote, Googuse, 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Kurykh, BarkerJr, Methnor, Deewhite, Famspear, Scarletsmith, Azumanga1, Nuklear, Amazon10x, Msgmsg~enwiki, Stiles, BryanG, Imajes, DMacks, Ultraexactzz, Mitchumch, Roger.lee, Mightyfastpig, Cvieg, Wg0867~enwiki, Mksword, Nareek, Adavidw, Neo Piper, Blahity, Gobonobo, Robo sh, Shattered, Davemcarlson, Oswald Glinkmeyer, Rickington, Levineps, T. Wong, Woodshed, Thricecube, Frank Lofaro Jr., Tawkerbot2, Heqs, Eastlaw, Fvasconcellos, Netaustin, Rszasz, Rndx, Ohthelameness, Antelopotamus, Robert Rossi, Meodipt, Wykebjs, Shanew2, Cydebot, Reywas92, Gogo Dodo, Travelbird, Khatru2, Hopping, Ibanix, Skittleys, Tawkerbot4, RXPhd, Kiko123, Arcayne, Omicronpersei8, Christopher Isar, Thegoodson, Schicksal, Transhumanist, The Person Who Is Strange, Ju66l3r, AntiVandalBot, Varlet16, Luna Santin, Mrath, CFang, Tillbury, Magioladitis, Puellanivis, ZPM, TheSlyFox, Dpd esq, Clmartin, Nyttend, Tins128, Inhumandecency, JaGa, Tracer9999, Pvosta, MartinBot, Onlynone, HeyWire, Nikpapag, Gaidheal1, ReaderMan, J.delanoy, Captain panda, Silverxxx, NeoPlatonist, MikeTheActuary, Iain marcuson, OAC, M-G, Zero Serenity, Floater uss, A.Arc, Student7, The Right Honourable, Richardmormegil, Pdcook, Camel guy, DrDentz, Alexandria, Philip Trueman, Oshwah, Shalom S., Someguy1221, Deepz2, PKDASD, Falcon8765, Katari Devi, Daveh4h, Dusti, BloodDoll, Barliner, Ketone16, Flyer22 Reborn, Ddxc, Ellusion, SimonTrew, Int21h, Danelo, Kumioko (renamed), Anchor Link Bot, Hamiltondaniel, Eigenman, Kallepash, ClueBot, Epsilon60198, TypoBoy, Trivialist, Terrorist96, Levipatick, Smit8678, NuclearWarfare, WillyOnWeelslol, RayquazaDialgaWeird2210, Sarsaparilla, BOTarate, Chimino, Ddperk80, DumZiBoT, Otr500, AlanM1, Guyatrandom, Jytdog, 132 CHAPTER 2. 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JuggaloICP, SP1977, AlexTheWhovian, Beren98, Mbcap, Tkadm30, A.Ho mann Lives, Cannabisparadise, Cannabisscientist, Jnowat, Oaizpurua002, Canna78, Vmartinez18 and Anonymous: 245 • Cannabinoid receptor Source: https://en.wikipedia.org/wiki/Cannabinoid_receptor?oldid=715420376 Contributors: The Anome, Fnielsen, Edward, Conti, Steinsky, Fuelbottle, Centrx, Ferre, PFHLai, Mearlon, Cacycle, ESkog, Jnestorius, Arcadian, Zachlipton, Howrealisreal, Riana, Mandarax, Canderson7, Rjwilmsi, Rpinz, Miserlou, JdforresterBot, Stevenfruitsmaak, YurikBot, Ino5hiro, SmackBot, David.Throop, Chris the speller, Thumperward, Feralcoder, Roadnottaken, Adamantios, Drphilharmonic, LightI3ulb, Mike1901, Paul venter, Goldengrape, CmdrObot, Meodipt, Gogo Dodo, Anthonyhcole, Ho meier, Murftown, Magioladitis, WLU, Nono64, Boghog, Imalipusram~enwiki, Mikael Häggstrﬁm, LittleHow, Enix150, VolkovBot, Kurgus, Flyer22 Reborn, Alexbrn, ClueBot, PixelBot, Panoramix303, 1ForTheMoney, Coenvanhasselt~enwiki, DumZiBoT, AngelHerraez, ErgoSum88, Ziggy Sawdust, Addbot, DOI bot, Tide rolls, OlEnglish, Luckas-bot, Yobot, Flikr, Dmarquard, Gﬁtz, Rjanag, Citation bot, Shcha, Dagrun, Capricorn42, Carrod65, Lunaintern, Custoo, FrescoBot, Citation bot 1, LittleWink, Tea with toast, Bharat2011, Wikielwikingo, Rogen123, EmausBot, Dcirovic, Lethebramble, DouglasMcHugh, Wol ol2, ClueBot NG, Osterluzei, Korrawit, Snotbot, Frietjes, Tryptamines, HMSSolent, BG19bot, Petrarchan47, Frze, Mariskaxo, Dexbot, SimonPerera, Seppi333, Logan Lynn Roberts, Parabolooidal, Monkbot, Mangokeylime, 分液漏⽃, Crazy5150760, Medgirl131, Bderiso and Anonymous: 84 • Cannabidiol Source: https://en.wikipedia.org/wiki/Cannabidiol?oldid=721216146 Contributors: Bryan Derksen, MadSurgeon, Julesd, Andrevan, Selket, Phil Boswell, Robbot, St3vo, Vanished user 1234567890, Ary29, Ukexpat, Alexrexpvt, Rich Farmbrough, Cacycle, Zaslav, Kwamikagami, Causa sui, Tgeller, Renice, Viriditas, Eric Kvaalen, Benjah-bmm27, Howrealisreal, Thoric, Axl, Animated Cascade, Ceyockey, Lofor, BD2412, DePiep, Rjwilmsi, Heah, FlaBot, A scientist, Margosbot~enwiki, SouthernNights, Shao, Physchim62, Bgwhite, WriterHound, ThunderPeel2001, Mikalra, Rsrikanth05, NawlinWiki, Nick, Revaaron, ASmartKid, Fjeinca, WhataMack, SmackBot, Alex