Bidirectional causality between addiction and cognitive deficits

Int Rev Neurobiol. 2021:157:371-407. doi: 10.1016/bs.irn.2020.11.001. Epub 2020 Dec 30.


Cognitive deficits are highly comorbid with substance use disorders. Deficits span multiple cognitive domains, are associated with disease severity across substance classes, and persist long after cessation of substance use. Furthermore, recovery of cognitive function during protracted abstinence is highly predictive of treatment adherence, relapse, and overall substance use disorder prognosis, suggesting that addiction may be best characterized as a disease of executive dysfunction. While the association between cognitive deficits and substance use disorders is clear, determining causalities is made difficult by the complex interplay between these variables. Cognitive dysfunction present prior to first drug use can act as a risk factor for substance use initiation, likelihood of pathology, and disease trajectory. At the same time, substance use can directly cause cognitive impairments even in individuals without preexisting deficits. Thus, parsing preexisting risk factors from substance-induced adaptations, and how they may interact, poses significant challenges. Here, focusing on psychostimulants and alcohol, we review evidence from clinical literature implicating cognitive deficits as a risk factor for addiction, a consequence of substance use, and the role the prefrontal cortex plays in these phenomena. We then review corresponding preclinical literature, highlighting the high degree of congruency between animal and human studies, and emphasize the unique opportunity that animal models provide to test causality between cognitive phenotypes and substance use, and to investigate the underlying neurobiology at a cellular and molecular level. Together, we provide an accessible resource for assessing the validity and utility of forward- and reverse-translation between these clinical and preclinical literatures.

Keywords: Alcohol; Amphetamine; Animal models of addiction; Cocaine; Cognitive flexibility; Drug consumption; Impulsivity; Prefrontal cortex; Response inhibition; Stimulants; Substance use disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Causality
  • Cognitive Dysfunction* / epidemiology
  • Humans
  • Substance-Related Disorders* / epidemiology