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The effects of cannabis and cannabinoids on the endocrine system

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Abstract

With the increase in cannabis use due to policy changes and areas of decriminalization, it is important to recognize the potential impact of these substances on endocrine processes. Cannabinoids have many effects by activating the endocannabinoid system. This system plays a role in the normal functioning of nearly every organ and consists of the body’s natural endocannabinoids, the cannabinoid receptors, and the enzymes and processes that regulate endocannabinoids. Exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC) are known to act through cannabinoid type 1 and 2 receptors, and have been shown to mimic endocannabinoid signaling and affect receptor expression. This review summarizes the known impacts of cannabis on thyroid, adrenal, and gonadal function in addition to glucose control, lipids, and bone metabolism, including: reduced female fertility, increased risk of adverse pregnancy outcomes, reduced sperm counts and function, lower thyroid hormone levels with acute use, blunting of stress response with chronic use, increased risk of prediabetes but lower risk of diabetes, suggested improvement of high density lipoproteins and triglycerides, and modest increase in fracture risk. The known properties of endocannabinoids, animal data, population data, and the possible benefits and concerns of cannabinoid use on hormonal function are discussed. The interconnectivity of the endocrine and endocannabinoid systems suggests opportunities for future therapeutic modalities which are an area of active investigation.

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Abbreviations

ECS:

Endocannabinoid system

eCB:

Endogenous cannabinoids

AEA:

Anandamide

2-AG:

2-arachidonoylglycerol

NADA:

N-arachidonoyl-dopamine

CBD:

Cannabidiol

THC:

Δ9-tetrahydrocannabinol

CB1R:

Cannabinoid type 1 receptor

CB2R:

Cannabinoid type 2 receptor

TRPV1:

Transient receptor potential vanilloid

PPAR:

Peroxisome proliferator-activated receptor

GABA:

γ-Aminobutyric acid

GnRH:

Gonadotropin releasing hormone

FSH:

Follicle stimulating hormone

LH:

Luteinizing hormone

LHRH:

Luteinizing hormone releasing hormone

PCOS:

Polycystic ovarian syndrome

TRH:

Thyroid releasing hormone

TSH:

Thyroid stimulating hormone

ERK:

Extracellular signal-regulated kinase

HPA:

hypothalamic-pituitary-adrenal

CRH:

Corticotrophin releasing hormone

ACTH:

Adrenocorticotropic hormone

T2DM:

Type 2 diabetes mellitus

BMI:

Body mass index

TG:

Triglycerides

HDL:

High-density lipoproteins

TRAP:

Tartrate Resistant Acid Phosphatase

BMD:

Bone mineral density

References

  1. Substance Abuse Center for Behavior Health Statistics and Quality. Results from the 2018 National Survey on drug use and Health: Detailed Tables. SAMHSA. 2018. https://www.samhsa.gov/data/report/2018-nsduh-detailed-tables. Accessed 18 Jul 2021.

  2. WHO. The health and social effects of nonmedical cannabis use. 2016. https://www.who.int/substance_abuse/publications/cannabis_report/en/index10.html. Accessed 20 Jul 2021.

  3. Pertwee R, Howlett A, Abood M, Alexander S, Di Marzo V, Elphick M, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62:588–631. https://doi.org/10.1124/PR.110.003004.

  4. Rock E, Parker L. Constituents of Cannabis Sativa. Adv Exp Med Biol. 2021;1264:1–13. https://doi.org/10.1007/978-3-030-57369-0_1.

    Article  CAS  PubMed  Google Scholar 

  5. Lewis M, Russo E, Smith K. Pharmacological Foundations of Cannabis Chemovars. Planta Med. 2018;84:225–33. https://doi.org/10.1055/S-0043-122240.

    Article  CAS  PubMed  Google Scholar 

  6. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344. https://doi.org/10.1111/J.1476-5381.2011.01238.X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Barnes M. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert Opin Pharmacother. 2006;7:607–15. https://doi.org/10.1517/14656566.7.5.607.

    Article  CAS  PubMed  Google Scholar 

  8. Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36:277–96. https://doi.org/10.1016/j.tips.2015.02.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gaoni Y, Mechoulam R. Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J Am Chem Soc. 2002;86:1646–7. https://doi.org/10.1021/JA01062A046.

    Article  Google Scholar 

  10. Devane WA, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–13. PMID: 2848184.

  11. Matsuda L, Lolait S, Brownstein M, Young A, Bonner T. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561–4. https://doi.org/10.1038/346561A0.

    Article  CAS  PubMed  Google Scholar 

  12. Devane W, Hanus L, Breuer A, Pertwee R, Stevenson L, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–9. https://doi.org/10.1126/SCIENCE.1470919.

    Article  CAS  PubMed  Google Scholar 

  13. Ehrenkranz J, Levine MA. Bones and Joints: The Effects of Cannabinoids on the Skeleton. J Clin Endocrinol Metab. 2019;104:4683–94. https://doi.org/10.1210/jc.2019-00665.

    Article  PubMed  Google Scholar 

  14. 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;27:73–100. https://doi.org/10.1210/ER.2005-0009.

    Article  CAS  PubMed  Google Scholar 

  15. 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;69:705–19. https://doi.org/10.5603/EP.a2018.0072.

    Article  CAS  PubMed  Google Scholar 

  16. Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin. 2019;40:309. https://doi.org/10.1038/S41401-018-0075-X.

    Article  CAS  PubMed  Google Scholar 

  17. Shahbazi F, Grandi V, Banerjee A, Trant J. Cannabinoids and cannabinoid receptors: The story so far. iScience. 2020;23. https://doi.org/10.1016/J.ISCI.2020.101301.

  18. Bie B, Wu J, Foss J, Naguib M. An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Curr Opin Anaesthesiol. 2018;31:407–14. https://doi.org/10.1097/ACO.0000000000000616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lu HC, MacKie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–25. https://doi.org/10.1016/j.biopsych.2015.07.028.

    Article  CAS  PubMed  Google Scholar 

  20. Elphick MR. The evolution and comparative neurobiology of endocannabinoid signalling. Philos Trans R Soc B Biol Sci. 2012;367:3201–15. https://doi.org/10.1098/rstb.2011.0394.

    Article  CAS  Google Scholar 

  21. Fowler C. Transport of endocannabinoids across the plasma membrane and within the cell. FEBS J. 2013;280:1895–904. https://doi.org/10.1111/FEBS.12212.

    Article  CAS  PubMed  Google Scholar 

  22. Garcia-Arencibia M, Molina-Holgado E, Molina-Holgado F. Effect of endocannabinoid signalling on cell fate: life, death, differentiation and proliferation of brain cells. Br J Pharmacol. 2019;176:1361. https://doi.org/10.1111/BPH.14369.

