Ethical Issues in Neuroscience Research on Substance Dependence Treatm ent and Prevention

Ethical Issues in Neuroscience Research on Substance Dependence Treatm ent and Prevention

Introduction

Previous chapters have presen ted the latest fin din gs in n euroscien ce research, an d h ave p oin ted to p oten tial treatm en t an d p reven tion strategies. However, th ere are m an y eth ical im p lication s of th e research itself, as well as th e treatm en t an d preven tion strategies, that m ust be con sidered. The rapid pace of ch an ge in th e field of n eu roscien ce brin gs with it a h ost of n ew eth ical issu es, wh ich n eed to be addressed. Th is ch ap ter con siders th e im p ortan t eth ical an d h u m an righ ts issu es th at are raised by n eu roscien ce research on p sych oactive su bstan ce dep en den ce.

Types of research on the neuroscience of substance dependence

Neu roscien ce research on su bstan ce dep en den ce is classified h ere in to five broad categories: an im al experim en ts; epidem iological research on substan ce

d e p e n d e n ce ; h u m a n e xp e rim e n t s; clin ica l t r ia ls o f p h a r m a co lo gica l t re a t m e n t s fo r su b st a n c e d e p e n d e n c e ; a n d t r ia ls o f p re ve n t ive p h arm acological in terven tion s.

Anim a l exp erim ents

An im a l e xp e r im e n t s in ve st iga t e t h e b io lo gica l p ro ce sse s u n d e rlyin g su b st a n c e d e p e n d e n c e u sin g a n im a l m o d e ls o f h u m a n su b st a n c e dep en den ce. Th e m ajor reason s for carryin g ou t th ese stu dies are th at m u ch greater exp erim en tal con trol is p ossible with an im als, an d m ore in vasive exp erim en ts can be don e on an im als th an wou ld be p erm itted in h u m an s.

Ep id em iologica l resea rch on sub sta nce d ep end ence

Alth ou gh n ot strictly n eu roscien ce research p er se, ep idem iological research in form s an d com p lem en ts n eu roscien ce research . Ep idem iological research on pattern s of substan ce use an d depen den ce in cludes: surveys in the gen eral p op u lation an d with in th e sp ecial p op u lation of dru g u sers an d dep en den t p erson s (An th on y & Helzer, 1991; Kessler et al., 1994; An drews, Hen derson & Hall, 2001), fam ily studies (Swen dsen et al., 2002), adop tion studies (Hjern ,

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Lin d b lad & Vin n erlju n g, 2002), twin stu d ies of th e gen etics of su b stan ce dep en den ce (Heath , 1995) an d lon gitu din al stu dies of su bstan ce u se an d its con sequen ces (Fergusson & Horwood, 2000; Kan del & Chen , 2000) an d am on g p erson s wh o h ave been treated for su bstan ce dep en den ce (Hser et al., 2001). Th e fin din gs of su ch stu dies in form n eu roscien ce research by describin g su b st a n c e d e p e n d e n c e p h e n o m e n a t h a t n e e d t o b e e xp la in e d b y n euroscien ce theories, for exam ple, the in dividual characteristics that predict su bstan ce u se an d th e develop m en t of su bstan ce dep en den ce an d oth er

d r u g- re la t e d p r o b le m s, a n d t h e ge n e t ic e p id e m io lo gy o f su b st a n ce dep en den ce fou n d in twin an d adop tion stu dies. Th e distin ction between epidem iological an d n euroscien ce research on substan ce depen den ce is also likely to becom e blu rred wh en ep idem iological stu dies in clu de biological m easu res, su ch as DNA, from wh ich sp ecific su scep tib ility gen es can b e tested, as well as oth er biological m arkers of risk.

Exp erim enta l stud ies in hum a ns

Hum an n euroscien ce exp erim en ts typ ically in volve laboratory studies un der con trolled con dition s of the effects of chron ic drug exposure on curren t brain fu n ction or th e acu te effects of exp osu re to dru gs, dru g an alogu es, or dru g- related cues (e.g. the presen ce of in jectin g equipm en t) on behaviour an d brain fu n ction (Adler, 1995). An in creasin gly com m on typ e of stu dy in volves th e u se of brain im agin g tech n ologies, su ch as PET, SPECT an d fMRI (Gilm an , 1998; Fu & McGu ire, 1999) to stu d y th e acu te effects of d ru gs an d th e n eurobiological con sequen ces of chron ic substan ce use an d depen den ce (Sell et al., 1999; Klin g et al., 2000; Martin -Soelch et al., 2001) (see Chapters 2 an d 4).

Clinica l tria ls of p ha rm a cothera p y for sub sta nce d ep end ence

Clin ical trials of p h arm acoth erap ies for su bstan ce dep en den ce com p are th e effects of differen t drug treatm en ts, an d som etim es placebos, on the pattern s of dru g u se, on h ealth , social adju stm en t an d well-bein g of p erson s wh o are dep en den t on dru gs (Brody, 1998). Th e dru gs th at are trialed are in creasin gly iden tified as p oten tial treatm en ts for su bstan ce dep en den ce as a resu lt of n eu roscien ce research on th e biological m ech an ism s u n derlyin g su bstan ce dep en den ce. Th ese m ay in clu de trials of dru gs th at assist in com p letin g th e withdrawal from a p sychoactive substan ce; drugs that are in ten ded to reduce relap se to su b stan ce d ep en d en ce after with d rawal; an d d ru gs th at are in ten ded to p rovide lon g-term m ain ten an ce of abstin en ce or p sych osocial stability.

Clin ical trials h ave som e ch an ce of b en efitin g p articip an ts in th e stu d y (Brod y, 1998). Th is m ay b e by ob tain in g access to good -qu ality treatm en t fo r su b st a n ce d e p e n d e n ce (in t h e e ve n t o f t h e ir re ce ivin g st a n d a rd treatm en t or a p laceb o) or access to a p rom isin g exp erim en tal treatm en t for su b stan ce d ep en d en ce (if th ey are assign ed to th e n ew treatm en t). As

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

with p articip an ts in exp erim en tal stu d ies, th ey m ay also b e exp osed to risks of th e dru g treatm en t, su ch as side-effects an d toxicity (Brody, 1998; Gorelick et al., 1999).

Tria ls of p ha rm a cothera p ies to p revent sub sta nce d ep end ence

Pre ve n t ive t r ia ls in vo lve co n t ro lle d e va lu a t io n s o f p h a rm a co lo gica l treatm en ts th at aim to p reven t th e develop m en t of su bstan ce dep en den ce. Th is m igh t be ach ieved by u sin g a dru g to treat a con dition th at in creases a p erson’s risks of develop in g su bstan ce dep en den ce (e.g. atten tion deficit

h yp eractivity disorder (ADHD), see Ch ap ter 4). It cou ld con ceivably in volve the adm in istration of a drug im m un otherapy (e.g. again st n icotin e or cocain e) to you n g p eop le wh o are at risk of su bstan ce dep en den ce in order to redu ce th eir ch an ces of develop in g su bstan ce dep en den ce.

Tria ls of p reven tive p h a rm a coth era p ies a re m ore a p rosp ect on th e

h o rizo n th a n a m a jo r u n d e rta kin g a t p re se n t; h owe ve r, two re se a rch

d evelop m en ts su ggest th at su ch trials m ay soon b e ad vocated . On e is th e

d e ve lo p m e n t o f im m u n o t h e ra p ie s a ga in st co ca in e a n d n ico t in e (se e Ch ap ter 4). Th e in itial m otive for d evelop in g th ese im m u n oth erap ies h as

b een to red u ce relap se to su b stan ce u se in p erson s wh o h ave b een treated for su b stan ce d ep en d en ce (Fox, 1997). However, th ese im m u n oth erap ies cou ld b e ad m in istered to ch ild ren an d ad olescen ts with th e in ten tion of redu cin g th eir likelih ood of becom in g dep en den t. Th e secon d develop m en t is th at of “early in terven tion s”, wh ich so far h ave in volved p erson s at h igh risk of d evelop in g sch izop h ren ia, b u t it is likely th at th e sam e cou ld b e p ro p o sed fo r su b sta n ce d ep en d en ce. Th ese in vo lve a co m b in a tio n o f p sych osocial an d p h arm acological in terven tion s. Becau se th is work h as

b een con troversial in th e field of p sych iatry, n eu roscien ce research ers on su b stan ce d ep en d en ce wou ld b en efit from d iscu ssion s of issu es th at m ay

a rise in tria ls of p reven tive p h a rm a cologica l trea tm en ts for su b sta n ce

d ep en d en ce.

Approach to ethical analysis

Over the past 30 years or so, an in fluen tial set of m oral prin ciples has em erged in An glo-Am erican an alyses of the ethics of biom edical research (Brody, 1998; Jon sen , 1998). Th ese are th e p rin cip les of au ton om y, n on -m aleficen ce, ben eficen ce, an d justice (Beaucham p & Childress, 2001). They have also been in clu d ed in in flu en tial in tern ation al statem en ts of eth ical p rin cip les for m edical research , su ch as th e Helsin ki Declaration (see Box 7.1) an d th e declaration s of Un ited Nation s organ ization s (Brody, 1998). Th ese p rin cip les can be regarded as a m oral baselin e for th e eth ical an alysis of n eu roscien ce research on su bstan ce dep en den ce; with th e p roviso th at th ey m ay n eed to

be su p p lem en ted to deal with n ewly-em ergin g issu es.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

BOX 7 .1 Declaration of Helsinki 1

Ethical principles for medical research involving human subjects A. Introduction

1 . The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research

involving human subjects includes research on identifiable human material or identifiable data.

2 . It is the duty of the physician to promote and safeguard the health of the people. The physician’s knowledge and conscience are dedicated to the fulfillment of this duty.

3 . The Declaration of Geneva of the World Medical Association binds the physician with the words, “The health of my patient will be my first consideration”, and the International Code of Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient”.

4 . Medical progress is based on research which ultimately must rest in par t on experimentation involving human subjects.

5 . In medical research on human subjects, considerations related to the well- being of the human subject should take precedence over the interests of science and society.

6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality.

7 . In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens.

8 . Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The par ticular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care.

9 . Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

B. Basic principles for all medical research

1 0 . It is the duty of the physician in medical research to protect the life, health,

privacy, and dignity of the human subject. 1 1 . Medical research involving human subjects must conform to generally

accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.

1 2 . Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.

1 3 . The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol. This protocol should be submitted for consideration, comment, guidance, and where appropr iat e, approval t o a spec ially appoint ed et hic al review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence. This independent committee should be in conformity with the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events. The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.

1 4 . The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the principles enunciated in this Declaration.

1 5 . Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent.

1 6 . Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available.

1 7 . Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

1 8 . Medical research involving human subjects should only be conducted if the

importance of the objective outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects are healthy volunteers.

1 9 . Medical research is only justified if there is a reasonable likelihood that the

populations in which the research is carried out stand to benefit from the results of the research.

2 0 . The subjects must be volunteers and informed participants in the research project.

2 1 . The right of research subjects to safeguard their integrity must always be

respected. Every precaution should be taken to respect the privacy of the subject, the confidentiality of the patient’s information and to minimize the impact of the study on the subject’s physical and mental integrity and on the personality of the subject.

2 2 . In any research on human beings, each potential subject must be adequately

informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject’s freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed.

2 3 . When obtaining informed c onsent for the researc h projec t the physic ian

should be par ticularly cautious if the subject is in a dependent relationship with the physician or may consent under duress. In that case the informed

c onsent should be obt ained by a well-inform ed physic ian who is not eng ag ed in the investig ation and who is c ompletely independent of this relationship.

2 4 . For a research subject who is legally incompetent, physically or mentally

incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons.

2 5 . When a subject deemed legally incompetent, such as a minor child, is able

to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative.

2 6 . Research on individuals from whom it is not possible to obtain consent,

including proxy or advance consent, should be done only if the physical/

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee. The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legally authorized surrogate.

2 7 . Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.

C. Additional principles for medical research combined with medical care

2 8 . The physician may combine medical research with medical care, only to the extent that the researc h is justified by its potential prophylac tic , diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the patients who are research subjects.

2 9 . The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.

3 0 . At the conclusion of the study, every patient entered into the study should

be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.

3 1 . The physician should fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study must never interfere with the patient-physician relationship.

3 2 . In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded, and, where appropriate, published. The other relevant guidelines of this Declaration should be followed.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Note of clarification on Paragraph 2 9

The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only

be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

— Where for compelling and scientifically sound methodological reasons its use

is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or

— Where a prophylactic, diagnostic or therapeutic method is being investigated

for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical and scientific review.

1 The Declaration of Helsinki is an official policy document of the World Medical Association, the global representative body for physicians. It was first adopted in 1 9 6 4 (Helsinki, Finland)

and revised in 1 9 7 5 (Tokyo, Japan), 1 9 8 3 (Venice, Italy), 1 9 8 9 (Hong Kong), 1 9 9 6 (Sommerset-West, South Africa) and 2 0 0 0 (Edinburgh, Scotland). Note of clarification on Paragraph 2 9 added by the WMA General Assembly, Washington, 2 0 0 2 .

Source: World Medical Association, 2 0 0 2 (available on web site http:/ / www.wma.net/ e/ policy1 7 -e_e.html).