Ex, KVDP, Edgar181, Ohnoitsjamie, HartzR, Elixir0219, Zachorious, Frantik~enwiki, Ioscius, Daqu, BullRangifer, Drphilharmonic, DMacks, Acdx, Fireemblem555, Gobonobo, Ckatz, Smith609, Beetstra, SandyGeorgia, DeLarge, Harej bot, ShelfSkewed, Meodipt, Linuxrocks123, Cydebot, Supposed, Mrt50, DumbBOT, Alaibot, Thijs!bot, CopperKettle, Subvertc, Headbomb, Nashmaximus, SummerPhD, Smartse, 18hands, Badgerbear, NLuchs, Noobeditor, Swpb, Cadsuane Melaidhrin, ChemNerd, Leyo, Fconaway, Boghog, Notreallydavid, Enix150, KylieTastic, Funandtrvl, Meiskam, Sergivs-en, MenasimBot, Oshwah, Wikieditor12, Benrr101, Wiae, LetTheSunshineIn, Cheryladay, Gamesguru2, Bororo23, Vvevo, Yintan, Flyer22 Reborn, Alexbrn, Danelo, Eplebel, Literaturegeek, 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Qxukhgiels, FoCuSandLeArN, Webclient101, Mogism, Will Sandberg, Steinsplitter, NotoriousPyro, UseTheCommandLine, ComfyKem, ScoutKnot, Michael Ten, Youtalkfunny, Tentinator, ArmbrustBot, Clr324, Mer , ArthurJomasSmith, Tired canadian, 2.1. TEXT 133 Glucuronide, SpeakerTR, Tankbank420, Dave Underbridge, HeyItsAedan, JaconaFrere, Zouloum, MissSpade602, ColRad85, Logan Lynn Roberts, C.o.young, Monkbot, Renamed user 51g7z61hz5af2azs6k6, Moonboy54, AKS.9955, Mattdavid22, Mangokeylime, Silent Singularitarian, Wendywhatnot, Daveyboy9999, Jakens84, JackDemarco 420, Medgirl131, Tristonlarsen, Rowanbiggs, Aethyta, Shirt0ripper0, DystoniaPatient, Beren98, Foutjeweg, Cheminded, Nuclearpharm, CannaBiDial, Drpetermj, J.alonso1, Listenforgood, Econ48, Cannabisparadise, Cannabisscientist, Madkamin, SettleGod, Mangofast, Ambitiouz79, Simonhellmans, Whammermam, Rareyes16, Ceherrera1986, Bossross93 and Anonymous: 211 • Cannabinol Source: https://en.wikipedia.org/wiki/Cannabinol?oldid=713181737 Contributors: Robbot, Rich Farmbrough, Cacycle, Pacula, Howrealisreal, Ceyockey, DePiep, Rjwilmsi, FlaBot, Physchim62, Pegship, SmackBot, Eskimbot, Frymaster, Edgar181, Lieutenant Colonel Frank Slade, Beetstra, Saxbryn, Cydebot, Ri eman 82, Absentis, Alaibot, Subvertc, Kaabi, ChemNerd, VolkovBot, MenasimBot, THC Loadee, Benrr101, Chem-awb, Anthonyvidal, Eeekster, Panoramix303, Stevem848, Vanished 45kd09la13, Addbot, DOI bot, LaaknorBot, Wormantson, Luckas-bot, Ptbotgourou, Fraggle81, CheMoBot, Anypodetos, AnomieBOT, Gﬁtz, ‫حس ع ي ا بط‬, Srich32977, P-kun80, Custoo, Micasta, Citation bot 1, A8UDI, RedBot, MastiBot, BogBot, PotatoBot, Peryeat, Osterluzei, Jonfarrimond, Bemopa, Nikos 1993, NotWith, ArmbrustBot, Garzfoth, Noyster, MissSpade602, Monkbot, Sentaloc, Medgirl131, Beren98, Cheminded, Cannabisscientist, Potguru and Anonymous: 19 • Cannabis sativa Source: https://en.wikipedia.org/wiki/Cannabis_sativa?oldid=718957748 Contributors: Bryan Derksen, Snoyes, Marteau, Bogdangiusca, Beck, Charles Matthews, Grendelkhan, Pollinator, Nufy8, Pigsonthewing, Altenmann, Hadal, Cyberia23, Dave6, Centrx, MPF, Fudoreaper, Everyking, Mboverload, JoJan, MacGyverMagic, Unti er, Sharavanabhava, Discospinster, Somegeek, Leyanese, Arthur Holland, Mani1, Bumhoolery, Paul August, Pjf, Dennis Brown, Jburt1, Dannown, Adambro, Renice, Peter Greenwell, Bobo192, Smalljim, MavereX, Alansohn, JYolkowski, Craigy144, Howrealisreal, Ekko, Lucky dog, Cdc, Eukesh, Djlayton4, SidP, Evil Monkey, Sciurinæ, Ndteegarden, Squiquifox, Mahanga, Stemonitis, Boothy443, Jannex, Commander Keane, Laurel Bush, Prashanthns, Tokek, Mandarax, RichardWeiss, Qwertyus, Ligar~enwiki, Rjwilmsi, Ricardo Carneiro Pires, Yamamoto Ichiro, Eubot, Awotter, Crazycomputers, Nivix, Choess, R Lee E, TheSun, Aspro, Chobot, Gdrbot, Bgwhite, Digitalme, WriterHound, Wavelength, RussBot, M dog, Splash, Chris Capoccia, CambridgeBayWeather, Seegoon, Chenome, Asarelah, Tzustrategy, Arouck, Theda, Btrujill, Kf4bdy, SmackBot, Vald, Hardyplants, Metagrapher, Gjs238, Ohnoitsjamie, Chris the speller, Master Jay, Bluebot, Rkitko, Sadads, Colonies Chris, A. B., Zachorious, Mladi lozof, Can't sleep, clown will eat