Are men and women equal before Cannabis?

It turns out that they are equal but different. Why is that?

The use and abuse of cannabis, for medical or other reasons, is undeniably on the rise. As the experience of the medical world with the plant and its products increases, we begin to see a difference that we had not realized before: Cannabis affects men differently from women in some respects. This difference extends to animals as well. It has a biological basis, and it is related to the different effects of hormones on the endocannabinoid system (ECS), a diffuse system consisting of endogenous lipid ligands (endocannabinoids, ECs), their receptors and the enzymes that produce, degrade and transport them. The fact that pregnenolone, the precursor of all steroid hormones, affects cannabinoid receptor activation corroborates the link between steroid hormones and the endocannabinoid system (Struik et al, 2018).

The matter has been extensively but inconclusively researched, due to the inherent difficulties encountered when studying something extremely variable, like the female ovulation cycle that varies both monthly and with age. Animal studies of cannabis use disorder (CUD) have additional difficulty, namely training animals to self-administration of cannabis, a factor that introduces biological biases. Apart from differences in the genetic background and the daily fluctuation of hormones, which both sexes have, the following have been identified:

The ovarian hormones significantly affect cannabinoid seeking and taking behavior in rats (Fattore et al., 2007). Male animals are four times more likely to try cannabis, as well as use higher doses more often. This is attributed to the fact that testosterone promotes risk-taking behaviors (eg the risk that accompanies the investigation of an unknown experience), while at the same time reducing the pleasure of psychoactivity. Females use cannabis more conservatively, but develop addiction faster than males, meaning that their neurochemical infrastructure has less tolerance, at least concerning the psychoactivity effect (Struik et al, 2018).

The levels of the anandamide (AEA) and 2-arachidonoyl-glycerole (2AG) significantly differ between males and females; they are affected by the menstrual cycle in female rats (González et al., 2000). Overlapping of several molecular pathways triggered by the classical cannabinoid receptors and estrogens or androgens has been documented; a possible differential role of the interplay of the ECS and the respective reproductive systems of males and females in the pathogenesis of common diseases, like atherosclerosis, osteoporosis and hormone-sensitive cancers, is under investigation (Dobovišek et al, 2016).

Studies in rats have shown that estradiol affects the control of mobility, social behavior and filtering of sensory stimuli in the brain, through modulation of the ECS; reciprocally, the activity level of the ECS affects the production of estradiol (Struik et al, 2018). In particular, female mice have different levels of endocannabinoids (ECs) and more sensitive receptors than males in areas of the brain associated with the said functions before and at ovulation time (Bradshaw et al, 2006). In other words, the complex interactions of the ECS and dopaminergic system depend on gender. Tonic signaling through 2AG upon inhibitory dopamine neurons has been shown to differ between sexes (Melis et al, 2013), further supporting the notion that there are quantitative differences in the endocannabinoid system in males and females, which likely contribute to altered cannabinoid sensitivity. Noteworthy, several sex differences in the endocannabinoid system are related to changes in steroid hormone levels and activity.

The importance to humans

Data available so far from human studies show that sex hormones regulate the response of men and women to cannabis. The following differences emerged: At a “high” state of mind, men tend to report predominantly increased appetite, enthusiasm, altered time perception, and sensitivity to music; women tend to report loss of appetite and increased urge to clean. During periods of withdrawal men tend to report insomnia and vivid dreams more than women; women tend to report nausea and anxiety more often than men; these differences were statistically significant (Cuttler et al, 2016). Like in animals, genetically and hormonally defined behaviors differ due to the sexual dimorphism of the ECS: Men and women process information differently, experience emotions differently, and their resistance to the development of addiction differs: Women usually show faster progression to CUD compared to men (Cooper & Haney, 2014). Cannabis receptors increase with age in women (Calakos et al, 2017), while estradiol levels decrease. The FAAH enzyme appears to be a major site of interaction between the ECS, sex hormones. Progesterone and estrogens down-regulate FAAH gene expression, thereby increasing free AEA; the matter is further confounded by factors like leptin, an up-regulator, and the individual balance of Th1/Th2 cytokines. The needs of the female ECS for phytocannabinoids and its response to them is therefore largely unpredictable. This explains the often controversial experimental observations; it also necessitates personalization of all therapeutic interventions, be it with medicinal cannabis or for the treatment of CUD.

