Delta-9 THC can be detected and quantified in the semen of men who are chronic users of inhaled cannabis

Abstract

Purpose

The purpose of this proof-of-concept study was to determine whether delta-9-tetrahydrocannabinol (THC) and THC metabolites (11-OH THC and THC-COOH) can be detected in semen.

Methods

Twelve healthy men aged 18–45 years who identified as chronic and heavy users of inhaled cannabis were recruited. THC and THC metabolite levels were measured in serum, urine, and semen of the participants. Semen analyses were performed. Serum reproductive hormones were measured.

Results

The median age and BMI of participants were 27.0 years and 24.7 kg/m2, respectively. Over half the participants were daily users of cannabis for over 5 years. Serum reproductive hormones were generally within normal ranges, except prolactin, which was elevated in 6 of 12 participants (mean 13.9 ng/mL). The median sperm concentration, motility, and morphology were 75.5 million/mL, 69.5%, and 5.5%, respectively. Urinary THC-COOH was detected in all 12 participants, and at least one serum THC metabolite was present in 10 of 12 participants. Two semen samples had insufficient volume to be analyzed. THC was above the reporting level of 0.50 ng/mL in the semen of two of the remaining participants. Seminal THC was moderately correlated with serum levels of THC (r = 0.66), serum 11-OH THC (r = 0.57), and serum THC-COOH (r = 0.67). Seminal delta-9 THC was not correlated with urinary cannabinoid levels or semen analysis parameters.

Conclusion

This is the first study to identify and quantify THC in human semen, demonstrating that THC can cross the blood-testis barrier in certain individuals. Seminal THC was found to be moderately correlated with serum THC and THC metabolites.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    United Nations Office on Drugs and Crime, World drug report 2017: Executive summary conclusions and policy implications.

  2. 2.

    Center for Behavioral Health Statistics and Quality. 2017 National survey on drug use and health: Detailed tables. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2018.

    Google Scholar 

  3. 3.

    Substance Abuse and Mental Health Services Administration. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Ser H-48, HHS Publ No 14-4863. Rockville, MD: Subst Abus Ment Heal Serv Adm; 2014. p. 1–143.

    Google Scholar 

  4. 4.

    Hartig H, Geiger A. 62% of Americans favor legalizing marijuana. Pew Research Center. Accessed online at https://www.pewresearch.org/facttank/2019/11/14/americans-suppssort-marijuana-legalization/ February 2019.

  5. 5.

    Kasman AM, Thoma ME, McLain AC, Eisenberg ML. Association between use of marijuana and time to pregnancy in men and women: findings from the National Survey of Family Growth. Fertil Steril. 2018;109(5):866–71.

    PubMed  Google Scholar 

  6. 6.

    Levin ED, Hawkey AB, Hall BJ, Cauley M, Slade S, Yazdani E, et al. Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring. Neurotoxicol Teratol. 2019;74:106806.

  7. 7.

    Gundersen TD, Jørgensen N, Andersson AM, Bang AK, Nordkap L, Skakkebæk NE, et al. Association between use of marijuana and male reproductive hormones and semen quality: Astudy among 1,215 healthy young men. Am J Epidemiol. 2015;182(6):473–81.

    PubMed  Google Scholar 

  8. 8.

    Nassan FL, Arvizu M, Mínguez-Alarcón L, Williams PL, Attaman J, Petrozza J, et al. Marijuana smoking and markers of testicular function among men from a fertility centre. Hum Reprod. 2019;34(4):715–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Nassan FL, Arvizu M, Mínguez-Alarcón L, Gaskins AJ, Williams PL, Petrozza JC, et al. Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies. Hum Reprod. 2019;34:1818–29.

  10. 10.

    Rapino C, Battista N, Bari M, Maccarrone M. Endocannabinoids as biomarkers of human reproduction. Hum Reprod Update. 2014;20:501–16.

    CAS  PubMed  Google Scholar 

  11. 11.

    Gérard CM, Mollereau C, Vassart G, Parmentier M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J. 1991;279(Pt 1):129–34.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008 Jan;153(2):199–215.

    CAS  PubMed  Google Scholar 

  13. 13.

    Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: An overview. Int. J. Obes. 2006;1:S13–S18.

  14. 14.

    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.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    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.

    CAS  PubMed  Google Scholar 

  16. 16.

