Cannabis sativa is a hallucinating drug used in different parts of the world from ancient time. This is used as a part of various religious and social practices. Cannabis is a special type of Marijuana which can provide temporary relief from analgesia, body pain, and some other clinical conditions. Thus, importance of Cannabis is mostly described as a narcotic analgesic agent. But, the impacts of Cannabis on the reproductive health of females and males are multi-faceted and differentially fatal. Current researches suggest that cannabis may negatively impact male and female fertility conditions. In females, Cannabis can reduce female fertility by disrupting the hypothalamic release of gonadotropin-releasing hormone (GnRH), leading to reduced estrogen and progesterone production and an ovulatory menstrual cycles. In males, cannabis can cause changes in different ways in the reproductive system. At the tissue level, under chronic administration testicular morphology is changed which can exert its effect on sperm quality. Sperm quality is marked by different parameters like semen quality, sperm morphology, sperm mortality, and sperm motility. Upon chronic cannabis treatment, it was noted that almost all of the sperm parameters are significantly reduced. Reduced sperm parameters, eventually affect male reproductive hormones i.e. testosterone, Interstitial Cell Stimulating Hormone (ICSH), Luteinizing Hormone (LH), and Follicle Stimulating Hormone (FSH). These physiological and hormonal parameters finally cause reduced libido which may even lead to oligospermia and infertility.  Till date, studies delineating cannabis effect on the male reproductive system is mostly centered on rodent models and it is mostly lacking in human and in sub-human primates.  Considering the primate male reproductive system, these kinds of studies are haphazard and scanty.   Thus, the lacunas of previous studies were identified and the present review focuses on the effects of cannabis on the male reproductive system in a systematic manner considering human and sub-human primates in particular.

1.     Ashton CH, Moore PB, Gallagher P, Young AH. Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential. J Psychopharmacol. 2005;19(3):293-300. doi: 10.1177/0269881105051541, PMID 15888515.

2.    Aversa A, Rossi F, Francomano D, Bruzziches R, Bertone C, Santiemma V, Spera G. Early endothelial dysfunction as a marker of vasculogenic erectile dys function in young habitual cannabis users. Int J Impot Res. 2008;20(6):566-73. doi: 10.1038/ijir.2008.43, PMID 18997809.

3.      Battista N, Pasquariello N, Di Tommaso MM, Maccarrone M. Interplay between endocannabinoids, steroids and cytokines in the control of human reproduction. J Neuroendocrinol. 2008;20;Supl 1:82-9. doi: 10.1111/j.1365-2826.2008.01684.x, PMID 18426505.

4.    Bayewitch M, Rhee MH, Avidor-Reiss T, Breuer A, Mechoulam R, Vogel Z. (-)-Delta9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase. J Biol Chem. 1996; 271(17):9902-5. doi: 10.1074/jbc.271.17.9902, PMID 8626625.

5.  Brown TT, Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol. 2002;42(S1);Suppl 1 [Suppl 90:90S-6S]:90S-6S. doi: 10.1002/j.1552-4604.2002.tb06008.x, PMID 12412841.

6.    Cacciola G, Chioccarelli T, Mackie K, Meccariello R, Ledent C, Fasano S, Pierantoni R, Cobellis G. Expression of type-1 cannabinoid receptor during rat postnatal testicular development: possible involvement in adult Leydig cell differentiation. Biol Reprod. 2008;79(4):758-65. doi: 10.1095/biolreprod.108.070128, PMID 18614700.

7.      Cobellis G, Cacciola G, Scarpa D, Meccariello R, Chianese R, Franzoni MF, Mackie K, Pierantoni R, Fasano S. Endocannabinoid system in frog and rodent testis: type-1 cannabinoid receptor and fatty acid amide hydrolase activity in male germ cells. Biol Reprod. 2006;75(1):82-9. doi: 10.1095/biolreprod.106.051730, PMID 16611862.

8.     Chakravarty I, Shah PG, Sheth AR, Ghosh JJ. Mode of action of delta-9-tetrahydrocannabinol on hypothalamo-pituitary function in adult female rats. J Reprod Fertil. 1979;57(1):113-5. doi: 10.1530/jrf.0.0570113, PMID 390133.