Princip les of b iom ed ica l ethics

i. Respect for au ton om y Resp ectin g au ton om y m ean s th at p eop le resp ect an d do n ot in terfere with

th e action s of ration al p erson s th at h ave a cap acity for au ton om ou s action , th at is, adu lts wh o are able to freely decide u p on a cou rse of action with ou t in flu en ce, coercion or force (Beau ch am p & Ch ildress, 2001). In th e con text of biom edical research, the prin ciple of respect for auton om y is usually taken t o re q u ire t h e fo llowin g: in fo rm e d co n se n t t o t re a t m e n t o r re se a rch p articip ation , volu n tarin ess in research p articip ation , an d m ain ten an ce of co n fid e n t ia lit y a n d p r iva cy o f in fo r m a t io n p rovid e d t o a re se a rch e r (Beau ch am p & Ch ildress, 2001).

ii. Non -m aleficen ce Th e p rin cip le of n on -m aleficen ce sim p ly m ean s, do n o h arm (Beau ch am p

& Ch ild ress, 2001). Followin g th e p rin cip le of n on -m aleficen ce req u ires p eop le to refrain from cau sin g h arm or in ju ry, or from p lacin g oth ers at risk of h arm or in ju ry. In th e con text of biom edical research , th e p rin cip le of n on -

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

m aleficen ce req u ires research ers to m in im ize th e risks associated with p articip ation in research (Brody, 1998; Beau ch am p & Ch ildress, 2001).

iii. Ben eficen ce Beaucham p an d Childress have iden tified “positive ben eficen ce” an d “utility”

as two elem en ts of th e p rin cip le of ben eficen ce (Beau ch am p & Ch ildress, 2001). Positive ben eficen ce requ ires p eop le to p erform action s th at resu lt in ben efit. Utility requ ires th at th e ben efits of p eop les’ action s ou tweigh th e bu rden s th ey im p ose u p on oth ers. Th e p rin cip le of ben eficen ce th erefore requ ires th at an action p rodu ces ben efits an d th at its ben efits ou tweigh its bu rden s. In th e con text of biom edical research , th is m ean s th at th e ben efits of th e research to society sh ou ld ou tweigh its risks to p articip an ts.

iv. Distribu tive ju stice Ju stice is p robably th e m ost con troversial of th e fou r m oral p rin cip les. For

th e p u rp ose of th is discu ssion , “ju stice” refers to “distribu tive ju stice” rath er than retributive (crim inal) or rectificatory (com pensatory) justice (Beaucham p & Ch ildress, 2001). In bioeth ics, th e p rin cip le of distribu tive ju stice h as been cen tral to debates abou t h ow to en su re equ itable access to h ealth care an d to redu ce u n equ al h ealth ou tcom es. In th e case of research , th e p rin cip le of distribu tive ju stice refers to th e equ itable distribu tion of th e risks, as well as th e ben efits of research p articip ation (Brody, 1998). A fair an d ju st research p olicy wou ld aim to ach ieve a distribu tion of th e ben efits an d bu rden s of research p articip ation th at is as fair an d equ itable as p ossible.

Hum a n rights

In 1948 th e Un iversal Declaration of Hu m an Righ ts (UDHR) set ou t an in tern ation al set of hum an rights that would be hon oured by all n ation s which sign ed th e d eclaration (Un ited Nation s Gen eral Assem b ly, 10 Decem b er, 1948). Th e UDHR recogn ised th at all p eop le h ave righ ts by virtu e of bein g

h u m an an d th at th ese were u n iversal in th e sen se of ap p lyin g equ ally to all p eop le arou n d th e world , regard less of wh o th ey are or wh ere th ey live (In tern ation al Fed eration of Red Cross an d Red Crescen t Societies an d Fran çois-Xavier Bagn ou d Cen ter for Health an d Hu m an Righ ts, 1999; Man n et al., 1999). Th e UDHR en join ed n ation s to treat all p eop le as equ al an d to prom ote an d protect the right to life, liberty an d security of person . It in cluded “n egative righ ts” su ch as th e righ ts n ot to be en slaved or in servitu de, n ot be to b e tortu red or su b ject to cru el, in h u m an an d d egrad in g treatm en t or p u n ish m en t. It also obliged sign atory states to afford p eop le equ al treatm en t before th e law an d th e equ al p rotection of th e law, with ou t discrim in ation , by requ irin g th at everyon e ch arged with a p en al offen ce sh ou ld be p resu m ed in n ocen t u n til p roved gu ilty (UDHR, 1948, article 11).

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Ethical prin ciples in m edicin e an d hum an rights both em body in jun ction s to behave in specific ways but they differ in to whom they apply (Man n , 1999). Eth ical p rin cip les typ ically ap p ly to in dividu als, u su ally h ealth care workers an d research ers, wh ereas h u m an righ ts im p ose obligation s on states an d govern m en ts to p ro m o te a n d p ro tect th e righ ts o f th eir citizen s fro m in frin gem en ts by th e state or by oth ers (Man n , 1999). Hu m an righ ts are m ost relevan t to th e way in wh ich treatm en ts an d in terven tion s d erived from n eu roscien ce research are u sed to treat an d p reven t su bstan ce dep en den ce. Th is is becau se treatm en t an d p reven tion m ay in volve th e use of th e coercive p owers o f th e sta te to th rea ten th e h u m a n righ ts o f p erso n s wh o a re dep en den t on p sych oactive su bstan ces (Gostin & Man n , 1999).

Ethics of anim al experim entation in neuroscience research

Th e u se of an im als in b iom ed ical research h as trad ition ally b een ju stified by th e argu m en t th at th e h arm in flicted u p on an im als in th e cou rse of research is ou tweigh ed by th e gain s in scien tific kn owled ge to h u m an s (an d an im als) (Resn ik, 1998). Th e scien tific com m u n ity h as gen erally accep ted th is d efen ce, b u t it h as n ot received sim ilar su p p ort from th e p u b lic as a resu lt of m ed ia rep ortin g of con troversial exam p les of an im al exp erim en - tation (Brod y, 1998).

An im al research h as p rovided som e sign ifican t ben efits to h u m an s, for exam p le, th e id en tification of m ech an ism s th at cau se d isease an d th e im p rovem en t of treatm en ts (Naqu et, 1993).

Alth ou gh th ere are altern atives to an im al m odels in som e situ ation s, su ch as tissu e cu ltu res an d com p u ter sim u lation (Resn ik, 1998), th ese m odels can n ot rep lace th e u se of an im als in research becau se th ey can n ot m odel the rich behavioural an d physiological en viron m en t of live an im als (Am erican Psych ological Association Scien ce Directorate, 2001).

A criticism of an im al exp erim en tation is th at th e an im als u sed do n ot p rovide good m odels of h u m an biology, p h ysiology an d p sych ology (Resn ik, 1998). For exam ple, research has shown that cortical organ ization in the brain varies between sp ecies an d th at som e p rim ates lack ch aracteristics fou n d in

h u m an s (Preu ss, 2000). It h as also b een argu ed th at th e p sych ology an d n eu robiology of su bstan ce dep en den ce are n ot well-m odelled in com m on ly u sed an im als su ch as m ice an d rats (Resn ik, 1998), an d th at n on -h u m an p rim a te m od els a re m ore d esira b le b eca u se th e cortica l a n a tom y a n d beh aviou ral rep ertoire of p rim ates m ore closely resem bles th ose of h u m an s (Na t io n a l Aca d e m y o f Scie n ce, 1996). Howe ve r, m u ch o f t h e cu rre n t kn owledge regardin g th e n eu roscien ce of su bstan ce dep en den ce h as com e from an im al experim en tation usin g a n um ber of differen t species. Gen etically en gin eered m ice, for exam p le, h ave been u sed to iden tify in itial targets for dru gs, su ch as th e CB1 can n abin oid recep tor, an d bioch em ical p ath ways in volved in cocain e m etabolism h ave been in vestigated (Nestler, 2000). Rats an d other n on -prim ate species have provided good m odels for certain aspects

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

of the p sychology an d n eurobiology of substan ce dep en den ce, thus reducin g th e n u m ber of p rim ates n eeded in research .

It seem s th at a societal com p rom ise exists b etween th ose wh o op p ose an im al exp erim en tation an d th ose wh o d eem it n ecessary (Varn er, 1994). Th e m oral objection s to an im al exp erim en tation h ave in creased th e bu rden of p roof th at d efen d ers of research m u st m eet (Varn er, 1994). Th is is a reason ab le ou tcom e as lon g as th e b u rd en of p roof is n ot in su rm ou n tab le.

In m ost cou n tries, legislation ad op ts on e of two p ersp ectives wh ich ackn owledge th e n eed for an im al exp erim en tation wh ile p lacin g restriction s on th e p ractice (Brody, 1998). Legislation in Eu rop e an d Am erica takes a “h u m an p riority” p osition in wh ich an im al su fferin g an d loss are m in im ized but the in terests of hum an s take p receden ce over those of an im als when they con flict (Brody, 1998). In con trast, legislation in Au stralia an d th e Un ited Kin gdom is based on a “balan cin g” p osition in wh ich th e in terests of h um an s are gen erally regarded as m ore im p ortan t th an th ose of an im als bu t th ey can som etim es be overridden in order to p rotect an im als (Brody, 1998). Un like legislation in Am erica an d Eu rop e, legislation in Au stralia an d th e Un ited Kin gdom requ ires th at du rin g th e eth ical review p rocess, th e ben efits of th e p rop osed exp erim en ts be weigh ed again st th e h arm th at will be in flicted on th e an im als (Brody, 1998).

Ethical principles in hum an biom edical research

Sin ce th e Nu rem berg trials of Germ an m edical research ers after World War

II, a con sen su s h as been develop ed abou t th e basic eth ical requ irem en ts for

b io m ed ica l resea rch o n h u m a n s (Bro d y, 1998; Jo n sen , 1998). In m o st

d e ve lo p e d co u n t r ie s, n a t io n a l e t h ica l co d e s se t o u t o b liga t io n s t h a t in vestigators m ust adhere to if their research is to be ethically an d scien tifically legitim ate. Alth ou gh sp ecific con dition s for eth ical ap p roval m ay differ from cou n try to cou n try th e sam e basic set of eth ical p rin cip les is fou n d in m ost n ation al gu idelin es (Brody, 1998). Th ese in clu de in dep en den t eth ical review of research p rop osals, resp ect for p atien t p rivacy, in form ed con sen t to p articip ate in research , an d p rotection of p rivacy an d con fid en tiality of in form ation (Brody, 1998).

Ind ep end ent ethica l review of risks a nd b enefits

In order for an y h u m an research to gain ap p roval, in vestigators m u st obtain eth ical ap p roval from an in d ep en d en t eth ical review com m ittee, u su ally an in stitu tion al eth ical review com m ittee. An extern al review of a stu d y p rotocol p rovid es an in d ep en d en t assessm en t of wh eth er th e b en efits of th e p rop osed trial ou tweigh an y risks th at it p oses to p articip an ts (Brod y, 1998).

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Inform ed consent

In form ed con sen t to p articip ate in a research stu dy is u su ally a m atter of askin g th e research p articip an t to con sen t to th eir p articip ation after a detailed discu ssion of wh at it will en tail an d a descrip tion of an y adverse even ts th at m ay occu r (Brody, 1998). Th e p articip ation of p erson s u n der th e age of 18 years wou ld n orm ally requ ire th e con sen t of a p aren t or gu ardian , alon g with th e assen t of th e p articip an t. An y u n certain ty abou t th e risks of p articip ation m u st be accu rately com m u n icated an d th ere m u st be close m on itorin g of an y adverse even ts, with m edical care p rom p tly p rovided for an y adverse ou tcom es. Th e in clu sion of p erson s with cogn itive im p airm en ts in a stu dy m ay requ ire sp ecial con sideration (see below). Con sen t m ay n eed to b e ob tain ed from a su rrogate wh o m akes a d ecision on b eh alf of th e im paired research participan t (Brody, 1998). This has im plication s for research in volvin g p erson s with su bstan ce dep en den ce if th e p erson h as lon g-term cogn itive, p sych iatric, or n eu rological dysfu n ction as a resu lt of su bstan ce u se (see Ch ap ter 4), or if th e p erson h as a con cu rren t p sych iatric illn ess (see Ch ap ter 6).

All form s of con sen t m u st be given after th e p articip an ts are in form ed of wh a t th eir in volvem en t in th e resea rch will req u ire of th em . Resea rch p articip an ts sh ou ld h ave tim e to reflect on an d con sider th eir obligation s at each stage of th e con sen t p rocedu re. Ideally, th e con sen t p rocess sh ou ld in clu de a th ird p arty, u su ally a clin ician n ot in volved in th e stu dy, to en su re th e in tegrity of th e p rocess. Particip an ts m u st be allowed to with draw from th e stu dy at an y tim e. If th ey decide to with draw, th eir decision m u st be re sp e ct e d a n d t h e y m u st b e in fo r m e d t h a t t h e y will n o t su ffe r a n y con sequ en ces, su ch as refu sal of rou tin e cou n sellin g or m edical care (Brody, 1998). If an y p articip an t with draws from th e stu dy, th e data collected from th em m u st be om itted from th e fin al resu lts.

Recruitm ent of sub jects

Th e con dition s u n der wh ich p erson s are recru ited in to a stu dy m u st n ot in vo lve a n y fo rm o f co ercio n o r th e u se o f excessive in d u cem en ts to participate (Brody, 1998). In recen t years, it has becom e com m on to reim burse p articip an ts for th eir in volvem en t in som e research stu d ies. Th e m ost com m on ju stification is th at reim bu rsem en ts m axim ize in itial recru itm en t an d reten tion of p articip an ts in a stu dy. Sm all reim bu rsem en ts are offered to com p en sate p articip an ts for th e tim e sp en t p articip atin g in a trial or for th eir travel exp en ses. Reim b u rsem en ts m ay b e in terp reted by som e p oten tial subjects as rewards for participation , an d by researchers as a way of in creasin g th e n u m b er of trial p articip an ts. Ash croft argu es th at in d u cem en ts are eth ically accep table if th e in du cem en t serves to recom p en se a p articip an t for th e in con ven ien ce, as lon g as it is n ot seen as a p aym en t for an y h arm cau sed (Ash croft, 2001). In Au stralia, for exam p le, it h as b een com m on

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

p ractice sin ce th e early 1980s for dru g research ers to p ay dru g u sers A$20 if they participate in research in terviews. The m on ey is in ten ded to com pen sate p articip an ts for th eir tim e, travel exp en ses an d in con ven ien ce. Paym en t of research p articip an ts is also stan dard p ractice in dru g research in Can ada an d th e USA.

In Au stralia th is strategy h as p roved to be a su ccessfu l way of recru itin g illicit dru g u sers for research stu dies of risk factors for th e tran sm ission of HIV, h ep atitis C an d oth er in fectiou s blood-born e diseases; p attern s of illicit am p h etam in e u se (in clu d in g in jectin g u se, th e reason s for m akin g th e tran sition to in jectin g, an d th e p revalen ce of p sych ological an d h ealth p roblem s cau sed by in jectin g u se); th e p revalen ce an d correlates of dru g overdoses am on g h eroin u sers; an d n ation al m on itorin g of tren ds in illicit dru g u se sin ce 1996. Th e in form ation collected in th ese stu dies cou ld n ot be easily obtain ed in an y oth er way. In terviewin g dru g u sers in treatm en t, for exam p le, wou ld b e of lim ited u se b ecau se m an y d ru g u sers d o n ot seek treatm en t, an d th ose wh o do u su ally do so after several years of p roblem dru g u se. Obtain in g in form ation in th is way p rovides advan ce warn in g of em ergin g tren ds in illicit dru g u se. It also creates an op p ortu n ity to p rovide

d ru g u sers with in form ation ab ou t th e risks of th eir d ru g u se, an d su ch in form ation m ay also h elp in th e design of edu cation al cam p aign s aim ed at illicit dru g u sers. Th e fin din gs of th ese stu dies are also regu larly p resen ted to staff at treatm en t cen tres to alert them to p roblem s em ergin g am on g p erson s seekin g th eir h elp.