    Article  CAS  PubMed  Google Scholar 

  23. Justinova Z, Solinas M, Tanda G, Redhi GH, Goldberg SR. The Endogenous Cannabinoid Anandamide and Its Synthetic Analog R(+)-Methanandamide Are Intravenously Self-Administered by Squirrel Monkeys. J Neurosci. 2005;25:5645–50. https://doi.org/10.1523/JNEUROSCI.0951-05.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Johansson E, Norén K, Sjövall J, Halldin M. Determination of delta 1-tetrahydrocannabinol in human fat biopsies from marihuana users by gas chromatography-mass spectrometry. Biomed Chromatogr. 1989;3:35–8. https://doi.org/10.1002/BMC.1130030109.

    Article  CAS  PubMed  Google Scholar 

  25. Gunasekaran N, Long L, Dawson B, Hansen G, Richardson D, Li K, et al. Reintoxication: the release of fat-stored Δ9-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure. Br J Pharmacol. 2009;158:1330. https://doi.org/10.1111/J.1476-5381.2009.00399.X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cifelli P, Ruffolo G, Felice E De, Alfano V, Vliet EA van, Aronica E, et al. Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission? Int J Mol Sci. 2020;21:723. https://doi.org/10.3390/IJMS21030723.

  27. Carvalho RK, Andersen ML, Mazaro-Costa R. The effects of cannabidiol on male reproductive system: A literature review. J Appl Toxicol. 2020;40:132–50. https://doi.org/10.1002/jat.3831.

    Article  CAS  PubMed  Google Scholar 

  28. Wang H, Dey S, Maccarrone M. Jekyll and hyde: two faces of cannabinoid signaling in male and female fertility. Endocr Rev. 2006;27:427–48. https://doi.org/10.1210/ER.2006-0006.

    Article  CAS  PubMed  Google Scholar 

  29. Steger RW, Murphy LL, Bartke A, Smith MS. Effects of psychoactive and nonpsychoactive cannabinoids on the hypothalamic-pituitary axis of the adult male rat. Pharmacol Biochem Behav. 1990;37:299–302. https://doi.org/10.1016/0091-3057(90)90338-I.

    Article  CAS  PubMed  Google Scholar 

  30. Murphy LL, Sieger RW, Smith MS, Barlke 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. 1990;52:316–21. https://doi.org/10.1159/000125604.

    Article  CAS  PubMed  Google Scholar 

  31. Rettori V, Aguila MC, Gimeno MF, Franchi AM, McCann SM. In vitro effect of Δ9-tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E2. Proc Natl Acad Sci U S A. 1990;87:10063–6. https://doi.org/10.1073/pnas.87.24.10063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wenger T, Rettori V, Snyder GD, Dalterio S, McCann SM. Effects of deita-9-tetrahydrocannabinol on thehypothalamic-pituitary control of luteinizing hormone and follicle-stimulating hormone secretion in adult male rats. Neuroendocrinology. 1987;46:488–93. https://doi.org/10.1159/000124870.

    Article  CAS  PubMed  Google Scholar 

  33. De Miguel R, Romero J, Muñoz RM, García-Gil L, González S, Villanua MA, et al. Effects of cannabinoids on prolactin and gonadotrophin secretion: Involvement of changes in hypothalamic γ-aminobutyric acid (GABA) inputs. Biochem Pharmacol. 1998;56:1331–8. https://doi.org/10.1016/S0006-2952(98)00185-3.

    Article  PubMed  Google Scholar 

  34. 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 Part B - Dev Reprod Toxicol. 2011;92:195–205. https://doi.org/10.1002/bdrb.20295.

    Article  CAS  Google Scholar 

  35. El-Talatini MR, Taylor AH, Konje JC. Fluctuation in anandamide levels from ovulation to early pregnancy in in-vitro fertilization-embryo transfer women, and its hormonal regulation. Hum Reprod. 2009;24:1989–98. https://doi.org/10.1093/humrep/dep065.

    Article  CAS  PubMed  Google Scholar 

  36. Walker O, Holloway A, Raha S. The role of the endocannabinoid system in female reproductive tissues. J Ovarian Res. 2019;12. https://doi.org/10.1186/S13048-018-0478-9.

  37. Mendelson JH, Mello NK, Ellingboe J. Acute effects of marihuana smoking on prolactin levels in human females. J Pharmacol Exp Ther. 1985;232.

  38. Mendelson J, Mello N, Ellingboe J, Skupny A, Lex B, Griffin M. Marihuana smoking suppresses luteinizing hormone in women. J Pharmacol Exp Ther. 1986;237:862–6. https://pubmed.ncbi.nlm.nih.gov/3012072/.

  39. Mumford S, Flannagan K, Radoc J, Sjaarda L, Zolton J, Metz T, et al. Cannabis use while trying to conceive: a prospective cohort study evaluating associations with fecundability, live birth and pregnancy loss. Hum Reprod. 2021;36:1405–15. https://doi.org/10.1093/humrep/deaa355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Klonoff-Cohen HS, Natarajan L, Chen RV. 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. https://doi.org/10.1016/j.ajog.2005.08.020.

    Article  CAS  PubMed  Google Scholar 

  41. Misner MJ, Taborek A, Dufour J, Sharifi L, Khokhar JY, Favetta LA. Effects of Delta-9 Tetrahydrocannabinol (THC) on Oocyte Competence and Early Embryonic Development. Front Toxicol. 2021;3: 647918. https://doi.org/10.3389/ftox.2021.647918.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wise LA, Wesselink AK, Hatch EE, Rothman KJ, Mikkelsen EM, Sørensen HT, et al. Marijuana use and fecundability in a North American preconception cohort study. J Epidemiol Community Health. 2018;72:208–15. https://doi.org/10.1136/jech-2017-209755.

    Article  PubMed  Google Scholar 

  43. Kasman A, Thoma M, McLain A, Eisenberg M. Association between use of marijuana and time to pregnancy in men and women: findings from the National Survey of Family Growth. Fertil Steril. 2018;109:866–71. https://doi.org/10.1016/J.FERTNSTERT.2018.01.015.

    Article  PubMed  Google Scholar 

  44. Brents LK. Marijuana, the endocannabinoid system and the female reproductive system. Yale J Biol Med. 2016;89:175–91. /pmc/articles/PMC4918871/.

  45. Hayatbakhsh MR, Flenady VJ, Gibbons KS, Kingsbury AM, Hurrion E, Mamun AA, et al. Birth outcomes associated with cannabis use before and during pregnancy. Pediatr Res. 2012;71:215–9. https://doi.org/10.1038/pr.2011.25.