9.   Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384(6604):83-7. doi: 10.1038/384083a0, PMID 8900284.

10.    Campbell VA. Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation. Neuropharmacology. 2001; 40(5): 702-9. doi: 10.1016/s0028-3908(00)00210-0, PMID 11311898.

11.    Dalterio S, Bartke A, Burstein S. Cannabinoids inhibit testosterone secretion by mouse testes in vitro. Science. 1977;196(4297):1472-3. doi: 10.1126/science.867048, PMID 867048.

12.    Singh SK, Chakravarty S. Antispermatogenic and antifertility effects of 20, 25-diazacholesterol dihydrochloride in mice. Reprod Toxicol. 2003;17(1):37-44. doi: 10.1016/s0890-6238(02)00075-8, PMID 12507656.

13.    Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946-9. doi: 10.1126/science.1470919, PMID 1470919.

14.    Dhawan K, Kumar S, Sharma A. Reversal of cannabinoids (delta9-THC) by the benzoflavone moiety from methanol extract of Passiflora incarnata Linneaus in mice: a possible therapy for cannabinoid addiction. J Pharm Pharmacol. 2002;54(6):875-81. doi: 10.1211/0022357021779069, PMID 12079005.

15.    Dixit VP, Lohiya NK. Effects of cannabis extract on the response of accessory sex organs of adult male mice to testosterone. Indian J Physiol Pharmacol. 1975;19(2):98-100. PMID 1158438.

16.    Dixit VP, Gupta CL, Agrawal M. Testicular degeneration and necrosis induced by chronic administration of cannabis extract in dogs. Endokrinologie. 1977;69(3):299-305. PMID 913356.

17.    EL-Gohary M, Eid MA. Effect of cannabinoid ingestion (in the form of bhang) on the immune system of high school and university students. Hum Exp Toxicol. 2004;23(3):149-56. doi: 10.1191/0960327104ht426oa, PMID 15119535.

18.    Gammon CM, Freeman Jr GM, Xie W, Petersen SL, Wetsel WC. Regulation of gonadotropin-releasing hormone secretion by cannabinoids. Endocrinology. 2005;146(10):4491-9. doi: 10.1210/en.2004-1672, PMID 16020480.

19.    Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86(8):1646-7. doi: 10.1021/ja01062a046.

20.    Gye MC, Kang HH, Kang HJ. Expression of cannabinoid receptor 1 in mouse testes. Arch Androl. 2005;51(3):247-55. doi: 10.1080/014850190898845, PMID 16025865.

21.    Bari M, Battista N, Pirazzi V, Maccarrone M. The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci (Landmark Ed). 2011;16:498-516. doi: 10.2741/3701, PMID 21196184.

22.    Substance Abuse and Mental Health Services Administration. Results from the 2013 national survey on drug use and health: summary of national findings. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014. Report No. : NSDUH Series H-48. HHS. Publication no. SBE OFFICE of multidisciplinary activities. p. 14-4863 [internet] [cited 11/9/2020]. Available from: http://www.samhsa.gov/data/sites/default/files/NSDUHresultsPDFwHTML2013/web/NSDUHresults2013.pdf.

23.    Grant BF, Saha TD, Ruan WJ, Goldstein RB, Chou SP, Jung J, Zhang H, Smith SM, Pickering RP, Huang B, Hasin DS. Epidemiology of DSM-5 drug use disorder: results from the national epidemiologic survey on alcohol and related conditions-III. JAMA Psychiatry. 2016;73(1):39-47. doi: 10.1001/jamapsychiatry.2015.2132,

24.    Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. Treatment episode data set (TEDS). Available from: https://www.samhsa.gov/data/sites/default/files/TEDS2012N_Web.pdf. National admission to substance abuse treatment services. Rockville, MD: SUBSTANCE ABUSE and mental health services administration; 2002-2012. p. 2014. Report No. : BHSiS Series S- 71, HHS Publication No. (SMA) 14-4850.

