Pharmacological and Psychological Aspects of Drugs of Abuse

Pharmacological and psychological aspects of drugs of abuse.

Topics covered:

  • Introduction
  • Why do people take drugs?
  • Drug use and misuse
  • Problem use, addiction, dependence, and craving
  • Psychological processes and treatment implications
  • Personality variables and the genetics of addiction
  • How abused substances affect the brain
  • The routes and risks of addiction
  • Relative risks of abused drugs 
  • References

Introduction

Drug abuse, misuse, and addiction are major issues in society because of their enormous personal, social, and economic costs. They also have important psychiatric components. Many drug treatment programmes are run by psychiatrists, and the evidence strongly supports the notion that a significant proportion of severe drug abusers are psychiatrically ill. Moreover, drug misuse is becoming more frequent in patients with other psychiatric disorders, where it can lead to problems in treatment and a poor outcome. It is therefore essential for all psychiatrists and related health professionals to have a good understanding of the basis of drug misuse.

Why do people take drugs?

A very common misconception is that drug misuse is simply a search for fun. In fact, people take drugs for many reasons other than to get the buzz or high. Indeed, studies have shown that straightforward pleasure seeking is the primary reason for initiation of drug use in fewer than 20 per cent of individuals. While the high or buzz is the most obvious pleasurable effect, many people also describe using drugs to feel comfortably numb, pleasantly drowsy, or full of energy and confidence. Many others will be chasing the high or buzz that they first experienced, always trying to attain the intensity of their initial experiences. Still others will be self-medicating for anxiety, strong emotions such as anger, for pain, boredom, lack of motivation, lack of self-confidence, and many other aversive states including withdrawal.

The main reason to try to ascertain the reasons for drug use is that in many cases identification of the cause can lead to effective interventions. For example, many alcoholics will point to anxiety as their reason for drinking; (1) indeed, social anxiety is one of the most common causes of alcoholism in young men. (2) If this can be treated (e.g. by selective serotonin reuptake inhibitors) then they are frequently able to become abstinent or even drink normally. Social anxiety is also a common reason for the use of stimulants by the young. Another psychiatric disorder associated with drug misuse is depression, which is particularly likely to lead to excess alcohol intake. A vicious cycle then develops because both alcohol and its withdrawal are depressogenic. Alcohol is also one of the most serious risk factors for suicide. There is increasing use of stimulants and cannabis by schizophrenic patients. In part this reflects the behaviour of their peer group but the use of stimulants may be in part due to the fact that they can offset some of the more negative aspects of neuroleptic treatment, especially the loss of drive and motivation. As both types of drug can worsen psychotic illness, dealing with drug misuse in this group is a priority.

Other factors affecting drug use may be less amenable to psychiatric intervention, such as pressure from peers or others. For instance, female opiate addicts often have a male partner who also uses drugs or even deals drugs. Following her withdrawal from drugs, relapse is almost certain to occur if she continues to live with this partner. Another reason for drug use is to reduce pain or boredom, the latter being a common reason given by disadvantaged youth in areas of high unemployment and poor environmental quality such as inner cities or out-of-town housing estates.

Other reasons for drug use, generally of psychedelics, include the search for meaning or for mystical experiences. Whilst not directly relevant to psychiatry, this use can precipitate psychotic episodes in susceptible individuals and may act as the trigger for schizophrenia.

Finally, it is important to remember that the reasons for use are not static. An opiate addict may use the same dose of heroin to get going in the morning, to ‘top off' a pleasant experience later in the day, to deal with angry feelings when they occur, and to promote sleep at night. Similarly during a drug-using career different motivations may become dominant. This has been well characterized in opiate users where for many the initial exploration was for pleasure or escape. Over months, as physical dependence becomes increasingly apparent, drug use becomes driven by the need to avoid withdrawal and feel normal at all costs.

Drug use and misuse

It is possible to view the issue of drug abuse from different perspectives, which range from the molecular and genetic through the pharmacological to the psychological and social. Each view has its merits and is important, but there is little doubt that an integrated view is necessary, because for most drugs and for most societies no one perspective can explain all the known features of drug abuse. However, for the purposes of this chapter we have concentrated on the psychological and pharmacological. (3)

Problem use, addiction, dependence, and craving

These are some of the most commonly used terms in discussions of drug misuse but at the same time they are also the most problematic. The use of drugs in any circumstance, therapeutic or otherwise, can be associated with problems, although the nature and scale of these varies. The terms problem use and misuse usually refer to use of drugs (presciption or other) for pleasure but with disregard for the personal or social dangers. For example, alcohol misuse can lead to irresponsible behaviour whilst intoxicated and, if prolonged, to liver, gastric, and nervous system damage without the individual neccessarily being addicted or dependent. Another important current example of potentially problematic excessive regular drug use is ecstasy, which may be neurotoxic at doses that are commonly used.