    Article  PubMed  Google Scholar 

  46. Gunn JKL, Rosales CB, Center KE, Nuñez A, Gibson SJ, Christ C, et al. Prenatal exposure to cannabis and maternal and child health outcomes: A systematic review and meta-analysis. BMJ Open. 2016;6. https://doi.org/10.1136/bmjopen-2015-009986.

  47. 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. https://doi.org/10.1093/humrep/dez098.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Klonoff-Cohen H, Lam-Kruglick P. Maternal and paternal recreational drug use and sudden infant death syndrome. Arch Pediatr Adolesc Med. 2001;155:765–70. https://doi.org/10.1001/archpedi.155.7.765.

    Article  CAS  PubMed  Google Scholar 

  49. Rizvi AA. Hyperprolactinemia and galactorrhea associated with marijuana use. Endocrinologist. 2006;16:308–10.

    Article  Google Scholar 

  50. Metz TD, Stickrath EH. Marijuana use in pregnancy and lactation: A review of the evidence. Am J Obstet Gynecol. 2015;213:761–78. https://doi.org/10.1016/j.ajog.2015.05.025.

    Article  PubMed  Google Scholar 

  51. Crume TL, Juhl AL, Brooks-Russell A, Hall KE, Wymore E, Borgelt LM. Cannabis Use During the Perinatal Period in a State With Legalized Recreational and Medical Marijuana: The Association Between Maternal Characteristics, Breastfeeding Patterns, and Neonatal Outcomes. J Pediatr. 2018;197:90–6. https://doi.org/10.1016/j.jpeds.2018.02.005.

    Article  PubMed  Google Scholar 

  52. Cui N, Yang Y, Xu Y, Zhang J, Jiang L, Hao G. Decreased expression of fatty acid amide hydrolase in women with polycystic ovary syndrome. Gynecol Endocrinol. 2017;33:368–72. https://doi.org/10.1080/09513590.2016.1269742.

    Article  CAS  PubMed  Google Scholar 

  53. Juan CC, Chen KH, Wang PH, Hwang JL, Seow KM. Endocannabinoid system activation may be associated with insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2015;104:200–6. https://doi.org/10.1016/j.fertnstert.2015.03.027.

    Article  CAS  PubMed  Google Scholar 

  54. du Plessis SS, Agarwal A, Syriac A. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. J Assist Reprod Genet. 2015;32:1575–88. https://doi.org/10.1007/s10815-015-0553-8.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Dalterio S, Bartke A, Roberson C, Watson D, Burstein S. Direct and pituitary-mediated effects of delta9-THC and cannabinol on the testis. Pharmacol Biochem Behav. 1978;8:673–8. https://doi.org/10.1016/0091-3057(78)90265-4.

    Article  CAS  PubMed  Google Scholar 

  56. Rossato M, Popa FI, 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;90:984–91. https://doi.org/10.1210/jc.2004-1287.

    Article  CAS  PubMed  Google Scholar 

  57. Rettori V, Gimeno M, Lyson K, Mccann SM. Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from the hypothalamus. Proc Natl Acad Sci U S A. 1992;89:11543–6. https://doi.org/10.1073/pnas.89.23.11543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Morgan DJ, Muller CH, Murataeva NA, Davis BJ, Mackie K. Δ 9-tetrahydrocannabinol (Δ 9-THC) attenuates mouse sperm motility and male fecundity. Br J Pharmacol. 2012;165:2575–83. https://doi.org/10.1111/j.1476-5381.2011.01506.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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. https://doi.org/10.1016/j.fertnstert.2008.03.075.

    Article  CAS  PubMed  Google Scholar 

  60. Argiolas A, Melis MR. Central control of penile erection: Role of the paraventricular nucleus of the hypothalamus. Prog Neurobiol. 2005;76:1–21. https://doi.org/10.1016/j.pneurobio.2005.06.002.

    Article  CAS  PubMed  Google Scholar 

  61. Shamloul R, Bella AJ. Impact of Cannabis Use on Male Sexual Health. J Sex Med. 2011;8:971–5. https://doi.org/10.1111/j.1743-6109.2010.02198.x.

    Article  PubMed  Google Scholar 

  62. Kolodny RC, Masters WH, Kolodner RM, Toro G. Depression of Plasma Testosterone Levels after Chronic Intensive Marihuana Use. N Engl J Med. 1974;290:872–4. https://doi.org/10.1056/nejm197404182901602.

    Article  CAS  PubMed  Google Scholar 

  63. Barnett G, Chiang CWN, Licko V. Effects of marijuana on testosterone in male subjects. J Theor Biol. 1983;104:685–92. https://doi.org/10.1016/0022-5193(83)90255-2.

    Article  CAS  PubMed  Google Scholar 

  64. 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;28:121–8. https://doi.org/10.1016/0376-8716(91)90068-A.

    Article  CAS  PubMed  Google Scholar 

  65. Coggins WJ, Swenson EW, Dawson WW, Fernandez-Salas A, Hernandez-Bolanos J, Jiminez-Antillon CF, et al. HEALTH STATUS OF CHRONIC HEAVY CANNABIS USERS. Ann N Y Acad Sci. 1976;282:148–61. https://doi.org/10.1111/j.1749-6632.1976.tb49894.x.

    Article  CAS  PubMed  Google Scholar 

  66. Cushman P. Plasma testosterone levels in healthy male marijuana smokers. Am J Drug Alcohol Abuse. 1975;2:269–75. https://doi.org/10.3109/00952997509002740.

    Article  CAS  PubMed  Google Scholar 

  67. Mendelson JH, Kuehnle J, Ellingboe J, Babor TF. Plasma Testosterone Levels before, during and after Chronic Marihuana Smoking. N Engl J Med. 1974;291:1051–5. https://doi.org/10.1056/nejm197411142912003.

    Article  CAS  PubMed  Google Scholar 

  68. Mendelson JH, Ellingboe J, Kuehnle JC, Mello NK. Effects of chronic marihuana use on integrated plasma testosterone and luteinizing hormone levels. J Pharmacol Exp Ther. 1978;207.

  69. Schaefer C, Gunn C, Dubowski K. Normal Plasma Testosterone Concentrations after Marihuana Smoking. N Engl J Med. 1975;292:867–8. https://doi.org/10.1056/nejm197504172921615.

    Article  CAS  PubMed  Google Scholar 

  70. 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: A Study among 1,215 Healthy Young Men. Am J Epidemiol. 2015;182:473–81. https://doi.org/10.1093/aje/kwv135.

    Article  PubMed  Google Scholar 

  71. 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;5:732–8. https://doi.org/10.1111/andr.12358.

  72. 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;63:376–87. https://doi.org/10.1002/mrd.90021.

