Molecular Targets of Cannabidiol warn against its consumption during pregnancy

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Emily Anne Bates, PhD Won Chan Oh


People use cannabidiol (CBD), the primary non-psychoactive cannabinoid of cannabis, as a treatment for symptoms that are commonly associated with pregnancy including nausea, pain, and anxiety. Many people believe CBD is safe to take during pregnancy. However, CBD crosses the placenta and affects the activity of protein targets that are expressed in the fetal brain. Cannabidiol alters the activity of ion channels including voltage-gated sodium, potassium, and calcium channels that control the electrical activity of neurons. Abnormal electrical activity could disrupt brain function via changes in axon growth and synapse structure and function. Furthermore, CBD alters the activity of G-protein coupled receptors that are expressed in the fetal brain and are important for axon growth and guidance suggesting that fetal exposure could prevent axons from reaching their correct targets. Indeed, cannabidiol exposure reduces axon growth in vitro and in vivo. This raises the possibility that CBD consumption during pregnancy could disrupt fetal brain development. Recent studies show that oral cannabidiol consumption during pregnancy alters the excitability of the pyramidal neurons of the prefrontal cortex and affects postnatal cognitive function in mouse offspring. Furthermore, fetal CBD exposure increases thermal pain sensitivity in offspring. Gestational cannabidiol exposure affects compulsivity and memory in a different rodent model. Here, we discuss how CBD affects various ion channels and G-protein coupled receptors, the roles of these proteins in neurodevelopment, and evidence that CBD affects brain development.

Keywords: Cannabidiol, pregnancy, Cannabidiol warn

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How to Cite
BATES, Emily Anne; OH, Won Chan. Molecular Targets of Cannabidiol warn against its consumption during pregnancy. Medical Research Archives, [S.l.], v. 12, n. 5, june 2024. ISSN 2375-1924. Available at: <>. Date accessed: 19 june 2024. doi:
Review Articles


1. Crume TL JA, Brooks-Russell A, Hall KE, Wymore E, Borgelt LM.. Use During the Perinatal Period in a State with Legalized Recreational and Medical Marijuana: The Association Between Maternal Characteristics, Breastfeeding Patterns, and Neonatal Outcomes. Cannabis J Pediatr. 2018;197:90-96.

2. Young-Wolff KC, Tucker LY, Alexeeff S, Armstrong MA, Conway A, Weisner C, et al. Trends in Self-reported and Biochemically Tested Marijuana Use Among Pregnant Females in California From 2009-2016. JAMA. 2017;318(24):2490-1.

3. Ko JY, Coy, K. C., Haight, S. C., Haegerich, T. M., Williams, L., Cox, S., Njai, R., & Grant, A. M. . Characteristics of Marijuana Use During Pregnancy - Eight States, Pregnancy Risk Assessment Monitoring System. Morbidity and Mortality Weekly Report. 2020(69(32), 1058–1063.).

4. Dickson B, Mansfield, C., Guiahi, M., Allshouse, A.A., Borgelt, L.M., Sheeder, J., Silver, R.M., Metz, T.D., Recommendations From Cannabis Dispensaries About First-Trimester Cannabis Use. Obstetrics & Gynecology. 2018;131, 1031–1038.

5. Westfall RE, Patricia A. Janssen, Philippe Lucas, Rielle Capler, https://Doi.Org/10.1016/j.Ctcp.2009.07.001. Reprint of: Survey of Medicinal Cannabis Use among Childbearing Women: Patterns of Its Use in Pregnancy and Retroactive Self-Assessment of Its Efficacy against ‘Morning Sickness’. Complementary Therapies in Clinical Practice. 2009;15: 4:Pages 242-6.

6. Project TC. [Available from:

7. Ochiai W KS, Kawamura T, Hatogai J, Harada S, Iizuka M, Ariumi M, Takano S, Nagai T, Sasatsu M, Sugiyama K. Maternal and Fetal Pharmacokinetic Analysis of Cannabidiol during Pregnancy in Mice. Drug Metab Dispos. 2021(49(4):337-343.).

8. Anand U, Jones B, Korchev Y, Bloom SR, Pacchetti B, Anand P, et al. CBD Effects on TRPV1 Signaling Pathways in Cultured DRG Neurons. J Pain Res. 2020;13:2269-78.

9. Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol. 2004;143(2):247-50.

10. Muller C, Reggio PH. An Analysis of the Putative CBD Binding Site in the Ionotropic Cannabinoid Receptors. Front Cell Neurosci. 2020;14:615811.