    Francavilla F, Battista N, Barbonetti A, MRC V, 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;150:4692–700.

    CAS  PubMed  Google Scholar 

  17. 17.

    Wang H, Xie H, Dey SK. Loss of cannabinoid receptor CB1 induces preterm birth. PLoS One. 2008;3(10):e3320.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Wang H, Guo Y, Wang D, Kingsley PJ, Marnett LJ, Das SK, et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med. 2004;10:1074–80.

    CAS  PubMed  Google Scholar 

  19. 19.

    Sun X, Dey SK. Endocannabinoid signaling in female reproduction. ACS Chem Neurosci. 2012;3(5):349–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Grimaldi P, Orlando P, Di Siena S, Lolicato F, Petrosino S, Bisogno T, et al. The endocannabinoid system and pivotal role of the CB2 receptor in mouse spermatogenesis. Proc Natl Acad Sci U S A. 2009;106(27):11131–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Grimaldi P, Di Giacomo D, Geremia R. The endocannabinoid system and spermatogenesis. Front Endocrinol (Lausanne). 2013;4:192.

    Google Scholar 

  22. 22.

    Maccarrone M. 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.

    CAS  PubMed  Google Scholar 

  23. 23.

    Cuttler C, Spradlin A. Measuring cannabis consumption: Psychometric properties of the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ-CU). PLoS One. 2017;12(5):e0178194.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kruger TF, Franken DR. Atlas of human sperm morphology evaluation. London: Taylor & Francis; 2004.

    Google Scholar 

  25. 25.

    Kruger TF, Acosta AA, Simmons KF, Swanson RJ, Matta JF, Oehninger S. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil Steril. 1988;(1):112–7.

    CAS  PubMed  Google Scholar 

  26. 26.

    McGilveray IJ. Pharmacokinetics of cannabinoids. Pain Res Manag. 2005 Autumn;10 Suppl A:15A–22A.

  27. 27.

    Huestis M. Pharmacokinetics of THC in inhaled and oral preparations. In: Nahas GG, Sutin KM, Harvey D, Agurell S, Pace N, Cancro R, editors. Marihuana and Medicine. Totowa, NJ: Humana Press; 1999.

    Google Scholar 

  28. 28.

    Agurell S, Leander K. Stability, transfer and absorption of cannabinoid constituents of cannabis (hashish) during smoking. Acta Pharm Suec. 1971 Sep;8(4):391–402.

    CAS  PubMed  Google Scholar 

  29. 29.

    Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther. 1992 Jul;52(1):31–41.

    CAS  PubMed  Google Scholar 

  30. 30.

    Lowe RH, Abraham TT, Darwin WD, Herning R, Cadet JL, Huestis MA. Extended urinary Δ9-tetrahydrocannabinol excretion in chronic cannabis users precludes use as a biomarker of new drug exposure. Drug Alcohol Depend. 2009;105:24–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Skopp G, Pötsch L. Cannabinoid concentrations in spot serum samples 24-48 hours after discontinuation of cannabis smoking. J Anal Toxicol. 2008;32:160–4.

    CAS  PubMed  Google Scholar 

  32. 32.

    Leighty EG, Fentiman AFJ, Foltz RL. Long-retained metabolites of delta9- and delta8-tetrahydrocannabinols identified as novel fatty acid conjugates. Res Commun Chem Pathol Pharmacol. 1976;14:13–28.

    CAS  PubMed  Google Scholar 

  33. 33.

    Johansson E, Halldin MM, Agurell S, Hollister LE, Gillespie HK. Terminal elimination plasma half life of delta 1 tetrahydrocannabinol (delta 1 THC) in heavy users of marijuana. Eur J Clin Pharmacol. 1989;37(3):273–7.

    CAS  PubMed  Google Scholar 

  34. 34.

    Brenneisen R, Meyer P, Chtioui H, Saugy M, Kamber M. Plasma and urine profiles of Δ9-tetrahydrocannabinol and its metabolites 11-hydroxy-Δ9-tetrahydrocannabinol and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol after cannabis smoking by male volunteers to estimate recent consumption by athletes. Anal Bioanal Chem. 2010;396:2493–502.

    CAS  PubMed  Google Scholar 

  35. 35.