Conclusions

· Gender differences and age should be taken into account when treating patients with cannabis.

· Programs for the prevention and treatment of CUD should take into account the gender and age of participants.

· The basic frame of biochemical interactions between the ECS and sex hormones is confounded by factors like leptin and cytokines, making the needs and the response of the system to phytocannabinoids largely unpredictable.

· For patients with hormone-sensitive cancers, parallel treatment with phytocannabinoids on the one hand, and either selective estrogen receptor modulators (SERMs, like tamoxifen), or aromatase inhibitors (substances with anti-estrogen activity) on the other, should also be planned carefully.

Referenced bibliography

Bradshaw, H. B., Rimmerman, N., Krey, J. F., & Walker, J. M. (2006). Sex and hormonal cycle differences in rat brain levels of pain-related cannabimimetic lipid mediators. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 291(2), R349–R358.

Calakos, K. C., Bhatt, S., Foster, D. W., & Cosgrove, K. P. (2017). Mechanisms Underlying Sex Differences in Cannabis Use. Curr Addict Rep, 4(4), 439–453.

Cooper, Z. D., & Haney, M. (2014). Investigation of sex-dependent effects of cannabis in daily cannabis smokers. Drug and Alcohol Dependence, 136, 85–91.

Cuttler, C., Mischley, L. K., & Sexton, M. (2016). Sex Differences in Cannabis Use and Effects: A Cross-Sectional Survey of Cannabis Users. Cannabis and Cannabinoid Research, 1(1), 166–175.

Dobovišek, L., Hojnik, M., & Ferk, P. (2016). Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review), 38(6), 1642–1651.

Fattore, L., Spano, M. S., Altea, S., Angius, F., Fadda, P., & Fratta, W. (2007). Cannabinoid self-administration in rats: sex differences and the influence of ovarian function, 152(5), 795–804.

González, S., Bisogno, T., Wenger, T., Manzanares, J., Milone, A., Berrendero, F., Di Marzo, V., et al. (2000). Sex Steroid Influence on Cannabinoid CB1 Receptor mRNA and Endocannabinoid Levels in the Anterior Pituitary Gland. Biochemical and Biophysical Research Communications, 270(1), 260–266.

Melis, M., Felice, M. D., Lecca, S., Fattore, L., & Pistis, M. (2013). Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats. Front. Integr. Neurosci., 7.

Struik, D., Sanna, F., & Fattore, L. (2018). The Modulating Role of Sex and Anabolic-Androgenic Steroid Hormones in Cannabinoid Sensitivity. Front. Behav. Neurosci., 12.

Additional bibliography

Women and cannabis ISBN 0–7890–2100–5, (E. Russo, M. Dreher, & M. L. Mathre, Eds.) New York: Haworth Press Inc.

Gorzalka, B. B., & Dang, S. S. (2012). Minireview: Endocannabinoids and Gonadal Hormones: Bidirectional Interactions in Physiology and Behavior. Endocrinology, 153(3), 1016–1024.

Hill, M. N., Karacabeyli, E. S., & Gorzalka, B. B. (2007). Estrogen recruits the endocannabinoid system to modulate emotionality. Psychoneuroendocrinology, 32(4), 350–357.

Maia, J., Almada, M., Silva, A., Correia-da-Silva, G., Teixeira, N., Sá, S. I., & Fonseca, B. M. (2017). The endocannabinoid system expression in the female reproductive tract is modulated by estrogen. The Journal of Steroid Biochemistry and Molecular Biology, 174, 40–47.

Peterson, B. M., Martinez, L. A., Meisel, R. L., & Mermelstein, P. G. (2016). Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine. Neuropharmacology, 110, 118–124.