Neuroscience of psychoactive substance use and dependence
Neuroscience of
psychoactive substance use
and dependence
WORLD HEALTH ORGANIZATION GENEVA
WHO Library Cataloguing-in-Publication Data
Neuroscience of psychoactive substance use and dependence. 1 . Psychotropic drugs - pharmacology
2 . Substance-related disorders - physiopathology
3 . Psychopharmacology 4 . Brain - drug effects I. World Health Organization.
ISBN 9 2 4 1 5 6 2 3 5 8 (LC/ NLM classification: WM 2 7 0 )
© World Health Organization 2 0 0 4
All rights reserved. Publications of the World Health Organization can be obtained from Marketing and Dissemination, World Health Organization, 2 0 Avenue Appia, 1 2 1 1 Geneva 2 7 , Switzerland (tel: + 4 1 2 2 7 9 1 2 4 7 6 ; fax: + 4 1 2 2 7 9 1 4 8 5 7 ; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to Publications, at the above address (fax: + 4 1 2 2 7 9 1 4 8 0 6 ; email: permissions@who.int).
The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of
a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
Text design by minimum graphics Cover design by Tushita Graphic Vision
Printed in Switzerland
Contents
Foreword ix Acknowledgements
xi List of background papers and contributors
xv Abbreviations
xvii
Chapter 1 . Introduction 1
Structure of the report 1 Psychoactive substances and their sociolegal status
1 Global use of psychoactive substances
4 Tobacco
4 Alcohol
5 Illicit use of controlled substances
9 Adverse effects of psychoactive substances and their mechanisms of action
10 Substance dependence in relation to neuroscience
12 The burden of harm to health from psychoactive substance use
Chapter 2 . Brain Mechanisms: Neurobiology and Neuroanatomy 19
Introduction 19 Organization of the brain
19 The neuron
25 Cell body
26 Dendrites
26 Axon
28 Terminal buttons
28 Neurotransmission
29 Action potential
29 Neurotransmitter release
33 γ -aminobutyric acid
33 Glutamate
33 Dopamine
34 Norepinephrine
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
Serotonin 35 Peptides
35 Genes
35 Cellular and neuronal effects of psychoactive substances
36 Cellular effects
36 Neuronal effects
38 Conclusion
Chapter 3 . Biobehavioural Processes Underlying Dependence 43
Introduction 43 Defining terms
44 Classical or Pavlovian conditioning
44 Instrumental or operant conditioning
48 Incentive-motivational responding
48 Drug reward alone does not explain drug dependence
48 Drug dependence as a response to incentive-motivation
49 Drug dependence as a response to drug withdrawal
50 Dopamine and reinforcement learning
50 Dependence-producing drugs as surrogates of conventional reinforcers
51 Dopamine and incentive sensitization
52 Psychomotor sensitization
53 Sensitization and drug reward
53 Sensitization and tolerance
54 Individual differences
55 Summary
Chapter 4 . Psychopharmacology of Dependence for Different Drug Classes
Introduction 67 Alcohol (ethanol)
69 Introduction
69 Behavioural effects
69 Mechanism of action
70 Tolerance and withdrawal
70 Neurobiological adaptations to prolonged use
72 Pharmacological treatment of alcohol dependence
72 Sedatives and hypnotics
73 Introduction
73 Behavioural effects
73 Mechanism of action
CONTENTS
Tolerance and withdrawal 74 Neurobiological adaptations to prolonged use
75 Tobacco
75 Introduction
75 Behavioural effects
75 Mechanism of action
76 Tolerance and withdrawal
77 Pharmacological treatment of nicotine dependence
78 Opioids
79 Introduction
79 Behavioural effects
79 Mechanism of action
80 Tolerance and withdrawal
80 Neurobiological adaptations to prolonged use
81 Pharmacological treatment of opioid dependence
81 Cannabinoids
84 Introduction
84 Behavioural effects
85 Mechanism of action
86 Tolerance and withdrawal
87 Neurobiological adaptations to prolonged use
88 Cocaine (hydrochloride and crack)
89 Introduction
89 Behavioural effects
89 Mechanism of action
89 Tolerance and withdrawal
91 Neurobiological adaptations to prolonged use
91 Pharmacological treatment of cocaine dependence
92 Amphetamines
93 Introduction
93 Behavioural effects
94 Mechanism of action
95 Tolerance and withdrawal
95 Neurobiological adaptations to prolonged use
96 Ecstasy
96 Introduction
96 Behavioural effects
99 Mechanism of action
99 Tolerance and withdrawal
100 Neurobiological adaptations to prolonged use
100 Volatile solvents
100 Introduction
100 Behavioural effects
101 Mechanism of action
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
Tolerance and withdrawal 103 Neurobiological adaptations to prolonged use
103 Hallucinogens
104 Introduction
104 Behavioural effects
105 Mechanism of action
105 Tolerance and withdrawal
105 Neurobiological adaptations to prolonged use
106 Summary
Chapter 5 . Genetic Basis of Substance Dependence 125
Introduction 125 Family, twin and adoption studies: estimations of heritability
127 Identifying chromosomal locations of interest: linkage studies
127 Candidate gene approach
128 Animal studies
128 Genetics of tobacco dependence
130 Heritability of tobacco dependence
130 Tobacco dependence and linkage studies
131 Candidate genes for tobacco dependence
131 Genetics of alcohol dependence
132 Heritability of alcohol dependence
132 Alcohol dependence and linkage studies
133 Candidate genes for alcohol dependence
134 Genetics of opioid dependence
136 Heritability of opioid dependence
136 Opioid dependence and linkage studies
136 Candidate genes for opioid dependence
136 Genetics of the combined risk of dependence on tobacco, alcohol, opioids and other psychoactive substances
138 Heritability of substance dependence
138 Linkage studies of substance dependence
139 Candidate genes involved in substance dependence
140 Confounding issues in linkage and candidate gene studies
147 Environment
147 Genetice heterogeneity
147 Phenotype
148 Comorbidity
148 Methodological issues
148 Future directions
149 Social and cultural aspects
150 Summary
Risk factors and protective factors for dependence: an overview
CONTENTS
Chapter 6 . Concurrent Disorders 169
Introduction 169 Hypotheses that may explain the observed comorbidity
170 Schizophrenia
171 Tobacco smoking and schizophrenia
171 Psychostimulant (cocaine and amphetamine) dependence and schizophrenia
174 Alcohol use and schizophrenia
Neurobiological interactions between schizophrenia and the effects
of psychoactive substances 176 Depression
180 Tobacco smoking and depression
181 Psychostimulant dependence and depression
182 Alcohol use and depression
Neurobiological interactions between depression and the effects
of psychoactive substances 184 Discussion and conclusions
Chapter 7 . Ethical Issues in Neuroscience Research on Substance Dependence Treatment and Prevention
