Cannabinoid exposure during pregnancy and its impact on immune function

Abstract

Cannabinoids are the most commonly abused illicit drugs worldwide. While cannabis can be beneficial for certain heath conditions, abuse of potent synthetic cannabinoids has been on the rise. Exposure to cannabinoids is also prevalent in women of child-bearing age and pregnant women. These compounds can cross the placental barrier and directly affect the fetus. They mediate their effects primarily through G-protein coupled cannabinoid receptors, CB1 and CB2. In addition to significant neurological effects, cannabinoids can trigger robust immunomodulation by altering cytokine levels, causing apoptosis of lymphoid cells and inducing suppressor cells of the immune system. Profound effects of cannabinoids on the immune system as discussed in this review, suggest that maternal exposure during pregnancy could lead to dysregulation of innate and adaptive immune system of developing fetus and offspring potentially leading to weakening of immune defenses against infections and cancer later in life. Emerging evidence also indicates the underlying role of epigenetic mechanisms causing long-lasting impact following cannabinoid exposure in utero.

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References

  1. 1.

    Hall W, Degenhardt L (2007) Prevalence and correlates of cannabis use in developed and developing countries. Curr Opin Psychiatry 20:393–397. https://doi.org/10.1097/YCO.0b013e32812144cc

    Article  PubMed  Google Scholar 

  2. 2.

    NIDA (2018) Drug facts: Marijuana. National Institute on Drug Abuse, Bethesda. https://www.drugabuse.gov/publications/drugfacts/marijuana. Accessed 31 Aug 2018

  3. 3.

    Freund SA, Banning AS (2017) Synthetic cannabinoids: a review of the clinical implications of a new drug of choice. JAAPA 30:1–4. https://doi.org/10.1097/01.JAA.0000525914.28344.e2

    Article  PubMed  Google Scholar 

  4. 4.

    Schrot RJ, Hubbard JR (2016) Cannabinoids: medical implications. Ann Med 48:128–141. https://doi.org/10.3109/07853890.2016.1145794

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Hill KP (2015) Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA 313:2474–2483. https://doi.org/10.1001/jama.2015.6199

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Murray RM, Morrison PD, Henquet C, Di Forti M (2007) Cannabis, the mind and society: the hash realities. Nat Rev Neurosci 8:885–895. https://doi.org/10.1038/nrn2253

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Svrakic DM, Lustman PJ, Mallya A et al (2012) Legalization, decriminalization and medicinal use of cannabis: a scientific and public health perspective. Mol Med 109:90–98

    Google Scholar 

  8. 8.

    Adams IB, Martin BR (1996) Cannabis: pharmacology and toxicology in animals and humans. Addiction 91:1585–1614. https://doi.org/10.1046/j.1360-0443.1996.911115852.x

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    ElSohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548. https://doi.org/10.1016/j.lfs.2005.09.011

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Zuardi AW, Crippa JAS, Hallak JEC et al (2012) A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. Curr Pharm Des 18:5131–5140

    CAS  Article  Google Scholar 

  11. 11.

    Di Marzo V, Petrocellis LD (2006) Plant, synthetic, and endogenous cannabinoids in medicine. Annu Rev Med 57:553–574. https://doi.org/10.1146/annurev.med.57.011205.135648

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Friedman D, Devinsky O (2015) Cannabinoids in the treatment of epilepsy. N Engl J Med 373:1048–1058. https://doi.org/10.1056/NEJMra1407304

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 367:3353–3363. https://doi.org/10.1098/rstb.2011.0381

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Nagarkatti P, Pandey R, Rieder SA et al (2009) Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1:1333–1349. https://doi.org/10.4155/fmc.09.93

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    WHO (2016) Management of substance abuse: Cannabis. World Health Organisation. http://www.who.int/substance_abuse/facts/cannabis/en.2016. Accessed 31 Aug 2018

  16. 16.

    Johnston L, O’Malley P, Bachman J, Schulenberg J (2012) Monitoring the Future national results on adolescent drug use: overview of key findings, 2011. Institute for Social Research, The University of Michigan, Ann Arbor

    Google Scholar 

  17. 17.

    Azofeifa A, Mattson ME, Schauer G et al (2016) National estimates of marijuana use and related indicators—National Survey on Drug Use and Health, United States, 2002–2014. MMWR Surveill Summ 65:1–28. https://doi.org/10.15585/mmwr.ss6511a1

    Article  PubMed  Google Scholar 

  18. 18.

    SAMHSA (2017) Center for Behavioral Health Statistics and Quality. 2015 National Survey on Drug Use and Health: Methodological resource book (Section 13, Statistical inference report). Substance Abuse and Mental Health Services Administration, Rockville. https://www.samhsa.gov/data. Accessed 31 Aug 2018

  19. 19.

    NIDA (2018) Drug facts: synthetic cannabinoids (K2/Spice). National Institute on Drug Abuse. https://www.drugabuse.gov/publications/drugfacts/synthetic-cannabinoids-k2spice. Accessed 30 Mar 2018

  20. 20.

    Wu L-T, Zhu H, Swartz MS (2016) Trends in cannabis use disorders among racial/ethnic population groups in the United States. Drug Alcohol Depend 165:181–190. https://doi.org/10.1016/j.drugalcdep.2016.06.002

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bridgeman MB, Abazia DT (2017) Medicinal cannabis: history, pharmacology, and implications for the acute care setting. P T 42:180–188

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Cascini F, Aiello C, Di Tanna G (2012) Increasing delta-9-tetrahydrocannabinol (Δ-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse Rev 5:32–40

    CAS  Article  Google Scholar 

  23. 23.

