1. Adams AJ, et al. “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N Engl J Med 2017;376:235–42.
2. Adams R. Marihuana. Science 1940;92:115–9.
3. Ashton H, et al. The seed and the soil: effect of dosage, personality and starting state on the response to delta-9-tetrahydrocannabinol in man. Br J Clin Pharmacol 1981;12:705–20.
4. Auwärter V, et al. ‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs? J Mass Spectrom 2009;44:832–7.
5. Bih CI, et al. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics 2015;12:699–730.
6. Bisogno T, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001;134:845–52.
7. Bócsa I, Mathé P, Hangyel L. Effect of nitrogen on tetrahydrocannabinol (THC) content in hemp (Cannabis sativa L.) leaves at different positions. J Int Hemp Assoc 1997;4:78–9.
8. Carroll CB, et al. Delta(9)-tetrahydrocannabinol (Delta(9)-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol Appl Neurobiol 2012;38:535–47.
9. Cascio MG, et al. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 2010;159:129–41.
10. Cohen K, Weizman A, Weinstein A. Positive and negative effects of cannabis and cannabinoids on health. Clin Pharmacol Ther 2019;105:1139–47.
11. Colizzi M, et al. Descriptive psychopathology of the acute effects of intravenous delta-9-tetrahydrocannabinol administration in humans. Brain Sci 2019;9:93.
12. Crivelaro do Nascimento G, et al. Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson’s disease. Neuropharmacology 2019;163:107808.
13. D’Souza DC, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 2004;29:1558–72.
14. de Meijer EP, et al. The inheritance of chemical phenotype in Cannabis sativa L. Genetics 2003;163:335–46.
15. de Meijer EPM, van der Kamp HJ, van Eeuwijk FA. Characterisation of cannabis accessions with regard to cannabinoid content in relation to other plant characters. Euphytica 1992;62:187–200.
16. De Petrocellis L, et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf) 2012;204:255–66.
17. De Petrocellis L, et al. Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 2011;163:1479–94.
18. De Petrocellis L, 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;325:1007–15.
19. Devane WA, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988;34:605–13.
20. Devane WA, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946–9.
21. Elmes MW, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 2015;290:8711–21.
22. ElSohly MA, et al. Phytochemistry of cannabis sativa L. Prog Chem Org Nat Prod 2017;103:1–36.
23. Esposito G, et al. Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPARgamma involvement. PLoS One 2011;6:e28668.
24. Fishbein-Kaminietsky M, Gafni M, Sarne Y. Ultralow doses of cannabinoid drugs protect the mouse brain from inflammation-induced cognitive damage. J Neurosci Res 2014;92:1669–77.
25. Galli JA, Sawaya RA, Friedenberg FK. Cannabinoid hyperemesis syndrome. Curr Drug Abuse Rev 2011;4:241–9.
26. Gaston TE, Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav 2017;70:313–8.
27. Gerard CM, et al. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 1991;279:129–34.
28. Ghovanloo MR, et al. Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem 2018;293:16546–58.
29. Gomes FV, Del Bel EA, Guimaraes FS. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. Prog Neuropsychopharmacol Biol Psychiatry 2013;46:43–7.
30. Gomes FV, Resstel LBM, Guimarães FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 2011;213:465–73.
31. Granja AG, et al. A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. J Neuroimmune Pharmacol 2012;7:1002–16.
32. Grunfeld Y, Edery H. Psychopharmacological activity of the active constituents of hashish and some related cannabinoids. Psychopharmacologia 1969;14:200–10.
33. Hejazi N, et al. Delta-9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. Mol Pharmacol 2006;69:991–7.
34. Hill AJ, et al. Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se. Neurosci Lett 2014;566:269–74.
35. Hill TD, et al. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 2013;170:679–92.
36. Hillard CJ, Harris RA, Bloom AS. Effects of the cannabinoids on physical properties of brain membranes and phospholipid vesicles: fluorescence studies. J Pharmacol Exp Ther 1985;232:579–88.
37. Hind WH, England TJ, O’Sullivan SE. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARgamma and 5-HT1A receptors. Br J Pharmacol 2016;173:815–25.
