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Review ArticleReview Article

Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review

Céline Nicolas, Natalie E. Zlebnik, Mehdi Farokhnia, Lorenzo Leggio, Satoshi Ikemoto and Yavin Shaham
Michael Nader, ASSOCIATE EDITOR
Pharmacological Reviews January 2022, 74 (1) 119-140; DOI: https://doi.org/10.1124/pharmrev.121.000367
Céline Nicolas
Neurocentre Magendie, University of Bordeaux, Bordeaux, France (C.N.); Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, Present address: Division of Biomedical Sciences, University of California Riverside, School of Medicine, Riverside, CA (N.E.Z.); Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD (M.F., L.L., S.I., Y.S.); and Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (M.F., L.L.)
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Natalie E. Zlebnik
Neurocentre Magendie, University of Bordeaux, Bordeaux, France (C.N.); Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, Present address: Division of Biomedical Sciences, University of California Riverside, School of Medicine, Riverside, CA (N.E.Z.); Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD (M.F., L.L., S.I., Y.S.); and Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (M.F., L.L.)
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Mehdi Farokhnia
Neurocentre Magendie, University of Bordeaux, Bordeaux, France (C.N.); Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, Present address: Division of Biomedical Sciences, University of California Riverside, School of Medicine, Riverside, CA (N.E.Z.); Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD (M.F., L.L., S.I., Y.S.); and Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (M.F., L.L.)
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Lorenzo Leggio
Neurocentre Magendie, University of Bordeaux, Bordeaux, France (C.N.); Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, Present address: Division of Biomedical Sciences, University of California Riverside, School of Medicine, Riverside, CA (N.E.Z.); Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD (M.F., L.L., S.I., Y.S.); and Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (M.F., L.L.)
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Satoshi Ikemoto
Neurocentre Magendie, University of Bordeaux, Bordeaux, France (C.N.); Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, Present address: Division of Biomedical Sciences, University of California Riverside, School of Medicine, Riverside, CA (N.E.Z.); Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD (M.F., L.L., S.I., Y.S.); and Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (M.F., L.L.)
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Yavin Shaham
Neurocentre Magendie, University of Bordeaux, Bordeaux, France (C.N.); Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD, Present address: Division of Biomedical Sciences, University of California Riverside, School of Medicine, Riverside, CA (N.E.Z.); Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD (M.F., L.L., S.I., Y.S.); and Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (M.F., L.L.)
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Michael Nader
Roles: ASSOCIATE EDITOR
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Abstract

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones’ role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not sufficiently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed provide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue- or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models.

Significance Statement This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed provide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking.

Footnotes

    • Received April 11, 2021.
    • Accepted August 15, 2021.
  • The authors declare that they do not have any conflicts of interest (financial or otherwise) related to the text of the paper. The write-up of the review was supported by funds to National Institutes of Health National Institute on Drug Abuse (NIDA) Intramural Research Program (to Y.S., L.L., M.F., and S.I.), National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research (to L.L., M.F.), NIDA [Grant K99 DA047419] (to N.E.Z.), and Fondation pour la recherche médicale fellowship [Grant ARF201909009147] (to C.N.).

  • The authors declare that they do not have any competing interests or conflicts of interest (financial or otherwise) related to the material presented in this manuscript. An earlier version of this paper appears in MedRxiv: https://www.medrxiv.org/content/10.1101/2021.03.30.21254644v1.

  • ↵1 C.N. and N.E.Z. contributed equally to this work.

  • dx.doi.org/10.1124/pharmrev.121.000367.

  • ↵Embedded ImageThis article has supplemental material available at pharmrev.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Pharmacological Reviews: 74 (1)
Pharmacological Reviews
Vol. 74, Issue 1
1 Jan 2022
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Review ArticleReview Article

Sex Differences in Drug Craving and Relapse

Céline Nicolas, Natalie E. Zlebnik, Mehdi Farokhnia, Lorenzo Leggio, Satoshi Ikemoto and Yavin Shaham
Pharmacological Reviews January 1, 2022, 74 (1) 119-140; DOI: https://doi.org/10.1124/pharmrev.121.000367

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Review ArticleReview Article

Sex Differences in Drug Craving and Relapse

Céline Nicolas, Natalie E. Zlebnik, Mehdi Farokhnia, Lorenzo Leggio, Satoshi Ikemoto and Yavin Shaham
Pharmacological Reviews January 1, 2022, 74 (1) 119-140; DOI: https://doi.org/10.1124/pharmrev.121.000367
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  • Article
    • Abstract
    • I. Introduction
    • II. Sex Differences in Drug Craving and Relapse: Clinical Studies
    • III. Sex Differences in Drug Craving and Relapse: Preclinical Studies
    • IV. Role of Menstrual and Estrous Cycle
    • V. Brain Mechanisms
    • VI. Conclusion and Clinical Implications
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