    Loeffler G, Delaney E, Hann M (2016) International trends in spice use: prevalence, motivation for use, relationship to other substances, and perception of use and safety for synthetic cannabinoids. Brain Res Bull 126:8–28. https://doi.org/10.1016/j.brainresbull.2016.04.013

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Palamar JJ, Acosta P (2015) Synthetic cannabinoid use in a nationally representative sample of US high school seniors. Drug Alcohol Depend 149:194–202. https://doi.org/10.1016/j.drugalcdep.2015.01.044

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Fattore L, Fratta W (2011) Beyond THC: the new generation of cannabinoid designer drugs. Front Behav Neurosci 5:60. https://doi.org/10.3389/fnbeh.2011.00060

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Castaneto MS, Gorelick DA, Desrosiers NA et al (2014) Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug Alcohol Depend 144:12–41. https://doi.org/10.1016/j.drugalcdep.2014.08.005

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Cooper ZD (2016) Adverse effects of synthetic cannabinoids: management of acute toxicity and withdrawal. Curr Psychiatry Rep 18:52. https://doi.org/10.1007/s11920-016-0694-1

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Gudsoorkar VS, Perez JA (2015) A new differential diagnosis: synthetic cannabinoids-associated acute renal failure. Methodist Debakey Cardiovasc J 11:189–191. https://doi.org/10.14797/mdcj-11-3-189

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Ford BM, Tai S, Fantegrossi WE, Prather PL (2017) Synthetic pot: not your grandfather’s marijuana. Trends Pharmacol Sci 38:257–276. https://doi.org/10.1016/j.tips.2016.12.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Felder CC, Joyce KE, Briley EM et al (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 48:443–450

    CAS  PubMed  Google Scholar 

  31. 31.

    Grotenhermen F (2004) Pharmacology of cannabinoids. Neuro Endocrinol Lett 25:14–23

    CAS  PubMed  Google Scholar 

  32. 32.

    Johnston M, O’Malley P, Bachman J (2000) Monitoring the future national survey results on drug use, 1975–1999. Volume II: College Students and Adults Ages 19–40. National Institute of Drug Abuse, Rockville. http://www.monitoringthefuture.org/pubs.html. Accessed 5 Oct 2018

  33. 33.

    Ebrahim SH, Gfroerer J (2003) Pregnancy-related substance use in the United States during 1996–1998. Obstet Gynecol 101:374–379

    PubMed  Google Scholar 

  34. 34.

    Lipari RN, Hedden SL, Hughes A (2013) Substance use and mental health estimates from the 2013 National Survey on Drug Use and Health: Overview of Findings. In: The CBHSQ Report. Substance Abuse and Mental Health Services Administration (US), Rockville

  35. 35.

    Gunn JKL, Rosales CB, Center KE et al (2016) Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open 6:e009986. https://doi.org/10.1136/bmjopen-2015-009986

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    SAMHSA (2014) Results from the 2013 National Survey on Drug Use and Health: summary of national findings. Substance Abuse and Mental Health Services Administration, Rockville

    Google Scholar 

  37. 37.

    Martin CE, Longinaker N, Mark K et al (2015) Recent trends in treatment admissions for marijuana use during pregnancy. J Addict Med 9:99–104. https://doi.org/10.1097/ADM.0000000000000095

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Braillon A, Bewley S (2018) Committee Opinion No. 722: marijuana use during pregnancy and lactation. Obstet Gynecol 131:164. https://doi.org/10.1097/AOG.0000000000002429

    Article  PubMed  Google Scholar 

  39. 39.

    Brancato A, Cannizzaro C (2018) Mothering under the influence: how perinatal drugs of abuse alter the mother–infant interaction. Rev Neurosci 29:283–294. https://doi.org/10.1515/revneuro-2017-0052

    Article  PubMed  Google Scholar 

  40. 40.

    Alpár A, Di Marzo V, Harkany T (2016) At the tip of an iceberg: prenatal marijuana and its possible relation to neuropsychiatric outcome in the offspring. Biol Psychiatry 79:e33–e45. https://doi.org/10.1016/j.biopsych.2015.09.009

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Campolongo P, Trezza V, Palmery M et al (2009) Developmental exposure to cannabinoids causes subtle and enduring neurofunctional alterations. Int Rev Neurobiol 85:117–133. https://doi.org/10.1016/S0074-7742(09)85009-5

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Hayatbakhsh MR, Flenady VJ, Gibbons KS et al (2012) Birth outcomes associated with cannabis use before and during pregnancy. Pediatr Res 71:215–219. https://doi.org/10.1038/pr.2011.25

    Article  PubMed  Google Scholar 

  43. 43.

    Jutras-Aswad D, DiNieri JA, Harkany T, Hurd YL (2009) Neurobiological consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome. Eur Arch Psychiatry Clin Neurosci 259:395–412. https://doi.org/10.1007/s00406-009-0027-z

    Article  PubMed  Google Scholar 

  44. 44.

    Wang X, Dow-Edwards D, Anderson V et al (2004) In utero marijuana exposure associated with abnormal amygdala dopamine D2 gene expression in the human fetus. Biol Psychiatry 56:909–915. https://doi.org/10.1016/j.biopsych.2004.10.015

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Brancato A, Lavanco G, Cavallaro A et al (2016) The use of the emotional-object recognition as an assay to assess learning and memory associated to an aversive stimulus in rodents. J Neurosci Methods 274:106–115. https://doi.org/10.1016/j.jneumeth.2016.09.010

    Article  PubMed  Google Scholar 

  46. 46.