me, TheKMan, Khoikhoi, PetterBudt, E. Sn0 =31337=, Simonapro, Dreadstar, Drooling Sheep, Trickse, Linnell, Coredesat, Ckatz, A. Parrot, Stwalkerster, Spydercanopus, Ryulong, LadyofShalott, Robinavery, Tawkerbot2, AbsolutDan, DManSeanyD, CmdrObot, DeLarge, Harej bot, Chmee2, Neelix, Chq, Cydebot, Nabokov, Flis~enwiki, Lewisskinner, Helvetica, Subvertc, Marek69, Jesuswa e, Dawnseeker2000, Escarbot, AntiVandalBot, Jj137, Cheesecycle, Alphachimpbot, Myanw, Bschott, JAnDbot, MER-C, Hydro, Michig, GoodDamon, Acroterion, Magioladitis, Bongwarrior, VoABot II, Xb2u7Zjzc32, Lucyin, Chondrite, Rich257, Cgingold, Allstarecho, Khalid Mahmood, Hbent, MartinBot, ChemNerd, Nono64, Pablo E$cobar, El0i, J.delanoy, Trusilver, Satnav (usurped), Ashcraft, Ignatzmice, Bergin, Jeepday, AWardEsq., Ljgua124, Plindenbaum, Buddha379, D-Kuru, CardinalDan, Idioma-bot, VolkovBot, Midoriko, ABF, GeorgeLTirebiter, BotKung, Penarc, Agyle, Billinghurst, Sessions211, Geanixx, Skarz, SylviaStanley, SieBot, MunkyJuce69, Gerry Wachovsky, Gabrasyag, Radon210, Terper, Bananastalktome, Rajking, N96, Iknowyourider, Rotovia, Dabomb87, Escape Orbit, ClueBot, The Thing That Should Not Be, Isatemple, Blanchardb, Michał Sobkowski, Nikion, Rodney420, Excirial, Rhododendrites, Ngebendi, Kakofonous, Mla s, Another Believer, Positron222, Wikiwikiwak23, Yonskii, Johnwill45, Helixweb, The lant, Jytdog, Ost316, TFOWR, Jibstarz, Alexius08, Kaiwhakahaere, Lemmey, Thatguy int, Addbot, JBsupreme, Garry Minor, Landon1980, Barnacles phd, Ronhjones, Fieldday-sunday, Cuaxdon, RTG, Belizeking, CUSENZA Mario, Cowzor, Flakinho, Campolongo, Luckas-bot, Yobot, Chavorz, Kartano, Andreasmperu, KaDa 310, Krayneeum, AnomieBOT, DemocraticLuntz, Gﬁtz, Killiondude, Ganjabro, Giles Martin, Citation bot, OllieFury, BrindenChandice, Dspeake, GB fan, MauritsBot, Xqbot, Rape porn, Jamaicascott94, Stanzilla, Rkasbohm, Groovenstein, ‫ب درچود‬, Crabjuicer, Kyng, Psychonaught, Shadowjams, Sesu Prime, Custoo, Simuliid, A little insigni cant, Cannolis, Krish Dulal, Pinethicket, A8UDI, MastiBot, Herbal Hi, Scottabis, Keri, FoxBot, Ferang, David Hedlund, Jesse V., Buddhaboss, Guruseeds, EmausBot, Ellis408, WikitanvirBot, Threelittlebirdies, Look2See1, Stonerwhat, Vanished user zq46pw21, K6ka, Dark ght, Alfredo ougaowen, Ronk01, Kinkysex32, Donner60, 14skateboi, DemonicPartyHat, Themist444, ClueBot NG, Somedi erentstu , CocuBot, Vjiced, 2ichar98, Jbeau18, Helpful Pixie Bot, Sainttex, BigT113, DBigXray, Northamerica1000, AvocatoBot, NotWith, Hiddekat, Aisteco, Fylbecatulous, TheBaur, ChrisGualtieri, Frosty, Michipedian, Clr324, Zachzierler, Vieque, Mangokeylime, Jacob7280, Satprem Ghose, LiphradicusEpicus, Lea yContent, Medgirl131, Goonsquad LCpl Mulvaney, Rowanbiggs, Aethyta, Kingraz203, Beren98, Cujo009, Non-pupulus-impilium, Flyingcocks, M.P. (MasterPiece), Agarcia0504, Ras Benjih, MCEllis, Aaron chopra, Somebodycall911, Rcsloan87, Katranito, Oaizpurua002, Canna78 and Anonymous: 420 • Cannabis indica Source: https://en.wikipedia.org/wiki/Cannabis_indica?oldid=721021776 Contributors: Bogdangiusca, Eugene van der Pijll, Pollinator, DocWatson42, Gdr, Sharavanabhava, Discospinster, RoyBoy, Dennis Brown, Stygian23, Stefantalpalaru, Stemonitis, Alvis, RichardWeiss, Zachjones4, Rjwilmsi, FlaBot, R Lee E, Gdrbot, WriterHound, YurikBot, Asarelah, TheMadBaron, SMcCandlish, DoriSmith, Hiddekel, Bstender~enwiki, Gjs238, Bluebot, Rkitko, Amex, Gruzd, Simonapro, OranL, Scientizzle, Trickse, Ckatz, Ri c, Iridescent, UncleDouggie, AbsolutDan, Heqs, Neelix, Chq, Doug Weller, Subvertc, Ransack., AntiVandalBot, Joe Schmedley, Alphachimpbot, JAnDbot, JaSsa, Magneez, Chondrite, Adavidb, Ljgua124, KylieTastic, Meiskam, Billinghurst, LoreMiles, Whichiswhich, Tlustulimu, Yonskii, Ost316, Addbot, First Light, Yobot, AnomieBOT, Gﬁtz, Jim1138, LilHelpa, Petropoxy (Lithoderm Proxy), Thehelpfulbot, Pinethicket, Orenburg1, Lotje, David Hedlund, Tbhotch, EmausBot, RA0808, Jak5246, Alfredo ougaowen, Ronk01, SadmAnn, DemonicPartyHat, ClueBot NG, Somedi erentstu , Vjiced, Widr, Helpful