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The Brain Disease Model of Addiction: Is It Supported by the Evidence and Has
It Delivered on Its Promises?

Article in The Lancet Psychiatry · January 2015

DOI: 10.1016/S2215-0366(14)00126-6

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 1

THE NIDA “BRAIN DISEASE” MODEL OF ADDICTION: IS IT SUPPORTED BY THE

EVIDENCE AND HAS IT DELIVERED ON ITS PROMISES?

Professor Wayne Hall PhD.,1,2,3,*, Adrian Carter PhD.3,4 and Cynthia Forlini PhD.3

1. The University of Queensland, Centre for Youth Substance Abuse Research,

Brisbane, Queensland, Australia
2. National Addiction Centre, King’s College London, London, UK
3. The University of Queensland Centre for Clinical Research, Brisbane,
Queensland, Australia
4. School of Psychological Sciences, Monash University, Melbourne, Victoria,
Australia

* Corresponding Author:
Professor Wayne Hall
Director, Centre for Youth Substance Abuse Research
Level K, Mental Health Buidling
The University of Queensland
Brisbane QLD 4029
Australia

Author Statement: The paper has not been submitted to another journal, and has not
been published in whole or in part elsewhere previously.

Word count: 3613 text; 5653 with abstract and references

 2

Abstract
Since 1997 a brain disease model of addiction (BDMA) has been promoted by the US
National Institute on Drug Abuse. We assess the strength of the evidence for the brain
disease model provided by animal studies, neuroimaging studies of addicted
individuals, and research on the role of genetics in addiction. We also critically
evaluate the claims made about the medical and social benefits of the brain disease
model because the latter are often presented as implicit reasons for accepting the
model. We argue: that the BDMA is not as well supported by animal and
neuroimaging evidence as its advocates argue; that it has not delivered more effective
treatments for addiction; and that its impact on public policies towards drugs and
addiction has been modest. We also argue that the BDMA’s focus on the disordered
neurobiology of a minority of severely addicted individuals risks undermining
effective and cost-effective population-based policies that discourage the whole
population from smoking tobacco and drinking heavily. We also question the pursuit
of high technology direct brain interventions to “cure” addiction when the majority of
addicted individuals do not have access to effective psychosocial and drug treatments
for addiction.
 3

Introduction
In 1997, Alan Leshner, then Director of the US National Institute on Drug Abuse
(NIDA), published a paper in Science in which he argued that addiction was best
conceptualised as a chronic, relapsing, brain disease.1 Drug use was initially
voluntarily, but he argued using animal studies that chronic drug use flicked a
neurochemical switch in the brain that made it very difficult for addicted persons to
stop using drugs and thereby explained the high relapse rates among persons treated
for addiction. Researchers at NIDA have since added a substantial number of
neuroimaging studies of addicted individuals which they argue explains how chronic
drug use “hijacks” the brain’s reward systems.2.

Proponents of the BDMA have been very influential in setting the funding priorities
of NIDA, and by extension the bulk of publically supported addictions research. In
1998, Leshner testified that NIDA “supports over 85 percent of the world’s research
on drug abuse and addiction”.3 The American Society of Addiction Medicine has
defined addiction as a “primary, chronic disease of brain reward, motivation, memory,
and related circuitry”.4 In July 2014, newly appointed acting US “drug czar” Michael
Botticelli launched a reformist national strategy with the claim that “decades of
research have demonstrated that addiction is a brain disorder – one that can be
prevented and treated”.5 The BMDA has also been widely promoted in leading
science journals 3, 6 and has recently been endorsed by the leading journal, Nature.7

In the US, advocates of the BDMA have also argued that it will deliver more effective
medical treatments for addiction that will be covered by health insurance and can
thereby be made more readily accessible to addicted persons.1, 2, 6 They have also
predicted that the greater acceptance of the BDMA will reduce stigma by replacing
the common view that addicted persons are weak or bad persons with a more science-
based view that depicts addicted individuals as persons with a brain disease requiring
medical treatment.

In this paper we briefly: (1) critically evaluate the scientific evidence used in
advocating for the BDMA in leading general scientific journals; and (2) assess the
extent to which the BDMA has produced, or is likely to produce, the social benefits
 4

that its advocates claim will flow from its acceptance. The BDMA is not co-extensive
with neuroscience-based explanations of addiction, and our paper is not intended as a
critique of all neuroscience research on addiction. Rather we focus is on a popular
simplification of work in this field that has had a major influence on popular
discourse on addiction in scientific journals and mainstream media.