    Brancato A, Cavallaro A, Lavanco G et al (2018) Reward-related limbic memory and stimulation of the cannabinoid system: an upgrade in value attribution? J Psychopharmacol (Oxford) 32:204–214. https://doi.org/10.1177/0269881117725683

    CAS  Article  Google Scholar 

  47. 47.

    Fergusson DM, Horwood LJ, Northstone K, ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood (2002) Maternal use of cannabis and pregnancy outcome. BJOG 109:21–27

    Article  Google Scholar 

  48. 48.

    Metz TD, Allshouse AA, Hogue CJ et al (2017) Maternal marijuana use, adverse pregnancy outcomes, and neonatal morbidity. Am J Obstet Gynecol 217:478.e1–478.e8. https://doi.org/10.1016/j.ajog.2017.05.050

    Article  Google Scholar 

  49. 49.

    De Petrocellis L, Cascio MG, Di Marzo V (2004) The endocannabinoid system: a general view and latest additions. Br J Pharmacol 141:765–774. https://doi.org/10.1038/sj.bjp.0705666

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Devane WA (1994) New dawn of cannabinoid pharmacology. Trends Pharmacol Sci 15:40–41

    CAS  Article  Google Scholar 

  51. 51.

    Mechoulam R, Fride E, Di Marzo V (1998) Endocannabinoids. Eur J Pharmacol 359:1–18

    CAS  Article  Google Scholar 

  52. 52.

    Luchicchi A, Pistis M (2012) Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol 46:374–392. https://doi.org/10.1007/s12035-012-8299-0

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356. https://doi.org/10.1016/j.chembiol.2007.11.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Cravatt BF, Giang DK, Mayfield SP et al (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87. https://doi.org/10.1038/384083a0

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Bari M, Battista N, Pirazzi V, Maccarrone M (2011) The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci (Landmark Ed) 16:498–516

    CAS  Article  Google Scholar 

  56. 56.

    Taylor AH, Amoako AA, Bambang K et al (2010) Endocannabinoids and pregnancy. Clin Chim Acta 411:921–930. https://doi.org/10.1016/j.cca.2010.03.012

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Battista N, Pasquariello N, Di Tommaso M, Maccarrone M (2008) Interplay between endocannabinoids, steroids and cytokines in the control of human reproduction. J Neuroendocrinol 20(Suppl 1):82–89. https://doi.org/10.1111/j.1365-2826.2008.01684.x

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Taylor AH, Ang C, Bell SC, Konje JC (2007) The role of the endocannabinoid system in gametogenesis, implantation and early pregnancy. Hum Reprod Update 13:501–513. https://doi.org/10.1093/humupd/dmm018

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Fride E (2008) Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development. J Neuroendocrinol 20(Suppl 1):75–81. https://doi.org/10.1111/j.1365-2826.2008.01670.x

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Maccarrone M, Valensise H, Bari M et al (2000) Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355:1326–1329. https://doi.org/10.1016/S0140-6736(00)02115-2

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Maccarrone M, Bisogno T, Valensise H et al (2002) Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer. Mol Hum Reprod 8:188–195

    CAS  Article  Google Scholar 

  62. 62.

    Habayeb OMH, Taylor AH, Bell SC et al (2008) Expression of the endocannabinoid system in human first trimester placenta and its role in trophoblast proliferation. Endocrinology 149:5052–5060. https://doi.org/10.1210/en.2007-1799

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Maccarrone M, Finazzi-Agrò A (2004) Anandamide hydrolase: a guardian angel of human reproduction? Trends Pharmacol Sci 25:353–357. https://doi.org/10.1016/j.tips.2004.05.002

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Schmid PC, Paria BC, Krebsbach RJ et al (1997) Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc Natl Acad Sci USA 94:4188–4192

    CAS  Article  Google Scholar 

  65. 65.

    Almada M, Amaral C, Diniz-da-Costa M et al (2016) The endocannabinoid anandamide impairs in vitro decidualization of human cells. Reproduction 152:351–361. https://doi.org/10.1530/REP-16-0364

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Fonseca BM, Correia-da-Silva G, Teixeira NA (2015) Anandamide restricts uterine stromal differentiation and is critical for complete decidualization. Mol Cell Endocrinol 411:167–176. https://doi.org/10.1016/j.mce.2015.04.024

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Schuel H, Burkman LJ, Lippes J et al (2002) Evidence that anandamide-signaling regulates human sperm functions required for fertilization. Mol Reprod Dev 63:376–387. https://doi.org/10.1002/mrd.90021

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    McIntosh AL, Martin GG, Huang H et al (2018) Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation. J Lipid Res 59:646–657. https://doi.org/10.1194/jlr.M082644

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Leishman E, Murphy M, Mackie K, Bradshaw HB (2018) Δ9-Tetrahydrocannabinol changes the brain lipidome and transcriptome differentially in the adolescent and the adult. Biochim Biophys Acta Mol Cell Biol Lipids 1863:479–492. https://doi.org/10.1016/j.bbalip.2018.02.001

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Karasu T, Marczylo TH, Maccarrone M, Konje JC (2011) The role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility. Hum Reprod Update 17:347–361. https://doi.org/10.1093/humupd/dmq058

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Maia J, Almada M, Silva A et al (2017) The endocannabinoid system expression in the female reproductive tract is modulated by estrogen. J Steroid Biochem Mol Biol 174:40–47. https://doi.org/10.1016/j.jsbmb.2017.07.023

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Maccarrone M, Di Rienzo M, Finazzi-Agrò A, Rossi A (2003) Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J Biol Chem 278:13318–13324. https://doi.org/10.1074/jbc.M211248200

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Maccarrone M, Bari M, Di Rienzo M et al (2003) Progesterone activates fatty acid amide hydrolase (FAAH) promoter in human T lymphocytes through the transcription factor Ikaros. Evidence for a synergistic effect of leptin. J Biol Chem 278:32726–32732. https://doi.org/10.1074/jbc.M302123200

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Maccarrone M, Valensise H, Bari M et al (2001) Progesterone up-regulates anandamide hydrolase in human lymphocytes: role of cytokines and implications for fertility. J Immunol 166:7183–7189

    CAS  Article  Google Scholar 

  75. 75.

