Cannabis Withdrawal: a Review of Neurobiological Mechanisms and Sex Differences


Purpose of Review

This report provides an updated overview of pre-clinical and clinical research on the etiology and biological substrates of the cannabis withdrawal syndrome.

Recent Findings

Long-term cannabis use is associated with downregulation of type-1 cannabinoid receptors (CB1). Reduced CB1 receptor density is related to increased withdrawal during early abstinence, and the reduction in CB1 receptor density reverses with extended abstinence. Females have been shown to have increased rate and severity of a subset of cannabis withdrawal symptoms compared with men.


Recent studies have extended knowledge of the biological processes and individual difference variables that influence cannabis withdrawal. However, caveats include small sample sizes in clinical studies, participant samples that are predominantly male, and limited examinations of endocannabinoids, enzymes that degrade endocannabinoids, negative allosteric modulators, and other neurobiological systems that may directly impact cannabis withdrawal symptom expression.

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Papers of particular interest, published recently, have been highlighted as: • Of importance

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Correspondence to Nicolas J. Schlienz.

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Conflict of Interest

Dr. Nicolas J. Schlienz, Dr. Alan J. Budney, and Dr. Dustin C. Lee have no conflicts to report. Dr. Ryan Vandrey has served as a consultant or received honoraria from Zynerba Pharmaceuticals, Insys Therapeutics, Battelle Memorial Institute, and CW Hemp.

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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This article is part of the Topical Collection on Cannabis

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Schlienz, N.J., Budney, A.J., Lee, D.C. et al. Cannabis Withdrawal: a Review of Neurobiological Mechanisms and Sex Differences. Curr Addict Rep 4, 75–81 (2017).

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  • Cannabis
  • Marijuana
  • Withdrawal
  • Cannabis use disorder
  • THC
  • Endocannabinoid system