Drug Abuse

The disease called addiction: emerging evidence in a 200-year debate
Roger E Meyer

Lancet 1996; 347: 162-66
Association of Academic Health Centers, Washington, DC 20036, USA (Roger E Meyer MD)

The concept of disease in drug and alcohol addiction has evolved over the past 200 years in the context of changing constructs in clinical medicine, public health, and psychiatry. In relation to alcoholism, the origin of this concept has been credited to Benjamin Rush in the USA and Thomas Trotter in Great Britain, after distilled alcohol became widely available commercially. Benjamin Rush (figure) was born in 1745 into a world informed by enlightenment philosophy. He received his MD at Edinburgh, where his teachers conceptualised disease as an imbalance of the nervous system. If distilled spirits were regarded as "strong nervous system stimulants" the excessive use of which would create an "imbalance" in the nervous system, it was a relatively straightforward step for Rush to identify alcoholism as a "disease" in which alcohol is the causal agent, loss of control over drinking behaviour being the characteristic symptom, and total abstinence the only , effective cure. His belief in the power of "reason" led to a major public education campaign in the USA to reduce public drunkenness. Per caput alcohol consumption fell substantially between 1810 and 1830.1

By the second half of the 19th century, views of disease became rooted in findings from pathology and microbiology. Contemporaneous views of alcohol addiction focused on the physical consequences of alcoholism, theoretical subtypes based on clinical observations, and treatment in asylums (and therefore away from family and unhealthy living conditions). 19th century physicians differentiated between chronic alcoholism (defined by the organ changes due to chronic alcohol use) and alcohol addiction (an uncontrollable craving for alcohol). Withdrawal symptoms, craving, and loss of control defined alcohol addiction.

The disease concept was also applied to opioid addiction and to cocaine; but, in the last quarter of the 19th century, temperance ideology moved from a concern a bout addiction to the role of alcohol in accidental injury, crime, labour unrest, and political corruption. In this century, the problem of addictive drugs in the USA, like the problem of alcohol during prohibition, was defined mostly by law enforcement. In both cases, physicians largely lost interest in the issues of addiction; at the same time, there was also a decline in per caput consumption and a focus on the association between substance use and crime.   ,

After the repeal of prohibition in the USA, the defining work on the disease concept of alcoholism was that of E M Jellinek, who reserved the disease category for those individuals with tolerance, withdrawal symptoms, and either "loss of control" or "inability to abstain" from alcohol . 2   These   individuals could not drink in moderation; and, with continued drinking, the disease was progressive and life-threatening. Jellinek also recognised that alcohol prevention would have to address complex cultural, demographic, political, and economic issues; and that the features of the disease (inability to abstain vs loss of control) would also be shaped by cultural factors. At a time when many alcoholics felt that the medical profession had turned its back on the treatment of alcoholism, Jellinek believed that the disease concept would increase the availability of services for alcoholics within established medical facilities.'

The 1960s were marked by the development of animal 5-1833)   behavioural models of addictive 3. after T Sully. (with   disorders, the introduction of methadone maintenance and narcotic antagonist treatments for heroin addiction, the funding of civil commitment and community-based treatments for addicts in the USA, and the beginning of a major epidemic of drug use and addiction among middle-class youth in North America and western Europe. These developments, along with the critique of the disease concept developed by various behavioural and social scientists,3-5 helped to shape the debate on the validity of the construct through much of the 1970s.

The findings of other investigators starting in the late 1970s;9-14 the emergence of explicit criteria for an alcohol dependence syndrome's (later extended to other addictive drugs in the DSM HIR, DSM IV, and ICD 10 criteria); and new findings on the neurobiology of addictions bring us to the present. The disease concept remains controversial.15

During the past 25 years, the individualised focus of allopathic medicine and the population-based emphasis of the public-health tradition have come together in the screening -and intervention for multiple-risk factors associated with cardiovascular and certain other diseases. The boundaries of what constitutes a disease have been expanded to include risk associated with family history, age, life style, and/or environment. They will be expanded further by research on the human genome. Addictions are clearly within this definition of disease, as in the following definition of alcoholism:" "Alcoholism is a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterised by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, mostly denial. Each of these symptoms may be continuous or periodic". Just as a virus can take over and direct the synthesis of proteins within a cell, these extrinsic reinforcers (alcohol and other addictive drugs) dominate brain mechanisms related to anticipation, and purposeful (motivated) behaviour. Although some addictive drugs (including alcohol) produce physical dependence, all addictive drugs activate neuronal circuits in the brain that underlie reinforcement,15 as well as circuits that produce powerful emotional memories."