    Article  CAS  PubMed  Google Scholar 

  73. 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. https://doi.org/10.1016/j.fertnstert.2005.08.027.

    Article  CAS  PubMed  Google Scholar 

  74. 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. 2010;293:298–309. https://doi.org/10.1002/ar.21042.

    Article  CAS  Google Scholar 

  75. 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. https://doi.org/10.1093/humrep/deu116.

    Article  PubMed  Google Scholar 

  76. Lacson JCA, 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;118:5374–83. https://doi.org/10.1002/cncr.27554.

    Article  CAS  PubMed  Google Scholar 

  77. Chopra GS, Jandu BS. Psycholoclinical 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. https://doi.org/10.1111/j.1749-6632.1976.tb49889.x.

  78. Tart CT. Marijuana intoxication: Common experiences. Nature. 1970;226:701–4. https://doi.org/10.1038/226701a0.

    Article  CAS  PubMed  Google Scholar 

  79. 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;20:566–73. https://doi.org/10.1038/ijir.2008.43.

    Article  CAS  PubMed  Google Scholar 

  80. Cates W, Pope JN. Gynecomastia and cannabis smoking. A nonassociation among US Army soldiers. Am J Surg. 1977;134:613–5. https://doi.org/10.1016/0002-9610(77)90447-0.

  81. Harmon J, Aliapoulios M. Gynecomastia in Marihuana Users. N Engl J Med. 1972;287:936–936. https://doi.org/10.1056/nejm197211022871824.

    Article  CAS  PubMed  Google Scholar 

  82. Fonseca B, Rebelo I. Cannabis and Cannabinoids in Reproduction and Fertility: Where We Stand. Reprod Sci. 2021. https://doi.org/10.1007/S43032-021-00588-1.

    Article  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;24:1749–54. https://doi.org/10.1016/0091-3057(86)90515-0.

    Article  CAS  PubMed  Google Scholar 

  84. Melis MR, Succu S, Mascia MS, Argiolas A. Antagonism of cannabinoid CB1 receptors in the paraventricular nucleus of male rats induces penile erection. Neurosci Lett. 2004;359:17–20.

    Article  CAS  Google Scholar 

  85. Yibrah M, Negesso A, Gebregziabher A, Challa F, Mudi K, Tesfay F, et al. Gonadal and Cortisol Hormone Profile among Male Chronic Khat, Marijuana, and Heroin Abuses. Int J Endocrinol. 2019;2019. https://doi.org/10.1155/2019/4178241.

  86. Porcella A, Marchese G, Casu MA, Rocchitta A, Lai ML, Luigi G, et al. Evidence for functional CB1 cannabinoid receptor expressed in the rat thyroid. Eur J Endocrinol. 2002;147:255–61. https://doi.org/10.1530/eje.0.1470255.

    Article  CAS  PubMed  Google Scholar 

  87. Rosenkrantz H, Esber HJ. Cannabinoid-induced hormone changes in monkeys and rats. J Toxicol Environ Health. 1980;6:297–313. https://doi.org/10.1080/15287398009529853.

    Article  CAS  PubMed  Google Scholar 

  88. Hillard CJ, Farber NE, Hagen TC, Bloom AS. The effects of δ9-tetrahydrocannabinol on serum thyrotropin levels in the rat. Pharmacol Biochem Behav. 1984;20:547–50. https://doi.org/10.1016/0091-3057(84)90303-4.

    Article  CAS  PubMed  Google Scholar 

  89. Lomax P. The effect of marihuana on pituitary-thyroid activity in the rat. Agents Actions. 1970;1:252–7. https://doi.org/10.1007/BF01968699.

    Article  CAS  PubMed  Google Scholar 

  90. Nazar B, Kairys DJ, Fowler R, Harclerode J. Effects of Δ9-tetrahydrocannabinol on serum thyroxine concentrations in the rat. J Pharm Pharmacol. 1977;29:778–9. https://doi.org/10.1111/j.2042-7158.1977.tb11465.x.

    Article  CAS  PubMed  Google Scholar 

  91. Malhotra S, Heptulla RA, Homel P, Motaghedi R. Effect of Marijuana Use on Thyroid Function and Autoimmunity. Thyroid. 2017;27:167–73. https://doi.org/10.1089/thy.2016.0197.

    Article  CAS  PubMed  Google Scholar 

  92. Parshad O, Kumar M, Melville GN. Thyroid-gonad relationship in marijuana smokers. A field study in Jamaica. West Indian Med J. 1983;32:101–5. https://pubmed.ncbi.nlm.nih.gov/6613099/.

  93. Bonnet U. Chronic cannabis abuse, delta-9-tetrahydrocannabinol and thyroid function. Pharmacopsychiatry. 2013;46:35–6. https://doi.org/10.1055/s-0032-1316342.

    Article  CAS  PubMed  Google Scholar 

  94. Winnicka MM, Zbucki R RŁ, Dadan J, Sawicki B, Hryniewicz A, Kosiorek P, Bialuk I, Puchalski Z. An immunohistochemical study of the thyroid parafollicular (C) cells in rats treated with cannabinoids - preliminary investigations. Folia Morphol (Warsz). 2003;62(4):419-21. https://pubmed.ncbi.nlm.nih.gov/14655131/.

  95. Lakiotaki E, Giaginis C, Tolia M, Alexandrou P, Delladetsima I, Giannopoulou I, et al. Clinical Significance of Cannabinoid Receptors CB1 and CB2 Expression in Human Malignant and Benign Thyroid Lesions. Biomed Res Int. 2015;2015. https://doi.org/10.1155/2015/839403.

  96. Pisanti S, Borselli C, Oliviero O, Laezza C, Gazzerro P, Bifulco M. Antiangiogenic activity of the endocannabinoid anandamide: Correlation to its tumor-suppressor efficacy. J Cell Physiol. 2007;211:495–503. https://doi.org/10.1002/jcp.20954.

    Article  CAS  PubMed  Google Scholar 

  97. Cozzolino R, Calì G, Bifulco M, Laccetti P. A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis. Invest New Drugs. 2010;28:115–23. https://doi.org/10.1007/s10637-009-9221-0.

    Article  CAS  PubMed  Google Scholar 

  98. Kushchayeva Y, Jensen K, Burman KD, Vasko V. Repositioning therapy for thyroid cancer: New insights on established medications. Endocrine-Related Cancer. 2014;21. https://doi.org/10.1530/ERC-13-0473.

  99. Hillard CJ. Endocannabinoids and the endocrine system in health and disease. In: Endocannabinoids. Springer International Publishing. 2015;317–39. https://doi.org/10.1007/978-3-319-20825-1_11.

