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HANDBOOK OF
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PATHOLOGIES
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HANDBOOK OF
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 Contents

List of Contributors  xv 9.  Cannabis, Migration, and Psychosis Onset 79

Preface  xxv A. KOKONA, I. TARRICONE, M. DI FORTI, E. CARRA

I 10.  The Global Epidemiology and Disease

Burden of Cannabis Use and Dependence 89
SETTING THE SCENE, BOTANICAL, L. DEGENHARDT, A.J. FERRARI, W.D. HALL
GENERAL AND INTERNATIONAL
ASPECTS 11.  International Aspects of Cannabis Use
and Misuse: the Australian Perspective 101
1.  The Cannabis Plant: Botanical Aspects 3 D.J. ALLSOP, W.D. HALL
S. FARAG, O. KAYSER

12.  International Aspects of Cannabis Use

2.  The Biosynthesis of Cannabinoids 13 and Misuse: Egypt 110
F. DEGENHARDT, F. STEHLE, O. KAYSER O.M.E. ABDEL-SALAM, A.F. GALAL, S.A. ELSHEBINEY,
A.E.D.M. GAAFAR

3.  Increasing Plant Concentrations of THC and 13.  Cannabis Body Packing: A Caribbean
Implications on Health Related Disorders 24 Perspective 122
V. VINDENES, J. MØRLAND S.O. CAWICH, D. DAN, V. NARAYNSINGH

4.  Age as a Predictor of Cannabis Use 33

D. BERGEN-CICO, R.D. CICO
II
PERSONAL, SOCIAL AND
5.  Lifetime Cannabis Use and Cognition COMMUNITY ASPECTS
in Psychosis Spectrum Disorders 44 OF CANNABIS USE
M.J. CUESTA, A.M. SÁNCHEZ-TORRES, R. LORENTE-OMEÑACA,
L. MORENO-IZCO
14.  Gender Differences in Cannabis
Use Disorders 131
6.  A Profile of Synthetic Cannabinoid Users 53 R. SECADES-VILLA, S. FERNÁNDEZ-ARTAMENDI
A.N. SANDERS, J.M. STOGNER

15.  The Role of Age in the Onset and Further

7.  Dual Disorders in Cannabis Misuse 61 Development of Cannabis Use Disorders 138
F. ARIAS-HORCAJADAS, N. SZERMAN, P. VEGA, S. BEHRENDT
I. BASURTE, B. MESÍAS

16.  Effects of Cannabis Use on Neurocognition

8.  Cannabis Use and Cognitive Function 70 in Adolescents and Emerging Adults 151
C. EVREN N.E. WRIGHT, K.E. MAPLE, K.M. LISDAHL

vii
viii CONTENTS

17.  Correlates and Consequences of Prenatal 27.  Cannabis Use and First-Episode Psychosis
Cannabis Exposure (PCE): Identifying and Patients (FEP) 257
Characterizing Vulnerable Maternal I. GONZÁLEZ-ORTEGA, M. MARTÍNEZ-CENGOTITABENGOA,
A. GONZÁLEZ-PINTO
Populations and Determining Outcomes for
Exposed Offspring 160
L.K. BRENTS 28.  Cannabis, Associative Memory, fMRI,
and the Implicit Association Test 267
S.L. AMES, A.W. STACY
18.  Cannabis and Clubbing: Relevance of
Cannabis and Polydrug Use in the Clubbing
Culture Today 171 29.  Stress Response in Cannabis Users
D.A. HERZIG, S. BACHMANN and Psychosis 278
M. BIOQUE, H.-H. TSENG, R. MIZRAHI

19.  Cannabis and Sexual Behavior 180

G. SCIMECA, C. CHISARI, M.R.A. MUSCATELLO, 30.  Motivation in Chronic Cannabis Use 288
C. CEDRO, G. PANDOLFO, R. ZOCCALI, A. BRUNO
R. HIRST, L. SODOS, S. GADE, L. RATHKE

20.  Friendships and Cannabis Use 188 31.  Cannabis Use and Its Association to Mental
J.H. BOMAN IV, C. HECK Illness: A Focus on Mood and Anxiety Disorders 298
S. LEV-RAN, D. FEINGOLD

21.  Students’ Knowledge of Cannabis 198

M. DROZD, J. SOBCZYN´SKI 32.  Cannabis Use and Well-Being 308
J. ALLEN, M.D. HOLDER, Z. WALSH

22.  Childhood Trauma and Cannabis:

Risk Factors in Severe Mental Disorders? 208 33.  Craving and Cannabis: A Potential Paradox 317
M. AAS, I. MELLE M.J. LOFLIN, M. EARLEYWINE

23.  Parent’s Influence on Children’s 34.  Delta-9-Tetrahydrocannabinol and

Cannabis Use 215 Catalepsy-Like Immobilization 326
S. MILLER, J.T. SIEGEL, W.D. CRANO N. EGASHIRA

24.  Cannabis Users and Premorbid 35.  The Interactive Nature of Cannabis
Intellectual Quotient 223 and Schizophrenia Risk Genes 335
T. KARL, J.C. ARNOLD
L. FERRARO, L. SIDELI, D. LA BARBERA

25.  Cannabis and Traffic Accidents 234 36.  Neuroimaging Findings in Adolescent
R.B. DE BONI, R.P. LIMBERGER, T.R.V. SOUSA
Cannabis Use and Early Phase Psychosis 345
C.E. CROCKER, J. COOKEY, P.G. TIBBO

III 37.  Cannabis Smoking in Adult Schizophrenia:

A Cognitive and Functional Magnetic
CANNABIS, BEHAVIOR, Resonance Imaging Perspective 357
PSYCHOPATHOLOGY AND K. PAQUIN, T. LECOMTE, S. POTVIN

NEUROPATHOLOGY
38.  The Long-Lasting Effects of Cannabis
26.  Drug-Related Pictures, Attentional Bias, Use on Movement and Brain Regions that
and Cannabis Use 247 Control Movement 372
D. ASMARO G. TODD, J.M. WHITE

  
 CONTENTS ix

39.  Assessment of Cannabis Acute Effects on 50.  Cardiovascular Effects of Cannabis Usage 481
Driving Skills: Laboratory, Simulator, and S. MENAHEM
On-Road Studies 379
P. BONDALLAZ, H. CHTIOUI, B. FAVRAT, E. FORNARI,
C. GIROUD, P. MAEDER 51.  Cannabis and Stroke 486
P.A. BARBER

40.  Chronic Cannabis Use and Axonal Fiber

Connectivity 391 52.  Cannabis Smoking and the Lung 494
N. SOLOWIJ, A. ZALESKY, V. LORENZETTI, M. YÜCEL D.P. TASHKIN

41.  Microglial Activation and Cannabis 53.  Cannabis and Hepatic Injury 505
Exposure 401 S.A. NADA, O.M.E. ABDEL-SALAM, A.A. SLEEM

L. CUTANDO, R. MALDONADO, A. OZAITA

54.  Cannabis Allergy: More Than a Bad Trip 517

42.  Cannabis and Psychosis: Correlation, A.L. VAN GASSE, V. SABATO, M.M. FABER, C.H. BRIDTS, D.G. EBO

Causality, and Consequences 413

D. BASU, P. PARAKH 55.  Marijuana and Breastfeeding 527
M.G. HILL, K.L. REED

43.  Cannabis Use in Bipolar Disorder 422

T.V. LAGERBERG 56.  Hypocretins/Orexins and Addiction: Role
in Cannabis Dependence 533
44.  Cannabis Use in Epilepsy—Risks Á. FLORES, R. MALDONADO, F. BERRENDERO

and Benefits 431

M. HOLTKAMP, M. HAMERLE 57.  Regulatory Role of Cannabinoids
for Skin Barrier Functions and
45.  Cannabis, Cannabinoids, and Visceral Pain 439 Cutaneous Inflammation 543
R. ABALO, M. ISABEL MARTÍN-FONTELLES T. TÜTING, E. GAFFAL

46.  Cannabis and Postoperative Analgesia 450

S.O CAWICH, U. DEONARINE, H.E. HARDING, D. DAN,
V. NARAYNSINGH
V
PHARMACOLOGY AND CELLULAR
ACTIVITIES OF CANNABINOIDS
IV AND ENDOCANNABINOIDS
CANNABIS, ORGANS, TISSUES
58.  Cannabinoids and the Cannabinoid
AND NON-CNS ASPECTS
Receptors: An Overview 553
D. LU, D.E. POTTER
47.  Chronic Cannabis Abuse and Thyroid
Function 461
U. BONNET 59.  Signaling and Regulation of the
Cannabinoid CB1 Receptor 564
M.R. HUNTER, D.B. FINLAY, M. GLASS
48.  Cannabis Hyperemesis Syndrome 466
U. BONNET
60.  Allosteric Modulation of the Cannabinoid
CB1 Receptor 573
49.  Cannabis and Cannabinoids and the Effects
E.E. CAWSTON, M.R. HUNTER, M. GLASS
on Gastrointestinal Function: An Overview 471
M. SAŁAGA, R. ABALO, J. FICHNA

  
x CONTENTS

61.  Polymorphisms of the CB2 Cannabinoid VI

Receptor 584
P. KUMAR, Z.-H. SONG EFFECTS OF SPECIFIC NATURAL
AND SYNTHETIC CANNABINOIDS
62.  Chemistry of Cannabinoid Receptor Agonists 592
M. AGHAZADEH TABRIZI, P.G. BARALDI
72.  The Role of 5-HT1A Receptor, and Nausea
and Vomiting Relief by Cannabidiol (CBD),
Cannabidiolic Acid (CBDA),
63.  The Endocannabinoid System as a Target and Cannabigerol (CBG) 703
for New Antiseizure Drugs 606 E.M. ROCK, L.A. PARKER
L.R. VILELA, A.C.P. DE OLIVEIRA, M.F. MORAES, F.A. MOREIRA,
R.N. TAKAHASHI
73.  Genetic and Molecular Aspects of Addiction
with Tetrahydrocannabinol 713
64.  Pharmacological Aspects of Anandamide
T. JANUS, A. MACHOY-MOKRZYŃSKA, K. BOROWIAK
and 2-Arachidonoyglycerol as Bioactive Lipids 616
M. ALHOUAYEK, G.G. MUCCIOLI
74.  Effects of ∆9-Tetrahydrocannabinol in
Human Breast Cancer 722
65.  Pharmacological Aspects of NMDA
S. TAKEDA, E. IKEDA, H. OKAZAKI, K. WATANABE, H. ARAMAKI
Receptors, mGluR5, and Endocannabinoids 630
Y. IZUMI, C.F. ZORUMSKI
75.  ∆9-THC and COX-2 Signaling 729
J. ZHANG, C. CHEN
66.  Peripheral CB1 Receptors and Ghrelin in
Feeding Regulation: Pharmacological Implications 639
L. ORIO, R. GÓMEZ DE HERAS, F. RODRÍGUEZ DE FONSECA 76.  Cannabinoids and the Addictive
Effects of Nicotine 739
L.V. PANLILIO, S.R. GOLDBERG
67.  Pharmacological Aspects of Novel
Antiobesity Agents Related to Cannabinoids 649
L. HERNANDEZ-FOLGADO 77.  Cannabinoid Regulation of Intraocular
Pressure: Human and Animal Studies, Cellular
and Molecular Targets 748
68.  Cannabinoid Reward and Dependence:
A. ALOWAY, A. KUMAR, A.S. LAUN, Z.H. SONG
Focus on the Main Psychoactive Ingredients
of Marijuana in Preclinical Studies 659
G. PANAGIS 78.  Ocular Delivery of Tetrahydrocannabinol 760
G.R. ADELLI, P. BHAGAV, M.A. REPKA, W. GUL, M.A. ELSOHLY,
S. MAJUMDAR
69.  Peroxisome Proliferator Activated Receptors
and Cannabinoids 671
E. MUÑOZ, F. POLLASTRO, O. TAGLIALATELA-SCAFATI, G. APPENDINO
79.  The Role of γ-Aminobutyric Acid in the
Interoceptive Effects of Oral
∆9-Tetrahydrocannabinol in Humans 770
70.  The Protein–Protein Interactions of Cannabinoid J.A. LILE, J.S. FOGEL, T.H. KELLY
Receptor Interacting Protein 1a (CRIP1a) and
Cannabinoid 1 Receptor: The Molecular
Mechanism Study Through an Integrated 80.  The Role of ∆9-Tetrahydrocannabinol in
Molecular Modeling Approach 680 Diabetes Mellitus 779
Z.M. COSKUN, S. BOLKENT
M.H. AHMED, Y. ZHANG

81.  Cannabidiol: An Overview of its

71.  Synthetic Cannabinoids: a Summary
Antipsychotic Properties 787
of Selected Phenomena with Respect to
F.F. PERES, V. ALMEIDA, V.C. ABILIO
Behavioral Pharmacology and Abuse Liability 691
B.T. BURROWS, L.R. WATTERSON, J. EGNATIOS, M.F. OLIVE

  
 CONTENTS xi

82.  Cannabidiol for the Treatment of 91.  Beneficial Effects of Cannabis and
Epilepsy: An Overview of Possible Related Compounds on Sleep 877
Mechanisms of Action and Preclinical and I.M.P. LINARES, J.A.S. CRIPPA, M.H.N. CHAGAS
Human Studies 795
R. GUIMARÃES DOS SANTOS, J.E.C. HALLAK, A.W. ZUARDI,
A.C. DE SOUZA CRIPPA, J.A. DE SOUZA CRIPPA 92.  Cannabinoid-Based Medicines for the
Treatment of Gilles de la Tourette Syndrome 883
A.S. KANAAN, K.R. MÜLLER-VAHL
83.  Cannabidiol and Neuroprotection: Evidence
from Preclinical Studies 802
N. SCHRÖDER, V.K. DA SILVA, J.E.C. HALLAK, 93.  Cannabidiol and Multiple Sclerosis 893
A.W. ZUARDI, J.A. DE SOUZA CRIPPA M. MECHA, A. FELIÚ, F.-J. CARRILLO-SALINAS, C. GUAZA

84.  Cannabinoids as Potent Inhibitors 94.  Cannabinoids and Their Effects on

of Human CYP1 Enzymes 813 Painful Neuropathy 905
K. WATANABE, S. YAMAORI, K. MASUDA, T. KATSU, D. SELVARAJAH, R. GANDHI, S. TESFAYE
S. NARIMATSU, I. YAMAMOTO

85.  The Synthetic Analog of 95.  Cannabis for Basal Ganglia Disorders
∆9-Tetrahydrocannabinol (THC): Nabilone. (Parkinson Disease and Huntington Disease) 917
O.M.E. ABDEL-SALAM
Pharmacology and Clinical Application 821
R.E BALTER, M. HANEY

96.  Medical Cannabis for the Treatment

86.  Synthetic Cannabinoids in Dementia 828 of Inflammatory Bowel Disease 931
S. AMANULLAH, K. SHIVAKUMAR, S. HASSAN, A. LAHAT
A. CANFIELD, J. COLE

97.  Cannabidiol for the Treatment

87.  Synthetic Cannabinoid Receptor of Drug Use Disorders 939
Agonists (Spice) as New Recreational R.G. DOS SANTOS, J.E.C. HALLAK, A.W. ZUARDI,
Psychoactive Substances 839 J.A. DE SOUZA CRIPPA

A. HELANDER

98.  Cannabinoids and Effects on the

88.  Accidents and Synthetic Cannabinoids Gastrointestinal Tract: A Focus on Motility 947
in Blood of Drivers 848 G. VERA, J. FICHNA, R. ABALO
S.S. TUV, V. AUWÄRTER, V. VINDENES

99.  Potential Medical Uses of Cannabigerol:

A Brief Overview 958
VII S. DEIANA

MEDICINAL CANNABIS USE

89.  Cannabis and Synthetic Cannabinoids

for Cancer Patients: Multiple Palliative VIII
Indications Together With Promising SCREENING, DIAGNOSIS,
Laboratory Antineoplastic Effects 859 AND TREATMENT
D. ZALMAN, G. BAR-SELA

100.  The Cannabis Abuse Screening

90.  The Use of Medical Marijuana in the Test (CAST) and Its Applications 971
Treatment of Psychiatric Disorders 869 L. BASTIANI, R. POTENTE, M. SCALESE, V. SICILIANO,
T. TELLIOĞLU, Z. TELLIOĞLU L. FORTUNATO, S. MOLINARO

  
xii CONTENTS

101.  Screening of Synthetic Cannabinoids 981 109.  Cognitive Behavioral Therapy in

E.L. ØIESTAD, R. KARINEN, K. HAUGLAND, Å.M.L. ØIESTAD Cannabis Use Disorder 1056
F.M. GUVEN, U.M. CAMSARI, O. SENORMANCI, G. OGUZ

102.  On-Site Drug Testing for Cannabis 998

A.A. FERNÁNDEZ 110.  The Cannabis Withdrawal Syndrome—
Symptoms and Time Course 1066
M. HESSE, B. THYLSTRUP
103.  Cannabinoids in Oral Fluid: Identification
and Interpretation of Analytical Results 1007
C. MOORE 111.  School-Based Cannabis Prevention
Programs 1074
C. ARIZA, F. SÁNCHEZ-MARTÍNEZ, A. PÉREZ
104.  Cannabinoids in Exhaled Breath 1018
O. BECK
112.  The CapOpus Trial for Cannabis
Use Disorders 1086
105.  Barriers to Treatment Seeking for
C.R. HJORTHØJ, M. NORDENTOFT
Cannabis Dependence 1025
P. GATES, J. COPELAND

113.  Treating Cannabis Use Disorders

106.  Pharmacotherapies for Cannabis Through Technology-Assisted Interventions:
Use Disorders 1030 The Telephone and Internet 1093
P. GATES, J. COPELAND
A.L. McRAE-CLARK

107.  Self-Initiated Cannabis Use Cessation 114.  Reducing Cannabis Use With a Real-Time
in Adolescents and Emerging Adults 1036 Intervention Using Mobile Technology 1101
J. TSAI, M. LITTLE, S. SUSSMAN M. KELLS, L.A. SHRIER

108.  Treating Cannabis-Dependent Adolescents Cannabis Neuropathology Resources and

with Family Therapy: The Case of Recommended Reading 1111
Multidimensional Family Therapy 1047 R. RAJENDRAM, V.B. PATEL, V.R. PREEDY
H. RIGTER

Index  1115

Online Contents
I II
SETTING THE SCENE, BOTANICAL, PERSONAL, SOCIAL AND
GENERAL AND INTERNATIONAL COMMUNITY ASPECTS
ASPECTS OF CANNABIS USE

e1.  Tetrahydrocannabinol Concentration e2.  Cannabis Use in Youth Subcultures e11

and Genetic Characterization of Cannabis e1 M. PAWSON, B.C. KELLY
F. CASCINI, I. BOSCHI

  
 ONLINE CONTENTS xiii

III e10.  Cannabis and the Use of Amphetamine-Like

Substances e101
CANNABIS, BEHAVIOR, A. PORCU, M.P. CASTELLI
PSYCHOPATHOLOGY AND
NEUROPATHOLOGY

e3.  Aggressive Behavior and Cannabis Use e19

V
W. LIU, H. PETRAS PHARMACOLOGY AND CELLULAR
ACTIVITIES OF CANNABINOIDS
AND ENDOCANNABINOIDS
e4.  COMT Genotypes, Cannabis Use, and
Psychosis: Gene-Environment Interaction
e11.  Cannabinoid Signaling in Glioma Cells
Evidence from Human Populations, and Its
and Therapeutic implications e111
Methodological Concerns e29
A. ELLERT-MIKLASZEWSKA, I. A. CIECHOMSKA, B. KAMINSKA
M. FATJÓ-VILAS, C. PRATS, L. FAÑANÁS

e5.  Neuroimaging and Genetics of the Acute VI

and Chronic Effects of Cannabis e42
R. MARTÍN-SANTOS, J.A. DE SOUZA CRIPPA, S. BHATTACHARYYA
EFFECTS OF SPECIFIC NATURAL
AND SYNTHETIC CANNABINOIDS

e6.  Gray Matter, Lateral Ventricle Volumes, e12.  Cannabidiol as an Antioxidant e122
and Executive Functioning in Cannabis Users R.S. BORGES, A.B.F. DA SILVA
with First-Episode Psychosis e53
P.J. CUNHA, P.G.P. ROSA, F.L.S. DURAN, L.C. SANTOS,
J.A.S. CRIPPA, G.F. BUSATTO, M.S. SCHAUFELBERGER
e13.  The Anxiolytic Effects of Cannabidiol
(CBD) e131
A.W. ZUARDI, J.A. DE SOUZA CRIPPA, J.E.C. HALLAK,
A.C. CAMPOS, F.S. GUIMARÃES
e7.  Cannabis Use and Attention-Deficit/
Hyperactivity Disorder: Potential Moderators e64
K.E. MAPLE, N.E. WRIGHT, K.M. LISDAHL e14.  New Ethological and Morphological
Perspectives for the Investigation of
Panicolytic-Like Effects of Cannabidiol e140
N.C. COIMBRA, J. MENDES-GOMES, J.A. DA SILVA,

IV T. DOS ANJOS-GARCIA, F. ULLAH, R.C. ALMADA

CANNABIS, ORGANS, TISSUES e15.  Spice Use Among United States

AND NON-CNS ASPECTS Military Personnel e150
H.A. MORRIS, J.M. STOGNER
e8.  Cannabis and Oral Health: Deleterious
Effects on Periodontitis and Dental Implants e72
G. NOGUEIRA-FILHO
VII
MEDICINAL CANNABIS USE
e9.  Does Cannabis Use Increase the Risk
of Developing Cancer in Humans? e80 e16.  Cannabis Use in Fibromyalgia e158
R.C. CALLAGHAN, M. VERDICHEVSKI, T.M. FYFE, J.M. GATLEY
M. FARRÉ, A. FARRÉ, J. FIZ, M. TORRENS

  
xiv ONLINE CONTENTS

VIII e18.  Self-report of Cannabis Use e185

T. VAN DER LINDEN
SCREENING, DIAGNOSIS,
AND TREATMENT
e19.  CANDIS Program: Modular Treatment
of Cannabis Use Disorders e193
e17.  Short Instruments to Screen for E. HOCH, H. ROHRBACHER
“Problematic” Cannabis Use in General
Population Surveys e168
B. ANNAHEIM, S. LEGLEYE e20.  Engaging Cannabis Users in Treatment e202
F. KAY-LAMBKIN, A. HEALEY, A. BAKER, W. SWIFT,
L. THORNTON, A. TURNER

  
 List of Contributors

M. Aas  NORMENT, KG Jebsen Centre for Psychosis G. Appendino  Department of Pharmaceutical Science,
Research, Division of Mental Health and Addiction, Oslo University of Piemonte Orientale, Novara, Italy
University Hospital & Institute of Clinical Medicine, H. Aramaki  Department of Molecular Biology, Daiichi
University of Oslo, Oslo, Norway University of Pharmacy; Drug Innovation Research Center,
R. Abalo  Area of Pharmacology and Nutrition, Faculty Daiichi University of Pharmacy, Fukuoka, Japan
of Health Sciences, University Rey Juan Carlos, Alcorcón; F. Arias-Horcajadas  Psychiatric Department, Doce de
Associated Unit I+D+i of the Institute of Medicinal Chemistry Octubre Hospital, Madrid, Spain
(IQM) and of the Institute of Research in Food Sciences (CIAL),
C. Ariza  Evaluation and Intervention Methods Service,
Spanish National Research Council (CSIC), Madrid, Spain
Public Health Agency, Barcelona, Spain
O.M.E. Abdel-Salam  Department of Toxicology and Narcotics,
J.C. Arnold  School of Medicine, Western Sydney University,
National Research Centre, Dokki, Greater Cairo, Egypt
Campbelltown; University of Sydney, Department of
V.C. Abilio  Department of Pharmacology, Federal Pharmacology, Bosch Institute, Sydney; Brain and Mind
University of Sao Paulo; Integrated Laboratory of Clinical Research Institute, Camperdown, NSW, Australia
Neurosciences (LiNC), Federal University of Sao Paulo,
D. Asmaro  Department of Psychology, Simon Fraser
Sao Paulo, Brazil
University, Burnaby, BC, Canada
G.R. Adelli  Department of Pharmaceutics and Drug
V. Auwärter  Department of Drug Abuse Research, Division
Delivery, School of Pharmacy, University of Mississippi,
of Forensic Sciences, Norwegian Institute of Public Health,
Oxford, MS, United States
Oslo, Norway; Forensic Toxicology Department, Medical
M.H. Ahmed  Department of Medicinal Chemistry, School Center, University of Freiburg, Institute of Forensic Medicine,
of Pharmacy and Institute for Structural Biology and Drug Freiburg, Germany
Discovery, Virginia Commonwealth University, Richmond,
S. Bachmann  Clienia AG, Littenheid, Switzerland
VA, United States
A. Baker  Priority Research Centre for Translational
M. Alhouayek  Bioanalysis and Pharmacology of Bioactive
Neuroscience and Mental Health, University of Newcastle,
Lipids Research Group, Louvain Drug Research Institute,
Callaghan, NSW, Australia
Université catholique de Louvain, Brussels, Belgium
R.E Balter  Division on Substance Abuse, New York State
J. Allen  Psychology Department, IKBSAS, University of
Psychiatric Institute and Department of Psychiatry, Columbia
British Columbia, Kelowna, BC, Canada
University Medical Center, New York, NY, United States
D.J. Allsop  Psychopharmacology Laboratory, School of
P.G. Baraldi  Department of Chemistry and Pharmaceutical
Psychology, University of Sydney, Sydney, NSW, Australia
Science, University of Ferrara, Ferrara, Italy
R.C. Almada  Laboratory of Neuroanatomy &
P.A. Barber  Department of Medicine, Centre for Brain
Neuropsychobiology, Department of Pharmacology,
Research, University of Auckland, Auckland, New Zealand
Ribeirão Preto Medical School of the University of São
Paulo (­FMRP-USP), Ribeirão Preto, São Paulo, Brazil G. Bar-Sela  Division of Oncology, Rambam Health Care
Campus and Faculty of Medicine, Technion—Israel Institute
V. Almeida  Department of Pharmacology, Federal
of Technology, Haifa, Israel
University of Sao Paulo; Integrated Laboratory of Clinical
Neurosciences (LiNC), Federal University of Sao Paulo, L. Bastiani  Institute of Clinical Physiology, The Italian
Sao Paulo, Brazil National Research Council (IFC-CNR), Pisa, Italy
A. Aloway  Department of Pharmacology and Toxicology, D. Basu  Drug De-addiction and Treatment Centre,
University of Louisville School of Medicine, Louisville, KY, Department of Psychiatry, Postgraduate Institute of Medical
United States Education and Research, Chandigarh, India
S. Amanullah  Woodstock General Hospital, Woodstock, I. Basurte  Gregorio Marañon Hospital, Madrid, Spain
ON, Canada; School of Medicine, University of Western O. Beck  Department of Laboratory Medicine, Section of
Ontario, London, ON, Canada; and Faculty of Medicine, Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden
Dalhousie University, NS, Canada S. Behrendt  Institute of Clinical Psychology and
S.L. Ames  School of Community and Global Health, Psychotherapy, Technische Universitaet Dresden, Dresden,
Claremont Graduate University, Claremont, CA, United States Germany
B. Annaheim  Institute for Biomedical Ethics (IBMB), D. Bergen-Cico  Department of Public Health, Addiction
University of Basel, Basel, Switzerland Studies, Syracuse University, Syracuse, NY, United States

xv
xvi LIST OF CONTRIBUTORS

F. Berrendero  Department of Experimental and Health U.M. Camsari  Department of Psychiatry and Psychology,
Sciences, Laboratory of Neuropharmacology, School Mayo Clinic Health System, and Mayo Clinic College of
of Health and Life Sciences, Pompeu Fabra University, Medicine, Rochester, MN, United States
Barcelona, Spain A. Canfield  University of Toronto, Toronto, ON, Canada
P. Bhagav  Department of Pharmaceutics and Drug Delivery, E. Carra  Department of Psychosis Studies, Institute of
School of Pharmacy, University of Mississippi, Oxford, MS, Psychiatry, Psychology and Neuroscience, King’s College
United States London, London, United Kingdom
S. Bhattacharyya  Department of Psychosis Studies, King’s F.-J. Carrillo-Salinas  Neurobiology and Functional Systems
College London, Institute of Psychiatry, Psychology & Department, Cajal Institute, CSIC, Madrid, Spain
Neuroscience, London, United Kingdom
F. Cascini  Public Health Institute, Department of Forensic
M. Bioque  Barcelona Clínic Schizophrenia Unit, Hospital Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
Clínic de Barcelona, Centro de Investigación Biomédica en
M.P. Castelli  Department of Biomedical Sciences, Division
Red de Salud Mental (CIBERSAM), Barcelona, Spain
of Neuroscience and Clinical Pharmacology, Cittadella
S. Bolkent  Department of Medical Biology, Cerrahpasa Universitaria, Monserrato, CA, Italy
Faculty of Medicine, Istanbul University, Istanbul, Turkey
S.O. Cawich  Department of Clinical Surgical Sciences,
J.H. Boman IV  Department of Criminal Justice, University University of the West Indies, St. Augustine Campus,
of Wyoming, Laramie, WY, United States St Augustine, Trinidad and Tobago
P. Bondallaz  Traffic Medicine and Psychology Unit, E.E. Cawston  Department of Pharmacology and Clinical
University Center of Legal Medicine, University Hospital of Pharmacology, Faculty of Medical and Health Sciences,
Geneva, Geneva, Switzerland University of Auckland, Auckland, New Zealand
U. Bonnet  Department of Psychiatry, Psychotherapy and C. Cedro  Department of Biomedical, Dental Sciences and
Psychosomatics, Evangelisches Krankenhaus Castrop-Rauxel, Morpho-functional Imaging, University of Messina, Messina,
Academic Teaching Hospital of the University of Duisburg- Italy
Essen, Castrop-Rauxel, Germany
M.H.N. Chagas  Department of Neurosciences and Behavior,
R.S. Borges  Faculty of Pharmacy, Institute of Health Faculty of Medicine, Ribeirão Preto, University of São Paulo,
Sciences, Federal University of Pará, Belém, Para, Brazil Ribeirão Preto; Barretos School of Health Sciences, Dr. Paulo
K. Borowiak  Department of Clinical and Forensic Prata, Barretos, São Paulo, Brazil
Toxicology, Pomeranian Medical University, Szczecin, C. Chen  Neuroscience Center of Excellence, School of
Poland Medicine, Louisiana State University Health Sciences Center,
I. Boschi  Public Health Institute, Department of Forensic New Orleans, LA, United States
Medicine, Università Cattolica del Sacro Cuore, Rome, Italy C. Chisari  University of York, York, United Kingdom
L.K. Brents  Brain Imaging Research Center, Psychiatric H. Chtioui  Department of Clinical Pharmacology and
Research Institute, University of Arkansas for Medical Toxicology, University Hospital of Lausanne, Lausanne,
Sciences, Little Rock, AR, United States Switzerland
C.H. Bridts  Faculty of Medicine and Health Science, R.D. Cico  Columbia University, New York, NY, United States
Department of Immunology-Allergology-Rheumatology,
I.A. Ciechomska  Laboratory of Molecular Neurobiology,
University of Antwerp, Antwerp, Belgium
Neurobiology Center, Nencki Institute of Experimental
A. Bruno  Department of Biomedical, Dental Sciences and Biology, Warsaw, Poland
Morpho-functional Imaging, University of Messina, Messina,
N.C. Coimbra  Laboratory of Neuroanatomy &
Italy
Neuropsychobiology, Department of Pharmacology,
B.T. Burrows  Department of Psychology, Arizona State Ribeirão Preto Medical School of the University of São
University, Tempe, AZ, United States Paulo (FMRP-USP); Neurobiology of Emotions Research
G.F. Busatto  Department of Psychiatry, Faculty of Medicine, Centre (NAP-USP-NuPNE), Ribeirão Preto Medical School
Laboratory of Psychiatric Neuroimaging (LIM-21), University of the University of São Paulo (FMRP-USP), Ribeirão Preto,
of São Paulo; Center for Interdisciplinary Research on Applied São Paulo, Brazil
Neurosciences (NAPNA), University of São Paulo, São Paulo, J. Cole  Queen Elizabeth Hospital, Charlottetown, PE, Canada
Brazil
J. Cookey  Department of Psychiatry, Dalhousie University,
R.C. Callaghan  Northern Medical Program, University of Halifax, NS, Canada
Northern British Columbia, Prince George, BC; Dalla Lana
J. Copeland  National Cannabis Prevention and Information
School of Public Health, University of Toronto, Toronto, ON;
Centre, University of New South Wales, Randwick, Sydney,
Human Brain Lab, Centre for Addiction and Mental Health,
NSW, Australia
Toronto, ON, Canada
Z.M. Coskun  Department of Molecular Biology and
A.C. Campos  Department of Pharmacology, Faculty of
Genetics, Faculty of Arts and Sciences, Istanbul Bilim
Medicine of Ribeirão Preto, University of São Paulo, Ribeirão
University, Istanbul, Turkey
Preto, São Paulo, Brazil