25.    Craft RM. Sex differences in behavioral effects of cannabinoids. Life Sci. 2005;77(20):2471-8. doi: 10.1016/j.lfs.2005.04.019, PMID 15958268.

26.    Herrmann ES, Weerts EM, Vandrey R. Sex differences in cannabis withdrawal symptoms among treatment-seeking cannabis users. Exp Clin Psychopharmacol. 2015;23(6):415-21. doi: 10.1037/pha0000053, PMID 26461168.

27.    Sherwood RA, Keating J, Kavvadia V, Greenough A, Peters TJ. Substance misuse in early pregnancy and relationship to fetal outcome. Eur J Pediatr. 1999;158(6):488-92. doi: 10.1007/s004310051126, PMID 10378398.

28.    García-Serra J, Ramis J, Simó S, Joya X, Pichini S, vall O, García-Algar O. Alternative biological materials to detect prenatal exposure to drugs of abuse in the third trimester of pregnancy. Ann Pediatr (Barc). 2012;77(5):323-8. doi: 10.1016/j.anpedi.2012.02.019, PMID 22513392.

29.    Ebrahim SH, Gfroerer J. Pregnancy-related substance use in the united states during 1996-1998. Obstet Gynecol. 2003;101(2):374-9. doi: 10.1016/s0029-7844(02)02588-7, PMID 12576263.

30.  Ghosh S, Rai SK. Chronic cannabis induced oxidative stress and reproductive containment in female mice. Int J Green Pharm. 2018;12:227. doi: 10.22377/ijgp.v12i03.1956.

31.    Huang HF, Nahas GG, Hembree WC 3rd. Effects of marihuana inhalation on spermatogenesis of the rat. Adv Biosci. 1978;22-23:419-27. doi: 10.1016/b978-0-08-023759-6.50037-8, PMID 756840.

32.    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. 2011;92(3):195-205. doi: 10.1002/bdrb.20295, PMID 21678546.

33.    Gundersen TD, Jørgensen N, Andersson AM, Bang AK, Nordkap L, Skakkebæk NE, Priskorn L, Juul A, Jensen TK. Association between use of marijuana and male reproductive hormones and semen quality: a study among 1,215 healthy young men. Am J Epidemiol. 2015;182(6):473-81. doi: 10.1093/aje/kwv135, PMID 26283092.

34.    Hembree WC 3rd, Nahas GG, Zeidenberg P, Huang HF. Changes in human spermatozoa associated with high dose marihuana smoking. Adv Biosci. 1978;22-23:429-39. doi: 10.1016/b978-0-08-023759-6.50038-x, PMID 574469.

35.  Zimmerman AM, Zimmerman S, Raj AY. Effects of cannabinoids on spermatogenesis in mice. Adv Biosci. 1978;22-23:407-18. doi: 10.1016/b978-0-08-023759-6.50036-6, PMID 756839.

36.  Generoso WM, Cain KT, Cornett CV, Shelby MD. Tests for induction of dominant-lethal mutations and heritable translocations with tetrahydrocannabinol in male mice. Mutat Res. 1985;143(1-2):51-3.

doi: 10.1016/0165-7992(85)90104-6, PMID 2987686.

37.   Berryman SH, Anderson RA Jr, Weis J, Bartke A. Evaluation of the co-mutagenicity of ethanol and delta 9-tetrahydrocannabinol with Trenimon. Mutat Res. 1992;278(1):47-60. doi: 10.1016/0165-1218(92)90285-8, PMID 1370119.

38.    Whan LB, West MC, McClure N, Lewis SE. Effects of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid in marijuana, on human sperm function in vitro. Fertil Steril. 2006;85(3):653-60. doi: 10.1016/j.fertnstert.2005.08.027, PMID 16500334.

39.   Barbonetti A, Vassallo MR, Fortunato D, Francavilla S, Maccarrone M, Francavilla F. Energetic metabolism and human sperm motility: impact of CB₁ receptor activation. Endocrinology. 2010;151(12):5882-92. doi: 10.1210/en.2010-0484, PMID 20962050.

40.    Badawy ZS, Chohan KR, Whyte DA, Penefsky HS, Brown OM, Souid AK. Cannabinoids inhibit the respiration of human sperm. Fertil Steril. 2009;91(6):2471-6. doi: 10.1016/j.fertnstert.2008.03.075, PMID 18565513.

