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Cannabinoid signalling and effects of cannabis on the male reproductive system

Nature Reviews Urology volume 18, pages 19–32 (2021)Cite this article

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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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References

  1. United Nations Office on Drugs and Crime. Executive summary: conclusions and policy implications. UNODC https://www.unodc.org/wdr2017/field/Booklet_1_EXSUM.pdf (2017).

  2. Substance Abuse Mental Health Services Administration. Results from the 2013 national survey on drug use and health: summary of national findings. US Department of Health and Human Services http://www.samhsa.gov/data/sites/default/files/NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.htm#ch2 (2013).

  3. Arcview. The State of Legal Marijuana Markets 5th edn (Arcview, 2017).

  4. Friedman, D., French, J. & Maccarrone, M. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol. 18, 504–512 (2019).

    CAS  PubMed  Google Scholar 

  5. Cohen, K., Weizman, A. & Weinstein, A. Positive and negative effects of cannabis and cannabinoids on health. Clin. Pharmacol. Ther. 105, 1139–1147 (2019).

    PubMed  Google Scholar 

  6. du Plessis, S. S., Agarwal, A. & Syriac, A. J. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. Assist. Reprod. Genet. 32, 1575–1588 (2015).

    Google Scholar 

  7. Maccarrone, M. et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36, 277–296 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Payne, K. S., Mazur, D. J., Hotaling, J. M. & Pastuszak, A. W. Cannabis and male fertility: a systematic review. J. Urol. 202, 674–681 (2019).

    PubMed  PubMed Central  Google Scholar 

  9. Nassan, F. L. et al. Marijuana smoking and markers of testicular function among men from a fertility centre. Hum. Reprod. 34, 715–723 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. El Sohly, M. & Gul, W. in Handbook of Cannabis (ed. Pertwee R. G.) 3–22 (Oxford Univ. Press, 2014).

  11. World Health Organization. Expert Committee on Drug Dependence, Section 1: Chemistry Cannabis plant and cannabis resin (WHO, 2018).

  12. Morales, P., Hurst, D. P. & Reggio, P. H. Molecular targets of the phytocannabinoids: a complex picture. Prog. Chem. Org. Nat. Prod. 103, 103–131 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Huestis, M. A. Human cannabinoid pharmacokinetics. Chem. Biodivers. 4, 1770–1804 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Small, E. Cannabis: a complete guide (CRC, 2017).

  15. Elliott, D. M., Singh, N., Nagarkatti, M. & Nagarkatti, P. S. Cannabidiol attenuates experimental autoimmune encephalomyelitis model of multiple sclerosis through induction of myeloid-derived suppressor cells. Front. Immunol. 9, 1782 (2018).

    PubMed  PubMed Central  Google Scholar 

  16. Carvalho, R. K. et al. Chronic cannabidiol exposure promotes functional impairment in sexual behavior and fertility of male mice. Reprod. Toxicol. 81, 34–40 (2018).

    CAS  PubMed  Google Scholar 

  17. Pertwee, R. G. et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol. Rev. 62, 588–631 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, H., Dey, S. K. & Maccarrone, M. Jekyll and Hyde: two faces of cannabinoid signaling in male and female fertility. Endocr. Rev. 27, 427–448 (2006).

    CAS  PubMed  Google Scholar 

  19. Fezza, F. et al. Endocannabinoids, related compounds and their metabolic routes. Molecules 19, 17078–17106 (2014).

    PubMed  PubMed Central  Google Scholar 

  20. Rapino, C., Battista, N., Bari, M. & Maccarrone, M. Endocannabinoids as biomarkers of human reproduction. Hum. Reprod. Update 20, 501–516 (2014).

    CAS  PubMed  Google Scholar 

  21. Barbonetti, A. et al. 2-arachidonoylglycerol levels are increased in leukocytospermia and correlate with seminal macrophages. Andrology 5, 87–94 (2017).