11. Chiocchetti R, Salamanca G, De Silva M, Gobbo F, Aspidi F, Cunha RZ, et al. Cannabinoid receptors in the inflammatory cells of canine atopic dermatitis. Front Vet Sci. 2022;9:987132.

12. Davila EM, Patricio F, Rebolledo-Bustillo M, Garcia-Gomez D, Hernandez JCG, Sanchez-Gaytan BL, et al. Interacting binding insights and conformational consequences of the differential activity of cannabidiol with two endocannabinoid-activated G-protein-coupled receptors. Front Pharmacol. 2022;13:945935.

13. Galiazzo G, De Silva M, Giancola F, Rinnovati R, Peli A, Chiocchetti R. Cellular distribution of cannabinoid-related receptors TRPV1, PPAR-gamma, GPR55 and GPR3 in the equine cervical dorsal root ganglia. Equine Vet J. 2021;54(4):788-98.

14. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037-43.

15. Esposito G SC, Valenza M, Togna GI, Latina V, De Filippis D, Cipriano M, Carratù MR, Iuvone T, Steardo L. . Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One. 2011;6(12):e28668.

16. O'Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol. 2009;612(1-3):61-8.

17. Vuckovic S, Srebro D, Vujovic KS, Vucetic C, Prostran M. Cannabinoids and Pain: New Insights From Old Molecules. Front Pharmacol. 2018;9:1259.

18. Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O'Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol. 2019;85(9):1888-900.

19. Millar SA, Stone NL, Yates AS, O'Sullivan SE. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front Pharmacol. 2018;9:1365.

20. Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2020;16(1):9-29.

21. Black T, Baccetto SL, Barnard IL, Finch E, McElroy DL, Austin-Scott FVL, et al. Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatal Cannabis smoke exposure. Sci Rep. 2023;13(1):21070.

22. Swenson KS, Gomez Wulschner LE, Hoelscher VM, Folts L, Korth KM, Oh WC, et al. Fetal cannabidiol (CBD) exposure alters thermal pain sensitivity, problem-solving, and prefrontal cortex excitability. Mol Psychiatry. 2023.

23. Wanner NM, Colwell M, Drown C, Faulk C. Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice. Clin Epigenetics. 2021;13(1):4.

24. Muller C, Morales P, Reggio PH. Cannabinoid Ligands Targeting TRP Channels. Front Mol Neurosci. 2018;11:487.

25. De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479-94.

26. De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, et al. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther. 2008;325(3):1007-15.

27. Funakoshi K, Nakano M, Atobe Y, Goris RC, Kadota T, Yazama F. Differential development of TRPV1-expressing sensory nerves in peripheral organs. Cell Tissue Res. 2006;323(1):27-41.

28. Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, et al. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron. 2016;89(1):37-53.

29. Nakazawa Y, Donaldson PJ, Petrova RS. Verification and spatial mapping of TRPV1 and TRPV4 expression in the embryonic and adult mouse lens. Exp Eye Res. 2019;186:107707.

30. Hutson MR, Keyte AL, Hernandez-Morales M, Gibbs E, Kupchinsky ZA, Argyridis I, et al. Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects. Sci Signal. 2017;10(500).

31. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O'Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34(36) :11929-47.

32. Mora-Jimenez L, Valencia M, Sanchez-Carpintero R, Tonnesen J, Fadila S, Rubinstein M, et al. Transfer of SCN1A to the brain of adolescent mouse model of Dravet syndrome improves epileptic, motor, and behavioral manifestations. Mol Ther Nucleic Acids. 2021;25:585-602.

33. Ding J, Li X, Tian H, Wang L, Guo B, Wang Y, et al. SCN1A Mutation-Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis. Front Neurol. 2021;12:743726.

34. Ding J, Wang L, Jin Z, Qiang Y, Li W, Wang Y, et al. Do All Roads Lead to Rome? Genes Causing Dravet Syndrome and Dravet Syndrome-Like Phenotypes. Front Neurol. 2022;13:832380.

35. Powers RM, Daza R, Koehler AE, Courchet J, Calabrese B, Hevner RF, et al. Growth cone macropinocytosis of neurotrophin receptor and neuritogenesis are regulated by neuron navigator 1. Mol Biol Cell. 2022;33(7):ar64.

36. Powers RM, Hevner RF, Halpain S. The Neuron Navigators: Structure, function, and evolutionary history. Front Mol Neurosci. 2022;15:1099554.