  
 LIST OF CONTRIBUTORS xvii
W.D. Crano  Division of Behavioral and Organizational S. Deiana  CNS Diseases Research Department, Boehringer
Sciences, School of Social Science, Policy and Evaluation, Ingelheim Pharma GmbH & Co. KG, Birkendorfer straße,
Claremont Graduate University, Claremont, CA, United Biberach an der Riss, Germany
States U. Deonarine  Department of Clinical Surgical Sciences,
J.A.S. Crippa  Department of Neuroscience and Behavior, University of the West Indies, St. Augustine Campus,
Faculty of Medicine, Ribeirão Preto, University of São Paulo, St Augustine, Trinidad and Tobago
Ribeirao Preto, Brazil M. Di Forti  Department of Psychosis Studies, Institute of
C.E. Crocker  Department of Psychiatry, Dalhousie Psychiatry, Psychology and Neuroscience, King’s College
University; Division of Neurology, Department of Medicine, London, London, United Kingdom
Dalhousie University, Halifax, NS, Canada T. dos Anjos-Garcia  Laboratory of Neuroanatomy
M.J. Cuesta  Department of Psychiatry, IdiSNA, Navarra & Neuropsychobiology, Department of Pharmacology,
Institute for Health Research, Pamplona, Spain Ribeirão Preto Medical School of the University of São Paulo
P.J. Cunha  Department of Psychiatry, Faculty of Medicine, (FMRP-USP), Ribeirão Preto, São Paulo, Brazil
Laboratory of Psychiatric Neuroimaging (LIM-21), University R. Guimarães dos Santos  Department of Neuroscience and
of São Paulo; Center for Interdisciplinary Research on Applied Behavior, Ribeirão Preto Medical School, University of São
Neurosciences (NAPNA), University of São Paulo, São Paulo, Paulo, Ribeirão Preto, Sao Paulo, Brazil
Brazil M. Drozd  Department of Pharmaceutics, Medical University
L. Cutando  Department of Experimental and Health of Lublin, Lublin, Poland
Sciences, Laboratory of Neuropharmacology, School F.L.S. Duran  Department of Psychiatry, Faculty of Medicine,
of Health and Life Sciences, Pompeu Fabra University, Laboratory of Psychiatric Neuroimaging (LIM-21), University
Barcelona, Spain of São Paulo; Center for Interdisciplinary Research on Applied
A.B.F. da Silva  Institute of Chemistry of São Carlos, Neurosciences (NAPNA), University of São Paulo, São Paulo,
University of São Paulo, São Carlos, Sao Paulo, Brazil Brazil
J.A. da Silva  Laboratory of Neuroanatomy & M. Earleywine  Department of Psychology, School of Arts
Neuropsychobiology, Department of Pharmacology, and Sciences, University at Albany, State University of New
Ribeirão Preto Medical School of the University of São Paulo York, Albany, NY, United States
(FMRP-USP), Ribeirão Preto, São Paulo, Brazil D.G. Ebo  Faculty of Medicine and Health Science,
V.K. da Silva  Neurobiology and Developmental Biology Department of Immunology-Allergology-Rheumatology,
Laboratory, Faculty of Biosciences, Pontifical Catholic University of Antwerp, Antwerp, Belgium
University, Porto Alegre, Rio Grande do Sul, Brazil N. Egashira  Department of Pharmacy, Kyushu University
D. Dan  Department of Clinical Surgical Sciences, University Hospital; Department of Neuropharmacology, Faculty of
of the West Indies, St. Augustine Campus, St Augustine, Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
Trinidad and Tobago J. Egnatios  School of Medicine, University of California San
R.B. De Boni  INI Evandro Chagas, FIOCRUZ, Rio de Diego, La Jolla, CA, United States
Janeiro, Rio de Janeiro, Brazil A. Ellert-Miklaszewska  Laboratory of Molecular
F. Rodríguez de Fonseca  Department of Psychobiology, Neurobiology, Neurobiology Center, Nencki Institute of
Faculty of Psychology, Complutense University of Madrid, Experimental Biology, Warsaw, Poland
Pozuelo de Alarcón, Madrid, Spain S.A. ElShebiney  Department of Toxicology and Narcotics,
R. Gómez de Heras  Department of Psychobiology, Faculty National Research Centre, Cairo, Egypt
of Psychology, Complutense University of Madrid, Pozuelo M.A. ElSohly  ElSohly Laboratories Inc., Oxford, MS,
de Alarcón, Madrid, Spain United States
A.C.P. de Oliveira  Department of Pharmacology, ICB, C. Evren  Research, Treatment and Training Center for
Federal University of Minas Gerais, Belo Horizonte, Minas Alcohol and Substance Dependence (AMATEM), Bakirkoy
Gerais, Brazil Training and Research Hospital for Psychiatry, Neurology and
A.C. de Souza Crippa  Health Sciences Sector, Federal Neurosurgery, Istanbul, Turkey
University of Paraná, Curitiba, Parana, Brazil L. Fañanás  Faculty of Biology, Anthropology Unit,
J.A. de Souza Crippa  Department of Neuroscience and Department of Animal Biology, University of Barcelona,
Behavior, Ribeirão Preto Medical School, University of São Biomedicine Institute of the University of Barcelona (IBUB),
Paulo, Ribeirão Preto, Sao Paulo, Brazil Barcelona; CIBER of Mental Health (CIBERSAM), Madrid,
F. Degenhardt  Laboratory of Technical Biochemistry, Spain
Department of Biochemical and Chemical Engineering, M.M. Faber  Faculty of Medicine and Health Science,
TU Dortmund University, Dortmund, Germany Department of Immunology-Allergology-Rheumatology,
L. Degenhardt  National Drug and Alcohol Research University of Antwerp, Antwerp, Belgium
Centre, University of New South Wales, Sydney, NSW, S. Farag  Technical University Dortmund, Technical
Australia Biochemistry Dortmund, Dortmund, Germany

  
xviii LIST OF CONTRIBUTORS

A. Farré  Dual Disorder Unit, Addiction Program, Institute S. Gade  Palo Alto University, Palo Alto, CA, United States
of Neuropsychiatry and Addiction—INAD, and Hospital del E. Gaffal  Laboratory of Experimental Dermatology,
Mar Medical Research Institute—IMIM, Barcelona, Spain Department of Dermatology and Allergy, University
M. Farré  Clinical Pharmacology Unit, Germans Trias i Pujol Hospital of the Friedrich-Wilhelm-University Bonn, Bonn,
University Hospital—IGTP, and Human Pharmacology Unit, Germany
Hospital del Mar Medical Research Institute—IMIM, and A.F. Galal  Department of Toxicology and Narcotics, National
Autonomous University of Barcelona, Barcelona, Spain Research Centre, Cairo, Egypt
M. Fatjó-Vilas  Faculty of Biology, Anthropology Unit, R. Gandhi  Academic Department of Diabetes and
Department of Animal Biology, University of Barcelona, Endocrinology, Sheffield Teaching Hospitals NHS
Biomedicine Institute of the University of Barcelona (IBUB), Foundation Trust, Sheffield, United Kingdom
Barcelona; CIBER of Mental Health (CIBERSAM), Madrid,
P. Gates  National Cannabis Prevention and Information
Spain
Centre, University of New South Wales, Randwick, Sydney,
B. Favrat  Traffic Medicine and Psychology Unit, University NSW, Australia
Center of Legal Medicine, University Hospital of Geneva,
J.M. Gatley  Northern Medical Program, University of
Geneva; Department of Ambulatory Care and Community
Northern British Columbia, Prince George, BC; Dalla Lana
Medicine, University Hospital of Lausanne, Lausanne,
School of Public Health, University of Toronto, Toronto, ON;
Switzerland
Human Brain Lab, Centre for Addiction and Mental Health,
D. Feingold  Department of Psychiatry, Sheba Medical Toronto, ON, Canada
Center, Tel Hashomer; Ariel University, Ariel, Israel
C. Giroud  Forensic Toxicology and Chemistry Unit,
A. Feliú  Neurobiology and Functional Systems Department, University Center of Legal Medicine, University Hospital of
Cajal Institute, CSIC, Madrid, Spain Lausanne, Lausanne, Switzerland
A.A. Fernández  Forensic Laboratory Institute of Legal M. Glass  Department of Pharmacology and Clinical
Medicine of Catalonia, Barcelona, Spain Pharmacology, Faculty of Medical and Health Sciences,
S. Fernández-Artamendi  Addictive Behaviors Research University of Auckland, Auckland, New Zealand
Group, Department of Psychology, University of Oviedo, S.R. Goldberg  Preclinical Pharmacology Section, Behavioral
Oviedo, Spain Neuroscience Branch, Intramural Research Program, National
A.J. Ferrari  School of Public Health, University of Institute on Drug Abuse, National Institutes of Health,
Queensland, Herston; Institute for Health Metrics and Baltimore, MD, United States
Evaluation, University of Washington, Seattle, WA, United I. González-Ortega  Department of Psychiatry, University
States; Queensland Centre for Mental Health Research, Wacol, Hospital of Alava-Santiago, CIBERSAM; University of the
QLD, Australia Basque Country; National Distance Education University
L. Ferraro  Biomedical Department of Internal and Specialist (UNED)-Centro Asociado de Vitoria, Vitoria, Spain
Medicine; Department of Experimental Biomedicine and A. González-Pinto  Department of Psychiatry, University
Clinical Neuroscience, School of Medicine, University of Hospital of Alava-Santiago, CIBERSAM; University of the
Palermo, Palermo, Italy Basque Country, Vitoria, Spain
J. Fichna  Department of Biochemistry, Faculty of Medicine, C. Guaza  Neurobiology and Functional Systems Department,
Medical University of Lodz, Lodz, Poland Cajal Institute, CSIC, Madrid, Spain
D.B. Finlay  Department of Pharmacology and Clinical V. Guillon  Service des enquêtes et des sondages, Paris,
Pharmacology, Faculty of Medical and Health Sciences, France
University of Auckland, Auckland, New Zealand
F.S. Guimarães  Department of Pharmacology, Faculty of
J. Fiz  EDIR, Center for Diagnosis and Rehabilitation, San Medicine of Ribeirão Preto, University of São Paulo, Ribeirão
Martín Santa Fe, Argentina Preto, São Paulo, Brazil
Á. Flores  Department of Experimental and Health Sciences, W. Gul  ElSohly Laboratories Inc., Oxford, MS, United
Laboratory of Neuropharmacology, School of Health and Life States
Sciences, Pompeu Fabra University, Barcelona, Spain
F.M. Guven  Turkish Association for Cognitive and
J.S. Fogel  Department of Psychology, University of Kentucky Behavioural Therapies, Istanbul; Department of Psychiatry,
College of Arts and Sciences, Lexington, KY, United States Alcohol & Substance Use Disorders Treatment Center, Lara
E. Fornari  CIBM, University Hospital of Lausanne, Anatolia Hospital, Antalya, Turkey
Lausanne, Switzerland W.D. Hall  Centre for Youth Substance Abuse Research,
L. Fortunato  Institute of Clinical Physiology, The Italian University of Queensland, Herston, QLD, Australia
National Research Council (IFC-CNR), Pisa, Italy J.E.C. Hallak  Department of Neuroscience and Behavior,
T. Fyfe  Northern Medical Program, University of Northern Ribeirão Preto Medical School, University of São Paulo,
British Columbia, Prince George, BC, Canada Ribeirão Preto, Sao Paulo, Brazil
A.E.D.M. Gaafar  Department of Photochemistry, Chemical M. Hamerle  Department of Psychiatry and Psychotherapy,
Industries Division, National Research Centre, Cairo, Egypt Ludwig-Maximilian-University Hospital, Munich, Germany

  
 LIST OF CONTRIBUTORS xix
M. Haney  Division on Substance Abuse, New York State T. Karl  Neuroscience Research Australia, Randwick; School
Psychiatric Institute and Department of Psychiatry, College of of Medicine, Western Sydney University, Campbelltown,
Physicians and Surgeons of Columbia University, New York, NSW, Australia
NY, United States T. Katsu  Department of Pharmacy, Faculty of Pharmacy,
H.E. Harding  Department of Surgery, University of the West Yasuda Women’s University, Hiroshima, Japan
Indies, Mona Campus, Kingston, Jamaica F. Kay-Lambkin  NHMRC Centre for Research Excellence in
S. Hassan  Dalhousie University, Dartmouth, NS, Canada Mental Health and Substance Use, National Drug and Alcohol
K. Haugland  National Criminal Investigation Service Research Centre, University of New South Wales, Randwick,
(NCIS) Norway, Forensic Science Department, Oslo, Norway NSW, Australia
A. Healey  School of Psychology, The University of Newcastle, O. Kayser  Technical University Dortmund, Technical
University Drive, Callaghan, NSW, Australia Biochemistry Dortmund, Dortmund, Germany
C. Heck  City and County of Denver, Crime Prevention and M. Kells  Division of Adolescent/Young Adult Medicine,
Control Commission, Denver, CO, United States Boston Children’s Hospital, Boston, MA, United States
A. Helander  Department of Laboratory Medicine, B.C. Kelly  Department of Sociology, Purdue University,
Karolinska Institutet, and Karolinska University Laboratory, West Lafayette, IN, United States
Stockholm, Sweden T.H. Kelly  Departments of Behavioral Science and Psychiatry,
L. Hernandez-Folgado  Institute of Medical Chemistry, University of Kentucky College of Medicine, and Department
CSIC, Madrid, Spain of Psychology, University of Kentucky College of Arts and
Sciences, Lexington, KY, United States
D.A. Herzig  Clienia AG, Littenheid, Switzerland
A. Kokona  Department of Medical and Surgical Sciences,
M. Hesse  Center for Alcohol and Drug Research, Aarhus
Bologna University, Bologna, Italy
University, Copenhagen Department, Copenhagen,
Denmark A. Kumar  Department of Pharmacology and Toxicology,
University of Louisville School of Medicine, Louisville, KY,
M.G. Hill  The University of Arizona, Tucson, AZ, United
United States
States
P. Kumar  Department of Pharmacology and Toxicology,
R. Hirst  Palo Alto University, Palo Alto, CA, United States
University of Louisville School of Medicine, Louisville, KY,
C.R. Hjorthøj  Mental Health Center Copenhagen, United States
Copenhagen University Hospital, Copenhagen, Denmark
D. La Barbera  Department of Experimental Biomedicine
E. Hoch  Department of Psychiatry, Ludwig Maximilian and Clinical Neuroscience, School of Medicine, University of
University, Munich, Germany Palermo, Palermo, Italy
M.D. Holder  Psychology Department, IKBSAS, University T.V. Lagerberg  NORMENT KG Jebsen Centre for Psychosis
of British Columbia, Kelowna, BC, Canada Research, Institute of Clinical Medicine, University of Oslo;
M. Holtkamp  Epilepsy-Center Berlin-Brandenburg, Division of Mental Health and Addiction, Oslo University
Department of Neurology, Charité – Universitätsmedizin Hospital, Oslo, Norway
Berlin, Berlin, Germany A. Lahat  Department of Gastroenterology, Chaim Sheba
M.R. Hunter  Department of Pharmacology and Clinical Medical Center, Tel-Hashomer, Israel
Pharmacology, Faculty of Medical and Health Sciences, H.J. Larsen  Mental Health Center Copenhagen, Copenhagen
University of Auckland, Auckland, New Zealand University Hospital, Copenhagen, Denmark
E. Ikeda  Department of Molecular Biology, Daiichi A.S. Laun  Department of Pharmacology and Toxicology,
University of Pharmacy, Fukuoka, Japan University of Louisville School of Medicine, Louisville, KY,
Y. Izumi  Department of Psychiatry; The Taylor Family United States
Institute for Innovative Psychiatric Research, Washington T. Lecomte  Research Centre of the University of
University School of Medicine, St. Louis, MO, United States Montreal Institute for Mental Health; Department of
T. Janus  Department of Clinical and Forensic Toxicology, Psychology, University of Montreal, Montreal, QC,
Pomeranian Medical University, Szczecin, Poland Canada
B. Kaminska  Laboratory of Molecular Neurobiology, S. Legleye  Institut national d’études démographiques
Neurobiology Center, Nencki Institute of Experimental (INED), Paris; University of Paris-Saclay, Univ. Paris-Sud,
Biology, Warsaw, Poland UVSQ, CESP, Inserm, Versailles, France
A.S. Kanaan  Clinic of Psychiatry, Social-Psychiatry and S. Lev-Ran  Department of Psychiatry, Sheba Medical
Psychotherapy, Hannover Medical School, Hannover; Center, Tel Hashomer; Sackler Faculty of Medicine, Tel Aviv
Nuclear Magnetic Resonance Unit, Max Planck Institute University, Tel Aviv, Israel
for Human Cognitive and Brain Sciences, Leipzig, J.A. Lile  Departments of Behavioral Science and Psychiatry,
Germany University of Kentucky College of Medicine, and Department
R. Karinen  Norwegian Institute of Public Health, Division of Psychology, University of Kentucky College of Arts and
of Forensic Sciences, Oslo, Norway Sciences, Lexington, KY, United States

  
xx LIST OF CONTRIBUTORS

R.P. Limberger  LABTOXICO: Laboratory of Toxicology, R. Martín-Santos  Department of Psychiatry and

Faculty of Pharmacy, Federal University of Rio Grande do Sul, Psychology, Hospital Clinic, IDIBAPS, University of
Porto Alegre, Rio Grande do Sul, Brazil Barcelona, CIBERSAM, Barcelona, Spain
I.M.P. Linares  Department of Neuroscience and Behavior, K. Masuda  Department of Physical Chemistry, Graduate
Faculty of Medicine, Ribeirão Preto, University of São Paulo, School of Clinical Pharmacy, Shujitsu University, Okayama,
Ribeirao Preto, Brazil Japan
K.M. Lisdahl  Department of Psychology, University of A.L. McRae-Clark  Medical University of South Carolina,
Wisconsin-Milwaukee, Milwaukee, WI, United States Charleston, SC, United States
M. Little  Center for Population Sciences, Department of M. Mecha  Neurobiology and Functional Systems Department,
Preventive Medicine, University of Tennessee Health Science Cajal Institute, CSIC, Madrid, Spain
Center, Memphis, TN, United States I. Melle  NORMENT, KG Jebsen Centre for Psychosis
W. Liu  NORC at the University of Chicago, Bethesda, MD, Research, Division of Mental Health and Addiction, Oslo
United States University Hospital & Institute of Clinical Medicine,
M.J. Loflin  Department of Psychology, School of Arts and University of Oslo, Oslo, Norway
Sciences, University at Albany, State University of New York, S. Menahem  Paediatric Cardiology Unit, Monash Health,
Albany, NY, United States Melbourne, Melbourne; Faculty of Medicine, Nursing and
R. Lorente-Omeñaca  Department of Psychiatry, IdiSNA, Health Sciences, Monash University, Clayton, VIC, Australia
Navarra Institute for Health Research, Pamplona, Spain J. Mendes-Gomes  Laboratory of Neuroanatomy &
V. Lorenzetti  Melbourne Neuropsychiatry Centre, Neuropsychobiology, Department of Pharmacology, Ribeirão
The University of Melbourne and Melbourne Health, Preto Medical School of the University of São Paulo (FMRP-
Melbourne; Brain & Mental Health Laboratory, Monash USP), Ribeirão Preto, São Paulo, Brazil
Institute of Cognitive and Clinical Neurosciences, School of B. Mesías  Instituto de Adicciones, Madrid, Spain
Psychological Sciences, Monash University, Clayton, VIC, S. Miller  Division of Behavioral and Organizational Sciences,
Australia School of Social Science, Policy and Evaluation, Claremont
D. Lu  Department of Pharmaceutical Sciences, Rangel Graduate University, Claremont, CA, United States
College of Pharmacy, Texas A&M University, Kingsville, TX, R. Mizrahi  Centre for Addiction and Mental Health
United States (CAMH), Research Imaging Centre, Toronto, ON, Canada
J. Mørland  Department of Drug Abuse Research, Division S. Molinaro  Institute of Clinical Physiology, The Italian
of Forensic Sciences, Norwegian Institute of Public Health, National Research Council (IFC-CNR), Pisa, Italy
Oslo, Norway
C. Moore  Toxicology Research and Development,
K.R. Müller-Vahl  Clinic of Psychiatry, Social-Psychiatry Immunalysis Corporation, Pomona, CA, United States
and Psychotherapy, Hannover Medical School, Hannover,
M.F. Moraes  Department of Physiology and Biochemistry,
Germany
ICB, Federal University of Minas Gerais, Belo Horizonte,
A. Machoy-Mokrzyńska  Department of Pharmacology, Minas Gerais, Brazil
Pomeranian Medical University, Szczecin, Poland
F.A. Moreira  Department of Pharmacology, ICB, Federal
P. Maeder  Department of Radiology, University Hospital of University of Minas Gerais, Belo Horizonte, Minas Gerais,
Lausanne, Lausanne, Switzerland Brazil
S. Majumdar  Department of Pharmaceutics and Drug L. Moreno-Izco  Department of Psychiatry, IdiSNA, Navarra
Delivery, School of Pharmacy, University of Mississippi, Institute for Health Research, Pamplona, Spain
Oxford, MS, United States
H.A. Morris  Department of Criminal Justice and
R. Maldonado  Department of Experimental and Health Criminology, University of North Carolina at Charlotte,
Sciences, Laboratory of Neuropharmacology, School Charlotte, NC, United States
of Health and Life Sciences, Pompeu Fabra University,
E. Muñoz  Department of Cell Biology, Physiology and
Barcelona, Spain
Immunology, University of Córdoba, Córdoba, Spain
K.E. Maple  Department of Psychology, University of
G.G. Muccioli  Bioanalysis and Pharmacology of Bioactive
Wisconsin-Milwaukee, Milwaukee, WI, United States
Lipids Research Group, Louvain Drug Research Institute,
M. Martínez-Cengotitabengoa  Department of Psychiatry, Université catholique de Louvain, Brussels, Belgium
University Hospital of Alava-Santiago, CIBERSAM; National
M.R.A. Muscatello  Department of Biomedical, Dental
Distance Education University (UNED)-Centro Asociado de
Sciences and Morpho-functional Imaging, University of
Vitoria, Vitoria, Spain
Messina, Messina, Italy
M. Isabel Martín-Fontelles  Area of Pharmacology and
S.A. Nada  Department of Pharmacology, National Research
Nutrition, Faculty of Health Sciences, University Rey Juan
Centre, Dokki, Greater Cairo, Egypt
Carlos, Alcorcón; Associated Unit I+D+i of the Institute of
Medicinal Chemistry (IQM) and of the Institute of Research V. Naraynsingh  Department of Clinical Surgical Sciences,
in Food Sciences (CIAL), Spanish National Research Council University of the West Indies, St. Augustine Campus,
(CSIC), Madrid, Spain St Augustine, Trinidad and Tobago

  
 LIST OF CONTRIBUTORS xxi
S. Narimatsu  Department of Health Chemistry, Graduate F. Pollastro  Department of Pharmaceutical Science,
School of Medicine, Dentistry and Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy
Okayama University, Okayama, Japan A. Porcu  Department of Biomedical Sciences, Division
G. Nogueira-Filho  School of Health Sciences, University of Neuroscience and Clinical Pharmacology, Cittadella
Salvador, Laureate International Universities, Salvador, Bahia, Universitaria, Monserrato, CA, Italy
Brazil R. Potente  Institute of Clinical Physiology, The Italian
M. Nordentoft  Mental Health Center Copenhagen, National Research Council (IFC-CNR), Pisa, Italy
Copenhagen University Hospital, Copenhagen, Denmark D.E. Potter  Department of Pharmaceutical Sciences, Rangel
G. Oguz  Turkish Association for Cognitive and Behavioural College of Pharmacy, Texas A&M University, Kingsville, TX,
Therapies, Istanbul; Department of Psychology, Canik Basari United States
University, Samsun, Turkey S. Potvin  Research Centre of the University of Montreal
Å.M.L. Øiestad  Norwegian Institute of Public Health, Institute for Mental Health; Department of Psychiatry,
Division of Forensic Sciences, Oslo, Norway Faculty of Medicine, University of Montreal, Montreal, QC,
E.L. Øiestad  Norwegian Institute of Public Health, Division Canada
of Forensic Sciences, Oslo, Norway C. Prats  Faculty of Biology, Anthropology Unit,
H. Okazaki  Drug Innovation Research Center, Daiichi Department of Animal Biology, University of Barcelona,
University of Pharmacy, Fukuoka, Japan Biomedicine Institute of the University of Barcelona (IBUB),
Barcelona; CIBER of Mental Health (CIBERSAM), Madrid,
M.F. Olive  Department of Psychology, Arizona State
Spain
University, Tempe, AZ, United States
V.R. Preedy  Faculty of Life Sciences and Medicine, King’s
L. Orio  Department of Psychobiology, Faculty of
College London, London, United Kingdom
Psychology, Complutense University of Madrid, Pozuelo de
Alarcón, Madrid, Spain R. Rajendram  Faculty of Life Sciences and Medicine, King’s
College London, London, United Kingdom
A. Ozaita  Department of Experimental and Health
Sciences, Laboratory of Neuropharmacology, School L. Rathke  Palo Alto University, Palo Alto, CA, United
of Health and Life Sciences, Pompeu Fabra University, States
Barcelona, Spain K.L. Reed  The University of Arizona, Tucson, AZ, United
A. Pérez  Evaluation and Intervention Methods Service, States
Public Health Agency, Barcelona, Spain M.A. Repka  Department of Pharmaceutics and Drug
G. Panagis  University of Crete, Department of Psychology, Delivery, School of Pharmacy, University of Mississippi,
Laboratory of Behavioral Neuroscience, Rethymnon, Crete, Oxford, MS, United States
Greece H. Rigter  Youth Interventions Foundation, Curium,
G. Pandolfo  Department of Biomedical, Dental Sciences and Department of Child and Adolescent Psychiatry, Leiden
Morpho-functional Imaging, University of Messina, Messina, University Medical Center, Leiden, The Netherlands
Italy E.M. Rock  Department of Psychology and Collaborative
L.V. Panlilio  Preclinical Pharmacology Section, Behavioral Neuroscience Program, University of Guelph, Guelph, ON,
Neuroscience Branch, Intramural Research Program, National Canada
Institute on Drug Abuse, National Institutes of Health, H. Rohrbacher  Practice for Cognitive Behaviour Therapy,
Baltimore, MD, United States Munich, Germany
K. Paquin  Research Centre of the University of Montreal P.G.P. Rosa  Department of Psychiatry, Faculty of Medicine,
Institute for Mental Health; Department of Psychology, Laboratory of Psychiatric Neuroimaging (LIM-21), University
University of Montreal, Montreal, QC, Canada of São Paulo; Center for Interdisciplinary Research on Applied
P. Parakh  Department of Psychiatry, Ruby General Hospital, Neurosciences (NAPNA), University of São Paulo, São Paulo,
Kolkata, India Brazil
L.A. Parker  Department of Psychology and Collaborative F. Sánchez-Martínez  Evaluation and Intervention Methods
Neuroscience Program, University of Guelph, Guelph, ON, Service, Public Health Agency, Barcelona, Spain
Canada A.M. Sánchez-Torres  Department of Psychiatry, IdiSNA,
V.B. Patel  University of Westminster, School of Life Sciences, Navarra Institute for Health Research, Pamplona, Spain
Department of Biomedical Science, London, United Kingdom M. Sałaga  Department of Biochemistry, Faculty of Medicine,
M. Pawson  Department of Sociology, The Graduate Center, Medical University of Lodz, Lodz, Poland
City University of New York, New York, NY, United States V. Sabato  Faculty of Medicine and Health Science,
F.F. Peres  Department of Pharmacology, Federal University Department of Immunology-Allergology-Rheumatology,
of Sao Paulo; Integrated Laboratory of Clinical Neurosciences University of Antwerp, Antwerp, Belgium
(LiNC), Federal University of Sao Paulo, Sao Paulo, Brazil A.N. Sanders  Department of Criminal Justice and
H. Petras  American Institutes for Research, Washington, DC, Criminology, University of North Carolina at Charlotte,
United States Charlotte, NC, United States

  
xxii LIST OF CONTRIBUTORS

L.C. Santos  Department of Psychiatry, Faculty of Medicine, F. Stehle  Laboratory of Technical Biochemistry, Department
Laboratory of Psychiatric Neuroimaging (LIM-21), University of Biochemical and Chemical Engineering, TU Dortmund
of São Paulo; Center for Interdisciplinary Research on Applied University, Dortmund, Germany
Neurosciences (NAPNA), University of São Paulo, São Paulo, J.M. Stogner  Department of Criminal Justice and
Brazil Criminology, University of North Carolina at Charlotte,
M. Scalese  Institute of Clinical Physiology, The Italian Charlotte, NC, United States
National Research Council (IFC-CNR), Pisa, Italy S. Sussman  Departments of Preventive Medicine and
M.S. Schaufelberger  Department of Psychiatry, Faculty of Psychology, and School of Social Work, Institute for Health
Medicine, Laboratory of Psychiatric Neuroimaging (LIM-21), Promotion and Disease Prevention Research, University of
University of São Paulo; Center for Interdisciplinary Research Southern California, Los Angeles, CA, United States
on Applied Neurosciences (NAPNA), University of São Paulo, W. Swift  NHMRC Centre for Research Excellence in Mental
São Paulo; Department of Neuroscience and Behavior, Faculty Health and Substance Use, National Drug and Alcohol
of Medicine, Ribeirão Preto, University of São Paulo, Ribeirao Research Centre, University of New South Wales, Randwick,
Preto, Brazil NSW, Australia
N. Schröder  Neurobiology and Developmental Biology N. Szerman  Gregorio Marañon Hospital, Madrid, Spain
Laboratory, Faculty of Biosciences, Pontifical Catholic
T. Tüting  Laboratory of Experimental Dermatology,
University, Porto Alegre, Rio Grande do Sul, Brazil
Department of Dermatology and Allergy, University
G. Scimeca  Department of Biomedical, Dental Sciences and Hospital of the Friedrich-Wilhelm-University Bonn, Bonn,
Morpho-functional Imaging, University of Messina, Messina, Germany
Italy
M. Aghazadeh Tabrizi  Department of Chemistry and
R. Secades-Villa  Addictive Behaviors Research Group, Pharmaceutical Science, University of Ferrara, Ferrara, Italy
Department of Psychology, University of Oviedo, Oviedo,
O. Taglialatela-Scafati  Department of Pharmacy, University
Spain
of Napoli Federico II, Napoli, Italy
D. Selvarajah  Department of Human Metabolism, Medical
R.N. Takahashi  Department of Pharmacology, CCB, Federal
School, University of Sheffield, Sheffield, United Kingdom
University of Santa Catarina, Florianópolis, Santa Catarina,
O. Senormanci  Department of Psychiatry, Bülent Ecevit Brazil
University School of Medicine, Zonguldak, Turkey
S. Takeda  Laboratory of Xenobiotic Metabolism and
K. Shivakumar  Health Sciences North, Department of Environmental Toxicology, Faculty of Pharmaceutical
Psychiatry, and Northern Ontario School of Medicine, Sciences, Hiroshima International University (HIU), Kure,
Sudbury, ON, Canada Hiroshima, Japan
L.A. Shrier  Division of Adolescent/Young Adult Medicine, I. Tarricone  Department of Medical and Surgical Sciences,
Boston Children’s Hospital, and Department of Pediatrics, Bologna University; Department of Mental Health, Bologna,
Harvard Medical School, Boston, MA, United States Italy
V. Siciliano  Institute of Clinical Physiology, The Italian D.P. Tashkin  Division of Pulmonary and Critical Care,
National Research Council (IFC-CNR), Pisa, Italy Department of Medicine, David Geffen School of Medicine at
L. Sideli  Department of Experimental Biomedicine and UCLA, Los Angeles, CA, United States
Clinical Neuroscience, School of Medicine, University of T. Tellioğlu  Brown University, Alpert Medical School,
Palermo, Palermo, Italy Substance Abuse Division, Rhode Island Hospital,
J.T. Siegel  Division of Behavioral and Organizational Providence, RI, United States
Sciences, School of Social Science, Policy and Evaluation, Z. Tellioğlu  Brown University, Alpert Medical School,
Claremont Graduate University, Claremont, CA, Rhode Island Hospital, Providence, RI, United States
United States
S. Tesfaye  Academic Department of Diabetes and
A.A. Sleem  Department of Pharmacology, National Endocrinology, Sheffield Teaching Hospitals NHS Foundation
Research Centre, Dokki, Greater Cairo, Egypt Trust, Sheffield, United Kingdom
J. Sobczyński  Department of Pharmaceutics, Medical L. Thornton  NHMRC Centre for Research Excellence in
University of Lublin, Lublin, Poland Mental Health and Substance Use, National Drug and Alcohol
L. Sodos  Palo Alto University, Palo Alto, CA, United States Research Centre, University of New South Wales, Randwick,
N. Solowij  School of Psychology, University of Wollongong, NSW, Australia
Wollongong, NSW, Australia B. Thylstrup  Center for Alcohol and Drug Research,
Z.-H. Song  Department of Pharmacology and Toxicology, Aarhus University, Copenhagen Department, Copenhagen,
University of Louisville School of Medicine, Louisville, KY, Denmark
United States P.G. Tibbo  Department of Psychiatry, Dalhousie University,
A.W. Stacy  School of Community and Global Health, Halifax, NS, Canada
Claremont Graduate University, Claremont, CA, G. Todd  School of Pharmacy and Medical Sciences,
United States University of South Australia, Adelaide, SA, Australia

  
 LIST OF CONTRIBUTORS xxiii
M. Torrens  Addiction Program, Institute of Neuropsychiatry Z. Walsh  Psychology Department, IKBSAS, University of
and Addiction—INAD, and Hospital del Mar Medical British Columbia, Kelowna, BC, Canada
Research Institute—IMIM, Barcelona, Spain K. Watanabe  Department of Hygienic Chemistry, Faculty
J. Tsai  Department of Preventive Medicine, Keck School of of Pharmaceutical Sciences, Hokuriku University, Kanazawa;
Medicine, University of Southern California, Los Angeles, CA, Pharmaceutical Education Support Center, Daiichi University
United States of Pharmacy, Fukuoka, Japan
H.-H. Tseng  Centre for Addiction and Mental Health L.R. Watterson  Department of Psychology, Arizona State
(CAMH), Research Imaging Centre, Toronto, ON, Canada; University, Tempe, AZ, United States
Department of Psychosis Studies, Institute of Psychiatry, J.M. White  School of Pharmacy and Medical Sciences,
King’s College London, London, United Kingdom University of South Australia, Adelaide, SA, Australia
A. Turner  Priority Research Centre for Translational N.E. Wright  Department of Psychology, University of
Neuroscience and Mental Health, University of Newcastle, Wisconsin-Milwaukee, Milwaukee, WI, United States
Callaghan, NSW, Australia
M. Yücel  Melbourne Neuropsychiatry Centre, The University
S.S. Tuv  Department of Drug Abuse Research, Division of Melbourne and Melbourne Health, Melbourne; Brain &
of Forensic Sciences, Norwegian Institute of Public Health, Mental Health Laboratory, Monash Institute of Cognitive
Oslo, Norway and Clinical Neurosciences, School of Psychological Sciences,
F. Ullah  Laboratory of Neuroanatomy & Neuropsychobiology, Monash University, Clayton, VIC, Australia
Department of Pharmacology, Ribeirão Preto Medical School of I. Yamamoto  Hokuriku University, Kanazawa, Japan
the University of São Paulo (FMRP-USP), Ribeirão Preto, São
S. Yamaori  Department of Pharmacy, Shinshu University
Paulo, Brazil
Hospital, Matsumoto, Japan
T. Van der Linden  Department Drugs and Toxicology,
A. Zalesky  Melbourne Neuropsychiatry Centre, The
National Institute of Criminalistics, Brussels, Belgium
University of Melbourne and Melbourne Health, Melbourne,
A.L. Van Gasse  Faculty of Medicine and Health Science, VIC, Australia
Department of Immunology-Allergology-Rheumatology,
D. Zalman  Division of Oncology, Rambam Health Care
University of Antwerp, Antwerp, Belgium
Campus and Faculty of Medicine, Technion—Israel Institute
P. Vega  Instituto de Adicciones, Madrid, Spain of Technology, Haifa, Israel
G. Vera  Area of Pharmacology and Nutrition, Faculty J. Zhang  Neuroscience Center of Excellence, School of
of Health Sciences, University Rey Juan Carlos, Alcorcón; Medicine, Louisiana State University Health Sciences Center,
Associated Unit I+D+i of the Institute of Medicinal Chemistry New Orleans, LA, United States
(IQM) and of the Institute of Research in Food Sciences
Y. Zhang  Department of Medicinal Chemistry, School of
(CIAL), Spanish National Research Council (CSIC), Madrid,
Pharmacy and Institute for Structural Biology and Drug
Spain
Discovery, Virginia Commonwealth University, Richmond,
M. Verdichevski  Northern Medical Program, University VA, United States
of Northern British Columbia, Prince George, BC, Canada
R. Zoccali  Department of Biomedical, Dental Sciences and
T.R. Vieira Sousa  Center for Drug and Alcohol Research, Morpho-functional Imaging, University of Messina, Messina,
Hospital de Clinicas de Porto Alegre, Federal University of Italy
Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
C.F. Zorumski  Department of Psychiatry; The Taylor
L.R. Vilela  Department of Pharmacology, ICB, Federal Family Institute for Innovative Psychiatric Research,
University of Minas Gerais, Belo Horizonte, Minas Gerais, Washington University School of Medicine, St. Louis, MO,
Brazil United States
V. Vindenes  Department of Drug Abuse Research, Division A.W. Zuardi  Department of Neuroscience and Behavior,
of Forensic Sciences, Norwegian Institute of Public Health, Ribeirão Preto Medical School, University of São Paulo,
Oslo, Norway Ribeirão Preto, Sao Paulo, Brazil

  
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 Preface

Cannabis is probably one of the most commonly however, addressed in The Handbook of Cannabis and
used drugs of misuse. It has a wide range of adverse Related Pathologies: Biology, Pharmacology, Diagnosis,
effects including impairing learning and memory. At and Treatment which embraces all aspects of canna-
the same time, the medical use of cannabis has been bis in a one-stop-shop approach. Where appropriate,
advocated due to its ability to relieve pain as an ex- positive aspects of cannabis and related metabolites
ample. Understanding the nature of the pleasure- are described.
seeking, disinhibition, and other effects have also The book is divided into eight major parts as follows:
paved the way for the specialized field of cannabis
1. Setting the Scene, Botanical, General, and
pharmacology. This includes elucidating the nature
International Aspects
of cannabinoid receptors, which has led to the devel-
2. Personal, Social, and Community Aspects of
opment of synthetic cannabinoid agonists. However,
Cannabis Use
the aforementioned is a rather simplistic synopsis.
3. Cannabis, Behavior, Psychopathology, and
The long-term use of cannabis may also increase the
Neuropathology
risk of schizophrenia, paranoia, and other psychoses.
4. Cannabis, Organs, Tissues, and non-CNS Aspects
Its use can affect cells, organs, individuals, families,
5. Pharmacology and Cellular Activities of
subcultures, groups, and communities. This is be-
Cannabinoids and Endocannabinoids
cause the interrelationships between cannabis and in-
6. Effects of Specific Natural and Synthetic
dividual components, diagnosis, screening, social and
Cannabinoids
community effects, psychopathology, neuropathol-
7. Medicinal Cannabis Use
ogy, non-CNS effects, polydrug use, medicinal appli-
8. Screening, Diagnosis, and Treatments
cations, treatments, and pharmacology are complex.
Furthermore, although the active agents in cannabis The Editor recognizes the difficulties in ascribing
are known, the individual steps between exposure chapters to particular sections, and even their location
by ingestion or inhalation and effects on cells and the within separate sections. This is because some chapters
body are multifactorial, and cut across many scientific can be categorized in many ways. However, this issue
disciplines. It is thus important to learn from these is resolved with the excellent indexing carried out by
interrelationships to embrace a multidisciplinary ap- Elsevier.
proach to understand all the threads and ramifications The Handbook of Cannabis and Related Pathologies: Biol-
of cannabis use, misuse, and applications. For exam- ogy, Pharmacology, Diagnosis, and Treatment transcends
ple, some cellular mechanisms elucidated by studying both multiple disciplinary and intellectual divides, as
one anatomical CNS component may also be relevant each chapter has:
to other areas of the CNS, or other fields of cannabis
• Key Facts
toxicity and pharmacology. Another example relates
• Mini-Dictionary
to the impact of cannabis on social dysfunction, which
• Summary Points
may also be relevant to other psychosocial scenarios,
or useful in devising new treatment strategies. An ad- Finally, there is a chapter on Resources and Recom-
ditional example relates to preclinical studies which mended Reading, suggested by some of the book’s con-
may be relevant to understanding clinical patholo- tributors.
gies, psychomorbidities, or therapeutic drugs. Un- The Handbook of Cannabis and Related Pathologies:
raveling these complex relationships is difficult, as Biology, Pharmacology, Diagnosis, and Treatment has been
there is a wide myriad of material related to canna- designed for those working in the field of cannabis
bis. In simple terms, the material on cannabis use and and cannabinoids, drug abuse workers, neurologists,
misuse has hitherto been either scattered, diffused, specialists in addictive behaviors, health scientists,
or crosses different disciplines. These limitations are, public health and community workers, doctors,

xxv
xxvi PREFACE

pharmacologists, research scientists, and other special- for undergraduates, postgraduates, lecturers, and aca-
ists. The book is valuable as a personal reference book, demic professors.
and also for academic libraries that cover the domains
of health sciences or addictions. Contributions are from Professor V.R. Preedy, BSc, PhD, DSc,
leading national and international experts, including FRSB, FRSH, FRIPHH, FRSPH, FRCPath, FRSC
those from world renowned institutions. It is suitable King’s College London, London, United Kingdom

  
 P A R T I

SETTING THE SCENE, BOTANICAL,

GENERAL AND INTERNATIONAL
ASPECTS
 1 The cannabis plant: Botanical aspects 3
 2 The biosynthesis of cannabinoids 13
 3 Increasing plant concentrations of THC and
implications on health related disorders 24
 4 Age as a predictor of cannabis use 33
 5 Lifetime cannabis use and cognition in psychosis
spectrum disorders 44
 6 A profile of synthetic cannabinoid users 53
 7 Dual disorders in cannabis misuse 61
 8 Cannabis use and cognitive function 70
 9 Cannabis, migration, and psychosis onset 79
10 The global epidemiology and disease burden
of cannabis use and dependence 89
11 International aspects of cannabis use and
misuse: the australian perspective 101
12 International aspects of cannabis use and
misuse: Egypt 110
13 Cannabis body packing: A caribbean perspective 122
Page left intentionally blank
 C H A P T E R

1
The Cannabis Plant: Botanical Aspects
S. Farag, O. Kayser
Technical University Dortmund, Technical Biochemistry Dortmund, Dortmund, Germany

LIST OF ABBREVIATIONS
SUMMARY POINTS
• This chapter focuses on the botanical aspects of CBD Cannabidiol
Cannabis. CBDA Cannabidiolic acid
• Cannabis trichomes can come in glandular and CBN Cannabinol
nonglandular shapes, including oil resin. GPP Geranylpyrophosphate
• Resin glands are the main producer of GRIN Germplasm Resources Information Network
cannabinoids. ISSR Inter simple sequence repeat
NPGS National Plant Germplasm System
• Recently, hybrid cannabis strains have been RAPD Random amplified polymorphic
developed. RFLP Restriction fragment length polymorphism
• Modern hydroponic techniques, coupled with RH Relative humidity
selective artificial lighting, are used in order to RFLP Restriction fragment polymorphisms
solve the issue of low-potency cannabis. THCA Tetrahydrocannabinolic acid
• However, we argue that it is necessary to apply THC ∆9-Tetrahydrocannabinol
transgenic Cannabis plants to facilitate the USDA United States Department of Agriculture
metabolic pathway for cannabinoid production
or agronomic traits.
INTRODUCTION

Cannabis sativa L. (marijuana; Cannabaceae) is an

annual dioeciously flowering plant. The first appear-
KEY FA C T S ance of Cannabis was believed to be central Asia about
• Most popular varieties of Cannabis are a combination 5000 BC. For millennia, the plant has also been used for
of two or three of C. sativa, C. indica or C. ruderalis. fiber, oil production, and traditional uses. It contains a
• Cannabis cultivated for fiber or oil, or narcotics number of medicinally important compounds, such as,
production. cannabinoids (Appendino, Chianese, & Taglialatela-
• Cannabinoids are the main active ingredient. Scafati,  2011), terpenoids (Ross & ElSohly,  1996), flavo-
• Cultivation and breeding of narcotic strains is not noids (Vanhoenacker, Van Rompaey, De Keukeleire, &
permitted in most countries. Sandra,  2002), alkaloids (Turner & Elsohly,  1976), and
• Only female plants are economically important for others (Brenneisen, 2007). Cannabinoids are a unique
producing resin in narcotic strains. class of terpenophenolic compounds to Cannabis plants,
• Indoor horticultural lighting is a new system to mimic accumulated mainly in the cavity of trichomes (Kim
sunlight. & Mahlberg,  1997). More than 80 cannabinoids have
• Indoor hydroponic technology is used for maximizing been isolated from C. sativa (Elsohly & Slade, 2005). The
cannabinoids. main psychoactive compound is ∆9-tetrahydrocannabi-
nol (THC), with well-known medicinal effects (Elbatsh,

Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00001-6

Copyright © 2017 Elsevier Inc. All rights reserved.
3
4 1.  The Cannabis Plant: Botanical Aspects

Moklas, Marsden, & Kendall, 2012). At present, cultiva- erect stems. The stems are usually angular, furrowed,
tion and breeding of Cannabis is prohibited in most coun- branched, with woody interior, sometimes hollow in the
tries, except by permission for purposes of research and internodes, and vary from 1 to 6 m in height. The branch-
pharmaceutical uses (ElSohly, 2002). Cannabis plants are ing is either opposite or alternate. The roots are advanta-
usually propagated through the seed (sexual reproduc- geous, with branched taproot, generally 30–60 cm deep,
tion; outdoor cultivation) or by vegetative propagation, up to 2.5 m in loose soils, very near to the surface, and
using stem cuttings (asexual reproduction; indoor cul- more branched in wet soils. Leaves are green and pal-
tivation) (Potter, 2004). However, both techniques have mate (seven lobes). However, the size and shape of the
advantages and disadvantages. This chapter is dedicat- leaflets differs markedly, according to genetic origin. The
ed to botanical aspects, including morphology, taxono- leaf arrangement is either opposite, or alternate or spiral.
my, genetics, conservation, geographical distribution, The leaflets are 6–11 cm (length) and 2–15 mm (width).
and cultivation forms. Leaf margins are coarsely serrated. The adaxial and abax-
ial surfaces are green, with scattered, resinous trichomes.
Inflorescences consist of numerous flower heads that
BOTANY OF CANNABIS
can be found on long, leafy stems from each leaf axil.
The staminate (male flower) consists of five pale-green,
Macroscopical Features hairy sepals about 2.5–4  mm long, and five pendulous
Information was published elsewhere, giving detailed stamens, with slender filaments and stamen. The pistil-
technical descriptions of Cannabis morphology (Clarke, late (female flowers) are almost sessile, and are in pairs.
1981; UNODC, 2009) Fig. 1.1. However, this information The fruit (seed), is an achene, contains a single seed with
has been simplified in the present text. C. sativa is an an- a hard shell tightly covered by the thin wall of the ovary,
nual, dioeciously (ie, male and female flowers are found and it is ellipsoid, slightly compressed, smooth, about
on separate plants), pollinated plant with strong taproot, 2–5 mm long, generally brownish and mottled.