    CAS  PubMed  Google Scholar 

  22. Maccarrone, M. Metabolism of the endocannabinoid anandamide: open questions after 25 years. Front. Mol. Neurosci. 10, 166 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. Francavilla, F. et al. Characterization of the endocannabinoid system in human spermatozoa and involvement of transient receptor potential vanilloid 1 receptor in their fertilizing ability. Endocrinology 150, 4692–4700 (2009).

    CAS  PubMed  Google Scholar 

  24. Lewis, S. E. M. et al. Differences in the endocannabinoid system of sperm from fertile and infertile men. PLoS ONE 7, e47704 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Maccarrone, M. et al. Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. Endocrinology 144, 20–28 (2003).

    CAS  PubMed  Google Scholar 

  26. Rossi, G. et al. Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells. Endocrinology 148, 1431–1439 (2007).

    CAS  PubMed  Google Scholar 

  27. Okamoto, Y., Tsuboi, K. & Ueda, N. Enzymatic formation of anandamide. Vitam. Horm. 81, 1–24 (2009).

    CAS  PubMed  Google Scholar 

  28. McKinney, M. K. & Cravatt, B. F. Structure and function of fatty acid amide hydrolase. Annu. Rev. Biochem. 74, 411–432 (2005).

    CAS  PubMed  Google Scholar 

  29. Bisogno, T. et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol. 163, 463–468 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002).

    CAS  PubMed  Google Scholar 

  31. Miller, M. R. et al. Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. Science 352, 555–559 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chicca, A., Marazzi, J., Nicolussi, S. & Gertsch, J. Evidence for bidirectional endocannabinoid transport across cell membranes. J. Biol. Chem. 41, 34660–34682 (2012).

    Google Scholar 

  33. Maccarrone, M., Dainese, E. & Oddi, S. Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochem. Sci. 35, 601–608 (2010).

    CAS  PubMed  Google Scholar 

  34. Wang, J. et al. Expression and secretion of N-acylethanolamine-hydrolysing acid amidase in human prostate cancer cells. J. Biochem. 144, 685–690 (2008).

    CAS  PubMed  Google Scholar 

  35. Bakali, E. et al. Distribution and function of the endocannabinoid system in the rat and human bladder. Int. Urogynecol. J. 24, 855–863 (2013).

    PubMed  Google Scholar 

  36. Kondo, S. et al. Accumulation of various N-acylethanolamines including N-arachidonoylethanolamine (anandamide) in cadmium chloride-administered rat testis. Arch. Biochem. Biophys. 354, 303–310 (1998).

    CAS  PubMed  Google Scholar 

  37. Godlewski, G., Offertáler, L., Wagner, J. A. & Kunos, G. Receptors for acylethanolamides–GPR55 and GPR119. Prostaglandins Other Lipid Mediat. 89, 105–111 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ückert, S. et al. Expression and distribution of key proteins of the endocannabinoid system in the human seminal vesicles. Andrologia 50, 12875 (2018).

    Google Scholar 

  39. Murphy, L. L., Steger, R. W., Smith, M. S. & Bartke, A. Effects of delta-9-tetrahydrocannabinol, cannabinol and cannabidiol, alone and in combinations, on luteinizing hormone and prolactin release and on hypothalamic neurotransmitters in the male rat. Neuroendocrinology 52, 316–321 (1990).

    CAS  PubMed  Google Scholar 

  40. Wenger, T., Ledent, C., Csernus, V. & Gerendai, I. The central cannabinoid receptor inactivation suppresses endocrine reproductive functions. Biochem. Biophys. Res. Commun. 284, 363–368 (2001).

    CAS  PubMed  Google Scholar 

  41. Scorticati, C. et al. The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen. Proc. Natl Acad. Sci. USA 101, 11891–11896 (2004).

    CAS  PubMed  Google Scholar 

  42. Wenger, T., Fernández-Ruiz, J. J. & Ramos, J. A. Immunocytochemical demonstration of CB1 cannabinoid receptors in the anterior lobe of the pituitary gland. J. Neuroendocrinol. 11, 873–878 (1999).