Pixie Bot, Sainttex, BigT113, Strike Eagle, KLBot2, Plantdrew, BG19bot, Cheywoodward2, Northamerica1000, AdventurousSquirrel, Altaïr, Meelika h, BattyBot, TheBaur, Justincheng12345-bot, Dexbot, Rakkalrast, NYBrook098, Buttchuckle50, Mangokeylime, LiphradicusEpicus, Hexthat, Lea yContent, Medgirl131, Goonsquad LCpl Mulvaney, Jameshelsing, Ihiyotl, Doobitastic, Lennonwoof, Beren98, Asdfjkl;90210, Drpetermj, Non-pupulus-impilium, KasparBot, MCEllis, Anniegreenjeans, Wolfdoggy and Anonymous: 83 • Cannabis ruderalis Source: https://en.wikipedia.org/wiki/Cannabis_ruderalis?oldid=720538359 Contributors: Bogdangiusca, Eugene van der Pijll, DocWatson42, Broux, Sonjaaa, Smalljim, Thoric, Stygian23, Redvers, Wayward, JHMM13, RexNL, Choess, Gdrbot, Semolo75, Gjs238, Rkitko, Gruzd, Simonapro, Rory096, Ri c, H, Tawkerbot2, Ruderalis13, Billy shzwei, The Man13, Bradmeister2006, Alaibot, ReverendG, Alphachimpbot, SilentWings, Chondrite, Quintrixer, Shellwood, GDW13, VolkovBot, Billinghurst, Flyer22 Reborn, Jojalozzo, GorillaWarfare, Gene93k, Boing! said Zebedee, John Nevard, Yonskii, Arlolra, Mjpresson, Brazzo di Lanzo, MystBot, Marchije, Addbot, Angrense, Yobot, Fraggle81, AnomieBOT, Materialscientist, 4twenty42o, Prari, Lothar von Richthofen, Krish Dulal, I dream of horses, Bgmur, Dadaist6174, Dcirovic, K6ka, Alfredo ougaowen, Le.Loup.Gris, Rcsprinter123, Donner60, EdoBot, DemonicPartyHat, ClueBot NG, Afner, Baphomet1001, Plantdrew, Megalibrarygirl, Northamerica1000, Chrisgedwards, Skybone, ChrisGualtieri, Khazar2, Dexbot, Michipedian, Midowo, Clr324, 134 CHAPTER 2. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES YiFeiBot, Turtire, ThatDandyMan, Mangokeylime, Hexthat, Thereppy, Medgirl131, Goonsquad LCpl Mulvaney, Rowanbiggs, Skeletalclown, Ihiyotl, Daawrfy, MCEllis, Baking Soda, Qzd, Hollyweed420 and Anonymous: 69 • Hashish Source: https://en.wikipedia.org/wiki/Hashish?oldid=720736286 Contributors: AxelBoldt, Mav, Bryan Derksen, Malcolm Farmer, Lightning~enwiki, Mbecker, Palnatoke, Pit~enwiki, Gabbe, Yann, Jwk, CatherineMunro, Angela, Jebba, Deisenbe, WhisperToMe, Wik, LMB, Thue, Pollinator, Carlossuarez46, Denelson83, Robbot, Clngre, Rebrane, UtherSRG, Isopropyl, Anthony, Matt Gies, Centrx, DocWatson42, Marnanel, Fudoreaper, Netoholic, Lupin, Everyking, Alison, Wolfe, Gilgamesh~enwiki, Mboverload, Eequor, Khalid hassani, SWAdair, Pne, Bobblewik, Kukuman, Antandrus, Mis tToys, Schwael, Jossi, Rdsmith4, Kesac, Anythingyouwant, Clarknova, Parakalo~enwiki, Ukexpat, Adashiel, Esperant, Mike Rosoft, Discospinster, Avriette, Guanabot, Kdammers, 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Richards, Matdrodes, EoGuy, Mild Bill Hiccup, Sinnefa~enwiki, Ottawa4ever, Barrett Ross, Veryhuman, IPodAddict181, Addbot, AllanHall38e, Cuax- 2.1. TEXT 135 don, OlEnglish, Noumenon, Luckas-bot, Yobot, AnomieBOT, Kmcmaster08, GrouchoBot, Omnipaedista, SassoBot, Psychonaught, Hamamelis, Metalman94, OgreBot, Yokin707, Animalparty, Obsidian Soul, EmausBot, Susfele, Westley Turner, Augurar, Coasterlover1994, SBaker43, Nzfauna, ClueBot NG, Satellizer, PaleCloudedWhite, Osterluzei, Sminthopsis84, Clr324, HalfGig, Morganclem, Rebirth71, FloraWilde, DanDanger06, Eteethan, Roohi.byakod and Anonymous: 84 • Hemp Source: https://en.wikipedia.org/wiki/Hemp?oldid=721030620 Contributors: Bryan Derksen, SimonP, Zadcat, JDG, Leandrod, Stevertigo, Edward, Paul Barlow, Gabbe, GTBacchus, Kosebamse, Ahoerstemeier, Julesd, Glenn, Bogdangiusca, Charles Matthews, Andrewman327, Furrykef, Taxman, LMB, Rei, Earthsound, AnthonyQBachler, Pollinator, Francs2000, Bo y b, Altenmann, Nurg, LGagnon, Davodd, Hadal, Antonin~enwiki, Arm, Xanzzibar, Alan Liefting, Jeremiah, Matt Gies, Centrx, MPF, Kbahey, Kapow, Tom harrison, Mark T, Enfors, Guanaco, Solipsist, Matthead, Foobar, Bobblewik, Golbez, Stevietheman, Pgan002, Slavering.dog, Antandrus, FelineAvenger, Jossi, Sharavanabhava, B.d.mills, Mschlindwein, Ukexpat, Cab88, Ashmodai, Thorwald, Shotwell, Mike Rosoft, Natrij, Eyrian, DanielCD, Discospinster, Rhobite, Pak21, Florian