Addiction is a term that had become so misused in general parlance and had acquired such a pejorative edge, that in the past two decades attempts have been made to remove it from the psychiatric lexicon. Unfortunately, the replacement terminology of dependence, or the dependence syndrome, has been similarly devalued by popular usage to the point where it is also almost meaningless. Journalists and even some ‘experts' mention dependence on drugs such as caffeine in the same breath as that on heroin. The reality is that there exists a spectrum of dependence ranging from physiological supplementation (as insulin in diabetes mellitus) through to life-altering dependence on illicit drugs such as heroin. Addiction is still a useful construct if it is reserved for the collection of phenomena that occur at the extreme end of the dependence spectrum, and includes concepts such as the social and personal decline as well as tolerance and withdrawal symptoms (cf. DSM-IV and ICD-10).

Another area of some confusion is the distinction between physical and psychological dependence, with its dualistic overtones. When originally conceived, this distinction was helpful in that it emphasized that drug dependence was more than just physical adaptation to drugs as manifest by withdrawal symptoms—psychological processes, especially drug liking, were also important. However, drugs without obvious physical withdrawal syndromes (e.g. stimulants) also result in physiological withdrawal changes which clinically are manifested as psychological withdrawal symptoms. In addition, new neuroimaging techniques such as positron emission tomography (PET), singlephoton emission CT, and functional magnetic resonance imaging are beginning to reveal the brain circuits underlying the pleasurable effects of drugs, and this has resulted in a blurring of the differentiation between the physical and psychological processes. Similar studies have revealed the brain regions involved in the pleasurable effects of opiates and stimulants. (4) Thus there is a clear convergence in terms of mechanisms, but in terms of treatment regimens the distinction between physical and psychological remains.

Craving is also a term that is widely used yet ill defined. Most commonly it is taken to mean a strong and sometimes irresistible desire to use a drug. The emotional valence of craving is not necessarily pleasurable. Craving can reliably be elicited in situations of negative valence. It is commonly found in withdrawal, when it can lead to relapse. Craving can also be present as an urge or desire to use a drug although the sufferer may be actively denying or resisting its presence. The complex interplay of physical and psychological processes is well exemplified by the physical responses that craving can produce. For example when opiate-dependent subjects are shown drug-related paraphernalia they may experience emotions that range from pleasurable anticipation to early withdrawal (shaking, tearing of the eyes, pupil dilatation, etc.). Each one of these experiences can lead to a desire to use the drug, i.e. craving.

Studies in both animals and humans have demonstrated that conditioning occurs to both the positive and negative aspects of craving. (5,6) Tolerance is to a large extent a conditioned response, particularly related to the environmental context in which a drug has been taken. (7) Thus an environmental context which is drug familiar results in physiological changes in the brain in preparation for the drug effect, and thus less actual drug effect occurs (i.e. tolerance). However, in a novel context, such preparatory changes do not occur so that a standard drug dose will result in a larger drug effect and a potentially fatal outcome. (8) Thus the lethality of a drug is largely dependent on the environment in which it is taken.

Attempts have been made to dissect out the subcomponents of craving using questionnaires. The best known of these are the set designed by Tiffany et al. (9) which independently rate the five main subcomponents of craving—urges and desires to use, intention and planning to use, anticipation of positive outcome, anticipation of relief from withdrawal or negative outcome, and loss of control over use. Ongoing neuroimaging studies are beginning to support this multiprocess view of craving by revealing activation or inhibition of different brain regions to be correlated with individual symptom clusters.

There is also increasing evidence that the particular cognitive sets of patients may be important for treatment, especially during withdrawal. Just as panic disorder patients have high anxiety sensitivity and related catastrophic cognitions, addicted patients may have a high fear of craving and other withdrawal symptoms in association with related catastrophic cognitions. This detoxification fear has been measured in opiate addicts, and shown to predict outcome. (10) Other expectations also play a significant role, (11) and a 15- to 30-min explanation of what the opiate detoxification involves may reduce the measured withdrawal distress by over one-third. (12) Indeed, such is the strength of psychological factors in addiction treatment, there is little doubt that drug treatments should always be combined with the appropriate psychological interventions.

