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Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility

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Abstract

Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Male factor infertility is on the increase, and the exposure to the cannabinoid compounds released by marijuana could be a contributing cause. The endocannabinoid system (ECS) is deeply involved in the complex regulation of male reproduction through the endogenous release of endocannabinoids and binding to cannabinoid receptors. Disturbing the delicate balance of the ECS due to marijuana use can negatively impact reproductive potential. Various in vivo and in vitro studies have reported on the empirical role that marijuana plays in disrupting the hypothalamus-pituitary-gonadal axis, spermatogenesis, and sperm function such as motility, capacitation, and the acrosome reaction. In this review, we highlight the latest evidence regarding the effect of marijuana use on male fertility and also provide a detailed insight into the ECS and its significance in the male reproductive system.

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References

  1. Bifulco M, Pisanti S. Medicinal use of cannabis in Europe: the fact that more countries legalize the medicinal use of cannabis should not become an argument for unfettered and uncontrolled use. EMBO Rep. 2015;16(2):130–2. doi:10.15252/embr.201439742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zimmerman AM, Zimmerman S, Raj AY. Effects of cannabinoids on spermatogenesis in mice. Adv Biosci. 1978;22–23:407–18.

    PubMed  Google Scholar 

  3. Schuel H, Schuel R, Zimmerman AM, Zimmerman S. Cannabinoids reduce fertility of sea urchin sperm. Biochem Cell Biol. 1987;65(2):130–6.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. Fronczak CM, Kim ED, Barqawi AB. The insults of illicit drug use on male fertility. J Androl. 2012;33(4):515–28. doi:10.2164/jandrol.110.011874.

    Article  CAS  PubMed  Google Scholar 

  6. WHO. Management of substance abuse: facts and figures. WHO. 2015. http://www.who.int/substance_abuse/facts/cannabis/en/. Accessed 11 Feb 2015 2015

  7. SAMHSA. National survey on drug use and health: summary of national findings. Department of Health and Human Services. 2013. http://www.samhsa.gov/data/sites/default/files/NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.htm#ch2. Accessed 18 Feb 2015

  8. Fasano S, Meccariello R, Cobellis G, Chianese R, Cacciola G, Chioccarelli T, et al. The endocannabinoid system: an ancient signaling involved in the control of male fertility. Ann N Y Acad Sci. 2009;1163:112–24. doi:10.1111/j.1749-6632.2009.04437.x.

    Article  CAS  PubMed  Google Scholar 

  9. Rossato M, Pagano C, Vettor R. The cannabinoid system and male reproductive functions. J Neuroendocrinol. 2008;20 Suppl 1:90–3. doi:10.1111/j.1365-2826.2008.01680.x.

    Article  CAS  PubMed  Google Scholar 

  10. Shamloul R, Bella AJ. Impact of cannabis use on male sexual health. J Sex Med. 2011;8(4):971–5. doi:10.1111/j.1743-6109.2010.02198.x.

    Article  PubMed  Google Scholar 

  11. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66(1):95–105. doi:10.1001/archgenpsychiatry.2008.519.

    Article  CAS  PubMed  Google Scholar 

  12. Grotenhermen F. Some practice-relevant aspects of the pharmacokinetics of THC. Forsch Komplementarmed. 1999;6 Suppl 3:37–9. doi:57155.

  13. Thakur GA, Duclos Jr RI, Makriyannis A. Natural cannabinoids: templates for drug discovery. Life Sci. 2005;78(5):454–66. doi:10.1016/j.lfs.2005.09.014.

    Article  CAS  PubMed  Google Scholar 

  14. Baker D, Pryce G, Giovannoni G, Thompson AJ. The therapeutic potential of cannabis. Lancet Neurol. 2003;2(5):291–8.

    Article  CAS  PubMed  Google Scholar 

  15. Sugiura T, Waku K. 2-Arachidonoylglycerol and the cannabinoid receptors. Chem Phys Lipids. 2000;108(1–2):89–106.

    Article  CAS  PubMed  Google Scholar 

  16. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–9.

    Article  CAS  PubMed  Google Scholar 

  17. Habayeb OM, Bell SC, Konje JC. Endogenous cannabinoids: metabolism and their role in reproduction. Life Sci. 2002;70(17):1963–77.

    Article  CAS  PubMed  Google Scholar 

  18. Meccariello R, Battista N. Updates in reproduction coming from the endocannabinoid system. Int J Endocrinol. 2014;2014:412354. doi:10.1155/2014/412354.