37. Ghovanloo MR, Choudhury K, Bandaru TS, Fouda MA, Rayani K, Rusinova R, et al. Cannabidiol inhibits the skeletal muscle Nav1.4 by blocking its pore and by altering membrane elasticity. J Gen Physiol. 2021;153(5).

38. Ghovanloo MR, Shuart NG, Mezeyova J, Dean RA, Ruben PC, Goodchild SJ. Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2018;293(43): 16546-58.

39. Huang CW, Lin PC, Chen JL, Lee MJ. Cannabidiol Selectively Binds to the Voltage-Gated Sodium Channel Na(v)1.4 in Its Slow-Inactivated State and Inhibits Sodium Current. Biomedicines. 2021;9(9).

40. Huang J, Fan X, Jin X, Jo S, Zhang HB, Fujita A, et al. Cannabidiol inhibits Na(v) channels through two distinct binding sites. Nat Commun. 2023;14(1):3613.

41. Le Marois M, Ballet V, Sanson C, Maizieres MA, Carriot T, Chantoiseau C, et al. Cannabidiol inhibits multiple cardiac ion channels and shortens ventricular action potential duration in vitro. Eur J Pharmacol. 2020;886:173542.

42. Liang L, Fazel Darbandi S, Pochareddy S, Gulden FO, Gilson MC, Sheppard BK, et al. Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain. Genome Med. 2021;13(1):135.

43. Ogiwara I, Miyamoto H, Tatsukawa T, Yamagata T, Nakayama T, Atapour N, et al. Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice. Commun Biol. 2018;1:96.

44. Wang T, Wang J, Ma Y, Zhou H, Ding D, Li C, et al. High genetic burden in 163 Chinese children with status epilepticus. Seizure. 2021;84:40-6.

45. Mason ER, Cummins TR. Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967. Int J Mol Sci. 2020;21(7).

46. Brysch W, Creutzfeldt OD, Luno K, Schlingensiepen R, Schlingensiepen KH. Regional and temporal expression of sodium channel messenger RNAs in the rat brain during development. Exp Brain Res. 1991;86(3):562-7.

47. Smith RS, Kenny CJ, Ganesh V, Jang A, Borges-Monroy R, Partlow JN, et al. Sodium Channel SCN3A (Na(V)1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development. Neuron. 2018;99(5):905 -13 e7.

48. Loussouarn G, Sternberg D, Nicole S, Marionneau C, Le Bouffant F, Toumaniantz G, et al. Physiological and Pathophysiological Insights of Nav1.4 and Nav1.5 Comparison. Front Pharmacol. 2015;6:314.

49. Wang J, Ou SW, Zhang ZY, Qiu B, Wang YJ. Molecular expression of multiple Nav1.5 splice variants in the frontal lobe of the human brain. Int J Mol Med. 2018;41(2):915-23.

50. Rook MB, Evers MM, Vos MA, Bierhuizen MF. Biology of cardiac sodium channel Nav1.5 expression. Cardiovasc Res. 2012;93(1):12-23.

51. Patel RR, Barbosa C, Brustovetsky T, Brustovetsky N, Cummins TR. Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain. 2016;139(Pt 8):2164-81.

52. Fukuoka T, Noguchi K. Comparative study of voltage-gated sodium channel alpha-subunits in non-overlapping four neuronal populations in the rat dorsal root ganglion. Neurosci Res. 2011;70(2):164-71.

53. Kamijo S, Ishii Y, Horigane SI, Suzuki K, Ohkura M, Nakai J, et al. A Critical Neurodevelopmental Role for L-Type Voltage-Gated Calcium Channels in Neurite Extension and Radial Migration. J Neurosci. 2018;38(24):5551-66.

54. Menghini R, Menini S, Amoruso R, Fiorentino L, Casagrande V, Marzano V, et al. Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice. Gastroenterology. 2009;136(2):663-72 e4.

55. Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J Biol Chem. 2008;283(23):16124-34.

56. Harding EK, Souza IA, Gandini MA, Gadotti VM, Ali MY, Huang S, et al. Differential regulation of Ca(v) 3.2 and Ca(v) 2.2 calcium channels by CB(1) receptors and cannabidiol. Br J Pharmacol. 2023;180(12):16 16-33.

57. Zemel BM, Ritter DM, Covarrubias M, Muqeem T. A-Type K(V) Channels in Dorsal Root Ganglion Neurons: Diversity, Function, and Dysfunction. Front Mol Neurosci. 2018;11:253.

