In this study, we evaluated the sex differences in MC-related AEs of patients with CNCP. To overcome the complexity of multiple cultivars in MC treatment, we calculated patients' monthly dose consumption of specific MC chemovar constituents. We found that although the weight-adjusted monthly dose of MC was similar among the sexes, and pain intensities were also similar, women reported on higher rates of MC-related AEs.
The higher rates of reported AEs in women may be due to physiological differences. An in vivo study in a rat model showed that the metabolism of the major phytocannabinoid Δ9-THC is different between the sexes; when given the same Δ9-THC dose, female rats produced higher levels of the active metabolite 11-hydroxy-THC in the brain and demonstrated lower pain sensitivity than male rats. Another preclinical study has shown that gonadal sex hormones affect cannabinoid concentrations in several brain areas. Previous studies have shown that the drug plasma concentrations could be affected by sex, in additional to other factors such as dose, administration route, frequency of consumption, drug–drug interaction, age, body weight, pathophysiology status, and smoking.[17,18] In the current study, we controlled for some of these factors, for example, by adjusting the dose to weight or by dividing the sample according to the administration route, but still, they cannot be excluded completely. It is important to note that women reported higher rates of MC-related AEs, although there was no difference in pain intensities between men and women. Contradictory to this, a study among recreational cannabis users found increased antinociception among healthy human men compared with women. A possible explanation from previous studies on recreational use is that women are more susceptible to the adverse effects of Δ9-THC at a low dose.
Another possible explanation for women reporting on higher rates of MC-related AEs is the unique MC cultivar combinations they consumed. Using a more in-depth perspective, we demonstrated that for most types of AEs, for the group of cultivars consumed by both men and women, the rate of AEs reports was either higher among women or similar. This suggested an inherent role of the sex itself on the AEs report. However, we discovered that some cultivar combinations were consumed only by a specific sex. We found that in these groups, women in the women only cultivar combination group reported on higher rates of AEs compared with the women in the common cultivar group, whereas men in the men only cultivar combinations group mostly reported on lower rates of AEs than the men in the common cultivar group. This finding suggests a role for the phytocannabinoid and terpenoid compositions as possible contributors for the differences in MC-related AEs, in addition to inherent sex differences.
Using our laboratory's unique analytical ability that allows for the quantification of phytocannabinoids and terpenoids,[7,20] we were able to evaluate all the weight-adjusted monthly doses of the compounds for each patient. We found that different weight-adjusted monthly doses of phytocannabinoids and terpenoids were consumed by the women only or men only cultivar combinations groups. We demonstrated that Δ9-THC doses were not significantly different between the groups. Women in the sex-specific cultivar combinations group consumed significantly higher monthly doses of the phytocannabinoids CBD and CBC and lower monthly doses of 373–15c and the terpenoid linalool, whereas men in the sex-specific cultivar combinations group consumed significantly higher monthly doses of the phytocannabinoid CBN and the terpenoid β-myrcene and lower monthly doses of the phytocannabinoid 331–18b. The different weight-adjusted monthly doses of these specific phytocannabinoids and terpenoids may be responsible to the higher rates of AEs reported by women. How these compounds contribute to the prevalence of AEs remains to be investigated.
The differences found between men and women in the consumed cultivar combinations can arise from either the individual choice of the patients or by the recommendations from physicians and cultivators that supplied them with the treatment. In the case of individual choice, it is possible that factors affected by the phytocannabinoid and terpenoid composition, such as the taste and smell of the MC treatment or other positive effects that were not assessed here, contributed to the choice of specific cultivars, leading men and women to consume different cultivar combinations.
The current study has a few limitations. First, self-report bias could have occurred. However, the questionnaire was anonymous and validated. Second, because of our study design, we did not have access to patient's data before MC treatment initiation, making it impossible to make causal conclusions. Third, because we investigated patients in the sample that consumed MC by inflorescence inhalation only, findings cannot be generalized to other consumption routes. Fourth, because report on AEs was performed after 1-month treatment for the entire month, a recall bias may have occurred. In addition, the specific characteristics of the prescribing physicians are unknown, and as such, selection bias could not be controlled for. Finally, because there was no direct contact with the patients and the MC cultivars for analysis were collected from the cultivators by matching name and batch, there is some measure of extrapolation when associating the patients' AEs reports.
Although CNCP is one of the most frequent indications for MC treatment, there is no knowledge regarding the response of specific subgroups of the patient population with CNCP to MC treatment. The current study results demonstrate that women are more susceptible to MC-related AEs, presumably because of both an inherent sex effect and to the consumption of specific phytocannabinoid and terpenoid compositions in the MC cultivar(s). These results may shed light on the differential effects of MC between sexes. Physicians and future clinical studies should address sex differences to establish safer MC treatments and better prepare patients for the expected prevalence of MC-related AEs.
All authors discussed the results and commented on the article. The study was partially funded by the Evelyn Gruss Lipper Charitable Foundation. This sponsor had no role or influence on the study or on this submission. The authors have no conflicts of interest to declare. The data that support the findings of this study are available from the corresponding author on reasonable request. Some data may not be made available because of privacy or ethical restrictions.
Pain. 2022;163(5):975-983. © 2022 Lippincott Williams & Wilkins