    PubMed Central  PubMed  Google Scholar 

  19. Cacciola G, Chioccarelli T, Ricci G, Meccariello R, Fasano S, Pierantoni R, et al. The endocannabinoid system in vertebrate male reproduction: a comparative overview. Mol Cell Endocrinol. 2008;286(1–2 Suppl 1):S24–30. doi:10.1016/j.mce.2008.01.004.

    Article  CAS  PubMed  Google Scholar 

  20. Battista N, Rapino C, Di Tommaso M, Bari M, Pasquariello N, Maccarrone M. Regulation of male fertility by the endocannabinoid system. Mol Cell Endocrinol. 2008;286(1–2 Suppl 1):S17–23. doi:10.1016/j.mce.2008.01.010.

    Article  CAS  PubMed  Google Scholar 

  21. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med. 2008;14(9):923–30. doi:10.1038/nm.f.1869.

    Article  CAS  PubMed  Google Scholar 

  22. Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev. 2008;108(5):1687–707. doi:10.1021/cr0782067.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Beltramo M, Piomelli D. Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport. 2000;11(6):1231–5.

    Article  CAS  PubMed  Google Scholar 

  24. Di Marzo V, De Petrocellis L. Why do cannabinoid receptors have more than one endogenous ligand? Phil Trans R Soc Lond Ser B Biol Sci. 2012;367(1607):3216–28. doi:10.1098/rstb.2011.0382.

    Article  CAS  Google Scholar 

  25. Ligresti A, Cascio MG, Di Marzo V. Endocannabinoid metabolic pathways and enzymes. Curr Drug Targets CNS Neurol Disord. 2005;4(6):615–23.

    Article  CAS  PubMed  Google Scholar 

  26. Starowicz K, Nigam S, Di Marzo V. Biochemistry and pharmacology of endovanilloids. Pharmacol Ther. 2007;114(1):13–33. doi:10.1016/j.pharmthera.2007.01.005.

    Article  CAS  PubMed  Google Scholar 

  27. Lewis SE, Maccarrone M. Endocannabinoids, sperm biology and human fertility. Pharmacol Res. 2009;60(2):126–31. doi:10.1016/j.phrs.2009.02.009.

    Article  CAS  PubMed  Google Scholar 

  28. McKinney MK, Cravatt BF. Structure and function of fatty acid amide hydrolase. Annu Rev Biochem. 2005;74:411–32. doi:10.1146/annurev.biochem.74.082803.133450.

    Article  CAS  PubMed  Google Scholar 

  29. Di Marzo V. Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators. Life Sci. 1999;65(6–7):645–55.

    Article  PubMed  Google Scholar 

  30. Di Marzo V, De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem. 2010;17(14):1430–49.

    Article  PubMed  Google Scholar 

  31. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161–202.

    Article  CAS  PubMed  Google Scholar 

  32. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–5. doi:10.1038/365061a0.

    Article  CAS  PubMed  Google Scholar 

  33. Howlett AC, Qualy JM, Khachatrian LL. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol. 1986;29(3):307–13.

    CAS  PubMed  Google Scholar 

  34. Howlett AC. Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol. 1995;35:607–34. doi:10.1146/annurev.pa.35.040195.003135.

    Article  CAS  PubMed  Google Scholar 

  35. Caulfield MP, Brown DA. Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol. 1992;106(2):231–2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561–4. doi:10.1038/346561a0.

    Article  CAS  PubMed  Google Scholar 

  37. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB(1) and CB(2). Pharmacol Rev. 2010;62(4):588–631. doi:10.1124/pr.110.003004.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77(2):299–318.

    Article  CAS  PubMed  Google Scholar 

  39. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87(5):1932–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. El-Talatini MR, Taylor AH, Elson JC, Brown L, Davidson AC, Konje JC. Localisation and function of the endocannabinoid system in the human ovary. PLoS One. 2009;4(2), e4579. doi:10.1371/journal.pone.0004579.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  41. Tambaro S, Mongeau R, Dessi C, Pani L, Ruiu S. Modulation of ATP-mediated contractions of the rat vas deferens through presynaptic cannabinoid receptors. Eur J Pharmacol. 2005;525(1–3):150–3. doi:10.1016/j.ejphar.2005.09.058.