58. Jepps TA, Barrese V, Miceli F. Editorial: Kv7 Channels: Structure, Physiology, and Pharmacology. Front Physiol. 2021;12:679317.

59. Zhang HB, Heckman L, Niday Z, Jo S, Fujita A, Shim J, et al. Cannabidiol activates neuronal Kv7 channels. Elife. 2022;11.

60. Zhan X, Drummond-Main C, Greening D, Yao J, Chen SWR, Appendino JP, et al. Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant. iScience. 2022;25(10):105092.

61. Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP. hERG K(+) channels: structure, function, and clinical significance. Physiol Rev. 2012;92(3):1393-478.

62. Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, et al. Modulation of glycine receptor function by the synthetic cannabinoid HU210. Pharmacology. 2009;83( 5):270-4.

63. Beyer C, Roberts LA, Komisaruk BR. Hyperalgesia induced by altered glycinergic activity at the spinal cord. Life Sci. 1985;37 (9):875-82.

64. Choi KH, Nakamura M, Jang IS. Presynaptic glycine receptors increase GABAergic neurotransmission in rat periaqueductal gray neurons. Neural Plast. 2013;2013:954302.

65. Foadi N, Leuwer M, Demir R, Dengler R, Buchholz V, de la Roche J, et al. Lack of positive allosteric modulation of mutated alpha(1)S267I glycine receptors by cannabinoids. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(5):477-82.

66. Gradwell MA, Boyle KA, Callister RJ, Hughes DI, Graham BA. Heteromeric alpha/beta glycine receptors regulate excitability in parvalbumin-expressing dorsal horn neurons through phasic and tonic glycinergic inhibition. J Physiol. 2017;595 (23):7185-202.

67. Jeong HJ, Jang IS, Moorhouse AJ, Akaike N. Activation of presynaptic glycine receptors facilitates glycine release from presynaptic terminals synapsing onto rat spinal sacral dorsal commissural nucleus neurons. J Physiol. 2003;550(Pt 2):373-83.

68. Liu Y, Huang D, Wen R, Chen X, Yi H. Glycine receptor-mediated inhibition of medial prefrontal cortical pyramidal cells. Biochem Biophys Res Commun. 2015; 456(2):666-9.

69. McCracken LM, Lowes DC, Salling MC, Carreau-Vollmer C, Odean NN, Blednov YA, et al. Glycine receptor alpha3 and alpha2 subunits mediate tonic and exogenous agonist-induced currents in forebrain. Proc Natl Acad Sci U S A. 2017;114(34):E7179-E86.

70. Salling MC, Harrison NL. Strychnine-sensitive glycine receptors on pyramidal neurons in layers II/III of the mouse prefrontal cortex are tonically activated. J Neurophysiol. 2014;112(5):1169-78.

71. Turecek R, Trussell LO. Presynaptic glycine receptors enhance transmitter release at a mammalian central synapse. Nature. 2001;411(6837):587-90.

72. Zou G, Zuo X, Chen K, Ge Y, Wang X, Xu G, et al. Cannabinoids Rescue Cocaine-Induced Seizures by Restoring Brain Glycine Receptor Dysfunction. Cell Rep. 2020;30 (12):4209-19 e7.

73. Watanabe E, Akagi H. Distribution patterns of mRNAs encoding glycine receptor channels in the developing rat spinal cord. Neurosci Res. 1995;23(4):377-82.

74. Thompson AJ, Lummis SC. 5-HT3 receptors. Curr Pharm Des. 2006;12(28):3615-30.

75. Yang KH, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J Pharmacol Exp Ther. 2010;333(2):547-54.

76. Oz M, Yang KS, Mahgoub MO. Effects of cannabinoids on ligand-gated ion channels. Front Physiol. 2022;13:1041833.

77. Koyama Y, Kondo M, Shimada S. Building a 5-HT3A Receptor Expression Map in the Mouse Brain. Sci Rep. 2017;7:42884.

78. Lee S, Hjerling-Leffler J, Zagha E, Fishell G, Rudy B. The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J Neurosci. 2010;30(50):16796-808.

79. Rosenbaum T, Islas LD. Molecular Physiology of TRPV Channels: Controversies and Future Challenges. Annu Rev Physiol. 2023;85:293-316.

80. Huffer KE, Aleksandrova AA, Jara-Oseguera A, Forrest LR, Swartz KJ. Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms. Elife. 2020;9.

