Common Comorbidities with Substance Use Disorders Research Report
Why is there comorbidity between substance use disorders and mental illnesses?

The high prevalence of comorbidity between substance use disorders and other mental illnesses does not necessarily mean that one caused the other, even if one appeared first. Establishing causality or directionality is difficult for several reasons. For example, behavioral or emotional problems may not be severe enough for a diagnosis (called subclinical symptoms), but subclinical mental health issues may prompt drug use. Also, people’s recollections of when drug use or addiction started may be imperfect, making it difficult to determine whether the substance use or mental health issues came first.

Three main pathways can contribute to the comorbidity between substance use disorders and mental illnesses:1

  1. Common risk factors can contribute to both mental illness and substance use and addiction.
  2. Mental illness may contribute to substance use and addiction.
  3. Substance use and addiction can contribute to the development of mental illness.

1. Common risk factors can contribute to both mental illness and substance use and addiction.

Both substance use disorders and other mental illnesses are caused by overlapping factors such as genetic and epigenetic vulnerabilities,27,33–35 issues with similar areas of the brain,2,3,36 and environmental influences such as early exposure to stress or trauma.3,27

Genetic Vulnerabilities

It is estimated that 40–60 percent of an individual’s vulnerability to substance use disorders is attributable to genetics.37 An active area of comorbidity research involves the search for that might predispose individuals to develop both a substance use disorder and other mental illnesses, or to have a greater risk of a second disorder occurring after the first appears.27,33,34 Most of this vulnerability arises from complex interactions among multiple genes and genetic interactions with environmental influences.33,38 For example, frequent marijuana use during adolescence is associated with increased risk of psychosis in adulthood, specifically among individuals who carry a particular gene variant.25–27

In some instances, a gene product may act directly, as when a protein influences how a person responds to a drug (e.g., whether the drug experience is pleasurable or not) or how long a drug remains in the body. Specific genetic factors have been identified that predispose an individual to alcohol dependence and cigarette smoking, and research is starting to uncover the link between genetic sequences and a higher risk of cocaine dependence, heavy opioid use, and cannabis craving and withdrawal.37 But genes can also act indirectly by altering how an individual responds to stress38 or by increasing the likelihood of risk-taking and novelty-seeking behaviors,3 which could influence the initiation of substance use as well as the development of substance use disorders and other mental illnesses. Research suggests that there are many genes that may contribute to the risk for both mental disorders and addiction, including those that influence the action of neurotransmitters—chemicals that carry messages from one neuron to another—that are affected by drugs and commonly dysregulated in mental illness, such as dopamine and serotonin.33,39

Epigenetic Influences

Scientists are also beginning to understand the very powerful ways that genetic and environmental factors interact at the molecular level.40,41 Epigenetics refers to the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence; that is, changes that affect how genetic information is read and acted on by cells in the body. Environmental factors such as chronic stress, trauma, or drug exposure can induce stable changes in gene expression, which can alter functioning in neural circuits and ultimately impact behavior.42 For more information on epigenetics, see Genetics and Epigenetics of Addiction DrugFacts.

Through epigenetic mechanisms, the environment can cause long-term genetic adaptations—influencing the pattern of genes that are active or silent in encoding proteins—without altering the DNA sequence. These modifications can sometimes even be passed down to the next generation.35 There is also evidence that they can be reversed with interventions or environmental alteration.41

The epigenetic impact of environment is highly dependent on developmental stage.42 Studies suggest that environmental factors interact with genetic vulnerability during particular developmental periods to increase the risk for mental illnesses42 and addiction.35 For example, animal studies indicate that a maternal diet high in fat during pregnancy can influence levels of key proteins involved in neurotransmission in the brain’s reward pathway.41 Other animal research has shown that poor quality maternal care diminished the ability of offspring to respond to stress through epigenetic mechanisms.41 Researchers are using animal models to explore the epigenetic changes induced by chronic stress or drug administration, and how these changes contribute to depression- and addiction-related behaviors.40 A better understanding of the biological mechanisms that underlie the genetic and biological interactions that contribute to the development of these disorders will inform the design of improved treatment strategies.40,42

