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Cannabinoid signalling and effects of cannabis on the male reproductive system

Abstract

Marijuana is the most widely consumed recreational drug worldwide, which raises concerns for its potential effects on fertility. Many aspects of human male reproduction can be modulated by cannabis-derived extracts (cannabinoids) and their endogenous counterparts, known as endocannabinoids (eCBs). These latter molecules act as critical signals in a variety of physiological processes through receptors, enzymes and transporters collectively termed the endocannabinoid system (ECS). Increasing evidence suggests a role for eCBs, as well as cannabinoids, in various aspects of male sexual and reproductive health. Although preclinical studies have clearly shown that ECS is involved in negative modulation of testosterone secretion by acting both at central and testicular levels in animal models, the effect of in vivo exposure to cannabinoids on spermatogenesis remains a matter of debate. Furthermore, inconclusive clinical evidence does not seem to support the notion that plant-derived cannabinoids have harmful effects on human sexual and reproductive health. An improved understanding of the complex crosstalk between cannabinoids and eCBs is required before targeting of ECS for modulation of human fertility becomes a reality.

Key points

  • Marijuana has the highest consumption rate of any recreational drug in the Western world.

  • Endocannabinoids and their receptors, enzymes and transporters, which together form the endocannabinoid system (ECS), are present in various components of the male reproductive tract, including male genital glands, testis and sperm.

  • Preclinical studies have shown that the ECS is involved in negative modulation of testosterone secretion by acting at both central and testicular levels.

  • As yet, clinical data are insufficient to conclude that cannabinoids have a harmful effect on human male sexual function and fertility.

  • Although cannabinoid receptors are present in the testes and sperm, the effects of cannabinoid exposure on spermatogenesis largely remain to be clarified.

  • The ECS has the potential to provide new drug targets in male reproductive disorders, and its components might be useful as biomarkers of male infertility.

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Fig. 1: The endocannabinoid system.
Fig. 2: Subcellular distribution of the main elements of the endocannabinoid system.
Fig. 3: Involvement of the endocannabinoid system in controlling rodent testicular steroidogenesis and spermatogenesis.
Fig. 4: The endocannabinoid system in human sperm.

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Acknowledgements

The authors thank all the colleagues who have contributed over the years to our studies on the role of endocannabinoid signalling in human male reproductive events, at University of L’Aquila, Tor Vergata University of Rome, Campus Bio-Medico University of Rome, Santa Lucia Foundation of Rome, University of Teramo and Leicester University.

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All authors researched data for the article, made substantial contributions to discussions of content and wrote the manuscript. M.M. reviewed and edited the manuscript before submission.

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Correspondence to Mauro Maccarrone.

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Glossary

Phytocannabinoids

Naturally occurring substances in the cannabis plant.

Sunflower oil

The non-volatile oil pressed from the seeds of sunflower.

Intracellular trafficking

A general and tightly regulated process used by a variety of molecules to cross the membranes of, and move inside, living cells.

Thermotaxis

Movement towards or away from a thermal stimulus.

Orphan enzyme

An enzyme for which activity has been experimentally characterized but amino acid sequences are lacking.

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Maccarrone, M., Rapino, C., Francavilla, F. et al. Cannabinoid signalling and effects of cannabis on the male reproductive system. Nat Rev Urol 18, 19–32 (2021). https://doi.org/10.1038/s41585-020-00391-8

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