81. Shibasaki K, Murayama N, Ono K, Ishizaki Y, Tominaga M. TRPV2 enhances axon outgrowth through its activation by membrane stretch in developing sensory and motor neurons. J Neurosci. 2010;30(13):4601-12.

82. Nabissi M, Morelli MB, Santoni M, Santoni G. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis. 2013;34(1):48-57.

83. Pumroy RA, Samanta A, Liu Y, Hughes TE, Zhao S, Yudin Y, et al. Molecular mechanism of TRPV2 channel modulation by cannabidiol. Elife. 2019;8.

84. Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM. TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci. 2008;28(24):6231-8.

85. Gochman A, Tan XF, Bae C, Chen H, Swartz KJ, Jara-Oseguera A. Cannabidiol sensitizes TRPV2 channels to activation by 2-APB. Elife. 2023;12.

86. Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, et al. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002;296(5575):2046-9.

87. De Petrocellis L, Orlando P, Moriello AS, Aviello G, Stott C, Izzo AA, et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf). 2012;204(2):255-66.

88. Su W, Qiao X, Wang W, He S, Liang K, Hong X. TRPV3: Structure, Diseases and Modulators. Molecules. 2023;28(2).

89. Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature. 2002;418(6894):181-6.

90. Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108(5):705-15.

91. Gouin O, L'Herondelle K, Lebonvallet N, Le Gall-Ianotto C, Sakka M, Buhe V, et al. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell. 2017;8(9):644-61.

92. Kowalski CW, Ragozzino FJ, Lindberg JEM, Peterson B, Lugo JM, McLaughlin RJ, et al. Cannabidiol activation of vagal afferent neurons requires TRPA1. J Neurophysiol. 2020;124(5):1388-98.

93. Sait LG, Sula A, Ghovanloo MR, Hollingworth D, Ruben PC, Wallace BA. Cannabidiol interactions with voltage-gated sodium channels. Elife. 2020;9.

94. Yamagata T, Ogiwara I, Tatsukawa T, Suzuki T, Otsuka Y, Imaeda N, et al. Scn1a-GFP transgenic mouse revealed Nav1.1 expression in neocortical pyramidal tract projection neurons. Elife. 2023;12.

95. Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159(1):122-8.

96. Beique JC, Campbell B, Perring P, Hamblin MW, Walker P, Mladenovic L, et al. Serotonergic regulation of membrane potential in developing rat prefrontal cortex: coordinated expression of 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 receptors. J Neurosci. 2004;24(20):4807-17.

97. Martinez-Aguirre C, Carmona-Cruz F, Velasco AL, Velasco F, Aguado-Carrillo G, Cuellar-Herrera M, et al. Cannabidiol Acts at 5-HT(1A) Receptors in the Human Brain: Relevance for Treating Temporal Lobe Epilepsy. Front Behav Neurosci. 2020; 14:611278.

98. Chen G, Staffen N, Wu Z, Xu X, Pan J, Inoue A, et al. Structural and functional characterization of the endogenous agonist for orphan receptor GPR3. Cell Res. 2024.

99. Eggerickx D, Denef JF, Labbe O, Hayashi Y, Refetoff S, Vassart G, et al. Molecular cloning of an orphan G-protein-coupled receptor that constitutively activates adenylate cyclase. Biochem J. 1995;309 ( Pt 3)(Pt 3):837-43.

100. Tanaka S, Ishii K, Kasai K, Yoon SO, Saeki Y. Neural expression of G protein-coupled receptors GPR3, GPR6, and GPR12 up-regulates cyclic AMP levels and promotes neurite outgrowth. J Biol Chem. 2007;282 (14):10506-15.

101. Tanaka S, Shimada N, Shiraki H, Miyagi T, Harada K, Hide I, et al. GPR3 accelerates neurite outgrowth and neuronal polarity formation via PI3 kinase-mediating signaling pathway in cultured primary neurons. Mol Cell Neurosci. 2022;118:103691.

102. Laun AS, Song ZH. GPR3 and GPR6, novel molecular targets for cannabidiol. Biochem Biophys Res Commun. 2017;490 (1):17-21.

103. Laun AS, Shrader SH, Brown KJ, Song ZH. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacol Sin. 2019;40(3):300-8.

104. Masuda S, Tanaka S, Shiraki H, Sotomaru Y, Harada K, Hide I, et al. GPR3 expression in retinal ganglion cells contributes to neuron survival and accelerates axonal regeneration after optic nerve crush in mice. Neurobiol Dis. 2022;172:105811.