    Schuel H, Goldstein E, Mechoulam R, Zimmerman AM, Zimmerman S. Anandamide (arachidonylethanolamide), a brain cannabinoid receptor agonist, reduces sperm fertilizing capacity in sea urchins by inhibiting the acrosome reaction. Proc Natl Acad Sci U S A. 1994;91(16):7678–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kolodny RC, Masters WH, Robert M, Kolodner RM, Toro G. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med. 1974;290:872–4.

    CAS  PubMed  Google Scholar 

  37. 37.

    Zimmerman AM, Zimmerman S, Raj AY. Effects of cannabinoids on spermatogenesis in mice. Adv Biosci. 1993;22–23:407–18.

    Google Scholar 

  38. 38.

    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;29:1629–36.

    PubMed  Google Scholar 

  39. 39.

    Whan LB, West MCL, McClure N, Lewis SEM. Effects of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid in marijuana, on human sperm function in vitro. Fertil Steril. 2006;85:653–60.

    CAS  PubMed  Google Scholar 

  40. 40.

    Schuel H, Chang MC, Berkery D, Schuel R, Zimmerman AM, Zimmerman S. Cannabinoids inhibit fertilization in sea urchins by reducing the fertilizing capacity of sperm. Pharmacol Biochem Behav. 1991;40:609–15.

    CAS  PubMed  Google Scholar 

  41. 41.

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

    CAS  PubMed  Google Scholar 

  42. 42.

    Badawy ZS, Chohan KR, Whyte DA, Penefsky HS, Brown OM, Souid AK. Cannabinoids inhibit the respiration of human sperm. Fertil Steril. 2009;91:2471–6.

    CAS  PubMed  Google Scholar 

  43. 43.

    Klonoff-Cohen HS, Natarajan L, Victoria CR. A prospective study of the effects of female and male marijuana use on in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT) outcomes. Am J Obstet Gynecol. 2006;194:369–76.

    CAS  PubMed  Google Scholar 

  44. 44.

    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.

    CAS  PubMed  Google Scholar 

  45. 45.

    Wenger T, Fernández-Ruizz ast JJ, Ramos JA. Immunocytochemical demonstration of CB1 cannabinoid receptors in the anterior lobe of the pituitary gland. J Neuroendocrinol. 1999;11(11):873-878.

  46. 46.

    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.

    CAS  PubMed  Google Scholar 

  47. 47.

    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 

  48. 48.

    Thistle JE, Graubard BI, Braunlin M, Vesper H, Trabert B, Cook MB, et al. Marijuana use and serum testosterone concentrations among U.S. males. Andrology. 2017;5(4):732–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Ranganathan M, Braley G, Pittman B, Cooper T, Perry E, Krystal J, et al. The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology (Berl). 2009;(4):737–44.

    CAS  PubMed  Google Scholar 

  50. 50.

    Olusi SO. Hyperprolactinaemia in patients with suspected cannabis-induced gynaecomastia. Lancet. 1980;1(8162):255.

    CAS  PubMed  Google Scholar 

  51. 51.

    Block RI, Farinpour R, Schlechte JA. Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend. 1991;28(2):121–8.

    CAS  PubMed  Google Scholar 

  52. 52.

    Bloomfield MAP, Ashok AH, Volkow ND, Howes OD. The effects of δ9-tetrahydrocannabinol on the dopamine system. Nature. 2016;539(7629):369–77.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Kelly Ann Sagar, M.S. and Staci Gruber, PhD, for their invaluable guidance and expertise and Mazhar Chaudhry and the BWH Reproductive Endocrinology Laboratory for their support.

Funding

This study was funded by the Expanding the Boundaries Grant Phase XXVIII from the Brigham and Women’s Hospital, Department of Obstetrics and Gynecology, and with special thanks to Debbie and Keith Gelb for their generous financial support.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Malinda S. Lee.

Ethics declarations

Human and animal rights and informed consent statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Partners Healthcare Institutional Review Board) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, M.S., Lanes, A., Ginsburg, E.S. et al. Delta-9 THC can be detected and quantified in the semen of men who are chronic users of inhaled cannabis. J Assist Reprod Genet 37, 1497–1504 (2020). https://doi.org/10.1007/s10815-020-01762-1

Download citation

Keywords

  • Marijuana
  • Cannabis
  • Male fertility
  • Seminal fluid
  • Endocannabinoids