Search Strategy and Selection Criteria

We searched PubMED, Web of Science and PsycINFO for peer-reviewed papers
describing the brain disease model of addiction by its leading advocates (e.g. Leshner,
Volkow, Koob, Li, O'Brien) and for authoritative reviews of the evidence on animal
models of addiction, neuroimaging studies of addicted persons, studies of the genetic
of addiction and the epidemiology of drug use and addiction. The following search
strategy was employed: “addiction” AND (“neuro*” OR “genetic*” OR “brain” OR
“epidemiolog*”). We also scanned the reference lists of these articles for any key
articles not retrieved by our search strategy. We limited our search to review articles
because it was not our intention to review the entire field of addiction neuroscience
but to identify consensus views in articles published in English between 1990 and the
present.

Evidence for the BDMA

Animal models have played a central role in the BDMA by providing insights into the
effects that chronic drug administration has on brain processes.8, 9 These models have
shown that: rats and other animals will self-administer psychoactive drugs at high
frequencies (e.g. by pressing a lever);9, 10 the drugs that animals will self-administer
are those that are addictive in humans; and self-administration of drugs is reduced by
electrical stimulation of the brain’s “reward centres”.9 Animal models have also
enabled researchers to identify the neural circuitry on which the major drugs of
addiction act, namely the “mesolimbic brain reward system”, which includes the
ventral striatum, nucleus accumbens, amygdala, and frontal cortices. Dopamine plays
a key role in this system.11, 12

These animal models reproduce some key features of human addiction.13 Animals
free access to drugs often increase the frequency and amount of drugs that they self-
administer and work harder to obtain drugs, mimicking the development of tolerance
 5

and dose escalation in humans. They continue to self-administer drugs in the face of
aversive stimuli (e.g. electrical foot shock). If self-administration has been
extinguished, animals will rapidly resume self-administration if they are given painful
stimuli, exposed to cues associated with the drug, or given a priming dose of the
drug.8, 12, 14

Findings from animal studies have been bolstered by neuroimaging studies of the role
of dopamine activation in the reward circuits in “normal” and “addicted” human
brains.
6, 15 16
These neuroimaging studies have also identified dopamine-mediated changes in
cortical areas that are correlated with impaired decision-making and poor impulse
control.17, 18 The persistence of many of these changes persist in addicted individuals
after long periods of abstinence is invoked to explain the high rates of relapse in
persons treated for addiction.19

Further support for a BDMA is provided by genetic research on addiction. Twin

studies indicate that genetic factors make a substantial contribution to the risk of
developing alcohol, nicotine and cannabis addiction.20, 21 Estimates of the heritability
of alcohol, nicotine and cannabis dependence range between 40 and 60%.21 Large
scale Genome Wide Association Studies have found correlations between genetic
markers and addiction risk. Risk alleles have been identified that influence drug
metabolism and the effects that drugs have on the mesolimbic reward system,
suggesting that addiction is the outcome of chronic drug use acting on the brains of
genetically vulnerable individuals.20, 21

A Critical Examination of the Evidence for a Brain Disease Model of Addiction

Is Addiction a Chronic Disorder?
Leading critics of the BDMA contest the claim that addiction is a chronic relapsing
disorder by citing epidemiological evidence that the majority of addicted persons
recover without treatment.22-24 Heyman, for example, points out that most persons
who meet diagnostic criteria for dependence in epidemiological surveys are not drug
dependent at the time of their interview, having ceased drug use years before, usually
in the absence of treatment.23 Similar evidence for high rates of recovery was
 6

provided by high rates of recovery in follow up studies of heroin-addicted US

Vietnam veterans.25
Critics also argue that it is difficult to reconcile a strong form of the BDMA with
evidence that addictive drug use is responsive to small changes in consequences.22, 23
For example, receiving small financial rewards or avoiding 24 hours in gaol for
providing clean urine samples, substantially reduce drug use in addicted persons.23, 26
The responsiveness of addictive drug use to these small incentives is hard to reconcile
with the claim that such drug use is a compulsive behaviour over which addicted
persons have little or no control.22, 23

We can reconcile the BDMA with the high rates of recovery from addiction if we
allow that addictive disorders vary in severity and that less severe disorders are the
most common and those most likely to remit without treatment.27 On this account,
chronic addiction occurs in a minority of addicted persons, those who use drugs into
their early 30s despite an accumulation of adverse health and social consequences.
These drug users seem to better fit the picture of a chronic relapsing brain disease
because they are most likely to seek treatment after failing to control their drug use.
They are also most likely to show alterations in brain function that may play a role in
their continued drug use.24