Introduction 209 Types of research on neuroscience of substance dependence
209 Animal experiments
209 Epidemiological research on substance dependence
209 Experimental studies in humans
210 Clinical trials of pharmacotherapy for substance dependence
210 Trials of pharmacotherapies to prevent substance dependence
211 Approach to ethical analysis
211 Principles of biomedical ethics
216 Human rights
217 Ethics of animal experimentation in neuroscience research
218 Ethical principles in human biomedical research
219 Independent ethical review of risks and benefits
219 Informed consent
220 Recruitment of subjects
220 Privacy and confidentiality
221 Emerging ethical issues in neuroscience research
222 Research on vulnerable persons
222 Are substance dependent people vulnerable persons?
223 Provocation studies
223 Ethical issues in epidemiological research on substance dependence
224 Ethical issues in clinical trials of pharmacological treatments for substance dependence
225 Trial design
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
Distributive justice 226 Conflicts of interest
226 Trials of preventive pharmacological interventions for substance dependence
227 Early intervention studies
227 Preventive use of drug immunotherapies
229 Implications of neuroscience research for models of substance dependence
231 Implications of neuroscience research for the treatment of substance dependence
232 Access to treatment
232 Legally coerced treatment
232 Summary and conclusions
Chapter 8 . Conclusion and Implications for Public Health Policy 241
Introduction 241 Advances in the neuroscience of psychoactive substance use and dependence and their implications
241 Potential advances in policy, prevention and treatment
243 Ethical issues in the application of neuroscience findings
244 Implications for public health policy
247 Conclusion
Index 251
Foreword
Substan ce use an d dep en den ce cause a sign ifican t burden to in dividuals an d societies th rou gh ou t th e world. Th e World Health Rep ort 2002 in dicated th at 8.9% of th e total b u rd en of d isease com es from th e u se of p sych oactive su bstan ces. Th e rep ort sh owed th at tobacco accou n ted for 4.1%, alcoh ol 4%, an d illicit dru gs 0.8% of th e bu rden of disease in 2000. Mu ch of th e bu rden attribu table to su bstan ce u se an d dep en den ce is th e resu lt of a wide variety of h ealth an d social p roblem s, in clu din g HIV/ AIDS, wh ich is driven in m an y cou n tries by in jectin g dru g u se.
Th is n eu ro scien ce rep o rt is th e first a ttem p t b y WH O to p rovid e a com p reh en sive overview of th e biological factors related to su bstan ce u se an d dep en den ce by su m m arizin g th e vast am ou n t of kn owledge gain ed in th e last 20-30 years. Th e rep ort h igh ligh ts th e cu rren t state of kn owledge of th e m ech an ism s of action of differen t typ es of p sych oactive su bstan ces, an d exp lain s h ow th e u se of th ese su bstan ces can lead to th e develop m en t of dep en den ce syn drom e.
Th o u gh th e fo cu s is o n b ra in m ech a n ism s, th e rep o rt n everth eless addresses th e social an d en viron m en tal factors wh ich in flu en ce su bstan ce use an d dep en den ce. It also deals with n euroscien ce asp ects of in terven tion s an d, in p articu lar, th e eth ical im p lication s of n ew biological in terven tion strategies.
Th e va rio u s h ea lth a n d so cia l p ro b lem s a sso cia ted with u se o f a n d
d ep en d en ce on tob a cco, a lcoh ol a n d illicit su b sta n ces req u ire grea ter atten tion by th e p u blic h ealth com m u n ity an d ap p rop riate p olicy resp on ses are n eeded to address these problem s in differen t societies. Man y gaps rem ain to be filled in ou r u n derstan din g of th e issu es related to su bstan ce u se an d dep en den ce bu t th is rep ort sh ows th at we already kn ow a great deal abou t th e n atu re of th ese p roblem s th at can be u sed to sh ap e p olicy resp on ses.
This is an im portan t report an d I recom m en d it to a wide audien ce of health care p rofession als, p olicy m akers, scien tists an d stu den ts.
LEE Jon g-wook Director Gen eral World Health Organ ization
Acknowledgem ents
The World Health Organ ization ackn owledges with than ks the m an y authors, reviewers, con su ltan ts an d WHO staff m em bers wh ose exp ertise m ade th is rep ort p ossible. Fran co Vaccarin o of th e Cen tre for Addiction an d Men tal Health an d th e Un iversity of Toron to, Toron to, Can ada, was th e p rin cip al editor for th e rep ort, with th e assistan ce of Su san Rotzin ger from th e Cen tre for Addiction an d Men tal Health . Th e op en in g an d closin g ch ap ters were written by Robin Room of th e Cen tre for Social Research on Alcoh ol an d Drugs, Un iversity of Stockholm , Stockholm , Sweden , with con tribution s from Isidore Obot an d Maristela Mon teiro of th e Dep artm en t of Men tal Health an d Su bstan ce Abu se, WHO.