    Bambang KN, Lambert DG, Lam PMW et al (2012) Immunity and early pregnancy events: are endocannabinoids the missing link? J Reprod Immunol 96:8–18. https://doi.org/10.1016/j.jri.2012.10.003

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Psychoyos D, Vinod KY (2013) Marijuana, Spice “herbal high”, and early neural development: implications for rescheduling and legalization. Drug Test Anal 5:27–45. https://doi.org/10.1002/dta.1390

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Psychoyos D, Vinod KY, Cao J et al (2012) Cannabinoid receptor 1 signaling in embryo neurodevelopment. Birth Defects Res B Dev Reprod Toxicol 95:137–150. https://doi.org/10.1002/bdrb.20348

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Oh H-A, Kwon S, Choi S et al (2013) Uncovering a role for endocannabinoid signaling in autophagy in preimplantation mouse embryos. Mol Hum Reprod 19:93–101. https://doi.org/10.1093/molehr/gas049

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Veenstra van Nieuwenhoven AL, Heineman MJ, Faas MM (2003) The immunology of successful pregnancy. Hum Reprod Update 9:347–357

    CAS  Article  Google Scholar 

  80. 80.

    Tafuri A, Alferink J, Möller P et al (1995) T cell awareness of paternal alloantigens during pregnancy. Science 270:630–633

    CAS  Article  Google Scholar 

  81. 81.

    Trundley A, Moffett A (2004) Human uterine leukocytes and pregnancy. Tissue Antigens 63:1–12

    CAS  Article  Google Scholar 

  82. 82.

    Luppi P, Haluszczak C, Trucco M, Deloia JA (2002) Normal pregnancy is associated with peripheral leukocyte activation. Am J Reprod Immunol 47:72–81

    CAS  Article  Google Scholar 

  83. 83.

    Luppi P, Haluszczak C, Betters D et al (2002) Monocytes are progressively activated in the circulation of pregnant women. J Leukoc Biol 72:874–884

    CAS  PubMed  Google Scholar 

  84. 84.

    Ueda Y, Hagihara M, Okamoto A et al (2003) Frequencies of dendritic cells (myeloid DC and plasmacytoid DC) and their ratio reduced in pregnant women: comparison with umbilical cord blood and normal healthy adults. Hum Immunol 64:1144–1151

    Article  Google Scholar 

  85. 85.

    Shi Y, Ling B, Zhou Y et al (2007) Interferon-gamma expression in natural killer cells and natural killer T cells is suppressed in early pregnancy. Cell Mol Immunol 4:389–394

    CAS  PubMed  Google Scholar 

  86. 86.

    Harbison RD, Mantilla-Plata B (1972) Prenatal toxicity, maternal distribution and placental transfer of tetrahydrocannabinol. J Pharmacol Exp Ther 180:446–453

    CAS  PubMed  Google Scholar 

  87. 87.

    Vardaris RM, Weisz DJ, Fazel A, Rawitch AB (1976) Chronic administration of delta-9-tetrahydrocannabinol to pregnant rats: studies of pup behavior and placental transfer. Pharmacol Biochem Behav 4:249–254

    CAS  Article  Google Scholar 

  88. 88.

    Blackard C, Tennes K (1984) Human placental transfer of cannabinoids. N Engl J Med 311:797. https://doi.org/10.1056/NEJM198409203111213

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Bailey JR, Cunny HC, Paule MG, Slikker W (1987) Fetal disposition of delta 9-tetrahydrocannabinol (THC) during late pregnancy in the rhesus monkey. Toxicol Appl Pharmacol 90:315–321

    CAS  Article  Google Scholar 

  90. 90.

    El Marroun H, Tiemeier H, Steegers EAP et al (2009) Intrauterine cannabis exposure affects fetal growth trajectories: the Generation R Study. J Am Acad Child Adolesc Psychiatry 48:1173–1181. https://doi.org/10.1097/CHI.0b013e3181bfa8ee

    Article  PubMed  Google Scholar 

  91. 91.

    Hurd YL, Wang X, Anderson V et al (2005) Marijuana impairs growth in mid-gestation fetuses. Neurotoxicol Teratol 27:221–229. https://doi.org/10.1016/j.ntt.2004.11.002

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Murphy LL, Gher J, Szary A (1995) Effects of prenatal exposure to delta-9-tetrahydrocannabinol on reproductive, endocrine and immune parameters of male and female rat offspring. Endocrine 3:875–879. https://doi.org/10.1007/BF02738892

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Cabral GA, Rogers TJ, Lichtman AH (2015) Turning over a new leaf: cannabinoid and endocannabinoid modulation of immune function. J Neuroimmune Pharmacol 10:193–203. https://doi.org/10.1007/s11481-015-9615-z

    Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Roth MD, Baldwin GC, Tashkin DP (2002) Effects of delta-9-tetrahydrocannabinol on human immune function and host defense. Chem Phys Lipids 121:229–239

    CAS  Article  Google Scholar 

  95. 95.

    Kaminski NE (1996) Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression. Biochem Pharmacol 52:1133–1140

    CAS  Article  Google Scholar 

  96. 96.

