Testing the consequences of alcohol, cannabis, and nicotine use on hippocampal volume: A quasi-experimental cotwin control analysis of young adult twins

Jeremy Harper, Sylia Wilson, Jessica L. Bair, Ruskin H Hunt, Kathleen M Thomas, Stephen M. Malone, William G. Iacono

Research output: Contribution to journalArticlepeer-review


Background Alcohol, cannabis, and nicotine use are highly comorbid and alarmingly prevalent in young adults. The hippocampus may be particularly sensitive to substance exposure. This remains largely untested in humans and familial risk may confound exposure effects. We extend prior work on alcohol and hippocampal volume in women by testing common and unique substance use effects and the potential moderating role of sex on hippocampal volume during emerging adulthood. A quasi-experimental cotwin control (CTC) design was used to separate familial risk from exposure consequences. Methods In a population-based sample of 435 24-year-old same-sex twins (58% women), dimensional measures (e.g. frequency, amount) of alcohol, cannabis, and nicotine use across emerging adulthood were assessed. Hippocampal volume was assessed using MRI. Results Greater substance use was significantly associated with lower hippocampal volume for women but not men. The same pattern was observed for alcohol, cannabis, and nicotine. CTC analyses provided evidence that hippocampal effects likely reflected familial risk and the consequence of substance use in general and alcohol and nicotine in particular; cannabis effects were in the expected direction but not significant. Within-pair mediation analyses suggested that the effect of alcohol use on the hippocampus may reflect, in part, comorbid nicotine use. Conclusions The observed hippocampal volume deviations in women likely reflected substance-related premorbid familial risk and the consequences of smoking and, to a lesser degree, drinking. Findings contribute to a growing body of work suggesting heightened risk among women toward experiencing deleterious effects of substance exposure on the still-developing young adult hippocampus.

Original languageEnglish (US)
JournalPsychological medicine
StateAccepted/In press - 2021

Bibliographical note

Funding Information:
This work was supported by National Institute on Drug Abuse grants R01DA036216 and K01DA037280 and National Institute on Alcohol Abuse and Alcoholism grants R21AA026632 and R21AA026919. J.H. was supported by National Institute on Drug Abuse grant T32DA037183. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The authors acknowledge the Minnesota Supercomputing Institute (MSI; http://www.msi.umn.edu ) and the Center for Magnetic Resonance Research (supported by grants NIBIB P41 EB027061 and 1S10OD017974-01) at the University of Minnesota for providing resources that contributed to the research results reported within this paper.

Publisher Copyright:
Copyright © The Author(s), 2021. Published by Cambridge University Press.


  • Alcohol
  • cannabis
  • cotwin control analysis
  • hippocampal volume
  • nicotine
  • sex differences
  • substance use


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