FIGURE 1.1  (A) female C. sativa; (B) portion of the female flowers; (C) pistillate female flower (stigmas, style, perigonal bract, and stipule); (D)
portion of the female flowers show anther; (E) mature seed.

I.  Setting the scene, botanical, general and international aspects

 Botany of Cannabis 5

FIGURE 1.2  Microscopic photographs of C. sativa trichomes. (A) Trichomes on the flower; (B) capitate-stalked trichome; (C) capitate-sessile
trichome; (D) bulbous trichome; (E) trichomes on the bract; (F) trichomes on the stem; (G) trichomes on the adaxial surface of a floral leaf. A big
capitate-sessile trichome is indicated with an arrow; (H) trichomes on the abaxial surface of a leaf. Present abundant small capitate-sessile and
bulbous trichomes. Source: Adapted from Happyana et al. (2013).

Microscopical Features centuries, as the result of breeding and selection. How-

ever, the Cannabis processed by these methods creates
In general, Cannabis trichomes comprise a diverse set many debates about further botanical classification. So
of structures and different types of trichomes (eg, glan- far, there is no general agreement about the taxonomic
dular and nonglandular) on a single leaf, when viewed rank of various groups within the genus Cannabis, and
through a hand lens (Fig.  1.2). Cannabis trichome re- consequently its monospecific or polyspecific character,
searchers have commonly described two types of the since the time of Linnaeus (late 18th century) (Hazekamp,
nonglandular trichome that have not been associated Justin, Lubbe, & Ruhaak, 2010). UNODC (1956) divided
with terpenoid development (Table  1.1). Three types domesticated Cannabis into three different groups:
of glandular trichome have been described on female
plants, namely bulbous, sessile, and capitate stalked • fiber hemp, long, unbranched plants, with poor seed
(Happyana et al., 2013). Male plants have been found to production
exhibit a fourth type—the antherial glandular trichome, • oil seed hemp, short, early maturing plants, with rich
which has only been found on anthers (Fairbairn, 1972). seed production
Glandular trichomes are made from a series of differenti- • drug hemp, short, strongly branched plants, with
ated cells with different functional properties, namely the small dark green leaves.
secretory cells, and stalk cells (Kim & Mahlberg, 1991). Schultes, Klein, Plowman, & Lockwood (1974) distin-
guished three species within the genus: C. sativa L., C.
Classification of Cannabis indica Lam., and C. ruderalis. Other authors referred to
The first official publication which recorded the use the same taxa only at subspecific level within one single
of Latin binomials is Linnaeus’s Species Plantarum, and species, C. sativa (Hoffmann, 1961). Small and Cronquist
it can be dated back to the year 1753. Afterward, the in- (1976) divided the single species C. sativa into the sub-
ternational community acknowledged it as the starting species sativa and indica, each consisting of a domesti-
point for modern botanical nomenclature. The species cated (Table 1.2) and wild varieties. Within the subspe-
name Cannabis means “cane-like,” while the genus name cies sativa, the domesticated and the wild varieties are
“sativa” has the meaning “planted or sown,” and signifies C. sativa subsp. sativa var. sativa (domesticated), C. sativa
that the plant is propagated from seed, and not from pe- subsp. sativa var. spontama (wild), C. sativa subsp. indica
rennial roots (Raman,  1998). According to the modern var. indica (domesticated), and C. sativa subsp. indica
system of classification, Cannabis belongs to the family var. kafiristanica (wild). However, it is commonly ac-
of Cannabaceae, along with the Humulus genus (hops) cepted that Cannabis is monotypic, and consists only of
(Turner, Elsohly, & Boeren, 1980a,b). Different varieties of a single species: C. sativa (Brenneisen,  1983; Beutler &
Cannabis have been developed over the course of many Dermarderosian, 1978).

I.  Setting the scene, botanical, general and international aspects

6 1.  The Cannabis Plant: Botanical Aspects

TABLE 1.1 A Summary of Cannabis Trichomes Classification, Structure, Distribution, Timing of Development, and Lifespan
Trichomes
Timing of
development/
Classification Structure Distribution density Lifespan References

Nonglandular (1) Noncystolithic trichomes: Lower side of Decreases The viability and (Fairbairn, 1972;
trichomesa long, unicellular, smooth, vegetative leaves with age functioning Hammond &
curved, covering and pistillate secretion is Mahlberg, 1977; Turner
trichomes bracts correlated with et al., 1977, 1980b, 1981;
senescence of Croteau, 1988;
(2) Cystolithic trichomes: epidermal cells Werker, 2000; Guy &
more squat, unicellular, claw Stott, 2005; Happyana
shape, cystolith covering et al., 2013)
trichomes, containing
calcium carbonate

Glandular (1) Bulbous: Vegetative leaves

trichomesb with smallest gland and pistillate
bracts

(2) Capitate-sessile (unstalked):

the structure is commonly
simple, and the trichomes
head connected directly to
the mesophyll cells.

(3) Capitate-stalked: Bracts and floral Increases with

the structure more complex, leaves age
they developed resin
head (also known as
the glandular head)
that resembles a golf
ball sitting on a tee (the
trichome’s stalk).

Antherial sessile Large size, with a diameter Underside of the

trichomesc of approximately anther lobes
70–80 µm
a
Nonglandular trichomes lack cannabinoids.
b
Glandular trichomes are the principal or sole site of storage of most cannabinoids, the content of ∆9-THC in pistillate flowers ranged between 10 and 12%, and in leaves ranged
between 1 and 2%.
c
Male plants are of no consequence in medicine production because they develop few glandular trichomes and, consequently, produce few cannabinoids or terpenes.

TABLE 1.2 Synopsis of C. sativa Sectional Species, Subspecies, and Varieties Recognized Based on Chemical, Genetic, and
Morphological Variation
Section sativa Section spontanea
a
C. sativa (L.) C. ruderalis (L)a
C. chinensis (Delile) C. sativa subsp. spontanea (Serebr.)
C. gigantea (Delile) var. spontanea
C. americana (Houghton) var. ruderalis
C. sativa subsp. Intersita (So.)
Section indica
subsp. culta (Serebr) C. indica (Lam.)a
subsp. Sativa (L.) C. macrosperma (Stokes)
var. sativa C. sativa subsp. indica (Lam.)

var. praecox var. indica
var. monoica var. kif
var. gigantea var. afghanica
var. Chinensis var. kafiristanica
var. pedemontana
a
Includes the endemic and domesticated populations (Raman, 1998; Sytsma et al., 2002; Hillig, 2005).

I.  Setting the scene, botanical, general and international aspects

 Botany of Cannabis 7

The current scientific classification of Cannabis (Sytsma developing new varieties. Newly hybrid varieties have
et al., 2002) been developed as a result of the crossbreds, such as,
  Class   Hamamelidae “super-sativa” (Clarke & Watson, 2002; de Meijer, 2004).
   Subclass    Rosales Recently, varieties of Cannabis have been licensed to
    Order     Cannabaceae GW Pharmaceuticals Ltd, as part of indoor breeding
     Family      Cannabis programs (de Meijer & Hammond, 2005). In the United
      Genus       sativa States, the majority of Cannabis cultivars were selected
       Species
from single landrace sources, or from multihybrid prog-
enies made from different landraces (de Meijer,  2004).
The marijuana potency monitoring project at the Uni-
Other Recent Taxonomic Studies
versity of Mississippi (USA) is breeding Sinsemilla,
CHEMOTAXONOMIC CLASSIFICATION Skunk 1, Four Way, Four Way-F, Thai/Skunk, Terbag
Recently, chemotaxonomic classification splits the W1, K2, and MX Cannabis of hybrid varieties (ElSohly,
phenotypes based on the quantitative differences in the Holley, & Turner, 1985; Elsohly, Holley, Lewis, Russell, &
cannabinoid ratio of tetrahydrocannabinolic acid (THC), Turner, 1984). In the Netherlands, there are three differ-
cannabinol (CBN), and cannabidiol (CBD), in the ratio of ent Cannabis varieties from sativa: Bedrocan, Bedrobinol,
[THC] + [CBN]/[CBD]. If the ratio exceeded 1, plants are and Bediol, and one variety from C. indica is Bedica –
classified as “chemo-type,” otherwise as “fiber-type,” and all studied and registered by Bedrocan BV (Fischedick,
this was the first study to differentiate between the drug- Hazekamp, Erkelens, Choi, & Verpoorte,  2010). Nowa-
and fiber-type, by Fetterman et al. (1971). Therefore, this days, many Cannabis hybrid cultivars (Table  1.3) and
ratio was subsequently used to discriminate chemotype, some selected pure strains have been commercialized in
intermediate type, and fiber-type (Turner, Cheng, Lewis, many private companies, and there are up to 20 more
Russell, & Sharma,  1979). Hillig and Mahlberg (2004) or less well defined strains for either indoor or outdoor
split Cannabis into putative species and subspecies, us- cultivation, in The Netherlands, but a sufficient data set
ing multivariate data analysis. Moreover, it was reported is not available, due to illegal cultivation. Today, the cul-
that, depending on age, the Cannabis plant can be classi- tivation and production of hemp is restricted and con-
fied into different morphotypes, at different time points trolled because of its association with narcotic use. Most
of its development. Although this classification was not of the hemp breeders cultivate fiber hemp with the ul-
comprehensive enough to elucidate infrageneric taxo- timate goal to reduce THC content below 0.2%, or even
nomic structure, and does not define the contents of can- to get noncannabinoid plants by breeding and crossing
nabinoids for each chemotype, it provides a usable tool experiments (de ­Meijer, 1995).
for classification (Hazekamp et al., 2010).

MOLECULAR CLASSIFICATION
Genetics of Cannabis
Several molecular techniques have been evaluated to Genome of Cannabis sativa
establish the genetic relationship among different variet- The genome of Cannabis (2n = 18 + XX for female, and
ies of Cannabis plants. Some recent studies have classi- 2n = 18 + XY for male) has a karyotype composed of nine
fied and identified C. sativa samples that cannot be dif- autosomes and a pair of sex chromosomes (X and Y). Sex
ferentiated by HPLC analysis alone, by using genomic chromosomes changes during the developmental stages
DNA, random amplified polymorphic DNA (RAPD), are claimed to occur in many dioecious plants, as a strat-
and restriction fragment polymorphisms (RFLP) analy- egy for survival (Flemming et  al., 2007). The genome
sis, but little work appears to have been conducted with was measured in both female (XX) and male plants (XY)
marker types that would be usable for breeding (Gillan, (Vyskot & Hobza, 2015). The estimated haploid genome
Cole, Linacre, Thorpe, & Watson, 1995; Faeti, Mandolino, sizes are 818 Mb for female plants, and 843 Mb for males
& Ranalli, 1996). Recently, Kojoma, Iida, Makino, Sekita, (Sakamoto et al., 1998). The genomic resources available
and Satake (2002) reported that different Cannabis were for Cannabis are mainly confined to transcriptome infor-
identified by means of inter simple sequence repeat mation: the NCBI database contains 12,907 ESTs and 23
(ISSR). ISSR is a technique offering the reproducibility unassembled RNA-Seq datasets of Illumina reads (Marks
and simplicity of RAPDs with high reliability (Galvan, et al., 2009). The genetic basis of cannabinoid variation in
Bornet, Balatti, & Branchard, 2003). C. sativa showed that the amount of THC versus CBD is
likely governed by one locus with two codominant al-
leles, B(d) and B(t) (de Meijer et al., 2003). One possible
Current Cannabis Varieties
explanation for these results is that the two alleles en-
Recently, Cannabis growers have become more code either THCA or CBDA synthase so that homozy-
aware to create variations between different strains for gous plants would contain either tetrahydrocannabinolic

I.  Setting the scene, botanical, general and international aspects

8 1.  The Cannabis Plant: Botanical Aspects

TABLE 1.3 Origin of Hemp Varieties Were Reported in acid (THCA) or cannabidiolic acid (CBDA) as the major
Literaturea cannabinoid, and heterozygotes would have an approxi-
Variety Country mately equal mixture of the two (Fig. 1.3). Another ex-
planation is that THCA and CBDA synthases are closely
Finola Finland
linked genes, perhaps produced as a result of a gene
Glukhov 33, Kuban, Uso 11, Zenica, USO 13, USO Ukraine duplication event. A recent study analyzed the THCA
15, USO 31, YUSO 14, YUSO 16 synthase sequences from drug (high-THC) and fiber
Asso, Carmagnola, CS (Carmagnola Selezionata), Italy (low-THC) varieties, and found that the amino acid se-
Carmono, Carma, Codimono, Eletta Campana, quence of THCA synthase from high-THC varieties dif-
Ferrara, Ermes, Fibrimor fered by 37 major substitutions, compared to low-THC
Fibranova
varieties (Kojoma, Seki, Yoshida, & Muranaka, 2006).
Fasamo, Ferimon Germany

Santhica 27, Epsilon 68, Fedora 17, Fedora 19, France Geographical Distribution
Fedrina 74, Felina 32, Felina 34, Fibrimon 21,
Fibrimon 24, Fibrimon 56, Futura, Futura 77, Small and Cronquist (1976) state that genus Canna-
Futura 75, Santhica 23, Dioica 88 bis geographically grows to the north of latitude 30°N
Kompolti Sargaszaru, Kinai unisexualis, Kompolti, Hungary and south of latitude 60°N (Hillig,  2005). The genus is
Kompolti Hybrid TC, Kompolti Hyper, Elite, believed to have originated in the Northwest Himalayas,
Fibriko and occurs widely in Africa.
Fibramulta 151, Irene, Lovrin 110, Moldovan, Romania
Secuieni 1
Agricultural Status
Beniko, Bialobrzeskie, LKCSD, Dolnoslaskie Poland
Nowadays, fiber hemp is cultivated in a number
Chamaeleon, Dutch “Yellow” line Netherlands
of countries around the world, and China represents
Ermakovskaya Mestnaya Russia the largest producer of hemp with focus on fiber-type
Delta 405, Delta-llosa Spain (Mediavilla, Bassetti, & Leupin, 1999). Nevertheless, cul-
tivation of medicinal Cannabis is prohibited in most of
Kenvir Turkey
countries, except by permission for purposes of research
Swissmix Swiss and pharmaceutical uses.
Ratslaviska Czech

Silistrensi, Mecnaja copt Bulgaria Conservation Initiatives

Pesnica Slovenia Cannabis populations are facing the threat of genetic
Flajsmanova, Novosadksa, Novosadska plus, Former drift—which has a direct effect on the changes to the
Novosadska konoplja ­Yugoslavia phenotype and chemical profile, due to allogamous (de
Kinai Egylaki, Kinai Ketlaki China Meijer & Vansoest, 1992). The conservation of Cannabis
germplasm is divided into two main strategies: in situ
Kozuhura Zairai Japan
and ex situ.
a
Low THC cultivars, less than 0.2% dry weight.
Ex Situ Conservation in Gene Banks
The Cannabis gene bank at Vavilov Research Insti-
tute of Plant Industry (St. Petersburg, Russia) main-
tained about 200 accessions, for more than 50 years (de
Meijer,  1998). In addition, the Hungarian gene bank at
the Research Center for Agrobiodiversity (Tápiószele,
Hungary) maintained about 70 accessions. Collections of
up to 20 accessions are preserved in other depositories in
Germany, Turkey, and Japan. In comparison with other
crops, the available number of well-documented Cannabis
accessions is limited (de Meijer & Vansoest, 1992). Now-
adays, several accessions are maintained by the United
States Department of Agriculture (USDA)/National
FIGURE 1.3  Inheritance of chemical phenotype in C. sativa “co-
dominant monogenic control,” homozygous THC producing BtBt Plant Germplasm System (NPGS), and associated data
genotypes are typically selected for recreational use. Source: From de can be accessed from the Germplasm Resources Infor-
Meijer et al. (2003). mation Network (GRIN) database.

I.  Setting the scene, botanical, general and international aspects

 Botany of Cannabis 9
In Situ Conservation as In Vitro Gene Banks Indoor Cultivation
In vitro conservation of encapsulated microcuttings This method of breeding is used for increasing resin
of Cannabis shootlets was attempted under slow growth potency, and avoiding unwanted male plants (Chandra,
conditions between 5 and 15°C (Lata, Chandra, Khan, Lata, Khan, & ElSohly, 2010). The complete growth cy-
& ElSohly,  2008; Lata, Chandra, Mehmedic, Khan, & cle, quality, and quantity of biomass can be regulated
ElSohly,  2012), but adaptation to in vitro conditions under controlled environmental conditions (6–8 weeks).
could induce mutants of the offspring plants, causing The successful indoor system requires an effective hy-
genetic and chemical drift (Larkin & Scowcroft, 1981). droponic system to deliver nutrients and oxygen, and
support the plants’ growth (Fig. 1.4). However, there is a
Cultivation Techniques of Cannabis number of different techniques that have been proposed
for the indoor horticulture of Cannabis, for example, the
Outdoor Cultivation
standing aerated technique, nutrient film technique, and
Cannabis plant can be propagated from seeds, and aeroponics technique. In hydroponic growing, the nutri-
the life cycle is completed within 4–6 months, depend- ent solution is best at a pH within a certain range (5.5–
ing on the time of the plantation and the variety. It can 6.5) for maximum uptake and good plant growth (Argo
reach up to 5 m (16 ft.) in height, in a 4–6 months grow- & Fischer, 2002). Indoor Cannabis crop cultivation needs
ing season (Raman, 1998; Clarke & Watson, 2002). Her- artificial light and compressed CO2 gas for photosyn-
maphroditic varieties of this plant have been bred for thesis, and for controlling flowering and plant biomass
industrial hemp production, as this allows more uni- (Jones, 1997). Here, selective vegetative female plants are
form crops (Leggett, 2006). The process of germination is used for making clones. Later, all clones are kept under
usually completed in 3–7 days (Clarke & Watson, 2002). standard environmental conditions (light, temperature,
The seedling stage is completed within 2–3 months. Lat- RH, and CO2 concentration) in a growing room for vegeta-
er, the plant is characterized by increased biomass and tion (18 h/day photoperiod) and for flowering (12 h/day
total growth under long day time lengths (vegetative photoperiod).
growth). It is easy to recognize the male and female sex
at this stage. Later in summer, the reproductive phase In vitro Micropropagation
of Cannabis begins when the plant is exposed to short The micropropagation system offers a number of
day time lengths (less light per day than darkness) of 12– clear advantages, including (1) human-controlled
14 h or less, depending on its latitude and genetic origin method with fast propagation in a comparably short
(Brenneisen,  1983). Once the male flowers ripened and time, due to high potential multiplication rates, (2) it
pollinated, the female flowers died directly. The pro- is independent of seasonal factors like climate and ge-
duced seeds after flowering have combinations of traits ography, and (3) the produced plants are usually free
from two parents, as a result of cross fertilization (Clarke from ­microorganism-borne diseases (Zafar, Aeri, &
& Watson, 2002). This method is mostly used for the cul- ­Datta, 1992). On the other hand, in vitro propagation of
tivation of Cannabis for hemp fiber, or Cannabis seed with C. sativa through the seed is possible in most of cultivars,
less than 0.2% THC. although the greatest problem with such a method is the

FIGURE 1.4  Indoor cultivation of C. sativa. Source: Photo provided from Bedrocan BV, the Netherlands.

I.  Setting the scene, botanical, general and international aspects

10 1.  The Cannabis Plant: Botanical Aspects

FIGURE 1.5  In vitro micropropagation of leaf-derived calli from C. sativa L. (A) Callus culture, (B) meristemoid formation, (C) shootlets
multiplication on Gamborg’s B5 medium supplemented with various combinations of auxins and cytokinins. Source: Photos provided from Sayed
Farag PhD project, Technische Universität Dortmund.

high level of heterozygosity that could lead to a rapid Micropropagation  In vitro technique for multiplying plant tissues
and dramatic profile shift of secondary metabolites through in vitro culture, either indirectly (with intervening callus
stage) or directly (without an intervening proliferative stage). This
from one generation to the next (Chandra et  al.,  2010). is achieved by altering the concentration of growth regulators,
In fact, in vitro propagation using explants or somatic mainly auxins and cytokinins.
embryogenesis has been reported (Lata et al., 2002). Be- Random amplified polymorphic DNA (RAPD)  A molecular
sides the progress in the field of plant biotechnology, technique for the rapid assignation of DNA-based character states
very little progress has been made to date toward devel- for phylogenetic analysis. The technique uses the polymerase
chain reaction (PCR) to amplify any genomic region containing
oping an in vitro regeneration from C. sativa. Previous single primer of nucleotide arbitrary sequence.
reports on de novo organogensis of C. sativa emerged Restriction fragment length polymorphism (RFLP)  A molecular
in early 1980s (Fisse, Braut, Cosson, & Paris, 1981), and technique for genome mapping, and variation analysis (genotyping,
subsequently from callus of different genotypes and ex- forensics, paternity tests, hereditary disease diagnostics, etc.). The
plant sources, including cotyledons and stem (Wielgus, technique uses restriction of endonucleases to cut DNA at specific
(generally 4–6 bp) recognition sites.
Luwanska, Lassocinski, & Kaczmarek,  2008), young Trichome  Defined as hair-like structures that extend from the
leaves (Lata, Chandra, Khan, & ElSohly,  2010), inter- epidermis of aerial tissues; are present on the surface of most
nodes, and axillary buds and petioles (Slusarkiewicz- terrestrial plants.
Jarzina, Ponitka, & Kaczmarek, 2005), and roots (Ranalli
& Mandolino,  1999). Alternatively, the use of meriste- References
matic callus for micropropagation was studied recently Appendino, G., Chianese, G., & Taglialatela-Scafati, O. (2011). Can-
(Farag & Kayser, unpublished results, Fig. 1.5). nabinoids: occurrence and medicinal chemistry. Current Medicinal
Chemistry, 18(7), 1085–1099.
Argo, W. R., Fischer, P. R. (2002). Understanding pH management for
Recommendations for Future Action container-grown crops. Meister, Willoughby, Ohio.
Beutler, J. A., & Dermarderosian, A. H. (1978). Chemotaxonomy of
Given the high therapeutic and commercial value of Cannabis .1. Cross breeding between Cannabis sativa and Cannabis
Cannabis, legal indoor breeding started in some pharma- ruderalis, with analysis of Cannabinoid content. Economic Botany,
ceutical companies. The biotechnological research for ge- 32(4), 387–394.
netic improvement has been minimal to date. Researches Brenneisen, R. (1983). Psychotropic drugs. I. Cannabis sativa L. (Canna-
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known as microsatellites, are tandem repeats of a few base pairs Croteau, R. (1988). Catabolism of monoterpenes in essential oil plants.
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fresh and air-dried buds of Cannabis sativa. Journal of Natural Prod- ships of glandular trichomes and cannabinoid content. 2. Develop-
ucts, 59(1), 49–51. ing vegetative leaves of Cannabis sativa L (Cannabaceae). Bulletin on
Sakamoto, K., Akiyama, Y., Fukui, K., Kamada, H., & Satoh, S. (1998). Narcotics, 33(3), 63–71.
Characterization: genome sizes and morphology of sex chromo- UNODC, United Nations, (2009). Recommended methods for identifi-
some in hemp (Cannabis sativa L.). Cytologia, 63, 459–464. cation and analysis of cannabis and cannabis products, New York.
Schultes, R. E., Klein, W. M., Plowman, T., & Lockwood, T. E. (1974). http://www.unodc.org/documents/scientific/ST-NAR-40-Ebook.
Cannabis: an example of taxonomic neglect. Harvard University Bo- pdf
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Slusarkiewicz-Jarzina, A., Ponitka, A., & Kaczmarek, Z. (2005). In- with particular reference to the breeding of varieties of hemp contain-
fluence of cultivar, explant source and plant growth regulator on ing little or no hashish, New York. http://www.unodc.org/unodc/
­callus induction and plant regeneration of Cannabis sativa L. Acta en/data-and-analysis/bulletin/bulletin_1956-01-01_3_page007.html
Biologica Cracoviensia Series Botanica, 47(2), 145–151. Vanhoenacker, G., Van Rompaey, P., De Keukeleire, D., & Sandra, P.
Small, E., & Cronquist, A. (1976). A practical and natural taxonomy for (2002). Chemotaxonomic features associated with flavonoids of can-
Cannabis. Taxon, 25, 405–435. nabinoid-free cannabis (Cannabis sativa subsp sativa L.) in relation to
Sytsma, K., Morawetz, J., Pires, J., Nepokroeff, M., Conti, E., Zjhra, M., hops (Humulus lupulus L.). Natural Product Letters, 16(1), 57–63.
Hall, J., & Chase, M. (2002). Urticalean rosids: circumscription, ro- Vyskot, B., & Hobza, R. (2015). The genomics of plant sex chromo-
sid ancestry, and phylogenetics based on rbcL, trnL-F, and ndhF somes. Plant Science, 236, 126–135.
sequences. American Journal of Botany, 89(9), 1531–1546. Werker, E. (2000). Trichome diversity and development. Advances in
Turner, C. E., & Elsohly, M. A. (1976). Anhydrocannabisativine, a new Botanical Research, 31, 1–35.
alkaloid isolated from Cannabis sativa. Lloydia, 39(6), 474–1474. Wielgus, K., Luwanska, A., Lassocinski, W., & Kaczmarek, Z. (2008).
Turner, J. C., Hemphill, J. K., & Mahlberg, P. G. (1977). Gland distri- Estimation of Cannabis sativa L. tissue culture conditions essential
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­American Journal of Botany, 64(6), 687–693. 5(3), 199–207.
Turner, C. E., Cheng, P. C., Lewis, G. S., Russell, M. H., & Sharma, G. K. Zafar, R., Aeri, V., & Datta, A. (1992). Application of plant tissue and
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I.  Setting the scene, botanical, general and international aspects

 C H A P T E R

2
The Biosynthesis of Cannabinoids
F. Degenhardt, F. Stehle, O. Kayser
Laboratory of Technical Biochemistry, Department of Biochemical and Chemical Engineering,
TU Dortmund University, Dortmund, Germany

SUMMARY POINTS • Two cannabigerol-like compounds were detected in

• This chapter focuses on the pathway which leads the aerial parts of Helichrysum umbraculigerum Less., a
to the biosynthesis of phytocannabinoids in plant common in the eastern parts of South Africa.
C. sativa L. • N-alkyl amides (cannabinomimetics), found in the
medicinal plants Echinaceae angustifolia and Echinaceae
• CBGA is the central precursor of
purpurea (purple cornflower), are known to interact
phytocannabinoid biosynthesis in Cannabis.
with the CB2 receptor.
• CBGAS, only three enzymes—THCAS, CBDAS,
and CBCAS—are involved in the biosynthesis of
phytocannabinoids in Cannabis plants. LIST OF ABBREVIATIONS
• Sequences of CBDAS and THCAS are known.
• The carboxyl group in CBGA seems to be AAE Acyl-activating enzyme
essential for the enzymatic reactions catalyzed by BBE Berberine bridge enzyme
CBDAS, CBCAS, and THCAS. CBC Cannabichromene
CBCA Cannabichromenic acid
• The diversity of more than 60 cannabinoids is the
CBCAS Cannabichromenic acid synthase
result of nonenzymatic modifications.
CBCVA Cannabichrovarinic acid
• Propyl cannabinoids occur by the prenylation of CBD Cannabidiol
divarinic acid (DA) with geranyl diphosphate CBDA Cannabidiolic acid
(GPP). CBDAS Cannabidiolic acid synthase
CBDV Cannabidivarin
CBDVA Cannabidivarinic acid
KEY FA C T S OF CBG Cannabigerol
PH YT OCA NNAB INOIDS —B ES IDE S CBGA Cannabigerolic acid (3-geranyl olivetolate)
C.  SATI VA CBGAS Cannabigerolic acid synthase
• Phytocannabinoids are plant-derived natural compounds CBGVA Cannabigerovarinic acid
that act as ligands to cannabinoid receptors (CB1 and CB2) CBN Cannabinol
or share chemical similarity with cannabinoids. CBNRA Cannabinerolic acid (cis-CBGA)
• C. sativa L. is intensively investigated for the presence CHS Chalcone synthase
of phytocannabinoids. To date, only a few plants are CsAAE1 C. sativa hexanoyl-CoA synthetase 1
discovered that contain phytocannabinoids other than CsAAE3 C. sativa hexanoyl-CoA synthetase 2
the ones known from Cannabis. CsHCS1 C. sativa hexanoyl-CoA synthetase 1
• The New Zealand liverwort Radula marginata and CsHCS2 C. sativa hexanoyl-CoA synthetase 2
Japanese liverwort Radula perrottetii contain perrotteti- DA Divarinic acid
nene, a naturally occurring bibenzyl cannabinoid. DABB Dimeric α + β barrel
DMAPP Dimethylallyl diphosphate
Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00002-8
Copyright © 2017 Elsevier Inc. All rights reserved.
13
14 2.  The Biosynthesis of Cannabinoids

DOXP 1-Deoxy-d-xylulose-5-phosphate for the biosynthesis of cannabinoids, the terpenopheno-

GOT Geranylpyrophosphate:olivetolate lic constituents that show psychoactive effects. But since
geranyltransferase other plants also have secondary metabolites that inter-
GPP Geranyl diphosphate act with the human cannabinoid receptors, a new defini-
HTAL Hexanoyltriacetic acid lactone tion had to be made. Hence, phytocannabinoids are now
IPP Isopentenyl diphosphate defined as any plant-derived natural compound that
MEP 2C-methyl-d-erythritol-4-phosphate can act as a ligand to human cannabinoid receptors (CB1
MVA Mevalonate and CB2) or share chemical similarity with cannabinoids
NPP Neryl diphosphate (Gertsch, Pertwee, & Di Marzo,  2010). Interestingly, all
OA Olivetolic acid parts of the Cannabis plant, with the exception of seeds,
OAC Olivetolic acid cyclase can contain cannabinoids, but they mainly accumulate
OLS Olivetol synthase in the glandular trichomes of female flowers (Gagne
PKS Polyketide synthase et al., 2012; van Bakel et al., 2011).
SNP Single nucleotide polymorphism The following chapter focuses on the pathway that
STS Stilbene synthase leads to the enzymatic biosynthesis of cannabinoids. For
THC Tetrahydrocannabinol a long time, it was postulated that the key intermedi-
THCA Tetrahydrocannabinolic acid ate is cannabidiol (CBD) or cannabidiolic acid (CBDA),
THCAS Tetrahydrocannabinolic acid synthase both resulting from a condensation of a monoterpene,
THCV Tetrahydrocannabivarin and olivetol or olivetolic acid (OA), respectively. In 1964,
THCVA Tetrahydrocannabivarinic acid Gaoni and Mechoulam postulated cannabigerol (CBG)
as the key intermediate, the condensation product of ge-
ranyl diphosphate (GPP), and olivetol or OA. Based on
INTRODUCTION this, they concluded that the cannabinoids CBD, tetrahy-
drocannabinol (THC) and cannabinol (CBN) are all de-
Cannabis sativa L. (hemp) is one of the oldest do- rived from CBG, and just differ in the way of cyclization
mestic plants in the history of mankind, and has been (Gaoni & Mechoulam, 1964). Finally, incorporation stud-
cultivated for at least 10,000  years (Schultes, Klein, ies with 13C-labeled glucose have shown that GPP and
Plowman, & Lockwood,  1974). Together with Humulus OA are indeed the precursors for formation of cannabig-
lupulus (hop), C. sativa belongs to the small family of erolic acid (CBGA). Thus, the general structure of canna-
Cannabaceae. Cannabis is an annual, usually dioecious, binoids is assembled by two parts: (1) a diphenol (resor-
wind-pollinated herb, with both male and female flow- cin) carrying an alkyl chain (OA); and (2) a monoterpene
ers growing on separate plants. The plant is well known moiety (GPP) (Fig.  2.1). Subsequently, Fellermeier and

FIGURE 2.1  General structure of cannabinoids and their precursors, olivetolic acid, and geranyl diphosphate. Cannabinoids are composed
of two parts: a cyclic monoterpene part (red), and a diphenol (resorcin) part, carrying an alkyl chain (blue). The dibenzopyran-numbering system
is used.