Brain Region Involvement

Many areas of the brain are affected by both substance use disorders and other mental illnesses. For example, the circuits in the brain that mediate reward, decision making, impulse control, and emotions may be affected by addictive substances and disrupted in substance use disorders, depression, schizophrenia, and other psychiatric disorders.2,3,34,43 In addition, multiple neurotransmitter systems have been implicated in both substance use disorders and other mental disorders including, but not limited to, dopamine,44–46 serotonin,47,48 glutamate,49,50 GABA,51 and norepinephrine.46,52,53

Environmental Influences

Many environmental factors are associated with an increased risk for both substance use disorders and mental illness including chronic stress, trauma, and adverse childhood experiences, among others. Many of these factors are modifiable and; thus, prevention interventions will often result in reductions in both substance use disorders and mental illness, as discussed in the Surgeon General’s report on alcohol, drugs, and health.


Stress is a known risk factor for a range of mental disorders and therefore provides one likely common neurobiological link between the disease processes of substance use disorders and mental disorders.3,38,54 Exposure to stressors is also a major risk factor for relapse to drug use after periods of recovery. Stress responses are mediated through the hypothalamic-pituitary-adrenal (HPA) axis, which in turn can influence brain circuits that control motivation. Higher levels of stress have been shown to reduce activity in the prefrontal cortex and increase responsivity in the striatum, which leads to decreased behavioral control and increased impulsivity.55  Early life stress and chronic stress can cause long-term alterations in the HPA axis, which affects limbic brain circuits that are involved in motivation, learning, and adaptation, and are impaired in individuals with substance use disorders and other mental illnesses.2,3,34,43

Importantly, dopamine pathways have been implicated in the way in which stress can increase vulnerability to substance use disorders. HPA axis hyperactivity has been shown to alter dopamine signaling, which may enhance the reinforcing properties of drugs.38,54,55 In turn, substance use causes changes to many neurotransmitter systems that are involved in responses to stress. These neurobiological changes are thought to underlie the link between stress and escalation of drug use as well as relapse. Treatments that target stress, such as mindfulness-based stress reduction, have been shown to be beneficial for reducing depression, anxiety, and substance use.56

Trauma and Adverse Childhood Experiences

Physically or emotionally traumatized people are at much higher risk for drug use and SUDs.57 and the co-occurrence of these disorders is associated with inferior treatment outcomes.57 People with PTSD may use substances in an attempt to reduce their anxiety and to avoid dealing with trauma and its consequences.58

The link between substance use disorder and PTSD is of particular concern for service members returning from tours of duty in Iraq and Afghanistan. Between 2004 and 2010, approximately 16 percent of veterans had an untreated substance use disorder, and 8 percent needed treatment for serious psychological distress (SPD).59 Data from a survey that used a contemporary, national sample of veterans estimated that the rate of lifetime PTSD was 8 percent, while approximately 5 percent reported current PTSD.60 Approximately 1 in 5 veterans with PTSD also has a co-occurring substance use disorder.61

2. Mental illnesses can contribute to drug use and addiction.

Certain mental disorders are established risk factors for developing a substance use disorder.62 It is commonly hypothesized that individuals with severe, mild, or even subclinical mental disorders may use drugs as a form of self-medication.1,28 Although some drugs may temporarily reduce symptoms of a mental illness, they can also exacerbate symptoms, both acutely and in the long run. For example, evidence suggests that periods of cocaine use may worsen the symptoms of bipolar disorder and contribute to progression of this illness.63 