    Klein TW, Newton C, Larsen K et al (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74:486–496. https://doi.org/10.1189/jlb.0303101

    CAS  Article  PubMed  Google Scholar 

  97. 97.

    Galiègue S, Mary S, Marchand J et al (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61

    Article  Google Scholar 

  98. 98.

    Howlett AC, Bidaut-Russell M, Devane WA et al (1990) The cannabinoid receptor: biochemical, anatomical and behavioral characterization. Trends Neurosci 13:420–423

    CAS  Article  Google Scholar 

  99. 99.

    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65. https://doi.org/10.1038/365061a0

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Kenney SP, Kekuda R, Prasad PD et al (1999) Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta. Am J Obstet Gynecol 181:491–497

    CAS  Article  Google Scholar 

  101. 101.

    Dennedy MC, Friel AM, Houlihan DD et al (2004) Cannabinoids and the human uterus during pregnancy. Am J Obstet Gynecol 190:2–9. https://doi.org/10.1016/j.ajog.2003.07.013

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Das SK, Paria BC, Chakraborty I, Dey SK (1995) Cannabinoid ligand-receptor signaling in the mouse uterus. Proc Natl Acad Sci USA 92:4332–4336

    CAS  Article  Google Scholar 

  103. 103.

    El-Talatini MR, Taylor AH, Elson JC et al (2009) Localisation and function of the endocannabinoid system in the human ovary. PLoS One 4:e4579. https://doi.org/10.1371/journal.pone.0004579

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Piccinni MP, Beloni L, Livi C et al (1998) Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med 4:1020–1024. https://doi.org/10.1038/2006

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Piccinni MP, Romagnani S (1996) Regulation of fetal allograft survival by a hormone-controlled Th1- and Th2-type cytokines. Immunol Res 15:141–150

    CAS  Article  Google Scholar 

  106. 106.

    Wolfson ML, Muzzio DO, Ehrhardt J et al (2016) Expression analysis of cannabinoid receptors 1 and 2 in B cells during pregnancy and their role on cytokine production. J Reprod Immunol 116:23–27. https://doi.org/10.1016/j.jri.2016.05.001

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    del Arco I, Muñoz R, Rodríguez De Fonseca F et al (2000) Maternal exposure to the synthetic cannabinoid HU-210: effects on the endocrine and immune systems of the adult male offspring. Neuroimmunomodulation 7:16–26

    CAS  Article  Google Scholar 

  108. 108.

    Lombard C, Hegde VL, Nagarkatti M, Nagarkatti PS (2011) Perinatal exposure to Delta9-tetrahydrocannabinol triggers profound defects in T cell differentiation and function in fetal and postnatal stages of life, including decreased responsiveness to HIV antigens. J Pharmacol Exp Ther 339:607–617. https://doi.org/10.1124/jpet.111.181206

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Miller JM, Goodridge C (2000) Antenatal marijuana use is unrelated to sexually transmitted infections during pregnancy. Infect Dis Obstet Gynecol 8:155–157. https://doi.org/10.1155/S106474490000020X

    Article  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Tindall B, Cooper DA, Donovan B et al (1988) The Sydney AIDS Project: development of acquired immunodeficiency syndrome in a group of HIV seropositive homosexual men. Aust N Z J Med 18:8–15

    CAS  Article  Google Scholar 

  111. 111.

    Bredt BM, Higuera-Alhino D, Shade SB et al (2002) Short-term effects of cannabinoids on immune phenotype and function in HIV-1-infected patients. J Clin Pharmacol 42:82S–89S

    CAS  Article  Google Scholar 

  112. 112.

    Di Franco MJ, Sheppard HW, Hunter DJ et al (1996) The lack of association of marijuana and other recreational drugs with progression to AIDS in the San Francisco Men’s Health Study. Ann Epidemiol 6:283–289

    Article  Google Scholar 

  113. 113.

    Abrams DI, Hilton JF, Leiser RJ et al (2003) Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Ann Intern Med 139:258–266

    CAS  Article  Google Scholar 

  114. 114.

    Noe SN, Nyland SB, Ugen K et al (1998) Cannabinoid receptor agonists enhance syncytia formation in MT-2 cells infected with cell free HIV-1MN. Adv Exp Med Biol 437:223–229

    CAS  Article  Google Scholar 

  115. 115.

    Peterson PK, Gekker G, Hu S et al (2004) Cannabinoids and morphine differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures. J Neuroimmunol 147:123–126

    CAS  Article  Google Scholar 

  116. 116.

    Rock RB, Gekker G, Hu S et al (2007) WIN55,212-2-mediated inhibition of HIV-1 expression in microglial cells: involvement of cannabinoid receptors. J Neuroimmune Pharmacol 2:178–183. https://doi.org/10.1007/s11481-006-9040-4

    Article  PubMed  Google Scholar 

  117. 117.

    Roth MD, Tashkin DP, Whittaker KM et al (2005) Tetrahydrocannabinol suppresses immune function and enhances HIV replication in the huPBL-SCID mouse. Life Sci 77:1711–1722. https://doi.org/10.1016/j.lfs.2005.05.014

    CAS  Article  PubMed  Google Scholar 

  118. 118.

    Rizzo MD, Crawford RB, Henriquez JE et al (2018) HIV-infected cannabis users have lower circulating CD16+ monocytes and IFN-γ-inducible protein 10 levels compared with nonusing HIV patients. AIDS 32:419–429. https://doi.org/10.1097/QAD.0000000000001704

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Ishida JH, Peters MG, Jin C et al (2008) Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 6:69–75. https://doi.org/10.1016/j.cgh.2007.10.021

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Hézode C, Roudot-Thoraval F, Nguyen S et al (2005) Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 42:63–71. https://doi.org/10.1002/hep.20733

    CAS  Article  PubMed  Google Scholar 

  121. 121.