I.  Setting the scene, botanical, general and international aspects

 Cannabinoid precursor biosynthesis 15
coworkers postulated CBGA as the central cannabinoid via the lipoxygenase pathway (Marks et al., 2009; Stout,
precursor (Fellermeier, Eisenreich, Bacher, & Zenk, 2001; Boubakir, Ambrose, Purves, & Page, 2012). Nevertheless,
Fellermeier & Zenk, 1998). Interestingly, free OA has nev- further studies are necessary to clarify the origin of the
er been detected in Cannabis plant material until now. hexanol moiety.
It is worthy to note that, although more than 60 can- Hexanoyl-CoA is a medium-chain fatty acyl-CoA that
nabinoids are known, only three enzymes, besides can- can be detected in high amounts in Cannabis flowers
nabigerolic acid synthase (CBGAS), namely tetrahydro- (Stout et al., 2012). It is synthesized by an acyl-activating
cannabinolic acid synthase (THCAS), cannabidiolic acid enzyme (AAE) called hexanoyl-CoA synthetase (Marks
synthase (CBDAS), and cannabichromenic acid synthase et  al.,  2009; Page & Stout,  2013). AAEs can use short,
(CBCAS), are involved in cannabinoid biosynthesis. The medium, long as well as very long-chain fatty acids as
resulting acidic cannabinoids are the most abundant ones carboxylic acid substrates. Two novel enzymes were
accumulating in Cannabis. The neutral and psychoactive identified, C. sativa hexanoyl-CoA synthetase 1 (CsHCS1
forms are the results of nonenzymatic decarboxylation or CsAAE1) and C. sativa hexanoyl-CoA synthetase 2
during storage, heat or sunlight; explaining the heating (CsHCS2 or CsAAE3) that are capable of producing
of plant material (ie, smoking or baking), during Canna- hexanoyl-CoA using hexanoate and CoA as substrates.
bis consumption (Fischedick, Hazekamp, Erkelens, Choi, Based on transcript levels, CsHCS1 seems to be tri-
& Verpoorte, 2010; Taura et al., 2007a). Thus, the broad chome-specific. Although CsHCS2 exhibits lower tran-
diversity of the different cannabinoids is mainly due to script levels, in comparison to CsHCS1, it is abundant in
nonenzymatic transformation or degradation of both all tissues. The gene of CsHCS1 consists of a 2163-nucle-
acidic and neutral cannabinoids by the effects of light otide open reading frame, and encodes a 720-amino acid
(UV irradiation) and auto-oxidation (Crombie, Ponsford, polypeptide chain. The gene of CsHCS2 is composed of
Shani, Yagnitinsky, & Mechoulam,  1968; Razdan, a 1632-nucleotide open reading frame, and encodes a
Puttick, Zitko, & Handrick, 1972). It is still unclear if all 543-amino acid polypeptide chain. Both CsHCSs gener-
these forms are present in living plants as natural or ar- ally require divalent cations for activity. This was shown
tefacts, due to storage and sample preparation (ElSohly by adding Mg2+, Mn2+, and Co2+ to the enzyme assays.
& Slade, 2005). Thus, CsHCS1 preferentially accepts Mg2+, and CsHCS2
Co2+. The highest enzyme activity was detected at 40°C
and pH 9 for both enzymes. Furthermore, both enzymes
can be inhibited by high concentrations of CoA (Page &
CANNABINOID PRECURSOR
Stout, 2013; Stout et al., 2012).
BIOSYNTHESIS
Taken together, the published data suggest that
CsHCS1 is the enzyme involved in the biosynthesis of
Polyketide Pathway Toward Olivetolic Acid cannabinoids: (1) it is the most abundant AAE in tri-
The origin of hexanoate in trichomes has not been chomes; (2) it is highly specific for short-chain fatty acyl-
elucidated so far. Suzuki, Kurano, Esumi, Yamaguchi, and CoA, particularly hexanoate (KM value in the nM range);
Doi (2003) showed that the side-chain moiety of alkyl- and (3) it is localized in the cytosol, as suggested for the
resorcinols is formed by fatty acid units, but it remains olivetol synthase (see later). In contrast, CsHCS2 is lo-
unclear if the moiety is the result of biosynthesis or deg- calized in the peroxisomes and accepts a broad range of
radation of fatty acids. Studies regarding the incorpora- substrates, while showing a KM value for hexanoate in
tion of 13C-labels into cannabinoids indicate that hexano- the mM range (Page & Stout, 2013; Stout et al., 2012).
ate is synthesized from acetyl-CoA as a starter unit, and The alkylresorcinol moiety of cannabinoids is de-
five molecules of malonyl-CoA. These building blocks rived from OA, the product of polyketide synthases
are precursors of the fatty acid biosynthesis (Fellermeier (PKSs) that catalyze the aldol condensation of hexanoyl-
et al., 2001). CoA with three molecules of malonyl-CoA (Fellermeier
Based on this, two pathways are feasibly possible, et  al.,  2001; Raharjo, Chang, Choi, Peltenburg-Looman,
after analysis of a cDNA/EST library generated from & Verpoorte, 2004) (Fig. 2.2). The second precursor mal-
female flowers (glands) of C. sativa. First, the hexanoyl onyl-CoA is predominantly derived from acetyl-CoA
residue could be obtained by an early termination of the by carboxylation. The ATP-dependent reaction is cata-
fatty acid biosynthesis. Subsequently, the hexanoyl moi- lyzed by an acetyl-CoA carboxylase (EC 6.4.1.2). The en-
ety of the resulting hexanoyl-ACP would be cleaved by a zyme utilizes the first step in the fatty acid biosynthesis
thioesterase or transferred to CoA by an ACP-CoA trans- (Chen, Kim, Weng, & Browse, 2011; Konishi, Shinohara,
acylase. Finally, acyl-CoA synthetase would catalyze the Yamada, & Sasaki, 1996). Taura et al. (2009) discovered
conversion of the obtained n-hexanol to hexanoyl-CoA a plant type III PKS in flowers and rapidly expanding
(Marks et  al.,  2009). Second, n-hexanol could be pro- leaves of C. sativa. The gene of olivetol synthase (OLS)
duced by the breakdown of C18 unsaturated fatty acids encodes a 385-amino acid polypeptide chain that does

I.  Setting the scene, botanical, general and international aspects

16 2.  The Biosynthesis of Cannabinoids

TABLE 2.1 Enzymes Involved In Cannabinoid Biosynthesis in C. sativa L

Enzyme Accession no.a EC no. References

Olivetol synthase OLS AB164375 2.3.1.206 Taura et al. (2009)

Olivetolic acid cyclase OAC AFN42527.1 4.4.1.26 Gagne et al. (2012)

Cannabigerolic acid synthase CBGAS US2012/0144523 2.5.1.102 Fellermeier and Zenk (1998);
A1b Page and Boubakir (2012)

Cannabichromenic acid synthase CBCAS 1.3.3.- Morimoto et al. (1998)

Cannabidiolic acid CBDAS AB292682 1.21.3.8 Taura et al. (2007a)

synthase

Tetrahydrocannabinolic acid synthase THCAS AB057805 1.21.3.7 Sirikantaramas et al. (2004)

The table lists the enzymes and the corresponding GenBank accession numbers involved in biosynthesis of C. sativa phytocannabinoids.
a
GenBank.
b
Patent number.

not contain a signal peptide (Table 2.1). The OLS protein Finally, using both OLS and OAC with hexanoyl-CoA
has a theoretical molecular mass of 43 kDa, as confirmed and malonyl-CoA in one assay, the formation of OA,
by SDS-PAGE analysis. However, size-exclusion chro- pentyldiacetic acid (triketide pyrone), and hexanoyltri-
matography experiments revealed a molecular mass of acetic acid lactone (HTAL; tetraketide pyrone) could be
about 89 kDa, indicating a homodimeric enzyme (Gagne demonstrated (Page & Gagne,  2013) (Fig.  2.2). It is as-
et al., 2012; Taura et al., 2009). OLS (PKS-1) was prelimi- sumed that OLS catalyzes the formation of an interme-
narily crystallized by Taguchi et al. (2008) and the struc- diate that is subsequently converted into OA by OAC
ture was finally published by Yang et al. (2016). It is of (Gagne et al., 2012; Taguchi et al., 2008).
interest that the enzyme does not produce OA, but olive-
tol, triketide pyrone, and tetraketide pyrone. Analysis of
Biosynthesis of Geranyl Diphosphate
the amino acid sequence displayed a high similarity with
those of Medicago sativa chalcone synthase (CHS), and The monoterpene moiety of cannabinoids (Fig. 2.2) is
other plant PKSs (60–70%). Additionally, the catalytic tri- derived from GPP. Its precursors, isopentenyl diphos-
ade residues of CHS (Cys164-His303-Asn336) are conserved phate (IPP), and dimethylallyl diphosphate (DMAPP),
(Taura et al., 2009). Since CHSs catalyze intramolecular are predominantly (>98%) biosynthesized via the
C6 → C1 Claisen condensations, Raharjo, and coworkers 2C-methyl-d-erythritol-4-phosphate (MEP) pathway
were the first to suggest in 2004 (Raharjo et al., 2004) that [also termed as nonmevalonate pathway or 1-deoxy-d-
OLS could be a stilbene synthase (STS). These enzymes xylulose-5-phosphate (DOXP) pathway] (Fellermeier
catalyze C2 → C7 aldol condensations, followed by a et al., 2001). These results are supported by Marks et al.
decarboxylation step. Additionally, studies by Austin, (2009). They isolated RNA from the glands of a tetra-
Bowman, Ferrer, Schröder, & Noel (2004) showed that hydrocannabinolic acid (THCA)-producing Cannabis
the cyclization reaction can be changed from a Claisen- strain and generated a cDNA library. After sequencing,
type (CHS) to an aldol-type (STS) by substitution of a they were able to identify all but one enzyme involved
few amino acids in CHS (= aldol switch). in the MEP pathway. Additionally, Stout et  al. (2012)
Nevertheless, since OLS alone is not capable to form found high expression of MEP pathway genes in Can-
OA, another enzyme/PKS might be involved in the nabis flowers. Furthermore, in higher plants the MEP
biosynthesis. The missing enzyme should catalyze a C2 pathway, mainly involved in secondary metabolism,
→ C7 intramolecular aldol condensation upon which is localized in plastids (described in detail elsewhere,
the carboxylate moiety is preserved. This is important for example, Eisenreich, Bacher, Arigoni, & Rohdich,
since CBGAS does not accept olivetol as a prenyl do- (2004), or Hunter (2007), whereas the mevalonate (MVA)
nor (Fellermeier & Zenk, 1998). Gagne et al. (2012) iso- pathway, predominantly contributing to primary me-
lated a gene encoding a 101-amino acid polypeptide tabolism, is localized in the cytosol. The compartmental
chain. This small protein (12 kDa) shows similarities to separation between these two pathways is not absolute.
a polyketide cyclase that belongs to the dimeric α + β The metabolites of both pathways can be transported bi-
barrel (DABB)-type protein family. Furthermore, the directionally across the plastid membranes (Eisenreich
identified gene exhibits high expression levels in glan- et al., 2004).
dular trichomes. Together, this made the polyketide Subsequently, the head-to-tail condensation of IPP
cyclase a promising candidate for the missing olivetolic and DMAPP to form GPP is catalyzed by geranyl di-
acid cyclase (OAC). phosphate synthase (Fig. 2.2) (Burke et al., 1999).

I.  Setting the scene, botanical, general and international aspects

 Cannabinoid precursor biosynthesis 17

FIGURE 2.2  Biosynthesis of cannabigerolic acid (CBGA). The biosynthesis of the central intermediate CBGA is colored in dark green. The
minor products CBNRA and CBGVA are shaded in light green. The precursor pathways are highlighted in light blue (GPP) and blue (OA). MEP,
2C-methyl-d-erythritol-4-phosphate; DOXP, 1-deoxy-d-xylulose-5-phosphate; MVA, mevalonate (Burke, Wildung, & Croteau,  1999; de Meijer
et al., 2009; Fellermeier & Zenk, 1998; Page & Gagne, 2013; Taura et al., 2009).

Cannabigerolic Acid Biosynthesis by mass spectrometry (MS) measurements as CBGA and

Cannabigerolic acid synthase (CBGAS) or geranylpy its cis-isomer cannabinerolic acid (CBNRA; Fellermeier
rophosphate:olivetolate geranyltransferase (GOT) pre- and Zenk, 1998, used CBNA instead of CBNRA). The en-
dominantly catalyzes the C-prenylation of OA by GPP zyme activity was found to be Mg2+-dependent. CBGAS
to form CBGA (Fig.  2.2). CBGA is presumed to be the seems to be specific for OA as a prenyl acceptor, but also
central precursor for cannabinoid biosynthesis, since dif- accepts different prenyl donors like GPP and, to a lesser
ferent cyclization of the prenyl moiety leads to THCA degree, neryl diphosphate (NPP) (Fig. 2.2). The produc-
or its isomers cannabichromenic acid (CBCA) and CBDA tion ratio of CBGA/CBNRA changes from 2:1 to 1:1
(Page & Boubakir,  2012; Sirikantaramas, Morimoto, & when NPP is used as a prenyl donor instead of GPP.
Shoyama, 2007). However, the aromatic prenyltransferase CBGAS
Fellermeier and Zenk (1998) detected the enzyme in seems to be a soluble enzyme, but Fellermeier and Zenk
crude homogenates of rapidly expanding young leaves (1998) could not completely exclude a membrane-bound
of C. sativa. This part of the plant contains the later en- activity. Besides, two soluble hop prenyltransferases,
zymes of the THCA biosynthetic pathway (Morimoto, involved in the biosynthesis of hop bitter acids, are de-
Komatsu, Taura, & Shoyama, 1997; Taura et al., 1995a). scribed by Zuurbier, Fung, Scheffer, & Verpoorte (1998).
There are indications that CBGAS, like other prenyl- Nevertheless, these are the only descriptions of soluble
transferases, is a membrane-bound prenyltransferase plant C-prenylating enzymes; until now, it was not pos-
(Yamamoto, Kimata, Senda, & Inoue,  1997). However, sible to get the sequence information or to isolate the cor-
Fellermeier and Zenk (1998) could not detect any enzyme responding genes or enzymes.
activity in particulate fractions, but in the soluble fraction Contradictorily, all known sequences of plant aro-
of the crude extract. Two major products were identified matic prenyltransferases belong to membrane-bound

I.  Setting the scene, botanical, general and international aspects

18 2.  The Biosynthesis of Cannabinoids

enzymes (Yamamoto et  al.,  1997; Yamamoto, Senda, & cations, whereas the highest enzyme activity was ob-
Inoue,  2000; Zhao, Inoue, Kouno, & Yamamoto,  2003). tained by using Mg2+ (Page & Boubakir, 2012).
This is in accordance with the second report dealing with
the CBGAS (Page & Boubakir, 2012). They published a
sequence of CBGAS that was mainly expressed in glan- CANNABINOID PATHWAY
dular trichomes of female flowers and young leaves
of Cannabis plants. The gene encodes a 395-amino acid CBGA, the central precursor of cannabinoid biosyn-
polypeptide chain showing a membrane-bound type of thesis, is converted by three enzymes (Fig. 2.3): CBDAS,
prenyltransferases. They were able to express the recom- CBCAS, and THCAS. They predominantly use CBGA
binant CBGAS in Sf9 insect as well as in Saccharomyces as substrate, and catalyze the stereoselective, oxida-
cerevisiae cells, and verified the CBGAS activity in the tive cyclization of the monoterpene moiety of CBGA to
microsomal fractions. Using MS measurements, CBGA CBDA, CBCA, or THCA, respectively. The THCAS and
(3-geranyl olivetolate; comparison with CBGA stan- CBDAS reactions are oxygen-dependent, producing hy-
dard) was identified as the major product, and 5-geranyl drogen peroxide proportional to either CBDA or THCA
olivetolate (identification only by LC-MS analysis) as the (Sirikantaramas et  al.,  2004; Taura et  al., 2007b). Re-
minor product. Furthermore, Page and Boubakir (2012) markably, the CBCAS reaction is oxygen independent,
showed that CBGAS is specific only to GPP as a prenyl and can be inhibited by hydrogen peroxide. Thus, the
donor, and approves OA, olivetol, phlorisovalerophe- enzyme seems not to be an oxygenase or a peroxidase
none, naringenin, and resveratrol as prenyl acceptor. Ad- (Morimoto, Komatsu, Taura, & Shoyama,  1998). Fur-
ditionally, the enzyme reaction is dependent on divalent thermore, all three enzymes also convert CBNRA, the

FIGURE 2.3  Biosynthesis of cannabinoids. The enzymatically catalyzed reactions are highlighted in dark green. All nonenzyme-dependent
modifications reactions are colored in light green. Biosynthesis of C3-cannabinoids starting from cannabigerovarinic acid (CBGVA) is carried out
by the same enzymes and for better clarity not shown (Crombie et al., 1968; de Meijer, 2011; Morimoto et al., 1998; Shoyama, Fujita, Yamauchi, &
Nishioka, 1968; Shoyama, Oku, Yamauchi, & Nishioka, 1972; Taura et al., 1995a; 1996).

I.  Setting the scene, botanical, general and international aspects

 Cannabinoid pathway 19
cis-isomer of CBGA, with a lower specificity (Morimoto acid substitutions. These substitutions seem to be the rea-
et  al.,  1998; Shoyama et  al.,  2012; Sirikantaramas, son for decreased THCAS activity in “fiber-type” strains
Morimoto, & Shoyama, 2007; Taura et al., 1995b; Taura, (Kojoma, Seki, Yoshida, & Muranaka,  2006). Minise-
Morimoto, & Shoyama, 1996). Since no enzymatic activ- quencing of samples from both types of Cannabis plants
ity was detectable using the neutral cannabinoid CBG, showed three different single nucleotide polymorphism
the carboxyl group in CBGA seems to be essential for the (SNP) genotypes. “Fiber-type” plants are homozygous
enzymatic reactions catalyzed by THCAS, CBDAS, and for the inactive THCAS form. “Drug-type” plants are
CBCAS (Morimoto et al., 1997; Taura et al., 1995a; Taura either homozygous or heterozygous for the active form
et al., 1996). of THCAS. It seems that only a single copy of the gene
Besides, it was postulated that THCA is biosyn- encoding the active THCAS form is necessary for the
thesized and stored in the storage cavity of the glan- biosynthesis of THCA (Rotherham & Harbison, 2011).
dular ­trichomes of Cannabis plants (Sirikantaramas,
­Morimoto, & Shoyama, 2007).
Cannabidiolic Acid Synthase
The gene of the wildtype CBDAS encodes a 544-amino
Tetrahydrocannabinolic Acid Synthase acid polypeptide (Table  2.1). According to Taura et  al.
The THCAS gene encodes a 545-amino acid polypep- (2007b), processed CBDAS consists of 517 amino ac-
tide chain (Table 2.1). According to Sirikantaramas et al. ids following cleavage of the 28 amino acid long signal
(2004), a 28 amino acid long signal peptide is cleaved peptide. The mature CBDAS has a theoretical molecu-
in the processed THCAS, leading to a protein of 517 lar mass of 59 kDa. An actual mass of about 74 kDa was
amino acids. The mature THCAS has a theoretical mo- detected by SDS-PAGE that is possibly caused by post-
lecular mass of 59 kDa. An actual mass of about 75 kDa translational glycosylation of seven Asn residues (Taura
was detected using SDS-PAGE (Taura et  al., 1995b). et al., 1996; Taura et al., 2007b). CBDAS is a monomeric
This could be explained by posttranslational modifica- enzyme with a pH optimum of 5.0 (Taura et  al.,  1996).
tions, since eight possible Asn glycosylation sites were A comparison between THCAS and CBDAS revealed a
confirmed (Sirikantaramas et  al.,  2004). Furthermore, sequence similarity of 84% (Taura et al., 2007b) (Figs. 2.4
deglycosylated THCAS indeed showed a molecular and 2.5). Like THCAS, CBDAS is a flavinated enzyme in
mass of 59 kDa, and remained fully active (Taura et al., which His114 and Cys176 are most likely the FAD-binding
2007b). THCAS is a monomeric enzyme with the high- sites. Since CBDAS exhibits structural and biochemical
est activity between pH 5.5 and pH 6.0 (Taura et  al., properties related to those of THCAS, it is probable that
1995b). Sequence comparison identified similarities the reaction mechanism of CBDAS is similar to that of
to the berberine bridge enzyme (BBE) of Eschscholzia THCAS (Taura et al., 2007b).
californica (Shoyama et  al.,  2012). BBE belongs to the
family of oxidoreductases and has a covalently bound
Cannabichromenic Acid Synthase (CBCAS)
FAD (Kutchan & Dittrich, 1995). The THCAS amino acid
sequence revealed a flavinylation consensus sequence The sequence of CBCAS is still unknown. Morimoto
(Arg110-Ser-Gly-Gly-His114) in which His114 is probably et al. (1998) purified the enzyme to apparent homogene-
the FAD-binding site (Sirikantaramas et al., 2004). This ity, but its sequence is not yet available in public databas-
could be confirmed by X-ray crystallography (PDB ID: es. According to van Bakel et al. (2011), possible CBCAS
3VTE) at a resolution of 2.75Å. The results show that candidates are currently analyzed biochemically.
the enzyme is composed of two domains and one FAD However, CBCAS was isolated and partially purified
binding pocket present in between. Besides His114, a from young leaves of C. sativa (Morimoto et  al.,  1997;
second residue, Cys176, could be identified to be cova- 1998). In contrast to CBDAS and THCAS, CBCAS seems
lently bound to the FAD (Shoyama et al., 2012). Based to be homodimer with a determined native molecular
on X-ray structure data and mutational analysis of mass of 136  kDa and a maximum activity at pH 6.5. A
THCAS, a possible catalytic reaction mechanism of molecular mass of 71 kDa was estimated for the mono-
THCAS was proposed by Shoyama et al. (2012), assign- mers using SDS-PAGE. According to kinetic data, CBCAS
ing a central role to Tyr484 in the catalytic mechanism has a higher affinity for CBGA than THCAS and CBCAS
(Fig. 2.5). Nevertheless, since the crystal structure was (Morimoto et al., 1998). CBCA and its neutral form CBC
published without substrate analoga, further studies are both racemic. Studies of Morimoto et al. (1997) sug-
are necessary to verify the suggested mechanism. gested that both enantiomers of CBCA are formed by
Cannabis plants can be divided into two groups: a CBCAS catalyzed reaction with a molar ratio of 5:1.
“fiber-type” and “drug-type” plants (see dictionary). But it is still unknown which of the two isomers is the
Alignment of THCAS coding sequences from “fiber- major product (Gaoni & Mechoulam,  1971; Morimoto
type” and “drug-type” plants showed 37 major amino et al., 1997; Taura et al., 2007a).

I.  Setting the scene, botanical, general and international aspects

20 2.  The Biosynthesis of Cannabinoids

FIGURE 2.4  Alignment of amino acid sequences of THCA synthase and CBDA synthase. The alignment was performed with CLUSTAL W
using the BLOSUM 62 matrix (Henikoff & Henikoff, 1992; Larkin et al., 2007). The signal peptide cleavage sites are indicated by a triangle. Second-
ary elements (α-alpha-helices; β-beta-sheets; TT-turns; η-310 helix) are shown for the THCAS. Fully conserved residues are shaded in black. The
sequences show an overall identity of 84%. The figure was made with ESPript 3.0 (Robert & Gouet, 2014). THCAS, tetrahydrocannabinolic acid
synthase; CBDAS, cannabidiolic acid synthase.

I.  Setting the scene, botanical, general and international aspects

 Mini-dictionary 21

FIGURE 2.5  X-ray structure of the active center of THCAS. The backbone is shown as cartoon diagram (PDB ID: 3VTE). The FAD molecule
(orange) is covalently attached to His114 and Cys176 (yellow). The active site residues are highlighted in green (Shoyama et al., 2012). The close-up of
active center was prepared with PyMOL. THCAS, tetrahydrocannabinolic acid synthase.

Cannabinoids with Propyl Side Chains (THCV) and/or cannabidivarin (CBDV) are usually only
detectable in Cannabis indica (de Zeeuw, 1972).
In contrast to the classic C5-phytocannabinoids,
which contain an n-pentyl side chain, cannabinoids with
an n-propyl side chain are called C3-phytocannabinoids MINI-DICTIONARY
or propyl cannabinoids. The C-prenylation of divarinic
acid (DA) instead of OA by GPP yields in cannabiger- Cannabinoids  Cannabinoids are a group of terpenophenolic
ovarinic acid (CBGVA) (Fig. 2.2) (de Meijer, Hammond, compounds. They show affinities to cannabinoid receptors (CB1,
& Micheler, 2009). The formation of propyl cannabinoids CB2) or are structurally related to tetrahydrocannabinol (THC).
Cannabinoids can be differentiated into phytocannabinoids,
does not occur by shortening the side chain of pentyl can-
synthetic cannabinoids, and endocannabinoids.
nabinoids (Kajima & Piraux, 1982). CBGVA is the central CBGA  Cannabigerolic acid (CBGA) is the central precursor of
branch-point intermediate in the biosynthesis of C3-can- phytocannabinoid biosynthesis. It is nonpsychoactive.
nabinoid acids, like CBGA for pentyl cannabinoid acids. “Drug-type” plants  These are THCA-rich plants. The THCA
The enzymes CBDAS, CBCAS, and THCAS are not se- is converted into psychoactive ∆9-THC by a nonenzymatic
decarboxylation that enables the plants to be labelled as THC-rich.
lective for the length of the alkyl side chain, and can use
“Fiber-type” plants  “Fiber-type” plants are also known as
both as a substrate. The resulting cannabinoids are called “nondrug” plants. These plants have a low (<0.2%) or no THCA
cannabidivarinic acid (CBDVA), cannabichrovarinic acid content, but they contain a high amount of cannabidiolic acid
(CBCVA), and tetrahydrocannabivarinic acid (THCVA). (CBDA).
The diverse amount of 2-carboxylic acids in different Phytocannabinoids  Phytocannabinoids are a unique group
of secondary metabolites (cannabinoids) occurring naturally
Cannabis strains is caused by dissimilar enzyme specifici-
in plants. Other names include natural cannabinoids or herbal
ties at the level of CBGA or CBGA-analogs formation (de cannabinoids (see Key facts).
Meijer et al., 2009; Shoyama, Hirano, & Nishioka, 1984). ∆8-THC  In Cannabis plants, ∆8-tetrahydrocannabinol (∆8-THC)
Relatively high amounts of tetrahydrocannabivarin is detectable in low amounts (<1% of the present ∆9-THC). Like

I.  Setting the scene, botanical, general and international aspects

22 2.  The Biosynthesis of Cannabinoids

∆9-THC, it is also psychoactive. Maybe ∆8-THC is an artefact of the National Academy of Sciences of the United States of America, 109,
extraction and/or analysis process. The term THC includes a 12811–12816.
combination of ∆8-THC and ∆9-THC. Gaoni, Y., & Mechoulam, R. (1964). Isolation, structure, and partial
∆9-THC  ∆9-Tetrahydrocannabinol (∆9-THC) and ∆1-THC synthesis of an active constituent of hashish. Journal of the American
describe the same compound, differing in the numbering system Chemical Society, 86, 1646–1647.
used (dibenzopyran-numbering and monoterpene-numbering Gaoni, Y., & Mechoulam, R. (1971). The isolation and structure of
system, respectively). ∆9-THC is responsible for the psychoactive ∆1-tetrahydrocannabinol and other neutral cannabinoids from
effects of Cannabis products. It binds to the human cannabinoid hashish. Journal of the American Chemical Society, 93, 217–224.
receptors located in the central and peripheral nervous system. Gertsch, J., Pertwee, R. G., & Di Marzo, V. (2010). Phytocannabinoids
Misleadingly, ∆9-THC is termed as the main component of drug- beyond the Cannabis plant – do they exist? British Journal of Phar-
type Cannabis plants (see THCA). macology, 160, 523–529.
∆9-THCA  ∆9-Tetrahydrocannabinolic acid (THCA), not THC, Henikoff, S., & Henikoff, J. G. (1992). Amino acid substitution matrices
is the main component of drug-type Cannabis plants. It is from protein blocks. Proceedings of the National Academy of Sciences of
nonpsychoactive. THCA is converted into neutral psychoactive ∆9- the United States of America, 89, 10915–10919.
THC by a nonenzymatic decarboxylation during heating or storage. Hunter, W. N. (2007). The non-mevalonate pathway of isoprenoid pre-
cursor biosynthesis. Journal of Biological Chemistry, 282, 21573–21577.
Kajima, M., & Piraux, M. (1982). The biogenesis of cannabinoids in
Acknowledgment Cannabis sativa. Phytochemistry, 21, 67–69.
Kojoma, M., Seki, H., Yoshida, S., & Muranaka, T. (2006). DNA poly-
We gratefully acknowledge Parijat Kusari for critically reading this
morphisms in the tetrahydrocannabinolic acid (THCA) synthase
manuscript.
gene in “drug-type” and “fiber-type” Cannabis sativa L. Forensic
Science International, 159, 132–140.
Konishi, T., Shinohara, K., Yamada, K., & Sasaki, Y. (1996). Acetyl-CoA
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I.  Setting the scene, botanical, general and international aspects

 Index

A Adaptive Poisson–Boltzmann Solver empirical support, e25, e26

AA. See Arachidonic acid (AA) (APBS), 686 theory, e24
α-Amino-3-hydroxy-5-methyl-4- ADB. See Aggressive, disruptive behavior leading to cannabis use in middle and high
isoxazolepropionic acid (ADB) school, e23
(AMPA), 803 ADCA. See Alcohol and other Drugs empirical studies supporting, e24
receptor, 330 Council of Australia (ADCA) theory, e23
Abdominal viscera, sensory innervation, 440 Addiction, 715 Agoraphobia, 65, 68
Ab initio protein folding, 684 molecular mechanisms, 715 Agouti-related protein (AgRP), 640
Aboriginal and Torres Strait Islanders Additive effects, 211, 212 Agricultural status, 8
(ATSI), 105 Adenylyl cyclase, 560 AgRP. See Agouti-related protein (AgRP)
Abstinence, 489, 1097 ADHD. See Attention-deficit/hyperactivity Airway dynamics, 495
Abstinence rates, e199 disorder (ADHD) AjA. See Ajulemic acid (AjA)
Abstinence violence effects (AVE), 1062 Adjunct therapy, 824 Ajulemic acid (AjA), 676
Abuse screening Adolescent AKT1 gene, 64, 82
urine sample, use of, 988 antidrug media campaign targeting, 216 Alcohol, 80, 321
chromatographic screening, 988 cannabis use, 311 Alcohol and other Drugs Council of Australia
immunoassay, 988 levels of endocannabinoids and (ADCA), 1078
AC. See Amygdaloid complex (AC) cannabinoid receptors, 30 Alcohol dependence, 1026
Academic performance as a phase of vulnerability for addiction, 143 Alcohol-IAT, 270
chronic marijuana use, impact of, 290 prevention and intervention program, 1037 Alcohol-induced steatosis, e123
ACC. See Anterior cingulate cortex (ACC) substance abuse, 1049 Alcohol, smoking and substance involvement
Acetaminophen, 453 vulnerability for THC effects in, 144 screening test (ASSIST), e171–e178
Acetylcholine (ACh), 830 Adult Memory and Information Processing psychometric performance, e178
Acetyl-CoA, 15 Battery Form A and B, 71 Alcohol use disorders identification test
carboxylase, 15 Advanced cancer (AUDIT), e169
Acetylhydrolase (AChE), 830 symptoms Alcohol withdrawal, 873
ACh. See Acetylcholine (ACh) anorexia/early satiety, 860 Alkylindole compound, 984
AChE. See Acetylhydrolase (AChE) constipation, 860 Alkylresorcinol moiety, 15
Achievement goal dry mouth, 860 Allergic contact dermatitis, 545
cannabis use, relation with, 289 dyspnea, 860 Allergic reaction, 518
Acidic precursor, 708 fatigue/lack of energy, 860 Allodynia, 906
ACP-CoA transacylase, 15 nausea/vomiting, 860 Allosteric agonism, 577
Acquired immunodeficiency syndrome pain, 860 Alpha-7 nicotinic receptors, 745
(AIDS), 106, 199 Adverse drug reaction (ADRs) ALS pharmacology, e103
ACR. See American College of Rheumatology associated with cannabinoids, 203 binge pattern, e105
(ACR) Adverse health effects, increased risk, 30 and cannabis, e105
Action outcome associations AEA. See Anandamide (AEA); See also animal studies, e105–e107
(A-O associations), 268 N-Arachidonoylethanol-amine (AEA) human studies, e107–e108
Acute cannabis exposure, 380 AER. See Ascending enteric reflex (AER) dopaminergic deficits, e105
driving ability, 380 2-AG. See 2-Arachidonoylglycerol (2-AG) exchange-diffusion model, e104
laboratory studies, 381 Age hyperthermia, e105
attention, 381 at first exposure to cannabis, 30 mephedrone, e105
brain imaging, 386 of first use is related to cannabis use METH-binging activate, e105
decision making, 381 disorder risk, 35 methylone, e105
motor inhibition and impulsivity, 381 Aggressive, disruptive behavior (ADB), e19 neurotoxicity, e105
time perception, 381 in elementary school leading to later serotoninergic deficits, e105
working memory, 381 cannabis use, e21 Alveolar macrophage number, 498
on-road studies, 387 analyzed data collected from Dutch Alzheimer disease (AD), 405, 734, 803,
simulator studies, 386 adolescents as part of TRAILS, e23 805, 963
Acute postoperative pain, 451 empirical support, e21, e22 Alzheimer’s dementia (AD), 829
mechanism, 451 theory, e21 American Academy of Neurology, 910
Acyl-activating enzyme (AAE), 15 using data from the Raising Health American College of Rheumatology
Acyl-CoA synthetase, 15 Children (RHC) study, e23 (ACR), e159
AD. See Alzheimer disease (AD); See also leading to ADB in middle and high American court responses to shared use, 194
Alzheimer’s dementia (AD) school, e24 American Criminal Justice System, 189, 195

1115
1116 Index

American drug court model, 194 regulation disorders, 299, 872

American soldier, drug abuse, e151 insulin-like growth factor-I, 866 cannabis, 304–305
Amidosulfone, 600 keratinocyte growth factor, 866 course of
γ-Aminobutyric acid (GABA), 559, 806 Anger, 182 cannabis use, effects of, 305
4-Aminopyridine (4-AP), 797 Angiogenesis, e118 dependence, 301
5-Aminosalicylic acid (5- ASA), 932 Animal models, e132, 538, 705, 709 incidence of CUD, risk of, 305
Amisulpride, 873, 887 of multiple sclerosis (MS) lifetime abuse, 301
Amitriptyline, e161 CBD, effect of, 899–900 marijuana, effect of, 872
Amotivational syndrome, 66, e204, 289 experimental autoimmune prevalence of past-year cannabis use, 301
AMP. See Amphetamine encephalomyelitis (EAE) model, 899 three-year incidence
AMPA. See α-Amino-3-hydroxy-5-methyl-4- Theiler’s murine encephalomyelitis virus lifetime cannabis user vs. nonuser, 302
isoxazolepropionic acid (AMPA) (TMEV) induced model, 899 like behaviors, e137, 651
AMPA glutamate receptor, 734 of Parkinson’s and Alzheimer’s disease, 49 Anxiolytic effects, e134
AMPH. See Amphetamine Animal studies, 507 4-AP. See 4-Aminopyridine (4-AP)
Amphetamine (AMPH), e102, e151, 181, ANS. See Autonomic nervous system (ANS) Apathy evaluation scale, 289
321, 1008 Antagonists, 535 motivation score, 290
as Benzedrine, e103 HcrtR1, 535 APBS. See Adaptive Poisson–Boltzmann
biological properties, e103 HcrtR2, 535 Solver (APBS)
chemical structures, e103 Anterior cingulate cortex (ACC), e54 Aphrodisiac, 181
dopaminergic neuronal activity, e104 Anticholinergics, 47 APINACA N-(4-hydroxypentyl), 985
physiological concentrations, e104 Anticipatory nausea (AN), 704 Apoptosis, e114, e116, e119
treatment for, attention-deficit/ Anticonvulsant effects, 434 cannabinoid, effect of MAPKs
hyperactivity disorder (ADHD), e103 Anticonvulsant properties, 432 stimulation, 865
Amplified fragment length polymorphisms Antidepressants, 47 APP. See Amyloid precursor protein (APP)
(AFLP), e7 Antidrug campaigns, e156 Appetite, 643, 655
AMPs. See Antimicrobial peptides (AMPs) Not in My Corps, e156 Appetitive behavior, 269
Amygdala, e54 Antidrug task forces, 124 Apprehended driver
Amygdala reactivity, 360 Antiepileptic drug (AED), 433, 435 finding, 851
Amygdaloid complex (AC), e141 pharmacoresistant epilepsy, 433 synthetic cannabinoid variants,
Amyloid precursor protein (APP), 829 Antiexcitotoxic and antiinflammatory detection of, 852
β-Amyloid protein, e137 properties, 49 Arachidonate-based lipids anandamide
AN. See Anticipatory nausea (AN) Antimicrobial peptides (AMPs), 544 (AEA), 283
Analgesia, 456, 823 Antinociception, 741 Arachidonic acid (AA), 731
cannabinoid, effect of, 961 Antiobesity agents, 654 Arachidonoyl ethanolamine, 878
Analysis of biological samples, 986–995 Antioxidant, 49 N-Arachidonoylethanol-amine (AEA), 631
blood, 986–987 Antioxidant capacity, e125 2-Arachidonoylglycerol (2-AG), 81, 407, 452,
other matrixes, 991–995 by electron transfer, e125 556, 607, 617, 641, 732, 878
urine, 988–991 by hydrogen transfer, e127 biosynthesis, 618
Analysis of plant material, 985 Antiproliferative activity of cannabinoids effects, 617
Analysis of pure substance, 985 intracellular mechanisms underlying, e114 metabolism, 617
Analytical challenge, 984–985 actions beyond CB1/CB2 receptors, e116 receptors, 621
Analytical issue, 1010 antitumoral action of cannabinoids in targets, 621
immunoassay, related to, 1010 vitro, e114 Arterial hypotension, 512
mass spectrometry (MS), related to, 1010 mechanism of cannabinoids proapoptotic Arvanil, 924
other cannabinoid, related to, 1010 action–inhibition of prosurvival 5- ASA. See 5-Aminosalicylic acid (5- ASA)
THC, related to, 1010 pathways, e114–e115 ASC. See Ascorbic acid (ASC)
Analytical technique, 982–983 ceramide in cannabinoid Ascending enteric reflex (AER), 932
Anandamide (AEA), 452, 512, 593, 617, 672, signaling, e115 Ascorbic acid (ASC), e127
789, 872, 878, 943 contribution of ER-stress and ASSIST. See Alcohol, smoking and substance
biosynthesis, 618 autophagy to cannabinoids-induced involvement screening test (ASSIST)
effects, 617 cell death, e117 Associative memory, 268
levels, 415 inhibition of prosurvival pathways in AT. See Attention
metabolism, 617 antitumoral action of cannabinoids, Atherosclerosis, 490
of network lipids, 620 e116 Atomoxetine, 1033, 1034
receptors, 621 role of ER stress and autophagy in Atopic dermatitis, 546
REM, effect on, 878 cannabinoid-induced cell death, Atrial fibrillation, 489
sleep induction e115–e116 Attention, 71, 155, 157, 262
adenosine, molecule, activation of, 879 Antipsychotic doses, 47 Attention-deficit/hyperactivity disorder
role in, 879 Antiretroviral therapy, 911 (ADHD), e65, e103
sleep modulation, effect on, 878 Anti-TNFα. See Antitumor necrosis factor associations between ADHD, ODD/CD,
SWS, effect on, 878 alpha (anti-TNFα) and cannabis use, e66
targets, 621 Antitumor necrosis factor alpha and cannabis use comorbidity, e65
Ancient Egypt (anti-TNFα), 932 causality, e66
historical perspectives, for cannabis Antiviral immunity, 509 childhood ADHD, e66
usage, 111 Anxiety, e132, 182, 824 cross-sectional research, e65
Androgen receptor activity cannabis, 311 externalizing disorders, e66
 Index 1117
impact of THC AND CBD content, e67–e69 B consequences of cannabis use, 427
mediating factors, e67 Baclofen, 773, 943, 1032, 1071 dose–response relationship between
retrospective studies, evidence for, e66 BACS symbol coding. See Brief assessment of cannabis use and age at onset,
Attention deficits, cannabis users, e65 cognition in schizophrenia (BACS) 425, 426
Attitude, 217, 218 symbol coding genetic vulnerability models, 426
AUDIT. See Alcohol use disorders BAD. See Bipolar affective disorder (BAD) environmental mediation of genetic
identification test (AUDIT) Barbiturates, 456 influences, 426
Australia Basal ganglia disorder gene-environment interaction, 426
alcohol use increases during cannabis cannabis, use of, 917 genetic confounding, 426
abstinence, 103 Huntington disease, 917 hypomanic/manic episode, 424
among young adults, cannabis use, 102 Parkinson disease, 917 neurobiology of cannabis in, 425
attitudes toward cannabis in 1994, 102 Basal ganglia–thalamocortical circuit, 919 cortical glutamate levels, role in, 425
cannabis cultivation, 102 Basophil activation test (BAT), 524 psychoactive compounds, 425
cannabis law in, brief history of, 105 principle, 524 pathophysiology and genetic risk, 424
cannabis law reform in, 105 BAT. See Basophil activation test (BAT) prevalence of cannabis use and use
cannabis use prevalence in states and Bath salts, e153 disorders, in United States, 423
territories, 103 Bayley Scales of Infant Development, 165–167 psychotic disorders, and cannabis use, 423
cigarette use increases during cannabis BBB. See Blood brain barrier (BBB) psychotic symptoms, 427
abstinence, 103 B-cells, 518, 932 relationship between cannabis use
effects of cannabis use on Australian epitopes, 518 disorders and, 424
communities, 107 BD. See Bipolar disorder (BD) self-medication hypothesis, 424, 427
indigenous cannabis use, 105 BDEOH. See Bond dissociation energy (BDEOH) sociodemographic factors, 427
epidemiology, 105 BDL rats. See Bile duct-ligated (BDL) rats symptoms and course of, 427
medicinal cannabis in, 106 BDNF. See Brain-derived neurotrophic factor types of, 422
cannabinoid replacement therapy (BDNF) Blood alcohol concentration (BAC), 239
(CRT), 106 BDS. See Botanical drug substance (BDS) Blood brain barrier (BBB), 432, 643
cannabis withdrawal symptoms, 107 Bed nucleus stria terminalis (BNST), e135 Blood-retinal barrier (BRB), 763
mid-1990s, cannabis, illicit drug in, 102 Behavioral learning, 318 Blood screening method
National Cannabis Policy (NCP), 106 Behavioral methods, 249 reversed phase LC coupled to mass
National Task Force on cannabis, 105 cue-induced craving, 250 spectrometry, use of, 986
patterns of cannabis usage in relation to reaction times, 249 sample preparation
other substance misuse, 102 Behavioral tests, 742 liquid–liquid extraction, use of, 986
prevalence of CUD, 132 Behavior-specific responses, 456 BMI. See Body mass index (BMI)
strategies for reducing misuse, 107 Benton-visual-retention-test (BVRT), 888 BNST. See Bed nucleus stria terminalis (BNST)
cannabis public information Benzimidazoles, 600 Body mass index (BMI), 589, 933
initiatives, 107 Benzodiazepines, 47, 456 after 3 months of cannabis treatment, 934
types of cannabis products: availability, antagonist flumazenil, 775 at study inception, 934
price, and purity, 104 chlordiazepoxide, 775 Body packers, 123
Australian Capital Territory (ACT), 105 Benzoylindoles, 721 demographics of, 124
Australian Institute of Criminology Betula verrucosa, 519 Body packing, 123
(AIC), 107 Bhageerath algorithm, 685 clinical perspective, 124
Australian Institute of Health and Welfare Bicyclic cores, 600 acute toxicity, 125
(AIHW), 102, 105 benzimidazoles, 600 bowel obstruction, 125–126
Authoritative style, 219 bicyclic pyrazoles, 602 intestinal perforation, 126
characterized by, 219 imidazopyridines, 602 ethical considerations, 126–127
Autonomic nervous system (ANS), 320 naphthyridines, 602 legal considerations, 124
Auto-oxidation, 15 pyrazolopyridines, 602 as means of smuggling, 123
Autophagy, e115, e117 quinolones, 602 security considerations, 127
Autosome, e4 Bicyclic pyrazoles, 602 Body stuffing, 123
Auxins, 10 Bile duct-ligated (BDL) rats, 512 Boidae snake, e143
Axial diffusivity (AD), 393 Bioactive lipids, 617 Bond dissociation energy (BDEOH), e124
Axon Biological matrices, 238 Botanical drug substance (BDS), 960
fiber connectivity, investigation of, 393 Biological receptors, 672 Botany of Cannabis, 4
axonal integrity, measures of, 396 Biological stressor, 282 macroscopical features, 4
DW-MRI data, 393, 394 Biological vulnerability factors, 62 microscopical features, 5
novel network-based statistic, 394 Bipolar affective disorder (BAD), 788 BPD. See Bipolar disorder (BPD)
right fimbria of hippocampus and, 395 Bipolar disorder (BD), 209, 300 Brain
streamlines interconnecting right age at onset, medication use, and suicide development, 152
precuneus with, 396 attempts in, 425 dopaminergic pathway, 280
white matter integrity perturbations, 394 anecdotal reports, 424 Brain changes and cognitive functioning,
white matter, whole-brain investigation cannabis use disorders, 423 in psychotic cannabis users over
of, 396 and symptoms, 427 time, e60
whole-brain tractography, 395 brain structure and functioning, 427 Brain-derived neurotrophic factor
hippocampus, morphology in, 397 cognition, 427 (BDNF), 717
mechanisms of disturbance, 397 childhood trauma, 427 Brazilian research Protocol for Illegal
Azathioprine, 932 clinical and epidemiological studies, 424 Drugs, e73
1118 Index

