Introduction to Special Issue on Tobacco and Other Substance Use Disorders: Links and Implications

The morbidity, mortality, and cost of tobacco, alcohol, and other substance use disorders is well established as is the need to develop more effective prevention and treatment strategies. Equally well established is the elevated prevalence of tobacco use in individuals with alcohol and other substance use disorders – approximately 75% of individuals being treated for alcohol use disorder (AUD) smoke cigarettes (1,2) and 47% to 88% of individuals being treated for substance use disorder (SUD) smoke, depending on the substance (1–5). Less well established is the role that: 1) tobacco/nicotine plays in establishing and maintaining AUD and other SUDs and 2) the role that non-nicotine substance use plays in establishing and maintaining tobacco use disorder (TUD). Regardless of causality, the elevated prevalence of smoking in individuals with AUD and/or other SUD (AUD/SUD) represents an important health issue that needs to be addressed; however, how best to address it depends, in part, on whether co-use plays a causal role in maintaining addiction.

This special issue includes a review of research pertinent to the questions of causation and potential causal mechanisms from across the translational research spectrum. Findings that the use of nicotine/tobacco plays a causal role in establishing and maintaining addiction to alcohol and other substances, or vice-versa, would have important implications for prevention and treatment. For example, if nicotine does, in fact, increase the likelihood that an individual will develop an AUD/SUD then the recent increase in non-tobacco nicotine products by adolescents would have public health implications well-beyond the health consequences of the use of these products or even the potential progression to TUD, demanding more vigorous prevention efforts. Findings that tobacco/nicotine co-use moderates treatment outcomes for the primary substance for which SUD treatment is sought would indicate that co-use may be a precision-medicine-factor (6,7), which should be used to help guide treatment planning. Findings of a causal relationship in co-occurring addiction could also have significant implications for treatment development, with potentially novel therapeutic targets yielded by an understanding of underlying mechanisms.

In this special issue, Dr. Richter and colleagues (8) reviewed, and contributed new data to, the epidemiological literature on the tobacco/nicotine link with other substances. They note that, while tobacco use initiation in adolescents has declined, the use of electronic cigarettes (e-cigarettes) and other electronic nicotine delivery systems has increased significantly in the past several years. Of particular concern is evidence that the use of any nicotine-containing product is associated with a greater likelihood of using and being addicted to other substances. The authors discuss the prevention and policy implications of these findings. While the epidemiological findings are consistent with a causal role for co-use in the development of addiction, the correlational nature of the data does not allow for causal determinations to be made. Thus, findings from pre-clinical research, which can establish causal relationships, are of critical import.

Three papers in this special issue, by Tarren and Bartlett (9), Kohut (10), and Cross et al. (11), review pre-clinical research findings. The paper by Drs. Tarren and Bartlett (9) describes pre-clinical models being utilized to more precisely delineate the neurobiological mechanisms underlying alcohol and nicotine co-dependence and discusses findings suggesting a role for nicotinic acetylcholine receptors (nAChRs) in co-dependence. This research suggests that nicotinic receptor antagonists may offer promising therapeutic agents in the treatment of co-occurring tobacco and alcohol use disorders, an important implication given evidence that concurrent use of nicotine and alcohol may alter the effectiveness of FDA-approved medications used to treat AUD and TUD. Dr. Kohut (10) reviewed findings from animal models evaluating the role of co-use in modifying the positive and negative effects of substances and the degree to which one substance can substitute for another. Overall, the evidence suggests that co-use plays a role in maintaining addiction but findings for the specific effects that nicotine has on other substances, and vice-versa, reveal a complex picture. Dr. Cross (11) and colleagues reviewed potential neurobiological mechanisms underlying the high prevalence of TUD with AUD and stimulant use disorders. They discuss evidence of a common genetic component for the three disorders, which may indicate a common liability for addiction, as well as evidence that, in adolescence, nicotine can increase the brain’s sensitivity to the rewarding properties of other substances of abuse. The potential role of the dopaminergic, cholinergic and serotonergic systems in co-dependence is discussed as is the importance of considering potential moderators of the co-use relationship, including age and sex.

Human laboratory research on co-occurring use offers the opportunity to evaluate potential causal relationships in ways infeasible for clinical research. For example, human laboratory studies can evaluate the impact that providing one substance has on the craving for, or self-administration of, a second substance. Drs. Verplaeste and McKee (12) reviewed findings from human laboratory research, with a primary focus on alcohol and nicotine co-use. While the impact of each substance on the other substance varies to some degree based on the characteristics of the study participants and experimental conditions, the body of evidence suggests that alcohol increases tobacco/nicotine craving and use and that tobacco/nicotine increases alcohol craving and use. The authors discuss implications for treatment and future research directions.

Positron emission tomography (PET) provides the ability to directly assess neurotransmitter functioning, including dopamine, in the human brain. Dr. LeFoll and colleagues (13) reviewed the PET literature relevant to co-use from the last 10 years. While PET research has increased our understanding of the dopaminergic system’s role in SUDs, very little research has evaluated whether the concurrent use of tobacco with another substance impacts dopaminergic functioning differently than the use of each substance separately. Instead, tobacco co-use has been largely treated as a nuisance variable; the manner in which co-use was controlled for in over 50 different studies is reviewed. The authors discuss the importance of conducting research to understand dopaminergic function in individuals with AUD/SUD with and without co-occurring TUD.

As noted by the Centers for Disease Control (CDC), smoking in individuals with an AUD/SUD constitutes an important health disparity (14). SUD treatment seems like a natural setting in which to address smoking and Dr. Knudsen (15) reviewed research on the provision of smoking-cessation interventions in SUD treatment programs. Despite evidence that a substantial proportion of individuals in treatment for AUD/SUD are interested in quitting smoking, research reveals poor rates of adoption and implementation of smoking-cessation treatment in this setting. Dr. Knudsen provides insights into programs that are more likely to be successful and outlines strategies for overcoming implementation barriers.

Together, the papers in this special issue offer several important insights. First, conflicting findings from research on co-occurring use disorders are not uncommon and there is a need to better understand the factors that moderate co-use relationships. These factors can include patient characteristics (e.g., age, sex, substance use history, etc.) and experimental methods (e.g., passive vs. self-administration of nicotine, length of abstinence, etc.). Second, the vast majority of research conducted in this area has evaluated the impact of nicotine/tobacco on AUD with a relative dearth of research evaluating the impact of nicotine/tobacco on other SUDs and the impact of substances of abuse on TUD. The disproportionate amount of research in alcohol compared to other substances of abuse is not surprising in that funding to evaluate the mechanisms of nicotine and alcohol co-dependence has been available since at least 2009. However, there have been recent, exciting changes in funding priorities and opportunities. Specifically, the importance of understanding the behavioral and neural mechanisms underlying co-occurring SUDs was outlined in the Collaborative Research on Addiction at NIH (CRAN) 2016-2021 strategic plan (16) and CRAN issued several program announcements in 2016 to fund research in this area. This special issue, in the end, is a call for action, particularly for more research to understand the mechanisms by which co-use may play a role in initiating and maintaining addiction. With CRAN’s new focus on co-occurring SUDs and current funding opportunities in this area, the time to act is now.