    Article  CAS  PubMed  Google Scholar 

  42. Walczak JS, Price TJ, Cervero F. Cannabinoid CB1 receptors are expressed in the mouse urinary bladder and their activation modulates afferent bladder activity. Neuroscience. 2009;159(3):1154–63. doi:10.1016/j.neuroscience.2009.01.050.

    Article  CAS  PubMed  Google Scholar 

  43. Matsuda LA, Bonner TI, Lolait SJ. Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol. 1993;327(4):535–50. doi:10.1002/cne.903270406.

    Article  CAS  PubMed  Google Scholar 

  44. Pertwee RG, Ross RA, Craib SJ, Thomas A. (−)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol. 2002;456(1–3):99–106.

    Article  CAS  PubMed  Google Scholar 

  45. Gye MC, Kang HH, Kang HJ. Expression of cannabinoid receptor 1 in mouse testes. Arch Androl. 2005;51(3):247–55.

    Article  CAS  PubMed  Google Scholar 

  46. Agirregoitia E, Carracedo A, Subiran N, Valdivia A, Agirregoitia N, Peralta L, et al. The CB(2) cannabinoid receptor regulates human sperm cell motility. Fertil Steril. 2010;93(5):1378–87. doi:10.1016/j.fertnstert.2009.01.153.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. Viscomi MT, Oddi S, Latini L, Pasquariello N, Florenzano F, Bernardi G, et al. Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci Off J Soc Neurosci. 2009;29(14):4564–70. doi:10.1523/jneurosci.0786-09.2009.

    Article  CAS  Google Scholar 

  49. Maccarrone M, Cecconi S, Rossi G, Battista N, Pauselli R, Finazzi-Agro A. Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. Endocrinology. 2003;144(1):20–8. doi:10.1210/en.2002-220544.

    Article  CAS  PubMed  Google Scholar 

  50. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A. 2008;105(7):2699–704. doi:10.1073/pnas.0711278105.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Moriconi A, Cerbara I, Maccarrone M, Topai A. GPR55: current knowledge and future perspectives of a purported “type-3” cannabinoid receptor. Curr Med Chem. 2010;17(14):1411–29.

    Article  CAS  PubMed  Google Scholar 

  52. Francavilla F, Battista N, Barbonetti A, Vassallo MR, Rapino C, Antonangelo C, et al. Characterization of the endocannabinoid system in human spermatozoa and involvement of transient receptor potential vanilloid 1 receptor in their fertilizing ability. Endocrinology. 2009;150(10):4692–700. doi:10.1210/en.2009-0057.

    Article  CAS  PubMed  Google Scholar 

  53. Toth A, Blumberg PM, Boczan J. Anandamide and the vanilloid receptor (TRPV1). Vitam Horm. 2009;81:389–419. doi:10.1016/s0083-6729(09)81015-7.

    Article  CAS  PubMed  Google Scholar 

  54. Pistis M, Melis M. From surface to nuclear receptors: the endocannabinoid family extends its assets. Curr Med Chem. 2010;17(14):1450–67.

    Article  CAS  PubMed  Google Scholar 

  55. Shalet SM. Normal testicular function and spermatogenesis. Pediatr Blood Cancer. 2009;53(2):285–8. doi:10.1002/pbc.22000.

    Article  PubMed  Google Scholar 

  56. Wenger T, Ledent C, Csernus V, Gerendai I. The central cannabinoid receptor inactivation suppresses endocrine reproductive functions. Biochem Biophys Res Commun. 2001;284(2):363–8. doi:10.1006/bbrc.2001.4977.

    Article  CAS  PubMed  Google Scholar 

  57. Scorticati C, Fernandez-Solari J, De Laurentiis A, Mohn C, Prestifilippo JP, Lasaga M, et al. The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen. Proc Natl Acad Sci U S A. 2004;101(32):11891–6. doi:10.1073/pnas.0404366101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Farkas I, Kallo I, Deli L, Vida B, Hrabovszky E, Fekete C, et al. Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons. Endocrinology. 2010;151(12):5818–29. doi:10.1210/en.2010-0638.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Fernandez-Solari J, Scorticati C, Mohn C, De Laurentiis A, Billi S, Franchi A, et al. Alcohol inhibits luteinizing hormone-releasing hormone release by activating the endocannabinoid system. Proc Natl Acad Sci U S A. 2004;101(9):3264–8. doi:10.1073/pnas.0307346101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Olah M, Milloh H, Wenger T. The role of endocannabinoids in the regulation of luteinizing hormone and prolactin release. Differences between the effects of AEA and 2AG. Mol Cell Endocrinol. 2008;286(1–2 Suppl 1):S36–40. doi:10.1016/j.mce.2008.01.005.