A con cern exp ressed by critics of th is p ractice of p ayin g p articip an ts is that the m on ey will serve as an in ducem en t because of its poten tial for buyin g drugs. The first question is whether drug users have the sam e rights as an yon e else to be com p en sated for the tim e an d in con ven ien ce of bein g in terviewed. Th e m on ey m ay well be u sed to p ay for tobacco, alcoh ol or illicit dru gs, bu t so m ay an y in com e th at dru g u sers obtain by em p loym en t, social welfare, or crim e. In term s of th e daily p attern of dru g u se of m ost in jectin g dru g u sers, $20 bu ys on ly a very sm all am ou n t of th e street dru gs n orm ally u sed p er day. Th is issu e is con troversial an d rem ain s u n resolved.

Priva cy a nd confid entia lity

Research ers are ob ligated to p rotect th e p rivacy of stu d y p articip an ts. Particip an ts’ p erson al in form ation m u st n ot be divu lged to an y in dividu al or grou p of in dividu als with ou t th eir direct con sen t, an d th ey sh ou ld n ot be iden tifiable from th e p u blish ed resu lts of th e stu dy (Brody, 1998). Th ese ru les

a re e sp e cia lly im p o rta n t wh e n stu d y p a rticip a n ts h a ve a stigm a tize d con dition su ch as m en tal illn ess or su bstan ce dep en den ce. Protectin g th e p rivacy of p articip an ts an d th e con fid en tiality of th e in form ation th at th ey p rovide is critical in research wh ere data are collected on su bstan ce u se. Th e u se of som e p sych oactive su bstan ces (e.g. can n abis, cocain e an d h eroin ) is illegal, as is th e u se of alcoh ol by p erson s wh o are

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

un der the m in im um legal drin kin g age. Surveys of drug use m ay also ask about illicit dru g u se an d th e com m ission of oth er illegal acts, su ch as drivin g wh ile in toxicated , sellin g illicit d ru gs or en gagin g in th eft, frau d or violen ce to fin an ce dru g u se. If su ch data were lin ked to an iden tified in dividu al an d given to th e p olice th en th e p articip an t cou ld face crim in al ch arges. In th e USA researchers can obtain certificates of con fiden tiality that provide subjects with an assuran ce that this will n ot hap p en . However, the legal status of these certificates is un clear, given that the certificate is issued federally; it is un clear if it wou ld h ave legal statu s in state cou rts. Fu rth erm ore, th e th reat of access to th ese docu m en ts from civil law su its is also u n clear. Th e legal situ ation in m ost oth er cou n tries is sim ilarly u n clear.

Con fiden tiality is m uch less of a problem when data are collected in a sin gle cross-section al in terview. Th e in form ation p rovid ed u su ally d oes n ot

con tain participan ts n am e or other iden tifiers because this in form ation n eed n ot be collected. Con fiden tiality becom es m ore of an issu e if in terviews are re co rd e d (e.g. o n ta p e ) b e ca u se th is co u ld b e u se d in a co u rt o f la w. Con fiden tiality becom es a p oten tially seriou s issu e in lon gitu din al stu dies in which data that perm it iden tification of subjects (e.g. the participan t’s n am e an d address, an d th e n am es an d addresses of th eir fam ily an d frien ds) are collected so th at in dividu als m ay be recon tacted for fu rth er in terviews at a later date. A stan dard p recau tion is to store n am es an d iden tifiers so th at t h e y a re se c u re , a n d t o ke e p t h e m se p a ra t e fr o m t h e su r ve y d a t a . Con fiden tiality will becom e an even m ore im portan t issue when DNA sam ples (or biological tissues from which DNA can be obtain ed) are collected because DNA p rovides a u n iqu e way of iden tifyin g all in dividu als (excep t iden tical twin s). Wh en lin ked with qu estion n aire or in terview d ata, DNA p erm its in form ation on self-rep orted illegal acts to be reliably lin ked to an in dividual. Sp e cia l p re ca u tio n s will th e re fo re b e n e ce ssa r y to p ro te ct p riva cy in ep idem iological studies of illicit drug use that also collect biological sam p les. Th is m ay requ ire legislation sim ilar to th at wh ich ap p lies in th e USA.

Em erging ethical issues in neuroscience research Resea rch on vulnera b le p ersons

Research in volvin g p erson s wh o h ave cogn itive or p h ysical im p airm en ts requ ires sp ecial eth ical con sideration (Brody, 1998). A m ajor eth ical issu e is wh eth er vu ln erab le p erson s are cap ab le of p rovid in g in form ed con sen t, sp ecifically wh eth er th ey are able u n derstan d th e ration ale beh in d a clin ical trial (Mora, 2000), un derstan d exactly what is required of them an d why (Stahl, 1996), an d give th eir free an d in form ed con sen t to p articip ate in th e stu dy (An th on y & Helzer, 1991).

A p erson m ay be vuln erable for on e or m ore of th e followin g th ree reason s: p erson al lim itation s to th eir freedom (in trin sic), en viron m en tal factors th at lim it th eir freedom (extrin sic), an d lim itation s on th eir freedom by virtu e of

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

a relation sh ip with an oth er p erson or grou p (relation al) (Roberts & Roberts, 1999).

Are sub sta nce d ep end ent p eop le vulnera b le p ersons?

Few stu dies h ave been con du cted on wh eth er p erson s wh o are su bstan ce dep en den t h ave an im p aired cap acity to con sen t to p articip ation in research (Ad ler, 1995; Gorelick et al., 1999). Most of th e recen t con troversy ab ou t n eu roscien ce research on vu ln erable p op u lation s h as been abou t research o n p e r so n s wit h sc h izo p h re n ia (Sh a m o o, 1998) a n d st r o ke (Alve s & Macciocch i, 1996). In th ese cases, th ere are seriou s d ou b ts ab ou t th e cap acity of som e p atien ts to give free an d in form ed con sen t becau se th ey are cogn itively im p aired, eith er in term itten tly or ch ron ically. Th ere are som e an alogies between th ese cases an d issu es con cern in g exp erim en tal research on p erson s wh o are su bstan ce dep en den t. Th ere are lon g-term n eu rological, cogn itive an d p sych iatric con sequ en ces of som e typ es of su bstan ce u se (see Ch ap ter 4), wh ich m ay affect th e ability of som e in dividu als to give in form ed con sen t.

Dru g dep en den t p erson s m ay be vu ln erable to coercion an d in du cem en t to p a rticip a te in resea rch wh en th ey a re in toxica ted or wh en th ey a re exp erien cin g acu te with drawal sym p tom s (Adler, 1995; Gorelick et al., 1999). Person s wh o are severely in toxicated by alcoh ol an d cocain e, for exam p le, su ffer sim ilar im p airm en ts to a p erson wh o is acu tely p sych otic. Sim ilarly, a p erson wh o is exp erien cin g acu te with drawal sym p tom s cou ld be in du ced to con sen t to p articip ate in research stu dies by offerin g th em th e su bstan ce on wh ich th ey are d ep en d en t, or m ed ication to relieve th eir with d rawal sym p tom s (Adler, 1995; Gorelick et al., 1999). In toxicated p erson s sh ou ld n orm ally be exclu ded from exp erim en tal stu dies on th e grou n ds of good research d esign , ap art from th e eth ical p rob lem s associated with th eir in clu sion . Issu es of in form ed con sen t arise in con du ctin g con trolled trials of dru gs th at are u sed to treat sym p tom s of dru g toxicity or overdose. In su ch cases wh ere a p erson is u n ab le to give con sen t, p roxy con sen t m ay b e requ ired.

Provoca tion stud ies

Provocation stu d ies in n eu roscien ce research on d ep en d en ce often u se n eu roim agin g to stu d y th e effects of a p sych oactive su b stan ce on b rain fu n ction in su bstan ce u sers an d su bstan ce dep en den t p erson s. For exam p le, p erson s dep en den t on h eroin m ay be in jected with a radioactively-labelled su bstan ce, p laced in a PET or SPECT scan (Fu & McGu ire, 1999), an d th en given an op ioid dru g or exp osed to dru g-related stim u li, with th e aim of iden tifyin g sites in th e brain at wh ich th e dru g acts (Sell et al., 1999; Klin g et al., 2000; Martin -Soelch et al., 2001). Th ese p rovocation stu dies in volve little or n o im m ediate prospect of therapeutic gain to participan ts. Their m ost likely

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

ben efits are an im p roved u n derstan din g of su bstan ce dep en den ce th at m ay ben efit fu tu re p atien ts by im p rovin g treatm en t ou tcom e.

In form ed -con sen t p roced u res for p rovocation stu d ies on su b stan ce dep en den ce n eed to m ake clear to p oten tial p articip an ts th e absen ce of an y therapeutic gain , an d the risks of participation . Participan ts who were seekin g treatm en t sh ou ld be actively referred to a treatm en t service (Gorelick et al., 1999). Steps also n eed to be taken to en sure that the capacity to give volun tary con sen t is n ot im p aired because p articip an ts are in toxicated or exp erien cin g wit h d ra wa l sym p t o m s. Th is m a y re q u ire scre e n in g fo r sym p t o m s o f in toxication an d with drawal at th e tim e of recru itm en t (Adler, 1995).

Dru g adm in istration in th ese stu dies is con siderably less risky th an dru g u se th at occu rs ou tside th e laboratory settin g. Sign ifican tly lower doses of p h arm aceu tically p u re dru gs are u sed in laboratory stu dies, in th e absen ce of con cu rren t dru g u se wh ich occu rs in th e com m u n ity. In addition , th e dru g is adm in istered u n der m edical su p ervision with p rotocols in p lace to deal with an y adverse even ts (Adler, 1995). Th e risks of dru g adm in istration can

be fu rth er redu ced by screen in g ou t p erson s wh o h ave exp erien ced adverse effects from drugs such as the psychostim ulan ts. The use of stim uli associated with su bstan ce u se is m u ch less in vasive an d p oses fewer risks th an exp osu re to d ru gs. Th e rad ioactively-lab elled su b stan ces u sed in som e form s of n eu roim agin g p ose very little risk to p articip an ts, an d th e n ewer im agin g m eth ods, su ch as fMRI, do n ot in volve exp osu re to radiation or radioactive su bstan ces (Gilm an , 1998).

Ethical issues in epidem iological research on substance dependence

Th e m ajor eth ical issu es in ep id em iological research are: en su rin g th at participan ts give free an d in form ed con sen t, an d protectin g their privacy an d th e con fid en tiality of an y in form ation th at is collected . Th ere are also con sideration s u n iqu e to ep idem iological stu dies. Sin ce n o exp erim en tal p rocedu res are in volved, th e m ajor risks th at research p articip an ts face arise from th e p ossible m is-u se of an y in form ation th at th ey p rovide. Th ese risks m ay p oten tially in clu de social ostracism an d stigm atization , if th eir dru g u se becom es kn own to fam ily, frien ds or n eigh bou rs; an d crim in al p rosecu tion , if an y in form ation th at th ey p rovide abou t illegal dru g u se or oth er crim in al beh aviou r becom es kn own to th e p olice in a way th at can be lin ked to th e in dividu al.

Justice an d the criteria for good epidem iological research both require that

a rep resen tative sam p le of th e p op u lation at risk is recru ited in to stu dies of p attern s of su bstan ce u se an d dep en den ce in th e p op u lation . Th ere m ay be issu es raised by p oorer reten tion in lon gitu din al stu dies of th e in digen t an d

h om eless, wh o m ay be at h igh er risk of develop in g su bstan ce dep en den ce. Ju stice m ay also be an issu e if th ere is a p rep on deran ce of stu dies of p erson s en terin g p u blicly-fu n ded treatm en t for su bstan ce dep en den ce, an d a lack of

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

rep resen tation of th ose wh o are treated by p rivate h ealth services or p rivate sp ecialist p h ysician s an d p sych iatrists. It is also p ossible th at th e resu lts of a study m ay poten tially lead to stigm atization of a group, if for exam ple, a study iden tifies a h igh rate of su bstan ce dep en den ce in a p articu lar social, cu ltu ral or eth n ic grou p.

Ethical issues in clinical trials of pharm acological treatm ents for substance dependence

Clin ical trials of n ew th erap eu tic dru gs are requ ired for dru g registration in m ost develop ed cou n tries an d are a n ow widely accep ted p art of m edical p ractice. Th ere is in tern ation al agreem en t on th e criteria for th e eth ical con du ct of su ch stu dies. In addition to th e p reviou sly discu ssed issu es of in d ep en d en t eth ica l review – i.e. free a n d in fo rm ed co n sen t b y stu d y participan ts; an acceptable risk–ben efit ratio for participan ts; an d protection of p atien t p rivacy an d con fiden tiality (Brody, 1998) – th ere are also issu es of trial design , con flict of in terest an d distribu tive ju stice.

Tria l d esign

A ran dom ized con trolled trial is widely accep ted as th e “gold stan dard” for treatm en t evalu ation in m edicin e becau se it m in im izes bias in determ in in g wh ich p a t ie n t s re ce ive wh ich t re a t m e n t s (Co ch ra n e, 1972). Ra n d o m assign m en t to treatm en t is ethically acceptable if there is gen uin e un certain ty abou t th e com p arative worth of th e two treatm en ts; if trial p articip an ts are aware th at th ey will be ran dom ized; an d if th ey are in form ed abou t th e typ e of treatm en t to wh ich th ey m ay be assign ed (e.g. active or p lacebo), an d th e risks of th ese treatm en ts in th e cou rse of obtain in g th eir in form ed con sen t to p articip ate in th e trial.