105. Iismaa TP, Kiefer J, Liu ML, Baker E, Sutherland GR, Shine J. Isolation and chromosomal localization of a novel human G-protein-coupled receptor (GPR3) expressed predominantly in the central nervous system. Genomics. 1994;24(2):391-4.

106. Zhang B, Ding J, Li Y, Wang J, Zhao Y, Wang W, et al. The porcine Gpr3 gene: molecular cloning, characterization and expression level in tissues and cumulus-oocyte complexes during in vitro maturation. Mol Biol Rep. 2012;39(5):5831-9.

107. Ikawa F, Tanaka S, Harada K, Hide I, Maruyama H, Sakai N. Detailed neuronal distribution of GPR3 and its co-expression with EF-hand calcium-binding proteins in the mouse central nervous system. Brain Res. 2021;1750:147166.

108. Isawi IH, Morales P, Sotudeh N, Hurst DP, Lynch DL, Reggio PH. GPR6 Structural Insights: Homology Model Construction and Docking Studies. Molecules. 2020;25(3).

109. Allende G, Chavez-Reyes J, Guerrero-Alba R, Vazquez-Leon P, Marichal-Cancino BA. Advances in Neurobiology and Pharmacology of GPR12. Front Pharmacol. 2020;11:628.

110. Li H, Zhang J, Yu Y, Luo F, Wu L, Liu J, et al. Structural insight into the constitutive activity of human orphan receptor GPR12. Sci Bull (Beijing). 2023;68(1):95-104.

111. Brown KJ, Laun AS, Song ZH. Cannabidiol, a novel inverse agonist for GPR12. Biochem Biophys Res Commun. 2017;493(1):451-4.

112. Saeki Y, Ueno S, Mizuno R, Nishimura T, Fujimura H, Nagai Y, et al. Molecular cloning of a novel putative G protein-coupled receptor (GPCR21) which is expressed predominantly in mouse central nervous system. FEBS Lett. 1993;336(2):317-22.

113. Eidne KA, Zabavnik J, Peters T, Yoshida S, Anderson L, Taylor PL. Cloning, sequencing and tissue distribution of a candidate G protein-coupled receptor from rat pituitary gland. FEBS Lett. 1991;292(1-2):243-8.

114. Ignatov A, Lintzel J, Hermans-Borgmeyer I, Kreienkamp HJ, Joost P, Thomsen S, et al. Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development. J Neurosci. 2003;23(3):907-14.

115. Marichal-Cancino BA, Fajardo-Valdez A, Ruiz-Contreras AE, Mendez-Diaz M, Prospero-Garcia O. Advances in the Physiology of GPR55 in the Central Nervous System. Curr Neuropharmacol. 2017;15(5):771-8.

116. Henstridge CM, Balenga NA, Schroder R, Kargl JK, Platzer W, Martini L, et al. GPR55 ligands promote receptor coupling to multiple signalling pathways. Br J Pharmacol. 2010;160(3):604-14.

117. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A. 2008;105(7):2699-704.

118. Ryberg E, Larsson N, Sjogren S, Hjorth S, Hermansson NO, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152(7):1092-101.

119. Cherif H, Argaw A, Cecyre B, Bouchard A, Gagnon J, Javadi P, et al. Role of GPR55 during Axon Growth and Target Innervation. eNeuro. 2015;2(5).

120. Son HW, Ali DW. Endocannabinoid Receptor Expression in Early Zebrafish Development. Dev Neurosci. 2022;44(3):142-52.

121. Altieri SC, Garcia-Garcia AL, Leonardo ED, Andrews AM. Rethinking 5-HT1A receptors: emerging modes of inhibitory feedback of relevance to emotion-related behavior. ACS Chem Neurosci. 2013;4(1):72-83.

122. Albert PR, Vahid-Ansari F. The 5-HT1A receptor: Signaling to behavior. Biochimie. 2019;161:34-45.

123. Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimaraes FS. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009;156(1):181-8.

124. Hillion J, Milne-Edwards JB, Catelon J, de Vitry F, Gros F, Hamon M. Prenatal developmental expression of rat brain 5-HT1A receptor gene followed by PCR. Biochem Biophys Res Commun. 1993;191(3):991-7.

125. Patel TD, Zhou FC. Ontogeny of 5-HT1A receptor expression in the developing hippocampus. Brain Res Dev Brain Res. 2005;157(1):42-57.