  100. Hill M, McLaughlin R, Morrish A, Viau V, Floresco S, Hillard C, et al. Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology. 2009;34:2733–45. https://doi.org/10.1038/NPP.2009.114.

    Article  CAS  PubMed  Google Scholar 

  101. Hill MN, Tasker JG. Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2012;204:5–16. https://doi.org/10.1016/j.neuroscience.2011.12.030.

    Article  CAS  PubMed  Google Scholar 

  102. Evanson NK, Tasker JG, Hill MN, Hillard CJ, Herman JP. Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology. 2010;151:4811–9. https://doi.org/10.1210/en.2010-0285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dewey W, Peng T, Harris L. The effect of 1-trans-delta 9-tetrahydrocannabinol on the hypothalamo-hypophyseal-adrenal axis of rats. Eur J Pharmacol. 1970;12:382–4. https://doi.org/10.1016/0014-2999(70)90094-4.

    Article  CAS  PubMed  Google Scholar 

  104. Kubena R, Perhach J, Barry H. Corticosterone elevation mediated centrally by delta 1-tetrahydrocannabinol in rats. Eur J Pharmacol. 1971;14:89–92. https://doi.org/10.1016/0014-2999(71)90128-2.

    Article  CAS  PubMed  Google Scholar 

  105. Puder M, Weidenfeld J, Chowers I, Nir I, Conforti N, Siegel R. Corticotrophin and corticosterone secretion following delta 1-Tetrahydrocannabinol, in intact and in hypothalamic deafferentated male rats. Exp Brain Res. 1982;46:85–8. https://doi.org/10.1007/BF00238101.

    Article  CAS  PubMed  Google Scholar 

  106. Manzanares J, Corchero J, Fuentes J. Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of delta(9)-tetrahydrocannabinol in rats. Brain Res. 1999;839:173–9. https://doi.org/10.1016/S0006-8993(99)01756-4.

    Article  CAS  PubMed  Google Scholar 

  107. Keller-Wood M, Dallman M. Corticosteroid inhibition of ACTH secretion. Endocr Rev. 1984;5:1–24. https://doi.org/10.1210/EDRV-5-1-1.

    Article  CAS  PubMed  Google Scholar 

  108. Ziegler CG, Mohn C, Lamounier-Zepter V, Rettori V, Bornstein SR, Krug AW, et al. Expression and function of endocannabinoid receptors in the human adrenal cortex. Horm Metab Res. 2010;42:88–92. https://doi.org/10.1055/s-0029-1241860.

    Article  CAS  PubMed  Google Scholar 

  109. Brown TT, Dobs AS. Endocrine Effects of Marijuana. J Clin Pharmacol. 2002;42:90S-96S. https://doi.org/10.1002/J.1552-4604.2002.TB06008.X.

    Article  CAS  PubMed  Google Scholar 

  110. Kleinloog D, Liem-Moolenaar M, Jacobs G, Klaassen E, Kam M de, Hijman R, et al. Does olanzapine inhibit the psychomimetic effects of Δ9-tetrahydrocannabinol? 2012;26:1307–16. https://doi.org/10.1177/0269881112446534.

  111. Klumpers L, Cole D, Khalili-Mahani N, Soeter R, Te Beek E, Rombouts S, et al. Manipulating brain connectivity with δ9-tetrahydrocannabinol: a pharmacological resting state FMRI study. Neuroimage. 2012;63:1701–11. https://doi.org/10.1016/J.NEUROIMAGE.2012.07.051.

    Article  CAS  PubMed  Google Scholar 

  112. Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. Handb Exp Pharmacol. 2005;168:691–717. https://doi.org/10.1007/3-540-26573-2_24.

    Article  CAS  Google Scholar 

  113. van Leeuwen AP, Creemers HE, Greaves-Lord K, Verhulst FC, Ormel J, Huizink AC. Hypothalamic-pituitary-adrenal axis reactivity to social stress and adolescent cannabis use: The TRAILS study. Addiction. 2011;106:1484–92. https://doi.org/10.1111/j.1360-0443.2011.03448.x.

    Article  PubMed  Google Scholar 

  114. Cuttler C, Spradlin A, Nusbaum AT, Whitney P, Hinson JM, McLaughlin RJ. Blunted stress reactivity in chronic cannabis users. Psychopharmacology (Berl). 2017;234:2299–309. https://doi.org/10.1007/s00213-017-4648-z.

    Article  CAS  PubMed  Google Scholar 

  115. Somaini L, Manfredini M, Amore M, Zaimovic A, Raggi M, Leonardi C, et al. Psychobiological responses to unpleasant emotions in cannabis users. Eur Arch Psychiatry Clin Neurosci. 2012;262:47–57. https://doi.org/10.1007/S00406-011-0223-5.

    Article  PubMed  Google Scholar 

  116. King GR, Ernst T, Deng W, Stenger A, Gonzales RMK, Nakama H, et al. Altered Brain Activation During Visuomotor Integration in Chronic Active Cannabis Users: Relationship to Cortisol Levels. J Neurosci. 2011;31:17923. https://doi.org/10.1523/JNEUROSCI.4148-11.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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;203:737–44. https://doi.org/10.1007/s00213-008-1422-2.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  119. Balsevich G, Petrie GN, Hill MN. Endocannabinoids: Effectors of glucocorticoid signaling. Front Neuroendocrinol. 2017;47:86–108. https://doi.org/10.1016/j.yfrne.2017.07.005.

    Article  CAS  PubMed  Google Scholar 

  120. Malenczyk K, Keimpema E, Piscitelli F, Calvigioni D, Björklund P, Mackie K, et al. Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture. Proc Natl Acad Sci U S A. 2015;112:E6185-94. https://doi.org/10.1073/pnas.1519040112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rosenstock J, Hollander P, Chevalier S, Iranmanesh A. SERENADE: The study evaluating rimonabant efficacy in drug-naive diabetic patients: Effects of monotherapy with rimonabant, the first selective CB 1 receptor antagonist, on glycemic control, body weight, and lipid profile in drug-naive type 2 diabetes. Diabetes Care. 2008;31:2169–76. https://doi.org/10.2337/dc08-0386.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Hollander PA, Amod A, Litwak LE, Chaudhari U. Effect of rimonabant on glycemic control in insulin-treated type 2 diabetes: The ARPEGGIO trial. Diabetes Care. 2010;33:605–7. https://doi.org/10.2337/dc09-0455.

    Article  CAS  PubMed  Google Scholar 

  123. Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171–80. https://doi.org/10.1210/jc.2005-2679.

    Article  CAS  PubMed  Google Scholar 

  124. Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005;54:2838–43. https://doi.org/10.2337/diabetes.54.10.2838.