Blaschke, Smyth, Dbachmann, Pavel Vozenilek, Tribble, Bender235, Mateo SA, Goplat, Mashford, Pedant, MisterSheik, CanisRufus, Ben Webber, British Ben, Laurascudder, The bellman, RoyBoy, Causa sui, Bastique, Bobo192, Longhair, Viriditas, Jericho4.0, Vortexrealm, Elipongo, Gira edata, MPerel, Nsaa, Alansohn, Nereocystis, Howrealisreal, Thoric, Mac Davis, Denniss, NTK, Hohum, Snowolf, ProhibitOnions, ComCat, Bsadowski1, JonSangster, LordAmeth, Gene Nygaard, Frankg, Geodejerry, Crosbiesmith, Jwanderson, Somedude, Kuohatti, Bobrayner, Thryduulf, Velho, Richard Arthur Norton (1958- ), Pekinensis, Woohookitty, Jannex, Derktar, StradivariusTV, EnSamulili, BmacD, Miss Madeline, Tabletop, Firien, Bluemoose, Steinbach, GregorB, Laurel Bush, Sendai2ci, Sin-man, RichardWeiss, Champthom, Deltabeignet, BD2412, Kbdank71, Kane5187, Josh Parris, Sjﬁ, Rjwilmsi, Salix alba, Vegaswikian, Bubba73, Bensin, DirkvdM, Ansbachdragoner, EvanSeeds, Loggie, JdforresterBot, Kerowyn, Klosterdev, Pathoschild, RexNL, Ewlyahoocom, Gurch, BjKa, Jrtayloriv, Fresheneesz, Aspro, Fourdee, David91, Bgwhite, WriterHound, Joseph11h, Vmenkov, Wavelength, Coltius, Sceptre, Hairy Dude, Mongol, Stu OfInterest, Dsii, GSchjetne, Jellocube27, Chris Capoccia, JabberWok, Raquel Baranow, Hydrargyrum, Adelaarvaren, Gaius Cornelius, Rsrikanth05, Skubasteve834, NawlinWiki, Turgonml, Curtis Clark, Badagnani, Arichnad, Malsdavis, Gizzame, HempKnight, ONEder Boy, R'son-W, Yoninah, Dogcow, Irishguy, Mooncowboy, Marknesbitt, Zagalejo, Paaskynen, Rallette, Martinwilke1980, Nlu, Miblo, Pb30, SV Resolution, Peyna, Shawnc, Andy Westcott, Xil, Jack Upland, Cheesewizard, N Yo FACE, Anthony717, Snalwibma, Yvwv, Attilios, SmackBot, Historian932, McGeddon, Pgk, C.Fred, Agonotheta, Jacek Kendysz, Eaglizard, Gjs238, Kintetsubu alo, Edgar181, Peter Isotalo, Gilliam, Portillo, Ohnoitsjamie, Eug, Awaggener, MagnusW, Jon513, Victorgrigas, Deli nk, Uthbrian, Robth, Gruzd, Brinerustle, Zymatik, Mladi lozof, Kotra, Can't sleep, clown will eat me, Shalom Yechiel, Metallurgist, Init~enwiki, Anicholo, Lantrix, Zazpot, VMS Mosaic, Dinjiin, Sloppyjoes7, Addshore, Bardsandwarriors, Davard, Edivorce, Abrahami, Nonforma, Cybercobra, Dwchin, Nakon, Lenbrazil, SpiderJon, DMacks, Sammy1339, Zzorse, Twir, Wintersweet, Kukini, Ged UK, Elfuegocaliente, AThing, Agradman, Andrewouss, U-571, NormalGoddess, Soap, Changtaiyeh~enwiki, John, Fanx, Rigadoun, Gobonobo, Sir Nicholas de Mimsy-Porpington, Michael Bednarek, Tim Q. 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TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES breeder, Roscoecat sh, Babapa, Sven Manguard, Whoop whoop pull up, Manytexts, ClueBot NG, Jaooo, Panjames, Kuber300, Nininga1, PainerJ, Hemp-cosmetics, Nickstarin nity, Bilrand, Mastahrolla, O.Koslowski, Biosketch, Widr, Hemp activist, Xdeath214, MerlIwBot, Helpful Pixie Bot, Crazymonkey1123 public, Ramaksoud2000, Abnerkadabra, BG19bot, Cheywoodward2, Nishantshreshth, Sterling.M.Archer, Thehawkseye, Petrarchan47, Emayv, Crocodilesareforwimps, Nickhemp, MusikAnimal, Supotmails, Benzband, Jcrusin, Fakini, MukashiEcho, Verdnase, Hempbuilding, Acornz11, Fylbecatulous, Jax555, BattyBot, Scottgilligansewell, David.moreno72, Susiedarling, Mr.Bawsaq, Pratyya Ghosh, Cyberbot II, Dawgseph, Khazar2, Guywholikesca2+, Endless being, Kioloss, Feliz Flor, Hmainsbot1, Mogism, Lugia2453, Deturtlemon1, Frosty, SFK2, Cholland420, Vano793, Project Osprey, Stewie.Gri n.254, Diogenes The Cynic II, Ilacin, Vanamonde93, I am One of Many, Melonkelon, ScienceandFitness, What-power, Sbinning, Clr324, Pheppel, Abschumann, Patsy Harmsen, Hnhemp, Colbey84, Amandanicpage, Lazaria, Meteor sandwich yum, GrahamJones1212, Calkuta, Monkbot, Willgood0, Seamurph, Mangokeylime, Wikinerd101boi, Weefon, Chrisw80, KatrinaJ84, TanaLee, ACanadianToker, Signedzzz, Paisarepa, Michelle wram, Tar-Elessar, LOMATSUI, 22Signals, Dracoshempemporium, Joshuapanek, Lluquis, MiserlyGira