    Teixeira-Clerc F, Julien B, Grenard P et al (2006) CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 12:671–676. https://doi.org/10.1038/nm1421

    CAS  Article  PubMed  Google Scholar 

  122. 122.

    Lavanco G, Castelli V, Brancato A et al (2018) The endocannabinoid-alcohol crosstalk: recent advances on a bi-faceted target. Clin Exp Pharmacol Physiol. https://doi.org/10.1111/1440-1681.12967

    Article  PubMed  Google Scholar 

  123. 123.

    Karsak M, Gaffal E, Date R et al (2007) Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316:1494–1497. https://doi.org/10.1126/science.1142265

    CAS  Article  PubMed  Google Scholar 

  124. 124.

    Hegde VL, Hegde S, Cravatt BF et al (2008) Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells. Mol Pharmacol 74:20–33. https://doi.org/10.1124/mol.108.047035

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Pandey R, Hegde VL, Singh NP et al (2009) Use of cannabinoids as a novel therapeutic modality against autoimmune hepatitis. Vitam Horm 81:487–504. https://doi.org/10.1016/S0083-6729(09)81019-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Nagarkatti M, Rieder SA, Hegde VL et al (2010) Do cannabinoids have a therapeutic role in transplantation? Trends Pharmacol Sci 31:345–350. https://doi.org/10.1016/j.tips.2010.05.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Hegde VL, Nagarkatti PS, Nagarkatti M (2011) Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One 6:e18281. https://doi.org/10.1371/journal.pone.0018281

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Pandey R, Hegde VL, Nagarkatti M, Nagarkatti PS (2011) Targeting cannabinoid receptors as a novel approach in the treatment of graft-versus-host disease: evidence from an experimental murine model. J Pharmacol Exp Ther 338:819–828. https://doi.org/10.1124/jpet.111.182717

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Katchan V, David P, Shoenfeld Y (2016) Cannabinoids and autoimmune diseases: a systematic review. Autoimmun Rev 15:513–528. https://doi.org/10.1016/j.autrev.2016.02.008

    CAS  Article  PubMed  Google Scholar 

  130. 130.

    Baker D, Jackson SJ, Pryce G (2007) Cannabinoid control of neuroinflammation related to multiple sclerosis. Br J Pharmacol 152:649–654. https://doi.org/10.1038/sj.bjp.0707458

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Antonucci R, Zaffanello M, Puxeddu E et al (2012) Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn. Curr Drug Metab 13:474–490

    CAS  Article  Google Scholar 

  132. 132.

    Li D-K, Liu L, Odouli R (2003) Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 327:368. https://doi.org/10.1136/bmj.327.7411.368

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Nakhai-Pour HR, Broy P, Sheehy O, Bérard A (2011) Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 183:1713–1720. https://doi.org/10.1503/cmaj.110454

    Article  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Young IR, Thorburn GD (1994) Prostaglandin E2, fetal maturation and ovine parturition. Aust N Z J Obstet Gynaecol 34:342–346

    CAS  Article  Google Scholar 

  135. 135.

    Koren G, Florescu A, Costei AM et al (2006) Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother 40:824–829. https://doi.org/10.1345/aph.1G428

    CAS  Article  PubMed  Google Scholar 

  136. 136.

    Hahn M, Baierle M, Charão MF et al (2017) Polyphenol-rich food general and on pregnancy effects: a review. Drug Chem Toxicol 40:368–374. https://doi.org/10.1080/01480545.2016.1212365

    CAS  Article  PubMed  Google Scholar 

  137. 137.

    Zielinsky P, Piccoli AL, Vian I et al (2013) Maternal restriction of polyphenols and fetal ductal dynamics in normal pregnancy: an open clinical trial. Arq Bras Cardiol 101:217–225. https://doi.org/10.5935/abc.20130166

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Vian I, Zielinsky P, Zílio AM et al (2017) Increase of prostaglandin E2 in the reversal of ductal constriction after polyphenol restriction. Ultrasound Obstet Gynecol. https://doi.org/10.1002/uog.18974

    Article  Google Scholar 

  139. 139.

    Ammenheuser MM, Berenson AB, Babiak AE et al (1998) Frequencies of hprt mutant lymphocytes in marijuana-smoking mothers and their newborns. Mutat Res 403:55–64

    CAS  Article  Google Scholar 

  140. 140.

    Feinshtein V, Erez O, Ben-Zvi Z et al (2013) Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study. Am J Obstet Gynecol 209:573.e1–573.e15. https://doi.org/10.1016/j.ajog.2013.08.005

    CAS  Article  Google Scholar 

  141. 141.

    Robison LL, Buckley JD, Daigle AE et al (1989) Maternal drug use and risk of childhood nonlymphoblastic leukemia among offspring. An epidemiologic investigation implicating marijuana (a report from the Childrens Cancer Study Group). Cancer 63:1904–1911

    CAS  PubMed  Google Scholar 

  142. 142.

    Grufferman S, Schwartz AG, Ruymann FB, Maurer HM (1993) Parents’ use of cocaine and marijuana and increased risk of rhabdomyosarcoma in their children. Cancer Causes Control 4:217–224

    CAS  PubMed  Google Scholar 

  143. 143.

    Kuijten RR, Bunin GR, Nass CC, Meadows AT (1990) Gestational and familial risk factors for childhood astrocytoma: results of a case–control study. Cancer Res 50:2608–2612

    CAS  PubMed  Google Scholar 

  144. 144.