Reliable diagnostic criteria with some predictive usefulness

In 1976, Edwards and Gross15 proposed seven criteria for an "alcohol dependence syndrome", a symptom-complex based on biological processes and learning (panel 1). They went on to define dependence along a continuum of severity, and they differentiated dependence from alcoholrelated biomedical and psychosocial disabilities. The latter may be influenced substantially by culture and coexisting psychopathology (eg, sociopathy). The syndrome emphasised impaired capacity to moderate drinking behaviour. Whereas six studies10.11.14,20-22 have found that severity of dependence, variously defined, has prognostic significance in clinical populations, others have not shown either prognostic significance=23 or the coherence of the symptom complex .24 Most clinicians in North America would agree with Babor and colleagues" who concluded

Panel 1: Essential elements of the alcohol dependence syndrome

Narrowing of the drinking repertoire Range of cues that signal drinking and personal drinking repertoire become increasingly stereotyped.

Salience of drink-seeking behaviour Priority is given to maintaining alcohol intake.

Increased tolerance to alcohol Ability to sustain an alcohol intake and sustain daily activities with a blood alcohol concentration that would incapacitate a non-tolerant drinker. Repeated withdrawal symptoms Four key symptoms are tremor, nausea, sweating, and mood disturbance.

Relief or avoidance of withdrawal symptoms by further drinking Requirement for alcohol to relieve or avoid withdrawal symptoms.

Subjective awareness of compulsion to drink Compulsion to drink. Desire for further alcohol is regarded as irrational; the desire is resisted, but additional drink is taken.

Reinstatement after abstinence Return of previous narrowly stereotyped pattern of drinking. that sustained moderate drinking is not a feasible outcome for those who are moderately to severely alcohol dependent. The prognostic significance of severity of dependence has not been systematically applied to treatment studies of other addictive disorders.

Clinical knowledge would benefit substantially from the identification of biological criteria that correlate with severity of dependence, although studies by Hodgson et al," Kaplan and co-workers,25 and I.aberg 26 found a relation between the "priming efficacy" of a low dose of alcohol (as judged by self-reported craving and/or drinking behaviour) and severity of dependence. Because of the confusion of the terms "dependence" and "physical dependence", which are not synonymous, the term "addiction syndrome" more dearly conveys the behavioural basis of the definition.

Risk factors

Substance availability
For most of this century (in the case of illegal drugs), and during prohibition in the USA (in the case of alcohol), public policy has focused on substance availability. In countries where per caput alcohol consumption is high (eg, France), including nations where there is cultural tolerance of public intoxication (eg, colonial America), alcoholism rates are high. In some impoverished communities in the USA, the availability of heroin and crack cocaine constitutes an underground economy that makes these illicit drugs more easily available than in more affluent communities. Generally, where there is widespread availability of as intoxicant and/or few or no cultural constraints against use or intoxication, it is less common to find comorbid psychopathology among treated addicts than where there are serious restrictions on availability. For example, the rate of sociopathy among alcoholics in Taiwan is high (>90%),27 whereas that among alcoholics in France is extremely low .26 Certainly, widespread availability is a risk factor for use and addiction; but addictive disorders tend to develop in the context of individual risk factors (eg, family history, some types of psychopathology), the environment, and the reinforcing potency of a drug and the way it is taken. Alcohol is a less potent reinforcer than cocaine or heroin, and the way it is taken does not deliver the pharmacological effect quickly to the brain. Therefore, it may take 10 years of heavy drinking to become alcohol dependent, whereas the progression to heroin dependence after smoking the drug or intravenous self-administration is much more rapid.

Heritability and family environment as risk/protective factors
The contribution of family history of illness as an otherwise unspecified risk factor for numerous diseases is one of the hallmarks of the concept of disease in late 20th century medicine. Four large and well-designed twin studies29-32 have confirmed earlier work suggesting that unspecified genetic factors increase the risk of developing alcohol addiction among people who drink (eg, refs 33 and 34). Additional support for a genetic model comes from the many studies on the pharmacogenetics of alcohol preference drinking in rodents (summarised by Meyer and Dolinslky35) and also from studies of potential markers/mediators of risk in sons of alcoholics.36-37 Schuckit's finding38 that a lower level of response to ethanol in young adult males predicted future alcoholism is of great interest because the study was longitudinal and because alcohol preference drinking in rodents also seems to be associated with decreased. initial response to ethanol."