Sp ecia l a ckn owled gem en t is m a d e to th e followin g in d ivid u a ls wh o con tribu ted reviews th at form ed th e basis for th e fin al rep ort: Helen a M. T. Barros, Federal Un iversity of Medical Scien ces Fou n dation , Porto Alegre, Brazil; Lucy Carter, In stitute for Molecular Bioscien ce, Un iversity of Qu een slan d, St Lu cia, Qu een slan d, Au stralia; David Collier, Section of Gen etics, In stitu te of Psych iatry, Lon d on , En glan d ; Gaetan o Di Ch iara, Dep artm en t of Toxicology, Un iversity of Cagliari, Cagliari, Italy; Patricia Erickson , Cen tre for Addiction an d Men tal Health , Toron to, On tario, Can ada; Sofia Gru skin , Dep artm en t of Pop u lation an d In tern ation al Health , Harvard Un iversity Sch ool of Pu blic Health , Boston , MA, USA; Wayn e Hall, In stitu te for Molecu lar Bioscien ce, Un iversity of Qu een slan d, St Lu cia, Qu een slan d, Au stralia; Jack Hen n in gfield, Joh n s Hop kin s Un iversity Sch ool of Medicin e, an d Pin n ey Associates, Bethesda, MD, USA; Kathleen M. Kan tak, Departm en t of Psych ology, Boston Un iversity, Boston , MA, USA; Brigitte Kieffer, Ecole Su p é rie u re d e Bio te ch n o lo gie d e Stra sb o u rg, Illkirch , Fra n ce ; Ha ra ld Klin gem an n , Sch ool of Social Work, Un iversity of Ap p lied Scien ces, Bern e, Switzerlan d ; Mary Jean n e Kreek, Lab oratory of th e Biology of Ad d ictive Diseases, Rockefeller Un iversity, New York, NY, USA; Sture Liljequist, Division of Dru g Dep en d en ce Research , Karolin ska In stitu te, Stockh olm , Swed en ; Ra fa el Ma ld o n a d o, La b o ra to ry o f Neu ro p h a rm a co lo gy, Po m p eu Fa b re Un iversity, Barcelon a, Sp ain ; Ath in a Markou , Scrip p s Research In stitu te, La Jolla, CA, USA; Gin a Morato, Fed eral Un iversity of San ta Catarin a, San ta Ca ta rin a , Bra zil; Ka th erin e Morley, In stitu te for Molecu la r Bioscien ce, Un iversity of Qu een slan d, St Lu cia, Qu een slan d, Au stralia; Karen Plafker, Dep artm en t of Pop u lation an d In tern ation al Health , Harvard Un iversity
NEUROSCIENCE OF PSYCHOACTVE SUBSTANCE USE AND DEPENDENCE
Sch ool of Pu blic Health , Boston , MA, USA; An drey Ryabin in , Oregon Health Scie n ce Un ive rsity, Po rtla n d , OR, USA; Alliso n Sm ith , De p a rtm e n t o f Pop u lation an d In tern ation al Health , Harvard Un iversity Sch ool of Pu blic Health , Boston , MA, USA; Rach el Tyn dale, Dep artm en t of Ph arm acology, Un ive rsit y o f To ro n t o, To ro n t o, On t a r io, Ca n a d a ; Cla u d e U e h lin ge r, Psych osocial Cen tre of Fribou rg, Fribou rg, Switzerlan d; Fran co Vaccarin o, Cen tre for Addiction an d Men tal Health , Toron to, On tario, Can ada; Fran k Vocci, Nation al In stitu te on Dru g Abu se, Beth esda, MD, USA; David Walsh , Nation al In stitu te on Media an d th e Fam ily, Min n eap olis, MN, USA.
Th an ks are also d u e to th e in tern ation al scien tific organ ization s th at p rovided docu m en ts reflectin g th eir views on research on an d treatm en t of su bstan ce dep en den ce. Notable am on g th ese are th e College on Problem s of Dru g Dep en d en ce (CPDD) a n d th e In tern a tio n a l So ciety o f Ad d ictio n Medicin e (ISAM).
Man y in dividu als p articip ated in th e variou s con su ltation s h eld to discu ss th e p roject. Th e first su ch con su ltation wh ich took p lace in New Orlean s, LA, USA, in 2000 was atten d ed by exp erts rep resen tin g several in tern ation al organ ization s, in clu din g th e CPDD, th e In tern ation al Society for Biom edical Research on Alcoh olism (ISBRA), th e Nation al In stitu te on Dru g Ab u se (NIDA), th e Nation al In stitu te of Men tal Health (NIMH) an d som e key scien tists in th e field (see list below). Th e secon d con su ltation was h eld in Mexico in Jun e 2002 durin g which a draft rep ort was p resen ted an d discussed exten sively. Th an ks are du e to th e followin g for th eir variou s con tribu tion s to th e rep ort:
Hector Velasq u ez Ayala, Facu lty of Psych ology, Un iversid ad Nacion al Au ton om a de Mexico, Mexico City, Mexico; Floyd Bloom , Scrip p s Research In st it u t e, La Jo lla , CA, U SA; De n n is Ch o i, De p a rt m e n t o f Ne u ro lo gy, Wash in gton Un iversity Sch ool of Medicin e, St Lou is, MO, USA; Patricia Di Cia n o, Un ive rsit y o f Ca m b rid ge, Ca m b rid ge, En gla n d ; Lin d a Co t t le r, Dep artm en t of Psych iatry, Wash in gton Un iversity, St. Lou is, MO, USA; Nady El-Gu eb aly, Facu lty of Med icin e, Un iversity of Calgary, Calgary, Alb erta, Can ada; Hu m berto Estan ol, Nation al Cou n cil Again st Addiction s of Mexico, Mexico City, Mexico; Ham id Gh odse, St. George’s Hosp ital Medical Sch ool, Lon don , UK; Steven Hym an , Nation al In stitu te of Men tal Health , Beth esda, MD, USA; Mark Jord an , Nyon , Switzerlan d ; Hu m b erto Ju arez, Nation al Cou n cil Again st Addiction s of Mexico, Mexico City, Mexico; Mich ael Ku h ar, Division of Ph arm acology, Em ory Un iversity, Atlan ta, GA, USA; Stan Ku tch er, Can adian In stitu tes of Health Research , Ottawa, On tario, Can ada; Mich el Le Moal, Nation al In stitu te of Health an d Medical Research , Bordeau x, Fran ce; Scott MacDon ald, Cen tre for Addiction an d Men tal Health , Toron to, On tario, Can ada; Gu illerm in a Natera, Nation al In stitu te of Psych iatry, Mexico City, Mexico; Ralu ca Pop ovici, Pin n ey Associates, Beth esd a, MD, USA; Lin d a Porrin o, Wake Forest Un iversity School of Medicin e, NC, Win ston -Salem , USA; David Roberts, Wake Forest Un iversity Sch ool of Medicin e, NC, Win ston - Salem , USA; Robin Room , Cen tre for Social Research on Alcoh ol an d Dru gs,
ACKNOWLEDGEMENTS
Un iversity of Stockh olm , Stockh olm , Swed en ; Ch ristin e A. Rose, Pin n ey Associates, Bethesda, MD, USA; Martin Stafstrom , Malm o Un iversity Hospital, Lu n d Un iversity, Lu n d, Sweden ; Ju lie Staley, Dep artm en t of Psych iarty, Yale Un ive rsit y Sch o o l o f Me d icin e, Ne w Ha ve n , CT, U SA; Howa rd St e a d , Laboratory an d Scien tific Section , Un ited Nation s Office on Drugs an d Crim e, Vien n a, Au stria; Boris Tabakoff, Un iversity of Colorado Sch ool of Medicin e, Boulder, CO, USA; Am bros Uchten hagen , In stitute for Research on Addiction , Zu rich , Switzerla n d ; Geo rge Uh l, Jo h n s Ho p kin s Un iversity Sch o o l o f Me d ic in e, Ba lt im o re , M D, U SA; No ra Vo lkow, Bro o kh a ve n Na t io n a l Laboratory, New York, NY, USA; Helge Waal, Oslo, Norway; Roy Wise, Nation al In stitu te on Dru g Abu se, Beth esda, MD, USA. WHO is also gratefu l to Victor Preed y, Kin g’s College, Un iversity of Lon d on , Lon d on , wh o p rovid ed a tech n ical review of th e fin al draft of th e docu m en t.