This modified form of the BDMA applies to a minority of those who meet diagnostic
criteria for addiction in epidemiological studies. Advocates of the BDMA who accept
this weaker formulation cannot equate the lifetime prevalence of addictive disorders
with the prevalence of the severe and chronic addictive disorders that exemplify the
BDMA. A critical analysis of neurobiological research on addiction, however, also
raises doubts about how compelling an explanation the BDMA provides of the
minority of addicted persons with severe, chronic forms of addiction.

A Critique of Neurobiological Research on Addiction

Animal Models of Addiction
Addictive patterns of behaviour are not the invariable outcome of chronic drug self-
administration in animals. Popular accounts of these studies underplay the extent to
which their results depend upon specifically bred strains of rats and the conditions
under which the animals are housed.28 Rats taught to self-administer opiates under
 7

standard conditions of addiction do not display this behaviour if housed in more

naturalistic conditions (e.g. with litter mates).29 Housing rats in ‘enriched
environments’ also affects patterns of drug self-administration and reinstatement.28
Rats that have been trained to self-administer drugs will abstain when given a choice
of other natural rewards.28

Animal models of addiction also have little to say about the high rates of recovery in
addiction in the absence of specific interventions.24 For example, Koob and
LeMoal’s12 analysis of analogies between animal models and “stages of human
addiction” does not include recovery. Their implicit assumption is that once addicted
an animal (or a person) will remain so unless treated, and if treated will be at high risk
of relapse. The epidemiological evidence reviewed above indicates that this is too
pessimistic.

Genetics of Addiction
Addiction is not a disorder that is confined to individuals who carry a small number of
“addiction” genes. Very large numbers of alleles are involved in the genetic
susceptibility to addiction and individually these alleles very weakly predict addiction
risk.20, 21, 30 Genetic risk scores based on combinations of multiple risk alleles do
predict addiction risk but no better than simple family history information (e.g.
number of smoking parents).31 More generally, genetic prediction of disease risk
(even using whole genome sequencing information) is unlikely to be informative for
most people who are at “average risk”.30, 32

Human Neuroimaging Studies

Neuroimaging studies of addiction 33report more statistically significant differences
between addicted and non-addicted persons than they should, given the small samples
studied and the size of average differences between groups.33, 34 The excess number of
significant findings reflects capitalisation on chance when performing large numbers
of comparisons of activation between brain regions or structures, the selective
publication of positive findings, and delays in publishing failures to replicate the
positive findings.35 In studies that do find differences between cases and controls,
there are large overlaps in the size of brain structures and “hypo-” or “hyper-
functionality” of specific brain regions between addicted and control groups.36
 8

Neuroimaging researchers in addiction clearly acknowledge these limitationse.g. 37

but more popular accounts often do not.

Case-control studies do not tell us whether addiction is a cause or a consequence of

differences in brain structure and function or some combination of the two.38
Differences in patterns of activation in brain scans between addicted and non-addicted
persons also do not show whether the drug use of addicted persons is compulsive.39
the fact that reduced activity in frontal brain regions is modestly correlated with self-
reported craving does not demonstrate that drug use is driven by irresistible
impulses.24

The Increasing Complexity of Addiction Neurobiology

The neurobiology of the BDMA has become progressively more complicated since
1997, as revealed in Volkow’s papers. The hypothesis that chronic drug use “hijacks”
the brain’s pleasure centres has expanded to acknowledge that drug use also affects
brain structures involved in higher cognitive control of impulses.15, 40 Volkow also
acknowledges the neuropharmacological complexity of addiction in recognising that
multiple neurotransmitter systems are implicated in addiction (e.g. GABA, NMDMA,
opioid, serotonin).17, 41 She also emphasises the importance of epigenetics (changes in
gene expression in brain systems produced by chronic drug use), which she identifies
as a new target for drug treatments of addiction. Despite these acknowledgments of
the complex neurobiology of addiction, the simplest form of the BDMA continues to
dominate public education materials.42

