Effects of illicit drugs on structural and functional impairment of testis, endocrinal disorders, and molecular alterations of the semen

Document Type : Review Article


1 Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

3 Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran

4 Department of Biomedicine, Neurosciences and Advanced Diagnostic, University of Palermo, Palermo, Italy

5 Department of Anatomical Sciences, School of Medicine, Babol University of Medical Sciences, Babol, Iran

6 Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran


Illicit drug use is growing among young people, which is one of the major problems in today’s society that can be associated with many medical issues, including infertility. Amphetamines, cocaine, opioids, and marijuana are the most common and the most used illicit drugs worldwide. The purpose of this review was to collect as much literature as possible about the impact of illicit drugs on male fertility and summarize their valuable data. Original studies and reviews were collected by searching the keywords “illicit drugs (all kinds of that) and male infertility”. The obtained information was also categorized based on the content of the “Infertility in the Male” book. Almost all studies suggested that taking all kinds of illicit drugs with the effects on different parts of the male reproductive system can result in subfertility or complete infertility in the consumers. Although the data in this field are not decisive and there are some confounding factors in human studies, it can be inferred that the use of any illicit drug with an effect on male sexual health reduces fertility potency. Therefore, it is recommended that couples, who are planning to conceive, avoid taking any illicit drugs before and during treatment.


1. Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37-45.
2. Fijak M, Pilatz A, Hedger MP, Nicolas N, Bhushan S, Michel V, et al. Infectious, inflammatory and ‘autoimmune’male factor infertility: How do rodent models inform clinical practice? Hum Reprod Update. 2018;24:416-441.
3. Jequier AM. Male infertility: A guide for the clinician: John Wiley & Sons; 2008.
4. Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, Alexander J. The premature ejaculation prevalence and attitudes (PEPA) survey: Prevalence, comorbidities, and professional help-seeking. Eur Urol 2007;51:816-823.
5. Bjorndahl L, Barratt CL, Mortimer D, Jouannet P. ‘How to count sperm properly’: checklist for acceptability of studies based on human semen analysis. Hum Reprod 2016;31:227-232.
6. Choobineh H, Kazemi M, Sadighi Gilani MA, Heydari T, Shokri S, Bazrafkan M, et al. Testosterone reduces spinal cord injury-induced effects on male reproduction by preventing CADM1 Defect. Cell J 2018;20:138-149.
7. Wang A, Stormont I, Siddiqui MM. A review of imaging modalities used in the diagnosis and management of scrotal trauma. Curr Urol Rep. 2017;18:98-102.
8. Brauner EV, Nordkap L, Priskorn L, Hansen AM, Bang AK, Holmboe SA, et al. Psychological stress, stressful life events, male factor infertility, and testicular function: a cross-sectional study. Fertil Steril. 2020;113:865-875.
9. Marcho C, Oluwayiose OA, Pilsner JR. The preconception environment and sperm epigenetics. Andrology 2020;8:924-942.
10.    Ladjouze A, Donaldson M. Primary gonadal failure. Best Pract Res Clin Endocrinol Metab 2019;33:101295.
11. Nazmara Z, Najafi M, Movahedin M, Zandiyeh Z, Shirinbayan P, reza Asgari H, et al. Correlation between protamine-2 and miRNA-122 in sperm from heroin-addicted men: A case-control study. Urol J 2020:5747-5765.
12.    Cicero TJ, O’Connor L, Nock B, Adams ML, Miller BT, Bell RD, et al. Age-related differences in the sensitivity to opiate-induced perturbations in reproductive endocrinology in the developing and adult male rat. J Pharmacol Exp Ther 1989;248:256-261.
13. Richards JR, Wang CG, Fontenette RW, Stuart RP, McMahon KF, Turnipseed SD. Rhabdomyolysis, methamphetamine, amphetamine and MDMA Use: Associated factors and risks. J Dual Diagn 2020;16:429-437.