e, Salvebrutta, Cotter01, GeneralizationsAreBad, Amccann421, Jerodlycett, Werallconnected, Fooorrest, SrajanMishra89, TinkerbellCB250, Emo4video, Ropeplus, Hemp Authority, Ingo Trautenberger, Permstrump, Chadith, Royto t, Allthefoxes, IceRayan2479, Potguru, IMALLWEED71, Park0582, Robbie souter glasgow darnley, HempFan, Liltwixs and Anonymous: 979 • Cannabis Source: https://en.wikipedia.org/wiki/Cannabis?oldid=720477972 Contributors: Damian Yerrick, AxelBoldt, Tobias Hoevekamp, Kpjas, MichaelTinkler, Carey Evans, Brion VIBBER, Eloquence, H.J., Vicki Rosenzweig, Mav, Bryan Derksen, 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When using this image in external sources it can be cited as: • File:Bodily_effects_of_cannabis.svg Source: https://upload.wikimedia.org/wikipedia/commons/e/ef/Bodily_effects_of_cannabis.svg License: Public domain Contributors: All used images are in public domain. Original artist: Mikael Häggstrﬁm • File:C3-cannabielsoic_acid_B.png Source: https://upload.wikimedia.org/wikipedia/commons/b/b7/C3-cannabielsoic_acid_B.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). • File:C3-cannabielsoin.png Source: https://upload.wikimedia.org/wikipedia/commons/3/37/C3-cannabielsoin.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. 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Original artist: No machinereadable author provided. Cacycle assumed (based on copyright claims). 2.2. IMAGES 139 • File:CBD-type_cyclization_of_cannabinoids.png Source: https://upload.wikimedia.org/wikipedia/commons/d/dc/CBD-type_cyclization_ of_cannabinoids.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). • File:CBE-type_cannabinoid.png Source: https://upload.wikimedia.org/wikipedia/commons/8/87/CBE-type_cannabinoid.png License: CCBY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machinereadable author provided. 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Cacycle assumed (based on copyright claims). • File:Cannabichromanone.png Source: https://upload.wikimedia.org/wikipedia/commons/a/aa/Cannabichromanone.png License: CC-BYSA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machinereadable author provided. Cacycle assumed (based on copyright claims). • File:Cannabichromene.png Source: https://upload.wikimedia.org/wikipedia/commons/c/cd/Cannabichromene.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabichromenic_acid_A.png Source: https://upload.wikimedia.org/wikipedia/commons/a/af/Cannabichromenic_acid_A.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). • File:Cannabichromevarine.png Source: https://upload.wikimedia.org/wikipedia/commons/3/34/Cannabichromevarine.png License: CC-BYSA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machinereadable author provided. Cacycle assumed (based on copyright claims). • File:Cannabichromevarinic_acid_A.png Source: https://upload.wikimedia.org/wikipedia/commons/4/4c/Cannabichromevarinic_acid_A. png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). • File:Cannabicitran.png Source: https://upload.wikimedia.org/wikipedia/commons/8/83/Cannabicitran.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). 140 CHAPTER 2. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES • File:Cannabicoumaronone.png Source: https://upload.wikimedia.org/wikipedia/commons/8/8a/Cannabicoumaronone.png License: CC-BYSA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machinereadable author provided. Cacycle assumed (based on copyright claims). • File:Cannabicyclol.png Source: https://upload.wikimedia.org/wikipedia/commons/4/49/Cannabicyclol.png License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Cannabicyclolic_acid_A.png Source: https://upload.wikimedia.org/wikipedia/commons/e/e9/Cannabicyclolic_acid_A.png License: CCBY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machinereadable author provided. Cacycle assumed (based on copyright claims). • File:Cannabicyclovarin.png Source: https://upload.wikimedia.org/wikipedia/commons/0/01/Cannabicyclovarin.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). • File:Cannabidiol-C4.png Source: https://upload.wikimedia.org/wikipedia/commons/a/a7/Cannabidiol-C4.