The Promised Policy Pay-offs of the Brain Disease Model of Addiction

Improved Drug Treatments of Addiction
Leshner predicted that the BDMA would deliver more effective treatments of
addiction.1, 6 by developing medications and behavioural treatments that reversed or
compensated for the brain changes responsible for addiction.1, p.46 The new drug
treatments that have been investigated have included: drug vaccines and implantable
agonists and antagonists to reduce relapse; genomic tests to match patients to the most
effective treatment; drugs to modulate the stress response; drugs to modify memories
of drug-related cues; and most recently, drugs to reverse epigenetic changes produced
by chronic drug use.43-45
 9

The treatment benefits of the BDMA remain uncashed promissory notes.46 Very few
new drug treatments have been approved for addiction over the past several decades.47
and the most widely used drug treatments for addiction (e.g. methadone and nicotine
replacement therapy (NRT)) preceded the BDMA by over 30 years. The few drugs
derived from neurobiological research (e.g. naltrexone, varenicline) only improve
modestly on older drugs, such as disulfiram and NRT.37, 48-50 NIDA’s investment in
research on vaccines for nicotine and cocaine dependence has also produced
disappointing results.51-53

Formidable obstacles remain to developing effective drug treatments for addiction.

Many of these are shared with drug development in biomedicine more generally.54
These include a very low success rate in replicating the findings of “promising drug
targets” identified in basic research55, 56 and the low replicability of the results of
small sample animal studies.57 Very few drugs show promise in animal models
progress to human clinical trials due to unacceptable human toxicity, while others fail
to show efficacy in phase II human trials.

There are also special challenges in developing new drug treatments for addiction.
Pharmaceutical company executives have been reluctant to invest because they doubt
that new drugs for addiction drugs will be profitable, given the limited capacity of
addicted individuals to pay for treatment, the lack of health insurance coverage for
addiction treatments in the USA, and the regulatory disincentives to the clinical use of
drugs that have similar effects to drugs of abuse.47 Drug companies may also fear that
the stigma of addiction will discourage other potentially more profitable uses of these
drugs (e.g. to treat chronic pain).47

Direct Brain Interventions for Addiction

Leshner’s argument that “attending to the brain needs to be a core part” of treating
addiction 46) has prompted proposals to directly intervene in the brains of addicted
individuals. In the early 2000s, Koob’s work was invoked to justify ablative
neurosurgery as a treatment for heroin addiction in China and Russia.58 Deep Brain
Stimulation (DBS) is now advocated as a more targeted and reversible alternative to
neurosurgical ablation.59, 60
 10

Advocates of DBS for addiction cite animal studies in which lesions in the
dopaminergic reward pathway have reduced drug self-administration (e.g. 61). They
also cite case reports of patients who have been treated with DBS for indications other
than addiction and who have reported en passant that their addictive behaviour was
reduced.62 There are now also case reports of the apparently successful use of DBS to
treat alcohol and heroin dependence.62

Advocates of DBS for addiction have argued that it will be an effective and cost-
effective way to reduce the economic and social costs of addiction.60 They overstate
its likely population impact in order to justify the high costs of the procedure (over
US$50,000 to implant a stimulator and US$10,000 p.a. to maintain it).63 If DBS were
to prove effective, it would will most likely be used to treat the minority of addicted
patients wealthy enough to afford the treatment; it would be least likely to be offered
to the addicted persons who generate the social and economic costs that have been
used to justify DBS trials.60

Overinvestment in High Risk Strategies for Legal Drugs

A major risk is that the BDMA will lead to the neglect of public health policies in
favour of a search for biomedical treatments of severely addicted persons.64, 65 This
prioritization is reflected in NIDA’s allocation of its current $1065.24 million
research budge: 23.8% to epidemiology, health services and prevention; 41.4% to
basic and clinical neuroscience; and 16.5% to pharmacotherapies, with the rest spent
on intramural research and research support.66

Imposing high taxes on cigarettes, enacting advertising bans and restricting where
people can smoke, have halved cigarette smoking rates in Australia67 and the US68
over the past three decades. These strategies are much more efficient than high-risk
strategies aimed at smokers and persons at risk of smoking.64 It is much cheaper to
increase taxes, ban advertising, and restrict opportunities to smoke than to screen
whole populations and intervene with the minority who are at high genetic risk of
addiction if they smoke tobacco.69 Similar evidence supports the greater efficiency of
population-based strategies in reducing the societal harms of alcohol misuse.70 The
effectiveness of population level approaches is not an argument against providing
 11

clinical treatment to addicted individuals. However, there is a real concern that an

overemphasis on the BDMA can undermine population level approaches when
misused by the alcohol and tobacco industries in opposing public health policies.71