The choice of a com parison condition for a random ized controlled trial raises the issue of when is it ethically acceptable to com pare the effectiven ess of a n ew drug treatm en t for substan ce depen den ce with a placebo. Som e authors have argued that it is un ethical to provide on ly a placebo treatm en t, if there is an existin g treatm en t that is effective for the con dition (Brody, 1998). This argum ent is relevant in the case of substance dependence, som e form s of which can be life-th reaten in g in th e absen ce of treatm en t. It wou ld be eth ically acceptable, however, to use a placebo com parison con dition if there was n o effective pharm acotherapy for the con dition , an d if both treatm en t groups received the best available psychosocial treatm en t (Gorelick et al., 1999). In t h is ca se, t h e clin ica l t r ia l wo u ld a n swe r t h e q u e st io n : d o e s a d d in g p h arm acoth erapy to good qu ality p sych osocial care im p rove ou tcom e by com parison with addin g a placebo? Sin ce it is likely that an y pharm acotherapy will u ltim ately b e u sed in com b in ation with good q u ality p sych osocial treatm en t (Fox, 1997), this is usually the m ost relevan t question to ask in a ran dom ized con trolled trial of a n ew pharm acotherapy for drug depen den ce.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Distrib utive justice

Ju stice an d th e criteria for sou n d clin ical trials both requ ire th at a rep resen - tative sam p le of th e p op u lation at risk is recru ited in to su ch stu dies (Brody, 1998). Sp ecial efforts m ay n eed to be m ade to en su re th at wom en , ch ildren an d m in ority grou p s are in clu ded in clin ical trials to en su re th at th ey h ave access to the ben efits of research participation an d that the results of research stu dies can be ap p lied to th ese grou p s if dru gs th at are trialed are even tu ally ap p roved an d registered for clin ical u se (Brody, 1998).

Conflicts of interest

An eth ical issu e of in creasin g sign ifican ce, given th e exten t of fu n din g of clin ical trials by p h arm aceu tical com p an ies, is en su rin g p u blic con fiden ce in the results (Davidoff et al., 2001; DeAn gelis, Fon tan arosa & Flan agin , 2001). Pu blic tru st h as been u n derm in ed in recen t years becau se in vestigators h ave failed to disclose th eir p erson al fin an cial in terests in th e ou tcom es of clin ical trials (e.g. as a resu lt of b ein g p aid large con su ltan cy fees for p rom otin g p h arm aceu ticals or sh ares in a p h arm aceu tical com p an y). Th is h as becom e an in creasin gly larger p roblem as p u blic fu n din g for m edical research an d u n iversities h as declin ed an d p h arm aceu tical com p an ies h ave becom e a m a jo r so u rce o f re se a rch fu n d s. Mo re ove r, re se a rch fu n d e d b y t h e se com p an ies h as been con du cted by con tract research organ ization s, with th e

c o n d it io n s in wh ic h d a t a c a n b e p u b lish e d b e in g c o n t ro lle d b y p h arm aceu tical sp on sors (DeAn gelis, Fon tan arosa & Flan agin , 2001; An on , 2001).

No m atter h ow scien tifically rigorous an d eth ically con ducted a study m ay

be, its fin din gs are of lim ited u se if th e p u blic does n ot h ave con fiden ce in their validity (Davidoff et al., 2001; DeAn gelis, Fon tan arosa & Flan agin , 2001).

A n u m ber of p olicies h ave been im p lem en ted by editors of leadin g m edical jou rn als in an effort to restore tru st in clin ical research . On e is th e decision by these editors to require that authors disclose fun din g sources an d poten tial con flicts of in terest, an d assert th at th ey h ave h ad com p lete con trol over th e stu dy data an d th eir an alysis (Davidoff et al., 2001; DeAn gelis, Fon tan arosa & Flan agin , 2001). An other policy has been the creation of a register of clin ical trial p rotocols before th e start of th e stu dy to m in im ize th e su p p ression of u n favou rable resu lts or ex p ost facto selection of resu lts an d m eth ods of an alysis in order to m ake a dru g look its best (Horton , 1997).

Addition al p olicy recom m en dation s h ave been m ade th at h ave n ot so far been im p lem en ted. Th ese in clu de: in dep en den t m on itorin g of com p lian ce with th e stu d y p rotocol, esp ecially with rep ortin g of an y ad verse even ts exp erien ced by p articip an ts; an d a requ irem en t th at in vestigators an d th e sp on sors of a trial com m it to p u b lish in g its resu lts with in two years of com p letin g d ata collection , as a con d ition of th e stu d y p rotocol b ein g ap p roved by an eth ics com m ittee (Reiden berg, 2001). Th e latter seem s well

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

b ased given th at th e m ajor eth ical ju stification for u n d ertakin g research studies is to con tribute to scien tific kn owledge (Brody, 1998), an d th is can n ot

h ap p en if trial resu lts are n ot p u blish ed (Reiden berg, 2001).

Trials of preventive pharm acological interventions for substance dependence

Psych osocial an d edu cation al in terven tion s h ave been widely u sed with th e aim of p reven tin g you n g p eop le from u sin g dru gs (Sp oon er & Hall, 2002). Un iversal in terven tion s are aim ed at all you n g p eop le, wh ile in d icated , targeted or selective in terven tion s are aim ed at th ose you n g p eop le wh o are iden tified as bein g at h igh er risk of in itiatin g dru g u se. Th e im p act of both u n iversal an d selective edu cation al in terven tion s on rates of dru g u se h as often been m odest (Nation al Research Cou n cil, 2001).

Psych osocial p reven tive in terven tion s raise eth ical issu es. Un iversal in terven tion s (th ose d irected at all you n g p eop le) raise con cern s ab ou t u n in t e n d e d a d ve r se c o n se q u e n c e s, su c h a s e n c o u ra gin g d r u g exp erim en tation in you n g p eop le. Targeted or in dicated in terven tion s raise addition al eth ical issu es becau se th ey requ ire th e iden tification of you n g p eop le wh o are at in creased risk of u sin g dru gs. Th eir con sen t an d th at of th eir p aren ts is requ ired for th em to p articip ate in p reven tive in terven tion s. In th e p rocess of obtain in g su ch con sen t, th e p aren ts an d th eir ch ildren m ay becom e acqu ain ted with th eir risk statu s. Particip ation in trials of p reven tive in terven tion s m ay also exp ose th e ch ild ren to social stigm atization an d discrim in ation , if it becom es kn own to th eir teach ers, p eers an d th eir p eers’ p aren ts. For exam p le, p aren ts wh ose ch ildren are ju dged to be at “low risk” m ay actively d iscou rage th eir ch ild ren from associatin g with “h igh -risk”

ch ildren , or th ey m ay in sist th at h igh -risk ch ildren be exclu ded or rem oved from sch ools. The sam e ethical issues of stigm atization an d discrim in ation are also raised by p h arm acological or im m u n ological in terven tion s th at aim to p reven t su bstan ce dep en den ce. Two su ch in terven tion s are discu ssed below: early p h arm acological in terven tion s in p erson s at risk of su bstan ce dep en den ce th at m ay be in sp ired by sim ilar efforts to p reven t p sych oses (McGorry, Yu n g & Ph illip s, 2001); an d th e p reven tive u se of im m u n oth erap ies again st dru g effects to redu ce risk of su bstan ce dep en den ce (Coh en , 1997).

Ea rly intervention stud ies

Early in terven tion s for substan ce dep en den ce have been discussed which would be an alogous to studies of schizophren ia that iden tify person s who are at in creased risk of developin g the disorder because they have a fam ily history of schizophren ia or they have psychological sym ptom s that m ay be early or “prodrom al” sym ptom s of the disorder. The aim of this approach is to preven t th e d e ve lo p m e n t o f sch izo p h re n ia b y a co m b in a tio n o f go o d q u a lity

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

psychosocial care an d low doses of the n euroleptic drugs that are used to treat schizophren ia (McGorry, Yun g & Phillips, 2001). Studies in Australia an d the USA have shown that it is possible, usin g stan dardized criteria, to iden tify a gro u p o f yo u n g p e o p le wh o h a ve a h igh risk (30–40%) o f d e ve lo p in g schizophren ia in the en suin g 6 to 12 m on ths (McGlashan , 2001; McGorry, Yun g & Phillips, 2001). A n um ber of quasi-experim en ts an d ran dom ized con trolled trials su ggest th at th e com b in ed in terven tion red u ces th e rate at wh ich schizophren ia occurs an d reduces its severity (McGorry, Yun g & Phillips, 2001). Sim ilar trials can be foreseen for substance dependence, once research clarifies the risk an d protective factors, gen etic predisposition , an d treatm en t option s.

Critics of th ese stu dies h ave raised a n u m ber of eth ical issu es (Corn blatt, Len cz & Kan e, 2001; DeGrazia, 2001). Th ese in clu de th e fact th at th ere is a

h igh false p ositive rate: 60% of th ose wh o are iden tified as bein g at risk of develop in g sch izop h ren ia do n ot develop th e disorder. Th is can also be seen to ap p ly to th e d evelop m en t of su b stan ce dep en den ce. Th ere is also th e p oten tia l for stigm a tiza tion a n d d iscrim in a tion a ga in st th ose wh o a re iden tified as bein g at risk. Even if th ere is n o discrim in ation , th ere is th e p ossibility th at th ere will be adverse effects on in dividu als of bein g labelled as at risk. There is also con cern about the capacity of children an d adolescen ts to con sen t to p articip ate in su ch stu dies, an d dou bts abou t th e accep tability of u sin g p roxy p aren tal con sen t. Lon g-term p reven tive treatm en t with dru gs m a y h a ve h ea lth con seq u en ces. McGorry, Yu n g & Ph illip s (2001) h a ve cou n tered, with resp ect to sch izop h ren ia, th at th e p oten tial ben efits (th e p reven tion of sch izop h ren ia an d early treatm en t of cases th at d o occu r) ou tweigh th e p oten tial risks of n eu rolep tic m edication an d stigm atization , both of wh ich th ey su ggest (on th e basis of con trolled stu dies) h ave been exaggerated.

An alogous ap p roach es to early in terven tion s could be taken for substan ce dep en den ce, alth ou gh to date n o trials h ave been exp licitly u n dertaken with the aim of usin g pharm acotherapies as preven tive in terven tion s for substan ce dep en den ce. It is likely th at m an y of th e sam e eth ical issu es wou ld arise. Psychostim ulan t drugs, such as m ethylphen idate an d dexam phetam in e, have

b e e n u se d t o t re a t c h ild re n a n d a d o le sc e n t s wit h a t t e n t io n d e fic it

h yp eractivity disorder (ADHD), an in terven tion th at is con troversial (Levy, 1997). Sin ce ADHD in com bin ation with con duct disorders in creases the risks o f d e ve lo p in g su b st a n c e u se d iso rd e r s (Lyn ske y & H a ll, 2001), a n d p sych ostim u lan t dru gs redu ce sym p tom s of ADHD (Swan son et al., 1998), an u n in ten d ed by-p rod u ct of p sych ostim u lan t m ed ication m ay b e th e p reven tion of su bstan ce u se disorders. However, n o on e h as so far argu ed for th e u se of p sych ostim u lan t m edication to p reven t su bstan ce dep en den ce, an d it is u n likely th at an yon e wou ld do so. Pu blic con cern abou t th e lon g- term u se of stim u lan t dru gs to treat ADHD su ggests th at an y su ch p rop osal will be op p osed an d su p p ort for th e ch ron ic u se of dru gs in late ch ildh ood or adolescen ce to p reven t th e develop m en t of su bstan ce dep en den ce wou ld seem to be even less likely.

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

Preventive use of d rug im m unothera p ies

An im al stu dies h ave sh own th at it is p ossible to in du ce th e form ation of an tibodies to substan ces such as cocain e (Fox et al., 1996; Carrera et al., 2000). Th ese an tib od ies in th e b lood com b in e with th e su b stan ce to p reven t it reach in g th e brain to exert its effects (Fox et al., 1996) (see Ch ap ter 4). An im al studies show that an tibodies again st cocain e m arkedly atten uate its stim ulan t effects an d block self-adm in istration in rats (Carrera et al., 1995; Joh n son & Ettin ger, 2000). If cocain e im m u n oth erap ies p rove safe an d effective in treatin g p erson s with cocain e dep en den ce, th ey cou ld be u sed to p reven t cocain e dep en den ce in adolescen ts an d you n g adu lts, as well as in adu lts an d in legally coerced treatm en t. Su ch p ossibilities h ave been raised an d briefly discu ssed (Coh en , 1997, 2000). Sim ilar argu m en ts will n o dou bt arise with th e p rop osed p reven tive u se of n icotin e im m u n oth erap ies.

If a con trolled clin ical trial d em on strates th at n icotin e an d cocain e im m un otherapies are safe an d effective treatm en ts of these types of substan ce

d ep en d en ce, th en a n u m b er o f eth ica l issu es co n cern in g th eir u se in volu n tary treatm en t of su bstan ce dep en den t adu lts n eed to be addressed (Cohen , 1997; Hall & Carter, 2002). The preven tive use of cocain e an d n icotin e im m u n oth erap ies wou ld b e eth ical in th e case of ad u lts wh o volu n tarily decided to u se th em after bein g in form ed of an y risks. Th e im m u n oth erap ies wou ld n eed to be sh own to be safe an d effective for th is p u rp ose, with h igh er stan dards of p roof gen erally requ ired for th e safety an d efficacy of p reven tive m e a su re s (H a ll & Ca r t e r, 2002). Th e fo re se e a b le r isks o f u sin g t h e im m u n oth erapy wou ld h ave to be com m u n icated to th e p erson , wh o wou ld

h ave given in form ed con sen t to its u se, an d step s wou ld n eed to be taken to p ro t e ct t h e p e rso n’s p r iva cy. Un d e r t h e se co n d it io n s, t h e vo lu n t a r y

ad m in istration of a cocain e im m u n oth erap y to con sen tin g ad u lts wh o con sidered th em selves to be su scep tible to cocain e dep en den ce wou ld be eth ically accep table (Hall & Carter, 2002). However, su ch u se is likely to be u n u su al.

A poten tially un ique feature of active im m un ization again st cocain e is that it m ay, in p rin cip le, h ave lon g-lastin g con seq u en ces, n am ely, creatin g an tibodies th at can be detected in th e blood of treated p atien ts for som e m on th s or years. Th ese an tibody levels m ay n ot be su fficien tly h igh to be th erap eu tic bu t th e fact th at th ey cou ld be detected raises th e eth ical issu es of p rivacy an d discrim in ation (Coh en , 1997).

Of sp ecial con cern is th e p ossible loss of p rivacy by recoverin g cocain e- dep en den t in dividu als if em p loyers an d in su ran ce com p an ies h ad access to th is in form ation . Em p loyers an d in su ran ce com p an ies often obtain detailed person al m edical in form ation an d, on occasion , blood sam ples from poten tial em p loyees or clien ts. Becau se th e com m u n ity often stron gly disap p roves of cocain e dep en den ce, th e loss of p rivacy by a recoverin g cocain e-dep en den t in dividu al m ay lead to em barrassm en t, at best, an d to social stigm atization an d ostracism by p eop le in th eir social en viron m en t an d in th e wid er

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

com m u n ity. In th e fu tu re, in creasin g social stigm atization of sm okers, an d th e p ossib ility of d iscrim in ation by em p loyers an d th e h ealth in su ran ce in dustry, m ay raise sim ilar issues for sm okers who use n icotin e im m un ization to stop sm okin g.