The alcohol and aldehyde dehydrogenase polymorphisms, ADH2 and ALDH2, are associated with lower vulnerability to alcoholism among Taiwanese and Koreans in North America and Asia. The finding that the A1 allele of the D2 dopamine receptor gene is associated with alcoholism has not been validated." Moreover, although there are various genes with moderately abundant and rare structural variants that may affect neurotransmission, their role in relation to alcoholism is unknown. One issue that is being examined in a large multicentre study in the USA concerns the validity of heritable subtypes of alcoholism that have been found in Swedish adoptees. Although studies on the heritability of other addictive disorders are less well developed compared with those on alcoholism, there is good evidence that smoking behaviour in parents influences their children's decision to smoke, and that some types of substance use among teenage students may correlate with patterns of intrafamilial drug use.

Previous psychopathology, childhood/adolescent behaviour, and previous substance use
The question of whether there is a causal connection between psychopathology and the development of addictive disorders has been emphasised in the traditional psychiatric published research in North America. The validity of the self-medication hypothesis has been questioned by studies showing that alcohol and drug addicts in treatment have. substantial psychiatric difficulties as a consequence of the substance use. The strongest connection between antecedent psychopathology and risk of addiction has been established for antisocial personality disorder (including childhood conduct disorder); 41,42 and in the theoretical relation between certain heritable personality traits (and the development of alcoholism) in people with a family history of alcoholism. The presence of a comorbid psychiatric disorder may affect the age of onset, rate of progression from use to addiction, types of psychosocial disability, and response to treatment in addicted patients (eg, ref 43). Behavioural characteristics of primary schoolchildren (shy aggressiveness) may be an early sign of vulnerability to the later development of alcoholism. These behavioural characteristics may or may not be related to the risk of developing antisocial personality disorder in adulthood and/or to a heritable subtype of alcoholism (type II) associated with a family history of criminality. Antisocial behaviours tend to cluster in adolescents. Because other drugs are available to this cohort, the sex-related antisocial traits that are associated with ethanol intoxication44 may also apply to other addictive drugs. Finally, there is evidence that the drug using patterns of peers influence decisions about drug use;" and the likelihood of progression to drugs that are more addictive such as heroin and cocaine is influenced by earlier decisions about tobacco, alcohol, and cannabis use."

Importance of animal models of addictive disorders

Panel 2: Animal behavioural models in addiction
1. Intravenous drug self-administration in rats and monkeys
2. Oral (and intragastric) alcohol self-administration (pharmacogenetic and behavioural models)
3. Intracerebral drug/alcohol self administration
4. Drug/alcohol stimulus discrimination paradigms
5. Conditioned place preference
6. Brain stimulation reward

Panel 2 shows the animal models that have been the most useful in modelling aspects of drug and alcohol addiction behaviours, and of the brain events associated with reinforcement. Using the drug self-administration model, researchers have shown that drugs which are misused by human beings (with the exception of hallucinogens and cannabis) are reinforcing in the rat and monkey." Over time, the behaviour associated with intravenous selfadministration comes under stimulus control-ie, the behaviour occurs when the animal has learned that the drug is available, and the animal will alter work output to maintain dosage if the dose per injection is changed.'48 The behaviour of monkeys and rats in intravenous opioid, cocaine, and stimulant self-administrative settings is strikingly similar to behavioural patterns of human drug dependence. Nutt (Jan 6, p 31)" highlights the evidence linking reinforcement to the effects of drugs on the mesolimbic dopamine system, especially the nucleus accumbens. In addition to dopamine, there is evidence that opioid self-administration and alcohol reinforcement are both also mediated through opioid receptors in this region, and the effects of alcohol may also be mediated by other receptors (y-arninobutyric acid agonist A-type [GABA A] N-methyl-D aspartate [NMDA], and serotoninergic receptors)."

Alcohol consumption in the rat can be substantially affected by schedules of reinforcement, the pairing of alcohol with other reinforcers, and pharmacogenetic factors.34 The selective breeding of rats differing in spontaneous preference or avoidance of alcohol drinking has enabled investigators to examine neurobiological differences in alcohol preferring . and non-preferring animals. The alcohol preferring strains of rats developed at Indiana University have lower serotonin concentrations in several brain regions and lower dopamine and serotonin concentrations in nucleus accumbens than do non-preferring rats."