Addiction Neurobiology and Illicit Drug Policy

There are striking transatlantic differences in the policy inferences drawn from
neurobiological research on addiction. In the USA, proponents of the BDMA have
largely been silent about its implications for US drug policy, arguably allowing the
BDMA to be in to support of an over-investment in law enforcement efforts to reduce
drug supply.72

NIDA has expended considerable resources in seeking to replace a moral view of

addiction with one that sees addiction as a treatable medical disorder.1, 2, 6 Until very
recently there have arguably been meagre returns on this investment. The most recent
positive development has been the inclusion of addiction treatment within the Patient
Protection and Affordable Care Act (PPACA), commonly referred to as ObamaCare.5

In the UK, by contrast, leading addiction neuroscientists have used their research to
question whether cannabis, MDMA and LSD should remain illegal. David Nutt has
argued that the harms caused by alcohol, cannabis, cocaine, heroin, MDMA and
tobacco do not justify the different legal status of these drugs.73

Neuroscience research on addiction cannot be, and ought not to be, the decisive factor
in setting drug policy. In democratic societies, drug policy should be the outcome of
societal trade-offs between competing goods and harms, such as the pleasurable
effects of drugs enjoyed by adults, the harms that drug use can cause, and the social
and economic costs and benefits of different ways of allowing or restricting their use
and sale. Ideally these trade-offs should be made by political representatives who are
well informed about epidemiological, sociological, economic and neurobiological
research on drug use and addiction.

Conclusions
There is considerable scientific value in neurobiological and genetic research on
addiction, but this research does not justify the simplified BDMA that dominates
 12

discourse about addiction in the USA and increasingly elsewhere. Nature was
mistaken to assume that the BMDA represents the consensus view in the addictions
field.7, as shown by a letter signed by 94 addiction researchers and clinicians
(including one of the authors).74 Our understanding of addiction, and the policies we
adopt to treat and prevent problem drug use, should give biology its due, but no more
than its due. The effects of chronic drug use can act on brain systems in ways that
may make cessation more difficult for some. But evidence from economics,
epidemiology and social sciences shows that neurobiology is not the over-riding
factor when formulating policies towards drug use and addiction.

The BMDA has not delivered the more effective treatments for addiction that were
originally promised by Leshner and its impact on public policies towards problem
drug use has been modest. The BMDA has arguably led to over-investment by US
research agencies in research on biological interventions to cure addiction that will
have a limited impact on addiction as a public health issue. Increased access to more
effective addiction treatment is a worthy goal that we support but this should not be
pursued at the expense of simpler, cheaper and more efficient population-based
policies that discourage the whole population from smoking tobacco and drinking
heavily. Nor should the pursuit of high technology “cures” distract us from increasing
access to currently available psychosocial and drug treatments for addiction, which
the majority of addicted individual are still unable to access.

Our rejection of the BDMA is not intended as a defence of the moral model of
addiction.65 We share many of the aspirations of those who advocate for the BDMA,
especially the delivery of more effective treatment and less punitive responses to
addicted persons. Addiction is a complex biological, psychological and social
disorder that needs to be addressed by a variety of clinical and public health
approaches.65 Neuroscience research on addiction has provided useful insights into
the neurobiology of decision-making, motivation and behavioural control. These
insights help to understand how chronic use of addictive drugs can impair cognitive
and motivational processes and may partially explain why some persons are more
vulnerable than others to developing an addiction. The challenge for all addiction
researchers - including neurobiologists - is to incorporate the emerging insights of
neuroscience research into those provided by economics, epidemiology, sociology,
 13

psychology, and political science so that we can better reduce the harms caused by
drug misuse and all forms of addiction.46

Acknowledgement
We would like to thank Sarah Yeates for comments on an earlier draft of this
manuscript and her assistance in doing literature searches for the paper. Wayne Hall
and Cynthia Forlini were funded by an NHMRC Australia Fellowship awarded to
Wayne Hall. Adrian Carter was supported by an NHMRC Post-Doctoral Fellowship.

Conflicts of Interest
The other authors declare no conflicts of interest.

Contributors
The study and drafting of the paper was led by WH. WH and AC designed the study
and conducted an initial search of the literature. All authors were involved in devising
the final search strategy, retrieving and critically reviewing the articles. WH prepared
the initial draft of the paper. All authors were involved in the subsequent writing and
editing of the manuscript.

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