Sex/Gender Differences in the Time-Course for the Development of Substance Use Disorder: A Focus on the Telescoping Effect

Abstract

Sex/gender effects have been demonstrated for multiple aspects of addiction, with one of the most commonly cited examples being the "telescoping effect" where women meet criteria and/or seek treatment of substance use disorder (SUD) after fewer years of drug use as compared with men. This phenomenon has been reported for multiple drug classes including opioids, psychostimulants, alcohol, and cannabis, as well as nonpharmacological addictions, such as gambling. However, there are some inconsistent reports that show either no difference between men and women or opposite effects and a faster course to addiction in men than women. Thus, the goals of this review are to evaluate evidence for and against the telescoping effect in women and to determine the conditions/populations for which the telescoping effect is most relevant. We also discuss evidence from preclinical studies, which strongly support the validity of the telescoping effect and show that female animals develop addiction-like features (e.g., compulsive drug use, an enhanced motivation for the drug, and enhanced drug-craving/vulnerability to relapse) more readily than male animals. We also discuss biologic factors that may contribute to the telescoping effect, such as ovarian hormones, and its neurobiological basis focusing on the mesolimbic dopamine reward pathway and the corticomesolimbic glutamatergic pathway considering the critical roles these pathways play in the rewarding/reinforcing effects of addictive drugs and SUD. We conclude with future research directions, including intervention strategies to prevent the development of SUD in women. SIGNIFICANCE STATEMENT: One of the most widely cited gender/sex differences in substance use disorder (SUD) is the "telescoping effect," which reflects an accelerated course in women versus men for the development and/or seeking treatment for SUD. This review evaluates evidence for and against a telescoping effect drawing upon data from both clinical and preclinical studies. We also discuss the contribution of biological factors and underlying neurobiological mechanisms and highlight potential targets to prevent the development of SUD in women.

Graphical abstract

Fig. 1

Biologic basis for the faster course from drug use to addiction/SUD in females. Females are more sensitive to the positive reinforcing effects of drugs and acquire drug self-administration faster than males. This is mediated through interactions of estradiol and mGlu5, both of which increase drug-evoked dopamine signaling in the mesolimbic reward pathway of females. Craving and motivation to use addictive drugs is typically low during early abstinence, particularly in females, but both features become progressively enhanced over a period of protracted abstinence. Molecular adaptations in response to chronic drug use and abstinence differ between males and females and may drive sex differences in anhedonia, craving, and relapse vulnerability during both early and late abstinence. Addiction-like features, including an enhanced motivation for the drug, compulsive drug use, and vulnerability to relapse, emerge sooner during abstinence and/or after less drug intake in females than males, indicating that the telescoping effect is biologic based. This effect is likely driven by interactions of estradiol and mGlu5, which cause an earlier recruitment of the glutamate system (i.e., AMPA receptors). Once addiction has developed, behavioral differences between males and females become subtle and often depend on estrous cycle phase (e.g., drug craving). The neuroadaptations that underlie addiction also differ between males and females (e.g., NMDA receptor signaling in the dorsomedial prefrontal cortex), even in the absence of behavioral differences. E2 = estradiol. DA = dopamine.

Fig. 2

Rat model of the telescoping effect with cocaine. Data are plotted as mean percent change (±S.E.M.) from the average number of infusions obtained during three baseline progressive-ratio sessions prior to extended-access cocaine self-administration (24-h/d, 4 discrete trials/h, 1.5 mg/kg/infusion, 7–10 days; refs) versus those obtained at retest following extended-access cocaine self-administration and 0, 7, 10, 14, or 60 days of abstinence. Motivation for cocaine increased progressively over abstinence following extended-access cocaine self-administration. Neither males nor females showed an increase in motivation for cocaine when responding was assessed immediately following extended-access self-administration (0 days abstinent; Lynch and Taylor 2005); in fact, motivation was significantly decreased from baseline in females in the 0-day group. Females, but not males, showed an increase in motivation for cocaine when responding was assessed following 7 (Towers et al., 2021) or 10 days of abstinence (Lynch and Taylor 2004). Both males and females showed an increase in motivation for cocaine when responding was assessed following 14 days of abstinence (Towers et al., 2021), and motivation was highest in both males and females when responding was assessed following 60 days of abstinence (Towers et al., 2021). The threshold for the development of an addiction-like phenotype, as defined by ≥15% increase from baseline and as represented by a dotted line, developed sooner during abstinence in females than males (following 7 vs. 14 days of abstinence). Significant difference from baseline/no change (*). Data were redrawn, with permission, from the previously cited references.