BRB. See Blood-retinal barrier (BRB) antioxidant property, 895 vs. cannabis, 943–944
Breast cancer cells as antipsychotic drug, 789 vs. nicotine, 942–943
prolactin downregulation, 866 antipsychotic effects, 790 vs. opiates/opioids, 941
Breast carcinoma, 865 anxiolytic effects, e136 vs. stimulants, 941–942
Breastfeeding, 528 arousal, effect on, 879 wakefulness, effect on, 879
initiation and continuation, factors biotransformation, 899 Cannabidiolic acid (CBDA), e2, 7, 708
influencing, 528 cannabinoid receptors, affinity with, 940 Cannabidiolic acid synthase (CBDAS),
levels of neonatal exposure, 529 CB1, 895, 940 e4, 15, 19
Brief assessment of cognition in CB2, 895, 940 Cannabidivarin (CBDV), 21, 607
schizophrenia (BACS) symbol cellular targets, 901 Cannabidivarinic acid (CBDVA), 21
coding, 1088 derivatives, e124 Cannabigero, glaucoma treatment, use in, 880
Brief strategic family therapy (BSFT), 1049 δ opioid receptors, effect on Cannabigerol (CBG), 104, 672, 709, 751, 959
Broaden and Build theory of positive allosteric modulation, 899 α2-adrenoceptor, effect on, 960
emotion, 313 dream retrieval, effect on, 879 anorexia-cachexia syndrome induced
Bronchoalveolar lavage, 498 electronic properties, e126 weight loss, treatment of, 964
BSFT. See Brief strategic family therapy (BSFT) endocannabinoid signaling system, effect anxiolytic effect, 964
Bullous lung disease, 501 on, 895 cancer cell line
Buproprion, 941, 943, 1031 excretion, 899 cell proliferation inhibition, 964
Burden of disease study methods, details functional activity modulation of cannabinoid type-1 (CB1R), effect on, 960
of, 90 amygdala-hippocampus complex, 940 cannabinoid type-2 (CB1R), effect on, 960
case definition, 90 cingulate cortex, 940 λ-carrageenan-evoked hypersensitivity,
DisMod-MR modeling, 91 parahippocampal gyrus, 940 effect on, 961
systematic reviews, 90 paralimbic regions, 940 COX inhibition, role in, 961
Bush cannabis, 104 temporo-limbic structure, 940 G-protein-coupled-receptor, effect on, 960
Buspirone, 943, 1032, 1071 glial modulating effects, 920 human oral epitheloid carcinoma,
glutamate-mediated neurotoxicity, effect inhibition of, 964
C on, 895 intra ocular pressure reduction, 965
CAGE-AID. See Cut down-annoyed-guilty- hangover effect, 879 keratinocyte proliferation, inhibition of, 965
eye opener-adapted to include 5-HT1A serotonin receptor, interaction medical use, 961–965
drug (CAGE-AID) with, 898 analgesia, 961–962
Calcitonin gene-related peptide (CGRP), 780 intraventricular administration, 880 cancer, 963–964
Calcium channels, 567 inverse agonist of CB2 receptor, 898 inflammation, 961–962
California verbal learning test-II, 295 lateral hypothalamus infusion, 880 inflammatory bowel disease (IBD),
learning and memory performance, 295 mechanisms of action, 789, 796, 895–899, 940 962–963
Callus culture, 10 neuroprotective effect, 898 mood disorders, 964
cAMP. See Cyclic adenosine monophosphate nucleoside-transporter-1, binding with, 898 neuroinflammation in multiple
(cAMP) µ opioid receptors, effect on sclerosis, 963
Canada, past year cannabis use by age allosteric modulation, 899 other, 964–965
group, 39 orphan receptor GPR55, antagonism of, 899 mesenchymal stem cell stimulation, 965
Cancer peroxisome proliferator-activated receptors metabolism, 959
cannabinoid, treatment with, 963 (PPARs), effect on, 899 pharmacokinetic, 959–961
Cancer anorexia–cachexia syndrome, 863–864 pharmacokinetics, 899 pharmacology, 959–961
anabolic factor, effect of, 863 pharmacology, 895–899 actions, 961
growth hormone, 863 potential beneficial effects in human, 901 targets, 961
insulin growth factor, 863 property phospholipase-A2 (PLA2), effect on, 960
thyroid hormone, 863 anticraving, 940 plasma and brain pharmacokinetic, 959
leptin regulation system, role of, 863 antidepressant, 940 prostate cancer cell, effect on, 964
proinflammatory cytokines, role of, 863 anxiolytic, 940 rat feeding behavior, effect on, 964
skeletal muscle breakdown, 863 mood stabilizer, 940 Staphylococcus aureus, activity against, 965
Candida albicans, e73 sedative, 940 testosterone synthesis in rat, inhibition
CANDIS treatment program. See Cannabis psychoactivity, lack of, 940 of, 965
disorder (CANDIS) treatment regional cerebral blood flow (rCBF), effect therapeutic application, 962
program on, 940 transient receptor potential (TRP) channels,
Cannabaceae, e2, 3 reuptake of endocannabinoid anandamide, effect on, 960
Cannabichromene (CBC), 104, 959 inhibition of, 940 uptake of dopamine, inhibition of, 960
Cannabichromenic acid synthase (CBCAS), schizophrenia, use in, 959 Cannabigerolic acid biosynthesis, 17
15, 19 side effects, 792 Cannabigerolic acid synthase (CBGAS), 15
Cannabidiol (CBD), 25, 63, 65, 80, 104, e123, sleep, effect on, 879–880 Cannabigerovarinic acid (CBGVA), 21
e132, 418, 432, 607, 672, 706, 751, 788, sleep-wake cycle, effect on, 879 Cannabimimetic compound, 982
796, 814, 829, 895, 940, 959, 1010 social anxiety disorder (SAD), effect on, 940 detection time, 982
activity of fatty acid amide hydrolase structure, e124 psychoactive effect, 982
(FAAH), inhibition of, 940 total sleep time, effect on, 879 Cannabimimetics, 554
adenosine signaling, enhancement, 898 toxicity, 899 Cannabinoid, 473, 536, 547, 554, 593, 718, 723,
animal model, effect on, 880 transient potential vanilloid receptor type-1 749, 761, 771, 940
antianxiety properties, e132 (TPVR-1), interaction with, 898 allergic skin diseases treatment, therapeutic
antiepileptic effects, in animal models, 798 uptake of dopamine, inhibition of, 941 potential, 547
 Index 1119
analgesics, as, 933 regulation, 577 enterochromaffin cells, effect on, 862
antitumor effect, 865–866 signaling, 577 for epilepsy, 436
biological activity, 718 allosteric modulators, 575 intoxication, 317
biosynthesis, e2 advantages, 575 neuroprotectant effect, 873
bone-forming cells, e78 binding of orthosteric ligands, 576 pathway, 18
bone physiology, impact on, e73 proposed, 579 pharmacodynamic, 860
bone-resorbing cells, e78 antagonism, 512 pharmacokinetic, 860
cannabis smoke-generating apparatus, antagonists, 646, 651, 667 potential therapeutic application, 953–955
smoke exposure, e74 associated ion channel modulation, 567 precursor biosynthesis, 15
Cannabis smoke, impact of, e77 calcium channels, 567 with propyl side chains, 21
cell mediated immunity, effect on, 933 potassium channels, 567 psychological effects, 865
chronic neuropathic pain, effect on, 933 in axonal growth, 397 serotonin receptors, effect on, 862
effect on bone metabolism, e78 brain dispersion, 861 side effect, 913
endocannabinoids, e72 canonical signaling, 566 dizziness, 913
endogenous, 593 CB1-D2 heterodimer, 579 dry mouth, 913
host response evaluation, in cell constitutive signaling, 568 feelings of intoxication, 913
cultures, e73 function, 861 gastrointestinal effects, 913
impact on immune cell activity, e78 GαI protein coupling, 566 hunger, 913
inflammatory pain, effect on, 933 G protein coupling promiscuity, 568 loss of balance, 913
intraocular pressure, 749 internalization, 853 sedation, 913
lipopolysaccharide (LPS), e72 inverse agonists, 653 specific receptor, 878
LPS-evoked macrophage activation, knockout mice, 920, 932 substance
inhibition, 933 location, 918 extracted from cannabis, 880
main component mediated anandamide signaling, 872 synthetic compound, 880
cannabidiol (CBD), 878 mood regulation, role in, 871 system, in psychiatric disorders, 62
tetrahydrocannabinol (THC), 878 neutral antagonist, 651 tetrad, 693
mast cell, inhibition, 933 orexin 1 receptor heterodimer, 580 ∆9-tetrahydocannabivarin, 948
molecular targets for, 753 receptors polymorphism, 283 and their precursors, 14
CB1, 753 regulation, 569 therapeutic use
CB2, 754 arrestin recruitment and signaling, 570 CINV, 862
neurobiological mechanisms, 536 desensitization, 569 vagal stimulation, effect on, 862
in pathophysiological states, 474 internalization and degradation, 570 and visceral pain, 441
colorectal cancer, 476 reward and habit development, role in, 269 gastrointestinal tract, 442
functional disorders of lower GI tract, 474 signaling, 682 small/large intestine, 444
inflammatory bowel diseases, 475 transductions, 560 stomach, 444
pharmacology, 595 stimulation of, 393 genitourinary tract, 445
in physiological states, 473 structural characteristics, 556 endometrium, 446
receptors, e73, 556 Cannabinoid receptor 2 (CB2), 415, 442, 498, kidney and ureter, 445
cell physiology, 559 554, 565, 584, 840, 848, 932, 940 ovary, 445
discovery of, 556 polymorphisms. See CB2 polymorphisms prostate, 446
endogenous ligands, 556 signal transductions, 560 testes and scrotum, 446
function, 559 structural characteristics, 556 urinary bladder and urethra, 445
location, 559 Cannabinoid receptors, 632, 723, 740 heart, 441
studies. See Histomorphometric study, in rats cannabinoid CB-1 receptor. See liver, 444
synthetic, 721 Cannabinoid receptor 1 (CB1) pancreas, 444
THC, 940 cannabinoid CB-2 receptor. See Cannabinoids on brain function, acute effects
Th1 cytokine production, effect on, 933 Cannabinoid receptor 2 (CB2) of, e44
Th2 cytokine production, effect on, 933 transmembrane receptor during cognitive tasks, e44
therapeutic potential in ocular disorders, 761 G protein-coupled receptor, 848 acute administration of delta-9-THC/
use in cancer, 859 Cannabinoid replacement therapy (CRT), 106 CBD/placebo condition, e44
vascular inflammatory diseases, influence Cannabinoids, 3, 14, 182, 185, 672, 932 attentional salience processing, e47
on, e73 analgesic effect, 864 emotional faces processing task, e46
visceral sensory nerve, effect on, 933 anandamide, 697 neuroimaging studies of acute
Cannabinoid based medicines (CBMs) antiemetic effect, 862 administration of THC and CBDin
adverse effect, 890 antitumor mechanisms, 865, 866 naïve cannabis users, e45
neuropsychological performance, effect biosynthesis of, 18 response inhibition task, e46
on, 890 cannabichromen, 948 sensory processing task, e46
Cannabinoid hyperemesis syndrome cannabidiol, 948 genetic vulnerability to the acute effects of
(CHS), 952 cannabidiolic acid, 948 cannabis, e47
Cannabinoid receptor 1 (CB1), 90, 269, 327, cannabidivarin, 948 acute effects on dopamine release, e48
392, 415, 442, 462, 495, 554, 565, 575, cannabigerol, 948 response inhibition task (Go, No-Go
609, 651, 667, 840, 848, 871, 932, 940 clinical symptom moderation Task) and AKT1 polymorphism, e47
agonists, 565 biochemical pathway, 860, 861 verbal learning task, e47
allosteric ligands, 575 dopamine receptors, effect on, 862 during resting state, e44
allosteric modulation effects on anxiety, 865 after acute administration of
dimerization, 579 emesis inhibition, 953 delta-9-THC or CBD, e44
1120 Index

Cannabinol (CBN), 104, 719, 751, 814, 880 consumption duration, 47 prevention. See Cannabis prevention
molecular composition, 719 craving, 1031, 1058, 1059 prolonged use
optical activity, 719 diary example, 1063 memory loss, 860
psychoactive, 719 scale, 1064 psychomimetic effects, 358
Cannabis, 48, e102, 358, 373, 478, 488, 495, daily-use and psychosis, 66, 82. See also Cannabis,
660, 740, 771 family socioeconomic status, effect and psychosis correlation
abstinence, 1030 of, 972 outcomes, 358
abuse, 943 dependence, 943, 1038, 1048, 1097 recreational use, 281, 840, 849
dependence, 41 face to face treatment related disorders (CRD), 730
acute effects on movement, 373 cognitive behavioral therapy psychosocial treatment, CBT, use of, 1057
addiction (CBT), 1049 related neural substrate
development and maintenance, contingency management, 1049 linking associative effect, 269
1058–1059 motivational interviewing, 1049 related problems, 25, 30
compulsive use, 1059 family therapy, 1048 resin usage, 478
high risk situations (HRS), 1058, 1059 brief strategic family therapy screening, 388
predisposing factor, 1058 (BSFT), 1049 biological matrices for, 388
addicts, 67 functional family therapy (FFT), 1049 self-initiated cessation
airway dynamics, acute effects, 495 MDFT, 1049 adolescent, 1037
allergens, 520 multisystemic therapy (MST), 1049 cultural values, role of, 1043
allergy. See Cannabis allergy problem behavior, associated, 1048 decision-making, role of, 1039
antineoplastic mechanism, 860 treatment, 1030 emerging adult, 1037
in Arabic medicine, 111 evaluated medications, 1032 ethnic culture, role of, 1043
arteritis, 483 dependent youth family cohesion, role of, 1040
associated stroke, 490 multidimensional family therapy, 1049 future intervention
association treatment need, 1048 cultural/attitudinal stream-derived
with lower respiratory infection, 500 detection and traffic, 238–239 intervention, 1043
with pneumothorax, dopamine system, effect on, 269 intrapersonal stream-derived
pneumomediastinum, and bullous effects of higher exposure of, 29 intervention, 1043, 1044
lung disease, 501 endocannabinoid signaling, 269 goal orientation, role of, 1040
based medicinal extract (CBME), 910 and executive functioning. See Cannabis on parental bonding, role of, 1042
based medicine administration executive functioning, effects of sibling influences, role of, 1042
sleep in human protocols, effect on, 881 extract, mental disorder, treatment, 878 social support system, role of, 1041
cannabinoid receptor, effect on, 269 functional imaging studies, 361 spousal interaction, role of, 1042
cannabis abuse screening test. See Cannabis herbal leaf, 478 strategies, 1042, 1043
abuse screening test (CAST) higher exposure, effects of, 29 distraction, 1042
cessation, 1037 hybrid cultivars, 7 stimulus removal, 1042
triadic theory of influence, 1038 hyperemesis syndrome. See Cannabis victimization, role of, 1040
cessation, preparation for, 1061 hyperemesis syndrome (CHS) self-medicating benefit, 1039
chemical compound induced psychosis, 48, 337 and sexual behavior. See Cannabis and
tetrahydrocannabinol (THC), 840 genetic aspects, studies examining, 337 sexual behavior
chronic pain management, 840 ischemic stroke, 487 smoking, 823
cigarette, 373 learning function, effect on, 1057 lung contamination with, 1018
classification of, 5 long-term use, changes in movement, 374 synaptic effects of endogenous
in clubbing drug users and lung cancer, 498 cannabinoid, effect on, 1057
rates of using, 174 lung, chronic effects on, 495 for therapeutic purposes. See Cannabis for
on cognition, effects of, 71 alveolar macrophage number, 498 therapeutic purposes (CTP)
and cognition in psychosis chronic respiratory symptoms, 495 and tobacco (CTS), 495
methodological issues to take into human bronchial pathology, 498 treatment. See Cannabis treatment
account, 46 lung function, 496 trichomes classification, 6
and cognitive deterioration, 65–66 lung pathology, 498 triggers psychosis, 49
cognitive effects, in nonpsychosis thoracic high-resolution computed use. See also Cannabis use (CU)
individuals, 360 tomography, 497 accidental problem, 1057
and cognitive functions, comprehensive in Medieval Arab World, 111 addiction, development of, 1057
reviews for, 73 memory, effect on, 1057 in adolescents, 74–75. See also Adolescent
on cognitive functions, tolerance to and mental disorders, 210 appetite stimulation, 933
effects of, 72 negative reinforcing effect, 1038 behavioral consequence, 1037
consumption, 122 patient reason, for not using, 1063 codependence to illicit substances, 1057
effect of intervention, 1088 patients with schizophrenia, 361 cognitive distortion, 1058
lifetime progression, 1075 cognitive performance, 361 energy metabolism, effect on, 933
progression neurofunctional alterations, 367 impulse control problem, 1057
comparative data of main positive affect, 1038 initiation of, 34
prevalence, 1075 potency, 25, 26, 28 as a learned behavior, 1058–1059
side effect and exposure to THC, 26 learning model, 1058
dependence, 940 preparation mental disorder, development of, 1057
euphoria, 940 hashish, 840 motivating factor
mental health side effect, 940 marijuana, 840 conformity, 1057
 Index 1121
emotional regulation, 1057 related problems gateway drug, e103
enjoyment, 1057 screening instrument, e169, e170, genetic factors, e103
experimentation, 1057 e178, e181 Cannabis dependence and mental
feeling high, 1057 screening instruments, e170 disorders, 64
getting rid of boredom, 1057 self-administrable, e172 anxiety disorders, 65
relaxation, 1057 self-report panic, 65
social enhancement, 1057 prevalence data, e188 posttraumatic stress disorder, 65
psychological consequence, 1037 Australian general population, e188 social phobia, 65
regulation of appetite, 933 European general population, e188 bipolar disorder, 65
sexually risky behavior, 1057 global drug survey, e188 depression, 64–65
weight gain stimulation, 933 United States general population, e188 Cannabis disorder (CANDIS) treatment
use disorder. See Cannabis use disorder youth, e188 program, e194–e196
(CUD) validity, e188–e190 aims, e195
use in adolescents, 74–75 affecting points, e189 case report, e197
use on cognitive functions concordance with biological delivery by
gender differences for effect of, 76 measurements, e189–e190 type of clinician, e195
use, social norms, and legal status, 38 smoking, e169 exclusion criteria, e195
withdrawal symptom, 133, 1038, Cannabis abuse screening test (CAST), inclusion criteria, e195
1067–1068, 1070 e178–e179, 972–973 study phase
N-acetylcysteine, effect of, 943 application, 972–973 I, e198
agonist replacement therapy, 943 Italian experience, 974–975 II, e199
buccal spray, use of, 943 computing a score therapy sessions, e196, e197
anxiety, 944 Italian validated version, use of, 973 treatment modules, e195–e196
clinical implication, 1070–1071 independent variable, 974 cognitive-behavioral strategies (CBTs),
pharmacological treatment, 1071 questionnaire, 973 e195–e196
psychosocial treatment, 1070 statistical analyses motivational enhancement therapy
DSM-5, according to, 1067–1068 main evidence, 975–977 (MET), e195
anger, 1067 Cannabis allergy, 520 problem solving training, e196
decreased appetite or weight clinical manifestations, 521 Cannabis expiation notice (CEN), 105
loss, 1068 diagnosis, 522 Cannabis for therapeutic purposes (CTP),
depressed mood, 1068 natural history, 525 312–313
insomnia, 1067 prevalence, 520 analgesic effect, 312
irritability, 1067 routes of exposure, 520 antiemetic property, 312
nervousness, 1067 sensitization, 520 appetite-stimulating, 312
other symptoms, 1068 treatment, 525 cancer-related chemotherapy, 312
physical symptom, 1068 Cannabis, and psychosis correlation, 414 future research direction, 314
restlessness, 1068 causality, 416–418 multiple sclerosis, 312
sleep difficulty, 1067 causes of, 417 pain-related anxiety, 313
vivid unpleasant dream, 1068 CBD/THC ratio and the risk of, 418 Parkinson’s diseases, 312
effects of CBD, 944 chronic disorders, 419 Cannabis hyperemesis syndrome
gabapentin, effect of, 943 component cause of, 416, 417 (CHS), 466
insomnia, 944 dopaminergic transmission, 416 complications, 468
lithium, effect of, 943 endocannabinoid signaling, 416 diagnosis, 468
lofexidine, effect of, 943 environmental factors, 418 features, 467
mirtazapine, effect of, 943 metaanalysis estimated in young adults, pathogenesis, 467
nefazodone, effect of, 943 United Kingdom, 419 treatment, 468
physical symptom exposure predicted severity of, 415 Cannabis indica, e2, 5, 873
fever, 1068 general population studies, effect of, 414 Cannabis intoxication acute, physical
stomach pain, 1068 genes and environment interact, 418 effects of, 81
sweating, 1068 genetic vulnerability, 417 Cannabis on executive functioning,
tremor, 1068 psychotogenic effects of, 418 effects of, 73
variations in time course, 1068–1070 schizophrenia, risk of, 417 attention, 74
demand characteristic, 1069–1070 Cannabis and sexual behavior, 182–185 planning and decision-making, 74
zolpidem, effect of, 943 main studies addressing, 184 verbal fluency, 74
withdrawal symptoms, 1030 positive and negative effects, 184 verbal learning and memory, 74
Cannabis, e132 proposed explanations, for positive effects working memory, 74
effects on brain, and impact on of cannabis at low doses, 185 Cannabis picture presentations
cognition, e54 Cannabis compound, other behavioral studies, 251
genome, e4 β-caryophyllin, 880 classical conditioning, 251
heterozygous state (BT/BD), e5 cannabigerol, 880 event-related potential research, 253
homozygous BT/BT genotype, e5 cannabinol, 880 fMRI research, 253
problematic use, e169, e170, e178–e180 dronabinol, 880 orbitofrontal cortex (OFC), 254
prevalence estimation, general nabilone, 880 orbitofrontal cortex in BESA brain
population, e169–e170 sleep, effect on, 880 space, 254
problems, e169 Cannabis consumers, e102 spatial resolution, 251
psychosocial hazards, e169 estimated number of people, e102 temporal resolution, 250, 251
1122 Index

Cannabis prevention treatment availability, 1026 important features of earlier CU as a risk

natural history of cannabis consumption, treatment cost, 1026 factor for CUD, 144
effect of, 1074–1076 barrier, implications of, 1028 negative association, 311
school-based program computer-based intervention, 1028 poor school performance, 290
affective-focused program, 1076 self-guided intervention, 1028 primary motive
best practice, 1078–1083 smartphone app, 1028 CTP, 310
Australian program, 1078 cognitive behavioral therapy, 1028 recreational, 310
characteristic, 1081–1082 family systems approach, 1028 problematic use motivation in early onset
European program, 1078 motivational enhancement therapy, 1028 CU, 146
identification process, 1081 Cannabis use (CU), 138 as a risk factor for psychosis, e30
North American program, 1078 above threshold risk of DSM-IV cannabis dependence by
other intervention and evaluation interpersonal sensitivity, e204 age at first CU, 140
detail, 1082–1083 obsessive-compulsiveness, e204 salutary effect, 309
characteristic, 1076–1077 paranoid ideation, e204 self-report, e185
individual component, 1077 phobic anxiety, e204 methods, e186–e187
booster session, 1077 psychoticism, e204 global drug survey (GDS), e187
program facilitator, 1077 somatization, e204 guidelines in Europe, e186–e187
program intensity, 1077 absenteeism, 290 surveys in Australia, e187
timing of delivery, 1077 across age groups, 36 surveys in United States, e187
interactive program, 1076 across the lifespan, trends in, 35 youth surveys, e187
intervention and evaluation detail, 1080 age at first CU and CUD onset and the young age at CU onset and its association
knowledge-focused, 1076 course of CUD, 148 with CUD risk, 139
main characteristic, 1077 by age group in US (percentage), 37 Cannabis use disorder (CUD), 34, 131, e194,
noninteractive program, 1076 among older adults, 39 e195, e198, e199, 299, 823, 940, 1026,
resistance skills training, 1076 anxiogenic effect, 311 1030, 1057, 1087
skills-focused program, 1076 associative memory assessment, 269–270 adolescent-community reinforcement
type, 1076 on brain structure and function, chronic approach (A-CRA), 133
selective or targeted, 1076 effects of, e48 age at onset, medication use, and suicide
universal, 1076 functional neuroimaging studies, e48 attempts in BD patients with and
Cannabis Problems Questionnaire for under cognitive tasks, e49 without, 425
adolescents (CPQ-A-S), e179 resting state, e48 anecdotal reports, 424
Cannabis-related knowledges genetic vulnerability to chronic approach, 1059
and attitudes in context of medical use of, cannabis use brain structure and functioning, 427
203–204 and its effect on brain structure, e49 clinical features, 132–134, 1060
cannabis use and views, 200 structural effects, e48 clinical studies, 425
drug prevention program at school, 203 challenges associated, impact and cognition, 427
gender differences, and risk perception minimization, e206–e208 cognitive behavioral therapy, use of
among Polish students, 205 bond in therapy, e208 case example, 1062–1064
relationship between self-reported concern/risk successful outcome, 1063–1064
cannabis use prevalence and risk target issues, e207–e208 therapeutic alliance, 1062
perception goals of therapy, e207–e208 unsuccessful outcome, 1062–1063
among European students, 200 internet/computerized treatment, comorbid disorder
risk and protection factors influencing, 203 e206–e207 pharmacotherapy, 1033–1034
sources of information on illicit drugs specialized cannabis clinics, e208 comorbidities, challenge of, 428, 1059
reported by European young depressive outcome diagnosis, 1059
people, 202 adjusted odds ratios (AORs), 303 disorder, treatment of, 76
substance use prevention programs, 201 confidence intervals (CIs), 303 dopamine and glutamate, 425
Cannabis ruderalis, e2, 5 early dose–response relationship, age at onset in
Cannabis sativa, 3, e72, 432, 441, 452, 554, 593, in CUD risk in the context of existing bipolar disorder, 426
607, 849, 860, 873, 877, 932 models of, 145 dysphoria and negative psychological
publication distribution, 878 as a risk factor for CUD, 143 experiences, link between, 424
sleep, effect on, 879 escalation of, 143 environmental mediation, genetic
sleep latency, decrease in, 879 euphoric effect, 309 influences, 426
sleep-wake cycle, effect on, 879 higher rates of suspension, 290 evaluation, 1059
Cannabis sativa hexanoyl-CoA synthetase 1 high-risk age periods for, 139 factor models, 427
(CsHCS1 or CsAAE1), 15 implicit association test, 269–270 gender differences in severity markers, 133
Cannabis sativa hexanoyl-CoA synthetase 2 later genetic vulnerability models, 426
(CsHCS2 or CsAAE3), 15 childhood adversity, association high-risk age periods for incidence, 139
Cannabis sativa subsp. indica var. indica with, 292 integrative model of role of younger age at
(domesticated), 5 novelty-seeking behavior, association CU onset in CUD risk, 146–148
Cannabis sativa subsp. indica var. kafiristanica with, 292 male to female ratio of lifetime cannabis
(wild), 5 parents with prior criminality, use, 132
Cannabis treatment, 1026, 1094 association with, 292 mesolimbic dopaminergic pathways, 425
barrier, 1026–1028 socially disadvantaged background, modular treatment
low perceived need, 1026 association with, 292 CANDIS program, e193
negative views from community, 1026 lower school satisfaction, 290 scientific evaluation, e198–e199
 Index 1123
neurobiological mechanisms, 425 DW-MRI data, 393, 394 Catalepsy, 330, 651, 730
pharmacotherapy, 1032–1033 novel network-based statistic, 394 Catalepsy-like immobilization, 327
antidepressants and anxiolytic, use right fimbria of hippocampus and, 395 THC-induced, 327
of, 1032 streamlines interconnecting right involvement of
cannabinoid agonist, use of, 1032 precuneus with, 396 CB1 receptor, 327
glutamatergic agents, use of, 1033 white matter integrity perturbations, 394 glutamatergic neuronal system, 330
other medication, use of, 1033 white matter, whole-brain investigation nucleus accumbens, 328
prevalence of cannabis use, 131 of, 396 serotonergic neuronal system, 329
prodromal phase, 424 whole-brain tractography, 395 Catechol-O-methyltransferase (COMT), 336
psychiatric disorder chronic inhibitor, 943
anxiety disorder, 1033 psychosocial stress Cathinone, e103
bipolar disorder, 1033 dopamine response, to, 281 chemical structures of, e104
depression, 1033 evidence for dysconnectivity, 393 CB1. See Cannabinoid receptor 1 (CB1)
quality of life, daily functioning, and, 428 adult and adolescent, white matter CB2. See Cannabinoid receptor 2 (CB2)
relationship between BD and, 423, 424 microstructural alterations in, 393 CBC. See Cannabichromene (CBC)
schizophrenia, 424 corpus callosum, 393 CB2 cannabinoid receptor gene (CNR2), 586
self-medication hypothesis, 424 DW-MRI studies, 393 CBD. See Cannabidiol (CBD)
stage white matter abnormalities, 393 CBDA. See Cannabidiolic acid (CBDA)
cognitive behavioral approach, 1061–1062 evidence, 397 CBDA synthase, e3
sobriety, maintainance, 1061 foot-in-the-door, e208 CBDA-synthase gene, e6
symptoms and course of BD, 427 future directions, 397 DNA sequencing electropherogram of a
technology-assisted intervention, 1094 non-face-to-face (non-F2F) treatment, e206 portion, e6
computer-based intervention, 1094 schizophrenia, development of, 392 CBD/THC ratio, e4, e5
high technology based, 1094 treatment engagement, e202 CBDV. See Cannabidivarin (CBDV)
interactive voice response importance, e203 CBG. See Cannabigerol (CBG)
intervention, 1094 influence by, e204–e205 CB-GABA interactions, 773
low technology based, 1094 cannabis use, e204 CBG-free-CBG-BDS, 960
mobile-based interventions, 1094 motivation, e204 CB1-knockout mice, e137
telemedicine, 1094 physiological effects of cannabis, e204 CBM. See Cognitive behavioral model (CBM)
telephone counseling, 1094 risk perceptions, e205 CBME. See Cannabis, based medicinal extract
transition from cannabis first use to, 132 therapeutic alliance, e205 (CBME)
treatment potential threats, e206 CBMs. See Cannabinoid based medicines
CBT method, 1060–1061 premature treatment dropout, e205 (CBMs)
cognitive restructuring, 1060–1061 Cannabis withdrawal syndrome CBN. See Cannabinol (CBN)
cognitive-behavioral approach, 1059 abstinence-induced sleep disruption, 1032 CB2 polymorphisms, 586
effectiveness, 135 pharmacotherapy, 1031–1032 and bipolar disorder, 589
services, 134–136 antidepressant, use of, 1031 and bone disorders, 588
in youth, effective treatment, 1048–1049 cannabinoid agonist, use of, 1031 and cardiovascular disorders, 587
Cannabis use disorders identification test evaluated medication, 1031 and CNS disorders, 588
(CUDIT), e170, e179–e180 mood stabilizer, use of, 1031 and eating disorders, 589
Cannabis use intervention other medication, use of, 1032 and immune system disorders, 586
computer-based, 1096 sedative hypnotic, use of, 1032 and liver disorders, 587
computer-based counselor-guided, 1095 Canonical signaling, 566 and schizophrenia, 589
high-tech delivery, 1095 CapOpus trial, 1087 CB2 Q63 polymorphism, 588
limitation, 1095 result, 1089 and alcoholism, 588
lost to follow-up, 1095 Capsaicin, 924 and depression, 589
participant anonymity breach, risk Capsazepine, 924 CBT. See Cognitive behavioral therapy (CBT)
of, 1095 Carbon tetrachloride-induced hepatic CCD. See Cross-reactive carbohydrate
vs. low-tech delivery, 1098 damage, 509 determinants (CCD)
low-tech delivery, 1097–1098 autoimmune hepatitis, 509 CCl4-induced cirrhosis, 512
limitation, 1098 liver fibrosis, effect of cannabinoids, 510 CD. See Celiac disease (CD); See also Crohn’s
participant dropout, 1098 Carboxyhemoglobin, 490 disease (CD)
participant self-report, risk of bias Carboxylation, 15 CD activity index (CDAI), 933
in, 1098 9-Carboxy-THC, 529 CDAI. See CD activity index (CDAI)
short follow-up assessment Cardiac embolism, 489 cDNA. See Complementary DNA (cDNA)
period, 1098 Cardiomyopathy, 482 cDNA/EST library, 15
telecounseling intervention, 1097 CART. See Cocaine, and amphetamine- CEDS. See Clinical endocannabinoid
technology-assisted regulated transcript (CART) deficiency syndromes (CEDS)
age, effect of, 1098 β-Caryophylline, 878 Celiac disease (CD), 587
comparison of, 1098 antiinflammatory effect, 880 Cellular pathways
gender, effect of, 1098 Case-control studies, 585 cannabinoid, effect of, 865
Cannabis use problems identification test Caspases, e114 neurotransmitters release inhibition, 865
(CUPIT), e180–e181 CAST. See Cannabis abuse screening Central nervous system (CNS), e105, e159,
Cannabis users, 1026 test (CAST) 534, 584, 593, 714, 796
axonal fiber connectivity, investigation CAT. See Catalase (CAT) Central neuropathic pain, by multiple
of, 393 Catalase (CAT), 782 sclerosis, 909–911
1124 Index