    Hall W, MacPhee D (2002) Cannabis use and cancer. Addiction 97:243–247

    Article  Google Scholar 

  145. 145.

    Bluhm EC, Daniels J, Pollock BH et al (2006) Maternal use of recreational drugs and neuroblastoma in offspring: a report from the Children’s Oncology Group (United States). Cancer Causes Control 17:663–669. https://doi.org/10.1007/s10552-005-0580-3

    Article  PubMed  Google Scholar 

  146. 146.

    Moeller MR, Doerr G, Warth S (1992) Simultaneous quantitation of delta-9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in serum by GC/MS using deuterated internal standards and its application to a smoking study and forensic cases. J Forensic Sci 37:969–983

    CAS  Article  Google Scholar 

  147. 147.

    Frazee CC, Kiscoan M, Garg U (2010) Quantitation of total 11-nor-9-carboxy-delta 9-tetrahydrocannabinol in urine and blood using gas chromatography-mass spectrometry (GC–MS). Methods Mol Biol 603:137–144. https://doi.org/10.1007/978-1-60761-459-3_13

    CAS  Article  PubMed  Google Scholar 

  148. 148.

    Fu S, Lewis J (2008) Novel automated extraction method for quantitative analysis of urinary 11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). J Anal Toxicol 32:292–297

    CAS  Article  Google Scholar 

  149. 149.

    Wall ME, Perez-Reyes M (1981) The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol 21:178S–189S

    CAS  Article  Google Scholar 

  150. 150.

    Huestis MA (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4:1770–1804. https://doi.org/10.1002/cbdv.200790152

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Schwilke EW, Schwope DM, Karschner EL et al (2009) Delta9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC. Clin Chem 55:2180–2189. https://doi.org/10.1373/clinchem.2008.122119

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev 46:86–95. https://doi.org/10.3109/03602532.2013.849268

    CAS  Article  PubMed  Google Scholar 

  153. 153.

    Sharma P, Murthy P, Bharath MMS (2012) Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry 7:149–156

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    de Mantovani C, Silva JPE, Forster G et al (2018) Simultaneous accelerated solvent extraction and hydrolysis of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in meconium samples for gas chromatography-mass spectrometry analysis. J Chromatogr B Analyt Technol Biomed Life Sci 1074–1075:1–7. https://doi.org/10.1016/j.jchromb.2018.01.009

    CAS  Article  PubMed  Google Scholar 

  155. 155.

    Koch M, Dehghani F, Habazettl I et al (2006) Cannabinoids attenuate norepinephrine-induced melatonin biosynthesis in the rat pineal gland by reducing arylalkylamine N-acetyltransferase activity without involvement of cannabinoid receptors. J Neurochem 98:267–278. https://doi.org/10.1111/j.1471-4159.2006.03873.x

    CAS  Article  PubMed  Google Scholar 

  156. 156.

    Burstein SH, Audette CA, Doyle SA et al (1989) Antagonism to the actions of platelet activating factor by a nonpsychoactive cannabinoid. J Pharmacol Exp Ther 251:531–535

    CAS  PubMed  Google Scholar 

  157. 157.

    Tius MA, Kannangara GSK, Kerr MA, Grace KJS (1993) Halogenated cannabinoid synthesis. Tetrahedron 49:3291–3304. https://doi.org/10.1016/S0040-4020(01)90158-9

    CAS  Article  Google Scholar 

  158. 158.

    Turcotte C, Chouinard F, Lefebvre JS, Flamand N (2015) Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol 97:1049–1070. https://doi.org/10.1189/jlb.3RU0115-021R

    CAS  Article  PubMed  Google Scholar 

  159. 159.

    Stebulis JA, Johnson DR, Rossetti RG et al (2008) Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells. Life Sci 83:666–670. https://doi.org/10.1016/j.lfs.2008.09.004

    CAS  Article  PubMed  Google Scholar 

  160. 160.

    Zurier RB, Sun Y-P, George KL et al (2009) Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A4. FASEB J 23:1503–1509. https://doi.org/10.1096/fj.08-118323

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Takeda S, Jiang R, Aramaki H et al (2011) Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors. J Pharm Sci 100:1206–1211. https://doi.org/10.1002/jps.22354

    CAS  Article  PubMed  Google Scholar 

  162. 162.

    Harvey D (1991) Metabolism and pharmacokinetics of the cannabinoids. In: Watson RR (ed) Biochemistry and physiology of substance abuse. CRC Press, Boca Raton, pp 279–365

    Google Scholar 

  163. 163.

    Ujváry I, Hanuš L (2016) Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 1:90–101. https://doi.org/10.1089/can.2015.0012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Mechoulam R, Tchilibon S et al (2010) United States Patent: 7759526—pharmaceutical compositions comprising cannabidiol derivatives. http://patft.uspto.gov. Accessed 5 Oct 2018

  165. 165.

    Chimalakonda KC, Seely KA, Bratton SM et al (2012) Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos 40:2174–2184. https://doi.org/10.1124/dmd.112.047530

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. 166.

    ElSohly MA, Gul W, Elsohly KM et al (2011) Liquid chromatography-tandem mass spectrometry analysis of urine specimens for K2 (JWH-018) metabolites. J Anal Toxicol 35:487–495

    CAS  Article  Google Scholar 

  167. 167.

    Brents LK, Reichard EE, Zimmerman SM et al (2011) Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One 6:e21917. https://doi.org/10.1371/journal.pone.0021917

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Fantegrossi WE, Moran JH, Radominska-Pandya A, Prather PL (2014) Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity? Life Sci 97:45–54. https://doi.org/10.1016/j.lfs.2013.09.017

    CAS  Article  PubMed  Google Scholar 

  169. 169.