    Article  CAS  PubMed  Google Scholar 

  61. Gonzalez S, Manzanares J, Berrendero F, Wenger T, Corchero J, Bisogno T, et al. Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology. 1999;70(2):137–45. doi:54468.

  62. Rossi G, Gasperi V, Paro R, Barsacchi D, Cecconi S, Maccarrone M. Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells. Endocrinology. 2007;148(3):1431–9. doi:10.1210/en.2006-0969.

    Article  CAS  PubMed  Google Scholar 

  63. McDonald CA, Millena AC, Reddy S, Finlay S, Vizcarra J, Khan SA, 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. 2006;20(3):608–18. doi:10.1210/me.2005-0245.

    Article  CAS  PubMed  Google Scholar 

  64. Aquila S, Guido C, Santoro A, Perrotta I, Laezza C, Bifulco M, et al. 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.

    Article  CAS  Google Scholar 

  65. Schuel H, Burkman LJ, Lippes J, Crickard K, Forester E, Piomelli D, et al. N-Acylethanolamines in human reproductive fluids. Chem Phys Lipids. 2002;121(1–2):211–27.

    Article  CAS  PubMed  Google Scholar 

  66. Amoako AA, Marczylo TH, Lam PM, Willets JM, Derry A, Elson J, et al. Quantitative analysis of anandamide and related acylethanolamides in human seminal plasma by ultra performance liquid chromatography tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2010;878(31):3231–7. doi:10.1016/j.jchromb.2010.09.024.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  68. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem. 2004;279(7):5298–305. doi:10.1074/jbc.M306642200.

    Article  CAS  PubMed  Google Scholar 

  69. Amoako AA, Marczylo TH, Marczylo EL, Elson J, Willets JM, Taylor AH, et al. Anandamide modulates human sperm motility: implications for men with asthenozoospermia and oligoasthenoteratozoospermia. Hum Reprod. 2013;28(8):2058–66. doi:10.1093/humrep/det232.

    Article  CAS  PubMed  Google Scholar 

  70. Aquila S, Guido C, Santoro A, Gazzerro P, Laezza C, Baffa MF, et al. Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm. Br J Pharmacol. 2010;159(4):831–41. doi:10.1111/j.1476-5381.2009.00570.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Gervasi MG, Osycka-Salut C, Caballero J, Vazquez-Levin M, Pereyra E, Billi S, et al. Anandamide capacitates bull spermatozoa through CB1 and TRPV1 activation. PLoS One. 2011;6(2), e16993. doi:10.1371/journal.pone.0016993.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Bernabo N, Palestini P, Chiarini M, Maccarrone M, Mattioli M, Barboni B. Endocannabinoid-binding CB1 and TRPV1 receptors as modulators of sperm capacitation. Commun Integr Biol. 2012;5(1):68–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Cobellis G, Cacciola G, Scarpa D, Meccariello R, Chianese R, Franzoni MF, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  74. Ricci G, Cacciola G, Altucci L, Meccariello R, Pierantoni R, Fasano S, et al. Endocannabinoid control of sperm motility: the role of epididymus. Gen Comp Endocrinol. 2007;153(1–3):320–2. doi:10.1016/j.ygcen.2007.02.003.

    Article  CAS  PubMed  Google Scholar 

  75. Maccarrone M, Barboni B, Paradisi A, Bernabo N, Gasperi V, Pistilli MG, et al. Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction. J Cell Sci. 2005;118(Pt 19):4393–404. doi:10.1242/jcs.02536.

    Article  CAS  PubMed  Google Scholar 

  76. Rossato M. Endocannabinoids, sperm functions and energy metabolism. Mol Cell Endocrinol. 2008;286(1–2 Suppl 1):S31–5. doi:10.1016/j.mce.2008.02.013.

    Article  CAS  PubMed  Google Scholar 

  77. Aquila S, Guido C, Laezza C, Santoro A, Pezzi V, Panza S, et al. A new role of anandamide in human sperm: focus on metabolism. J Cell Physiol. 2009;221(1):147–53. doi:10.1002/jcp.21837.