126. Pompeiano M, Palacios JM, Mengod G. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci. 1992;12(2):440-53.

127. Clement Y, Kia KH, Daval G, Verge D. An autoradiographic study of serotonergic receptors in a murine genetic model of anxiety-related behaviors. Brain Res. 1996;709(2):229-42.

128. Kia HK, Brisorgueil MJ, Daval G, Langlois X, Hamon M, Verge D. Serotonin1A receptors are expressed by a subpopulation of cholinergic neurons in the rat medial septum and diagonal band of Broca--a double immunocytochemical study. Neuroscience. 1996;74(1):143-54.

129. Kia HK, Miquel MC, Brisorgueil MJ, Daval G, Riad M, El Mestikawy S, et al. Immunocytochemical localization of serotonin1A receptors in the rat central nervous system. J Comp Neurol. 1996;365(2):289-305.

130. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561-4.

131. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365 (6441):61-5.

132. Ibsen MS, Connor M, Glass M. Cannabinoid CB(1) and CB(2) Receptor Signaling and Bias. Cannabis Cannabinoid Res. 2017;2(1):48-60.

133. Ibsen MS, Finlay DB, Patel M, Javitch JA, Glass M, Grimsey NL. Cannabinoid CB1 and CB2 Receptor-Mediated Arrestin Translocation: Species, Subtype, and Agonist-Dependence. Front Pharmacol. 2019;10:350.

134. Krishna Kumar K, Robertson MJ, Thadhani E, Wang H, Suomivuori CM, Powers AS, et al. Structural basis for activation of CB1 by an endocannabinoid analog. Nat Commun. 2023;14(1):2672.

135. Galve-Roperh I, Rueda D, Gomez del Pulgar T, Velasco G, Guzman M. Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor. Mol Pharmacol. 2002;62(6):1385-92.

136. Shahbazi F, Grandi V, Banerjee A, Trant JF. Cannabinoids and Cannabinoid Receptors: The Story so Far. iScience. 2020;23(7):101301.

137. Zhang PW, Ishiguro H, Ohtsuki T, Hess J, Carillo F, Walther D, et al. Human cannabinoid receptor 1: 5' exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry. 2004;9(10):916-31.

138. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232(1):54-61.

139. Li X, Hua T, Vemuri K, Ho JH, Wu Y, Wu L, et al. Crystal Structure of the Human Cannabinoid Receptor CB2. Cell. 2019;176 (3):459-67 e13.

140. Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL. Cannabinoid Receptor 2 (CB(2)) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes. ACS Pharmacol Transl Sci. 2019;2(6):414-28.

141. Li X, Chang H, Bouma J, de Paus LV, Mukhopadhyay P, Paloczi J, et al. Structural basis of selective cannabinoid CB(2) receptor activation. Nat Commun. 2023;14(1):1447.

142. Lanciego JL, Barroso-Chinea P, Rico AJ, Conte-Perales L, Callen L, Roda E, et al. Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. J Psychopharmacol. 2011;25(1):97-104.

143. Liu QR, Pan CH, Hishimoto A, Li CY, Xi ZX, Llorente-Berzal A, et al. Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav. 2009;8(5):519-30.

144. Garcia-Gutierrez MS, Garcia-Bueno B, Zoppi S, Leza JC, Manzanares J. Chronic blockade of cannabinoid CB2 receptors induces anxiolytic-like actions associated with alterations in GABA(A) receptors. Br J Pharmacol. 2012;165(4):951-64.

145. Navarrete F, Perez-Ortiz JM, Manzanares J. Cannabinoid CB(2) receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice. Br J Pharmacol. 2012;165(1):260-73.

146. Li Y, Kim J. Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus. Neuroscience. 2015;311:253-67.

147. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310(5746):329-32.

148. Fogaca MV, Campos AC, Coelho LD, Duman RS, Guimaraes FS. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology. 2018;135:22-33.

149. Argaw A, Duff G, Zabouri N, Cecyre B, Chaine N, Cherif H, et al. Concerted action of CB1 cannabinoid receptor and deleted in colorectal cancer in axon guidance. J Neurosci. 2011;31(4):1489-99.

150. Duff G, Argaw A, Cecyre B, Cherif H, Tea N, Zabouri N, et al. Cannabinoid receptor CB2 modulates axon guidance. PLoS One. 2013;8(8):e70849.

151. Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Urban GM, et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science. 2007;316(5828):1212-6.