Discrim in ation m ay arise if workp lace-based dru g testin g were to screen for cocain e an tibodies before an d durin g em ploym en t. A recoverin g cocain e- dep en den t p erson wou ld be at risk of losin g an em p loym en t op p ortu n ity or

h is or h er job if cocain e an tibodies were detected in a blood sam p le. If th is in form ation were m ore widely dissem in ated to oth er workers it cou ld h ave a

d e va sta tin g e ffe ct o n th e e m p loym e n t p ro sp e cts a n d re cove r y o f th e in dividu al (Coh en , 1997). On e way of avoidin g th ese ou tcom es m ay be to accep t Coh en’s p rop osal th at a society th at wish es to h ave th e ben efits of a cocain e im m u n oth erapy “m u st in stitu te legal an d b eh aviou ral ch an ges th at p reserve p rivacy an d con fiden tiality” (Coh en , 1997). Th is requ ires a cu ltu re th at en cou rages an d supports the recovery of person s with substan ce depen den ce. Legislation that p u n ish es discrim in atory beh aviou r towards recoverin g p erson s h as been

ad op ted in th e case of HIV-in fected p erson s. Th e ad op tion of a sim ilar ap p roach to p eop le wh o h ave been treated for cocain e dep en den ce wou ld

be an im portan t step towards reducin g discrim in ation an d protectin g privacy. Th e risks of loss of p rivacy an d discrim in ation cou ld also be m in im ized by u sin g “p assive” rath er th an “active” im m u n ization to p reven t relap se (e.g. by

ad m in isterin g an tib od ies to cocain e rath er th an an im m u n ization ). Th is ap p roach wou ld n ot p rodu ce an en du rin g ch an ge in th e p erson’s im m u n e system an d th e an tibodies wou ld disap p ear over a p eriod of weeks. Th ese advan tages wou ld be gain ed at th e exp en se of a sh orter p eriod of p rotection (with ou t a booster in jection ) th at m ay redu ce treatm en t effectiven ess. Th is m ay be a trade-off th at a p atien t con cern ed about p rivacy would be p rep ared to m ake, bu t it is a ch oice th at th ey sh ou ld be offered (Hall & Carter, 2002).

Th e p reven tive “im m u n ization” of ch ild ren an d ad olescen ts again st cocain e dep en den ce is a m uch m ore ethically com p lex issue. Children would presum ably be im m un ized again st cocain e depen den ce at the request of their p aren ts. Th eir p aren ts wou ld con sen t on beh alf of th eir ch ildren wh o, as m in ors, wou ld n ot be legally able to give in form ed con sen t. Paren ts already m ake ch oices on beh alf of th eir ch ildren th at will affect th eir fu tu re (e.g. re ga rd in g d ie t a n d e d u c a t io n ). So m e h a ve a r gu e d , t h e re fo re , t h a t im m un ization again st cocain e depen den ce would sim ply be an other decision th at som e p aren ts wou ld m ake for th eir ch ildren (Coh en , 1997). On th e basis of th is argu m en t, a p aren t wou ld h ave th e righ t to im m u n ize th eir ch ildren again st cocain e dep en den ce in m u ch th e sam e way as th ey h ave th e righ t to im m un ize them again st m easles or other in fectious diseases (Kaebn ick, 2000).

Cocaine use m ay begin in adolescence. Adolescents under the age of m ajority have sufficien t capacity to be in volved in decision s about their future, such as whether they wan t to be im m un ized again st cocain e depen den ce. Even if it is ethically acceptable for parents to consent on behalf of their children, the assent

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

of an adolescen t or an older child should be sought, an d if they fail to give it, their decision should rarely be overridden an d on ly if there is a stron g reason for doin g so (Brody, 1998). It m ust be rem em bered that n ot everyon e who uses cocain e for the first tim e goes on to becom e depen den t.

Im plications of neuroscience research for m odels of substance dependence

Th ere h as been a lon g-stan din g con flict between m oral an d m edical m odels of substan ce depen den ce (Gerstein & Harwood, 1990; Leshn er, 1997). A m oral m odel of su bstan ce dep en den ce sees it as largely a volu n tary beh aviou r in wh ich p eop le freely en gage. Drug users wh o offen d again st th e crim in al code are th erefore to be p rosecu ted an d im p rison ed if fou n d gu ilty (Szasz, 1985).

A m edical m odel of substan ce depen den ce, by con trast, recogn izes that, while m an y p eop le u se certain p sych oactive dru gs with ou t develop in g su bstan ce depen den ce, a sm all proportion of users develop substan ce depen den ce that requ ires sp ecific treatm en t (Lesh n er, 1997).

Medical m odels of su bstan ce dep en den ce m ay n ot be a wh olly p ositive develop m en t if th ey lead to over-sim p lified social p olicies. For exam p le, th e idea th at su bstan ce dep en den ce is a categorical disease en tity len ds itself to

a sim p lification in th e case of alcoh ol, n am ely, th at if p eop le wh o are gen etically vu ln erable to alcoh ol dep en den ce are iden tified, th en th ere m ay

be an assu m p tion th at th e rest of th e p op u lation can u se alcoh ol with ou t develop in g dep en den ce (Hall & San n ibale, 1996). Th is view does n ot take in to accou n t th e adverse p u blic h ealth effects of alcoh ol in toxication . It is also at odds with th e m u lti-dim en sion al n atu re of alcoh ol an d illicit dru g u se an d sym p tom s of su bstan ce dep en den ce, an d with th e gen etic eviden ce th at m u ltip le gen es are in volved in vu ln erability to su bstan ce dep en den ce (see Chapter 5). It can also lead users to abdicate respon sibility for their behaviour (Nelkin & Lin dee, 1996), an d to a p reoccu p ation with in dividu al exp lan ation of behaviour with a correspon din g lack of atten tion towards rem ediable social cau ses an d social p olicy op tion s for redu cin g th e p revalen ce of su bstan ce dep en den ce, in clu din g dru g con trol p olicies.

The im plication s of a n euroscien ce view of substan ce depen den ce for drug con trol p olicy (discu ssed below) are also n ot as sim p le as th ey m ay seem . Exp osu re to dru g u se rem ain s a n ecessary con dition for th e develop m en t of su bstan ce dep en den ce. Th u s societal efforts still n eed to be m ade (wh eth er by crim in al law or p u blic h ealth m easu res) to lim it access to dru gs by you n g p eop le (Lesh n er, 1997). Socia l d isa p p rova l rem a in s a p oten t m ea n s of

d isco u ra gin g d ru g u se. It is h o p ed th a t n eu ro scien ce exp la n a tio n s o f su bstan ce dep en den ce m ay tem p er social stigm atization an d ostracism of p eop le with su b stan ce d ep en d en ce. Dem on stration s of th e greater cost- effectiven ess of treatm en t com p ared with im p rison m en t m ay also p rovide an econ om ic ju stification for a m ore h u m an e, as well as a m ore effective an d efficien t, societal resp on se to su bstan ce dep en den ce.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Th e ch allen ge for th e n eu roscien ce com m u n ity in th e field of su bstan ce dep en den ce is to exp lain su bstan ce dep en den ce in biological term s with ou t

d ep ictin g p eop le with su b stan ce d ep en d en ce as au tom aton s u n d er th e con trol of recep tors in th eir brain s (Valen stein , 1998). Th is m ean s viewin g su bstan ce dep en den ce as th e resu lt, in p art, of ch oices th at are m ade by in dividu als, n ot always in dep en den tly. In th e case of you n g p eop le, m an y of th em op erate with a sh ort-term view, a sen se of p erson al in vu ln erability, an d with scep ticism towards th eir elders’ warn in gs abou t th e risks of su bstan ce use. Adolescen ts are particularly vuln erable to m arketin g pressures, especially with regard to tobacco an d alcoh ol u se. It will also m ean viewin g su bstan ce dep en den ce as a m atter of degree, with dep en den t dru g u sers retain in g th e cap acity to ch oose to becom e abstin en t an d to seek h elp to do so. It will also m ean ackn owledgin g th at p h arm acological treatm en t is on ly th e begin n in g of th e p rocess of recovery an d rein tegration of th e dru g dep en den t p erson in to th e com m u n ity. Moreover it will requ ire atten tion to a broader ran ge of social p olicies in seekin g to p reven t dru g u se by you n g p eop le (Sp oon er & Hall, 2002).

Im plications of neuroscience research for the treatm ent of substance dependence

Access to trea tm ent

If p h arm acological treatm en ts derived from n eu roscien ce research p rove to

be effective, th e issu e of en su rin g equ al access to treatm en t for all th ose wh o m ay n eed it is an eth ical issu e th at n eeds to be addressed. If a su bstan tial p rop ortion of su bstan ce-dep en den t p erson s are u n able to access treatm en t

b ecau se th ey can n ot afford it, p u b lic fu n d in g m ay b e n eed ed (Gerstein & Harwood, 1990). Pu blic p rovision of su ch treatm en t will requ ire econ om ic ju stification , esp ecially in th e case of p erson s wh o are dep en den t on illicit dru gs, m an y of wh om will be in digen t an d u n able to p ay for th eir treatm en t. Advocates for p u blicly su bsidized dru g treatm en t will n eed to m ake clear th e com p arative econ om ic an d social costs of treatin g dru g dep en den t p eop le, as again st th e cu rren t p olicy in m an y cou n tries of dealin g with su bstan ce depen den ce solely through the crim in al justice system (Gerstein & Harwood, 1990; Nation al Research Cou n cil, 2001).

Lega lly coerced trea tm ent

Th e p oten tial u se of a p h arm acological treatm en t for su bstan ce dep en den ce or a d ru g im m u n oth erapy u n d er legal coercion n eed s to b e con sid ered (Coh en , 1997). It is often th e first p ossible u se raised wh en th e con cep t of a dru g im m u n oth erapy is m en tion ed; com m u n ity con cern abou t th is way of u sin g dru g im m u n oth erap ies m ay also adversely affect attitu des towards oth er th erap eu tic u ses. Th e issu e accordin gly n eeds to be discu ssed, even if

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

it is a lon g way from bein g realized. Th ere are good reason s for cau tion abou t an y coerced u se of a p h arm acological treatm en t or a dru g im m u n oth erapy. The com m un ity has little sym pathy for drug depen den t offen ders who en gage in p rop erty-related an d oth er crim es, so p articu lar atten tion m u st be p aid to p rotectin g th e legal an d h u m an righ ts of dru g offen ders.

Th e ration ale for treatm en t u n der legal coercion Legally coerced dru g treatm en t is en tered in to by p erson s ch arged with or

c o n vic t e d o f a n o ffe n c e t o wh ic h t h e ir su b st a n c e d e p e n d e n c e h a s con tributed. It is m ost often p rovided as an altern ative to im p rison m en t, an d u su ally u n der th e th reat of im p rison m en t if th e p erson fails to com p ly with treatm en t (Hall, 1997; Sp oon er et al., 2001).

On e of th e m ajor ju stification s for treatm en t u n der coercion is th at it is an effective way of treatin g offen ders’ su bstan ce dep en den ce th at will redu ce th e likelih ood of th eir re-offen d in g (Gerstein & Harwood , 1990; In ciard i & McBride, 1991). Th is ap p roach h as h istorically been m ost often u sed in th e treatm en t of offen ders wh o are dep en den t on h eroin (Leu kefeld & Tim s, 1988) alth ou gh it h as m ost recen tly b een u sed with cocain e-d ep en d en t offen ders in “dru g cou rts” in th e USA (Nation al Research Cou n cil, 2001). On e issu e is wh eth er th ere sh ou ld be a h igh er stan dard of p roven effectiven ess for coerced rath er th an for volu n tary treatm en t. An oth er issu e is th at if th e treatm en t is cou rt-m an dated, th ere m ay be a ten den cy for th e treatm en t p eriod to last at least as lon g as wou ld th e jail term . Th u s, th e form an d du ration of th e treatm en t are bein g set by criteria wh ich relate to th e ju dicial system , an d n ot n ecessarily to th erap eu tic best p ractice.

Th e adven t of HIV/ AIDS h as p rovided an addition al argu m en t for treatin g rath er th an im p rison in g dru g-dep en den t offen ders. Prison ers wh o in ject dru gs are at h igh er risk of h avin g con tracted HIV an d h ep atitis C viru s by n eed le-sh arin g p rior to im p rison m en t (Dolan , 1996). Th ey are at risk of tran sm ittin g th ese in fectiou s diseases to oth er in m ates by n eedle-sh arin g an d p en etrative sexu al acts wh ile th ey are in p rison (Vlah ov & Polk, 1988) an d also to their sexual partn ers before or after im prison m en t. Providin g drug treatm en t u n d er coercion in th e com m u n ity is on e way of red u cin g HIV tra n sm issio n . Th e co rrectio n a l a n d p u b lic h ea lth a rgu m en ts fo r d ru g treatm en t u n der coercion are rein forced by th e econ om ic argu m en t th at it is less costly to treat offen ders wh o are dru g dep en den t in th e com m u n ity th an it is to im p rison th em (Gerstein & Harwood, 1990).

Form s of legal coercion Offen ders m ay be coerced in to dru g treatm en t in a variety of ways (Gostin ,

1991; Sp oon er et al., 2001). After an offen ce h as been detected th e p olice m ay decide n ot to ch arge th e offen der if h e or sh e agrees to en ter dru g treatm en t. This form of coercion is n ot gen erally favoured because it is n ot un der judicial

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

oversigh t an d th u s is op en to abu se. Coercion in to treatm en t m ay also occu r after an offen der h as been ch arged an d before bein g p rocessed by th e cou rt. Th is is th e case in USA dru g cou rts, wh ere adju dication m ay be p ostp on ed u n til treatm en t h as been com p leted (Gen eral Accou n tin g Office, 1995).

An offen der m ay be coerced in to treatm en t after con viction . If th is is don e before sen ten cin g, th e cou rt m ay m ake com p letion of treatm en t a con dition of a su sp en ded sen ten ce. Altern atively, an offen der m ay be en cou raged to en ter dru g treatm en t to h elp h im or h er to rem ain abstin en t wh ile a sen ten ce is su sp en ded. Dru g treatm en t m ay also be requ ired after p art of a sen ten ce

h as been served: en rolm en t in dru g treatm en t m ay be m ade a con dition of relea se o n p a ro le. Altern a tively, en ro lm en t in d ru g trea tm en t m a y b e en cou raged as a way of rem ain in g free of illicit dru gs wh ile on p arole.