Gra t e fu l t h a n ks a re d u e t o t h e U .K. De p a rt m e n t fo r In t e r n a t io n a l De ve lo p m e n t (DFID), t h e Be lgia n Gove r n m e n t , a n d t h e In st it u t e o f Neuroscien ces, Men tal Health an d Addiction of the Can adian In stitutes of Health Research for their fin an cial con tribution s to the project.
Th e p roject leadin g to th is rep ort was in itiated by Maristela Mon teiro, wh o also directed all activities related to its p rep aration , review an d p u blication . Isidore Obot coordin ated th e editin g an d p rodu ction of th e rep ort. Particu lar th a n ks a re d u e to Derek Ya ch a n d Ben ed etto Sa ra cen o wh o p rovid ed lead ersh ip for th e p roject an d con trib u ted com m en ts on variou s d rafts. Than ks are also due to th e followin g staff of the Dep artm en t of Men tal Health an d Substan ce Abuse for their con tribution s to the project: Vladim ir Pozn yak, José Bertolote, an d Shekhar Saxen a. The report also ben efited from the in puts of th e followin g form er an d cu rren t WHO staff wh o assisted in d ifferen t cap acities: Carolin e Allsop p, Alexan der Cap ron , Joan n Du ffil, Kelvin Kh ow, Tess Narciso, Mylen e Sch reiber, Raqu el Sh aw Moxam , an d Toku o Yosh ida.
Th is report h as been produ ced w ith in th e fram ew ork of th e m en tal h ealth Global Action Program m e (m h GAP) of th e Departm en t of Men tal Health an d Su b st a n ce Ab u se, W orld Hea lt h Orga n iz a t ion , u n d er t h e d irect ion of Dr Ben edetto Saracen o.
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
List of Background Papers and Contributors
Helena M. T. Barros , Th e basic p sych op h arm acology of th e addictive su bstan ces. David A Collier , Th e gen etics of h eroin abu se. Michael J. Kuhar , Views of the College on Problem s of Drug Depen den ce regardin g
advan ces in research on dru g abu se. Gaetano Di Chiara , Psych obiology of dru g addiction . Patricia G Erickson , Resp on din g to su bstan ce dep en den ce from an in tegrated
p u blic h ealth p ersp ective. Wayne Hall and Lucy Carter , Eth ical issu es in trialin g an d u sin g cocain e vaccin es
to treat an d p reven t cocain e dep en den ce. Wayne Hall, Lucy Carter and Katherine Morley , Eth ical issu es in n eu roscien ce
research on addiction . Sofia Gruskin, Karen Plafker & Allison Sm ith , A h u m an righ ts fram ework for
p reven tin g p sych oactive su bstan ce u se by you th , in th e con text of u rban ization . Jack E Henningfield , Neu robiology of tobacco dep en den ce. Nady El-Gue baly , Views of th e In tern ation al Society of Ad d iction Med icin e
(ISAM). Kathleen M. Kantak , Pre-clin ical an d clin ical stu dies with th e cocain e vaccin e. Brigitte L. Kieffer , Neu ral basis of addictive beh aviou rs: role of th e en dogen ou s
op ioid system . Harald Klingem ann , Cu ltu ral an d social asp ects of dru g dep en den ce. Mary Jeanne Kreek , Th e efficacy of m eth adon e an d levom eth adyl acetate. Sture Liljequist , The n eurochem ical basis of cravin g an d abstin en ce to substan ce
abu se. Rafae l Maldo n ado , Recen t a d va n ces in th e n eu ro b io lo gy o f ca n n a b in o id
dep en den ce. Athina Markou , Com orbidity of dru g abu se with m en tal illn ess p rovides in sigh ts
in to th e n eu rob iological ab n orm alities th at m ay m ed iate th ese p sych iatric disorders.
Gina Morato , Biological basis for eth an ol toleran ce in an im als an d im p lication s for eth an ol dep en den ce.
An d re y E. Rya b i n i n , Ge n e t ic s a n d n e u ro s c ie n c e o f a lc o h o l a b u s e a n d dep en den ce: con tribu tion s from an im al m odels
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
Rachel Tyndale , Gen etics of alcoh ol an d tobacco u se in h u m an s. Claude Uehlinger , Motivation au x ch an gem en ts de com p ortem en ts addictifs. Frank J. Vocci , Bu p ren orp h in e as a treatm en t for op iate dep en den ce. David Walsh , Slip p in g u n der th e radar: advertisin g an d th e m in d.