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). • File:Cannabidiol.png Source: https://upload.wikimedia.org/wikipedia/commons/3/3f/Cannabidiol.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. 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Cacycle assumed (based on copyright claims). • File:Cannabidiol_numbering.png Source: https://upload.wikimedia.org/wikipedia/commons/9/9f/Cannabidiol_numbering.png License: Public domain Contributors: SYNTHESIS OF DELTA-3-CANNABIDIOL AND THE DERIVED RIGID ANALOGS, 1987, p. 20 (37 in PDF le) Original artist: NAGARAJA, KODIHALLI NANJAPPA • File:Cannabidiolic_acid.png Source: https://upload.wikimedia.org/wikipedia/commons/d/d2/Cannabidiolic_acid.png License: CC-BY-SA3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. Cacycle assumed (based on copyright claims). • File:Cannabidiolic_acid_A_cannabitriol_ester.png Source: https://upload.wikimedia.org/wikipedia/commons/b/b8/Cannabidiolic_acid_ A_cannabitriol_ester.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. 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Original artist: Erik Fenderson • File:Cannabis_Plant.jpg Source: https://upload.wikimedia.org/wikipedia/commons/e/ec/Cannabis_Plant.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: Cannabis Training University • File:Cannabis_Sativa_Querschnitt.JPG Source: https://upload.wikimedia.org/wikipedia/commons/8/8a/Cannabis_Sativa_Querschnitt.JPG License: CC BY-SA 3.0 Contributors: Own work Original artist: Fenrisul r • File:Cannabis_harvesting_(USSR,_1956).png Source: https://upload.wikimedia.org/wikipedia/commons/0/0c/Cannabis_ Copyrighted free use Contributors: "Э я " Origiharvesting_%28USSR%2C_1956%29.png License: nal artist: Unknown<a href='//www.wikidata.org/wiki/Q4233718' title='wikidata:Q4233718'><img alt='wikidata:Q4233718' src='https://upload.wikimedia.org/wikipedia/commons/thumb/f/ff/Wikidata-logo.svg/20px-Wikidata-logo.svg.png' width='20' height='11' srcset='https://upload.wikimedia.org/wikipedia/commons/thumb/f/ff/Wikidata-logo.svg/30px-Wikidata-logo.svg.png 1.5x, https://upload.wikimedia.org/wikipedia/commons/thumb/f/ff/Wikidata-logo.svg/40px-Wikidata-logo.svg.png 2x' data- le-width='1050' data- le-height='590' /></a> • File:Cannabis_indica.jpg Source: https://upload.wikimedia.org/wikipedia/commons/7/77/Cannabis_indica.jpg License: FAL Contributors: 1. Ward, A Holmes, B (1985): Nabilone: a preliminary review of its pharmacological properties and therapeutic use. Drugs 30, 127-144. 2. Gagnon,B Bruera,E (1998): A review of the drug treatment of cachexia associated with cancer. Drugs 55, 675-688. 142 CHAPTER 2. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 3. Nahas,G Sutin,K Bennett,WM (2000): Review of Marihuana and medicine. N Engl J Med 343, 514-515. 4. Tinklenberg,JR (1975): What a physician should know about marihuana. Rat Drug Ther 9/7, 1-6. 5. Grinspoon,L Bakalar,JB (1995): Marihuana as medicine. A plea for reconsideration. JAMA 273, 1875γ1876. 6. Voth,EA Schwartz,RH (1997): Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 126, 791γ798. 7. Merritt,JC Crawford,WJ Alexander,PC Anduze,AL Gelbart,SS (1980): E ect of marijuana on intraocular and blood pressure in glaucoma. Ophthalmology 87, 222γ228. 8. Morris,K (1997): The cannabis remedy- wonder worker or evil weed? Lancet 350, 1828. Original artist: Axsadi Sánchez de Tagle • File:Cannabis_indica_Selkem.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/c0/Cannabis_indica_Selkem.jpg License: GPL Contributors: ? Original artist: ? • File:Cannabis_leaf.svg Source: https://upload.wikimedia.org/wikipedia/commons/a/a8/Cannabis_leaf.svg License: CC BY-SA 3.0 Contributors: This vector image was created with Inkscape. Original artist: Oren neu dag • File:Cannabis_leaf_2.svg Source: https://upload.wikimedia.org/wikipedia/commons/4/44/Cannabis_leaf_2.svg License: CC BY-SA 3.0 Contributors: Own work by uploader, referenced public domain photograph Image:Potleaf.jpg uploaded by User:Dohduhdah Original artist: Christopher Thomas • File:Cannabis_male_flowers.JPG Source: https://upload.wikimedia.org/wikipedia/commons/c/c0/Cannabis_male_flowers.JPG License: CC-BY-SA-3.0 Contributors: ? 