14. Yilmaz B, Konar V, Kutlu S, Sandal S, Canpolat S, Gezen MR, et al. Influence of chronic morphine exposure on serum LH, FSH, testosterone levels, and body and testicular weights in the developing male rat. Arch Androl 1999;43:189-196.
15. Simin F, Zahra T. Effect of heroin used in Iran on male fertility of mice. Int J Pharmacol 2007;3:406-410.
16. Xiong X, Zhang L, Fan M, Han L, Wu Q, Liu S, et al. β-Endorphin induction by psychological stress promotes leydig cell apoptosis through p38 MAPK pathway in male rats. Cells 2019;8:1265-1279.
17. Bawor M, Bami H, Dennis BB, Plater C, Worster A, Varenbut M, et al. Testosterone suppression in opioid users: a systematic review and meta-analysis. Drug Alcohol Depend 2015;149:1-9.
18. Semet M, Paci M, Saïas‐Magnan J, Metzler‐Guillemain C, Boissier R, Lejeune H, et al. The impact of drugs on male fertility: A review. Andrology 2017;5:640-663.
19. Bari M, Battista N, Pirazzi V, Maccarrone M. The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci 2011;16:498-516.
20. Alvarez S. Do some addictions interfere with fertility? Fertil Steril. 2015;103:22-26.
21. Nudmamud-Thanoi S, Sueudom W, Tangsrisakda N, Thanoi S. Changes of sperm quality and hormone receptors in the rat testis after exposure to methamphetamine. Drug Chem Toxicol 2016;39:432-438.
22. Samplaski MK, Bachir BG, Lo KC, Grober ED, Lau S, Jarvi KA. Cocaine use in the infertile male population: a marker for conditions resulting in subfertility. Curr Urol 2014;8:38-42.
23. González B, Pantoja CRG, Sosa MH, Vitullo AD, Bisagno V, González CR. Cocaine alters the mouse testicular epigenome with direct impact on histone acetylation and DNA methylation marks. Reprod Biomed Online 2018;37:269-278.
24. Dixit VP, Gupta CL, Agrawal M. Testicular degeneration and necrosis induced by chronic administration of cannabis extract in dogs. Endokrinologie 1977;69:299-305.
25. Tajaddini Mahani S, Behnam B, Abbassi M, Asgari H, Nazmara Z, Shirinbayan P, et al. Tsga10 expression correlates with sperm profiles in the adult formalin-exposed mice. Andrologia 2016;48:1092-1099.
26. Akhgari M, Jokar F, Bahmanabadi L, Aleagha AE. Street-level heroin seizures in Iran: A survey of components. J Subst Use 2012;17:348-355.
27. Heidari Z, Mahmoudzadeh-Sagheb H, Kohan F. A quantitative and qualitative study of rat testis following administration of methadone and buprenorphine. Int J High Risk Behav Addict 2012;1:12-15.
28. El-Ghawet HA. Effects of tramadol on the reproductive function of wistar albino rats. Eur J Exp Biol 2015;5:56-64.
29. Takzare N, Samizadeh E, Shoar S, Majidi Zolbin M, Naderan M, Lashkari A, et al. Impacts of morphine addiction on spermatogenesis in rats. Int J Reprod Biomed 2016;14:303-308.
30. Sansone A, Di Dato C, de Angelis C, Menafra D, Pozza C, Pivonello R, et al. Smoke, alcohol and drug addiction and male fertility. Reprod Biol Endocrinol 2018;16:3-13.
31. Ross MH, Pawlina W. Histology: A Text and Atlas: With correlated cell and molecular biology: Lippincott Williams & Wilkins; 2019.
32. Mai HN, Chung YH, Shin E-J, Jeong JH, Jung TW, Sharma N, et al. Overexpression of glutathione peroxidase-1 attenuates cocaine-induced reproductive dysfunction in male mice by inhibiting nuclear factor κB. Chem Biol Interact 2019;307:136-146.
