Sex-dependent effects of cannabis-induced analgesia

Abstract

Background Preclinical studies demonstrate that cannabinoid-mediated antinociceptive effects vary according to sex; it is unknown if these findings extend to humans. Methods This retrospective analysis compared the analgesic, subjective and physiological effects of active cannabis (3.56 - 5.60% THC) and inactive cannabis (0.00% THC) in male (N = 21) and female (N = 21) cannabis smokers under double-blind, placebo-controlled conditions. Pain response was measured using the Cold-Pressor Test (CPT). Participants immersed their hand in cold water (4°C); times to report pain (pain sensitivity) and withdraw the hand (pain tolerance) were recorded. Subjective drug ratings were also measured. Results Among men, active cannabis significantly decreased pain sensitivity relative to inactive cannabis (p < 0.01). In women, active cannabis failed to decrease pain sensitivity relative to inactive. Active cannabis increased pain tolerance in both men women immediately after smoking (p < 0.001); a trend was observed for differences between men and women (p < 0.10). Active cannabis also increased subjective ratings of cannabis associated with abuse liability (‘Take again,’ ‘Liking,’ ‘Good drug effect’), drug strength, and ‘High’ relative to inactive in both men and women (p < 0.01). Conclusions These results indicate that in cannabis smokers, men exhibit greater cannabis-induced analgesia relative to women. These sex-dependent differences are independent of cannabis-elicited subjective effects associated with abuse-liability, which were consistent between men and women. As such, sex-dependent differences in cannabis's analgesic effects are an important consideration that warrants further investigation when considering the potential therapeutic effects of cannabinoids for pain relief.

Mechanisms Underlying Sex Differences in Cannabis Use

“…In humans, cannabis exposure increases heart rate in both women and men [45, 46], but to a lesser extent in women [46–48]. Women have reported greater sedative effects [46] and dizziness [49] compared to men in response to cannabis, though amount of cannabis per body weight was not adjusted.…”

“…Conflicting evidence may be due to smoking status differences in the populations of each study, as well as differences in THC capsule dosing indicated in each experimental design. Cannabis-induced increases in “good” and “take again” ratings were shown to be enhanced in women compared to men [11], but also shown to be gender-independent [48]. In a female-only study, cannabis exposure increased ratings of confusion among regular and intermittent cannabis users, although this effect was stronger among intermittent users [45].…”

An evaluation of the anti‐hyperalgesic effects of cannabidiolic acid‐methyl ester in a preclinical model of peripheral neuropathic pain

“…There are known sex differences in pain perception and neuroimmune responses (Sorge & Totsch, ), as well as sex‐dependent cannabinoid‐mediated effects (Cooper & Craft, ; Craft, Marusich, & Wiley, ). Therefore, potential sexual dimorphisms that may underlie the treatment efficacy of different cannabinoids in the context of neuropathic pain need to be addressed (Cooper & Haney, ), especially as these agents are being clinically applied with mixed outcomes, which could be due to a patient's sex, as well as being influenced by gender roles. The aim of this investigation was to assess the early treatment efficacy of CBDA‐ME in a preclinical sciatic nerve cuff model of neuropathic pain (Mosconi & Kruger, ) in both males and females.…”

Cannabinoids in the Management of Acute Pain: A Systematic Review and Meta-analysis

“…Although there are a number of human experimental acute pain studies, we excluded them for several reasons. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] First, there are significant differ-ences in trial design and patient population compared with clinical trials. As well, cannabinoid impact on experimental acute pain was recently explored as the primary topic of a well-done systematic review and meta-analysis.…”