152. Njoo C, Agarwal N, Lutz B, Kuner R. The Cannabinoid Receptor CB1 Interacts with the WAVE1 Complex and Plays a Role in Actin Dynamics and Structural Plasticity in Neurons. PLoS Biol. 2015;13(10):e1002286.

153. Roland AB, Ricobaraza A, Carrel D, Jordan BM, Rico F, Simon A, et al. Cannabinoid-induced actomyosin contractility shapes neuronal morphology and growth. Elife. 2014;3:e03159.

154. Watson S, Chambers D, Hobbs C, Doherty P, Graham A. The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation. Mol Cell Neurosci. 2008;38(1):89-97.

155. Saez TMM, Fernandez Bessone I, Rodriguez MS, Alloatti M, Otero MG, Cromberg LE, et al. Kinesin-1-mediated axonal transport of CB1 receptors is required for cannabinoid-dependent axonal growth and guidance. Development. 2020;147(8).

156. Rani M, Kanungo MS. Expression of D2 dopamine receptor in the mouse brain. Biochem Biophys Res Commun. 2006; 344(3):981-6.

157. Seeman P. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl Psychiatry. 2016;6(10):e920.

158. Fish EW, Murdaugh LB, Zhang C, Boschen KE, Boa-Amponsem O, Mendoza-Romero HN, et al. Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction. Sci Rep. 2019;9(1):16057.

159. Parra LM, Zou Y. Sonic hedgehog induces response of commissural axons to Semaphorin repulsion during midline crossing. Nat Neurosci. 2010;13(1):29-35.

160. Lim JH, Stafford BK, Nguyen PL, Lien BV, Wang C, Zukor K, et al. Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat Neurosci. 2016;19(8):1073-84.

161. Juric DM, Bulc Rozman K, Lipnik-Stangelj M, Suput D, Brvar M. Cytotoxic Effects of Cannabidiol on Neonatal Rat Cortical Neurons and Astrocytes: Potential Danger to Brain Development. Toxins (Basel). 2022;14(10).

162. Mato S, Victoria Sanchez-Gomez M, Matute C. Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. Glia. 2010;58(14):1739-47.

163. Sun S, Hu F, Wu J, Zhang S. Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons. Redox Biol. 2017;11:577-85.

164. Yucel M, Lorenzetti V, Suo C, Zalesky A, Fornito A, Takagi MJ, et al. Hippocampal harms, protection and recovery following regular cannabis use. Transl Psychiatry. 2016;6(1):e710.

165. Volkow ND HB, Compton WM, Blanco C. . Marijuana Use During Stages of Pregnancy in the United States. Ann Intern Med. 2017;166(10):763-764.

166. Kalayasiri R, Boonthae S. Trends of cannabis use and related harms before and after legalization for recreational purpose in a developing country in Asia. BMC Public Health. 2023;23(1):911.

167. Hayatbakhsh M, Flenady, V., Gibbons, K. et al. . Birth outcomes associated with cannabis use before and during pregnancy. Pediatr Res. 2012(71):215–9.

168. Gillies R, Lee K, Vanin S, Laviolette SR, Holloway AC, Arany E, et al. Maternal exposure to Delta9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat. Reprod Toxicol. 2020;94:84-91.

169. Kim J, de Castro A, Lendoiro E, Cruz-Landeira A, Lopez-Rivadulla M, Concheiro M. Detection of in utero cannabis exposure by umbilical cord analysis. Drug Test Anal. 2018;10(4):636-43.

170. Lee K, Hardy DB. Metabolic Consequences of Gestational Cannabinoid Exposure. Int J Mol Sci. 2021;22(17).

171. Luke S, Hobbs AJ, Smith M, Riddell C, Murphy P, Agborsangaya C, et al. Cannabis use in pregnancy and maternal and infant outcomes: A Canadian cross-jurisdictional population-based cohort study. PLoS One. 2022;17(11):e0276824.

172. Corroon J, Phillips JA. A Cross-Sectional Study of Cannabidiol Users. Cannabis Cannabinoid Res. 2018;3(1):152-61.

173. Rock EM, Limebeer CL, Pertwee RG, Mechoulam R, Parker LA. Therapeutic Potential of Cannabidiol, Cannabidiolic Acid, and Cannabidiolic Acid Methyl Ester as Treatments for Nausea and Vomiting. Cannabis Cannabinoid Res. 2021;6(4):266-74.

174. Goodman S, Wadsworth E, Schauer G, Hammond D. Use and Perceptions of Cannabidiol Products in Canada and in the United States. Cannabis Cannabinoid Res. 2022;7(3):355-64.