    CAS  PubMed  Google Scholar 

  43. Wittmann, G. et al. Distribution of type 1 cannabinoid receptor (CB1)-immunoreactive axons in the mouse hypothalamus. J. Comp. Neurol. 503, 270–279 (2007).

    CAS  PubMed  Google Scholar 

  44. Wenger, T., Rettori, V., Snyder, G. D., Dalterio, S. & McCann, S. M. Effects of delta-9-tetrahydrocannabinol on the hypothalamic-pituitary control of luteinizing hormone and follicle-stimulating hormone secretion in adult male rats. Neuroendocrinology 46, 488–493 (1987).

    CAS  PubMed  Google Scholar 

  45. Gammon, C. M. et al. Regulation of gonadotropin-releasing hormone secretion by cannabinoids. Endocrinology 146, 4491–4499 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Farkas, I. et al. Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons. Endocrinology 151, 5818–5829 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Watanabe, M., Fukuda, A. & Nabekura, J. The role of GABA in the regulation of GnRH neurons. Front. Neurosci. 8, 387 (2014).

    PubMed  PubMed Central  Google Scholar 

  48. Todman, M. G., Han, S.-K. & Herbison, A. E. Profiling neurotransmitter receptor expression in mouse gonadotropin-releasing hormone neurons using green fluorescent protein-promoter transgenics and microarrays. Neuroscience 132, 703–712 (2005).

    CAS  PubMed  Google Scholar 

  49. Cristino, L. et al. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139, 1405–1415 (2006).

    CAS  PubMed  Google Scholar 

  50. Cacciola, G. et al. Expression of type-1 cannabinoid receptor during rat postnatal testicular development: possible involvement in adult leydig cell differentiation. Biol. Reprod. 79, 758–765 (2008).

    CAS  PubMed  Google Scholar 

  51. Jakubovic, A., McGeer, E. G. & McGeer, P. L. Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig cells in vitro. Mol. Cell. Endocrinol. 15, 41–50 (1979).

    CAS  PubMed  Google Scholar 

  52. List, A., Nazar, B., Nyquist, S. & Harclerode, J. The effects of delta9-tetrahydrocannabinol and cannabidiol on the metabolism of gonadal steroids in the rat. Drug Metab. Dispos. 5, 268–272 (1977).

    CAS  PubMed  Google Scholar 

  53. Banerjee, A., Singh, A., Srivastava, P., Turner, H. & Krishna, A. Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. Birth Defects Res. B Dev. Reprod. Toxicol. 92, 195–205 (2011).

    CAS  PubMed  Google Scholar 

  54. Fujimoto, G. I., Morrill, G. A., O’Connell, M. E., Kostellow, A. B. & Retura, G. Effects of cannabinoids given orally and reduced appetite on the male rat reproductive system. Pharmacology 24, 303–313 (1982).

    CAS  PubMed  Google Scholar 

  55. McDonald, C. A. et al. Follicle-stimulating hormone-induced aromatase in immature rat Sertoli cells requires an active phosphatidylinositol 3-kinase pathway and is inhibited via the mitogen-activated protein kinase signaling pathway. Mol. Endocrinol. 20, 608–618 (2006).

    CAS  PubMed  Google Scholar 

  56. Grimaldi, P. et al. The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1. Cell. Mol. Life Sci. 69, 4177–4190 (2012).

    CAS  PubMed  Google Scholar 

  57. Chioccarelli, T. et al. Cannabinoid receptor 1 influences chromatin remodeling in mouse spermatids by affecting content of transition protein 2 mRNA and histone displacement. Endocrinology 151, 5017–5029 (2010).

    CAS  PubMed  Google Scholar 

  58. Dixit, V. P., Gupta, C. L. & Agrawal, M. Testicular degeneration and necrosis induced by chronic administration of cannabis extract in dogs. Endokrinologie 69, 299–305 (1977).