Psychological processes and treatment implications

One of the most influential models in addiction treatment is known as the stages of change model. (13,14) The stage of change that a person can be identified as being at determines the therapeutic approach and type of treatment offered. Thus at the precontemplation stage where there is no recognition of a need for treatment, there is no point in offering intensive treatment interventions. Similarly, at the contemplation stage when treatment is being considered, the appropriate intervention is to help the person clarify their views and build their motivation to change rather than offering active treatment. Indeed, it is only in the decision and action stages that treatment should be actively offered and facilitated.

The brief counselling technique of motivational interviewing (15,16) has been proved to improve outcome effectively, and ties in well with the stages of change model. In the early stages the therapy is focused on encouraging the patient to reduce or resolve their ambivalence which acts as their psychological barrier to treatment. The patient in a client-centred but focused therapy is facilitated to discover the solutions to their own problems themselves. This approach of accepting the client' current level of thinking (rather than offering ready-made solutions, or confronting them, or trying to argue them into the solution) has been shown to be surprisingly effective in the clinical trials. (17) The effectiveness of this technique has resulted in a new understanding of motivation, which is seen as a dynamic state rather than as a fixed state, and one which can be influenced by the therapeutic stance.

Other cognitive therapies also make significant contributions to treatment. Relapse prevention involves the teaching of cognitive and behavioural strategies for dealing with high-risk situations and mental states. (18,19) Other cognitive–behavioural therapies, including extinction of conditioning, contingency management, community reinforcement techniques,(20) and indeed Beck's cognitive therapy, (21) have been effectively applied to substance misuse. The recent very large Project MATCH (matching alcoholism treatments to client heterogenity) study of alcohol treatments compared three types of treatment and found that motivational enhancement, 12-step facilitation, and cognitive–behavioural therapy were equally effective overall, although each therapy excelled in certain subgroups. (22,23) Based on these results it seems likely that specific therapies targetted at specific issues of importance in patients with addiction are roughly equally effective overall, but that we do not yet know enough to confidently match specific patient subtypes to specific therapies.

A number of other therapies have also been shown to be effective, particularly in the alcohol field, including self-control training, self-help groups, marital and family therapy, coping and social skills training, anxiety and stress management, aversion therapies, and brief intervention strategies. (24,25)

Personality variables and the genetics of addiction

The role of personality in addiction is a major issue, with some believing in an ‘addictive personality' and others suggesting different personality types might predispose to different aspects or forms of drug misuse. (26,27) In this highly controversial field a few facts are generally agreed. Predisposition to experiment with both licit and illicit drugs is more likely in those with sensation-seeking or impulsive behaviour traits, and in extroverts rather than introverts. However, once drug dependence is established, those with obsessional, dependent, or anxious characteristics find it hardest to stop. (28)

The genetics of drug abuse are beginning to be unravelled and already these studies have thrown up some important insights in relation to personality. The best studied dependence is that on alcohol, where the Scandinavian adoption studies have found the risk of alcoholism in male children of male alcoholics is the same regardless of whether the child is reared with the alcoholic father or by a non-drinking adoptive family. Building on these data, Cloninger (27) has identified two main forms of alcoholism. Type I is the late-onset form that has low inheritance and is associated with anxiety and stress which drinking is used to relieve, often in binges. In contrast, type II alcoholism starts at a younger age with a heavy regular intake and is associated with antisocial personality traits and criminality. This form is male limited, is associated with impulsivity, and may be related to underfunctioning of brain 5-hydroxytryptamine systems, as genetic polymorphisms of 5-hydroxytryptamine receptors and enzymes have been found in these subjects. (29)

How abused substances affect the brain

The brain works by transmitting information between neurones using the primary neurotransmitters. The primary neurotransmitters are glutamate, which is stimulatory (i.e. it turns cells on), and the closely related amino acid g-aminobutyric acid (GABA) which is inhibitory (i.e. it turns neurones off). The appropriate balance between these neurotransmitters leads to the brain processes underlying action, sensation, learning, and memory. Secondary transmitters are the monoamines and peptides such as dopamine, 5-hydroxytryptamine, noradrenaline (norepinephrine), acetylcholine, and endogenous opiates. These add the tone, valence, and emotion to the primary processes, and some such as noradrenaline are important in memory formation. All ‘drugs' (probably even solvents through indirect effects) act by interfering with these neurotransmitters in various ways.(30,31) However, it is important to realize that the brain has its own ‘addictive' neurotransmitters. The best known are the endogenous opioid peptides such as the endorphins and enkephalins, but there are also endogenous cannabinoids (anandamide) and probably others. (32) It is not yet known whether these endogenous substances are mediators of addiction to cannabis or other drugs, although this would certainly seem possible.