Abbreviations
2-DG 2-deoxyglu cose ADH
alcoh ol deh ydrogen ase ADHD
atten tion deficit h yp eractivity disorder
AIDS
Acqu ired Im m u n odeficien cy Syn drom e
ALDH2 aldeh yde deh ydrogen ase AMPA
α -am in o3-h ydroxy-5-m eth yl-isoxazole-4-p rop ion ate ASPD
an tisocial p erson ality disorder ATS
am p h etam in e-typ e stim u lan ts cAMP
cyclic aden osin e m on op h osp h ate CCK
ch olecystokin in COMT
catech ol-O-m eth yltran sferase CRA
com p arative risk an alysis CREB
cAMP resp on se elem en t bin din g p rotein
CRF corticotrop in -releasin g factor (CRF) CYP26
Cytoch rom e P-450 RA1 CYP2D6
Cytoch rom e P-450 2D6 CYP2E1
Cytoch rom e P-450 2E1 DALY
disability-adju sted life years DBH
dop am in e beta h ydroxylase DMT
dim eth yltryp tam in e DNA
deoxyribon u cleic acid DOM
dim eth oxy-4-m eth ylam p h etam in e DRD1
dop am in e recep tor D1 DRD3
dop am in e recep tor D3 DRD4
dop am in e recep tor D4 DRD5
dop am in e recep tor D5 DSM-IV
Diagn ostic an d Statistical Man u al of Men tal Disorders- Fou rth Edition
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
EMCDDA Eu rop ean Mon itorin g Cen tre for Dru gs an d Dru g Addiction ESPAD
Eu rop ean Sch ool Su rvey Project on Alcoh ol an d Oth er Dru gs EEG
electroen cep h alograp h y FDA
Un ited States Food an d Dru g Adm in istration FDG
flu orodeoxyglu cose fMRI
fu n ction al m agn etic reson an ce im agin g GABA
γ -am in obu tyric acid GBD
Global Bu rden of Disease HIV
Hu m an Im m u n odeficien cy Viru s ICD-10
Ten th Revision of th e In tern ation al Statistical Classification of Diseases an d Related Health Problem s
IDU in jectin g dru g u se LAAM
Levo-alp h a-acetyl-m eth adol LSA
d-lysergic acid am in e LSD
lysergic acid dieth ylam ide MAO
m on oam in e oxidase MAOI
m on oam in e oxidase in h ibitor MDA
m eth ylen edioxyam p h etam in e MDMA
3,4-m eth ylen edioxym eth am p h etam in e MET
m otivation al en h an cem en t th erapy MRI
m agn etic reson an ce im agin g m RNA
m essen ger ribon u cleic acid n ACh R
n icotin ic acetylch olin e recep tor NHSDA
Nation al Hou seh old Su rvey on Dru g Abu se NIDA
Nation al In stitu te on Dru g Abu se NMDA
N-m eth yl-D-asp artate NPY
n eu rop ep tide Y PCP
p h en cyclidin e PET
p ositron em ission tom ograp h y PMA
p aram eth oxyam p h etam in e QTL
qu an titative trait loci SACENDU
Sou th African Com m u n ity Ep idem iology Network on Dru g Use SPECT
sin gle p h oton em ission com p u ted tom ograp h y
SSRI seroton in selective reu p take in h ibitors SUD
su bstan ce u se disorders
ABBREVIATIONS
TH tyrosin e h ydroxylase THC
tetrah ydrocan n abin ol TMA
trim eth oxyam p h etam in e TPH
tryp top h an h ydroxylase UDHR
Un iversal Declaration of Hu m an Righ ts UNDCP
Un ited Nation s In tern ation al Dru g Con trol Program m e UNODC
Un ited Nation s Office on Dru gs an d Crim e UNODCCP Un ited Nation s Office for Dru g Con trol an d Crim e Preven tion USDHHS
Un ited States Dep artm en t of Health an d Hu m an Services VTA
ven tral tegm en tal area WHO
World Health Organ ization WMA
World Medical Association
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
1 . INTRODUCTION
CHAPTER 1
Introduction
Th is rep ort d escrib es ou r cu rren t u n d erstan d in g of th e n eu roscien ce of psychoactive substan ce use an d depen den ce. It draws on the explosive growth in kn owled ge in th is area in recen t d ecad es, wh ich h as tran sform ed ou r u n derstan din g of th e bioch em ical action of p sych oactive su bstan ces, an d con tribu ted n ew in sigh ts in to wh y m an y p eop le u se th em , an d wh y som e u se th em to th e exten t of cau sin g h arm or of becom in g dep en den t on th em .
Structure of the report
The report is divided in to eight chapters. The presen t in troductory chapter is in ten ded to provide the con text an d backgroun d for the report. Chapter 2 p rovid e s a b r ie f ove r vie w o f b a sic n e u ro a n a t o m y, n e u ro b io lo gy a n d n eurochem istry. Chapter 3 presen ts the “biobehavioural” view of depen den ce, which is based on both learn in g theory an d kn owledge of the brain’s fun ction s. Chapter 4 discusses the pharm acology an d behavioural effects of differen t classes of p sych oactive su b stan ces, a b ran ch of scien ce also kn own as psychopharm acology. In Chapters 2–4 we con sider n eurobiological processes wh ich are to a large exten t th e com m on h eritage of all h u m an bein gs. In Ch a p t e r 5, we t u r n t o ge n e t ic st u d ie s, wh ich fo cu s in st e a d o n t h e differen tiation s that m ay exist between hum an s in their gen etic heritage. The
ch a p ter reviews th e evid en ce fo r a gen etic co n trib u tio n to su b sta n ce depen den ce, an d com pares the in teraction of gen etics an d en viron m en tal factors in th e d evelop m en t an d m ain ten an ce of d ep en d en ce. Ch ap ter 6 con siders the n euroscien tific eviden ce on specific in tercon n ection s between substan ce use an d m en tal disorders, focusin g particularly on schizophren ia an d depression . The fram e of referen ce chan ges again in Chapter 7, which is con cern ed with eth ical issu es in research , treatm en t an d p reven tion of su bstan ce u se disorders, an d in p articu lar h ow th ese issu es m ay ap p ly to n euroscien tific research an d its application s. Chapter 8 deals with the public
h e a lth im p lica tio n s o f n e u ro scie n ce re se a rch a n d e n d s with sp e cific recom m en dation s for policy.
Psychoactive substances and their sociolegal status
Psych oactive su bstan ces, m ore com m on ly kn own as p sych oactive dru gs, are su b stan ces th at, wh en taken , h ave th e ab ility to ch an ge an in d ivid u al’s
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
con sciou sn ess, m ood or th in kin g p rocesses. As later ch ap ters will exp lain , advan ces in n eu roscien ce h ave given u s a m u ch better u n derstan din g of th e p h ysical p rocesses by wh ich th ese su bstan ces act. Psych oactive su bstan ces act in th e brain on m ech an ism s th at exist n orm ally to regu late th e fu n ction s of m ood, th ou gh ts, an d m otivation s. In th is rep ort, ou r em p h asis will be on alcoh ol an d oth er h yp n otics an d sed atives, n icotin e, op ioid s, can n ab is,
c o c a in e , a m p h e t a m in e s a n d o t h e r st im u la n t s, h a llu c in o ge n s, a n d p sych oactive in h alan ts. Use of th ese su bstan ces is defin ed in to th ree categories accordin g to th eir sociolegal statu s. First, m an y of th e su bstan ces are u sed as m edication s. Western an d oth er system s of m edicin e h ave lon g recogn ized th e u sefu ln ess of th ese su bstan ces as m edication s in relievin g p ain , p rom otin g eith er sleep or wakefu ln ess, an d relievin g m ood disorders. Cu rren tly, m ost p sych oactive m e d ica t io n s a re re st rict e d t o u se u n d e r a d o ct o r’s o rd e rs, t h ro u gh a p re scr ip t io n syst e m . In m a n y co u n t rie s, a s m u ch a s o n e -t h ird o f a ll p rescrip tion s written are for su ch m edication s. An exam p le of th is is th e u se o f th e stim u la n t m eth ylp h en id a te to trea t ch ild h o o d a tten tio n d eficit
h yp eractivity d isord er (ADHD), wh ich will b e d iscu ssed in Ch ap ter 4. As described in Ch ap ter 6, som e of th e su bstan ces are also often u sed as “self- m ed ication s” to relieve d istress from m en tal or p h ysical d isord ers, or to alleviate th e side-effects of oth er m edication s.
