NIH – Integrative Research on Polysubstance Abuse and Disorder (R61/R33 Clinical Trial Optional)

October 22, 2019 by


Collaborative Research on Addiction (CRAN) is a National Institutes of Health (NIH) partnership between the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Drug Abuse (NIDA), and the National Cancer Institute (NCI). The mission of CRAN is to provide a strong collaborative framework to leverage resources and expertise that will meet public health needs by broadening the research focus of participating institutes to better address poly- or multiple substance use, abuse, and dependence. To this end, the purpose of this FOA is two-fold: (1) to compare the similarities and differences between PSU and single drug use across antecedent and consequential behavioral, neurobiological, genetic, and epigenetic changes; and (2) to rapidly integrate findings across a translational pipeline, consisting of basic science research in animals, human-based laboratory investigations, epidemiological, therapeutic development, and services research studies. The goal of this initiative is to support investigations on tobacco, alcohol, cannabis, and other licit and illicit drugs of abuse. Applicants should focus on two primary drugs of abuse to facilitate the integration of findings and aid interpretability, with the understanding that the human condition often involves the use of multiple substances. This FOA will not support research projects focused on studying food addiction, gambling, or internet/gaming addictions.


Polysubstance use (PSU) is defined as the use of two or more addictive drugs simultaneously or concurrently and polysubstance use disorder (PSUD) is the presence of 2 or more substance use disorders (SUD). Simultaneous PSU is characterized as the use of multiple drugs at the same time whereas concurrent PSU refers to the use of multiple substances within a specified period of time, but not simultaneously. Polysubstance users report that the simultaneous ingestion of two addictive substances can produce additive/synergistic euphoric effects and concurrent use is intended to alleviate the negative consequences of another drug. For example, the co-administration of heroin and cocaine, otherwise known as “speedballing,” produces enhanced reinforcing effects when compared to the delivery of either drug alone. Alternatively, benzodiazepines, opioids, or alcohol are commonly used to relieve the aversive symptoms during a cocaine “crash,” an anhedonic state that is characterized by general dysphoria, agitation, and anxiety.

Importantly, the incidence and clinical impact of PSU are increasing. Increases in PSU may be related to demand driven by the above desired effects and/or the increased availability of polysubstance products.  The growing clinical impact is evidenced by the increase in fatal and nonfatal overdoses involving PSU. Epidemiological data from national surveys indicate that approximately 20% to 30% of youth and young adults engage in PSU and the majority of treatment seekers are polysubstance abusers. Polysubstance users typically initiate drug use at an earlier age than single drug users, and PSU occurs more frequently in males. Compared to users of a single drug, polysubstance users are more likely to present with comorbid mental health conditions, misuse or abuse prescription drugs, are at a greater risk for other health complications, and are more likely to report higher ratings on the Addiction Severity Index. Moreover, polysubstance abuse and PSUD are associated with social disadvantages including elevated risk of academic failure and non-completion, higher frequency of employment and legal issues, poorer quality of life, and a greater likelihood of engaging in physical violence. Together, these data suggest that PSU is common and increasing in drug users and is associated with worse health and societal consequences than single drug use.

While clinicians and epidemiologists have long recognized that PSU is prevalent among drug users, this ‘real-world’ context has not been fully investigated in basic animal and clinical human research. There is a paucity of studies addressing drivers and patterns of PSU, biological effects of PSU and relevant drug interactions that could impact acute and chronic toxicity or effects on substance dependence.  In particular, there is a lack of mechanistic research on topics relevant to polysubstance misuse.  Barriers affecting the integration of PSU into clinical and animal basic research include the need for additional control groups, complexities of data interpretation, and challenges of modeling human phenomena using animal research. Limited investigations of PSU in basic science research hinders a full exploration and comprehension of the underlying processes and mechanisms that underlie poorer health and social outcomes that are associated with this pattern of use. This FOA will address this knowledge gap by requiring a translational component in the research applications to encourage applicants to identify similarities and differences between PSU and single drug use.

Award Project Period

The project period is limited to 2 years for the R61 phase and up to 3 years for the R33 phase. The total project period may not exceed 5 years.


Application direct costs are limited to $300,000 during each year of the R61 phase and $500,000 during each year of the R33 phase.

Key Dates

Open Date: February 17, 2020

Letter of Intent Due Date(s): 30 days prior to the application due date
Application Due Date(s): March 17, 2020, July 17, 2020, November 17, 2020, March 17, 2021, July 19, 2021, November 17, 2021, March 17, 2022, July 19, 2022, November 7, 2022
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Filed Under: Funding Opportunities