    CAS  PubMed  Google Scholar 

  59. Lewis, S. E. M. et al. Long-term use of HU210 adversely affects spermatogenesis in rats by modulating the endocannabinoid system. Int. J. Androl. 35, 731–740 (2012).

    CAS  PubMed  Google Scholar 

  60. Berryman, S. H., Anderson, R. A., Weis, J. & Bartke, A. Evaluation of the co-mutagenicity of ethanol and Δ9-tetrahydrocannabinol with Trenimon. Mutat. Res. 278, 47–60 (1992).

    CAS  PubMed  Google Scholar 

  61. López-Cardona, A. P. et al. Effect of chronic THC administration in the reproductive organs of male mice, spermatozoa and in vitro fertilization. Biochem. Pharmacol. 157, 294–303 (2018).

    PubMed  Google Scholar 

  62. Pagotto, U. et al. Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level. J. Clin. Endocrinol. Metab. 86, 2687–2696 (2001).

    CAS  PubMed  Google Scholar 

  63. Vescovi, P. P. et al. Chronic effects of marihuana smoking on luteinizing hormone, follicle-stimulating hormone and prolactin levels in human males. Drug Alcohol. Depend. 30, 59–63 (1992).

    CAS  PubMed  Google Scholar 

  64. Kolodny, R. C., Masters, W. H., Kolodner, R. M. & Toro, G. Depression of plasma testosterone levels after chronic intensive marihuana use. N. Engl. J. Med. 290, 872–874 (1974).

    CAS  PubMed  Google Scholar 

  65. Mendelson, J. H., Kuehnle, J., Ellingboe, J. & Babor, T. F. Plasma testosterone levels before, during and after chronic marihuana smoking. N. Engl. J. Med. 291, 1051–1055 (1974).

    CAS  PubMed  Google Scholar 

  66. Cushman, P. Plasma testosterone levels in healthy male marijuana smokers. Am. J. Drug Alcohol Abuse 2, 269–275 (1975).

    CAS  PubMed  Google Scholar 

  67. Gundersen, T. D. et al. Association between use of marijuana and male reproductive hormones and semen quality: a study among 1,215 healthy young men. Am. J. Epidemiol. 182, 473–481 (2015).

    PubMed  Google Scholar 

  68. Thistle, J. E. et al. Marijuana use and serum testosterone concentrations among U.S. males. Andrology 5, 732–738 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Rajanahally, S. et al. The relationship between cannabis and male infertility, sexual health, and neoplasm: a systematic review. Andrology 7, 139–147 (2019).

    CAS  PubMed  Google Scholar 

  70. Elbendary, M. A., El-Gamal, O. M. & Salem, K. A. Analysis of risk factors for organic erectile dysfunction in Egyptian patients under the age of 40 years. J. Androl. 30, 520–524 (2009).

    PubMed  Google Scholar 

  71. Aversa, A. et al. Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual cannabis users. Int. J. Impot. Res. 20, 566–573 (2008).

    CAS  PubMed  Google Scholar 

  72. Johnson, S. D., Phelps, D. L. & Cottler, L. B. The association of sexual dysfunction and substance use among a community epidemiological sample. Arch. Sex. Behav. 33, 55–63 (2004).

    PubMed  Google Scholar 

  73. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 3rd edn (American Psychiatric Association, 1980).

  74. Smith, A. M. A. et al. Cannabis use and sexual health. J. Sex. Med. 7, 787–793 (2010).

    PubMed  Google Scholar 

  75. Allen, M. S. & Walter, E. E. Health-related lifestyle factors and sexual dysfunction: a meta-analysis of population-based research. J. Sex. Med. 15, 458–475 (2018).

    PubMed  Google Scholar 

  76. Vallejo-Medina, P. & Sierra, J. C. Effect of drug use and influence of abstinence on sexual functioning in a Spanish male drug-dependent sample: a multisite study. J. Sex. Med. 10, 333–341 (2013).