Central sensitization, 906 Ciliary muscle, 756 Cognitive functions, 47, 48, 50, e54, e55,
Ceramide, e114, e115, e119 CINV. See Chemotherapy-induced nausea e59, e60, 71, 262
in cannabinoid signaling, e115 and vomiting (CINV) in cannabis users, 48
Cerebellar motor impairment, 408 Cirrhotic mesenteric arteries, 512 in current IQ, verbal memory, working
Cerebellum, 71 Cirrhotic rats, 512 memory span, and planning
Cerebral vasculitis, 490 Cisplatin-induced delayed emesis, 953 ability, 49
Cerebral vasoconstriction, 490 Citalopram, 329 key facts of, 70
Cerebrospinal fluid (CSF), 64, 283, 789 Client satisfaction questionnaire psychotic patients, using cannabis, 48.
Cerebrovascular effects, 483 (CSQ), 1088 See also Explicative hypothesis
CF. See Cognitive functions Climate schools model (CSM) program, related with cannabis use
CFC models. See Contextual fear 1078, 1082 risk factors and treatment of
conditioning (CFC) models Clinical Antipsychotic Trials of Intervention impairments in, 76
CGRP. See Calcitonin gene-related peptide Effectiveness (CATIE) project, 48 in schizophrenia, 49
(CGRP) Clinical endocannabinoid deficiency Cognitive impairments, 45
Chalcone synthase (CHS), 15 syndromes (CEDS), e162 Cognitive independence model, 1060
CHC. See Chronic hepatitis C (CHC) Clinical test of impairment (CTI), 851 Cognitive inhibitory control, 293
Chemical phenotype, e3 Clinical trials, 453 Cognitive performance, 45, 47
Chemokines, 544 acute postoperative pain treatment with THC, effect of, 874
Chemopreventive agents, 818 cannabinoids, 453 Cognitive restructuring method
Chemoreceptor trigger zone (CTZ), 862 Clubbing community, reasons for cannabis behavioral, 1061
Chemotaxonomic classification, 7 use in, 176 cognitive, 1060–1061
Chemotherapy-induced nausea and vomiting gateway theory, 176–177 emotional, 1061
(CINV), 860, 862–863, 953 short-term effects, 176 Colonic transit
neurotransmitters, role of, 862 Clubbing culture, 171 ∆9-tetrahydrocannabinol, effect of, 950
dopamine, 862 Clubbing drugs, 172, 176 Colorectal cancer (CRC), 476
histamine, 862 Club drugs, e12, e15 Communication, 219
muscarine, 862 CM. See Contingency management (CM) Comorbid, 47, 48, 75
serotonin, 862 Cannabinoids, 585 attention deficit hyperactivity disorder
pathogenesis, 862 CNR2. See CB2 cannabinoid receptor gene marijuana, effect of, 874
Chibouque, 111, 119 (CNR2) drug usage, 47
Childhood trauma CNR1, CNR2, and FAAH genes, 64 major depression, 1026
age at onset, substance abuse CNR1 polymorphisms, 62 Companionship, 310
and childhood trauma abuse dose CNS. See Central nervous system (CNS) Comparative risk assessment (CRA), 91
effect, 212 Cocaine, 48, 162, 172, 181, 182, 321, 373, 1008 Compatible trial, regions of activity within
history link between cannabis use and amphetamine-regulated transcript group, 274
and severe mental disorders, 211 (CART), 780 Complementary DNA (cDNA), 556
interaction between childhood sexual dependence, 281 Component resolved diagnosis (CRD), 524
abuse, cannabis abuse, and, 212 marijuana, effect of, 874 Composite International Diagnostic
and mental disorders, 209 smuggling, 123 Interview (CIDI), 47
prone to illicit drug use, 210 Cognition, 48, 122, 361 COMT. See Catechol-O-methyltransferase
questionnaire (CTQ), 211 in psychosis, 46 (COMT)
substance abuse and childhood trauma Cognitive areas, studied in psychosis related COMT gene, 64, 66, 337, 418
abuse dose effect, 211 to cannabis use, 46 and cannabis use interactions, and the
Chinese hamster ovary K1 (CHO K1) cell Cognitive assessment, 47 effect on risk for psychosis, e32
line, 566 Cognitive behavioral model (CBM), 1058 evidences from case-only and case-
CHIP assay. See Chromatin Cognitive behavioral therapy (CBT), 135, control studies, e33
immunoprecipitation (CHIP) assay e194–e196, e203, 1057, 1087, evidences from experimental and
Chloroplast DNA (cpDNA), e8 1094, 1103 experience sampling method based
Chlorpromazine (CPZ), 730, 862 coping with cravings and urges, e196 studies, e37
CHO K1 cell line. See Chinese hamster ovary marijuana use treatment, 1103 evidences from longitudinal studies, e32
K1 (CHO K1) cell line principle, 1060 evidences from neuroimaging
Cholinergic systems, 741 psychoeducation, e195 studies, e37
Chromatin immunoprecipitation (CHIP) refusal/social competence training, e196 cannabis use interaction, studies on, e37
assay, 724 relapse prevention (RP), e196, 1057 environmental factors interaction, e38
Chronic cannabis, 490 sobriety state, effect on, 1057 genetic interactions and other biological
abuse, 463 target day preparation, e196 mechanisms, e38
effects, 81 understanding consumption patterns, e196 methodological concerns and challenges,
Chronic hepatitis C (CHC), 587 Cognitive deficits, 44 e38–e39
Chronic obstructive pulmonary disease Cognitive disorder, 874 pleiotropic biological and behavioral
(COPD), 496 marijuana, effect of, 874 effects of COMT gene, e37
Chronic pain model, 451 Cognitive domains, 225 and effect of Val158Met polymorphism on
mechanism, 451 Cognitive effects, 823 COMT activity, e32
Chronic pelvic pain syndrome, 446 cannabis use in healthy subjects, 45 molecular variability and the risk for
Chronic prostatitis, 446 long-term use of cannabis in psychotic psychosis, e30
CHS. See Cannabinoid hyperemesis patients, 45 COMT inhibitor. See Catechol-O-methyl
syndrome (CHS) nicotine, 47 transferase (COMT) inhibitor
 Index 1125
COMT Val158Met polymorphism, 337 Crohn’s disease (CD), 475, 932 Cyclooxygenase (COX), 796
Conceptual model of achievement enhanced endocannabinoid, 954 inhibition assay, 960
effects on substance use during gastrointestinal (GI) tract, effect on, 932 inhibitor indomethacin, 512
adolescence, 291 marijuana smoking, effect of, 954 Cyclooxygenase-2 (COX-2), 724, 803
Conditioned gaping, 705 Cross-reactivity, 518 pathway, 731
acute nausea, 705 carbohydrate determinants (CCD), 520 Cyclopropanoylindoles, 721
anticipatory nausea, 705 syndrome, 521 CYP. See Cytochromes P450 (CYP450)
Conditioned place preference (CPP), 666 Cross-sectional data CYP1A1 inhibitors, 814
Condition interaction limitation, 302 CYP1A2 inhibitors, 814
significant regions of activity, 275 significance, 302 CYP1 enzymes
Conduct disorder (CD), e23, e66 Cross-sectional studies, 46 active-site cavity, 817
Confounding effect, 224 CRT. See Cannabinoid replacement inhibition, 816
Confounding factor, 311 therapy (CRT) significance, 818
cannabis use assessment, 311 Cryptotis parva, 953 Cysteinyl leukotrienes, 512
polydrug use, 311 Crystallization, 687 Cytochromes P450 (CYP450), 621, 814
sample selection, 311 CSA. See Controlled Substances Act (CSA) enzymes, e123
Confounding variables, 48 CSF. See Cerebrospinal fluid (CSF) Cytokinins, 10
Conservation initiatives, 8 CSM program. See Climate schools model
Constitutive signaling, 568 (CSM) program D
Consultant-participant alliance, 1087 CSQ. See Client satisfaction questionnaire DAGL. See Diacylglycerol lipase (DAGL)
Contact allergic inflammation, 545 (CSQ) d-amphetamine, 941
proinflammatory chemokines, CTP. See Cannabis for therapeutic purposes D1 and D2 receptors, 64
secretion of, 545 (CTP) DAST-10. See Drug abuse screening test-10
Content of successful drug prevention CTQ. See Childhood trauma, questionnaire (DAST-10)
program at school, 203 (CTQ) DAST-28. See Drug abuse, screening test
Contextual fear conditioning (CFC) CTS. See Cannabis, and tobacco (CTS) (DAST-28)
models, e135 CTT. See Critical tracking task (CTT) DAT. See Divided attention task (DAT)
Contingency management (CM), e194 CTZ. See Chemoreceptor trigger zone (CTZ) DBSNP. See Single nucleotide polymorphism
Continuous performance test (CPT), e55, 1088 CU. See Cannabis use (CU) database (DBSNP)
Contrave, clinical trial, 650 CUD. See Cannabis use disorder (CUD) DC. See Dendritic cell (DC)
Controlled drug CUDIT. See Cannabis use disorders Decision-making (DM), 71
identity determination identification test (CUDIT) Deep layers of the superior colliculus
chemical structure Cue-elicited craving, 320 (dlSC), e141
infrared spectroscopy (IR), 982 Cue-reactivity Degree of tolerance, 456
mass spectrometry (MS), 982 cannabis study, 322–323 ∆Eiso. See Stabilization energy (∆Eiso)
nuclear magnetic resonance paradigm, 321 Delinquency, 216, 219
spectroscopy (NMR), 982 virtual reality experiment, 323 Delta-9-Tetrahydrocannabinol, effect of
Controlled Substances Act (CSA), e155 Cultivation techniques, of Cannabis, 9 vs. cannabidiol, 875
COPD. See Chronic obstructive pulmonary indoor cultivation, 9 Delusions, 44
disease (COPD) outdoor cultivation, 9 Dementia, 829, 874
Cortisol-awakening response, 280 in vitro micropropagation, 9 marijuana, effect of, 874
COX. See Cyclooxygenase (COX) Cultural/attitudinal predictor Demographics
COX-2. See Cyclooxygenase-2 (COX-2) attitudes, 1041 characteristics, 54
Cox regression, 499 cognitive processing, 1040–1041 of drug trade, 123
C3-phytocannabinoids, 21 emerging adulthood (EA), 1040–1041 Dendritic cell (DC), 518
C5-phytocannabinoids, 21 larger social environment, 1040 Dendritic spines, 734
CPP. See Conditioned place preference (CPP) pro-drug use myth, 1041 Density Functional Theory (DFT)
C-prenylation of divarinic acid (DA), 21 CUPIT. See Cannabis use problems methodology, e124
CPZ. See Chlorpromazine (CPZ) identification test (CUPIT) Department of Health and Human Services
CRAFFT, e179 Current Cannabis varieties, 7 (DHHS), e187
Cranial mesencephalon, e145 Current drug dependence diagnosis, 47 Depolarization-induced suppression of
Craving Current scientific classification, of Cannabis, 7 inhibition (DSI), 632
cannabis, 317 Cut down-annoyed-guilty-eye opener-adapted Depression, 182
cue-reactivity, 320–321 to include drug (CAGE-AID), e169 cannabis, 311
environment stimuli, 319 CVS. See Cyclic vomiting syndrome (CVS) cannabis dependence, 311
memory encoding disruption, 322 Cyclic adenosine monophosphate Depressive symptoms, 415
reason for relapse, 317 (cAMP), 593 Descriptive epidemiology of aggressive/
theoretical etiology, 318–319 accumulation, 579 disruptive behavior, e20
theoretical issue, 321–322 assays, 586 Descriptive epidemiology of cannabis
CRC. See Colorectal cancer (CRC) dependent protein kinase A, 566 use, e20
CRD. See Cannabis, related disorders (CRD) inhibition, 822 Designer drugs, e151, 841
Criminal justice system, 216 Cyclic vomiting syndrome (CVS), 467 Detection of drivers under the influence of
CRIP1a, 683 Cycloalkylcarboxamide group, 600 cannabis (DUIC), 387
3D structure prediction, 683 Cyclobenzaprine, e161 Developmental periods, risk factors for
CRIP1a-CB1R model, 685 Cyclohexylphenol (CP) synthetic cannabis use during, e21
Critical tracking task (CTT), 380 cannabinoid, 841 Deviant social milestones, 58
1126 Index

DFT methodology. See Density Functional neurons, e30 Drug discrimination, 771
Theory (DFT) methodology pathway, 319 interoceptive effects, 772
DHHS. See Department of Health and ventral tegmental area (VTA), 319 neuropharmacological interactions, 772
Human Services (DHHS) producing neurons, 918 Drug-free children, best practices for
Diabetes mellitus (DM), 780 release amphetamine-induced, 281 raising, 220
Diabetic dyslipidemia, 780 reward-sensitive stimuli, 320 Drug interactions, 47, 437
Diabetic neuropathy, 912 synthesis capacity, 290 Drug readministration, 667
Diacylglycerol lipase (DAGL), 283, 618 uptake blocker and releaser, 941 Drug recognition expert (DRE)
inhibition, 624 ventral striatum level, 321 protocol, 849
Diagnostic and Statistical Manual of Mental Dopamine cells, 741 Drug-related activities, 124
Disorders (DSM), e170, 299, 1067 Dopaminergic agonists, 788 Drug-relevant stimuli, 320
Diaphoresis, 467 Dopaminergic hyperactivity, 824 Drug replacement, 57
Diazepam, 775 Dopaminergic mesocorticolimbic Drugs and sexual behavior, 181
Dibenzopyran-numbering system, 14 system, 534 type of, 182
Diffeomorphic registration algorithm Dopaminergic system, 714 Drug-seeking behavior, 318
(DARTEL), e55 DOPE scoring, 685 effect of CBD, 941
Differential association theory, 189, 190 Dorsal motor nucleus of the vagus Drugs, for pregnant and nonpregnant
Diffusion tensor imaging (DTI), 347, 393 (DMV), 948 women, 168
in adolescent cannabis use, 348 Dorsal portions of periaqueductal gray Drug substitution, 54, 58, 59
in early phase psychosis, 347 (DPAG), e135 Drug testing, e152
Diffusion-weighted imaging (DWI), 491 Dorsal raphe nucleus (DRN), 705 Drug use disorders, cannabidiol, treatment
Digital necrosis, 483 Dorsolateral striatum (putamen), 269 with, 940
Digit-symbol-substitution task, 773 Dorsomedial striatum (caudate), 269 Drug use disorders identification test
Dihydrocodeine, 912 Dose–response cannabis effects, 30, 49, 415 (DUDIT), e170
2, 5-Dimethoxy-4-iodoamphetamine Dose–response relationships, 47 Drug use in general population, 172–174
(DOI), 329 Dose–response theory, 312 DRUID. See Driving-under-the-influence-of-
2, 4-Dinitro-1-fluorobenzene (DNFB), 545 DPAG. See Dorsal portions of periaqueductal drugs (DRUID)
Diphenhydramine, 912 gray (DPAG) DSI. See Depolarization-induced suppression
1, 1-Diphenyl-2-picryhydrazyl (DPPH), e127 DPPH. See 1, 1-diphenyl-2-picryhydrazyl of inhibition (DSI)
Disability-adjusted life years (DALYs), 95–98 (DPPH) DSM-5. See Diagnostic and Statistical Manual
Disability assessment schedule, 1088 Dravet syndrome, 434–436 of Mental Disorders (DSM)-5
Disability weights, 91 clinical trial on cannabidiol, 436 ∆9-Tetrahydrocannabinol (∆9-THC), 3, 62, 71,
calculation of YLDs, YLLs and DALYs, 91 Driving ability, 380 80, 373, 433, 440, 462, 467, 472, 660,
comorbidity adjustments, 91 attention, 380 704, 714, 723, 740, 782, 789, 796, 803,
comparative risk assessment (CRA), 91 critical tracking, 380 814, 829, 940
data on regular (weekly or more frequent) decision-making, 380 cannabidiol effects on brain stimulation
cannabis use in the past year, 92 reaction time, 380 reward, 660
DISC1 gene. See Disrupted-in- Driving under influence of cannabis chemical structure of, 720
schizophrenia-1 (DISC1) gene blood/serum concentrations of synthetic in dyslipidemia, 782
Disrupted-in-schizophrenia-1 (DISC1) cannabinoids, 850 effect on CPP, 666
gene, 346 epidemiology of, 235 in food intake and energy homeostasis, 783
Divalproex, 943, 1031 fatal crash studies, 237–238 functional analogs, 719
Divided attention task (DAT), 380 hospital studies, 237 immunosuppressive effects, 783
dlSC. See Deep layers of the superior roadside surveys, 235–237 metabolic route, 463
colliculus (dlSC) Driving-under-the-influence-of-drugs metabolites excretion in urine, 784
DM. See Decision-making (DM) (DRUID), 849, 1003 narcotic properties, 720
DMV. See Dorsal motor nucleus of the DRN. See Dorsal raphe nucleus (DRN) in oxidative stress, 782
vagus (DMV) Dronabinol, 528, 912, 943, 953, 1071 physical dependence, 667
DNA banding, e3 awoke less often, effect on, 880 role in reward and dependence, 661
DNA methylation, 726 sleep-wake cycle, effect on, 880 in secretion of insulin, 782
DNA microarray, 726 synthetic CB1 receptor agonist, 880 self-administration, 665
DNFB. See 2, 4-Dinitro-1-fluorobenzene Drug abuse, e151 self-administration in experimental
(DNFB) craving, function of, 318 animals, 665
Doctor–patient relationship, 531 dependence development, 281 three-dimensional shape, 719
DOI. See 2, 5-Dimethoxy-4-iodoamphetamine in females, 182 ∆9-THC. See ∆9-Tetrahydrocannabinol
(DOI) screening test (DAST-28), 973 (∆9-THC)
Domeperidone, 862 side effects of, 181 DTI. See Diffusion tensor imaging (DTI)
Doose syndrome, 799 Drug abuse screening test-10 Dual pathology, 67
Dopamine (DA), 181, 254, 279, 425, 535, 714 (DAST-10), e181 DUDIT. See Drug use disorders identification
craving development, 322 Drug addicts, 182 test (DUDIT)
D2/D3 receptor, 321 THC analysis, chromatogram, 1023 DUIC. See Detection of drivers under the
examination, 290 Drug control and treatment of addiction influence of cannabis (DUIC)
mesolimbic release, 319 fund (DCTAF), 119 Duloxetine, e161
mesolimbic reward system, 293 Drug courts, 195 Duration, frequency, and amount of
mesolimbic system, 289, 321 Drug dependence, 873 cannabis usage, 73
neuronal firing, 416 Drug detection kits, 999 DWI. See Diffusion-weighted imaging (DWI)
 Index 1127
Dyskinesia, 824, 833 Eicosanoids, 617 in bipolar disorder, 63
cannabinoid induced, 922 Electroencephalographic (EEG) activity, composition
l-dopa-induced, 922 433, 611 biochemical apparatus, 878
effect of cannabinoids, 923 Electronic dance music (EDM), e15 endogenous agonist, 878
human study, 922 Elevated T-maze (ETM), e132 receptor, 878
nonhuman primates study, 922 Eligible Studies in depression, 62
Dysthymia, 1033 cases-control, key characteristics, e84 implicated in the pathogenesis of
Cohort, key characteristics of, e83 depression, 63
E pooled approach/re-analysis of secondary link between stress, continuous cannabis
EA. See Emerging adulthood (EA) data, e81 use, and psychosis, 282–283
EAE. See Experimental autoimmune ELISA. See Enzyme-linked immunosorbent in psychosis, 64
encephalopathy (EAE) assays (ELISA) schematic representation, 610
Early onset cannabis use, 73 EMA. See Ecological momentary assessment sensory innervation, 440
EAS. See Encephalic aversion system (EAS) (EMA); See also European Medicines sleep modulation, role in, 878
ECA. See Epidemiological catchment Agency (EMA) sleep, relation with, 878–879
area (ECA) EMCDDA. See European Monitoring Centre Endocannabinoid system (ECS), 641, 651
eCBs. See Endocannabinoids (eCBs) for Drugs and Drug Addiction Endogenous acetylcholine, 746
Ecological momentary assessment (EMCDDA) Endogenous cannabinoid system (ECS), 71,
(EMA), 1103 Emerging adulthood (EA), 1040 e162, 472, 544, 948. See also Microglia
Ecological momentary intervention characteristic 2-arachidonoylglycerol, e162
(EMI), 1103 endless possibilities, belief on, 1040 cannabinoid agonists, direct effect on
mobile technology, 1108 feeling in-between, 1040 receptors, 405–407
usage lifestyle, 1040 abnormal-cannabidiol receptors
addictive behavior change, 1103 own identity establishment, 1040 (abn-CBD), 406
alcohol dependence, 1103 self-focused, 1040 neurodegenerative diseases, treatment
mental health disorders, 1103 EMI. See Ecological momentary intervention in, 405
self-monitoring, 1103 (EMI) peroxisome proliferator-activated
smoking cessation, 1103 Emotional regulation, 62 receptor (PPAR), 406
ECS. See Endogenous cannabinoid system Emperical article potential sites, sensitive to cannabinoid
(ECS) summary of finding, 1042 compounds, 406
Ecstasy, e102, 162, 172, 373 EMT. See Endocannabinoid membrane synthetic cannabinoid analogs, 406
EDDRA. See Exchange on drug demand transporters (EMT) transient receptor potential cation
reduction action (EDDRA) Encephalic aversion system (EAS), e141 channel (TRP), 406
EDM. See Electronic dance music (EDM) Endocannabinoid, e72, e136, e141, e162, 753 cannabinoid receptors, e162
EDTA. See Ethylenediaminetetraacetic acid 2-arachidonoylglycerol (2-AG), e141 CB1 receptors, 948
(EDTA) arachidonylethanolamide, 753 CB2 receptors, 948
Education, 48 2-arachidonylglycerol, 753 downstream effector of ECS
EEG activity. See Electroencephalographic N-arachidonoyl ethanolamide, e141 deregulation, 408–410
(EEG) activity O-arachidonoylethanolamine, e141 downregulation and desensitization
EETs. See Epoxyeicosatrienoic acid (EETs) other receptor, binding with of, 408
Effect sizes, 47 vanilloid-1 receptor (TRPV1), 878 effect of THC exposure in the neuronal
Egypt palmitoylethanolamide, 753 circuit, 408
cannabis abuse in selected population in pre- and postsynaptic neurons, e31 experimental data on impact of
groups, 115 receptor subchronic exposure to THC and
cannabis use in CB1, 878 withdrawal, 410
patients with drug overdose, 115 CB2, 878 experimental data supporting, 409
patients with other medical Endocannabinoid-hydrolysis inhibitors, 607 microglial reactivity in cerebellum, 408
conditions, 116 Endocannabinoid membrane transporters gut innervation controlling motility, role
psychiatric patients, 116 (EMT), 473 in, 948
school and university students, 115 Endocannabinoid metabolism, 621 ligands anandamide, e162
cannabis, source of, 113 Endocannabinoids anandamide, 327 localization of components in
cigarette smoking and cannabis, 118 Endocannabinoid signaling system (ECS), gut, 472
current status of cannabis use in, 113 282–283, 416 in neurodegenerative diseases, 405
gender and demographic differences in component, 284 nonclassical receptor, 948
cannabis abuse, 116 HPA function, mediation of, 283 peroxisome proliferator-activated
hashish during 18th–20th Centuries, 111 psychosis risk, 283–284 receptor, 948
initiation of drug/cannabis abuse, 117 stress regulation, role in, 283–284 transient receptor potential vanilloid-1
drug abuse pattern among different stress-responsive neural circuit, 282 (TRPV1) channel, 948
categories, 119 Endocannabinoids Endometriosis, 446
Upper Egypt, 117 N-arachidonoylethanolamine, 617 eNOS protein expressions, 513
prevalence of factors associated with, and Endocannabinoids (eCBs) system, 63, 64, 81, ENS. See Enteric nervous system (ENS)
affecting, cannabis abuse, 114 392, 405, 416, 452, 512, 609, 631, 651, Entacapone, 943
relevance of cannabis use to educational 672, 741, 789, 860, 982 Enteric nervous system (ENS), 472
level and marital status in Lower anandamide, 840 Enzyme inhibitors, 754
Egypt, 118 in anxiety, 63 Enzyme-linked immunosorbent assays
social and economic factors, 118 2-arachidonoylglycerol, 840 (ELISA), 988
1128 Index

Enzymes involved in cannabinoid European School Survey Project on Alcohol F

biosynthesis, 16 and Other Drugs (ESPAD), e178, FA. See Fractional anisotropy (FA)
Epidemiological catchment area (ECA), 299 e187, 199 FAAH. See Fatty acid amide hydrolase
Epidemiological studies, 415 Exchange-diffusion model, e104 (FAAH)
cannabis and psychosis, 82 Exchange on drug demand reduction action FAAH-related activities, 445
migration and psychosis, 83 (EDDRA), 1078 Face-to-face (F2F) treatment, e207
Epigenetics, 718 Excitatory postsynaptic potentials (EPSPs), 5F-APINACA N-(4-hydroxypentyl), 985
Epilepsy, 437, 607, 796. See also Epileptic 632 Fatty acid amide hydrolase (FAAH), 283,
seizures Excitotoxicity, 803, 804, 829 510, 556, 594, 609, 619, 675, 724,
risks/benefits, 432 Executive functions (EF), 47, e55, e59, 940, 948
cannabis safe and well tolerated in e65–e67, 71, 152, 153, 262 enzyme inhibitors, 63
patients, 437 impairment of, 144 FAAHinhibitor URB597, 445
pro- and anticonvulsant effects of, 434 Exhaled breath pharmacological blockade
compounds in established epilepsy, after smoking of cannabis colonic propulsion, delay in, 950
434–436 mean concentration of THC, 1022 GI transit, delay in, 950
people without epilepsy, 434 after smoking of THC Fatty acid derivatives, 655
seizure, pathophysiological basis of, THC, individual concentration, 1021 FDA. See Food and Drug Administration
432–434 alcohol testing, use for, 1019 (FDA)
syndromes, 436 amphetamine presence, 1018 Feddan, 113
treatment, 608 analytical aspect, 1022 Federal Analogue Act, e155
Epileptic seizures, 432, 433, 436 cannabinoid presence, 1018 Feeding behavior, 643
cannabis use and effects, 435 cannabinoid, studies on, 1021–1022 Feeding inhibitors, 646
clinical signs and symptoms, 432 collection FEP. See First-episode psychosis (FEP)
first seizures, stratification of, 433 electrostatic filter technology, 1019 FES. See First-episode schizophrenia (FES)
treatment algorithm, 434 component collection FEV1. See Forced expired volume in 1s
Episodic memory, 71 tenax tube, use of, 1019 (FEV1)
Epoxyeicosatrienoic acid (EETs), 621 drug testing FFT. See Functional family therapy (FFT)
EPS. See Extrapyramidal side effects (EPS) liquid chromatography-mass F2F treatment. See Face-to-face (F2F)
EPSPs. See Excitatory postsynaptic potentials spectrometry (LC-MS), use of, 1019 treatment
(EPSPs) sampling device, 1020 Fibromyalgia, e159
EQ-5D health survey, 934 workflow, 1023 pathogenesis, e159
ERα. See Estrogen receptor α (ERα) drug testing, use for, 1019 symptoms, e159
ERK. See Extracellular-signal-regulated 11-hydroxy-THC presence, 1019 treatment, e160
kinases (ERK) lipid, presence of, 1019 nonpharmacological therapies, e160
EROD assay. See 7-Ethoxyresorfin O- nonvolatile component, presence pharmacological therapies, e160
deethylase (EROD) assay of, 1019 Fibromyalgia (FM), 824, 872
Escitalopram, 943, 1032, 1071 particle, presence of, 1019 Fibromyalgia Impact Questionnaire (FIQ),
ESPAD. See European School Survey Project on protein, presence of, 1019 e163
Alcohol and Other Drugs (ESPAD) sampling, 1022 FIQ. See Fibromyalgia Impact Questionnaire
Estrogen, 672 collection time, 1022 (FIQ)
Estrogen receptor α (ERα), 724 exhaled breath condensate, 1022 First cannabis use, univariate logistic
Estrogen signaling pathways, 726 impactor technology, 1022 regression, 975
Ethanol, 665 specimen for First-episode psychosis (FEP),
Ethnicity, 83, 84 drugs of abuse testing, 1019 e55, 257
Ethological models, e144 toxicology investigation, 1019 adherence and functionality, 260
7-Ethoxyresorfin O-deethylase (EROD) THC presence, 1018 cannabis use and adherence, 260
assay, 814 carboxylic acid, 1019 cannabis use and functionality, 261
comparison of Ki values for inhibition, 815 Exogenous cannabinoid cannabis use as a risk factor for
inhibition, kinetic parameters for, 815 CB1 receptor stimulation, 284 psychosis, 258
Ethylenediaminetetraacetic acid (EDTA), 766 Experimental autoimmune encephalopathy high rate of cannabis use among, 258
ETM. See Elevated T-maze (ETM) (EAE), 673 impact of cannabis use on cognitive
Euphoria, 122 Explanatory models, 366 functioning in, 262
Eurobarometer telephone-based survey, 199 lower vulnerability hypothesis, 368 influence of cannabis use on clinical and
Europe neuro-protection hypothesis, 366 functional outcomes, 259
age as a predictor of cannabis use, 34 social hypothesis, 368 role of depressive symptoms in, 259
emphasis on cannabis control, 38 Explicative hypothesis structural magnetic resonance studies
past month cannabis use by age group and of cognitive functioning related to cannabis in patients and cannabis
country, 37, 40 use in psychotic disorders, 48 use, e56
past year cannabis use by age group, 39 Ex situ conservation in gene banks, 8 treatment for cannabis users, 263
percentage of past year cannabis use by age Externalizing disorders, 133 ventricular alterations in cannabis users
group, 36 Extracellular domain, 558 with, e59
European Medicines Agency (EMA), Extracellular-signal-regulated kinases (ERK) First-episode schizophrenia
e160, 651 cell differentiation, role in, 865 (FES), e55
European Monitoring Centre for Drugs and phosphorylation, 566 First synthetic cannabinoids,
Drug Addiction (EMCDDA), 25, 33, Extrapyramidal side effects (EPS), 327 chemical structures, 841
e170, 841, 972, 984, 1078 Extrinsic sensory neurons, 473 FLAIR imaging, 491
 Index 1129
Fluorescence resonance energy, 579 Gastroesophageal reflux disease (GERD) Geographical distribution, 3, 8
Fluoxetine, 943, 1033, 1071 cannabinoid, effect of, 953 Geranyl diphosphate, 14
Fluvoxamine, 814 mechanism biosynthesis of, 16
fMRI. See Functional magnetic resonance transient lower esophageal sphincter GERD. See Gastroesophageal reflux
imaging (fMRI) relaxations (TLESRs), 953 disease (GERD)
Focal cerebral ischemia (FCI), 407 symptom German version of the auditory verbal
Food and Drug Administration (FDA), heartburn, 953 learning test (VLMT), 888
e103, 941 regurgitation, 953 Germplasm Resources Information Network
Food intake, 473 retrosternal pain, 953 (GRIN) database, 8
Forced expired volume in 1 s (FEV1), 496 Gastrointestinal (GI), 472 GH. See Growth hormone (GH)
Forced swimming test, 964 inflammation GHB (gamma-hydroxybutyrate), 172
Forced vital capacity (FVC), 496 endogenous cannabinoids, role of, 951 Ghrelin (GHRL), 643, 780
Fourier transform infrared spectroscopy exogenous cannabinoids, role of, 951 basal levels, 643
(FT-IR) TRP channel, role of, 962 central administration, 644
functional group determination, 985 motility, 474 interaction with peripheral CB1
Fractional anisotropy (FA), 347, 393 cannabinoid, effect of, 949–952 receptors, 644
Friends, influencing marijuana use, 190 motor function receptors, 644
early adolescence, 190 cannabinoid, effect of, 948 GHRH. See Growth hormone releasing
early adulthood, middle adulthood, cisplatin-treated rat hormone (GHRH)
and beyond, 193–194 WIN55, 212-2, effect of, 954 GHRL. See Ghrelin (GHRL)
emerging adulthood, 192–193 endocannabinoid system GI. See Gastrointestinal (GI)
late adolescence, 191 role of, 951 Gilles de la Tourette syndrome (GTS), 884
late childhood, 190 targetting drug, effect of, 952 alternative forms of treatment, 885
middle adolescence, 191 extrinsic neural control, 951 cannabinoid based medicines (CBMs),
Frontotemporal dementia (FTD), 829 muscle contraction treatment with, 885, 886
FTD. See Frontotemporal dementia (FTD) CB1receptor agonists, effect of, 949 adverse effect, 890
Functional family therapy (FFT), 1049 origin, cannabinoid involvement in visceral cannabinoids, treatment with, 885, 886
Functional implications, of cannabis use, pain, 443 performance-enhancing effect, 887
155–156 Gastrointestinal (GI) tract, 442, 948 Cannabis sativa, treatment with, 886–887
Functional magnetic resonance imaging small/large intestine, 444 case report, 886
(fMRI), e135, 270, 361, 940 stomach, 444 controlled trials, 887
cognitive process, neural activation, 270 Gatehouse project (GP), 1081 prospective survey, 887
FVC. See Forced vital capacity (FVC) GC. See Gas chromatography (GC) causes
GC-MS. See Gas chromatography mass environmental factor, 884
G spectrometry (GC-MS) multiple genetic susceptibility factor,
GABA. See γ-Aminobutyric acid GDS. See Global Drug Survey (GDS) quantitative effect of, 884
(GABA) Gene–environment interaction (GxE), e31, 426 comorbid condition
GABAergic inhibition, 635 Gene expression, 714 attention deficit hyperactivity disorder
GABAergic interneurons, 536 Generalized anxiety disorder (GAD), (ADHD), 884
GABAergic neurons, 824 e161, 304 obsessive compulsive behavior
GABAergic pathways, e144, 721 General substance use, common liability (OCB), 884
GABAergic transmission, 374, 833 to, 177 diagnosis, 884
Gabapentin, e161, 943, 1033, 1071 Genetic and environmental risk factors etiology, 884
Gabapentinoids, e161 (GxE), 336 fatty acid amide hydrolase (FAAH)
GABA receptors, 771 Genetic confounding, 426 inhibitor, effect of, 887
allosteric modulation, 774 Genetic markers, for forensic features
global CNS elevation, 772 identification, e7 motor tics, 884
tiagabine-induced, 774 Genetic mouse models, 338 vocal tics, 884
GAD. See Generalized anxiety disorder Genetic polymorphisms, 585, 714 pathophysiology, 884
(GAD) Genetics, of Cannabis, 7 endocannabinoid system and
GαI protein coupling, 566 “Gene x environment” (GxE) interaction neurotransmitter pathways, role
Galvanic skin-conductance response, model, 82 of, 885
320, 321 Genitourinary tract, 445 imbalances in the dopaminergic (DA)
Gamma-aminobutyric acid (GABA), 62–64, endometrium, 446 system, 884
e161, 1033 kidney and ureter, 445 cortico-striato-thalamo-cortical (CSTC)
Ganja goo ball, e15 ovary, 445 circuitry, 884
Gas chromatography (GC), 982 prostate, 446 THC, treatment with, 887–888
drugs of abuse analysis, 982 testes and scrotum, 446 adverse effects, 888
Gas chromatography mass spectrometry urinary bladder and urethra, 445 randomized controlled trials, 888
(GC-MS), 239, 982, 999 Genome, of Cannabis sativa, 7 uncontrolled single case study, 887
golden standard for qualitative Genome-wide association studies treatment, practical aspect, 890–891
analysis, 985 (GWAS), 585 treatment strategies, 885
GASP1. See GPCR-associated sorting protein Genotypes and chemical phenotypes of alternative medicine, 885
1 (GASP1) cannabis, e7 behavioral therapy, 885
Gastric emptying, ∆9-tetrahydrocannabinol, Genotyping, 585 deep brain stimulation, 885
effect of, 950 Genuine cannabis allergy, 521 pharmacological therapy, 885
1130 Index

