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Cellular and Molecular Life Sciences

, Volume 76, Issue 4, pp 729–743 | Cite as

Cannabinoid exposure during pregnancy and its impact on immune function

  • Catherine Dong
  • Jingwen Chen
  • Amy Harrington
  • K. Yaragudri Vinod
  • Muralidhar L. Hegde
  • Venkatesh L. HegdeEmail author
Review

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.

Keywords

Fetus Immune system Marijuana Metabolites Neurological Pregnancy Perinatal Prenatal Substance abuse 

Notes

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).

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 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 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 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 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 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 109:90–98Google 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 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 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 18:5131–5140Google 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 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 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 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 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 ArborGoogle 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 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 Google Scholar
  21. 21.
    Bridgeman MB, Abazia DT (2017) Medicinal cannabis: history, pharmacology, and implications for the acute care setting. P T 42:180–188Google 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 5:32–40Google 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 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 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 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 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 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 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 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 48:443–450Google Scholar
  31. 31.
    Grotenhermen F (2004) Pharmacology of cannabinoids. Neuro Endocrinol Lett 25:14–23Google 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 101:374–379Google 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), RockvilleGoogle Scholar
  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 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, RockvilleGoogle 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 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 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 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 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 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 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 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 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 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 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 109:21–27Google 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 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 Google Scholar
  50. 50.
    Devane WA (1994) New dawn of cannabinoid pharmacology. Trends Pharmacol Sci 15:40–41Google Scholar
  51. 51.
    Mechoulam R, Fride E, Di Marzo V (1998) Endocannabinoids. Eur J Pharmacol 359:1–18Google 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 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 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 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) 16:498–516Google 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 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 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 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 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 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 8:188–195Google 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 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 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 94:4188–4192Google 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 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 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 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 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 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 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 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 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 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 166:7183–7189Google 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 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 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 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 Google Scholar
  79. 79.
    Veenstra van Nieuwenhoven AL, Heineman MJ, Faas MM (2003) The immunology of successful pregnancy. Hum Reprod Update 9:347–357Google Scholar
  80. 80.
    Tafuri A, Alferink J, Möller P et al (1995) T cell awareness of paternal alloantigens during pregnancy. Science 270:630–633Google Scholar
  81. 81.
    Trundley A, Moffett A (2004) Human uterine leukocytes and pregnancy. Tissue Antigens 63:1–12Google Scholar
  82. 82.
    Luppi P, Haluszczak C, Trucco M, Deloia JA (2002) Normal pregnancy is associated with peripheral leukocyte activation. Am J Reprod Immunol 47:72–81Google 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 72:874–884Google 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 64:1144–1151Google 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 4:389–394Google Scholar
  86. 86.
    Harbison RD, Mantilla-Plata B (1972) Prenatal toxicity, maternal distribution and placental transfer of tetrahydrocannabinol. J Pharmacol Exp Ther 180:446–453Google 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 4:249–254Google 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 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 90:315–321Google 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 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 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 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 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 121:229–239Google 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 52:1133–1140Google 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 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 232:54–61Google Scholar
  98. 98.
    Howlett AC, Bidaut-Russell M, Devane WA et al (1990) The cannabinoid receptor: biochemical, anatomical and behavioral characterization. Trends Neurosci 13:420–423Google 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 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 181:491–497Google 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 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 92:4332–4336Google 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 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 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 15:141–150Google 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 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 7:16–26Google 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 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 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 18:8–15Google 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–89SGoogle 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 6:283–289Google 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 139:258–266Google 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 437:223–229Google 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 147:123–126Google 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 13:474–490Google 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 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 Google Scholar
  134. 134.
    Young IR, Thorburn GD (1994) Prostaglandin E2, fetal maturation and ovine parturition. Aust N Z J Obstet Gynaecol 34:342–346Google 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 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 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 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 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 403:55–64Google 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 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 63:1904–1911Google 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 4:217–224Google 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 50:2608–2612Google Scholar
  144. 144.
    Hall W, MacPhee D (2002) Cannabis use and cancer. Addiction 97:243–247Google 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 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 37:969–983Google 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 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 32:292–297Google 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–189SGoogle Scholar
  150. 150.
    Huestis MA (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4:1770–1804.  https://doi.org/10.1002/cbdv.200790152 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 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 Google Scholar
  153. 153.
    Sharma P, Murthy P, Bharath MMS (2012) Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry 7:149–156Google 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 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 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 251:531–535Google 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 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 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 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 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 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 279–365Google 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 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 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 35:487–495Google 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 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 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 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 Google Scholar
  171. 171.
    Bird A (2007) Perceptions of epigenetics. Nature 447:396–398.  https://doi.org/10.1038/nature05913 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 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 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 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 288:36810–36826Google 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 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 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 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 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 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 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 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 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 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 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 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 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 Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.School of MedicineMedical University of South CarolinaCharlestonUSA
  2. 2.School of PharmacyMedical University of South CarolinaCharlestonUSA
  3. 3.Department of Chemistry and Biochemistry, College of Arts and SciencesUniversity of South CarolinaColumbiaUSA
  4. 4.Department of Pathology, Microbiology and Immunology, School of MedicineUniversity of South CarolinaColumbiaUSA
  5. 5.Division of Analytical PsychopharmacologyNathan Kline Institute for Psychiatric ResearchOrangeburgUSA
  6. 6.Emotional Brain InstituteOrangeburgUSA
  7. 7.Child and Adolescent PsychiatryNew York School of MedicineNew YorkUSA
  8. 8.Department of Radiation Oncology, Institute for Academic Medicine and Research InstituteThe Houston Methodist Research Institute (HMRI)HoustonUSA

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