When an individual develops a mental illness, associated changes in brain activity may increase the vulnerability for problematic use of substances by enhancing their rewarding effects, reducing awareness of their negative effects, or alleviating the unpleasant symptoms of the mental disorder or the side effects of the medication used to treat it.1 For example, neuroimaging suggests that ADHD is associated with neurobiological changes in brain circuits that are also associated with drug cravings, perhaps partially explaining why patients with substance use disorders report greater cravings when they have comorbid ADHD.64–66

3. Substance use and addiction can contribute to the development of mental illness.

Substance use can lead to changes in some of the same brain areas that are disrupted in other mental disorders, such as schizophrenia, anxiety, mood, or impulse-control disorders.2,36 Drug use that precedes the first symptoms of a mental illness may produce changes in brain structure and function that kindle an underlying predisposition to develop that mental illness.

The Comorbidity Between Mental Illness and Tobacco Use—Highlight on Schizophrenia

Based on nationally representative survey data from 2016, 30.5 percent of respondents who have a mental illness smoked cigarettes in the past month, which is about 66 percent higher than the rate among those with no mental illness. There is a strong association between mental illness, particularly depression and schizophrenia, and use of tobacco products.67–69 People with schizophrenia have the highest prevalence of smoking (70 to 80 percent)70—with rates up to 5 times higher than the general population.68

Smoking may reduce or help individuals cope with the symptoms of these illnesses, such as poor concentration, low mood, and stress.43,67,68 Such alleviation of symptoms may explain why people with mental illnesses are less likely to quit smoking compared with those in the general population.68,71,72 Unfortunately, high rates of smoking and difficulty quitting among people with schizophrenia may contribute to their greater prevalence of cardiovascular disease and shorter life expectancy.68

Research on Schizophrenia and Nicotine

Research on how both nicotine and schizophrenia affect the brain has generated other possible explanations for the high rate of smoking among people with schizophrenia.43 The presence of abnormalities in particular circuits of the brain may predispose individuals to schizophrenia and increase the rewarding effects of drugs like nicotine, and/or reduce an individual’s ability to quit smoking.43,73 These mechanisms are consistent with the observation that both nicotine and the medication clozapine (which also acts at nicotinic acetylcholine receptors, among others) are effective in treating individuals with schizophrenia,17,74 and can serve as replacements for the nicotine obtained through cigarette smoking, thus making it easier to quit smoking.74

The dorsal anterior cingulate cortex (dACC) is involved in decision-making and planning, focusing attention, and controlling impulses and emotions. Researchers have found that connections between this region and several other brain areas—including some involved in memory, emotion, and reward—are weaker among patients with schizophrenia compared with those without the disorder. This circuit was impaired among people with schizophrenia regardless of whether they smoked or not, as well as among the close relatives of people with schizophrenia. Several of these neural circuits were also less active among individuals with severe nicotine use disorder, suggesting that this brain circuit is impaired in both schizophrenia and nicotine dependence.73

A lower level of nicotinic acetylcholine receptors is a neurobiological hallmark of schizophrenia. These receptors, which are involved in cognition and memory,75 are naturally activated by the neurotransmitter acetylcholine—but they can also be activated by nicotine. Researchers are working to develop medications that stimulate these specific receptors, which can counter the cognitive impairments associated with schizophrenia without the addictive potential of nicotine or the negative health consequences of smoking.75 Understanding how and why patients with schizophrenia use nicotine may help inform the development of new treatments for both schizophrenia and nicotine dependence.

Although there is a great need for new treatments for both schizophrenia and nicotine dependence, people with these comorbid disorders can quit without worsening their mental health when they have appropriate support.67,76 For example, bupropion increases smoking abstinence rates in people with schizophrenia, with no apparent worsening of psychotic symptoms.77,78 Adding motivational incentives (rewarding patients for biologically verified abstinence) to bupropion medication may help prevent relapse during the initial phase of smoking cessation.78 Varenicline may also improve smoking cessation rates in schizophrenia, but this medication may worsen psychiatric symptoms and requires additional research.78,79