Eth ical issu es in coerced treatm en t Coerced treatm en t in volves th e u se of state p ower to force p eop le to receive

treatm en t an d so u n avoidably raises eth ical an d h u m an righ ts issu es (Man n , 1999). Eviden ce from the USA suggests that treatm en t for heroin depen den ce, su ch as m eth adon e m ain ten an ce, th erap eu tic com m u n ities an d dru g free cou n sellin g, is of ben efit to th ose wh o receive it (Gerstein & Harwood, 1990). However, th e ben efits for an y in dividu al are still u n certain sin ce treatm en t assists on ly abou t 50% of th ose wh o receive it (Gerstein & Harwood, 1990), an d relap se to h eroin u se after treatm en t is h igh . Th e treatm en t of cocain e dep en den ce is m u ch less effective th an treatm en t for op ioid dep en den ce (Platt, 1997). Th is weaken s th e eth ical ju stification for “civil com m itm en t” for cocain e d ep en d en ce b u t it m ay n ot ru le ou t less coercive form s of treatm en t.

A con sen su s view on dru g treatm en t u n der coercion p rep ared for WHO (Porter, Arif & Cu rran , 1986) con clu ded th at su ch treatm en t was legally an d eth ically ju stified on ly if th e righ ts of th e in dividu als were p rotected by “du e p rocess” (in accordan ce with h u m an righ ts p rin cip les) (Mora, 2000), an d if effective an d h u m an e treatm en t was p rovided (Stah l, 1996).

Th e u n certain ben efits of coerced treatm en t h ave led som e p rop on en ts to argue that offen ders should be allowed two “con strain ed choices” (Fox, 1992). Th e first con strain ed ch oice wou ld b e wh eth er th ey p articip ate in d ru g treatm en t or n ot. If th ey declin ed to be treated, th ey wou ld be dealt with by th e crim in al justice system in th e sam e way as an yon e ch arged with th e sam e offen ce. Th e secon d con strain ed ch oice wou ld be given to th ose wh o agreed to p articip ate in dru g treatm en t: th ey wou ld be given th e ch oice of th e typ e of treatm en t th at th ey received. Th ere is som e em p irical su p p ort for th ese recom m en dation s in th at th ere is better eviden ce for th e effectiven ess of coerced treatm en t th at requ ires som e “volu n tary in terest” by th e offen der (Gerstein & Harwood, 1990).

Th e m ost eth ically defen sible form of legally coerced treatm en t for dru g depen den t offen ders is the use of im prison m en t as an in cen tive for treatm en t

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

en try, an d fear of retu rn to p rison as a reason for com p lyin g with d ru g treatm en t. Offen ders sh ou ld h ave a con strain ed ch oice as to wh eth er th ey take u p treatm en t or n ot, an d, if th ey ch oose to do so, th ey sh ou ld be able to

ch oose from a ran ge of treatm en t op tion s. Moreover, th e p rocess sh ou ld be su bject to ju dicial oversigh t an d review. If drug im m un oth erap ies an d p h arm acological treatm en ts are used un der legal coercion , th eir safety, effectiven ess an d cost-effectiven ess sh ou ld be rigorou sly evalu ated (Nation al Research Cou n cil, 2001). An y su ch u se sh ou ld

be cau tiou sly trialed an d evalu ated, an d on ly after con siderable exp erien ce

h as been acqu ired in th eir th erap eu tic u se with volu n tary p atien ts.

Sum m ary and conclusions

Su b sta n ce d e p e n d e n ce is a se rio u s p e rso n a l a n d p u b lic h e a lth issu e th rou gh ou t th e world. Man y form s of su bstan ce dep en den ce are difficu lt to t re a t b e ca u se o f a la ck o f e ffe ct ive p sych o so cia l o r p h a rm a co lo gica l treatm en ts.

Experim en tal studies on hum an s of the n eurobiological basis of substan ce dep en den ce raise a n u m ber of eth ical issu es, on e of wh ich is th e cap acity of dep en den t p erson s to give th eir con sen t to p articip ate in su ch stu dies. As lon g a s p a rticip a n ts a re n ot in toxica ted or su fferin g a cu te with d ra wa l sym p tom s at th e tim e th ey give con sen t, th ere is n o com p ellin g reason for believin g th at p erson s wh o are su bstan ce dep en den t can n ot give free an d in form ed con sen t. Th e risks of ad m in istration of d ru gs, an d th e u se of n euroim agin g m ethods in these exp erim en ts, gen erally do n ot p ose a serious risk to p articip an ts.

Th e eth ical issu es raised by clin ical trials of n ew p h arm acoth erap ies h ave been exten sively debated an d a con sen sus has evolved on the con dition s that m u st be m et. Th ese in clu de free an d in form ed con sen t, an accep table risk– ben efit ratio, an d p rotection of p articip an t p rivacy an d con fiden tiality. Trials with su bstan ce dep en den t p erson s requ ire sp ecial atten tion to in form ed con sen t in order to en su re th at p erson s are n ot in toxicated or exp erien cin g with d ra wa l sym p to m s wh en d ecid in g to p a rticip a te in tria ls. Pla ceb o com p arison s m ay be eth ically accep table in su ch trials if th ere is n o effective p h a r m a c o t h e ra p y a n d if p a r t ic ip a n t s a re a lso o ffe re d go o d q u a lit y p sych osocial care.

Preven tive p h arm acological in terven tion s for su bstan ce dep en den ce do n ot yet exist an d are likely to be h igh ly con troversial if th ey are develop ed. It is a p ossibility th at m ay loom larger in th e fu tu re with th e develop m en t of in terven tion s th at h ave a p oten tial p reven tive u se, forem ost am on g wh ich are dru g im m u n oth erap ies. Th e eth ical issu es raised by th ese ap p roach es n eed to be debated n ow. Th e risks of stigm atization an d discrim in ation th at are raised by an y p reven tive in terven tion th at iden tifies h igh -risk su bjects will n eed to be dealt with . So too will issu es of con sen t in m in ors, an d th e p oten tial risks to p articip an ts of im m u n ological in terven tion s.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Th e u se of p h arm acoth erap ies an d dru g im m u n oth erap ies u n der legal coercion is likely to be con ten tiou s. It is an argu ably eth ical p olicy if th e p rocess is u n der ju dicial oversigh t an d if offen ders are offered con strain ed

ch oices of wh eth er or n ot to accep t treatm en t, an d of th e typ e of treatm en t th at th ey accep t. An y coerced u se of a cocain e im m u n oth erapy sh ou ld be don e cautiously an d on ly after con siderable clin ical experien ce of its use with volu n tary p atien ts. It sh ou ld be trialed, an d its safety, effectiven ess an d cost- effectiven ess sh ou ld be rigorou sly evalu ated. Su ch an evalu ation also n eeds to exam in e an y adverse social or eth ical con sequ en ces.

References

Ad ler MW (1995) Hu m an su b ject issu es in d ru g ab u se research : college on p roblem s of dru g dep en den ce. Dru g an d Alcoh ol Depen den ce, 37:167–175.

Alves WA, Macciocch i SN (1996) Eth ical con sideration s in clin ical n eu roscien ce: cu rren t con cep ts in n eu roclin ical trials. Stroke, 27:1903–1909.

Am erican Psych ological Association Scien ce Directorate (2001) Research w ith an im als in psych ology . Wash in gton , DC, Am erican Psych ological Association .

An drews G, Hen derson S, Hall W (2001) Prevalen ce, com orbidity, disability an d service u tilisation : overview of th e Au stralian n ation al m en tal h ealth su rvey. British Jou rn al of Psych iatry , 178:145–153.

An on (2001) Th e tigh ten in g grip of big p h arm a. Lan cet, 357:1141. An thon y JC, Helzer J (1991) Syn drom es of drug abuse an d depen den ce. In : Robin s

LN, Regier DA, eds. Psych iatric disorders in Am erica. New York, NY, Academ ic Press:116–154.

Ash croft R (2001) Selection of h u m an research su bjects. In : Ch adwick R, Ed. Th e con cise en cyclopedia of th e eth ics of n ew tech n ologies . New York, NY, Academ ic Press:255–266.

Beaucham p TL, Childress JF (2001) Prin ciples of biom edical ethics. Oxford, Oxford Un iversity Press.

Brody BA (1998) Th e eth ics of biom edical research : an in tern ation al perspective. Oxford, Oxford Un iversity Press.

Carrera MR et al. (1995) Su p p ression of p sych oactive effects of cocain e by active im m u n ization . Natu re, 378:727–730.

Carrera MR et al. (2000) Cocain e vaccin es: an tibody p rotection again st relap se in a rat m odel. Proceedin gs of the Nation al Academ y of Scien ces of the Un ited States of Am erica , 97:6202–6206.

Coch ran e AL (1972) Effectiven ess an d efficien cy: ran dom reflection s on h ealth services . Abin gdon , Berksh ire, Nu ffield Provin cial Hosp itals Tru st.

Coh en PJ (1997) Im m u n ization for p reven tion an d treatm en t of cocain e abu se: legal an d eth ical im p lication s. Dru g an d Alcoh ol Depen den ce, 48:167–174.

Coh en PJ (2000) No m ore kicks. New Scien tist, 166:23–36.

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

Corn blatt BA, Len cz T, Kan e JM (2001) Treatm en t of th e sch izop h ren ia p rodrom e: is it p resen tly eth ical? Sch izoph ren ia Research , 51:31–38.

Davidoff F et al. (2001) Spon sorship, authorship, an d accoun tability. New En glan d Jou rn al of Medicin e , 345:825–827.

de An gelis CD, Fon tan arosa PB, Flan agin A (2001) Rep ortin g fin an cial con flicts of in terest an d relation ships between in vestigators an d research spon sors. Jou rn al of th e Am erican Medical Association , 286:89–91.

de Grazia D (2001) Eth ical issu es in early-in terven tion clin ical trials in volvin g m in ors at risk for sch izop h ren ia. Sch izoph ren ia Research , 51:77–86.

Dolan K (1996) HIV risk behaviour of IDUs before, durin g an d after im prison m en t in New Sou th Wales. Addiction Research , 4:151–160.

Fergu sson DM, Horwood LJ (2000) Can n ab is u se an d d ep en d en ce in a New Zealan d birth coh ort. New Zealan d Medical Jou rn al, 113:156–158.

Fox BS (1997) Develop m en t of a th erap eu tic vaccin e for th e treatm en t of cocain e addiction . Dru g an d Alcoh ol Depen den ce, 48:153–158.

Fox BS et al. (1996) Efficacy of a th erap eu tic cocain e vaccin e in roden t m odels. Natu re Medicin e , 2:1129–1132.

Fox RG (1992) Th e com p u lsion of volu n tary treatm en t in sen ten cin g. Crim in al Law Jou rn al , 16:37–54.

Fu CH, McGu ire PK (1999) Fu n ction al n eu roim agin g in p sych iatry. Ph ilosoph ical Tran saction s of th e Royal Society of Lon d on (Series B: Biological Scien ces), 354 :1359–1370.

Gen eral Accou n tin g Office (1995) Dru g cou rts: in form ation on a n ew approach to address dru g-related crim e . Wash in gton , DC, Un ited States Gen eral Accou n tin g Office.

Gerstein DR, Harwood HJ (1990) Treatin g d ru g p roblem s. Vol. 1. A stu d y of effect iven ess an d fin an cin g of p u blic an d p rivat e d ru g t reat m en t syst em s . Wash in gton , DC, Nation al Academ y Press.

Gilm an S (1998) Im agin g th e brain : first of two p arts. New En glan d Jou rn al of Medicin e , 338:812–820.

Gorelick D et al. (1999) Clin ical research in su bstan ce abu se: h u m an su bjects issu es. In : Pin cu s HA et al., eds. Eth ics in psych iatric research : a resou rce m an u al for h u m a n su b ject s p rot ect i on . Wa s h in gt o n , D C, Am e r ic a n Ps yc h ia t r ic Association :177–218.

Go st in LO (1991) Co m p u lso r y t re a t m e n t fo r d r u g- d e p e n d e n t p e r so n s: justification s for a public health approach to drug depen den cy. Milban k Qu arterly,

69 :561–593. Gostin LO, Man n JM (1999) Toward th e develop m en t of a h u m an righ ts im p act

assessm en t for the form ulation an d evaluation of public health policies. In : Man n JM et al., eds. Health an d h u m an righ ts: a reader. Lon don , Rou tledge:54–71.

Hall W (1997) Th e role of legal coercion in th e treatm en t of offen ders with alcoh ol an d h eroin p rob lem s. Au stralian an d New Zealan d Jou rn al of Crim in ology,

30 :103–120. Hall W, San n ibale C (1996) Are th ere two typ es of alcoh olism ? Lan cet, 348:1258.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Hall W, Carter L (2002) Eth ical an d p olicy issu es in trialin g an d u sin g a cocain e vaccin e to treat an d p reven t cocain e dep en den ce. Bu lletin of th e World Health Organ ization , (in p ress).

Heath AC (1995) Gen etic in flu en ces on alcoh olism risk: a review of adop tion an d twin stu dies. Alcoh ol Health an d Research World, 19:166–171.

Hjern A, Lin dblad F, Vin n erlju n g B (2002) Su icide, p sych iatric illn ess, an d social m alad ju stm en t in in tercou n try ad op tees in Swed en : a coh ort stu d y. Lan cet, 360 :443–448.

Horton R (1997) Medical editors trial am n esty. Lan cet, 350:756. Hser YI et al. (2001) A 33-year follow u p of n arcotic addicts. Arch ives of Gen eral

Psych iatry , 58:503–508. In ciardi JA, McBride DC (1991) Treatm en t altern atives to street crim e: h istory,

experien ces an d issu es . Rockville, MD, Nation al In stitu te of Dru g Abu se. In tern ation al Federation of Red Cross an d Red Crescen t Societies an d Fran cois-

Xavier Bagn ou d Cen ter for Health an d Hu m an Righ ts (1999) Hu m an righ ts: an in trodu ction . In : Man n JM et al., eds. Health an d h u m an righ ts: a reader. Lon don , Rou tledge:21–28.

Joh n son MW, Ettin ger RH (2000) Active cocain e im m u n ization atten u ates th e

d is c r im in a t ive p r o p e r t ie s o f c o c a in e. Ex p erim en t a l a n d Clin ica l Psych oph arm acology , 8:163–167.