GIRK. See G-protein-coupled inwardly- Gray matter (GM), e54, e55, 153 Herbal cannabis, THC and CBD levels, 25
rectifying K+ channels (GIRK) brain structural analysis displaying Herbal smoking blend. See also Smoking
GI tract. See Gastrointestinal (GI) tract clusters of significant decreased synthetic cannabinoid, use of
Glandular trichome, e3 gray matter, e58 chemical structures, 844
Glaucoma, 749, 761 GRK. See GPCR kinase (GRK) Herbal smoking mixture, 840
intraocular pressure, 749 Grooved pegboard test, 376 hERG potassium channel assay, 653
intraocular pressure lowering, 761 Growth hormone (GH), 643 Heroin self-administration
retinal neuroprotection, 762 Growth hormone releasing hormone effect of CBD, 941
treatment, 749 (GHRH), 645 Heterocycles, 655
Glial fibrillary acidic protein (GFAP), e105 GSK-3β. See Glycogen synthase kinase Heterodimerization, 574, 579, 725
Glial tumors, e112 3β(GSK-3β) Heteromers, 579
multimodal action of cannabinoids GTS. See Gilles de la Tourette syndrome Heterosynaptic LTD, 633
against, e117, e118 (GTS) HETEs. See Hydroxyeicosatetraenoic acid
antitumoral action of cannabinoids in GTS-CGI. See Tourette’s syndrome clinical (HETEs)
vivo, e117 global impression scale (GTS-CGI) Hexanoyl-CoA synthetase, 15
effects of cannabinoids on angiogenesis, Guanine-nucleotide-binding proteins HFS. See High frequency stimulation (HFS)
cell migration, and invasion, (G-proteins), 558 5-HIAA. See 5-Hydroxyindoleacetic acid
e118–e119 Gut disorder, cannabis, use of, 948 (5-HIAA)
Glioblastoma multiforme (GBM), e112, 866 GWAS. See Genome-wide association studies High Ambiguity Driven DOCKing
cannabinoid, effect of, 866 (GWAS) (HADDOCK), 685
expression of CB2 receptor in human GxE. See Genetic and environmental risk Higher exposure, to THC and risk of adverse
glioblastoma, e113 factors (GxE) health effects, 28
Gliomas Higher potency cannabis, and plasma THC
alterations of major components of H levels, 26
cannabinoid system in, e113 Habit formation Highest occupied molecular orbital
cell culture associative memory processes, role of, 269 (HOMO), e124
cannabinoid, effect of, 866 neuroscience of dual systems, role of, 269 High frequency stimulation (HFS), 633
therapeutic potential of cannabinoids Habitual cannabis, 66 High-resolution computed tomography
against human gliomas, e119 HADDOCK. See High Ambiguity Driven (HRCT), 497
results from a pilot clinical DOCKing (HADDOCK) High resolution mass spectrometry
study, e119 HADS. See Hospital Anxiety Depression (HR-MS), 983
risks and constrains, e119 Scale (HADS) advantage, 983
safety profile of therapeutic Hallucinations, 44, 80 nontargeted compound, data-dependent
cannabinoids, e119 Haloperidol, 330, 862 acquisition of, 983
Global burden of disease (GBD), 90 Harvey–Bradshaw index, 933 metabolic patterns of synthetic
Global drug survey (GDS), e187 result, 935 cannabinoid, use in, 983
Globus pallidus, 918 Hashish during 18th–20th Centuries, 111 urine biomarker identification, use in, 983
Glucocorticoid, 672 HBCC. See Human breast cancer cell (HBCC) Hippocampus, e54, 71
Glucose homeostasis, 782 HBSC. See Health behavior in school-aged Histomorphometric study, in rats
Glutamate, 321, 425 children (HBSC) activity of osteoblasts, e75
Glutamate receptors, 631 HD. See Huntington’s disease (HD) bone formation, e75
Glutamatergic neuronal system, 330 Head and neck cancers bone inflammation around teeth, e76
Glutamatergic neurons, 330 alcohol and tobacco use, e96 bone loss, during ligature-induced
Glutamatergic synapses, 330 mutagenic effects of, e96 periodontitis, e76
Glutathione peroxidase (GPx) risk factors, e97 bone resorption, e75
enzymes, 782 case-control study in, Boston, e96 bone-to-implant contact, reduction in, e76
Glycogen synthase kinase 3β(GSK-3β), 805 INHANCE Consortium, e97 cannabinoid receptors (CB1 and CB2),
Goza, 113 marijuana use and, e96 activation, e75
GPCR. See G protein-coupled receptor epidemiological studies, e98 cannabis smoke inhalation, e76
(GPCR) potential relation, e96 cannabis smoking, cancellous bone healing
GPCR-associated sorting protein 1 sexual behavior, confounding by, e96 impact of, e73
(GASP1), 560 Health behavior in school-aged children degree of bone-to-implant contact, e73
GPCR kinase (GRK), 566 (HBSC), e187 effect of marijuana inhalation, e76
GPR55, orphan G-protein linked Health risk, 30 endocortical osteoblast number,
receptor, e114 Healthy life style trial enhancement, e76
G-protein-coupled inwardly-rectifying K+ tobacco smokers with psychosis, e207 furcation region of rat molar, e77
channels (GIRK), 560 Heart, 441 immune targets, cannabinoid-based
G-protein coupled receptor (GPCR), 558, 565, disease, 489 drugs, e75
574, 584 HEIA. See Homogeneous enzyme periodontal inflammation, regulation
allosteric modulation, 574 immunoassay (HEIA) of, e76
signaling, 683 Heme oxygenase-1 enhanced portal periodontitis, effects of cigarette
G protein coupling promiscuity, 568 hypertension, 513 smoking, e73
G-proteins. See Guanine-nucleotide-binding Hemp, e2, e4, e5 photomicrographic illustration, bone
proteins (G-proteins) varieties, 8 healing in implant surface, e74, e75
GPx enzymes. See Glutathione peroxidase Hepatic CYP isozymes, 437 retention device for, oral
(GPx) enzymes Hepatic stellate cells (HSCs), 506 microorganisms, e76
 Index 1131
risk factor for, e76 Hydrophilic prodrug derivatization, 766 Illegal recreational drug
tetrahydrocannabinol (THC) detection in, Hydrophobic interactions, 685 cannabis, 940
urine samples, e75 11-Hydroxy-delta 9-tetrahydrocannabinol stimulant, 940
THC effect in, inhibiting CB2 (11-OH-THC), 1010, 1011, 1013 Illicit Drug Reporting System (IDRS), 104
expression, e76 6-Hydroxydopamine-induced apoptosis, 920 Illicit drugs, e12, 131, 161, 171, 201
thirty Wistar rats, e73 6-Hydroxydopamine lesioned rat, Illness-inducing agent, 705
titanium implants, decrease bone mass 920, 922 Imidazopyridines, 602
around, e73, e75 Hydroxyeicosatetraenoic acid (HETEs), 621 Immune cells, 559
HIV painful neuropathy (HIV-PN), 911 5-Hydroxyindoleacetic acid (5-HIAA), 706 Immune thrombocytopenic purpura
HIV-PN. See HIV painful neuropathy Hydroxylation, 238 (ITP), 587
(HIV-PN) 5-Hydroxy-l-tryptophan (5-HTP), 329 Immunoallergic vasculitis, 490
1
H-MRS. See Proton magnetic resonance N-(4-Hydroxyphenyl)-arachidonamide, 920 Immunoassay screening
spectroscopy (1H-MRS) Hydroxypropyl methyl cellulose (HPMC), urine screening, 982
Homicide rates, 127 766 Immunocytochemical analyses, 559
HOMO. See Highest occupied molecular 11-Hydroxy-THC (11-OH-THC), 238 Immunohistochemical analyses, 444
orbital (HOMO) 5-Hydroxytryptamine (5-HT), 329 Immunohistochemistry, e113
Homodimeric enzyme, 15 5-Hydroxytryptamine1A (5-HT1A) Immunological methods, 239
Homogeneous enzyme immunoassay receptors, 704 Immunosuppression, 437
(HEIA), 988 agonists, 706 Implicit association test (IAT), 269
Homosynaptic LTD, 634 antagonists, 706 attitude examination, 269
Homovanillic acid elevation, 282 Hyperalgesia, 906 behavior-related associative memory
Homozygous THC producing BtBt Hyperemesis, 467 structure, examination
genotypes, 8 Hyperglycemia, 780 of, 269
Hopkins verbal learning test, 1088 Hyperpolarization, 577 imaging, 270
Hospital Anxiety Depression Scale (HADS), Hypertelorism, 163 INCANT. See International cannabis need of
e162 Hyperthermia, e105 treatment trial (INCANT)
HPA. See Hypothalamic-pituitary-adrenal Hypocretinergic system, 538 Incarceration, 124
axis (HPA) Hypocretin system, 534 Incidence rate ratio
HPMC. See Hydroxypropyl methyl cellulose addictive properties of drugs abuse, CapOpus group
(HPMC) role in, 535 vs. TAU, 1089
HPT-axis. See Hypothalamic-pituitary- cannabinoid dependence, role in, 538 Incompatible trial
thyroid axis (HPT-axis) mRNA levels, 538 regions of activity within group, 274
HRCT. See High-resolution computed potential therapeutic utility, 536 Indole, 593
tomography (HRCT) Hypokinesia biological data, 595
HR-MS. See High resolution mass haloperidol-induced, 887 chemical structures, 596
spectrometry (HR-MS) Hypolocomotion, 741 Indoor cultivation, of C. sativa, 9
HSCs. See Hepatic stellate cells (HSCs) Hypomania, 422 Inducible nitric oxide synthase
5-HT. See 5-Hydroxytryptamine (5-HT) Hypomotility, 651 (iNOS), 963
5-HT1A receptors. See 5-Hydroxytryptamine1A Hypothalamic-pituitary-adrenal axis Inferior colliculus (IC), e141
(5-HT1A) receptors (HPA), 279 Inflammatory bowel disease (IBD), 475, 932,
5-HTP. See 5-Hydroxy-l-tryptophan (5-HTP) long-term cannabis use, effect 953, 962
HU-210, 920 of, 952 cannabis, treatment with, 918
HU-308, 920 Hypothalamic-pituitary-thyroid axis beneficial effects, 921
Human breast cancer cell (HBCC), 723 (HPT-axis), 462 hospitalization risk, 922
Human bronchial pathology, 498 Hypothermia, 651, 741 side effect, 922
Human colon adenocarcinoma cell line Hypoxic-ischemic brain injury, 803 surgery risk, 922
HT29 CBG, 960 cannabis user vs. nonusers of cannabis,
Human functional imaging technique, 270 I 922, 927
Human ghrelin, chemical structure, 643 IBD. See Inflammatory bowel disease (IBD) Crohn disease (CD), 954
Human in vivo neuroimaging techniques, 346 IBS. See Irritable bowel syndrome (IBS) patient, beneficial effects of cannabis, 925
Human motor cortex, 374 Ibuprofen, 824 treatment
Human studies, 506 IC. See Inferior colliculus (IC) inhaled cannabis, 921
Human trials, 749 ICD. See International classification of option, 932
Humulus lupulus (hop), 14 diseases (ICD) self-administration of cannabis, 921
Huntington’s disease (HD), 405, 434, ICD-10 criteria, 1087 ulcerative colitis (UC), 954
806, 829 ICH. See Intracerebral hemorrhage (ICH) Inflammatory steatohepatitis, 587
cannabinoid signaling, 924 ICSS paradigm. See Intracranial self- Inheritance of chemical phenotype, in
characteristic stimulation (ICSS) paradigm C. sativa “codominant monogenic
behavioral deficits, 918 IgE-mediated reaction, 518 control, ”, 8
cognitive, 918 primary, 518 Inhibition, 152, 153, 156
motor dysfunction, 918 principles, 518 iNOS. See Inducible nitric oxide synthase
effect of cannabinoids, 924 secondary, 518 (iNOS)
clinical data, 924 ILAE. See International League Against In situ conservation as in vitro gene
genetic model, 926–927 Epilepsy (ILAE) banks, 9
effect of cannabinoids, 927 Ill-being, cannabis, 311 Insomnia, 824
Hydromorphone, 771 Illegal drug usage, e155 marijuana, use of, 872
1132 Index

Instrumental conditioning, 318 Ionization potential (IP), e124 Legislation, 239

Instruments, for assessing premorbid Ionomycin, 962 approaches to, 239
IQ, 226 Iowa gambling task (IGT), 293 Australia, 240
Instruments selection performance, differences in Canada, 240
from the literature, e170–e171 between chronic marijuana users and European Union, 240
Intellectual quotient (IQ), 224 control, 294 impairment legislation, 239
Flynn–Dickens model, 227 PET activation, differences in United States, 240
longitudinal studies on premorbid IQ, between chronic marijuana users and zero-tolerance laws, 239
227–229 control, 294 Lennox–Gastaut syndrome, 436, 799
premorbid IQ and cannabis IP. See Ionization potential (IP) Leonotis leonurus, 840
findings from longitudinal IQ scores, e59 Leonurus sibiricus, 840
studies, 229 Irritable bowel syndrome (IBS), 953 Levonantradol, 862
risk, 229–231 characteristic Leydig cell, 965
Intensive forms, of drug use, 973 abdominal discomfort, 954 LFP. See Local field potential (LFP)
Internalizing disorders, 133 altered bowel habits, 954 Libido, 181
International cannabis need of bloating, 954 Life satisfaction, 289
treatment trial (INCANT), 1048, IRT analysis. See Item response theory (IRT) Life skills training (LST), 1078, 1082
1050, 1051 analysis Likert-type scale, 1028
flow diagram, 1051 Ischemia, 407 Limbic-motor interface regulating stress
outcomes, 1051 reperfusion injury, 507 response, 872
treatment site characteristic, 1050 Ischemic ulcers, 483 Limits of detection (LOD), 854
International classification of diseases (ICD), Islets of Langerhans, 780 Lipopolysaccharide (LPS), 405
90, e170, 299 Item response theory (IRT) analysis, 318 Lipoxin A4, 579
International League Against Epilepsy ITP. See Immune thrombocytopenic purpura Lipoxygenases (LOX), 621
(ILAE), 607 (ITP) pathway, 15
International Lung Cancer Liquid chromatography (LC), 982, 986, 995
Consortium, e95 J aqueous biological sample analysis, 982
Interpersonal predictor, 1041–1042 Jam band performance, e14 bioanalysis, 982
family influence, 1042 Joints, e169 Liquid chromatography coupled to mass
peer influence, 1041 JWH-018, 841 detector (LC-MS or LC-MS/MS),
Interpretation of result, 1014–1015 JWH-081, 982 239, 999, 1019, 1022
historical use, 1015 JWH-122, 982 Literatures
medicinal use, 1015 JWH-210, 982 regarding impairment after long-term use
proof of use, 1015 JWH chemical compounds, e153 of cannabis, 29
recent use, 1014 regarding impairment of acute cannabis
Inter simple sequence repeat amplification effects, 28
(ISSR), e7 K Lithium, 1071
Kaempferol, 814
Intervention, 1087–1088 Lithium carbonate, 1031
Kainic acid model, 611
CapOpus trial, 1087–1088 Liver, 444
Karyotype, e4
treatment as usual (TAU), 1088 disorders, 587
Keratinocytes, 453, 544
Intervention design Liver cirrhosis
atopic-like inflammation, regulation
marijuana use reduction, 1104 effect of cannabinoids, 510
of, 547
Intervention group hemodynamic changes, 512
endogenous cannabinoid system, 544
time to first psychiatric emergency room Local field potential (LFP), 797
proinflammatory chemokines, secretion
contact, 1090 LOD. See Limits of detection (LOD)
time to first psychiatric hospital of, 546 Lofexidine, 1031, 1032, 1071
Ketamine, 172, 173, 175, 636, 790
contact, 1091 Longitudinal studies, 35
Ketoprofen, 453
Intestinal inflammatory condition on premorbid IQ, 227–229
Khat plant, e103
cannabinoid, effect of, 953–955 Long-term depression (LTD), 714, 734
K2/Spice, synthetic cannabinoids, 441, 849
Intoxications, 224, 433 Long-term marijuana use. See also Marijuana
Kupffer cells, 513
Intracerebral hemorrhage (ICH), 488 brain, effect on, 874
Intracranial self-stimulation (ICSS) paradigm, Long-term potentiation (LTP), 714, 734
660, 941 L Long-term video-EEG, 436
Intraocular pressure, 749 l-α-Lysophosphatidylinositol (LPI), 407 Lorcaserin, 650
cannabinoid-induced reduction, cellular Lapse situation Lower GI tract, functional disorders, 474
mechanisms, 755 intervention strategy, 1061–1062 Lower urinary tract symptoms (LUTS), 441
ciliary epithelium, 755 Lateral septum (LSV), 339 Lower vulnerability hypothesis, 368
trabecular meshwork, 755 Laxatives, 123 Lowest unoccupied molecular orbital
Intrapersonal predictor, 1038–1039 LC. See Liquid chromatography (LC) (LUMO), e124
cognitive processing, 1039 Learning theory, 318 LSD (lysergic acid diethylamide), 172
neurobiological, 1038–1039 Leeds Sleep Evaluation Questionnaire LSEQ. See Leeds Sleep Evaluation
self-image and deviant behavior, 1039 (LSEQ), e165 Questionnaire (LSEQ)
In vitro micropropagation of leaf-derived Left inferior frontal gyrus, 270 LST. See Life skills training (LST)
calli from C. sativa L., 10 Legal considerations, 124 LSV. See Lateral septum (LSV)
Ion channel transient receptor potential A1 Legal drugs, e153 LTD. See Long-term depression (LTD)
(TRPA1), 445 Legal highs, e151, 841, 854 LTP. See Long-term potentiation (LTP)
 Index 1133
LUMO. See Lowest unoccupied molecular legalization, 1102 Maternal breast milk, 529
orbital (LUMO) in the United States, 195 Matrix metalloproteinase 2 (MMP-2)
Lung adenocarcinoma motherhood, legal concerns, 531 activity, 509
mice animal model, 865 physiological effects, 482 Maximal finger tapping, 375
Lung cancer, 498 picture, 271 MCF-7 cells, 724
and alcohol use, e81 polydrug use, 1102 MD. See Molecular dynamics (MD)
case control study in New Zealand, e82 primary care, brief treatment, 1102 MDA. See Malondialdehyde (MDA)
data from, Maghrebian region, e95 recreational use, 1102 MDFT. See Multidimensional family therapy
family history, e82 smoker, 1019 (MDFT)
histological changes in, tracheobronchial smoking, in form of blunts within hip-hop MDMA. See 3, 4-Methylenedioxymetham-
epithelium, e82 subculture, e12, e13 phetamine (MDMA)
logistic-regression models, e95 structural brain change, 1102 MDMA (3, 4-methylenedioxy-N-
marijuana use in late adolescence/early substance use disorder, 1102 methylamphetamine), 172
adulthood, e81, e95 and tobacco use, e81 reinforcing effects, e105
epidemiological studies, e98 trajectories, use for those in early Mean diffusivity (MD), 393
risk of, e95 adulthood, 193 Meconium, 162
and tobacco use, e81 treatment project, 1030 Median raphe nucleus (MRN), 705
usage, e81 Medicago sativa, 15
M adolescent, 1102 Medical cannabis, 34
Mad hatter, 988 among jazzmen, e12 well being, direct effect on, 310
MAGL. See Monoacylglycerol lipase behavioral study, 269, 1102 well being, indirect effect on, 310
(MAGL) contextual factor, 1102–1103 Medical marijuana, 869–871. See also
Magnetic resonance imaging (MRI), e59, 433 disorder, 871 Marijuana
Magnetic resonance spectroscopy (MRS), effect acute immune deficiency syndrome
350, 375 apathy, 289 (AIDS), effect on, 870
in cannabis use, 351 lack of motivation, 289 antiemetic properties, 870
in early psychosis, 351 lethargy, 289 central nervous system effect, 870
Main myenteric neuronal population habit-related change, 274 epilepsy, effect on, 870
endocannabinoid system, components implicit association toward, 271 insomnia medicine, 870
of, 950 intervention mental disorder, effect on, 871
Major depressive disorder (MDD), 300, 310 counseling plus mobile technology, multiple sclerosis (MS), effect on, 870
Major histocompatibility complex use of, 1104 short-term physical effect, 870
(MHC), 894 mean momentary desire, 1107 Medication, 823
Malignant cardiac arrhythmia, 482 momentary factor, 1102–1103 compliance, 203
Malondialdehyde (MDA), 782 performance on a motivational task, 294 Medicinal properties, of cannabis
Malonyl-CoA, 15 positive subjective-effect rating, increase plant, 451
Manchester short assessment of quality of life in, 1102 Medicines and Healthcare Products
(MANSA), 1088 sense of euphoria production, 1102 Regulatory Agency (MHRA), 822
Mania, 422 social anxiety, effect of, 1103 Mental health
Manolis study from 1983, 1019 social environment, effect of, 1103 human endocannabinoid system, effect
MANSA. See Manchester short assessment of young adult, 1102 of, 301
quality of life (MANSA) user vs. nonuser, 269 Mental illness
MAPKs. See Mitogen-activated protein withdrawal symptoms, 871 cannabis use, cooccurrence with,
kinases (MAPKs) Marijuana-IAT imaging, 270–271 299–302
Marijuana, e2, 3, e12, 25, 39, e80, 162, 181, 189, incompatible trial cross-sectional data, 302
194, 481, 527, 730 temporal layout of, 272 cannabis user, 301
abuse, 1070 inferior frontal gyrus, 272 concurrent cannabis use
and alcohol use, e81 interaction effect, 273 mechanism, 301
Cannabis sativa, 440 orbitofrontal cortex, 272 prevalence of cannabis use, 300
cardiovascular consequences, 482 paradigm, 271–274 5-MeODMT. See 5-Methoxy-N, N-
cardiomyopathy, 482 Marijuana plant dimethyltryptamine (5-MeODMT)
cerebrovascular effects, 483 cannabidiol (CBD), 872 6-Mercaptopurine, 932
myocardial infarction, 482 delta-9-tetrahydrocannabinol (THC), 872 Meristemoid formation, 10
myocardial ischemia, 482 Marijuana substitute, 840 Mesolimbic dopamine system, 289
peripheral vascular disease, 483 bay bean, 840 Mesolimbic/mesocortical DA system, 282
cigarette, 818 blue lotus, 840 MET. See Motivational enhancement
consumption, 181 honeyweed, 840 therapy (MET)
desire, 1102 Indian warrior, 840 Metabolic disturbances, 433
detection in biological specimen, 1008 lion’s tail, 840 Metabotropic glutamate receptors
development of cancer, e81 maconha brava, 840 (mGluRs), 631
electronic dance music (EDM), e15–e16 Marinol, 862, 1010 METH. See Methamphetamine
eligible articles, e81 Mass spectrometry (MS) Methadone, 940
friends impact use, 189 clinical application, 982 improved substance abuse outcome, 940
immunoassay test, 982 forensic analysis, 982 Methadone induction, 874
inhalation route, 527 Mast cell, 932 Methamphetamine (MA), 48, 172,
jam band subculture, e14–e15 Master’s-level university librarian (TF), e81 181, 373, 941
1134 Index

Methamphetamine (METH), e102 Microscopic photographs of C. sativa Momentary self-monitoring and feedback +
annual prevalence of, in United States, e103 trichomes, 5 motivational enhancement
as crystal/chalk/ice, e103 Midazolam, 775 therapy (MOMENT) intervention,
dopaminergic neuronal activity, e104 Midbrain tectum (MT), e143 1103–1108
Methionine (Met) allele, 418 Migration phenomena, 83 component, 1103, 1104
Methodological limitations, 50 cannabis use, and psychosis design, 1104
Methotrexate, 932 onset, 85 formative research, 1104
5-Methoxy-N, N-dimethyltryptamine causing psychotic disorders, 84 MET sessions
(5-MeODMT), 329 risk factors for first episode psychosis field note, 1107
Methylenedioxymethamphetamine (MDMA), in migrants, 85 mobile technology, use of, 1104
e12, e15 risk of first episode psychosis (FEP) momentary reporting, 1105
3, 4-Methylenedioxymethamphetamine in populations, 84 pilot study, 1104
(MDMA), e15, 655 types of, 83, 84 data collection, 1105
cathinone, e103 Military substance use, e154 pilot study phase
consumption, e104 media coverage, e154 momentary, daily, and individual
dopaminergic neuronal activity, e104 Milnacipran, e161 outcome
dopaminergic stimulation, e103 Mineralocorticoid, 672 differences in, 1106
dysphoric symptoms of, ecstasy, e103 Miniature inhibitory postsynaptic currents individual-level mean, 1106
psychostimulant drugs, e103 (mIPSCs), 578 standard deviation, 1106
in synthesis of styptic drugs, e104 mIPSCs. See Miniature inhibitory potential challenges to implement, 1108
Methylphenidate, 771, 885, 941 postsynaptic currents (mIPSCs) randomized controlled trial, 1105
1-Methyl-4-phenyl pyridinium [MPP(+)] MIS. See Multifocal arterial stenosis responsive messaging, 1105
induced cell death, 920 (MIS) Monoacylglycerol lipase (MAGL), 283, 340,
1-Methyl-4-phenyl-1, 2, 3, MIST. See Montreal imaging stress task 556, 609, 618, 631, 948, 960
6-tetrahydropyridine (MPTP) (MIST) Monoamines dopamine (DA), e103
neurotoxic effect, 920 Mitochondria dysfunction, 831 Monocyclic cores, 597
Metochlopramide, 862 Mitogen-activated protein kinases biological data, 596
MGL. See Monoacylglycerol lipase (MGL) (MAPKs), 452, 560, 632, 682 chemical structures, 597
mGluRs. See Metabotropic glutamate MMP-2 activity. See Matrix metalloproteinase pyridines, 598
receptors (mGluRs) 2 (MMP-2) activity pyrimidines, 598
MHC. See Major histocompatibility complex Mobile technology sulfamoyl benzamides, 598
(MHC) ecological momentary intervention (EMI), Monte Carlo simulation, 684
MHRA. See Medicines and Healthcare delivery of, 1108 Montreal imaging stress task (MIST),
Products Regulatory Agency marijuana use reduction, 1104 280–281
(MHRA) Modafinil, 941 Mood disorder, 871
MI. See Motivational interviewing (MI) Modeling, earlier age of onset of cannabinoids, effect of, 864
Mice xenograft model, 865 schizophrenia, 92 cannabis, 302–303
Michigan alcohol screening test, e181 additional burden attributable to course of
Microglia, 674 cannabis use as a risk factor cannabis use, effects of, 303
activation process for schizophrenia, 93 and insomnia, 864–865
activated state, 402 burden of cannabis dependence, 93 marijuana, effect of, 871
as active sensors, 402 country-level DALYs, 97 serotonergic system, effect of, 864
antiinflammatory effects, 404 estimated DALYs attributable to regular three-year incidence
cannabinoid receptors, 404 cannabis use as a risk factor for lifetime cannabis user
chemokine-receptor, 404 schizophrenia, 2010, 98 vs. nonuser, 302
effector cells, 403 estimated DALYs for cannabis, by sex and tryptophan, effect of, 864
expression of “Off” signals, 403, 404 region, 2010, 96 Morphine, 455
motility control depends on ATP, 402 estimated prevalence and number brain reward function
“On” signals, triggering process, 403, 404 of cases of cannabis dependence effect of CBD, 941
proinflammatory genes activation, 403 in 2010, by sex and region, 95 reward-facilitating effect
purinergic 2X ionotropic receptors, 403 global cannabis dependence DALYs effect of CBD, 941
P2Y metabotropic receptors, 403 (all YLDs) by age and sex, 95 Morphine-dependent rodent
resting state, 402 implications of findings, 96 abstinence scores
signal regulatory protein α (SIRPα) limitations, 99 effects of CBD, 941
receptor, 404 modelling increased severity of naloxone-precipitated withdrawal, 941
toll-like receptors (TLR), 403 Schizophrenia, 92 withdrawal
endogenous cannabinoid system pooled regional prevalence of cannabis effects of CBD, 941
cannabinoid agonists, direct effect of, 405 dependence, 2010, 94 Morphine withdrawal symptoms
cannabinoid agonists, direct effect on prevalence of cannabis dependence, 92 naloxone-precipitated, 874
receptors, 405–407 proportion of DALYs due to Motherhood, 531
downstream effector of ECS cannabis dependence Motivation, 319
deregulation, 408–410 relative to, 98 for achievement
endocannabinoids (eCBs), 405 Modulatory sites, 574 during high school, 290
in neurodegenerative diseases, 405 Molecular classification, 7 theory, 291–292
hematopoietic origin, 402 Molecular dynamics (MD), 686 cannabis use, educational under-
im central nervous system (CNS), 402 MOLPROBITY, 684 achievement lead, 292
 Index 1135
educational under-achievement, outpatient treatment program, 1053 fibromyalgia, effect on, 880
cannabis use lead, 291 vs. comparison treatment, 1052 synthetic CB1 receptor agonist, 880
problem behavior theory, 292 Multifocal arterial stenosis (MIS), 487 Nabiximols, 910, 1071
during university, 291 Multimodal therapy, 453 NAc. See Nucleus accumbens (NAc)
cannabis intoxication, effect of, 293 Multiple choice vocabulary test N-Acetyl-aspartate (NAA), 350
cannabis use, 310 (Mehrfachwahl-Wortschatztest, N-Acetylcysteine, 1033, 1071
chronic cannabis user, 289 MWT-B), 888 N-Acylethanolamine acid amidase
laboratory measure, 289, 293–295 Multiple sclerosis (MS), 106, 405, 806, 894, 963 (NAAA), 960
acute effect, 293 antiinflammatory treatment, 895 N-Acylethanolamine-hydrolyzing acid
effects of chronic use, 293–295 characteristic amidase (NAAA), 619
marijuana use, effect of, 289 autoimmune disease, 894 N-Acylethanolamines (NAEs), 619
research demyelination, 894 N-Acyl phosphatidylethanolamine
limitation, 292 multifocal inflammation, 894 phospholipase (NAPE), 283
cultural difference, 292 neuronal injury NADA. See N-Arachidonoyl dopamine
multiple forms of substance use, 292 brain, 894 (NADA)
self-report, 289–290 optic nerve, 894 NAEs. See N-Acylethanolamines (NAEs)
dopamine examination, 290 spinal cord, 894 NAFLD. See Nonalcoholic fatty liver
Motivational enhancement therapy (MET), chronic inflammatory demyelinating disease (NAFLD)
135, e195, 1032, 1094, 1103, 1104, disease, 963 NAPE. See N-Acyl phosphatidylethanolamine
1107, 1108 first-line medication phospholipase (NAPE)
Motivational index score glatiramer acetate, 895 Naphthoylindoles, 692, 721, 982
chronic alcohol user immunomodulatory medication, 895 Naphthoylpyrroles, 721
vs. healthy volunteer, 295 immunosuppressive medication, 895 Naphthylmethylindenes, 692
Motivational inhibitory control, 293 interferon-β, 895 Naphthylmethylindoles, 692
Motivational interviewing (MI), e194, 1104 microglial activation, 963 Naphthylpyrroles, 692
Motivation enhancement training (MET), neuropathic pain Naphthyridines, 602
e203 CBD/THC combination, effect of, 899 N-Arachidonoyl dopamine (NADA), 510,
Motor disorders, 824 patient 632, 878
Motor expressions, 607 expanded disability status scale N-Arylamide oxadiazoles, 600
clonic, 608 (EDSS), 894 NASH. See Nonalcoholic steatohepatitis
myoclonic, 608 risk factor (NASH)
tonic, 608 environmental, 894 Nasopharyngeal cancers, e96
tonic-clonic, 608 Epstein–Barr virus infection, 894 National adult reading test, 1088
Motor global scale, 888 Herpesvirus 6 infection, 894 National Campaign against Drug Abuse
Mouse cerebellar granule cell, 920 multiple genetic, 894 (NCADA), 105
Mouse model of ileus Theiler’s murine encephalomyelitis virus National Cannabis Policy (NCP), 106
cannabidiol, effect of, 955 (TMEV) model, 963 National Cannabis Prevention and
MPP(+). See 1-Methyl-4-phenyl pyridinium treatment, 896 Information Centre
[MPP(+)] cannabidiol (CBD), use of, 895 (NCPIC), 107
MPTP. See 1-Methyl-4-phenyl-1, 2, 3, sativex compounds, use of, 895 National Center for Biotechnology
6-tetrahydropyridine (MPTP) Multiple substance use, rates of, including Information (NCBI), 586
MPTP-induced parkinsonism, 921 cannabis, 174 National comorbidity survey (NCS), 299
MPTP-marmoset model, 921 Multisystemic therapy (MST), 1049 National Council for Addiction Treatment
MPTP-treated rhesus monkey, 921 Multivariate multinomial analysis, 977–978 and Prevention (NCATP), 119
MRN. See Median raphe nucleus (MRN) Murine colitis National Drugs Campaign (NDC), 108
mRNA second messenger, 456 dinitrobenzene sulfonic acid (DNBS) National Drug Strategy Household Survey
MRS. See Magnetic resonance spectroscopy model, 963 (NDSH), 102, e187
(MRS) Muscimol, 775 National Epidemiologic Survey on
MS. See Multiple sclerosis (MS) Mutagen-activated protein kinases (MAPKs) Alcohol and Related Conditions
MST. See Multisystemic therapy (MST) apoptosis, role in, 865 (NESARC), 299
MS therapy pipeline, 901 Mutation, e3 National Fibromyalgia and Chronic Pain
MT. See Midbrain tectum (MT) Myeloperoxidase, 804 Association (NFCPSA), e163
Multidimensional family therapy (MDFT), Myenteric neuron National Institute on Drug Abuse (NIDA),
1049–1050 endocannabinoid system, relation with, 949 199, 463, 1000
certified therapist Myocardial infarction (MI), 482, 587 National Registry of Evidence-based
requiremen, for, 1053 Myocardial ischemia, 482 Programs and Policies
effects of, 1050–1051 (NREPP), 1078
implementation in Europe, 1051–1054 N National Survey on Drug Use and Health
accreditation, 1051–1052 NAA. See N-Acetyl-aspartate (NAA) (NSDUH), e95, e187, 300
innovation, 1053–1054 NAAA. See N-Acylethanolamine-hydrolyzing National Survey on Mental Health and
licensing, 1053 acid amidase (NAAA) Wellbeing (NSMHWB), 301
number of team, 1053 Nabilone, 822, 862, 872, 912, 943, 953, 1071 Nausea, 705
team requirement, 1053 chemical structures, 822 Nausea and emesis
training, 1053 chronic insomnia, effect on, 880 cannabinoid, effect of, 953
treatment center manager, 1052 comorbid posttraumatic stress disorder, Nausea and vomiting
intervention, 1050 effect on, 880 pathogenesis, 862
1136 Index