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Published and copyrighted by GeraUntermhaus, FE Kﬁhler in 1887 (1883–1914). Obtained from http://caliban.mpiz-koeln.mpg.de/~{}stueber/koehler/ . Originally uploaded to wikipedia by w:User:Chmod007 on 19:57, 14 November 2004. An enhanced version was uploaded to wikipedia by w:User:DarkEvil on 17:39, 14 December 2006 Original artist: This is a retouched picture, which means that it has been digitally altered from its original version. Modi cations: Enhanced contrast, sharpness. • File:Cannabis_sativa_leaf_diagnostic_venation_2012_01_23_0829_c.jpg Source: https://upload.wikimedia.org/wikipedia/commons/d/ d4/Cannabis_sativa_leaf_diagnostic_venation_2012_01_23_0829_c.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: JonRich eld • File:Cannabissativadior.jpg Source: https://upload.wikimedia.org/wikipedia/commons/5/5f/Cannabissativadior.jpg License: Public domain Contributors: Scan aus: Pedanius Dioscurides – Der Wiener Dioskurides. Codex medicus Graecus 1 der Österreichischen Nationalbibliothek, Graz: Akademische Druck- und Verlagsanstalt 1999 Band 1 fol. 167 verso. Kommentar von Otto Mazal: S. 70 ISBN 3-201-01699-3 Original artist: Unknown<a href='//www.wikidata.org/wiki/Q4233718' title='wikidata:Q4233718'><img alt='wikidata:Q4233718' src='https://upload.wikimedia. org/wikipedia/commons/thumb/f/ff/Wikidata-logo.svg/20px-Wikidata-logo.svg.png' width='20' height='11' srcset='https://upload.wikimedia. org/wikipedia/commons/thumb/f/ff/Wikidata-logo.svg/30px-Wikidata-logo.svg.png 1.5x, https://upload.wikimedia.org/wikipedia/commons/ thumb/f/ff/Wikidata-logo.svg/40px-Wikidata-logo.svg.png 2x' data- le-width='1050' data- le-height='590' /></a> • File:Cannabitetrol.png Source: https://upload.wikimedia.org/wikipedia/commons/b/b8/Cannabitetrol.png License: CC-BY-SA-3.0 Contributors: No machine-readable source provided. Own work assumed (based on copyright claims). Original artist: No machine-readable author provided. 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Based on Image:Question book.png created by User:Equazcion Original artist: Tkgd2007 • File:Recoltechv.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/c3/Recoltechv.jpg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Aleks • File:Rod_of_Asclepius2.svg Source: https://upload.wikimedia.org/wikipedia/commons/e/e3/Rod_of_Asclepius2.svg License: CC BY-SA 3.0 Contributors: This le was derived from: Rod of asclepius.png Original artist: • Original: CatherinMunro • File:Row(Purple_Kush).jpg Source: https://upload.wikimedia.org/wikipedia/commons/5/5c/Row%28Purple_Kush%29.jpg License: CC BY 3.0 Contributors: Own work Original artist: hexthat 146 CHAPTER 2. 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Cacycle assumed (based on copyright claims). • File:Trichomes.jpg Source: https://upload.wikimedia.org/wikipedia/commons/3/34/Trichomes.jpg License: Public domain Contributors: your mother Original artist: Psychonaught (talk) • File:Trichomes_Close_Cannabis.jpg Source: https://upload.wikimedia.org/wikipedia/commons/e/e8/Trichomes_Close_Cannabis.jpg License: Public domain Contributors: Own work (Original text: I created this work entirely by myself.) Original artist: Psychonaught (talk) • File:USO-xx_and_Zolotoniski-xx_hemp_strains_010.jpg Source: https://upload.wikimedia.org/wikipedia/commons/f/f7/USO-xx_and_ Zolotoniski-xx_hemp_strains_010.jpg License: CC BY-SA 3.0 Contributors: http://ludovikxiv.livejournal.com/342890.html Original artist: А Ч • File:US_Cannabis_Arrests.svg Source: https://upload.wikimedia.org/wikipedia/commons/1/13/US_Cannabis_Arrests.svg License: CC0 Contributors: • 1965-1993: Marijuana Research: Uniform Crime Reports - Marijuana Arrest Statistics. 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