    Article  CAS  PubMed  Google Scholar 

  78. Pierantoni R, Cobellis G, Meccariello R, Cacciola G, Chianese R, Chioccarelli T, et al. CB1 activity in male reproduction: mammalian and nonmammalian animal models. Vitam Horm. 2009;81:367–87. doi:10.1016/s0083-6729(09)81014-5.

    Article  CAS  PubMed  Google Scholar 

  79. Rapino C, Battista N, Bari M, Maccarrone M. Endocannabinoids as biomarkers of human reproduction. Hum Reprod Update. 2014;20(4):501–16. doi:10.1093/humupd/dmu004.

    Article  CAS  PubMed  Google Scholar 

  80. Murphy LL, Munoz RM, Adrian BA, Villanua MA. Function of cannabinoid receptors in the neuroendocrine regulation of hormone secretion. Neurobiol Dis. 1998;5(6 Pt B):432–46.

    Article  CAS  PubMed  Google Scholar 

  81. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27(1):73–100. doi:10.1210/er.2005-0009.

    Article  CAS  PubMed  Google Scholar 

  82. Wang H, Dey SK, Maccarrone M. Jekyll and hyde: two faces of cannabinoid signaling in male and female fertility. Endocr Rev. 2006;27(5):427–48. doi:10.1210/er.2006-0006.

    Article  CAS  PubMed  Google Scholar 

  83. 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.

    Article  CAS  PubMed  Google Scholar 

  84. 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.

    Article  CAS  PubMed  Google Scholar 

  85. Kolodny RC, Masters WH, Kolodner RM, Toro G. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med. 1974;290(16):872–4. doi:10.1056/nejm197404182901602.

    Article  CAS  PubMed  Google Scholar 

  86. 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.

    Article  CAS  PubMed  Google Scholar 

  87. Hembree WC, Zeidenberg P, Nahas GG. Marihuana’s effects on human gonadal function. In: Nahas GG, editor. Marihuana, chemistry, biochemistry and cellular effects. New York: Springer; 1976. p. 521–32.

    Google Scholar 

  88. Huizink AC, Ferdinand RF, Ormel J, Verhulst FC. Hypothalamic-pituitary-adrenal axis activity and early onset of cannabis use. Addiction. 2006;101(11):1581–8. doi:10.1111/j.1360-0443.2006.01570.x.

    Article  PubMed  Google Scholar 

  89. 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.

    Article  CAS  PubMed  Google Scholar 

  90. Smith RG, Besch NF, Besch PK, Smith CG. Inhibition of gonadotropin by delta9-tetrahydrocannabinol:mediation by steroid receptors? Science. 1979;204(4390):325–7.

    Article  CAS  PubMed  Google Scholar 

  91. Wenger T, Fernandez-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.

    Article  CAS  PubMed  Google Scholar 

  92. Friedrich G, Nepita W, Andre T. Serum testosterone concentrations in cannabis and opiate users. Beitr Gerichtl Med. 1990;48:57–66.

    CAS  PubMed  Google Scholar 

  93. Smith CG, Moore CE, Besch NF, Besch PK. The effect of marihuana delta 9—tetrahydrocannabinol on the secretion of sex hormones in the mature male rhesus monkey. Clin Chem. 1976;22(7):1184.

    Google Scholar 

  94. 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. 1977;5(3):268–72.

    CAS  PubMed  Google Scholar 

  95. Lee SY, Oh SM, Chung KH. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds. Toxicol Appl Pharmacol. 2006;214(3):270–8. doi:10.1016/j.taap.2005.12.019.

    Article  CAS  PubMed  Google Scholar 

  96. Fujimoto GI, Morrill GA, O’Connell ME, Kostellow AB, Retura G. Effects of cannabinoids given orally and reduced appetite on the male rat reproductive system. Pharmacology. 1982;24(5):303–13.

    Article  CAS  PubMed  Google Scholar 

  97. Lacson JC, Carroll JD, Tuazon E, Castelao EJ, Bernstein L, Cortessis VK. Population-based case–control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. Cancer. 2012;118(21):5374–83. doi:10.1002/cncr.27554.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Harclerode J, Nyquist SE, Nazar B, Lowe D. Effects of cannabis on sex hormones and testicular enzymes of the rodent. Adv Biosci. 1978;22–23:395–405.

    PubMed  Google Scholar 

  99. Yassa HA, Dawood Ael W, Shehata MM, Abdel-Hady RH, Aal KM. Subchronic toxicity of cannabis leaves on male albino rats. Hum Exp Toxicol. 2010;29(1):37–47. doi:10.1177/0960327109354312.