A secon d category of u se is illegal, or illicit, u se. Un der th ree in tern ation al con ven tion s (see Box 1.1), m ost n ation s h ave bou n d th em selves to ou tlaw trade in an d n on -m edical u se of op iates, can n abis, h allu cin ogen s, cocain e an d m an y oth er stim u lan ts, an d m an y h yp n otics an d sedatives. In addition to th is list, cou n tries or local ju risdiction s often add th eir own p roh ibited su bstan ces, e.g. alcoh olic beverages an d variou s in h alan ts.
Desp ite th ese p roh ibition s, illicit u se of p sych oactive su bstan ces is fairly widesp read in m an y societies, p articu larly am on g you n g adu lts, th e u su al p u rp ose bein g to en joy or ben efit from th e p sych oactive p rop erties of th e su bstan ce. Th e fact th at it is illegal m ay also add an attractive frisson , an d th u s stren gth en th e iden tification of u sers with an alien ated su bcu ltu re.
Th e th ird category of u se is legal, or licit, con su m p tion , for wh atever p u rp ose th e con su m er ch ooses. Th ese p u rp oses m ay be qu ite varied, an d are n ot n ecessarily con n ected with th e p sych oactive p rop erties of th e su bstan ce. For in stan ce, an alcoh olic beverage can be a sou rce of n u trition , of h eatin g or coolin g th e b od y, or of th irst-qu en ch in g; or it m ay serve a sym bolic purpose in a roun d of toastin g or as a sacram en t. However, whatever th e p u rp ose of u se, th e p sych oactive p rop erties of th e su bstan ce in evitably accom p an y its u se.
Th e m ost widely u sed p sych oactive su bstan ces are th e followin g: caffein e an d related stim u lan ts, com m on ly u sed in th e form of coffee, tea an d m an y soft drin ks; n icotin e, curren tly m ost often used by sm okin g tobacco cigarettes; an d alcoh olic beverages, wh ich com e in m an y form s, in clu din g beer, win e
1 . INTRODUCTION
BOX 1 .1 United Nations drug control conventions
The three major international drug control treaties are mutually supportive and complementary. An impor tant purpose of the first two treaties is to codify internationally applicable control measures in order to ensure the availability of narcotic drugs and psychotropic substances for medical and scientific purposes, and to prevent their diversion into illicit channels. They also include general provisions on illicit trafficking and drug abuse.
Single Convention on Narcotic Drugs, 1 9 6 1
This Convention recognizes that effective measures against abuse of narcotic drugs require coordinated and international action. There are two forms of intervention and control that work together. First, it seeks to limit the possession, use, trade in, distribution, impor t, expor t, manufacture and production of drugs exc lusively t o m edic al and sc ient ific pur poses. Sec ond, it c om bat s dr ug traffic king through international c ooperation to deter and disc ourage drug traffickers.
Convention on Psychotropic Substances, 1 9 7 1
The Convention noted with concern the public health and social problems resulting from the abuse of certain psychotropic substances and was determined to prevent and combat abuse of such substances and the illicit traffic which it gives rise to. The Convention establishes an international control system for psychotropic substances by responding to the diversification and expansion of the spectrum of drugs of abuse, and introduced controls over a number of synthetic drugs according to their abuse potential on the one hand and their therapeutic value on the other.
United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1 9 8 8
This Convention sets out a comprehensive, effective and operative international treaty that was directed specifically against illicit traffic and that considered various aspects of the problem as a whole, in par ticular those aspects not envisaged in the existing treaties in the field of narcotic drugs and psychotropic substances. The Convention provides comprehensive measures against drug trafficking, including provisions against money laundering and the diversion of prec ursor c hemic als. It provides for international c ooperation through, for example, extradition of drug traffickers, controlled deliveries and transfer of proceedings.
Source: United Nations Office for Drug Control and Crime Prevention (available on the Internet at http:/ / www.odccp.org/ odccp/ un_treaties_and_resolutions.html).
Note: In October 2 0 0 2 the United Nations Office for Drug Control and Crime Prevention (ODCCP) changed its name to the United Nations Office on Drugs and Crime (ODC).
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
an d distilled sp irits. Becau se th e u se of caffein ated su bstan ces is relatively u n p roblem atic, it is n ot fu rth er con sidered in th is rep ort. Wh ile in h alan ts are also widely available, they are m ostly used for psychoactive purposes by those
b elow th e age of easy access to alcoh ol, tob acco an d oth er p sych oactive su bstan ces. Wh ile th ere is a clear ration ale for a sep arate legal statu s for m edication s, t h e ra t io n a le fo r t h e d ist in ct io n b e t we e n su b st a n ce s t h a t a re u n d e r in tern ation al con trol an d th ose th at are n ot is m ore p rob lem atic. Th e su b stan ces wh ich are in clu d ed in th e in tern ation al con ven tion s reflect
h istorical u n derstan din gs in p articu lar cu ltu ral settin gs abou t wh at sh ou ld
be viewed as u n iqu ely dan gerou s or alien . Som e p sych op h arm acologists or ep idem iologists today, for in stan ce, wou ld argu e th at alcoh ol is in h eren tly n o less dan gerou s or h arm fu l th an th e dru gs in clu ded in th e in tern ation al con ven tion s. Moreover, as d iscu ssed b elow, d ep en d en ce on n icotin e in tobacco is associated with m ore death an d ill-h ealth th an dep en den ce on oth er p sych oactive su bstan ces. As will be seen in th e ch ap ters wh ich follow, th e growin g kn owledge of th e n eu roscien ce of p sych oactive su bstan ce u se
h as em p h asized th e com m on alities in action wh ich sp an th e th ree sociolegal statu ses in to wh ich th e su bstan ces are divided.