    Article  CAS  PubMed  Google Scholar 

  125. Laychock SG, Hoffman JM, Meisel E, Bilgin S. Pancreatic islet arachidonic acid turnover and metabolism and insulin release in response to delta-9-tetrahydrocannabinol. Biochem Pharmacol. 1986;35:2003–8. https://doi.org/10.1016/0006-2952(86)90733-1.

    Article  CAS  PubMed  Google Scholar 

  126. Jourdan T, Godlewski G, Cinar R, Bertola A, Szanda G, Liu J, et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med. 2013;19:1132–40. https://doi.org/10.1038/nm.3265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Juan-Picó P, Fuentes E, Javier Bermúdez-Silva F, Díaz-Molina FJ, Ripoll C, Rodríguez de Fonseca F, et al. Cannabinoid receptors regulate Ca2+ signals and insulin secretion in pancreatic β-cell. Cell Calcium. 2006;39:155–62.

  128. Kumawat VS, Kaur G. Therapeutic potential of cannabinoid receptor 2 in the treatment of diabetes mellitus and its complications. Eur J Pharmacol. 2019;862. https://doi.org/10.1016/j.ejphar.2019.172628.

  129. Lipina C, Rastedt W, Irving AJ, Hundal HS. New vistas for treatment of obesity and diabetes? Endocannabinoid signalling and metabolism in the modulation of energy balance. BioEssays. 2012;34:681–91. https://doi.org/10.1002/bies.201200031.

    Article  CAS  PubMed  Google Scholar 

  130. Bermudez-Silva FJ, Cardinal P, Cota D. The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. J Psychopharmacol. 2012;26:114–24. https://doi.org/10.1177/0269881111408458.

    Article  CAS  PubMed  Google Scholar 

  131. Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Bátkai S, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006;55:3053–60. https://doi.org/10.2337/db06-0812.

    Article  CAS  PubMed  Google Scholar 

  132. Côté M, Matias I, Lemieux I, Petrosino S, Alméras N, Després JP, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes. 2007;31:692–9. https://doi.org/10.1038/sj.ijo.0803539.

    Article  CAS  Google Scholar 

  133. Di Marzo V, Côté M, Matias I, Lemieux I, Arsenault BJ, Cartier A, et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: Associations with changes in metabolic risk factors. Diabetologia. 2009;52:213–7. https://doi.org/10.1007/s00125-008-1178-6.

    Article  CAS  PubMed  Google Scholar 

  134. Geurts L, Muccioli GG, Delzenne NM, Cani PD. Chronic Endocannabinoid System Stimulation Induces Muscle Macrophage and Lipid Accumulation in Type 2 Diabetic Mice Independently of Metabolic Endotoxaemia. PLoS One. 2013;8. https://doi.org/10.1371/journal.pone.0055963.

  135. Trillou CR, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol - Regul Integr Comp Physiol. 2003;284(2):53–2. https://doi.org/10.1152/ajpregu.00545.2002.

    Article  Google Scholar 

  136. Tam J, Vemuri VK, Liu J, Bátkai S, Mukhopadhyay B, Godlewski G, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010;120:2953–66. https://doi.org/10.1172/JCI42551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Trillou CR, Delgorge C, Menet C, Arnone M, Soubrié P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes. 2004;28:640–8. https://doi.org/10.1038/sj.ijo.0802583.

    Article  CAS  Google Scholar 

  138. Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, et al. The endogenous cennabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112:423–31. https://doi.org/10.1172/JCI17725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298–305. https://doi.org/10.1172/jci23057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Rohrbach K, Thomas MA, Glick S, Fung EN, Wang V, Watson L, et al. Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight. Diabetes Obes Metab. 2012;14:555–64. https://doi.org/10.1111/j.1463-1326.2012.01563.x.

    Article  CAS  Google Scholar 

  141. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462. https://doi.org/10.1124/pr.58.3.2.

    Article  CAS  PubMed  Google Scholar 

  142. Bermudez-Silva FJ, Sanchez-Vera I, Suárez J, Serrano A, Fuentes E, Juan-Pico P, et al. Role of cannabinoid CB2 receptors in glucose homeostasis in rats. Eur J Pharmacol. 2007;565:207–11. https://doi.org/10.1016/j.ejphar.2007.02.066.

    Article  CAS  PubMed  Google Scholar 

  143. Bermúdez-Silva FJ, Suárez J, Baixeras E, Cobo N, Bautista D, Cuesta-Muñoz AL, et al. Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia. 2008;51:476–87. https://doi.org/10.1007/s00125-007-0890-y.

    Article  CAS  PubMed  Google Scholar 

  144. Li C, Bowe JE, Huang GC, Amiel SA, Jones PM, Persaud SJ. Cannabinoid receptor agonists and antagonists stimulate insulin secretion from isolated human islets of Langerhans. Diabetes Obes Metab. 2011;13:903–10. https://doi.org/10.1111/j.1463-1326.2011.01422.x.

    Article  CAS  Google Scholar 

  145. Jenkin KA, McAinch AJ, Briffa JF, Zhang Y, Kelly DJ, Pollock CA, et al. Cannabinoid receptor 2 expression in human proximal tubule cells is regulated by albumin independent of ERK1/2 signaling. Cell Physiol Biochem. 2013;32:1309–19. https://doi.org/10.1159/000354529.

    Article  CAS  PubMed  Google Scholar 

  146. Jenkin KA, O’Keefe L, Simcocks AC, Briffa JF, Mathai ML, McAinch AJ, et al. Renal effects of chronic pharmacological manipulation of CB2 receptors in rats with diet-induced obesity. Br J Pharmacol. 2016;173:1128–42. https://doi.org/10.1111/bph.13056.

    Article  CAS  PubMed  Google Scholar 

  147. Woodhams SG, Sagar DR, Burston JJ, Chapman V. The role of the endocannabinoid system in pain. Handb Exp Pharmacol. 2015;227:119–43. https://doi.org/10.1007/978-3-662-46450-2_7.

    Article  CAS  PubMed  Google Scholar 

  148. Hollister LE, Reaven GM. Delta-9-tetrahydrocannabinol and glucose tolerance. Clin Pharmacol Ther. 1974;16:297–302. https://doi.org/10.1002/cpt1974162297.

    Article  CAS  PubMed  Google Scholar 

  149. Podolsky S, Pattavina CG, Amaral MA. Effect of Marijuana on the Glucose-Tolerance Test. Ann N Y Acad Sci. 1971;191:54–60.

    Article  CAS  Google Scholar 

  150. Akturk HK, Taylor DD, Camsari UM, Rewers A, Kinney GL, Shah VN. Association Between Cannabis Use and Risk for Diabetic Ketoacidosis in Adults With Type 1 Diabetes. JAMA Intern Med. 2019;179:115. https://doi.org/10.1001/JAMAINTERNMED.2018.5142.