Jon sen AR (1998) Th e birth of bioeth ics. Oxford, Oxford Un iversity Press. Kaeb n ick GE (2000) Vaccin ation s again st b ad h ab its. Hastin gs Cen ter Report,

30 :48. Kan d el DB, Ch en K (2000) Typ es of m ariju an a u sers by lon gitu d in al cou rse.

Jou rn al of Stu dies on Alcoh ol , 61:367–378. Ke ssle r RC e t a l. (1994) Life tim e a n d 12-m o n th p re va le n ce o f DSM-III-R

p sych iatric disorders in th e Un ited States: resu lts from th e Nation al Com orbidity Su rvey. Arch ives of Gen eral Psych iatry, 51:8–19.

Klin g MA e t a l. (2000) Op io id re ce p t o r im a gin g wit h p o sit ro n e m issio n tom ography an d [(18)F]cyclofoxy in lon g-term , m ethadon e-treated form er heroin addicts. Jou rn al of Pharm acology an d Experim en tal Therapeu tics, 295:1070–1076.

Lesh n er AI (1997) Addiction is a brain disease, an d it m atters. Scien ce, 278:45–47. Leu kefeld CG, Tim s FM (1988) Com p u lsory treatm en t: a review of th e fin din gs.

In : Leu kefeld CG, Tim s FM, eds. Com pu lsory treatm en t of dru g abu se. Rockville, MD, Nation al In stitu te of Dru g Abu se:236–251.

Levy F (1997) Atten tion deficit h yp eractivity disorder. British Medical Jou rn al, 315 :894–895.

Lyn skey MT, Hall W (2001) Atten tion deficit h yp eractivity disorder an d su bstan ce u se disorders: is th ere a cau sal lin k? Addiction , 96:815–822.

McGlashan TH (2001) Psychosis treatm en t prior to psychosis on set: ethical issues. Sch izoph ren ia Research , 51:47–54.

McGorry PD, Yu n g A, Ph illip s L (2001) Eth ics an d early in terven tion in p sych osis: keep in g u p th e p ace an d stayin g in step. Sch izoph ren ia Research , 51:17–29.

7. ETHICAL ISSUES IN NEUROSCIENCE RESEARCH ON SUBSTANCE DEPENDENCE TREATMENT AND PREVENTION

Man n JM (1999) Medicin e an d p u blic h ealth , eth ics an d h u m an righ ts. In : Man n JM et al., eds. Health an d h u m an righ ts: a reader. Lon don , Rou tledge:439–452.

Man n JM et al. (1999) Health an d h u m an righ ts. In : Man n JM et al., eds. Health an d h u m an righ ts: a reader . Lon don , Rou tledge:7–20.

Martin -Soelch C et al. (2001) Reward m ech an ism s in th e brain an d th eir role in depen den ce: eviden ce from n europhysiological an d n euroim agin g studies. Brain Research Review s , 36:139–149.

Mora F (2000) Th e brain an d th e m in d. In : Gelder MG, Lop ez-Ibor JJ, eds. Th e n ew Oxford textbook of psych iatry . Oxford, Oxford Un iversity Press:153–157.

Naqu et R (1993) Eth ical an d m oral con sideration s in th e design of exp erim en ts. Neu roscien ce , 57:183–189.

Nation al Academ y of Scien ce (1996) Path w ays of addiction : opportu n ities in dru g abu se research . Wash in gton , DC, Nation al Academ y Press.

Nation al Bioeth ics Advisory Com m ission (1999) Research in volvin g person s w ith m en tal d isord ers th at m ay affect d ecision -m ak in g cap acity . Rockville, MD, Nation al Bioeth ics Advisory Com m ission .

Nation al Research Coun cil (2001) In form in g Am erica’s policy on illegal dru gs: w hat w e don’t k n ow k eeps h u rtin g u s . Wash in gton , DC, Nation al Academ y Press.

Nelkin D, Lin dee MS (1996) “Gen es m ade m e do it”: th e ap p eal of biological exp lan ation s. Politics an d Life Scien ces, 15:95–97.

Nestler EJ (2000) Gen es an d addiction . Natu re Gen etics, 26:277–281. Platt JJ (1997) Cocain e addiction : th eory, research , an d treatm en t. Cam bridge, MA,

Harvard Un iversity Press. Porter L, Arif AE, Curran WJ (1986) The law an d the treatm en t of dru g- an d alcohol-

depen den t person s: a com parative stu dy of existin g legislation . Gen eva, World Health Organ ization .

Preu ss TM (2000) Takin g th e m easu re of diversity: com p arative altern atives to th e m o d el-a n im a l p a ra d igm in co rtica l n eu ro scien ce. Brain Beh avior an d Evolu tion , 55:287–299.

Reiden berg MM (2001) Releasin g th e grip of big p h arm a. Lan cet, 358:664. Resn ik DB (1998) Th e eth ics of scien ce: an in trodu ction . Lon don , Rou tledge. Roberts LW, Roberts B (1999) Psych iatric research eth ics: an overview of evolvin g

gu idelin es an d cu rren t eth ical dilem m as in th e stu dy of m en tal illn ess. Biological Psych iatry , 46:1025–1038.

Sell LA et al. (1999) Activation of reward circu itry in h u m an op iate ad d icts. Eu ropean Jou rn al of Neu roscien ce , 11:1042–1048.

Sh am oo AE (1998) Eth ics in n eu robiological research w ith h u m an su bjects: th e Baltim ore Con feren ce on Eth ics . Am sterdam , Gordon & Breach .

Sp oon er C, Hall W (2002) Preven tin g su bstan ce m isu se am on g you n g p eop le: we n eed to do m ore th an “ju st say n o”. Addiction , 97:478-481.

Sp oon er C et al. (2001) An overview of d iversion strategies for d ru g-related offen ders. Dru g an d Alcoh ol Review , 20:281–294.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Stahl SM (1996) Essen tial psychopharm acology: n eu roscien tific basis an d practical application s . Cam bridge, Cam bridge Un iversity Press.

Swan son JM et al. (1998) Atten tion -deficit hyperactivity disorder an d hyperkin etic disorder. Lan cet, 351:429–433.

Swen dsen JD et al. (2002) Are p erson ality traits fam ilial risk factors for su bstan ce use disorders: results of a con trolled fam ily study. Am erican Jou rn al of Psych iatry, 159 :1760–1766.

Szasz TS (1985) Cerem on ial ch em istry. Holm es Beach , FL, Holm es Learn in g Pu blication s.

Valen stein ES (1998) Blam in g th e brain : th e tru th abou t dru gs an d m en tal h ealth. New York, NY, Th e Free Press.

Varn er GE (1994) Th e p rosp ects for con sen su s an d con vergen ce in th e an im al righ ts debate. Hastin gs Cen ter Report, 24:24–28.

Vlah ov D, Polk BF (1988) In traven ou s dru g u se an d h u m an im m u n odeficien cy viru s (HIV) in fection in p rison . AIDS Pu blic Policy Jou rn al, 3:42–46.

World Med ical Organ ization (1996) Declaration of Helsin ki. British Medical Jou rn al , 313:1448–1449.

8 . CONCLUSION AND IMPLICATIONS FOR HEALTH POLICY

CHAPTER 8

Conclusion and Im plications for Public Health Policy

Introduction

Th ere is n ow a m u ch better u n derstan din g of th e m ech an ism s of action of differen t p sychoactive substan ces in the brain , an d of why p eop le exp erien ce p leasu re or th e relief of p ain from u sin g th e su bstan ces. Su bstan ces differ with resp ect to th e p articu lar class of recep tors th ey affect in th e brain , bu t th ere a re a lso co n sid era b le co m m o n a lities b etween th em . Th e n eu ra l pathways that psychoactive substan ces affect are also those which are affected by m an y oth er h u m an beh aviou rs, in clu din g eatin g a m eal, h avin g sex, an d gam blin g for m on ey. In th is sen se, th e u se of p sych oactive su bstan ces, at least in itially, is on e p art of th e sp ectru m of h u m an b eh aviou rs wh ich p o t e n t ia lly b rin g p le a su re o r a vo id p a in . De p e n d in g o n t h e ro u t e o f adm in istration , the substan ces m ay have an especially in ten se effect an d high con cen tration s of som e of th em are leth al.

Advances in the neuroscience of psychoactive substance use and dependence and their im plications

Psychoactive substan ces also differ in their n on -n eural biological effects. The form an d m ean s of adm in istration of th e su bstan ce are im p ortan t in th is dim en sion . Th u s th e p oten tial for adverse h ealth effects from n icotin e taken in as cigarette sm oke is h igh com p ared with th at from n icotin e in ch ewin g gu m . Th ere is th u s a stron g p u b lic h ealth in terest in d ifferen tiatin g th e availability of differen t form s of th e su bstan ce accordin g to th eir adverse

h ealth effects. Ap art from th eir toxic biological effects, th ere are two oth er m ech an ism s by which psychoactive substan ces m ay have adverse health an d social effects, as ou tlin ed in Ch ap ter 1 (Fig. 1.2). On e is th rou gh th eir p sych oactive effects, an d p articu larly th rou gh in toxication . Differen t p sych oactive su b stan ces differ in th e n atu re an d severity of th eir in toxicatin g effects. Th ose of alcoh ol, for in stan ce, are great, an d th e p oten tial for adverse casu alty con sequ en ces accordin gly large, while the effects of n icotin e as usually con sum ed are sm all. Lim itin g th e h arm from in toxication , n ot on ly to th e su bstan ce u ser bu t also to oth ers, is an im p ortan t objective for p u blic h ealth -orien ted con trols of th e u se of p sych oactive su bstan ces.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

The third m ajor m echan ism by which psychoactive substan ces m ay have adverse effects is through depen den ce. As techn ically defin ed, the con cept of dependence includes elem ents which are directly biologically m easurable, such as toleran ce an d withdrawal an d those which are cogn itive an d experien tial, such as cravin g an d im pairm en t or loss of con trol. These latter elem en ts can

be m odelled in or in ferred from biological m easurem en ts, but can n ot yet be directly m easured. Thus, while n euroscien ce research can directly m easure states an d effects which are relevan t to con cepts of depen den ce it can n ot m easure depen den ce itself. Depen den ce is seen as a m ajor con tributor to the

h ealth an d social h arm from p sych oactive su bstan ce u se accordin g to its defin ition as the m otor of con tin uin g use. In fact, on e elem en t of the defin ition of depen den ce is by im putation back from the occurren ce of harm : that use has con tin ued despite kn owledge of the harm (Chapter 1, Box 1.2, Criterion 3). Th e stren gth of effect on th e variou s com p on en ts of d ep en d en ce d iffers between differen t psychoactive substan ces, an d accordin g to the dosage an d dosage schedule. The poten tial of a given substan ce to produce various aspects of depen den ce is also affected by the sociocultural circum stan ces in which it is used an d by in dividual gen etic in heritan ce.

Depen den ce is a com plex disorder; how an in dividual becom es depen den t on d ru gs is p rob ab ly as com p lex as th e b rain itself. Som e asp ects of th e syn drom e are clear, but m uch rem ain s to be learn ed, for in stan ce in th e areas of cravin g an d loss of con trol. Th ere is n o lin ear relation sh ip between th e am ou n t of a su b stan ce u sed an d th e severity of d ep en d en ce, n o sin gle relation sh ip between p attern of u se an d on set of dep en den ce, an d n o fixed relation sh ip between exp erim en tation an d dep en den ce. Th u s, desp ite ou r kn owledge abou t su ch m atters as vu ln erability, m ech an ism s of toleran ce, with drawal an d cravin g, we p resen tly can n ot p redict wh o will lose con trol over use an d becom e depen den t. A lot thus rem ain s to be learn ed about these processes when studyin g the n euroscien ce an d social scien ce of depen den ce- related beh aviou rs.

Thus far, on e side of the fin din gs from n euroscien ce has been em phasized:

h ow p sych o a ctive su b sta n ce s a ct in te rm s o f th e co m m o n b io lo gica l in heritan ce shared by all hum an s. The other side of the n euroscien ce research, reflected in Chapter 5 an d partly in Chapter 6, is to som e exten t a coun terpoin t to th is. Th e gen etic research focu ses on th e d ifferen ces in action of th e su b stan ces b etween on e h u m an an d an oth er wh ich are attrib u tab le to differen t gen etic in h eritan ces. Th e fin din gs from th is literatu re su ggest th at gen etics m odu lates m an y asp ects of th e action s of p sych oactive su bstan ces in h u m an s. Th u s gen etic differen ces can m ake th e u se of th e su bstan ce m ore or less p leasu rable or aversive to a p articu lar in dividu al an d can affect th e toxicity of th e su bstan ce, both in term s of overdose an d of ch ron ic h ealth effects. Gen etics can also affect the in ten sity of psychoactive effects of a given fo rm u la tio n a n d d o se o f a su b sta n ce, a s well a s th e likelih o o d o f th e occurren ce of differen t aspects of depen den ce, i.e. toleran ce an d withdrawal, an d th ose asp ects wh ich are n ot directly biologically m easu rable.

8 . CONCLUSION AND IMPLICATIONS FOR HEALTH POLICY

As with ou r kn owledge of m ech an ism s of dep en den ce, m u ch rem ain s to

be learn ed abou t th e gen etics of dep en den ce. We are far from gen etically iden tifyin g which in dividuals will becom e depen den t or will experim en t with dru gs. Gen etic vu ln erability tells little abou t th e in dividu al p robability of p sych oactive su bstan ce u se an d its related p roblem s.

Th ere is a n eed for govern m en ts to su p p ort, to wh atever exten t p ossible, n euroscien ce research, to develop a cadre of expertise, an d to facilitate lin kin g n eu roscien ce with social scien ce. Govern m en ts in d evelop ed cou n tries should provide support for in tern ation al collaboration s an d aid to developin g cou n tries to bu ild local cap acity.

Potential advances in policy, prevention and treatm ent from the neuroscience findings

Neu roscien ce fin din gs in recen t years h ave tran sform ed ou r u n derstan din g of th e action s of p sych oactive su bstan ces. Th is kn owledge sh ou ld be u sed n ot on ly for th e p reven tion an d treatm en t of disorders an d p roblem s arisin g from acu te an d lon g-term u se of th ese su bstan ces, bu t also for u p datin g h ow they are con trolled both un der in tern ation al drug con ven tion s an d in n ation al an d local laws an d p olicies.