    CAS  PubMed  Google Scholar 

  77. Androvicova, R. et al. Endocannabinoid system in sexual motivational processes: is it a novel therapeutic horizon? Pharmacol. Res. 115, 200–208 (2017).

    CAS  PubMed  Google Scholar 

  78. Tart, C. T. Marijuana intoxication common experiences. Nature 226, 701–704 (1970).

    CAS  PubMed  Google Scholar 

  79. Halikas, J., Weller, R. & Morse, C. Effects of regular marijuana use on sexual performance. J. Psychoactive Drugs 14, 59–70 (1982).

    CAS  PubMed  Google Scholar 

  80. Sun, A. J. & Eisenberg, M. L. Association between marijuana use and sexual frequency in the United States: a population-based study. J. Sex. Med. 14, 1342–1347 (2017).

    PubMed  Google Scholar 

  81. Murphy, S. K. et al. Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics 13, 1208–1221 (2018).

    PubMed  PubMed Central  Google Scholar 

  82. Close, C. E., Roberts, P. L. & Berger, R. E. Cigarettes, alcohol and marijuana are related to pyospermia in infertile men. J. Urol. 144, 900–903 (1990).

    CAS  PubMed  Google Scholar 

  83. Pacey, A. A. et al. Modifiable and non-modifiable risk factors for poor sperm morphology. Hum. Reprod. 29, 1629–1636 (2014).

    PubMed  Google Scholar 

  84. Tremellen, K. Oxidative stress and male infertility–a clinical perspective. Hum. Reprod. Update 14, 243–258 (2008).

    CAS  PubMed  Google Scholar 

  85. Castellini, C. et al. Relationship between leukocytospermia, reproductive potential after assisted reproductive technology, and sperm parameters: a systematic review and meta-analysis of case-control studies. Andrology 8, 125–135 (2020).

    CAS  PubMed  Google Scholar 

  86. World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen and Sperm-Cervical Mucus Interaction 5th edn (WHO, 2010).

  87. Kasman, A. M., Thoma, M. E., McLain, A. C. & Eisenberg, M. L. Association between use of marijuana and time to pregnancy in men and women: findings from the National Survey of Family Growth. Fertil. Steril. 109, 866–871 (2018).

    PubMed  Google Scholar 

  88. Francavilla, F. et al. Within-subject variation of seminal parameters in men with infertile marriages. Int. J. Androl. 30, 174–181 (2007).

    CAS  PubMed  Google Scholar 

  89. Rossato, M., Ion Popa, F., Ferigo, M., Clari, G. & Foresta, C. Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. J. Clin. Endocrinol. Metab. 90, 984–991 (2005).

    CAS  PubMed  Google Scholar 

  90. Agirregoitia, E. et al. The CB2 cannabinoid receptor regulates human sperm cell motility. Fertil. Steril. 93, 1378–1387 (2010).

    CAS  PubMed  Google Scholar 

  91. Schuel, H. et al. Evidence that anandamide-signaling regulates human sperm functions required for fertilization. Mol. Reprod. Dev. 63, 376–387 (2002).

    CAS  PubMed  Google Scholar 

  92. Aquila, S. et al. A new role of anandamide in human sperm: focus on metabolism. J. Cell Physiol. 221, 147–153 (2009).

    CAS  PubMed  Google Scholar 

  93. Aquila, S. et al. Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm. Br. J. Pharmacol. 159, 831–841 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Amoako, A. A. et al. Anandamide modulates human sperm motility: implications for men with asthenozoospermia and oligoasthenoteratozoospermia. Hum. Reprod. 28, 2058–2066 (2013).

    CAS  PubMed  Google Scholar 

  95. Francou, M. M. et al. Human sperm motility, capacitation and acrosome reaction are impaired by 2-arachidonoyl glycerol endocannabinoid. Histol. Histopathol. 32, 1351–1358 (2017).