    Article  PubMed  Google Scholar 

  151. Després J-P, Golay A, Sjöström L. Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia. N Engl J Med. 2005;353:2121–34. https://doi.org/10.1056/nejmoa044537.

    Article  PubMed  Google Scholar 

  152. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368:1660–72. https://doi.org/10.1016/S0140-6736(06)69571-8.

    Article  CAS  PubMed  Google Scholar 

  153. Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O’Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol. 2019;85:1888–900. https://doi.org/10.1111/bcp.14038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, et al. Efficacy and safety of cannabidiol and tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallel group pilot study. Diabetes Care. 2016;39:1777–86. https://doi.org/10.2337/dc16-0650.

    Article  CAS  PubMed  Google Scholar 

  155. Tham M, Yilmaz O, Alaverdashvili M, Kelly M, Denovan-Wright E, Laprairie R. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol. 2019;176:1455–69. https://doi.org/10.1111/BPH.14440.

    Article  CAS  PubMed  Google Scholar 

  156. Rajavashisth TB, Shaheen M, Norris KC, Pan D, Sinha SK, Ortega J, et al. Decreased prevalence of diabetes in marijuana users: Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III. BMJ Open. 2012;2. https://doi.org/10.1136/bmjopen-2011-000494.

  157. Alshaarawy O, Anthony JC. Brief Report: Cannabis Smoking and Diabetes Mellitus: Results from Meta-analysis with Eight Independent Replication Samples. Epidemiology. 2015;26:597–600. https://doi.org/10.1097/EDE.0000000000000314.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Penner EA, Buettner H, Mittleman MA. The impact of marijuana use on glucose, insulin, and insulin resistance among US adults. Am J Med. 2013;126:583–9. https://doi.org/10.1016/j.amjmed.2013.03.002.

    Article  CAS  PubMed  Google Scholar 

  159. Muniyappa R, Sable S, Ouwerkerk R, Mari A, Gharib AM, Walter M, et al. Metabolic effects of chronic cannabis smoking. Diabetes Care. 2013;36:2415–22. https://doi.org/10.2337/dc12-2303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Vidot DC, Prado G, Hlaing WWM, Florez HJ, Arheart KL, Messiah SE. Metabolic Syndrome Among Marijuana Users in the United States: An Analysis of National Health and Nutrition Examination Survey Data. Am J Med. 2016;129:173–9. https://doi.org/10.1016/j.amjmed.2015.10.019.

    Article  PubMed  Google Scholar 

  161. Yankey BNA, Strasser S, Okosun IS. A cross-sectional analysis of the association between marijuana and cigarette smoking with metabolic syndrome among adults in the United States. Diabetes Metab Syndr Clin Res Rev. 2016;10:S89-95. https://doi.org/10.1016/j.dsx.2016.03.001.

    Article  Google Scholar 

  162. Rodondi N, Pletcher MJ, Liu K, Hulley SB, Sidney S. Marijuana Use, Diet, Body Mass Index, and Cardiovascular Risk Factors (from the CARDIA Study). Am J Cardiol. 2006;98:478–84. https://doi.org/10.1016/j.amjcard.2006.03.024.

    Article  PubMed  Google Scholar 

  163. Zand A, Ibrahim K, Patham B. Prediabetes: Why Should We Care? Methodist DeBakey Cardiovasc J. 2018;14:289–97. https://doi.org/10.14797/mdcj-14-4-289.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Bancks MP, Pletcher MJ, Kertesz SG, Sidney S, Rana JS, Schreiner PJ. Marijuana use and risk of prediabetes and diabetes by middle adulthood: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Diabetologia. 2015;58:2736–44. https://doi.org/10.1007/s00125-015-3740-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Francois H, Lecru L. The Role of Cannabinoid Receptors in Renal Diseases. Curr Med Chem. 2018;25:793–801. https://doi.org/10.2174/0929867324666170911170020.

    Article  CAS  PubMed  Google Scholar 

  166. Barutta F, Piscitelli F, Pinach S, Bruno G, Gambino R, Rastaldi MP, et al. Protective role of cannabinoid receptor type 2 in a mouse model of diabetic nephropathy. Diabetes. 2011;60:2386–96. https://doi.org/10.2337/db10-1809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kong M, Xie K, Lv M, Li J, Yao J, Yan K, et al. Anti-inflammatory phytochemicals for the treatment of diabetes and its complications: Lessons learned and future promise. Biomed Pharmacother. 2021;133:110975.

  168. Horváth B, Mukhopadhyay P, Kechrid M, Patel V, Tanchian G, Wink DA, et al. β-caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radic Biol Med. 2012;52:1325–33. https://doi.org/10.1016/j.freeradbiomed.2012.01.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003;100:10529–33. https://doi.org/10.1073/pnas.1834309100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. McDonnell C, Leánez S, Pol O. The inhibitory effects of cobalt protoporphyrin IX and cannabinoid 2 receptor agonists in type 2 diabetic mice. Int J Mol Sci. 2017;18. https://doi.org/10.3390/ijms18112268.

  171. Jahanabadi S, Hadian MR, Shamsaee J, Tavangar SM, Abdollahi A, Dehpour A, et al. The effect of spinally administered win 55,212–2, a cannabinoid agonist, on thermal pain sensitivity in diabetic rats. Iran J Basic Med Sci. 2016;19:394–401. https://doi.org/10.22038/ijbms.2016.6811.

    Article  PubMed  PubMed Central  Google Scholar 

  172. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737–53. https://doi.org/10.1111/bph.12944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Hytti M, Andjelic S, Josifovska N, Piippo N, Korhonen E, Hawlina M, et al. CB2 receptor activation causes an ERK1/2-dependent inflammatory response in human RPE cells. Sci Rep. 2017;7. https://doi.org/10.1038/S41598-017-16524-W.

  174. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A. 2002;99:10819–24. https://doi.org/10.1073/pnas.152334899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Wu A, Hu P, Lin J, Xia W, Zhang R. Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction. Front Pharmacol. 2018;9:1292.https://doi.org/10.3389/FPHAR.2018.01292.

  176. Rezkalla S, Kloner RA. Cardiovascular effects of marijuana. Trends Cardiovasc Med. 2019;29:403–7. https://doi.org/10.1016/j.tcm.2018.11.004.

    Article  CAS  PubMed  Google Scholar 

  177. Lazarte J, Hegele RA. Cannabis effects on lipoproteins. Curr Opin Lipidol. 2019;30:140–6. https://doi.org/10.1097/MOL.0000000000000575.

