Sex Differences in Medical Cannabis-Related Adverse Effects

Joshua Aviram; Gil M. Lewitus; Yelena Vysotski; Paula Berman; Anna Shapira; Shiri Procaccia; David Meiri


Pain. 2022;163(5):975-983. 

In This Article

Abstract and Introduction


Studies have shown that women are more susceptible to adverse effects (AEs) from conventional drugs. This study aimed to investigate the differences of medical cannabis (MC)-related AEs between women and men in patients with chronic noncancer pain (CNCP). This is a cross-sectional study of adult patients licensed for MC treatment who were also diagnosed as patients with CNCP by a physician. Data included self-reported questionnaires and comprehensive MC treatment information. Simultaneously, identification and quantification of phytocannabinoids and terpenoids from the MC cultivars were performed. Comparative statistics were used to evaluate differences between men and women. Four hundred twenty-nine patients with CNCP (64% males) reported fully on their MC treatment. Subgrouping by sex demonstrated that the weight-adjusted doses were similar between men and women (0.48 [0.33–0.6] gr for men and 0.47 [0.34–0.66] gr for women). Nonetheless, women reported more than men on MC-related AEs. Further analysis revealed that women consumed different MC cultivar combinations than men, with significantly higher monthly doses of the phytocannabinoids CBD and CBC and significantly lower monthly doses of the phytocannabinoid 373–15c and the terpenoid linalool. Our findings demonstrate sex differences in MC-related AEs among patients with CNCP. Women are more susceptible to MC-related AEs, presumably because of both the inherent sex effect and the consumption of specific phytocannabinoid compositions in the MC cultivar(s). The understanding of these differences may be crucial for planning MC treatments with safer phytocannabinoid and terpenoid compositions and to better inform patients of expected AEs.


Chronic noncancer pain (CNCP) is the most common qualifying medical condition reported among patients consuming medical cannabis (MC).[9] About half of the patients consuming MC are women.[12] In a 2016 survey of 1000 patients diagnosed with rheumatoid arthritis, more than half of the respondents who reported current cannabis use were women.[24] In addition, in 2 recent multicenter prospective studies of patients with chronic and cancer pain under MC treatment in Israel, women involved were over 40% and over 50% of the samples, respectively.[1,3] Moreover, in a cross-sectional study of patients with migraine under MC treatment in Israel, almost 70% were women.[5] These demographics are similar for other patient populations who use MC to alleviate symptoms other than pain. For instance, over 50% of patients with cancer who received a license for MC to manage appetite, weakness, nausea, and pain were women.[28] Recreational cannabis use rates are consistently higher among men,[10] but data from surveys of MC users demonstrate that the difference between sexes is narrowing.

This equal prevalence of use between men and women raises questions regarding sex-dependent effects related to MC. Nevertheless, very few studies evaluated sex-dependent efficacy of MC treatment and even fewer evaluated MC-related adverse effects (AEs).[15] Importantly, although CNCP is currently the most researched indication for MC treatment, with over 40 randomized controlled trials, producing many reviews, meta-analyses, and even systemic reviews of systemic reviews on this issue,[25] there is still a vast gap in knowledge of sex-related differences.

In general, AEs from conventional drugs are more frequent and severe in women than in men, based on the FDA Adverse Event Reporting System.[23] These differences may be due to pharmacokinetic or pharmacodynamic factors, polypharmacy, or differences in reporting patterns. Adding to the complexity of sex differences in MC treatment is the fact that cannabis is not a single plant. There are over a 1000 of different cannabis cultivars or chemovars, each with a unique chemical composition and therefore each with potentially different biological activity. Nonetheless, current regulations do not take into account the sex of patients for monthly dose, cultivars selection, and the MC chemical composition.[16]

We have recently demonstrated, in a cross-sectional prospective study following up naturalistically on patients with CNCP with a prolonged MC treatment period, that pain intensities and other clinical outcomes remain stable. Although 86% reported on at least 1 AE, the most frequent AEs were gastrointestinal (70%), central nervous system (60%), psychological (45%), ophthalmic (34%), musculoskeletal (31%), and cardiovascular (10%) and were also stable during the follow-up.[2] However, we did not investigate whether these considerable rates of AEs could be explained by sex differences. Thus, in the current study, using the same database, we attempted to examine whether there are sex differences in MC-related rates of AEs and whether such differences are associated with the chemical composition of the MC treatment.