    Article  CAS  PubMed  Google Scholar 

  100. Mandal TK, Das NS. Testicular toxicity in cannabis extract treated mice: association with oxidative stress and role of antioxidant enzyme systems. Toxicol Ind Health. 2010;26(1):11–23. doi:10.1177/0748233709354553.

    Article  CAS  PubMed  Google Scholar 

  101. 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.

    CAS  PubMed  Google Scholar 

  102. 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.

    Article  CAS  PubMed  Google Scholar 

  103. Chakravarty I, Ghosh JJ. Influence of cannabis and delta-9-tetrahydrocannabinol on the biochemistry of the male reproductive organs. Biochem Pharmacol. 1981;30(4):273–6.

    Article  CAS  PubMed  Google Scholar 

  104. Nahas GG, Frick HC, Lattimer JK, Latour C, Harvey D. Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature apoptosis of spermatozoa. Hum Psychopharmacol. 2002;17(2):103–13. doi:10.1002/hup.369.

    Article  CAS  PubMed  Google Scholar 

  105. Hembree 3rd WC, Nahas GG, Zeidenberg P, Huang HF. Changes in human spermatozoa associated with high dose marihuana smoking. Adv Biosci. 1978;22–23:429–39.

    PubMed  Google Scholar 

  106. Pacey AA, Povey AC, Clyma JA, McNamee R, Moore HD, Baillie H, et al. Modifiable and non-modifiable risk factors for poor sperm morphology. Hum Reprod. 2014;29(8):1629–36. doi:10.1093/humrep/deu116.

    Article  PubMed  Google Scholar 

  107. Barbonetti A, Vassallo MR, Fortunato D, Francavilla S, Maccarrone M, Francavilla F. Energetic metabolism and human sperm motility: impact of CB(1) receptor activation. Endocrinology. 2010;151(12):5882–92. doi:10.1210/en.2010-0484.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. 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.

    Article  CAS  PubMed  Google Scholar 

  109. Zimmerman AM, Bruce WR, Zimmerman S. Effects of cannabinoids on sperm morphology. Pharmacology. 1979;18(3):143–8.

    Article  CAS  PubMed  Google Scholar 

  110. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet. 2009;374(9698):1383–91. doi:10.1016/s0140-6736(09)61037-0.

    Article  CAS  PubMed  Google Scholar 

  111. Morgan DJ, Muller CH, Murataeva NA, Davis BJ, Mackie K. Delta9-Tetrahydrocannabinol (Delta9-THC) attenuates mouse sperm motility and male fecundity. Br J Pharmacol. 2012;165(8):2575–83. doi:10.1111/j.1476-5381.2011.01506.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. 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.

    Article  CAS  PubMed  Google Scholar 

  113. Perez LE, Smith CG, Asch RH. Delta 9-tetrahydrocannabinol inhibits fructose utilization and motility in human, rhesus monkey, and rabbit sperm in vitro. Fertil Steril. 1981;35(6):703–5.

    CAS  PubMed  Google Scholar 

  114. du Plessis SS, Agarwal A, Mohanty G, van der Linde M. Oxidative phosphorylation versus glycolysis: what fuel do spermatozoa use? Asian J Androl. 2014. doi:10.4103/1008-682x.135123.

    PubMed Central  Google Scholar 

  115. Argiolas A, Melis MR. Central control of penile erection: role of the paraventricular nucleus of the hypothalamus. Prog Neurobiol. 2005;76(1):1–21. doi:10.1016/j.pneurobio.2005.06.002.

    Article  CAS  PubMed  Google Scholar 

  116. Chowdhury AR. Effect of pharmacological agents on male reproduction. Adv Contracept Deliv Syst. 1987;3(4):347–52.

    CAS  PubMed  Google Scholar 

  117. Abel EL. Marihuana and sex: a critical survey. Drug Alcohol Depend. 1981;8(1):1–22.

    Article  CAS  PubMed  Google Scholar 

  118. Chopra GS, Jandu BS. Psychoclinical effects of long-term marijuana use in 275 Indian chronic users. A comparative assessment of effects in Indian and USA users. Ann N Y Acad Sci. 1976;282:95–108.