What is certain is that some of the most addictive agents (especially the full agonist opiates such as heroin/morphine) act on the endogenous opioid neurotransmitter pathway, but with a much greater effect than the natural transmitter. The profound ability of opiates such as heroin to produce addiction is because these drugs highjack the natural transmitter system leaving normal levels of stimulation seeming tame by comparison, especially early in withdrawal. Treatment with partial agonist opiates such as buprenorphine offer a compromise in that they are less addicting than heroin yet restore some of the brain's deficiency of opiate tone. They also have the advantage of being much safer than full agonists in overdose and rarely cause death from respiratory depression.

Other drugs, in particular alcohol, seem to act in part by indirectly stimulating the endogenous opioid system, which is why opioid antagonists such as naltrexone can be useful treatments. (33) Other drugs act on the natural stimulant transmitter dopamine. Dopamine deficiency (for instance in Parkinson's disease) has long been known to limit motor behaviour. Stimulant drugs increase energy and stamina by increasing the synaptic levels of dopamine, either by increasing the release or by blocking its reuptake in the basal ganglia. Many drugs of addiction can also increase dopamine availability in other brain regions, the two most important being the nucleus accumbens and the prefrontal cortex. (34) A huge body of evidence points to the nucleus accumbens as being a critical gateway in drug misuse. Almost all abused substances (the only exception being the benzodiazepines) act to increase dopamine release in this area. How they do this varies; cocaine and nicotine act at the level of the dopamine terminals, while heroin and alcohol activate the cell bodies on the brain stem. The net effect is to increase dopamine transmission out of the nucleus accumbens into the basal ganglia and thalamus, frontal cortex, amygdala, and hypothalamus. (26,30)

This circuit is the one that was shown by Olds in the 1950s to sustain electrical self-stimulation and is the brain's own reward circuit. It is normally activated by positive reinforcers, such as food, water, and sex, that are critical to survival. Because drugs of abuse produce greater effects than the natural reinforcers, the resultant effect is that the brain directs its normal drives away from the natural reinforcers and towards the more pleasurable drugs. In severe addiction, which frequently occurs with the most powerful reinforcers (such as heroin and cocaine), all natural drives may be subsumed to an overwhelming search for and use of the drug. Thus addicts may give up sex, grooming, hygiene, and work, hardly eat or drink, and ignore health problems.

The routes and risks of addiction

In addition to the impact of drug misuse on the social aspects of life, it can lead to significant medical problems. The dangers of drug abuse relate to two main factors; the route of use of the drug and the effects it has in the brain outside of the reinforcement circuit.

For most drugs of abuse the faster the drugs reach their target site in the brain the better they are liked and the more psychologically reinforcing they are. Indeed, the ‘pharmaceutical' history of most abused drugs illustrates the progressive refinement of their preparation, in order to accelerate their rate of entry into the brain. A good example is cocaine. The Andean Indians originally used it by chewing coca leaves which produced low levels of cocaine over a period of time. An increase in vigour and a resistance to fatigue is produced, but little pleasure. Over the centuries cocaine has become more refined, first to paste and then to cocaine hydrochloride powder (snow) which when taken nasally produces high levels in the brain within 5 to10 minutes and a clear ‘high.' Further refinement to the free base produces a more lipophilic form (crack) that can be smoked, resulting in entry into the brain in seconds. Intravenous drug use also serves the same purpose of getting the drug to the active site very fast. (35)

A similar process of pharmaceutical refinement to accelerate brain entry has taken place with the opiates. Smoking opium is a method of delivering morphine and related substances reasonably quickly but in low amounts. Refining opium into its active constituents (e.g. morphine) means that higher doses are more easily ingested. However, morphine crosses the blood–brain barrier relatively slowly and has therefore been largely supplanted by opiates such as heroin that cross more rapidly. Heroin is a diacetylated synthetic derivative of morphine that is more lipophilic, meaning that it is able to enter the brain more rapidly and give a better rush. Interestingly, the active form of heroin is morphine; heroin has to be deacetylated before it can act, which proves that pharmacokinetic differences are the critical variable with opiate preference. Similarly, codeine is also inactive until metabolized to morphine, but because this happens very slowly codeine has less abuse potential than morphine.