In the light of the n euroscien ce fin din gs, there is in creasin g un derstan din g th a t su b sta n ce u se d iso rd ers a re like m a n y o th er d iso rd ers in h a vin g

b io lo gica l, p sych o lo gica l a n d so cia l d e te rm in a n ts. Howe ve r, a m a jo r differen ce in th e case of su bstan ce dep en den ce is th e extrem e stigm a with wh ich th e disorder is regarded in m an y societies. A WHO stu dy of attitu des to 18 disabilities in 14 coun tries foun d that “drug addiction” ran ked at or n ear the top in term s of social disap p roval or stigm a, an d that “alcoholism” ran ked closely beh in d in m ost of th e societies (Room et al., 2001). Rein tegratin g back in to society p erson s treated for p roblem s with p sych oactive su bstan ce u se will requ ire develop in g an d dissem in atin g effective ap p roach es to redu cin g th is stigm a.

With resp ect to p reven tion strategies, th e m ain p oten tial ap p lication of n eu roscien ce fin d in gs so far wou ld b e from th e gen etic stu d ies. Gen etic scre e n in g, b a se d o n t h e re se a rch fin d in gs, ca n p o t e n t ia lly id e n t ify su b grou p s of th e p op u lation with a greater su scep tib ility to d ep en d en ce or

h a r m fr o m a p a r t ic u la r p s yc h o a c t ive s u b s t a n c e . At p re s e n t , s u c h id en tification is in term s of p rob ab ilities rath er th an certain ties. Action s wh ich co u ld b e ta ken o n th e b a sis o f a p o sitive screen m igh t in clu d e n otification of th e affected p erson (or of th e p erson’s p aren ts or gu ard ian , in th e case of a ch ild ), an d p reven tive in terven tion s su ch as th erap eu tic

ed u cation , or th ose targeted at red u cin g vu ln erab ility to su b stan ce u se an d

d e p e n d e n c e . Po s s ib le p re ve n t ive m e a s u re s r e s u lt in g fr o m o t h e r n eu roscien tific research in clu d e p reven tive im m u n oth erap ies, e.g. again st cocain e or n icotin e, p erform ed eith er on th e gen eral p op u lation or on th ose id en tified gen etically or oth erwise as b ein g at h igh risk. As d iscu ssed in

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Ch ap ter 7 an d below, th ere are im p ortan t eth ical con sideration s in an y su ch gen etic screen in g or p reven tive im m u n oth erapy.

With resp ect to treatm en t strategies derivin g from n eu roscien ce research , im m u n oth erap ies cou ld also p resu m ab ly b e ap p lied to cases com in g to treatm en t. Fu tu re d evelop m en ts in n eu roscien ce m ay p rod u ce gen etic m odification s wh ich wou ld alter su scep tibility to u se of or dep en den ce on p articu lar classes of su bstan ces, th ou gh su ch develop m en ts p resen tly seem qu ite far in th e fu tu re.

Ap art from th e ab ove, th ere seem to b e two m ain ch oices in term s of biological in terven tion s. Both of th ese are already on th e scen e, an d th e m ain p ay-off from th e n eu roscien ce research is likely to be in im p rovem en ts in th e p articu lar m ed ication or form u lation u sed . Th e first ch oice is th e u se of m edication s or p rocedu res wh ich in terfere in on e way or an oth er with th e action of th e su bstan ce in th e body, takin g away th e p ositive rewards from u sin g th e su bstan ce or m akin g its u se aversive. Su ch m edication s h ave been in u se for m ore th an h alf a cen tu ry. Exten sive exp erien ce su ggests th at th e m ain p roblem with th ese in terven tion s is lack of p atien t com p lian ce, wh ere th ose with a h istory of exten sive u se of a su bstan ce often p rove u n able to keep to an y com m itm en t th ey h ave m ade to con tin u al u se of th e an tagon ist or aversive su bstan ce.

The other choice is the use of substances which are wholly or partially agonists, replacin g the problem atic substan ce or m ode of adm in istration with an other which produces at least som e of the sam e biological an d experien tial effects. This choice has been m ost widely explored an d used for opioids, with codein e, m ethadon e, bupren orphin e an d other substan ces substitutin g for heroin or other opiates. Nicotin e replacem en t therapy, which substitutes for cigarettes, is n ow widely used thereby elim in atin g m ost of the public health harm .

Ethical issues in the application of the neuroscience findings

In th e broadest sen se, eth ical issu es h ave always been im p ortan t in th e u se of p sych oactive su bstan ces, an d in societal resp on ses to th eir u se. Wh eth er th ey sh ou ld be u sed at all con tin u es to be a con ten tiou s issu e. Th u s, for in stan ce, Islam an d som e bran ch es of oth er m ajor world religion s forbid th e u se of alcoh ol to faith fu l adh eren ts. Eth ical ju dgem en ts are written in to th e m ajor in tern ation al dru g con trol con ven tion s (see Box 1.1). On th e oth er

h an d , argu m en ts again st th e crim in alization of su b stan ce u se are also frequ en tly cou ch ed in eth ical term s (e.g. Hu sak, 2002). With in th e som ewh at n arrower fram e of eth ics in h ealth an d h u m an services, research an d in terven tion s, Chapter 7 has con sidered in som e detail m an y of th e eth ical issu es wh ich are relevan t to n eu roscien ce research an d th e ap p lication of its fin din gs. On ly a few of th ese are em p h asized h ere, with p articu lar referen ce to th eir p oten tial ap p lication s m en tion ed above.

Perh ap s th e m ost u rgen t eth ical con sid eration s arise arou n d th e issu e of gen etic screen in g, wh ich is alread y on th e h orizon . A p erson id en tified

8 . CONCLUSION AND IMPLICATIONS FOR HEALTH POLICY

b y a ge n e t ic s c re e n a s b e in g vu ln e r a b le o r a t r is k is p o t e n t ia lly

d isad van taged by th at id en tification in a n u m b er of ways. In th e first p lace, th e p erson’s self-esteem m ay b e red u ced ; as a m in im u m requ irem en t, a su b stan tial tan gib le b en efit from th e id en tification wou ld b e n eed ed to

b a la n ce th is risk. Th e p e rso n’s fin a n cia l a n d sta tu s in te re sts m a y b e

ad versely affected if th e id en tification is availab le to an yon e else; for exam p le, an in su ran ce com p an y m ay refu se in su ran ce, an em p loyer m ay

ch oose n ot to em p loy, a p erson m ay refu se to m arry. At p resen t, in m an y co u n t rie s, t h e se a d ve rse e ffe ct s o f su ch id e n t ifica t io n a re n o t a t a ll th eoretical: for in stan ce, in su ran ce com p an ies m ay h ave rou tin e access to

h ealth record s, or m ay requ ire su ch access as a con d ition for issu in g an in su ran ce (th ereby coercin g con sen t). There is an urgen t n eed to con sider the ethical issues raised by such gen etic iden tification s in th e cou rse of p rovidin g h ealth services in an in tern ation al con text, as well as at n ation al an d local levels. Th e issu e is n ot lim ited to th e field of p sych oactive su bstan ce u se an d dep en den ce, an d WHO h as given gen eral con sideration to th ese issu es in th e con text of gen etic cou n sellin g. For in stan ce, “p rop osed eth ical gu idelin es for gen etic screen in g an d testin g” (WHO, 1998) p rovide th at “resu lts sh ou ld n ot be disclosed to em p loyers, in su rers, sch ools or oth ers with ou t th e in dividu al’s con sen t, in order to avoid p ossib le d iscrim in ation”. However, as th e gen etic research im p roves its p redictive p ower, th e stigm atization of an d discrim in ation often associated with p sych oactive su b stan ce u se m ake it a p articu larly u rgen t issu e th at requ ires action b eyon d su ch gen eral gu id elin es, as th e gen etic research im p roves its p redictive p ower.

As d iscu sse d in Ch a p te r 5, th e u se o f im m u n o th e ra p ie s a n d o th e r n eu rological in terven tion s, esp ecially to th e exten t th at th ey are irreversible, wou ld raise difficu lt eth ical issu es. Th e n eu roscien ce fin din gs th at th e u se of p sych oactive su b stan ces sh ares m an y p ath ways in th e b rain with oth er hum an activities raise the question of what other pleasures or activities m ight

b e ad versely affected by su ch in terven tion s. Th e ap p lication of gen etic m odification s, p articu larly if h eritable, wou ld raise m an y of th e sam e eth ical issu es cu rren tly bein g discu ssed in th e con text of h u m an clon in g.

Th e m ain eth ical issu es con cern in g th erap ies wh ich in terfere with th e p sych o a ctive e ffe cts o f su b sta n ce u se, o r wh ich a re a ve rsive, a re th e requ irem en t for p atien t con sen t to treatm en t, th e p atien t’s ability to give it, an d the ethics of coerced treatm en t (see Chapter 7). The m edication s or other biological in terven tion s at issu e h ere are on ly on e asp ect of th e m ean s by which societies or groups coerce in dividuals regardin g un wan ted behaviours,

a n d a ll su ch m ea n s a re su b ject to sim ila r eth ica l co n sid era tio n s. On e

a d d it io n a l co n sid e ra t io n fo r p re scr ip t io n m e d ica t io n s a n d m e d ica l p rocedu res is th e sp ecial eth ical in ju n ction s an d con strain ts by wh ich th e m edical p rofession an d oth er h ealth p rofession s are gu ided (e.g. Declaration of Helsin ki, see Box 7.1). Moreover, an y treatm en t m odality wh ich is coerced sh ou ld p resu m ably h ave been sh own to be effective.

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Su b stitu tion th erapy—u sin g a m ed icin e th at is p h arm acologically related to th e dep en den ce-p rodu cin g su bstan ce—h as often been con tro- versial, with the argum en t stated in ethical term s. On the on e han d, it is stated to be u n eth ical for th e state, or a treatm en t p rofession al, to con tribu te to th e con tin u ation of th e dep en den ce, even if on a su bstitu te regim e. On th e oth er

h an d, th e cou n ter-argu m en ts of th e dem on strated redu ction s in h arm to society (e.g. crim in al activity) or to th e in dividu al (e.g. HIV in fection ) from th e su bstitu te th erapy are also eth ical at th eir core. Th e gen eral accep tan ce of n icotin e rep lacem en t th erapy m igh t be regarded as in dicatin g a gradu al sh ift away from regardin g th e dep en den ce itself as th e h arm , an d towards a p u blic h ealth focu s on th e h ealth an d social h arm wh ich com e from th e u se, wh eth er dep en den t or n ot.

It sh ou ld be n oted th at th e top ics discu ssed h ere an d in Ch ap ter 7 do n ot exh au st th e ran ge of eth ical issu es arou n d p sych oactive su bstan ces in th e con text of health practice an d research. For in stan ce, special ethical problem s arise wh en p sych oactive m edication s are used to treat beh avioural p roblem s in ch ildren ; th is m ay set u p lifelon g p roblem s (i.e. p redisp osin g th em to later p roblem atic drug use) an d m ay reflect over-p rescrip tion of these substan ces. An oth er exam p le is th e eth ics of “wash -ou t” stu dies to stu dy p sych oactive m edication s, in wh ich p atien ts in treatm en t facilities are en tered in to trials in wh ich th ey are first taken off all th e p sych oactive m edication s th ey h ave been takin g (wh eth er as self-m edication or by p rescrip tion ), to evaluate th eir “baselin e” con dition .

A n um ber of con cep tual an d p olicy issues m ight be addressed by scien tific organ ization s an d in tergovern m en tal agen cies in light of these developm en ts in n eu ro-scien tific an d oth er research . Th ese in clu de su ch m atters as th e con ceptual basis an d em pirical fin din gs relevan t to defin ition s of depen den ce an d oth er su b stan ce u se d isord ers in th e In tern ation al Classification of Diseases (ICD-10) an d th e Diagn ostic an d Statistical Man u al of Men tal Disord ers (DSM-IV); th e effectiven ess of treatm en ts for su b stan ce u se disorders, an d th eir p lace in system s of h ealth an d social services; an d in p articu lar th e effectiven ess, availability, an d eth ics of th e u se of m edication s an d oth er biom edical in terven tion s in treatm en t. As discu ssed earlier in th is

ch ap ter, each su ch th erapy wh ich is cu rren tly in effect or still on th e h orizon , carries its own set of eth ical issu es, an d th ese sh ou ld be con sidered in th e con text of develop in g in tern ation al stan dards for h u m an righ ts in h ealth services.

WHO already plays the role of a scien tific arbiter on “scien tific an d m edical” asp ects in th e classification of con trolled su bstan ces u n der th e in tern ation al dru g con trol treaties (Bru u n , Pan & Rexed, 1975; Bayer & Gh odse, 1999). It

e xe rcise s t h is ro le p r im a r ily t h ro u gh a n Exp e r t Co m m it t e e o n Dr u g Dep en den ce, wh ich m eets every two years. As th e in tergovern m en tal agen cy with prim ary respon sibility for global public health, WHO has respon sibilities an d in terests con cern in g p sych oactive su bstan ces wh ich exten d beyon d th e scop e of th e in tern ation al treaties. On e m ean s for addressin g th ese wider

8 . CONCLUSION AND IMPLICATIONS FOR HEALTH POLICY

resp on sibilities h as been to exp an d th e scop e of th e Exp ert Com m ittee, at least in som e years (WHO, 1993), in ord er to cover th e wh ole ran ge of p sych oactive su bstan ces an d to con sider a broader p u blic h ealth ap p roach . However, reach in g an exp ert ju d gem en t an d b u ild in g a glob al resp on se con cern in g these m atters will require other resources an d expertise alon gside th e existin g m ech an ism of th e WHO Exp ert Com m ittee.

Im plications for public health policy

A su b sta n tia l p ortion of th e glob a l b u rd en of d isea se a n d d isa b ility is attribu table to p sych oactive su bstan ce u se. In tu rn , a su bstan tial p ortion of th e bu rden attribu table to su bstan ce u se is associated with dep en den ce. Tobacco an d alcoh ol u se are p articu larly p rom in en t con tribu tors to th e total

b u rd en . Measu res to red u ce th e h arm from tob acco, alcoh ol an d oth er p sych oactive su bstan ces are th u s an im p ortan t p art of h ealth p olicy. Neu roscien ce is a fast growin g field of scien tific research . Th ou gh th e kn owledge base is far from com plete, there is a con siderable am oun t of useful data with en orm ou s p oten tial for in flu en cin g p olicies to redu ce th e bu rden of d isease an d d isab ility associated with su b stan ce u se. Th e followin g recom m en d ation s are m ad e to facilitate greater op en n ess an d assist all stakeh olders in m obilizin g action :