33. Du Plessis SS, Agarwal A, Syriac A. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. J Assist Reprod Genet 2015;32:1575-1588.
34. Rajanahally S, Raheem O, Rogers M, Brisbane W, Ostrowski K, Lendvay T, et al. The relationship between cannabis and male infertility, sexual health, and neoplasm: a systematic review. Andrology 2019;7:139-147.
35. Barchi M, Innocenzi E, Giannattasio T, Dolci S, Rossi P, Grimaldi P. Cannabinoid receptors signaling in the development, epigenetics, and tumours of male germ cells. Int J Mol Sci 2019;21:25-45.
36. Dai JB, Wang ZX, Qiao ZD. The hazardous effects of tobacco smoking on male fertility. Asian J Androl. 2015;17:954-960.
37. Vuong C, Van Uum SH, O’Dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 2010;31:98-132.
38. Safarinejad MR, Asgari SA, Farshi A, Ghaedi G, Kolahi AA, Iravani S, et al. The effects of opiate consumption on serum reproductive hormone levels, sperm parameters, seminal plasma antioxidant capacity and sperm DNA integrity. Reprod Toxicol 2013;36:18-23.
39. Nargund VH. Effects of psychological stress on male fertility. Nat Rev Urol 2015;12:373-382.
40. Sengupta P, Arafa M, Elbardisi H. Hormonal regulation of spermatogenesis.  Molecular Signaling in Spermatogenesis and Male Infertility: CRC Press; 2019:41-49.
41. Oduwole OO, Peltoketo H, Huhtaniemi IT. Role of follicle-stimulating hormone in spermatogenesis. Front Endocrinol 2018;9:763.
42. 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;151:5818-5829.
43. Huizink AC, Ferdinand RF, Ormel J, Verhulst FC. Hypothalamic-pituitary-adrenal axis activity and early onset of cannabis use. Addiction 2006;101:1581-1588.
44. Watanabe K, Motoya E, Matsuzawa N, Funahashi T, Kimura T, Matsunaga T, et al. Marijuana extracts possess the effects like the endocrine disrupting chemicals. Toxicology 2005;206:471-478.
45. John WS, Martin TJ, Nader MA. Cannabinoid modulation of food-cocaine choice in male rhesus monkeys. J Pharmacol Exp Ther 2020;373:44-50.
46. Borowska M, Czarnywojtek A, Sawicka-Gutaj N, Woliński K, Płazińska MT, Mikołajczak P, et al. The effects of cannabinoids on the endocrine system. Endokrynol Pol. 2018;69:705-719.
47. Wehbeh L, Dobs AS. Opioids and the Hypothalamic-Pituitary-Gonadal (HPG) Axis. J Clin Endocrinol Metab. 2020;105:417.
48. Mirin SM, Mendelson JH, Ellingboe J, Meyer RE. Acute effects of heroin and naltrexone on testosterone and gonadotropin secretion: A pilot study. Psychoneuroendocrinology 1976;1:359-369.
49. Weems PW, Witty CF, Amstalden M, Coolen LM, Goodman RL, Lehman MN. κ-Opioid receptor is colocalized in GnRH and KNDy cells in the female ovine and rat brain. Endocrinology. 2016;157:2367-2379.
50. Farag A, Basha M, Amin S, Elnaidany N, Elhelbawy N, Mostafa M, et al. Tramadol (opioid) abuse is associated with a dose‐and time‐dependent poor sperm quality and hyperprolactinaemia in young men. Andrologia 2018;50:13026-13035.
51. Paice JA, Penn RD, Ryan WG. Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage 1994;9:126-131.
52. Bolelli G, Lafisca S, Flamigni C, Lodi S, Franceschetti F, Filicori M, et al. Heroin addiction: Relationship between the plasma levels of testosterone, dihydrotestosterone, androstenedione, LH, FSH, and the plasma concentration of heroin. Toxicology 1979;15:19-29.