    Tai S, Fantegrossi WE (2017) Pharmacological and toxicological effects of synthetic cannabinoids and their metabolites. Curr Top Behav Neurosci 32:249–262. https://doi.org/10.1007/7854_2016_60

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Rajasekaran M, Brents LK, Franks LN et al (2013) Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. Toxicol Appl Pharmacol 269:100–108. https://doi.org/10.1016/j.taap.2013.03.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Bird A (2007) Perceptions of epigenetics. Nature 447:396–398. https://doi.org/10.1038/nature05913

    CAS  Article  PubMed  Google Scholar 

  172. 172.

    Martin C, Zhang Y (2007) Mechanisms of epigenetic inheritance. Curr Opin Cell Biol 19:266–272. https://doi.org/10.1016/j.ceb.2007.04.002

    CAS  Article  PubMed  Google Scholar 

  173. 173.

    Szutorisz H, Hurd YL (2016) Epigenetic effects of cannabis exposure. Biol Psychiatry 79:586–594. https://doi.org/10.1016/j.biopsych.2015.09.014

    CAS  Article  PubMed  Google Scholar 

  174. 174.

    Zumbrun EE, Sido JM, Nagarkatti PS, Nagarkatti M (2015) Epigenetic regulation of immunological alterations following prenatal exposure to marijuana cannabinoids and its long term consequences in offspring. J Neuroimmune Pharmacol 10:245–254. https://doi.org/10.1007/s11481-015-9586-0

    Article  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Hegde VL, Tomar S, Jackson A et al (2013) Distinct MicroRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Δ9-tetrahydrocannabinol in vivo regulation of CCAAT/enhancer-binding protein α by microRNA-690. J Biol Chem 288:36810–36826

    CAS  Article  Google Scholar 

  176. 176.

    Yang X, Hegde VL, Rao R et al (2014) Histone modifications are associated with Delta(9)-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses. J Biol Chem 289:18707–18718. https://doi.org/10.1074/jbc.M113.545210

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Szutorisz H, Hurd YL (2018) High times for cannabis: epigenetic imprint and its legacy on brain and behavior. Neurosci Biobehav Rev 85:93–101. https://doi.org/10.1016/j.neubiorev.2017.05.011

    CAS  Article  PubMed  Google Scholar 

  178. 178.

    Möhnle P, Schütz SV, Schmidt M et al (2014) MicroRNA-665 is involved in the regulation of the expression of the cardioprotective cannabinoid receptor CB2 in patients with severe heart failure. Biochem Biophys Res Commun 451:516–521. https://doi.org/10.1016/j.bbrc.2014.08.008

    CAS  Article  PubMed  Google Scholar 

  179. 179.

    Chandra LC, Kumar V, Torben W et al (2014) Chronic administration of Δ9-tetrahydrocannabinol induces intestinal anti-inflammatory microRNA expression during acute SIV infection of rhesus macaques. J Virol 89:1168–1181. https://doi.org/10.1128/JVI.01754-14

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Tomasiewicz HC, Jacobs MM, Wilkinson MB et al (2012) Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability. Biol Psychiatry 72:803–810. https://doi.org/10.1016/j.biopsych.2012.04.026

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Rotter A, Bayerlein K, Hansbauer M et al (2013) CB1 and CB2 receptor expression and promoter methylation in patients with cannabis dependence. Eur Addict Res 19:13–20. https://doi.org/10.1159/000338642

    Article  PubMed  Google Scholar 

  182. 182.

    Hegde VL, Nagarkatti M, Nagarkatti PS (2010) Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol 40:3358–3371. https://doi.org/10.1002/eji.201040667

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Bronte V (2009) Myeloid-derived suppressor cells in inflammation: uncovering cell subsets with enhanced immunosuppressive functions. Eur J Immunol 39:2670–2672. https://doi.org/10.1002/eji.200939892

    CAS  Article  PubMed  Google Scholar 

  184. 184.

    Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174. https://doi.org/10.1038/nri2506

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Mecha M, Feliú A, Machín I et al (2018) 2-AG limits Theiler’s virus induced acute neuroinflammation by modulating microglia and promoting MDSCs. Glia 66:1447–1463. https://doi.org/10.1002/glia.23317

    Article  PubMed  Google Scholar 

  186. 186.

    Jackson AR, Nagarkatti P, Nagarkatti M (2014) Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction. PLoS One 9:e93954. https://doi.org/10.1371/journal.pone.0093954

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Perera F, Herbstman J (2011) Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol 31:363–373. https://doi.org/10.1016/j.reprotox.2010.12.055

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Thompson RF, Einstein FH (2010) Epigenetic basis for fetal origins of age-related disease. J Womens Health (Larchmt) 19:581–587. https://doi.org/10.1089/jwh.2009.1408

    Article  Google Scholar 

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Acknowledgements

Catherine Dong and Amy Harrington received the Magellan Fellowships from the University of South Carolina. The authors’ research on cannabinoids was supported by the US National Institutes of Health (Grants DA034892 to VLH and DA020531 to KYV).

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Correspondence to Venkatesh L. Hegde.

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Dong, C., Chen, J., Harrington, A. et al. Cannabinoid exposure during pregnancy and its impact on immune function. Cell. Mol. Life Sci. 76, 729–743 (2019). https://doi.org/10.1007/s00018-018-2955-0

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Keywords

  • Fetus
  • Immune system
  • Marijuana
  • Metabolites
  • Neurological
  • Pregnancy
  • Perinatal
  • Prenatal
  • Substance abuse