41.     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. 2005;90(2):984-91. doi: 10.1210/jc.2004-1287, PMID 15562018.

42.    Chianese R, Ciaramella V, Scarpa D, Fasano S, Pierantoni R,Meccariello R. Endocannabinoids and Endovanilloids: A Possible Balance in the Regulation of the Testicular GnRH Signalling. Int J Endocrinol. Volume 2013, Article ID 904748, 9 pages. doi: 10.1155/2013/904748.

43.   Aquila S, Guido C, Santoro A, Perrotta I, Laezza C, Bifulco M, Sebastiano A. Human sperm anatomy: ultrastructural localization of the cannabinoid1 receptor and a potential role of anandamide in sperm survival and acrosome reaction. Anat Rec (Hoboken). 2010;293(2):298-309. doi: 10.1002/ar.21042, PMID 19938110.

44.  Schuel H, Burkman LJ. A tale of two cells: endocannabinoid-signaling regulates functions of neurons and sperm. Biol Reprod. 2005;73(6):1078-86. doi: 10.1095/biolreprod.105.043273, PMID 16120829.

45.   Schuel H, Burkman LJ, Lippes J, Crickard K, Mahony MC, Giuffrida A, Picone RP, Makriyannis A. Evidence that anandamide-signaling regulates human sperm functions required for fertilization. Mol Reprod Dev. 2002;63(3):376-87. doi: 10.1002/mrd.90021, PMID 12237954.

46.  Maccarrone M, Barboni B, Paradisi A, Bernabò N, Gasperi V, Pistilli MG, Fezza F, Lucidi P, Mattioli M. Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction. J Cell Sci. 2005;118(19):4393-404. doi: 10.1242/jcs.02536, PMID 16144868.

47.   Cone EJ, Johnson RE, Moore JD, Roache JD. Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol Biochem Behav. 1986;24(6):1749-54. doi: 10.1016/0091-3057(86)90515-0, PMID 3016764.

48.   Wenger T, Rettori V, Snyder GD, Dalterio S, McCann SM. Effects of delta-9-tetrahydrocannabinol on the hypothalamic-pituitary control of luteinizing hormone and follicle-stimulating hormone secretion in adult male rats. Neuroendocrinology. 1987;46(6):488-93. doi: 10.1159/000124870, PMID 2827048.

49.   Vescovi PP, Pedrazzoni M, Michelini M, Maninetti L, Bernardelli F, Passeri M. Chronic effects of marihuana smoking on luteinizing hormone, follicle-stimulating hormone and prolactin levels in human males. Drug Alcohol Depend. 1992;30(1):59-63. doi: 10.1016/0376-8716(92)90036-c, PMID 1591981.

50.   Martín-Calderón JL, Muñoz RM, Villanúa MA, del Arco I, Moreno JL, de Fonseca FR, Navarro M. Characterization of the acute endocrine actions of (-)-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210), a potent synthetic cannabinoid in rats, [De Fonseca FR, Navarro M]. Eur J Pharmacol. 1998;344(1):77-86. doi: 10.1016/S0014-2999(97)01560-4, PMID 9580419.

51.  Wenger T, Fernández-Ruiz JJ, Ramos JA. Immunocytochemical demonstration of CB1 cannabinoid receptors in the anterior lobe of the pituitary gland. J Neuroendocrinol. 1999;11(11):873-8. doi: 10.1046/j.1365-2826.1999.00402.x,

52.   Mendelson JH, Kuehnle J, Ellingboe J, Babor TF. Plasma testosterone levels before, during and after chronic marihuana smoking. N Engl J Med. 1974;291(20):1051-5. doi: 10.1056/NEJM197411142912003, PMID 4415097.

53.  Thistle JE, Graubard BI, Braunlin M, Vesper H, Trabert B, Cook MB, McGlynn KA. Marijuana use and serum testosterone concentrations among U.S. males. Andrology. 2017;5(4):732-8. doi: 10.1111/andr.12358, PMID 28395129.