    Article  CAS  PubMed  Google Scholar 

  119. Dhawan K, Sharma A. Restoration of chronic-delta 9-THC-induced decline in sexuality in male rats by a novel benzoflavone moiety from Passiflora incarnata Linn. Br J Pharmacol. 2003;138(1):117–20. doi:10.1038/sj.bjp.0705015.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Murphy LL, Gher J, Steger RW, Bartke A. Effects of delta 9-tetrahydrocannabinol on copulatory behavior and neuroendocrine responses of male rats to female conspecifics. Pharmacol Biochem Behav. 1994;48(4):1011–7.

    Article  CAS  PubMed  Google Scholar 

  121. Gorzalka BB, Hill MN, Chang SC. Male–female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function. Horm Behav. 2010;58(1):91–9. doi:10.1016/j.yhbeh.2009.08.009.

    Article  CAS  PubMed  Google Scholar 

  122. Tart CT. Marijuana intoxication common experiences. Nature. 1970;226(5247):701–4.

    Article  CAS  PubMed  Google Scholar 

  123. Halikas J, Weller R, Morse C. Effects of regular marijuana use on sexual performance. J Psychoactive Drugs. 1982;14(1–2):59–70. doi:10.1080/02791072.1982.10471911.

    Article  CAS  PubMed  Google Scholar 

  124. Di Marzo V, De Petrocellis L, Bisogno T. The biosynthesis, fate and pharmacological properties of endocannabinoids. Handb Exp Pharmacol. 2005;168:147–85.

    Article  PubMed  Google Scholar 

  125. Mialon A, Berchtold A, Michaud PA, Gmel G, Suris JC. Sexual dysfunctions among young men: prevalence and associated factors. J Adolesc Health. 2012;51(1):25–31. doi:10.1016/j.jadohealth.2012.01.008.

    Article  PubMed  Google Scholar 

  126. Aversa A, Rossi F, Francomano D, Bruzziches R, Bertone C, Santiemma V, et al. Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual cannabis users. Int J Impot Res. 2008;20(6):566–73. doi:10.1038/ijir.2008.43.

    CAS  PubMed  Google Scholar 

  127. Smith AM, Ferris JA, Simpson JM, Shelley J, Pitts MK, Richters J. Cannabis use and sexual health. J Sex Med. 2010;7(2 Pt 1):787–93. doi:10.1111/j.1743-6109.2009.01453.x.

    Article  PubMed  Google Scholar 

  128. Park B, McPartland JM, Glass M. Cannabis, cannabinoids and reproduction. Prostaglandins Leukot Essent Fat Acids. 2004;70(2):189–97.

    Article  CAS  Google Scholar 

  129. Alvarez S. Do some addictions interfere with fertility? Fertil Steril. 2015;103(1):22–6. doi:10.1016/j.fertnstert.2014.11.008.

    Article  PubMed  Google Scholar 

  130. Lotti AF, Corona G, Vitale P, Maseroli E, Rossi M, Fino MG, et al. Current smoking is associated with lower seminal vesicles and ejaculate volume, despite higher testosterone levels, in male subjects of infertile couples. Hum Reprod. 2015;30(3):590–602.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by financial assistance from the American Center for Reproductive Medicine, Cleveland Clinic, USA, the Harry Crossley Foundation, and the NRF, South Africa.

Conflict of interests

The authors declare that they have no relevant financial and competing interests.

Author contributions

S.S.D.P. conceived the idea, researched data, and wrote the article. All authors made substantial contributions to the discussion of content and reviewed/edited the manuscript before submission.

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Authors and Affiliations

  1. Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa

    Stefan S. du Plessis

  2. American Center for Reproductive Medicine, Cleveland Clinic, 10681 Carnegie Avenue, Cleveland, OH, 44195, USA

    Stefan S. du Plessis, Ashok Agarwal & Arun Syriac

Authors
  1. Stefan S. du Plessis
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  2. Ashok Agarwal
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  3. Arun Syriac
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Corresponding author

Correspondence to Ashok Agarwal.

Additional information

Capsule We highlight the latest evidence regarding the effect of marijuana use on male fertility and provide a detailed insight into its significance in the male reproductive system. Marijuana and its compounds can influence male fertility at multiple levels by acting through both the cannabinoid and vanilloid receptors.

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du Plessis, S.S., Agarwal, A. & Syriac, A. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. J Assist Reprod Genet 32, 1575–1588 (2015). https://doi.org/10.1007/s10815-015-0553-8

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  • DOI: https://doi.org/10.1007/s10815-015-0553-8

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