    Article  CAS  PubMed  Google Scholar 

  178. Bellocchio L, Cervino C, Pasquali R, Pagotto U. The endocannabinoid system and energy metabolism. J Neuroendocrinol. 2008;20:850–7. https://doi.org/10.1111/j.1365-2826.2008.01728.x.

    Article  CAS  PubMed  Google Scholar 

  179. Ruby MA, Nomura DK, Hudak CSS, Mangravite LM, Chiu S, Casida JE, et al. Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins. Proc Natl Acad Sci U S A. 2008;105:14561–6. https://doi.org/10.1073/pnas.0807232105.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Le Strat Y, Le Foll B. Obesity and cannabis use: Results from 2 representative national surveys. Am J Epidemiol. 2011;174:929–33. https://doi.org/10.1093/aje/kwr200.

    Article  PubMed  Google Scholar 

  181. Meier MH, Caspi A, Cerdá M, Hancox RJ, Harrington H, Houts R, et al. Associations between cannabis use and physical health problems in early midlife a longitudinal comparison of persistent cannabis vs tobacco users. JAMA Psychiatry. 2016;73:731–40. https://doi.org/10.1001/jamapsychiatry.2016.0637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Meier MH, Pardini D, Beardslee J, Matthews KA. Associations Between Cannabis Use and Cardiometabolic Risk Factors: A Longitudinal Study of Men. Psychosom Med. 2019;81:281–8. https://doi.org/10.1097/PSY.0000000000000665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Smit E, Crespo CJ. Dietary intake and nutritional status of US adult marijuana users: results from the Third National Health and Nutrition Examination Survey. Public Health Nutr. 2001;4:781–6. https://doi.org/10.1079/phn2000114.

    Article  CAS  PubMed  Google Scholar 

  184. Thompson CA, Hay JW. Estimating the association between metabolic risk factors and marijuana use in U.S. adults using data from the continuous National Health and Nutrition Examination Survey. Ann Epidemiol. 2015;25:486–91. https://doi.org/10.1016/j.annepidem.2015.01.013.

  185. Ngueta G, Bélanger RE, Laouan-Sidi EA, Lucas M. Cannabis use in relation to obesity and insulin resistance in the inuit population. Obesity. 2015;23:290–5. https://doi.org/10.1002/oby.20973.

    Article  CAS  PubMed  Google Scholar 

  186. Bab I, Zimmer A. Cannabinoid receptors and the regulation of bone mass. Br J Pharmacol. 2008;153:182–8. https://doi.org/10.1038/sj.bjp.0707593.

    Article  CAS  PubMed  Google Scholar 

  187. Bab I, Zimmer A, Melamed E. Cannabinoids and the skeleton: From marijuana to reversal of bone loss. Ann Med. 2009;41:560–7. https://doi.org/10.1080/07853890903121025.

    Article  CAS  PubMed  Google Scholar 

  188. Rossi F, Siniscalco D, Luongo L, De Petrocellis L, Bellini G, Petrosino S, et al. The endovanilloid/endocannabinoid system in human osteoclasts: Possible involvement in bone formation and resorption. Bone. 2009;44:476–84. https://doi.org/10.1016/j.bone.2008.10.056.

    Article  CAS  PubMed  Google Scholar 

  189. Rossi F, Tortora C, Punzo F, Bellini G, Argenziano M, Di Paola A, et al. The endocannabinoid/endovanilloid system in bone: From osteoporosis to osteosarcoma. Int J Mol Sci. 2019;20. https://doi.org/10.3390/ijms20081919.

  190. Bourne D, Plinke W, Hooker ER, Nielson CM. Cannabis use and bone mineral density: NHANES 2007–2010. Arch Osteoporos. 2017;12. https://doi.org/10.1007/s11657-017-0320-9.

  191. Whyte LS, Ford L, Ridge SA, Cameron GA, Rogers MJ, Ross RA. Cannabinoids and bone: Endocannabinoids modulate human osteoclast function in vitro. Br J Pharmacol. 2012;165:2584–97. https://doi.org/10.1111/j.1476-5381.2011.01519.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Sophocleous A, Robertson R, Ferreira NB, McKenzie J, Fraser WD, Ralston SH. Heavy Cannabis Use Is Associated With Low Bone Mineral Density and an Increased Risk of Fractures. Am J Med. 2017;130:214–21. https://doi.org/10.1016/j.amjmed.2016.07.034.

    Article  CAS  PubMed  Google Scholar 

  193. Bellini G, Torella M, Manzo I, Tortora C, Luongo L, Punzo F, et al. PKCβII-mediated cross-talk of TRPV1/CB2 modulates the glucocorticoid-induced osteoclast overactivity. Pharmacol Res. 2017;115:267–74. https://doi.org/10.1016/j.phrs.2016.11.039.

    Article  CAS  PubMed  Google Scholar 

  194. Rossi F, Bellini G, Luongo L, Torella M, Mancusi S, De Petrocellis L, et al. The endovanilloid/endocannabinoid system: A new potential target for osteoporosis therapy. Bone. 2011;48:997–1007. https://doi.org/10.1016/j.bone.2011.01.001.

    Article  CAS  PubMed  Google Scholar 

  195. Rossi F, Bellini G, Torella M, Tortora C, Manzo I, Giordano C, et al. The genetic ablation or pharmacological inhibition of TRPV1 signalling is beneficial for the restoration of quiescent osteoclast activity in ovariectomized mice. Br J Pharmacol. 2014;171:2621–30. https://doi.org/10.1111/bph.12542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, et al. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet. 2005;14:3389–96. https://doi.org/10.1093/hmg/ddi370.

    Article  CAS  PubMed  Google Scholar 

  197. Kogan NM, Melamed E, Wasserman E, Raphael B, Breuer A, Stok KS, et al. Cannabidiol, a major non-psychotropic cannabis constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts. J Bone Miner Res. 2015;30:1905–13. https://doi.org/10.1002/jbmr.2513.

    Article  CAS  PubMed  Google Scholar 

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  1. Endocrinology Section, Medical Service, VA Hospital, Hines, Illinois, USA

    Farah Meah, Nicholas Emanuele & Lily Agrawal

  2. Department of Internal Medicine, Loyola University Medical Center, Maywood, IL, USA

    Michelle Lundholm

  3. Department of Medicine, Division of Endocrinology, Loyola University Health Care System, Maywood, Illinois, USA

    Hafsa Amjed, Caroline Poku & Mary Ann Emanuele

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Meah, F., Lundholm, M., Emanuele, N. et al. The effects of cannabis and cannabinoids on the endocrine system. Rev Endocr Metab Disord 23, 401–420 (2022). https://doi.org/10.1007/s11154-021-09682-w

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