Global use of psychoactive substances Tob a cco
Man y typ es of tobacco p rodu cts are con su m ed th rou gh ou t th e world bu t th e m o st p o p u la r fo rm o f n ico tin e u se is ciga rette sm o kin g. Sm o kin g is a u b iqu itou s activity: m ore th an 50 b illion cigarettes are m an u factu red an n u ally an d th ere are 1.2 b illion sm okers in th e world . Th is n u m b er is expected to in crease to 2 billion by 2030 (Mackay & Eriksen , 2002; World Ban k, 1999). Sm okin g is sp read in g rap id ly in d evelop in g cou n tries an d am on g wom en . Cu rren tly, 50% of m en an d 9% of wom en in develop in g cou n tries sm oke, as com p ared with 35% of m en an d 22% of wom en in d evelop ed cou n tries. Ch in a, in p articu lar, con tribu tes sign ifican tly to th e ep idem ic in develop in g cou n tries. In deed, th e p er cap ita con su m p tion of cigarettes in Asia an d th e Far East is h igh er th an in oth er p arts of th e world, with th e Am ericas an d eastern Eu rop e followin g closely beh in d (Mackay & Eriksen , 2002).
A con cep tu al fram ework for describin g th e differen t stages of cigarette sm okin g ep idem ics in differen t region s of th e world h as been p rop osed by Lop ez, Collish aw & Pih a (1994). In th is m odel, th ere are fou r stages of th e ep idem ic on a con tin u u m ran gin g from low p revalen ce of sm okin g to a stage in wh ich abou t on e-th ird of death s am on g m en in a p articu lar cou n try are
a t t rib u t a b le t o sm o kin g. In St a ge 1, le ss t h a n 20% o f t h e m e n a n d a con siderably lower p ercen tage of wom en sm oke. Available ep idem iological data sh ow th at m an y cou n tries in su b-Sah aran Africa fall in to th is category
1 . INTRODUCTION
alth ou gh sm okin g is in creasin g in th is region . It h as been sh own th at an n u al per capita con sum ption of cigarettes there is less than 100 (Corrao et al., 2000). There is widespread use of other tobacco products (such as sn uff an d chewin g tobacco) in som e cou n tries, bu t th e exten t of adverse h ealth con sequ en ces of u se of th ese form s of tobacco is still n ot clear.
In Stage 2 of th e ep idem ic, abou t 50% of th e m en sm oke an d th ere is an in creasin g percen tage of wom en sm okers. This is the case in Chin a an d Japan , an d in som e coun tries in n orthern Africa an d Latin Am erica. In con trast, Stage
3 describes a situ ation in wh ich th ere is a n oticeable decrease in sm okin g am on g m en an d wom en b u t th ere is in creased m ortality from sm okin g- related diseases. Som e cou n tries in Latin Am erica an d eastern an d sou th ern Eu rop e fall in to th is category. A fin al stage is m arked by decreasin g sm okin g p revalen ce, a p eakin g of death s from tobacco-related disease am on g m en (accou n tin g for abou t on e-th ird of th e total), an d a con tin u ed in crease in deaths from tobacco-related disease am on g wom en . This is curren tly the case in Au stralia, Can ada, th e USA, an d western Eu rop e. Table 1.1 sh ows th e rates of sm okin g for m ales an d fem ales an d p er cap ita con su m p tion of cigarettes in selected cou n tries with data from all categories of sm okers.
Table 1 .1 Prevalence of smoking among adults and youths in selected countries
Annual Prevalence of smoking (%) per capita consumption
Youths Country
Adults
of cigarettes
Males
Females
Males Females
1 0 .5 7 .5 Sri Lanka
2 7 .5 2 4 .2 Source: Mackay & Eriksen, 2 0 0 2 .
Alcohol
Alcoh ol an d tobacco are sim ilar in several ways: both are legal su bstan ces, both are widely available in m ost p arts of th e world, an d both are m arketed
NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE
aggressively by tran sn ation al corp oration s th at target you n g p eop le in advertisin g an d p rom otion cam p aign s. Accordin g to th e Global statu s rep ort o n a lco h o l ( WH O, 1999) a n d a s sh own in Fig. 1.1 b e low, th e le ve l o f con su m p tion of alcoh ol h as declin ed in th e p ast twen ty years in develop ed cou n tries bu t is in creasin g in develop in g cou n tries, esp ecially in th e Western Pacific Region where the an n ual per capita con sum ption am on g adults ran ges from 5 to 9 litres of p u re alcoh ol, an d also in cou n tries of th e form er Soviet Un io n ( WH O, 1999). To a gre a t e xt e n t t h e rise in t h e ra t e o f a lco h o l con su m p tion in develop in g cou n tries is driven by rates in Asian cou n tries. Th e level of con su m p tion of alcoh ol is m u ch lower in th e African , Eastern Mediterran ean , an d Sou th -East Asia Region s.
Th ere is a lon g tradition of research on th e ep idem iology of alcoh ol u se in develop ed cou n tries an d we h ave learn t m u ch abou t th e distribu tion an d
d e t e r m in a n t s o f d r in kin g in d iffe re n t p o p u la t io n s. Fo r m a n y ye a rs, re se a rch e r s fo cu se d o n a ve ra ge vo lu m e o f a lco h o l co n su m p t io n in determ in in g th e level of drin kin g in a p articu lar cou n try. Usin g p rodu ction or sales data from official records has ten ded to un derestim ate con sum ption , especially in developin g coun tries, where un recorded con sum ption of locally brewed beverages is sign ifican t. In order to im p rove th e m easu rem en t of p er
Fig. 1 .1 Annual per capita alcohol consumption among adults aged 1 5 years or more
Developed countries Developing countries Former Soviet Union
Source: Room et al., 2002
1 . INTRODUCTION
cap ita con su m p tion , WHO h as sp on sored research p rojects in fou r cou n tries (Brazil, Ch in a, In d ia an d Nigeria) to d eterm in e th e level of u n record ed con su m p tion in th ese cou n tries.