The animal models shown in panel 2 were developed to screen drugs for misuse potential and to assess reinforcing properties. Only recently have they been successfiilly used to screen compounds for efficacy in addiction treatment. The use of naltrexone in the treatment of alcoholism50,51 was derived from studies on the effects of narcotic antagonists on alcohol consumption in the rat." These models have yet to be developed as predictors of drug efficacy in addiction treatment in human beings. Although the animal models have brought substantial understanding of the behavioural and biological effect of drugs as reinforcers, questions persist about the specific neuroadaptive changes due to chronic administration that result in addiction (including the persistent risk of relapse after withdrawal).

Potential pathophysiological models
There are at least two theories to explain the persistence of addictive behaviour and the high risk of relapse after drug withdrawal-conditioning models and homoeostatic models. They are not mutually exclusive, and may be additive. Conditioning models relate relapse to Pavlovian conditioning, which pairs environmental stimuli to subjective states likely to trigger drug use (conditioned craving). In a detailed critique of this research, Stewart and colleagues" argued that although there is evidence of Pavlovian conditioning of drug withdrawal reactions," "learned tolerance", and drug-like effects,55 only drug-like effects can account for the tendency of alcoholics and addicts to return to high-risk settings where they have previously been intoxicated. This behaviour is similar to conditioned place preference (panel 2), in which rats prefer locations in a maze where they have previously received drug injections. The proposed model is also consistent with the "priming" effects of low doses of a preferred drug (see above) as well as recent data on conditioned sensitisation." In alcohol-experienced animals, there seems to be a role for the mesolimbic dopamine system in conditioned (as well as unconditioned) drug reinforcement, in the conditioned components of behavioural sensitisation, and in the possible neurobiology of anticipatory states before alcohol consumption. There is also evidence that excitatory aminoacids have a role in the conditioned drug effects and drug-induced sensitisation associated with stimulants. Until recently, studies of Pavlovian conditioning in addictive disorders were focused on the peripheral nervous system. Modern methods of brain imaging and techniques such as in-vivo microdialysis in animal behavioural models should make it possible to devise new methods to screen pharmacotherapies targeted at conditioned craving as a factor in addiction and relapse.

Relapse to addictive drug use is most likely to happen in the first 3-6 months of abstinence. This period may be marked by physiological abnormalities, mood dysregulation, and various somatic symptoms (eg, insomnia in alcoholics), which have been linked to relapse. Martin and Jasinski56 characterised this period as "protracted abstinence" in heroin addicts, the implication being that they do not feel "normal" without their drug. Kreek and her colleagues57 have shown that, in methadone-maintained former heroin addicts, hypothalmic-pituitary-adrenal axis function is normal, whereas in drug-free heroin addicts it is abnormal.

Numerous studies of chronic alcohol, cocaine, and opioid administration in rodents suggest that there are probable changes in gene expression (or other factors) associated with administration of each of these drug classes, as well as changes common to all three classes. Changes in receptor-binding characteristics may be secondary to changes in subunit composition (eg, BZ GABA receptor after chronic ethanol exposure), the phosphorylation state of the receptor protein,58 or other factors that may affect signal transduction. Acute ethanol administration has been characterised by anxiolysis and psychomotor depression, and enhanced chloride flux at the BZ GABA receptor and blockade of calcium flux at the NMDA receptor." These behavioural and receptor effects are diminished with the development of tolerance. Acute withdrawal is characterised by increased anxiety, motor activity, and seizures; and also upregulation of NMDA receptors and downregulation of BZ GABA receptors.60 Grant and Lovinger60 propose a functional interaction of the effects of ethanol (and ethanol withdrawal) at these receptors. Hope et al°' have reported changes in Fos-like transcription factors in target neurons after chronic cocaine administration in rats. Compensations in signal transduction elements and associated proteins in the mesolimbic dopamine system may represent common cellular responses to addictive drugs that could underlie addictive behaviour.62

The most robust evidence of persistent deficits in homoeostasis comes from clinical studies in alcoholics and heroin addicts. We need to identify persistent residual abnormalities in receptor function and gene expression that might be linked to clinical observations and the development of new pharmacotherapies. But there is a real excitement about the possibilities offered by molecular neurobiology to increase understanding of the pathophysiology of addiction. Molecular biologists studying rat strains that differ in drug or alcohol preference (or differential drug reinforcement) might also be able to account for (a) the differential initial reinforcing properties of drugs/alcohol, (b) the differential vulnerability to conditioning of the reinforcing stimulus properties of drugs/alcohol and sensitisation, and (c) the differential changes in gene expression of neurons in the mesolimbic dopamine system that might explain mechanisms of addiction and relapse. These animal models offer promise in understanding the molecular basis of "risk", and of characterising the pathophysiology of addictive disease(s) that have intrigued physicians for 200 years

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