53. Nazmara Z, Najafi M, Rezaei-Mojaz S, Movahedin M, Zandiyeh Z, Shirinbayan P, et al. The effect of heroin addiction on human sperm parameters, histone-to-protamine transition, and serum sexual hormone levels. Urol J 2019;16:289-294
54. Spasovska Trajanovska A, Vujovic V, Ignjatova L, Janikevik Ivanovska D, Chibishev A. Sexual dysfunction as a side effect of hyperprolactinemia in methadone maintenance therapy. Med Arch 2013;67:48-50.
55. Diamond F, Jr, Ringenberg L, MacDonald D, Barnes J, Hu CS, Duckett G, et al. Effects of drug and alcohol abuse upon pituitary-testicular function in adolescent males. J Adolesc Health Care 1986;7:28-33.
56. Chakravarty I, Ghosh JJ. Influence of cannabis and delta-9-tetrahydrocannabinol on the biochemistry of the male reproductive organs. Biochem Pharmacol. 1981;30:273-276.
57. Rokach A. The Effect of Psychological Conditions on Sexuality: A Review. Psychopharmacology 2019;29:259-266.
58. McCabe MP, Sharlip ID, Lewis R, Atalla E, Balon R, Fisher AD, et al. Incidence and prevalence of sexual dysfunction in women and men: a consensus statement from the fourth international consultation on sexual medicine 2015. J Sex Med 2016;13:144-152.
59. Mialon A, Berchtold A, Michaud PA, Gmel G, Suris JC. Sexual dysfunctions among young men: prevalence and associated factors. J Adolesc Health 2012;51:25-31.
60. Park B, McPartland JM, Glass M. Cannabis, cannabinoids and reproduction. Prostaglandins Leukot Essent Fatty Acids 2004;70:189-197.
61. Smith AM, Ferris JA, Simpson JM, Shelley J, Pitts MK, Richters J. Cannabis use and sexual health. J Sex Med 2010;7:787-793.
62. Grover S, Mattoo SK, Pendharkar S, Kandappan V. Sexual dysfunction in patients with alcohol and opioid dependence. Indian J Psychol Med 2014;36:355-365.
63.Vázquez-Martínez ER, García-Gómez E, Camacho-Arroyo I, González-Pedrajo B. Sexual dimorphism in bacterial infections. Biol Sex Differ 2018;9:1-20.
64. Evelina L, Eugen C. Tuberculosis evolution and treatment outcome in drug addicted patients. Moldovan Med J 2018;61.
65. Lozano GM, Bejarano I, Espino J, González D, Ortiz Á, García JF, et al. Density gradient capacitation is the most suitable method to improve fertilization and to reduce DNA fragmentation positive spermatozoa of infertile men. Anatolian J Obstet Gynecol 2009; 3: 1-7.
66.    Murphy SK, Itchon-Ramos N, Visco Z, Huang Z, Grenier C, Schrott R, et al. Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics 2018;13:1208-1221.
67. 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;85:653-660.
68. 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;286:24-30.
69. Amini M, Shirinbayan P, Behnam B, Roghani M, Farhoudian A, Joghataei MT, et al. Correlation between expression of CatSper family and sperm profiles in the adult mouse testis following Iranian Kerack abuse. Andrology 2014;2:386-393.
70.    Rezaei-Mojaz S, Nazmara Z, Najafi M, Movahedin M, Zandieh Z, Shirinbayan P, et al. Evaluation of enkephalin-degrading enzymes in sperm from heroin-addicted men. Int J Fertil Steril 2019;13:301-306.
71. Ebrahimi B, Forouzanfar F, Azizi H, Khoshdel-Sarkarizi H, Sadeghnia H, Rajabzadeh A. Effect of electroacupuncture and glibenclamide on blood glucose level and oxidative stress parameters in streptozotocin-induced diabetic rats and possible human implications. Acupunct Electro-Therapeutics Res. 2020;44:213-228.
