Psychoactive Drugs Tobacco, Alcohol, and Illicit Substances

4. How does drug addiction develop?

• 4.1 How do drug users become drug dependant?
• 4.2 How can genetic factors influence drug use and addiction?

4.1 How do drug users become drug dependant?

The source document for this Digest states:

Dependence as a learning process involving key brain regions

The development of dependence can be seen as part of a learning process, in the sense that enduring changes in behaviour result from interactions with psychoactive substances and their associated environments. A person takes a substance and experiences the psychoactive effect, which is highly rewarding or reinforcing, and which activates circuits in the brain that will make it more likely that this behaviour will be repeated.

However, the rewarding effects of substances alone cannot account for why some psychoactive substances can lead to all of the behaviours associated with dependence (Box 2). Similarly, physical dependence on substances, as evidenced by withdrawal symptoms when substance use is discontinued, may contribute to substance use and dependence, but cannot alone explain why substance dependence develops and is maintained, especially after long periods of abstinence. What is it about psychoactive substances that causes people to lose their jobs and families in pursuit of these substances? What is the process by which substance- taking behaviour, in certain individuals, evolves into compulsive patterns of substance-seeking and substance-taking behaviour that take place at the expense of most other activities; and what causes the inability to cease substance-taking, that is, the problem of relapse? A complex interplay of psychological, neurobiological and social factors appears to be responsible.

Biobehavioural processes underlying dependence

The brain has systems that have evolved to guide and direct behaviour toward stimuli that are critical to survival. For example, stimuli associated with food, water, and a mate all activate specific pathways, and reinforce the behaviours that lead to the obtaining of corresponding goals. Psychoactive substances artificially activate these same pathways, but very strongly, leading to enhanced motivation to continue this behaviour. Thus, according to this theory, dependence is the result of a complex interaction of the physiological effects of substances on brain areas associated with motivation and emotion, combined with ‘‘learning’’ about the relationship between substances and substance-related cues.

Figure 5. Mesolimbic dopamine pathway.

Mesolimbic dopamine pathway

Although each class of psychoactive substance has its own unique primary pharmacological mechanism of action
(Table 4), many also activate the mesolimbic dopamine pathway
(See Fig. 5), although through different mechanisms depending on the substance. The mesolimbic dopamine pathway resides in an area of the brain known as the midbrain, and is the system that is most strongly implicated in the dependence-producing potential of psychoactive substances (17). Two areas that are very important in substance dependence are the ventral tegmental area (VTA), and a region that it communicates with, known as the nucleus accumbens. The ventral tegmental area is an area that is rich in neurons containing the neurotransmitter dopamine. The cell bodies of these neurons send projections to regions of the brain involved in emotions, thoughts, memories, and planning and executing behaviours. The nucleus accumbens is a very important brain area involved in motivation and learning, and signalling the motivational value of stimuli (18, 19). Psychoactive substances increase the release of dopamine in the nucleus accumbens, which is thought to be an important event in reinforcement.

Motivation and incentive

Motivation and incentive are important concepts with regard to substance dependence. The mesolimbic dopamine pathway of the brain has been shown to be closely involved in motivational processes: that is to say, stimuli that are recognized as being important to survival are given special importance in the brain. Motivation is the allotment of attentional and behavioural resources to stimuli in relation to their predicted consequences. Incentives are stimuli that elicit a response on the basis of their predicted consequences. For example, if a person is not hungry, the visual and olfactory stimuli associated with food (incentives) will have little effect on his or her behaviour or attention (motivation). However, if the person is hungry, the sight and smell of food may cause him or her to pay attention, and to take steps to obtain food. If the person is starving and has no means of obtaining food, he or she might even steal or commit a crime to obtain it. This is known as incentive- motivational responding, or responding in terms of both the incentive value of the stimulus and the motivation to obtain the stimulus.

In substance dependence, psychoactive substances repeatedly activate the motivational systems of the brain that are normally activated by such important stimuli as food, water, danger, and mates. The brain is ‘‘tricked’’ by the substances into responding as if the substances and their associated stimuli are biologically needed. With repeated exposure, the association becomes stronger and stronger, evoking a larger behavioural and neurochemical response. This is known as incentive sensitization, whereby psychoactive substances and the stimuli associated with their use take on increasing motivational and behavioural significance (20). Through associative learning processes, the motivation to use psychoactive substances can be strongly activated by stimuli (environments, people, objects) associated with substance use, causing the desire or craving that can overwhelm people and cause relapse to substance use, even after long periods of abstinence. This also contributes to our understanding of why withdrawal symptoms alone are not enough to explain the full spectrum of substance dependence, because even people who have completely withdrawn from a particular substance can relapse to substance use in response to a variety of different situations.