The benzodiazepines were abused relatively rarely until the advent of gel-filled capsules of temazepam. These provided experienced intravenous opiate users with a convenient source of a concentrated drug which they began to experiment with in the late 1980s. In an attempt to stop this, the drug was reformulated in wax. Unphased by this change, the users started heating up the caplets until they melted and then injecting the hot solution into their veins (hot lining). At body temperature the wax solidified and tended to block the veins and arteries (with missed injections) into which it was administered. Severe ischaemia leading to gangrene and the loss of the limb sometimes resulted. Since there are no therapeutic advantages of temazepam over other benzodiazepines that are much less abusable, this drug has recently been put under a higher degree of control in order to deter its prescription.

As well as affecting the relative reinforcing actions of abused drugs, the rate of brain entry also contributes to risk. A very rapid drug entry makes dose adjustments difficult or impossible and so predisposes to overdose. This is most obvious for intravenous use of opiates where respiratory depression is the main cause of death, but is less common with smoked opiates as intake can more easily be titrated to the desired effect.

The route of use also affects risk, most notably with the risk of infection from intravenous use, especially when needles are not cleaned or are shared. The majority of current intravenous users are hepatitis C positive and we can therefore expect cirrhosis to become a major cause of their death in the next decade or so. This also raises ethical and economic issues; interferon treatment significantly reduces the progression of the disease but is costly and its routine use in addicts would be massively expensive and likely to cause public disquiet. The other main infections are hepatitis B and AIDS. The frightening rise of AIDS in drug abusers, where it occurred faster than in any other group, was the main impetus to the harm-reduction approach becoming the treatment style of the 1990s. Needle-exchange programmes and increased methadone availability were both proven to reduce the spread of AIDS and have become the cornerstone of treatment in many countries.

Relative risks of abused drugs

This is a critical issue in relation to directing legal as well as medical inputs into drug abuse. There are four main factors which have to be taken into account in determining relative risk:

  1. risk due to the route of use
  2. risk of the drug itself
  3. extent drug controls behaviour (addictiveness)
  4. ease of stopping.

The risks due to the route have been covered above. The risks of the drugs themselves are determined by standard tests and clinical experience and can be encapsulated in concepts such as the therapeutic index. This is the ratio of toxic dose to therapeutic (or usual) dose. The ratio is very low for heroin and similar opiates, for cocaine especially crack, and for intravenous temazepam and oral ecstasy. It is quite high for psychedelics, cannabis, benzodiazepines, and orally used stimulants such as amphetamines. Another important consideration is the health complications of long-term use which by and large reflects the therapeutic index. An exception to this is the opiates, which, provided sterile administration is used, are thought to have little detrimental effect, even when used chronically and intravenously. Chronic cocaine can lead to cardiac damage, and heavy cannabis smoking causes precancerous change in the same way as tobacco smoking, as well as causing greater levels of chronic bronchitis.

The degree of control over behaviour the drug elicits is a major factor in drug dependence, and is the closest concept to addictiveness. Although the route of administration is another critical variable, we can make some reasonable generalizations. Strong opiates and cocaine are the most addictive, being in the same class as nicotine. The benzodiazepines, ecstasy, and psychedelics are the least addictive, and are significantly less addictive than alcohol.

There are three main factors contributing to drugs gaining control over behaviour, all of which affect the ease with which a drug may be stopped. The first is the pleasure a drug produces—the positive drive for use (pleasure giving and seeking). The others both involve the pain of abstinence—withdrawal in both physical and psychological terms—which leads to drug use to relieve it (discomfort escape). The pattern of drug use during an addiction career generally begins with the quest for pleasure and progressively evolves into the escape from withdrawal pain as neuroadaptive processes develop. In this context it may be thought that withdrawal discomfort is best limited to symptoms with a clear physical symptomatology, i.e. the autonomic symptoms indicative of physical dependence. But in terms of addictiveness, psychological withdrawal may in fact be more important than physical withdrawal. This is illustrated by the finding that those dependent on opiates for medical reasons, although physically dependent, experience little craving and risk of relapse once detoxified, provided the reason for being on the opiate resolves. The ease of stopping the drug thus depends on both the physical and psychological withdrawal symptoms, as well as the ability of the drug to provide positive reinforcement.

It is possible to provide rough guides for these three processes for each drug so that the overall addictiveness potential can be gauged. 

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