It is exp ected th at m ore p recise estim ates of alcoh ol u se will lead to better u n derstan din g of th e association between u se an d p roblem s. In th is regard th e com p arative risk an alysis (CRA) p roject of WHO is n oteworth y. Th e CRA u ses p er cap ita con su m p tion data togeth er with p attern s of drin kin g to lin k u se to disease bu rden (Reh m et al., 2002). A p attern s ap p roach to alcoh ol con su m p tion assu m es th at th e way in wh ich alcoh ol is con su m ed is closely lin ked to disease ou tcom e. Drin kin g du rin g m eals, for exam p le, is associated with less risk of p roblem s th an drin kin g du rin g fiestas or drin kin g in p u blic p laces. In th e CRA an alysis, fou r p attern valu es h ave been develop ed, with 1 as th e least h azardou s an d 4 as th e m ost detrim en tal. At p attern valu e 1 th ere are few occasion s of h eavy drin kin g, an d drin kin g is often don e with m eals, wh ile p attern valu e 4 is ch aracterized by m an y h eavy drin kin g occasion s an d drin kin g ou tside m eals. Table 1.2 sh ows th e p attern valu es for differen t WHO region s, with each region divided in to at least two subregion s. Values for som e region s are based on lim ited aggregate data an d are on ly in dicative of th e p attern of drin kin g in th ese region s.
In th e African Region , th ere was a stead y rise in p er cap ita con su m p tion in th e 1970s an d a d eclin e b egin n in g from th e early 1980s. However, th e p attern of d rin kin g h as ten d ed toward s th e h igh er levels with m en in m ost cou n tries d rin kin g at p attern valu e 3 of th e CRA estim ates. Th is is th e case for Gab on , Gh an a, Ken ya, Lesoth o, Sen egal, an d Sou th Africa, for exam p le. However, it is on ly in very few cou n tries (e.g. Zam b ia an d Zim b abwe) th at th e p attern valu e is 4. Th e d etrim en tal p attern of d rin kin g in m an y su b - Sah aran cou n tries h as been sh own in several su rveys (e.g. Mu ston en , Beu kes & Du Preez, 2001; Ob ot, 2001). In m ost cou n tries wom en d rin k m u ch less th an m en an d in som e of th ese cou n tries th e ab sten tion rate for old er wom en is very h igh .
In th e Region of th e Am ericas, h eavy drin kin g (i.e. drin kin g five or m ore drin ks on at least on e occasion in th e p ast m on th ) is a com m on drin kin g
b eh aviou r am on g you n g p eop le. Both alcoh ol con su m p tion an d h eavy drin kin g are rep orted m u ch m ore often am on g m ales th an fem ales in both Mexico an d th e USA (WHO, 1999; Medin a-Mora et al., 2001). Th ou gh Mexico
h as a relatively low p er cap ita con su m p tion of alcoh ol, th e p attern valu e for th at cou n try is 4. Th is is becau se th ere is h igh frequ en cy of h eavy drin kin g, esp ecially by you n g p eop le, on fiesta occasion s.
Heavy drin kin g am on g youn g people is also com m on in the Western Pacific Region . Th ou gh th ere h as b een som e d eclin e in th e rates of d rin kin g in Au stralia an d New Zealan d, 50% of m ale you th s in th ese cou n tries as well as in Sou th Korea an d Jap an often d rin k to in toxication . Tab le 1.2 sh ows absten tion rates for m ales an d fem ales, an n u al p er cap ita con su m p tion in the gen eral population an d am on g drin kers, an d pattern s of drin kin g in WHO subregion s.
Table 1 .2 Estimated rate of abstention from alcohol and patterns of hazardous drinking in selected WHO subregions a
WHO subregion
Rate of abstention
Annual per capita
Annual per capita
Pattern
from alcohol (%)
consumption
consumption
of hazardous
of alcohol
of alcohol
drinking b
Males
Females
in the general
among drinkers
population (litres)
(litres)
African Region – D (e.g. Algeria, Nigeria)
2 .3 C S African Region – E (e.g. Ethiopia, South Africa)
2 .0 E O Region of the Americas – B (e.g. Brazil, Mexico)
Region of the Americas – A (e.g. Canada, Cuba, USA)
3 .1 F P Region of the Americas – D (e.g. Bolivia, Peru)
3 .1 S Y South-East Asia Region – B (e.g. Indonesia, Thailand)
2 .5 C O H South-East Asia Region – D (e.g. Bangladesh, India)
3 .0 C A European Region – A (e.g. France, Germany,
IV T 8 United Kingdom)
1 .3 E S European Region – B1 (e.g. Bulgaria, Poland, Turkey)
2 .9 U B European Region – B2 (e.g. Armenia, Azerbaijan, S
A T Tajikistan)
3 .0 C N European Region – C (e.g. Russian Federation, Ukraine) 1 1
3 .6 E U Eastern Mediterranean Region – B (e.g. Iran,
E S Saudi Arabia)
2 .0 N A Eastern Mediterranean Region – D (e.g. Afghanistan,
D D Pakistan)
2 .0 P E E Western Pacific Region – A (e.g. Australia, Japan)
1 .0 D N Western Pacific Region – B (e.g. China, Philippines,
E Viet Nam)
Source: Based on estimates for the comparative risk assessment within the WHO Global Burden of Disease 2 0 0 0 Study (see Rehm et al., 2 0 0 2 ). a To aid in cause of death analyses, burden of disease analyses, and comparative risk assessment, the 191 Member States of WHO have been divided into five mortality strata on the basis of their levels of child mortality under 5 years of age and mortality among men aged 15–59 years. The mortality strata are
defined as follows: A: very low child, very low adult; B: low child, low adult; C: low child, high adult; D: high child, high adult; E: high child, very high adult. b Scored on a level of 1 –4 , where level 1 is the least hazardous and level 4 is the most detrimental.
1 . INTRODUCTION
Illicit use of controlled sub sta nces
Data from th e Un ited Nation s Office on Dru gs an d Crim e (ODC) sh ow large- scale seizures of cocain e, heroin , can n abis an d am phetam in e-type stim ulan ts in differen t p arts of th e world. Availability of cocain e, h eroin an d can n abis dep en ds on th e level of cu ltivation in sou rce cou n tries an d on th e su ccess or failu re of traffickin g organ ization s. However, even with in creased levels of law en forcem en t activities, th ere always seem s to be en ou gh dru gs available to u sers.
Accordin g to ODC estim ates (UNODCCP, 2002), abou t 185 m illion p eop le m ake illicit u se of on e typ e of illicit su bstan ce or an oth er. Table 1.3 sh ows that can n abis is con sum ed by the largest n um ber of illicit drug users, followed by am p h etam in es, cocain e an d th e op iates.