Source & ©: WHO  Neuroscience of psychoactive substance use and dependence, Summary (2004),
Neurobiological and biobehavioural basis of the development of substance dependence, p.20-22

4.2 How can genetic factors influence drug use and addiction?

The source document for this Digest states:

In thinking about dependence, it is important to remember that over a lifespan many people experiment with a variety of potentially dependence-producing substances, but most do not become dependent. There are also individual differences in susceptibility to substance dependence due to environmental and genetic factors

Genetic basis of individual differences in susceptibility to substance dependence

There are many individual, cultural, biological, social and environmental factors that converge to increase or decrease the odds that a particular individual will consume a psychoactive substance, and to what extent. Though the factors shown in Box 3 are more related to the initiation of substance use than to dependence, many of them are common to both phenomena.

Box 3. Risk and protective factors for substance use

Risk factors	Protective factors
Environmental availability of drugs poverty social change peer culture occupation cultural norms, attitudes policies on drugs, tobacco and alcohol	Environmental economic situation situational control social support social integration positive life events
Individual genetic disposition victim of child abuse personality disorders family disruption and dependence problems poor performance at school social deprivation depression and suicidal behaviour	Individual good coping skills self-efficacy risk perception optimism health-related behaviour ability to resist social pressure general health behaviour

Source & ©: reproduced from references 21-24

One aspect of neuroscience research examines how psychoactive substances act in terms of the common biological inheritance shared by all humans. The counterpoint to this is the genetic research that focuses on the differences in action of the substances between one human and another that are attributable to different genetic inheritances. In addition to social and cultural factors, differences in genetic makeup explain a substantial proportion of the variation in psychoactive substance use and dependence among individuals. However, it is not a simple task to identify the genes that are involved.

Although some illnesses are caused by a single gene, such as in Huntington’s disease, other disorders, known as complex disorders, appear to be caused by the interaction of several genes with environmental factors. Substance dependence is one such complex disorder. Thus, exposure to psychoactive substances could have a much greater effect on somebody who carries a genetic vulnerability to substance dependence, than on someone who does not. This also makes the study of the genetics of substance dependence more complicated, although great progress has been made in recent years to identify the genes that may contribute to the development of dependence. Studies of patterns of inheritance in families, in identical and fraternal twins, and in adopted individuals, provide information on the extent to which inherited factors play a role in substance dependence. Other types of studies look at the inheritance of related traits, to try to identify regions of genes that might be important. Candidate gene studies examine genes that might reasonably be thought to be involved in substance dependence, such as opioid receptor genes for opioid dependence.

There is evidence of significant heritability of tobacco use among different populations, sexes, and ages (25, 26). Studies suggest that there are likely to be many different genes that contribute to the development and persistence of smoking (27-29). Genes involved in nicotine metabolism may be important risk factors for smoking; and variation in these genes is likely to be a major determinant of brain nicotine levels and accumulation.

There is significant heritability of alcohol dependence, as well as heritability of frequency and quantity of alcohol consumed (30-37). Genes that may be important for this association are involved with alcohol metabolism (38), and receptors for the neurotransmitters GABA (38), serotonin (39), and dopamine (38). Genetic variations in alcohol metabolizing enzymes have also been identified as possibly underlying some of the variation in alcohol consumption (40-42). There is evidence from some studies that the heritability of opioid dependence is high, estimated at almost 70% (e.g. 43). This may be due to inherited differences in opioid receptors or opioid metabolizing enzymes.

There is also a genetic contribution to the use of and dependence on the combination of alcohol, tobacco and other substances together (30, 43-48). One estimate is that there is an eight-fold increased risk of substance dependence amongst relatives of people with substance dependence compared to controls, when applied to a wide range of substances including opioids, cannabis, sedatives and cocaine (49, 50).

The genetic findings provide an indication of the promise that genetic research offers. These genetic data can and have been used to improve our understanding of the origins of substance dependence, and variation in risk beween individuals. Once genes which alter the predisposition to dependence are identified, a major challenge will be to understand how the function of these genes interacts with the environmental influences on dependence (51). This information may form the basis for novel diagnostic tools as well as the basis of novel behavioural and pharmacological treatments.

Genetic screening, based on the research findings, can potentially identify subgroups of the population with a greater liability to dependence or harm from a particular psychoactive substance. However, this raises many ethical issues, as the identification is in terms of probabilities rather than certainties. Actions that could be taken on the basis of a positive screen might include notification of the affected person (or of the person’s parents or guardian, in case of a child), and preventive interventions such as therapeutic education or other interventions targeted at reducing vulnerability to substance use and dependence. There are obvious ethical implications in terms of stigmatization, privacy, and consent to treatment.

Genetic differences may influence many aspects of substance use, for example, subjective pleasurable effects. Genetic factors may also greatly affect the toxicity of a substance, both in terms of overdose and of chronic health effects. Genetics may also affect the intensity of psychoactive effects of a given formulation and dose of a substance, the development of tolerance, withdrawal, and craving. In addition, substance dependence may share neurobiological commonalities with several different forms of mental illness, suggesting that common treatment and prevention strategies may help both conditions.

Source & ©: WHO  Neuroscience of psychoactive substance use and dependence, Summary (2004),
Genetic basis of individual differences in susceptibility to substance dependence, p.22-25