Navy Drug Screen, e154 Neuropeptide (NPY), 640 Noncontrolled clinical trials, e163
NCBI. See National Center for Biotechnology Neurophysiological tests, 742 Non-F2F treatment. See Non-face-to-face
Information (NCBI) Neuro-protection hypothesis, 366 (non-F2F) treatment
NDD. See Neurodegenerative disorders Neuroprotective effect, 49 Nongastrointestinal origin
(NDD) Neuropsychological assessment battery cannabinoid involvement in visceral
NDSHS. See National drug strategy maze, 1088 pain, 443
household survey (NDSHS) Neuropsychological deficits, 225 Nonmilitary drug use, e155
Nefazodone, 1031, 1032 Neuroticism, 310 Nonrandomized clinical trials, e163
Neonatal fecal levels, 529 Neurotoxicity, 225 Nonspecific lipid transfer protein (ns-LTP),
Neonate, 530 Neurotransmission, 445, 830 519
marijuana exposure, long-term effects, 530 modulation, 830 Nonsteroidal antiinflammatory drugs
marijuana exposure, short-term effects, 530 systems, 66 (NSAIDs), e161, 441, 624, 730
NESARC. See National Epidemiologic Survey Neurotransmitter 11-Nor-9-carboxy-∆9-tetrahydrocannabinol
on Alcohol and Related Conditions pleasurable experience, 319 (THC-COOH), e189, 238, 1010,
(NESARC) New psychoactive substances (NPS), e103, 1011, 1013
Neural network model, 269 172, 173, 841 Not for human consumption, e155
Neuregulin 1 (NRG1), 336 bath salts, e104 3NP. See 3-Nitropropionic acid (3NP)
Neuroadaptation, 321, 456 discovery of, e103 NPS. See New psychoactive substances (NPS)
Neuroanatomical analysis, 348 exchange-diffusion model, e104 NPY. See Neuropeptide (NPY)
Neurobiological stimulation, 318 indirect monoaminergic agonists, e104 NREPP. See National Registry of Evidence-
Neuroblastoma cells, 566, 920 neurobiological interactions, e103 Based Programs and Policies
Neurocognitive abnormalities, 157 plant fertilizers, e104 (NREPP)
Neurocognitive deficits, in emerging adult rates of cannabis use in users of, 175 NRG1. See Neuregulin 1 (NRG1)
cannabis, 153 reported to the EMCDDA, 842 NRG1-cannabis interactions, 336, 339
Neurocognitive effects, 152, 157, 224 representative packaging of, e104 NRG1 signaling pathway, 346
Neurocognitive implications, of cannabis New synthetic cannabinoids, 843 NRS. See Numeric Rating Scale (NRS)
use, 152 New Zealand Cancer Registry, e96 NRs. See Nuclear receptors (NRs)
Neurodegenerative disorders (NDD), 804 NFCPSA. See National Fibromyalgia and NSAID-induced gastric hemorrhages, 444
Neurodevelopmental impairment, 231 Chronic Pain Association (NFCPSA) NSAIDs. See Nonsteroidal antiinflammatory
Neuroimaging studies, methodological NF-kB. See Nuclear factor kappa B (NF-kB) drugs (NSAIDs)
limitations of, e50 Nicotine, 48, 321, 665 NSDUH. See National survey on drug use
Neuroimaging technique, 250, 320, 375 consumption, 162 and health (NSDUH)
event-related potentials, 250–251 dependence, Fagerström test, e169 ns-LTP. See Nonspecific lipid transfer protein
functional magnetic resonance NIDA. See National Institute on Drug Abuse (ns-LTP)
imaging, 251 (NIDA) NSMHWB. See National Survey on Mental
functional magnetic resonance imaging Nigrostriatal damage Health and Wellbeing (NSMHWB)
(fMRI), 281 6-hydroxydopamine induced NTS. See Nucleus of the solitary tract (NTS);
positron emission tomography (PET), 281 effect of cannabinoids, 921 See also Nucleus of tractus solitarius
Neuroinflammation, 673, 831 1-methyl-4-phenyl pyridinium [MPP(+)] (NTS)
Neuroinflammatory disorders, 673 induced Nuclear factor kappa B (NF-kB), 733
Neuromaturational changes, 157 effect of cannabinoids, 922 Nuclear magnetic resonance spectroscopy
Neuromodulation, 714 1-methyl-4-phenyl-1, 2, 3, (NMR), 982, 985
Neuronal maturation, 346 6-tetrahydropyridine (MPTP) Nuclear receptors (NRs), 672
Neuropathic pain, 823 induced Nucleus accumbens (NAC), 328, 534, 743
approach to the management, 910 effect of cannabinoids, 922 Nucleus of the solitary tract (NTS), 862
cannabinoids, role of Nigro-tectal pathway activity, e145 Nucleus of tractus solitarius (NTS), 642
future clinical study, 913 Nitric oxide (NO), 796 Numeric Rating Scale (NRS), e162
cannabinoids, use of, 864, 909 synthase, 472, 498
common causes, 906 3-Nitropropionic acid (3NP), 806 O
mechanism, 906 NK cell, 932 OAS. See Oral allergy syndrome (OAS)
pathogenesis NMDA. See N-Methyl-d-aspartate (NMDA) Obesity, 473, 650
l-glutamate, role of, 864 NMDA receptor Obsessive compulsive disorder (OCD), e132
pathological process, 906, 907 N-Methyl-d-aspartate (NMDA) OCD. See Obsessive compulsive disorder
diabetic polyneuropathies, 906 induced neuronal death, 873 (OCD)
postherpetic neuralgia, 906 receptor, 330, 762, 803 Ocular pain and inflammation, 762
postsurgical/traumatic neuropathies, 906 antagonists, 330 Ocular tumors, 762
spinal cord injury, 906 amantadine, 330 Odds ratio (OR), 92, 211, 212
trigeminal neuralgia, 906 MK-801, 330 OEA. See Oleoylethanolamide (OEA)
pharmacological treatment, 908, 909 NO. See Nitric oxide (NO) OF. See Oral fluid (OF)
symptoms and sign, 906 Nocturnal motor activity 11-OH-THC. See 11-Hydroxy-delta
Neuropathy THC, effect on, 874 9-tetrahydrocannabinol
diabetic distal symmetrical sensorimotor Nonaffective psychosis, 46 (11-OH-THC)
polyneuropathy, 912 Nonalcoholic fatty liver disease Oleoylethanolamide (OEA), 646
HIV infection, due to, 911 (NAFLD), 587 Olivetolic acid, 14, 15
spinal cord injury, 912 Nonalcoholic steatohepatitis (NASH), 587 Olivetolic acid cyclase (OAC), 16
 Index 1137
Olivetol synthase (OLS), 15, 16 sample cannabinoid, effect of, 955
OLS protein, 15 from frequent marijuana smoker symptom
Ondasetron, 863 concentration of cannabinoid, 1012 bloating, 955
One-leg stand (OLS) test, 851 median concentration of distension, 955
On-site device cannabinoids, 1013 emesis, 955
cutoffs for cannabis, 1000 marijuana positive gas and secretion accumulation, 955
sensitivity for, cannabis in oral cannabinoid composition, 1014 visceral pain, 955
fluid, 1002 sativex user Parental communication and children’s
specificity for, cannabis in oral fluid, 1002 median cannabinoid ratios, 1015 substance use, 219
three matrices, comparison of results, 1003 THC recovery, 1009 Parental influence, on adolescent cannabis
two matrices, comparison of results, 1003 THC stability, 1009 use, 216–217
On-site drug testing, 999 Oral mucosal disease, e73 future directions in, 220
alere DDS V Test, 1001 Oral tongue cancers, e97 Parental monitoring, 972
detection limit, 1000 marijuana use and, e97 Parental warmth
matrix of choice, 999–1000 Orchialgia, chronic, 446 and monitoring, 218
on-site oral fluid testing, 1002 Orexigenic effect, 644 and parenting style, 219
on-site urine testing, 1001 Orexin system, 534 Parenting style, 219
use of addictive properties of drugs abuse, role Parkinson’s disease (PD), 792, 805, 918, 963
emergency department, 1003 in, 535 cannabinoids, effect of, 919
forensic autopsies, 1002–1004 cannabinoid dependence, role in, 538 characteristic
primary health care, 1004 potential therapeutic utility, 536 bradykinesia, 918
schools, 1003 ORG27569 allosteric modulators, 575 postural instability, 918
Opiates/opioids, 182, 665 binding site, elucidation of, 578 rigidity, 918
animal exposure in vivo studies, 578 tremor, 918
effects of CBD, 942 ORG27759 allosteric modulators, 575 endocannabinoid system, 918
drug-related death, 941 ORG29647 allosteric modulators, 575 6-hydroxydopamine model, 920
Opiates use disorder Organon compounds, 575 l-dopa treatment, 918
treatment strategy ORG27569, 575 1-methyl-4-phenyl-1, 2, 3,
methadone use, 940 ORG27759, 575 6-tetrahydropyridine model, 920
µ−Opioid receptors, 941 ORG29647, 575 primate models, 921
Opioids, 452 Oromucosal spray administration, 895 rotenone model, 920
Opioid withdrawal symptoms Oropharyngeal cancers, e97 Past month cannabis use
THC, effect of, 874 Orthosteric ligands, 574 by age group and country, 37
Oppositional defiant disorder, e66 Otenabant, 653 by age group, Europe and the United
Oral allergy syndrome (OAS), 519 development program, 653 States, 40
Oral fluid (OF), 1008 Overweight, 650 Past year cannabis use
analysis Oxidative stress, 780, 831 by age group, Europe, Canada, and the
gas chromatography–mass spectrometry beta cells dysfunction, 781 United States, 39
(GC/MS), 1010 Oxytocin, 1071 Pathogenesis, 467
immunoassay screening, 1010 Patient flow
liquid chromatography with P through the study, e198
tandem mass spectrometry PAG. See Periaqueductal gray matter (PAG) Pavlovian conditioning, 318
(LC-MS/MS), 1010 PAHs. See Polycyclic aromatic hydrocarbons PBC. See Primary biliary cirrhosis (PBC)
time of flight (TOF) detection, 1010 (PAHs) PBE. See Poisson–Boltzmann equation (PBE)
collection device, 1008–1009 Pain control PCE. See Prenatal cannabis exposure (PCE)
cannabinoid recovery, 1011 endogenous cannabinoids, role of, 909 PCU. See Problematic cannabis user (PCU)
desirable characteristic, 1008 opioids, role of, 909 PD. See Parkinson’s disease (PD)
collection pad, 1009 Pain Disability Index (PDI), e162 PDI. See Pain Disability Index (PDI)
transportation buffer, 1009 Painful neuropathy, 912 pDomTHREADER, 683
THC recovery, 1009 Pain management, 824, 864 PEA. See Palmitoylethanolamide (PEA)
composition, 1008 cannabinoids, use of, 864 Pedicularis densiflora, 840
cholesterol, 1008 pharmocotherapy class Peer influence, nature of, 189–190
electrolyte, 1008 dorsal horn inhibitory mechanism, 908 Peers vs. friends, 189
enzyme, 1008 membrane stabilizing agents, 908 Pelvic viscera, sensory innervation, 440
epithelial cell, 1008 Palliative cancer, symptoms relief Pentylenetetrazole (PTZ) model, 797
mucin, 1008 approved cannabinoid, 862 Pepcan-12, 579
protein, 1008 Palmitoylethanolamide (PEA), 675 Pep pills, e152
vitamin, 1008 N-Palmitoylethanolamine, 626, 951 Peptide YY(PYY), 780
water, 1008 Pancreas, 444, 780 Perceived behavioral control, 218–220
disposition of cannabinoid, 1010–1013 Pancreatic polypeptide (PP), 780 Percentage
marijuana smoking, 1011 Panic attack-like behaviors, e142 of current age cohorts and corresponding
oral administration, 1013 PANSS. See Positive and negative syndrome age of first use for cannabis, 37
smoking and oral administration, 1013 scale (PANSS) of past year cannabis use by age group and
drug stability, 1008–1009 Papyrus, 112 country, 36
marijuana recovery, 1008–1009 Paralytic ileus Perception of drugs, 201
1138 Index

Periaqueductal gray matter (PAG), e141 Polyketide synthases (PKSs), 15 Pretreatment dropout, 1026
Perinatal exposure, 741 Polysubstance dependence, 1058 Prevalence of dual pathology, in cannabis
Periodontal disease, e77 Polysubstance use, 75 addicts in treatment, 67
Peripheral signals, 640 POMC. See Proopiomelanocortin (POMC) age for cannabis use vs. mental
Peripheral vascular disease, 483 Popular media, e154 disorders, 68
Peroxisome proliferator-activated receptor POSIT. See Problem-oriented screening current diagnoses of axis I disorders
(PPAR) instrument for teenagers (POSIT) assessed by the MINI, 67
alpha agonist, 744 Positive and negative syndrome scale distribution of lifetime comorbid mental
Peroxisome proliferator-activated receptor-γ (PANSS), 29, 792, 1088 disorders, 67
(PPARγ), 406, 805, 960 Positive well-being distribution of personality disorders in
Personality disorders, 66 cannabis, 309–310 patients with lifetime cannabis
Personalized medicine, 590 future directions, 313 misuse, 67
Pertussis toxin (PTX), 566, 732 limitations, 313 Madrid study on, 67
PET. See Positron emission tomography (PET) component Primary biliary cirrhosis (PBC), 587
PGE2. See Prostaglandin E2 (PGE2) happiness, 309, 310 Primary dystonias, 833
Pharmacokinetic activity, 162 life satisfaction, 309, 310 Problematic cannabis user (PCU), 974
Pharmacokinetic (PK) models, 387 Positron emission tomography (PET), 293, negative variables, with
Pharmacological studies 375, 789, 918 multivariate multinomial logistic
in rats, e105 Posterior cingulate cortex (PCC), e55 regression, 977
Pharmacology, 822 Postnatal day (PND), 634 variables positive, with
Pharmacotherapy trial, 1032 Postoperative pain, 453 multivariate multinomial logistic
Phencyclidine, 665 multidimensional model for regression, 978
Phenobarbital, 665 pathophysiology, 452 Problematic use of cannabis (PUC), e181
Phenothiazines, 456 Postsynaptic density protein 95 (PSD-95), 734 Problematic use of marijuana (PUM), e181
Phentermine, 650 Posttraumatic stress disorder (PTSD), e132, 872 Problem behavior theory (PBT), e19
Phenylacetylindoles, 692, 721 marijuana, effect of, 872 Problem-oriented screening instrument for
Phosphatidylinositide-3-kinases (PI3K), nightmares, 825 teenagers (POSIT), 973
560, 566 Potassium channels, 567 Processing speed, e67, 74, 262
Phospholipase C, 631 Potency, 25, 26 Proconvulsant effects, 434
Phosphorylation, 566 PP. See Pancreatic polypeptide (PP) of cannabis, 434
of ERK by CB1, 566 PPAR. See Peroxisome proliferator-activated medically administered CBD, 434
Phytocannabinoids, 14, 555, 607, 609, 654, receptor (PPAR) Prodromal nausea, 467
706, 749 PPARα receptors, 473 Progesterone, 672
chemical structures, 555 PPARγ. See Peroxisome proliferator-activated Program agenda for the drug court
effects, 609 receptor-γ (PPARγ) model, 194
intraocular pressure, effect on, 750 Preclinical studies, 773 Proinflammatory cytokines, 559
cat, 750 Preclinical work, 775 Proliferator-activated receptors (PPARs), 744
dog, 751 Prefrontal cortex (PFC), e54, 71, 152 Proopiomelanocortin (POMC), 640
human, 749 Pregabalin, e161 Propyl cannabinoids, 21
monkey, 751 Pregnancy, 162, 531 Prostacyclin, 731
rabbit, 750 characteristics of women, using cannabis Prostaglandin biosynthesis
rat, 751 during, 162 cannabigerol, role of, 963
PI3K. See Phosphatidylinositol-3-kinase Prelimbic frontal cortex (PL), e135 Prostaglandin E2 (PGE2), 724, 730, 796
(PI3K) Premammillary hypothalamic nucleus, e143 Prostaglandin production pathway
Pilocarpine and pentylenetetrazol (PTZ), 608 Premorbid IQ, and cannabis CBG, effect of, 960
Pittsburgh Sleep Quality Index (PSQI), e163 findings from longitudinal studies, 229 Prostaglandins, 731
PKC. See Protein kinase C (PKC) possible explanation of link to cannabis Prostate carcinoma, 866
PK models. See Pharmacokinetic (PK) models use, and psychosis, 230 pathogenesis, 866
PL. See Prelimbic frontal cortex (PL) Premorbid neuropsychological abilities, 224 Prostatectomy, 455
Placebo, 824 Prenatal cannabis exposure (PCE), 161 Prostatic serum antigen (PSA), 866
Plasma cells, 518 detection methods and accuracy of Protein folding, 829
Pleasure pathway, 319 prevalence estimates, 162 Protein kinase A (PKA), e104
P42/44 MAP kinase, 756 effects on offspring, 163–166 Protein kinase C (PKC), e104, 534
PND. See Postnatal day (PND) Bayley scales of infant development, 165 Protein–protein docking, 685
Pneumomediastinum, 501 behavioral alterations in children Proteome, e3
Pneumothorax, 501 prenatally exposed to cannabis, 167 Proton magnetic resonance spectroscopy
POC. See Point-of-collection (POC) cardiovascular changes associated (1H-MRS), 350
Point-of-collection (POC), 999 with, 163 Prunus persica, 519
Poisson–Boltzmann equation (PBE), 686 gestation and infant mortality, 165 PSD-95. See Postsynaptic density protein 95
Poisson regression analysis, e3 neurocognitive development, 166 (PSD-95)
Polycyclic aromatic hydrocarbons size effects associated with, 164 PSQI. See Pittsburgh Sleep Quality Index
(PAHs), 498 neuroimaging studies, 165 (PSQI)
Polydipsia, 467 prevalence and behavioral patterns across Psychiatric comorbidity, 75, 133
Polydrug, 162, 203 pregnancy, 161 Psychiatric treatment
problems associated with, 175–176 SAMHSA report, 161 level, CapOpus, effects of, 1090
Polyketide pathway, 15 Stanford-Binet Intelligence Scale, 165 Psychoactive drugs, e151
 Index 1139
Psychoactive substances, 41 Rapid eye movement (REM), 878 Rodents, e142, 741
Psychological and relational problems, Rave culture, e15 behavior, e142
experienced by substance users, 183 ecstasy, e15–e16 Romberg’s test, 851
Psychological effects ideology of PLUR, e15 Root mean square deviation (RMSD), 687
of acute cannabis intoxication, 81 RCT. See Randomized clinical trials (RCT) Root mean square fluctuation (RMSF), 687
present in drug addicts, 183 RCVS. See Reversible vasoconstriction ROS. See Reactive oxygen species (ROS)
Psychopathological symptoms, 48 syndrome (RCVS) RP. See Relapse prevention (RP)
Psychopharmacological effects, 54 Reaction time (RT), 381 RPE. See Retinal pigmented epithelium (RPE)
Psychosis, 25, 29, 80, 414, 873 Reactive oxygen species (ROS), 677, 803 RT. See Reaction time (RT)
cannabis use, effect of, 283 Recency of parents’ cannabis use and RXR. See Retinoid X receptor (RXR)
dopamine release children’s initiation, 217
stress-induced, 281–282 Recent-onset schizophrenia (ROS), e55 S
ECS, effect on, 283 Receptor–agonist interactions, 718 SAD. See Social anxiety disorder (SAD)
gene–environment interaction, 282 Receptor trafficking, 734 Saliva, biochemical composition, 1008
inducing effects of cannabis, 30 Recreational drug Salting out technique (SALLE), 991
self-medication by marijuana, 872 online available, 844 SAMHSA. See Substance Abuse and Mental
Psychosocial derailment, and problem Recreational drugs, 162 Health Services Administration
accumulation, 146 Recreational use, cannabis, future research (SAMHSA)
Psychosocial stress, 281. See also Psychosis directions, 314 Sativex, 943, 1010, 1071
Psychostimulants, 535, 665 Reference spectrum, 985 oromucosal spray
Psychotic disorder, e30 Register of Australian Drug and Alcohol spasticity, treatment, 959
marijuana, effect of, 873 Research (RADAR), 1078 Sativex compound, 895
Psychotic illness, 47, 48 Relapse prevention (RP), e194, 1057, 1061 SBIRT. See Screening, brief intervention, and
Psychotic patients, 49 strategies, 1062 referral to treatment (SBIRT)
Psychotic spectrum disorder, 281 cannabis craving, understanding of, 1062 SC. See Synthetic cannabinoids (SC)
Psychotic symptoms, 66, 415 cognitive distortion, 1062 SCBs. See Synthetic cannabinoids (SCBs)
Psychotomimetic effects, 49 cognitive skill acquiring, 1062 Schedules for, clinical assessment in
Psychotropic effects, 414 emotion, 1062 neuropsychiatry (SCAN)
PTSD. See Posttraumatic stress disorder psychoeducation, 1062 interview, 1087
(PTSD) role play, 1062 Schizophrenia, 47, 66, 80, 224, 336, 346, 358,
PTX. See Pertussis toxin (PTX) REM. See Rapid eye movement (REM) 414, 788, 1087
PTZ. See Pilocarpine and pentylenetetrazol Resin (hash), 25 attribution style, 358
(PTZ) Resin-type cannabis, e3 candidate genes, 336
PUC. See Problematic use of cannabis (PUC) Resistance indices, 163 and cannabis, 337
Pulsatility indices, 163 Response inhibition, e67 cognition, 358
PUM. See Problematic use of marijuana Restriction fragment polymorphisms deficits in social knowledge, 358
(PUM) (RFLP), 7 diagnoses, 336
Purkinje cell excitability, 408 Retinal ganglion cell (RGC), 761 disorders, 361
PyMOL molecular graphics system, 686 Retinal pigmented epithelium (RPE), 763 emotion recognition, 358
Pyrazolopyridines, 602 Retinoid X receptor (RXR), 672 functional imaging studies, 361
Pyrazolylidene, 600 Reversible cerebral cannabis arteriopathy, 490 gene–cannabis interactions, 337
Pyridine, 598 Reversible vasoconstriction syndrome catechol-O-methyltransferase, 337
Pyrimidine, 598 (RCVS), 487 neuregulin 1, 338
PYY. See Peptide YY(PYY) Reviews and metaanalyses on cannabis gene–environment interactions, 336
and cognition, 225 heritability for, 80
Reynaud phenomena, 483 marijuana, effect of, 873
Q RGC. See Retinal ganglion cell (RGC) negative symptoms, 788
QLIP. See Quality of Lfe Impairment by Pain
Rhesus monkeys, 697 anhedonia, 788
(QLIP)
Rho-GTPase signaling pathways, 565 apathy, 788
Qsymia, 650
Right censoring, 139 social withdrawal, 788
Quality of Lfe Impairment by Pain (QLIP),
Right inferior frontal gyrus (RIFG), 274 neurofunctional Alterations, 360
e162
Rimonabant, 473, 651, 697, 920, 964 and nonaffective psychosis, 46
QUARK algorithm, 684
antihypokinetic activity, 920 patients, 46
Quetiapine, 943, 1032
glutamate release, effect on, 920 prevalence, 336
Quinolones, 602
Risk and protection factors influencing rates of, 80
substance use, 203 related disorder
R Risperidone, 887 amphetamine-induced DA release, 282
RADAR. See Register of Australian Drug and RMSD. See Root mean square deviation spectrum psychosis, 1087
Alcohol Research (RADAR) (RMSD) symptoms, 336
Radial diffusivity (RD), 348, 393 RMSF. See Root mean square fluctuation anhedonia, 336
Radioimmunoassay, 48 (RMSF) cognitive, 336
Random amplified polymorphic DNA Roadside Testing Assessment project, 1000 impairment of sensorimotor gating, 336
(RAPD), 7 Road traffic accident social withdrawal, 336
Randomized clinical trials (RCT), e161 cause, driving under the influence (DUI) theory of mind, 358
Randomized controlled clinical trials, e164 of drugs, 849 Schizophreniform psychosis, 414
Randomized controlled trials, 434 Robetta’s algorithm, 684 School-based drug prevention program, 201
1140 Index

School-oriented programs, 202 Shisha, 115 SNPSTR database, e7–e8

SCN1A gene mutation, 434 Short Form 36 Health Survey (SF-36), e163 SNr. See Substantia nigra pars reticulata
Screening, brief intervention, and referral to Short inflammatory bowel disease (SNr)
treatment (SBIRT), 1102 questionnaire (SIBDQ) Social anxiety disorder (SAD), e134, 872
Screening instruments score, 918 Social cognition, 46
characteristics, e171–e181 Short inventory of problems-alcohol and Social development model, 292
process of selection and analysis, e171 drugs (SIP-AD), e181 Social drug, 189, 194
Screening tests, by immunoassay, 239 SIBDQ score. See Short inflammatory Social hypothesis, 368
SDS-PAGE analysis, 15 bowel disease questionnaire Social network during adolescence, 192
Seized material analysis, GC-MS, use of, 985 (SIBDQ) score Social phobia, 434
Selective serotonin and norepinephrine Siblings, 46, 49 SOD. See Superoxide dismutase (SOD)
reuptake inhibitor (SSNRI), e161 SIDS. See Sudden infant death syndrome Sources of information on illicit drugs,
Selective serotonin reuptake inhibitors (SIDS) reported by European young
(SSRIs), e161, 490, 885 Signaling pathways, 577 people, 202
Self-help for alcohol and other drug use and Simulation of the public speaking test Specialized addiction treatment, 1027
depression (SHADE), e207 (SPST), e134 SPECT. See Single photon emission computed
Self-medication, 303 Single nucleotide polymorphism (SNP) tomography (SPECT)
hypothesis, 415, 424 assay, e4 Spice, 840, 849, 986
theory, 312 Single nucleotide polymorphism database diamond, 986
Self-report (DBSNP), 586 neurologic effects, 844
of adult population Single nucleotide polymorphisms (SNPs), psychoactive component
cannabis use prevalence, e187 336, 340, 585 identification, 841
and biological measurements nonsynonymous, 586 sympathomimetic effects, 844
concordance between, e186 Single photon emission computed variant
concordance with tomography (SPECT), spice diamond, 840, 841
armed forces, e190 e134, 940 spice gold, 841
driving population, e189 Sinsemilla (skunk), 25, 29, 418 Sprague Dawley rats, 653, 660
drug users in treatment, e190 SIP-AD. See Short inventory of problems— SPST. See Simulation of the public speaking
emergency department patients, e190 alcohol and drugs (SIP-AD) test (SPST)
HIV-infected youth, e190 Skills, 49 SPT. See Skin prick tests (SPT)
pregnant women, e190 based programs, 201, 202 SR141716A
university students, e189 Skin, 544 rapid eye movement (REM), effect
Self-validation, 310 Skin lesions, 546 on, 878
Sensation seeker, 56 Skin prick tests (SPT), 522 slow wave sleep (SWS), effect
Sensorimotor gating, 337 Sleep disorders, 872–873 on, 878
deficits, 338 marijuana, use of, 872 wakefulness induction, role
Serotonergic neuronal system, 329 THC, effect of, 865 in, 878
Serotonergic systems, 329 Sleep latency, acute administration of Src activation pathways, 580
Serotonin1A, 705 marijuana, effect of, 872 SSNRI. See Selective serotonin and
Serotoninergic agents, 721 Sleep, physiological role of norepinephrine reuptake inhibitor
SERS. See Surface enhanced Raman endocannabinoid, 878 (SSNRI)
spectroscopy (SERS) Sleep-wake cycle, 535 SSRIs. See Selective serotonin reuptake
Set-shifting, 46 cannabis, effect of, 878 inhibitors (SSRIs)
Sexual SLF. See Superior longitudinal Stabilization energy (∆Eiso), e124
attitudes, 182 fasciculus (SLF) Staphylococcus aureus, 965
behavior, 181, 182 Slow transit constipation Steatosis, 587
effect of drugs on, 183 cannabinoid, effect of, 955 Stilbene synthase (STS), 15
desire, 182 Slow wave sleep (SWS), 878 Stimulants, e152
difficulties, 184 Smokers, effects of CBD, 943 abuse and dependence treatment
disorders, 181 Smoking inhibition dopamine uptake blockers and releasers,
excitement, 182 CBD inhaler, use of, 942 use of, 941
expectations, 185 CBD, use of abuse potential, 941
function, 182 mechanism of action amphetamine, 940
performance, 182, 183 CB1 receptor antagonist, 942 animal exposure
pleasure, 183 FAAH inhibition, 942 effects of CBD, 942
satisfaction, 181 use of low dose CBD, 942 cocaine, 940
violence, 182 Smoking, lead to increased total exposure of dependence
Sexually transmitted diseases, 183 THC, 30 pharmacotherapies, development
SF-36. See Short Form 36 Health Survey Smoking, synthetic cannabinoids, 445 of, 941
(SF-36) Smuggling, 122 dopamine level, increase in, 941
SF-36 health survey SNc. See Substantia nigra pars compacta euphoria, 941
results, 934 (SNc) methamphetamine, 940
SHADE. See Self-help for alcohol and other SNpr. See Substantia nigra pars reticulata Stimulus–response (S-R) association, 268
drug use and depression (SHADE) (SNpr) STN. See Subthalamic nucleus (STN)
Shapiro Tourette syndrome severity scale SNPs. See Single nucleotide polymorphisms Street drug, 869
(STSSS), 888 (SNPs) Streptozotocin (STZ), 780
 Index 1141
Stress, 62 Superoxide dismutase (SOD), 782 JWH-019, 984
brain response, 280 Surface enhanced Raman spectroscopy JWH-073, 984
DA-related mental illnesses, 279 (SERS), 1022 JWH-122, 984
drugs use disorders, 279 Survey of young people in Egypt (SYPE), 114 separation of, 984
evaluation, 280 Swallowers, 123 K2, 849
induction, 280 SWS. See Slow wave sleep (SWS) legal responses to, 56
and mental disorder, 279–280 Sympathetic nervous system (SNS), 279 legislation, 854
neuropsychiatric disorder, 279 Synaptic plasticity, 633 metabolite, 985
schizophrenia, 279 Synaptic potentiation, 635 nonclassical, 752
psychosis illnesses, 280 Synaptic stripping, 402 abnormal cannabidiol, 752
related HPA activity, 279 Synopsis of C. sativa sectional species, profile of users, 57
study, 280 subspecies, and varieties, 6 psychoactive effect
animal models, 280 Synthetic analogs, 593 calmness, 842
Stressful interviewing protocol, 280 Synthetic cannabinoids (SCBs), 54, e151, 173, euphoria, 842
Striatal damage 607, 632, 692, 751, 982 relaxation, 842
3-nitropropionic acid-induced, 924–926 aminoalkylindoles, 752, 982 reasons for usage, 54–56
quinolinic acid-induced, 926 WIN55212-2, 752 receptor agonist, 982
in vitro study, 926 behavioral effects, 693 recreational use, 986
STR locus, e7 anxiety, 692 replacement user, 58
Stroke, 489 confusion, 692 research chemicals, 985, 988
onset, 489 psychosis, 692 seized product, 988
Structural implications, cannabis use of, speech, 692 serum or blood analysis
153–155 blood concentration in suspected driver, quantitative method, 989
gray matter, 153 851–852 spice, 849
moderating factors, 155 brand names, 55 structure, 983
potential confounding, 155 cannabis-like effects, 849 summary of the four profiles, 56
white matter, 154 classical, 751 5th generation
STSSS. See Shapiro Tourette syndrome BW146Y, 751 APINACA, 982
severity scale (STSSS) HU-211, 751 5F-PB-22, 982
STZ. See Streptozotocin (STZ) nabilone, 751 UR-144, 982
Subcortical dementias, 833 clinical consequence, 842–844 timeline of major legal and media events in
Subjective effects, 823 clinical effects, 692 the United States, 56
Subjective norms, 218 hypertension, 692 tolerance, 853
Substance Abuse and Mental Health hyperventilation, 692 urine analysis
Services Administration mydriasis, 692 quantitative method, 992
(SAMHSA), 1051, 1078 nausea, 692 users, types, 54
guideline, 985 reddened conjunctivae, 692 Synthetic cathinones, e105, e151
Substance abuse and mental health services vomiting, 692 Synthetic Drug Abuse Prevention Act
administration (SAMHSA), e187 clinical presentation, of intoxication, 850 (2012), e153
Substance abuse prevention, 1078 concentration in biological media, 984
Substance-related problem, 317 consumption effect, typical performance T
Substance use deficit, 849 Tail-flick assay, 445
controlled, e169 demographics associated with, 57 TAs. See Traffic accidents (TAs)
harmful, e169 detection, analytical challenge, 853 TAU. See Treatment as usual (TAU)
nonproblematic, e169 discriminative stimulus effects, 696 Tau hyperphosphorylation, 830
problematic, e169 cross-tolerance, 697 Tauopathy, 831
risky, e169 tolerance, 697 Tautomerization, 676
Substance use disorder (SUD), 62, 873–874, driving skills, effect on, 853 TCAs. See Tricyclic antidepressants (TCAs)
e169, e170, 972, 1057, 1059, 1087 drug aficionado, 59 T2D. See Type 2 diabetes (T2D)
cognitive behavioral therapy, use of, 1058 drug testing, 845 TEAC. See Trolox equivalent antioxidant
marijuana, role of, 873 immunoassays, 845 capacity (TEAC)
role of early CU in CUD risk in context liquid chromatography-mass Telescoping effect, 132
of, 143 spectrometry, 845 Temporal perception, 185
self-monitoring, 1103 standard urine drug testing Tenax collection method, 1019
Substance use intervention, 1102 procedures, 845 Terpenophenolic, 3
Substance use problem, 1026 effects, 611 constituents, 14
Substance use treatment, 1028 of legislation, 841–842 Tesofensine, 650
Substantial problem, e154 safe driving, interfere with, 851 Testicular germ cell tumors
Substantia nigra pars compacta (SNc), 918 experimental user, 58 logistic regression model, e97
Substantia nigra pars reticulata (SNpr), frequently detected marijuana use and, e97
e144, 918 AM-2201, 850 multivariate adjustment, e97
Subthalamic nucleus (STN), 918 JWH-018, 850 nonseminoma, e97
Sudden infant death syndrome (SIDS), 530 habitual user, 59 pure seminoma, e97
Sulfamoyl benzamides, 598 herbal smoking blend, use as, 985 Test of memory malingering, 295
Suncus murinus, 953 isobaric compound Testosterone, 182
Superior longitudinal fasciculus (SLF), 347 JWH-015, 984 lowering medicaments (TLM), 965
1142 Index

Tetrahydrocannabinol (THC), e189, 299, Thyroid-stimulating hormone (TSH), 462 TSGS. See Tourette syndrome global
321, 415, 593, 763, 959, 1008, 1018, Thyroxin-binding-globulin (TGB), 463 scale (TSGS
1019, 1021, 1031, 1068, 1087. See also TIA. See Transient ischemic attack (TIA) TSH. See Thyroid-stimulating hormone (TSH)
∆9-Tetrahydrocannabinol (THC) Tiagabine, 775 TSLP. See Thymic stromal lymphopoietin
anxiety-like symptom, 304 Timeline follow-back (TLFB), 1088 (TSLP)
awakenings, effect on, 879 Titration of THC intake during smoking, 26 TTI. See Theory of triadic influence (TTI)
bicyclic analogs, 593 TLESRs. See Transient lower esophageal Tumor necrosis factor (TNF), 796
changes in concentrations in blood sphincter relaxations (TLESRs) Tumor-promoting effects, 500
samples, 27 TLFB. See Timeline follow-back (TLFB) Two-option experimental task, 293
chemical structures, 841 TLP. See Thaumatin-like proteins (TLP) nonwork option, 293
concentrations in biological samples, 27 TLR4-dependent pathway, 473 work option, 293
content in different plants varies according TM. See Trabecular meshwork (TM) Type 2 diabetes (T2D), 673
to a number of factors, 25 TNF. See Tumor necrosis factor (TNF) TZDs. See Thiazolidinediones (TZDs)
detection, gas chromatographic-mass Tobacco, 80
spectrometric method, use of, 1019 cigarette smoking, 495 U
drowsiness, effect on, 879 TOC. See α-Tocopherol (TOC) UC. See Ulcerative colitis (UC)
ocular delivery, 763 α-Tocopherol (TOC), e127 Ulcerative colitis (UC), 475, 932, 954
challenges, 763 Toll-like receptors (TLR), 403 Unambiguous structure elucidation
positive driver, 850 Tourette’s syndrome clinical global NMR, use of, 985
psychomimetic effect, 281 impression scale (GTS-CGI), 888 United Nations Office on Drugs and Crime
sleep efficiency, effect on, 879 Tourette syndrome, 833 (UNODC), 90, 107, 870, 982
sleep latency, effect on, 879 Tourette syndrome global scale (TSGS), 887 United States
sleep-wake cycle, effect on, 879 Tourette syndrome symptom list (TSSL), 888 past month cannabis use by age group, 40
standard substance, 1019 Towards No Drug Abuse (TND), 1081, 1082 past year cannabis use by age group, 39
treatment Trabecular meshwork (TM), 749 percentage of older adults using cannabis
vs. placebo Traffic accidents (TAs), 235 in past year, 41
STSSS score, changes in, 889 Global Status Report on Road Safety, United States Drug Enforcement Agency, 123
TS-CGI score, changes in, 890 report, 235 United States Food and Drug Administration
YGTSS score, changes in, 889 risk factors, 235 (FDA), e160
tricyclic analogs, 593 and synthetic cannabinoid, 852–853 Univariate logistic regression model, 975
∆9-Tetrahydrocannabinol (∆9-THC), e127, vehicular risk factors, 235 covariate
e132, e141 Trail making test, 1088 family/friendly/scholastic
Tetrahydrocannabinolic acid (THCA), e2, 7 Transcranial magnetic brain stimulation, 374 environments, 977
Tetrahydrocannabinolic acid synthase Transcription factor, 538 lifestyle and use of leisure time, 977
(THCAS), 15, 19 Transcriptomes, e5 self-opinion, 977
Tetrahydrocannabivarian (THC-V), 21, 104 Transient ischemic attack (TIA), 486, 487 UNODC. See United Nations Office on Drug
Tetrahydrocannabivarinic acid (THCVA), 21 Transient lower esophageal sphincter and Crime (UNODC)
Tetramethylcyclopropy, 598 relaxations (TLESRs), 953 Unprovoked seizure, 433
TGB. See Thyroxin-binding-globulin (TGB) Transient receptor potential cation channel Urinalysis assessments, e154
Thaumatin-like proteins (TLP), 521 (TRP), 406 Urinalysis testing, e151
THC. See ∆9-tetrahydrocannabinol (THC); Transient receptor potential cation channel Urine drug screening (UDS), 162
∆9-tetrahydro-cannabinol (THC) ubfamily V member 1 (TRPV1), e141 Urine sample analysis
THCA synthase (THCAS), e2, e4, e5 Transient receptor potential (TRP) enzyme-linked immunosorbent assays
activity, e6 channels, e137 (ELISA), use of, 988
THC carboxylic acid (THCCOOH), 1019, Transient receptor potential vanilloid type-1 homogeneous enzyme immunoassay
1021, 1022 (TRPV1) channels, 607, 612, 632 (HEIA), use of, 988
THC/CBD ratio, 25, 26 Transmembrane domains (TMs), 558 Users of new psychoactive substances
THC/CBD ratios, e58 Transporter inhibitors, 755 rates of cannabis use in, 175
THCCOOH. See THC carboxylic acid Treatment as usual (TAU), 1087, 1088 US National Survey on Drug Use and Health
(TH-COOH) Treatment attrition, 1095 (NSDUH) data, 39
THC-COOH. See 11-nor-9-carboxy- Treatment facility, contact with, 1089
delta 9-tetrahydrocannabinol T regulatory cells, 509 V
(THC-COOH) Triaryl derivatives, 600 Vagal nodose ganglia, 644
Theories and empirical support, e20 Triazolam, 771 Vagotomy, 643
Theories of synergism, 455 Trichomes, 3 Vagus nerve, 644
Theory of planned behavior, 218 Tricyclic antidepressants (TCAs), e161 role in ghrelin actions, 644
Theory of triadic influence (TTI), 1037 Tricyclic cores, 602 Valine (Val) allele, 418
Therapeutic alliance domain, e206 Trolox equivalent antioxidant capacity Val66Met BDNF gene polymorphism, 717
Therapeutic Goods Administration (TEAC), e127 Vanilloid-1 receptor (TRPV1), 878
(TGA), 106 TRP. See Transient receptor potential cation VAS. See Visual Analog Scale (VAS)
Thiazolidinediones (TZDs), 673 channel (TRP) Vascular imaging, 490
Thiazolylidene, 600 TRPV1 Vasoconstriction effect, 483
Thromboxane, 512, 731 TRPV1 channels. See Transient receptor Venlafaxine, 943, 1033, 1071
Thymic stromal lymphopoietin (TSLP), 546 potential vanilloid type-1 (TRPV1) Ventral tegmental area (VTA), 534
Thyroid function tests, 463 channels Ventricular alterations, e54
 Index 1143
Verbal learning, 74 WAT. See White adipose tissue (WAT) Y
VGCCs. See Voltage-gated calcium channels Weight-loss drugs, 650 Yale global tic severity scale (YGTSS), 888
(VGCCs) White adipose tissue (WAT), 651 Y chromosome, e4
Videobronchoscopy, 498 White House Office of National Drug Control Years lived with disability (YLDs), 90
Visceral cancer pain, 441 Policy, 869 Years lost due to premature mortality
Visceral hypersensitivity, 441 White matter, 154 (YLLs), 90
Visceral pain, 441 WHO. See World Health Organization YGTSS. See Yale global tic severity scale
anatomic and functional features of, 442 (WHO) (YGTSS)
cannabinoids, 441 WIN55, 212-2 YMRS. See Young mania rating scale (YMRS)
Visual acuity, 122 induced gastric emptying delay, 951 Young age at CU onset and its association
Visual analog scale (VAS), 773 neuroprotective effect, 920 with CUD risk, 139
Visual reaction time, 71 repeated administration in rat, effect of, 951 empirical evidence, 139
Visuomotor tracking, 373 in vivo effect in rat, 950 epidemiological studies on earlier onset of
Visuospatial memory, 152 Wisconsin Card Sorting Test (WCST), e54 CU in CUD risk, 141
Voltage-gated calcium channels Wistar audiogenic rats (WAR), 608 important methodological aspects
(VGCCs), 1033 Wistar rats, e145, 666 of studies on early onset of substance use
Voxel-based morphometry (VBM), e55 Withdrawal symptom and substance use disorder risk, 143
VTA. See Ventral tegmental area (VTA) newly abstinent drug user, 321 methodological considerations, 139
Vulnerability WM. See Working memory possible explanations
general heritable, for disinhibitory Working memory, 46, 47, 49, e67, 71, for association between a younger age at
behavior and psychopathology, 146 155–157 first CU and CUD risk, 140
as a phase of vulnerability for addiction, in World Health Organization (WHO), 92, 113, Young mania rating scale (YMRS), 792
adolescence, 143 e171, 860, 1008 Youth cultures, e12
for THC effects in adolescence, 144 traffic accidents estimate, 235 Youth interventions foundation, 1051

W X Z
Walk-and-turn (WAT) test, 851 X chromosome, e4 ZNF804A gene, 347
WAR. See Wistar audiogenic rats (WAR) Xerostomia, e73 Zolpidem, 1032
Warrant treatment, 1027 X-ray structure, of active center THCAS, 21 Zornia latifolia, 840
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