How important are sex differences in cannabinoid action?

Abstract

In humans as in animals, males and females are dissimilar in their genetic and hormonally driven behaviour; they process information differently, perceive experience and emotions in different ways, display diverse attitudes, language and social skills, and show sex-related differences in the brain anatomy and organization. Drug addiction is a widespread relapsing illness that affects both men and women. Sex-dependent differences have been frequently observed in the biological and behavioural effects of substances of abuse, including cannabis. Beside sex differences observed in the cannabinoid-induced effects related to cannabis abuse and dependence, cannabinoids have been shown to exert sex-dependent effects also in other physiological and behavioural aspects, such as food intake and energy balance (more evident in males), or anxiety and depression (more evident in females). Research has just begun to identify factors which could provide a neurobiological basis for gender-based differences in cannabinoid effects, among which, gonadal hormones seem to play a crucial role. Yet, cannabinoid pharmacodynamic and pharmacokinetic may also be important, as sex differences in cannabinoid effects might be due, at least in part, to differences in muscle mass and fat tissue distribution between males and females. Here, we will review both clinical and laboratory-based research evidence revealing important sex-related differences in cannabinoid effects, and put forward some suggestions for future studies to fill the gap in our knowledge of gender-specific bias in cannabinoid pharmacology.

Figure 1

Sex-dependent differences in cannabinoid effects. Blue: cannabinoid-induced effects that are more evident in males. Pink: cannabinoid-induced effects more evident in females. Grey: fields where the effects of cannabinoids are not dependent on sex (i.e. impulsivity), are incongruent between clinical and animal studies (i.e. addiction) or data are still controversial (i.e. hypothermia).

Figure 2

Number of clinical (top) and preclinical (bottom) studies using either male (blue) or female (pink) subjects, or specifically focused on the study of sex differences in cannabinoid effects (grey) published during 5 year time intervals. Source: Pub-Medical. Searching for human studies was conducted using ‘cannabinoid + male + men’ (blue), ‘cannabinoid + female + women’ (pink), and ‘cannabinoid + sex differences’ (grey) as keywords, and limiting the search to the following types of studies: Clinical Trial, Randomized Controlled Trial, Case Reports, Clinical Conference, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial. Searching for animal studies was conducted using ‘cannabinoid + male’ (blue) or ‘cannabinoid + female’ (pink) or ‘cannabinoid + sex differences’ as keywords, and limiting the search to the following types of studies: Classical Article, Journal Article.