Sex differences in opioid and psychostimulant craving and relapse: a critical review

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/or not a priori designed to detect sex differences. Additionally, fMRI 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 priming-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 heroin in rodent models.

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance

“…Another finding in our study was that, in the vehicle condition, we found no evidence for sex differences in the four relapse‐related measures. These results agree with those from our previous study with oxycodone in which we did not observe sex differences in extinction responding, context‐induced reinstatement and reacquisition (Bossert et al, 2020), and other studies using the extinction‐reinstatement procedure showed similar magnitude of reinstatement of opioid seeking in males and female rats (Nicolas et al, 2021). Our negative sex differences data also agree with those from our recent studies on relapse to opioid seeking after voluntary abstinence induced by either providing rats with alternative rewards (palatable food or social interaction) in a choice procedure or exposing them to an electric barrier near the drug‐paired lever (Fredriksson et al, 2020, 2021; Reiner et al, 2020; Venniro et al, 2017, 2019).…”

Opioid and Sucrose Craving Are Accompanied by Unique Behavioral and Affective Profiles after Extended Abstinence in Male and Female Rats

“…Preclinical studies reveal that there are relatively fewer sex differences associated with opioid-related behaviors, including relapse ( Nicolas et al, 2021 ). Here, males and females show similar patterns of relapse-like behavior, and yet females do not display an increase in 50-kHz USVs during the late abstinence relapse test when craving is high.…”

D-amphetamine maintenance therapy reduces cocaine use in female rats

“…Compared to men, women are likely to consume more cocaine, can have a shorter latency from first cocaine use to abuse, and can be more vulnerable to craving and relapse after abstinence (Elman et al, 2001;Haas & Peters, 2000;McCance-Katz et al, 1999;McKay et al, 1996) but see (Nicolas et al, 2021). Similar sex differences are also reported in rats (Algallal et al, 2020;Becker & Koob, 2016;Calipari et al, 2017;Lynch & Carroll, 2000;Lynch, 2017;Nicolas et al, 2021;Roberts et al, 1989;Roth & Carroll, 2004). Some, but not all, of these sex differences involve estradiol.…”

“…Cocaine addiction afflicts both women and men, and studying addiction treatments in both female and male subjects is especially important because the sexes can differ in the transition to addiction (Becker, 2017;Becker & Koob, 2016;Carroll & Lynch, 2016). Compared to men, women are likely to consume more cocaine, can have a shorter latency from first cocaine use to abuse, and can be more vulnerable to craving and relapse after abstinence (Elman et al, 2001;Haas & Peters, 2000;McCance-Katz et al, 1999;McKay et al, 1996) but see (Nicolas et al, 2021). Similar sex differences are also reported in rats (Algallal et al, 2020;Becker & Koob, 2016;Calipari et al, 2017;Lynch & Carroll, 2000;Lynch, 2017;Nicolas et al, 2021;Roberts et al, 1989;Roth & Carroll, 2004).…”

“…With IntA cocaine intake, female rats show more robust psychomotor sensitization than male rats do (Algallal et al, 2020;Carr et al, 2020), and females also more readily develop incentive sensitization, as indicated by earlier and greater increases in the motivation for cocaine (Kawa et al, 2019a) and more cocaine seeking when the drug is unavailable (Nicolas et al, 2019). These observations reflect the female 'telescoping effect', whereby in people vulnerable to addiction, women can transition more readily from initiation of drug use to addiction than men do (Becker, 2017, see also Nicolas et al (2021)).…”