    CAS  PubMed  Google Scholar 

  96. Badawy, Z. S. et al. Cannabinoids inhibit the respiration of human sperm. Fertil. Steril. 91, 2471–2476 (2009).

    CAS  PubMed  Google Scholar 

  97. Catanzaro, G., Rapino, C., Oddi, S. & Maccarrone, M. Anandamide increases swelling and reduces calcium sensitivity of mitochondria. Biochem. Biophys. Res. Commun. 388, 439–442 (2009).

    CAS  PubMed  Google Scholar 

  98. Barbonetti, A. et al. Energetic metabolism and human sperm motility: impact of CB1 receptor activation. Endocrinology 151, 5882–5892 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Rossato, M. Endocannabinoids, sperm functions and energy metabolism. Mol. Cell. Endocrinol. 286, S31–S35 (2008).

    CAS  PubMed  Google Scholar 

  100. Mukai, C. & Okuno, M. Glycolysis plays a major role for adenosine triphosphate supplementation in mouse sperm flagellar movement. Biol. Reprod. 71, 540–547 (2004).

    CAS  PubMed  Google Scholar 

  101. Koppers, A. J., De Iuliis, G. N., Finnie, J. M., McLaughlin, E. A. & Aitken, R. J. Significance of mitochondrial reactive oxygen species in the generation of oxidative stress in spermatozoa. J. Clin. Endocrinol. Metab. 93, 3199–3207 (2008).

    CAS  PubMed  Google Scholar 

  102. Barbonetti, A. et al. Involvement of cannabinoid receptor-1 activation in mitochondrial depolarizing effect of lipopolysaccharide in human spermatozoa. Andrology 2, 502–509 (2014).

    CAS  PubMed  Google Scholar 

  103. De Toni, L. et al. Heat sensing receptor TRPV1 is a mediator of thermotaxis in human spermatozoa. PLoS ONE 11, e0167622 (2016).

    PubMed  PubMed Central  Google Scholar 

  104. Martínez-León, E. et al. Fibronectin modulates the endocannabinoid system through the cAMP/PKA pathway during human sperm capacitation. Mol. Reprod. Dev. 86, 224–238 (2019).

    PubMed  Google Scholar 

  105. Thomas, P. & Meizel, S. Phosphatidylinositol 4,5-bisphosphate hydrolysis in human sperm stimulated with follicular fluid or progesterone is dependent upon Ca2+ influx. Biochem. J. 264, 539–546 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Baldi, E. et al. Nongenomic activation of spermatozoa by steroid hormones: facts and fictions. Mol. Cell. Endocrinol. 308, 39–46 (2009).

    CAS  PubMed  Google Scholar 

  107. Baggelaar, M. P., Maccarrone, M. & van der Stelt, M. 2-Arachidonoylglycerol: a signaling lipid with manifold actions in the brain. Prog. Lipid Res. 71, 1–17 (2018).

    CAS  PubMed  Google Scholar 

  108. Amoako, A. A. et al. Relationship between seminal plasma levels of anandamide congeners palmitoylethanolamide and oleoylethanolamide and semen quality. Fertil. Steril. 102, 1260–1267 (2014).

    CAS  PubMed  Google Scholar 

  109. Berdyshev, E. V., Schmid, P. C., Krebsbach, R. J. & Schmid, H. H. Activation of PAF receptors results in enhanced synthesis of 2-arachidonoylglycerol (2-AG) in immune cells. FASEB J. 15, 2171–2178 (2001).

    CAS  PubMed  Google Scholar 

  110. Di Marzo, V. et al. Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur. J. Biochem. 264, 258–267 (1999).

    PubMed  Google Scholar 

  111. Liu, J. et al. Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-κB independently of platelet-activating factor. J. Biol. Chem. 278, 45034–45039 (2003).

    CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, L’Aquila, Italy

    Mauro Maccarrone

  2. School of Veterinary Medicine, University of Teramo, Teramo, Italy

    Cinzia Rapino

  3. Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy

    Felice Francavilla & Arcangelo Barbonetti

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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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