Genetics and substance abuse

DEFINITION: Substance abuse is broadly defined as the inappropriate or illegal use of substances, either drugs or alcohol, which may result in legal and safety issues. While historically, such abuse has been considered the result of either moral or behavioral failings, evidence has accumulated that suggests some forms of abuse may be caused or exacerbated by genetic factors.

Genetic Evidence

The human body's response to specific chemicals has long been known to have a genetic basis. In general, these effects can be considered to fall within two themes: in the presence of receptors on the cell surface that can be activated following the binding of a chemical and in the regulation of a metabolic pathway through the mechanism of chemical activation of specific enzymes. This is particularly true when applied to brain chemistry.

The functions of specific regions within the brain, including pleasure centers or those that control other forms of reactions to specific drugs, are subject to hereditary control. The expression of cell receptors and the production of enzymes that control pathways in the brain, each regulating the ability to respond to drugs, have an underlying genetic control.

Historically, the treatment of substance abuse, including that involving alcohol and drug addictions (both legal and illegal), has centered primarily on the moral or behavioral aspects of the problem. Treatment once believed that the individual with an addiction chose to use the substance and then to continue its use until addiction removed any personal control. While there is certainly a behavioral component involved—the initial use of the substance is affected by voluntary action and environmental factors—increasing evidence suggests a genetic predisposition to the addiction that may follow. Additionally, modern scientific evidence supports a medical approach to addiction as a disease rather than a morally corrupt, conscious decision.

Most historical studies attempted to establish a genetic basis for addiction utilizing twin studies. These studies involve a comparison between twins, ideally living separate lives so as to avoid environmental influences in the study, in which the prevalence of substance abuse and addiction may be compared. Numerous epidemiological studies of twins have shown a significantly increased level of risk, even in the absence of environmental influences: If one twin developed an addiction, the other also demonstrated a significantly higher level of risk of doing so.

Adoption studies have reinforced the conclusions reached through twin studies. If a birth parent exhibited problems in the use of alcohol, then the child demonstrated a significantly increased risk of exhibiting the same behaviors. However, if the child was adopted and thus did not share genetic features with the adoptive parent, the child exhibited no increased risk. Similar results also were found in cases of drug addiction.

The development of biochemical methods for studying brain chemistry and regulation of pleasure pathways has provided a means to investigate addiction at the molecular level. Studies have shown that some forms of addiction may be exacerbated by the expression of specific genes or pathways in the brain, which are controlled by the drugs in question. Another challenge in attempting to sort out what genes might be involved in addiction is that, often, no single gene is always involved. Rather, the interaction of a variety of genes, and in some cases, metabolic pathways in the brain, contributes to addiction. Researchers believe genetic factors make up about 50 percent of the risk of substance use disorders.

Genetics of Alcohol Addiction

There is some indication that alcoholism may, at some level, be subject to genetic factors. Scientists agree that alcoholism frequently repeats through family generations. As noted, studies of twins and comparisons between adoptive or biological children in which a parent exhibits alcohol problems support the argument for a genetic component to alcohol addiction. It remains unclear if alcoholism is primarily genetic or whether addiction tendencies reflect the environment in which the person is raised. Experts agree that alcoholism may result from a combination of factors. Studies suggest that the environment may play a more significant part in the initiation of alcohol use. In contrast, the development of alcohol use disorder and heavy alcohol use appears to be more strongly influenced by genetics.

Supporting the argument that genetics may play a role in alcoholism was the discovery of a genetic link between a specific gene that encodes alcohol addiction and a molecule called the cyclic AMP responsive element binding protein (CREB). The CREB gene plays a role in the regulation of brain function during development; in particular, it has an association with the portion of the brain known as the amygdala. The scientific evidence for the role of the CREB gene supports what is known about the function of the amygdala, the region in the central brain that determines a portion of the body’s response to emotional disorders and stress.