72. Bafadam S, Beheshti F, Khodabakhshi T, Asghari A, Ebrahimi B, Sadeghnia HR, et al. Trigonella foenum-graceum seed (Fenugreek) hydroalcoholic extract improved the oxidative stress status in a rat model of diabetes-induced memory impairment. Horm Mol Biolo Clin Investig 2019;39:1-13.
73. Lombardo F, Sansone A, Romanelli F, Paoli D, Gandini L, Lenzi A. The role of antioxidant therapy in the treatment of male infertility: An overview. Asian J Androl 2011;13:690-697.
74. Ma J, Yuan X, Qu H, Zhang J, Wang D, Sun X, et al. The role of reactive oxygen species in morphine addiction of SH-SY5Y cells. Life Sci 2015;124:128-135.
75. Sayed RK, Mokhtar DM, Fernández-Ortiz M, Escames G, Acuña-Castroviejo D. Retinoid-related orphan nuclear receptor alpha (RORα)-deficient mice display morphological testicular defects. Lab Invest 2019;99:1835-1849.
76.    Agirregoitia E, Valdivia A, Carracedo A, Casis L, Gil J, Subiran N, et al. Expression and localization of delta-, kappa-, and mu-opioid receptors in human spermatozoa and implications for sperm motility. J Clin Endocrinol Metab 2006;91:4969-4975.
77. Wang Y, Zhao X, Gao X, Gan Y, Liu Y, Zhao X, et al. Original endomorphin-1 analogues exhibit good analgesic effects with minimal implications for human sperm motility. Bioorg Med Chem Lett 2017;27:2119-2123.
78. Subiran N, Agirregoitia E, Valdivia A, Ochoa C, Casis L, Irazusta J. Expression of enkephalin-degrading enzymes in human semen and implications for sperm motility. Fertil Steril 2008;89:1571-1577.
79. Singh AP, Rajender S. CatSper channel, sperm function and male fertility. Reprod Biomed Online 2015;30:28-38.
80. Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, et al. All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proc Natl Acad Sci USA 2007;104:1219-1223.
81. Kim JH, Jee BC, Lee JM, Suh CS, Kim SH. Histone acetylation level and histone acetyltransferase/deacetylase activity in ejaculated sperm from normozoospermic men. Yonsei Med J 2014;55:1333-1340.
82. Aoki VW, Liu L, Carrell DT. Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males. Hum Reprod 2005;20:1298-1306.
83. Miller D, Brinkworth M, Iles D. Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction 2010;139:287-301.
84. Cao J, Sun L, Aramsangtienchai P, Spiegelman NA, Zhang X, Huang W, et al. HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2. Proc Natl Acad Sci USA 2019;116:5487-5492.
85. Nazmara Z SP, Asgari HR, Ahadi R, Asgari F, Maki CB, et al. The epigenetic alterations of human sperm cells caused by heroin use disorder. Andrologia 2020;00:e13799.
86.    Wang C, Yang C, Chen X, Yao B, Yang C, Zhu C, et al. Altered profile of seminal plasma microRNAs in the molecular diagnosis of male infertility. Clin Chem 2011;57:1722-1731.
87.    Abu-Halima M, Backes C, Leidinger P, Keller A, Lubbad AM, Hammadeh M, et al. MicroRNA expression profiles in human testicular tissues of infertile men with different histopathologic patterns. Fertil Steril 2014;101:78-86.
88.    Wenger T, Ledent C, Csernus V, Gerendai I. The central cannabinoid receptor inactivation suppresses endocrine reproductive functions. Biochem Biophys Res Commun 2001;284:363-368.
89. Yamamoto Y, Yamamoto K, Hayase T, Abiru H, Shiota K, Mori C. Methamphetamine induces apoptosis in seminiferous tubules in male mice testis. Toxicol Appl Pharmacol 2002;178:155-160.