According to the United Nations Office on Drugs and Crime (UNODC), an estimated 228 million adults used cannabis in 2022, making it one of the most widely used psychoactive substances worldwide (UNODC. World Drug Report, 2024). Historically, the prevalence of cannabis use has been higher among men than among women across different metrics of cannabis use (e.g., lifetime use, past-month use, daily use, problematic use) and in many counties globally (Matheson, 2023, Greaves L, 2020, Legleye et al., 2014, Connor et al., 2021). Yet, more recently, the sex/gender gap in cannabis use prevalence appears to be narrowing. For example, the man-to-woman ratio of past-month cannabis use prevalence in the United States (US) declined from a high of 2.125 in 2002 to a low of 1.25 in 2020, which seems to be largely driven by an increase in cannabis use among women (UNODC. World Drug Report, 2022). Unfortunately, the cannabis field has a history of androcentrism (i.e., a focus on men and male bodies) (Matheson and Le Foll, 2023) and birth-assigned males are over-represented in clinical studies of cannabis effects (Barkholtz and Bates, 2023). Thus, there is a persistent lack of understanding of how the biological construct of sex influences the health effects of cannabis, including consequences associated with acute intoxication that may be more likely or more severe in birth-assigned females (Cooper and Craft, 2018).

Exposure to cannabis produces acute, transient pleasant effects such as a subjective drug “high” (which may include feelings of relaxation and contentment) and potential dysphoric or undesirable effects such as paranoia, anxiety, and changes in cognition (Curran et al., 2016). Acute cannabis effects are mediated primarily by the interaction of delta-9-tetrahydrocannabinol (THC; the primary intoxicating component of cannabis) with the cannabinoid type-1 receptor (CB1R) (Huestis et al., 2007, Huestis et al., 2001). The CB1R is part of the endocannabinoid system (ECS), a lipid signaling system involved in many physiological and psychological processes, including cognition (Ligresti et al., 2016, Ronan et al., 2016, Puighermanal et al., 2012). Human laboratory experiments have found causal evidence that acute exposure to cannabis or isolated THC negatively impacts verbal episodic memory (especially verbal word list recall performance), spatial and verbal working memory, attention (especially divided attention performance), and executive functions (especially behavioural inhibition) (Matheson et al., 2023, Broyd et al., 2016, Zhornitsky et al., 2021). Cognitive effects of cannabis are of particularly interest given the potential for cannabis to impair performance (McCartney et al., 2021), which may underlie the increased risk of motor vehicle collisions associated with cannabis exposure prior to driving (Hartman and Huestis, 2013, Asbridge et al., 2012, Brands et al., 2021). Importantly, mounting evidence has demonstrated that cognitive effects are not consistently observed with cannabis exposure; the nature and severity of these effects are dependent on multiple factors, including prior exposure to cannabis, dose, route of administration, and sex (Matheson et al., 2023, Broyd et al., 2016).

Research in animal models has found relatively consistent evidence of sex differences in the acute effects of cannabinoid drugs, as well as interactions between gonadal hormones and the ECS (Cooper and Craft, 2018). Much of this evidence has documented greater motor and anti-nociceptive effects of cannabinoids in female rodents compared to males, with some evidence of greater reinforcing effects of cannabinoids in females (Cooper and Craft, 2018). These findings might be due to sex differences in cannabinoid pharmacokinetics. Female rodents metabolize THC primarily to the psychoactive metabolite 11-hydroxy-delta-9-THC (11-OH-THC), whereas males metabolize THC to a variety of mostly inactive metabolites (Narimatsu et al., 1991, Tseng et al., 2004, Britch et al., 2017). However, these behavioural sex differences might instead be explained by interactions between gonadal hormones and pharmacodynamic factors (Kim et al., 2023); estradiol levels and estrous cycle stage have been associated with changes in both expression and density of CB1Rs (Wakley et al., 2014, Castelli et al., 2014) and fluctuations in endocannabinoid levels (Bradshaw et al., 2006). Importantly, estrogens can directly modulate endocannabinoid synthesis in multiple brain regions, including the hippocampus (a brain region integral to memory) (Kim et al., 2023), and several rodent studies have documented interactions between estrogens and cannabinoids in impacting cognition and memory (Chahkandi et al., 2022, Chahkandi et al., 2021, Potier et al., 2023). Despite this robust animal literature, human studies are few in number and have not produced consistent results (Cooper and Craft, 2018).

In two previous human laboratory studies, our team found no evidence of sex differences in the acute cognitive effects of smoked cannabis, despite finding that male participants smoked a greater amount of cannabis and/or had higher THC concentrations in blood than female participants (Matheson et al., 2020, Wright et al., 2021). Importantly, these studies used an ad libitum smoking paradigm where participants were instructed to smoke to their desired high, which meant female and male participants did not receive equivalent doses of THC; this led us to speculate that sex differences in cognitive effects of cannabis might be observed in studies using different exposure paradigms.

Thus, our primary research question was: What are the sex differences in the acute effects of cannabis (including isolated THC) on cognition in humans? Further, because cannabis can impair one or more cognitive domains while sparing performance in other domains (Matheson et al., 2023, Broyd et al., 2016), and since sex/gender differences in cognition also differ by cognitive domain tested (Kheloui et al., 2023), we were interested to know if sex differences in the acute effects of cannabis vary by cognitive domain. A further aim was to evaluate whether differences in route of administration or dosing paradigm could explain sex differences. We acknowledge that both sex (a biological construct) and gender (a culturally and historically specific social construct) can impact cannabis effects (Matheson, 2023, Greaves L, 2020) and human cognition (Kheloui et al., 2023). However, we retain the language “sex differences” throughout this article since our review did not identify any published papers that distinguish between sex assigned at birth and any component of gender (e.g., gender identity).