Persons subject to alcoholism frequently have abnormal reactions to stress, a problem that may be ameliorated by alcohol. Depression and other abnormal responses to stress seem to reflect abnormalities in signaling patterns and gene expression within the amygdala. These abnormalities, in turn, seem to be caused by improper CREB protein regulation, or they involve the genes MAOA, SLC6A4, or COMT. Alcohol appears to reverse this process. In the presence of increased levels of alcohol, the CREB protein becomes functional, activates the signals within the amygdala, and alleviates the effects of stress. Reduced levels of the CREB protein in the amygdala exacerbate the anxiety levels of the subject, which then increases the subject’s desire (and need) for alcohol.

While most of these studies have been carried out in nonhuman animals, many of the identical physiological changes that occur in the brains of test animals, such as rats and mice, have identical counterparts in the human brain and their response to alcohol. Among the questions that should be addressed is whether the need for alcohol forms the basis for addiction or whether the long-term abuse of alcohol results in changes found within the brain.

The genes alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) aid in the metabolism of alcohol but serve as an inherited prevention of alcohol use disorder. Individuals with this gene variant will find drinking makes them ill. Conversely, the GABRA2 and CHRM2n genes are associated with alcohol use disorder, and the presence of both in an individual increases the likeliness that they will begin unhealthy alcohol use early in life.

Genetics and Stimulants

Stimulants such as cocaine, amphetamines (for example, methylene-dioxymethamphetamine, or ecstasy), and even tobacco and caffeine seem to have in common the ability to utilize common mechanisms within the brain. One mechanism in particular on which addiction studies have focused is the regulation of certain neurotransmitters, chemicals released by neurons in the brain that act to stimulate nerve endings on adjacent nerve cells.

Neurotransmitters such as dopamine, long known for its association with Parkinson’s disease, control neural pathways in the portion of the brain known as the striatum, the portion of the forebrain that controls emotions such as pleasure and certain behaviors. Stimulants such as cocaine or amphetamines increase the level of dopamine—cocaine by inhibiting the reuptake of dopamine and amphetamines by increasing their release. Regardless of their mechanism, stimulants cause drug-induced highs.

Studies in mice that have attempted to identify those genes that are particularly sensitive to the presence of stimulants have identified several genes that likely play a role: the post-synaptic density-95 (PSD-95) gene and the HIST1H2BD gene. The product of PSD-95 appears to function in regulating the structure of the receptor that serves as the target for dopamine in the pleasure centers of the striatum. Reduced levels of the PSD-95 protein in mice led to an increased response following exposure to cocaine. The sensitivity of mice to cocaine appears to correlate with the level of the PSD-95 protein.

Because most stimulants, including tobacco and alcohol, likewise act in part by increasing the level of dopamine within the striatum, the PSD-95 protein may represent a common feature in response to the presence of these drugs. Genetic variation in the activity of the PSD-95 gene may be one of the determining factors in both the behavioral response to using stimulants and in the likelihood the user may ultimately become addicted.

The gene CHRNA2 is associated with cannabis use disorder.

Bibliography

Deak, Joseph D., and Emma C. Johnson. "Genetics of Substance Use Disorders: A Review." Psychological Medicine, vol. 51, no. 13, 2021, pp. 2189-2200, DOI: 10.1017/S0033291721000969. Accessed 1 Dec. 2022.

"Family History and Genetics." National Council on Alcoholism and Drug Dependence, ncaddnational.org/addiction‗articles/family-history-and-genetics. Accessed 15 Sept. 2024.

Kendler, Kenneth, and Carol Prescott. Genes, Environment, and Psychopathology: Understanding the Causes of Psychiatric and Substance Use Disorders. New York, Guilford, 2007.

Kipper, David, and Steven Whitney. The Addiction Solution: Unraveling the Mysteries of Addiction through Cutting-Edge Brain Science. Emmaus, Rodale, 2010.

Miller, William, and Kathleen Carroll. Rethinking Substance Abuse. New York, Guilford, 2006.

"New NIH Study Reveals Shared Genetic Markers Underlying Substance Use Disorders." National Institute on Drug Abuse, 22 Mar. 2023, nida.nih.gov/news-events/news-releases/2023/03/new-nih-study-reveals-shared-genetic-markers-underlying-substance-use-disorders Accessed 13 Sept. 2024.

Wand, Gary. “The Anxious Amygdala: CREB Signaling and Predisposition to Anxiety and Alcoholism.” Journal of Clinical Investigation 115 (2005): 2697–99.