38. Hollister LE. Structure-activity relationships in man of cannabis constituents, and homologs and metabolites of Δ9-tetrahydrocannabinol. Pharmacology 1974;11:3–11.
39. Huizenga MN, Sepulveda-Rodriguez A, Forcelli PA. Preclinical safety and efficacy of cannabidivarin for early life seizures. Neuropharmacology 2019;148:189–98.
40. Iannotti FA, et al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 2014;5:1131–41.
41. Izzo AA, et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009;30:515–27.
42. Jarbe TU, DiPatrizio NV. Delta-9-THC induced hyperphagia and tolerance assessment: interactions between the CB1 receptor agonist delta-9-THC and the CB1 receptor antagonist SR-141716 (rimonabant) in rats. Behav Pharmacol 2005;16:373–80.
43. Kaczocha M, et al. Fatty acid-binding proteins transport N-acylethanolamines to nuclear receptors and are targets of endocannabinoid transport inhibitors. J Biol Chem 2012;287:3415–24.
44. Kaplan JS, et al. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 2017;114:11229–34.
45. Laprairie RB, et al. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 2015;172:4790–805.
46. Laprairie RB, et al. Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons. J Biol Chem 2014;289:24845–62.
47. Leweke FM, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2012;2:e94.
48. Ligresti A, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 2006;318:1375–87.
49. Long LE, Malone DT, Taylor DA. Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology 2006;31:795–803.
50. Lotsch J, Weyer-Menkhoff I, Tegeder I. Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings. Eur J Pain 2018;22:471–84.
51. Maccarrone M, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 2015;36:277–96.
52. Martin BR, et al. Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol Biochem Behav 1991;40:471–8.
53. Matsuda LA, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–4.
54. McGuire P, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. Am J Psychiatry 2018;175:225–31.
55. McPartland JM, et al. Are cannabidiol and delta-9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 2015;172:737–53.
56. Mechoulam R, Carlini EA. Toward drugs derived from cannabis. Die Naturwissenschaften 1978;65:174–9.
57. Mechoulam R, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995;50:83–90.
58. Mechoulam R, Shvo Y. Hashish–I: The structure of Cannabidiol. Tetrahedron 1963;19:2073–8.
59. Mechoulam R. Marihuana chemistry. Science 1970;168:1159–66.
60. Mishima K, et al. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 2019;36:1077.
61. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61–5.
62. O’Sullivan SE, et al. Novel time-dependent vascular actions of delta-9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem Biophys Res Commun 2005;337:824–31.
63. O’Sullivan SE, et al. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol 2009;612:61–8.
64. O’Sullivan SE, Kendall DA, Randall MD. Further characterization of the time-dependent vascular effects of delta-9-tetrahydrocannabinol. J Pharmacol Exp Ther 2006;317:428–38.
65. Patel RR, et al. Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Brain 2016;139:2164–81.
66. Pisanti S, Bifulco M. Medical cannabis: A plurimillennial history of an evergreen. J Cell Physiol 2019;234:8342–51.
67. Pretzsch CM, et al. Effects of cannabidivarin (CBDV) on brain excitation and inhibition systems in adults with and without autism spectrum disorder (ASD): a single dose trial during magnetic resonance spectroscopy. Transl Psychiatry 2019;9:313.
68. Pryce G, Baker D. Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors. Br J Pharmacol 2007;150:519–25.
69. Rock EM, et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT1A somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol 2012;165:2620–34.
70. Rock EM, et al. Interaction between non-psychotropic cannabinoids in marihuana: effect of cannabigerol (CBG) on the anti-nausea or anti-emetic effects of cannabidiol (CBD) in rats and shrews. Psychopharmacology (Berl) 2011;215:505–12.
71. Rodriguez de Fonseca F, et al. The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol 2005;40:2–14.
72. Rohleder C, et al. Cannabidiol as a potential new type of an antipsychotic. A critical review of the evidence. Front Pharmacol 2016;7:422.
73. Rosenthaler S, et al. Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures. Neurotoxicol Teratol 2014;46:49–56.
74. Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Δ9-tetrahydrocannabinol and cannabidiol. J Biol Chem 2008;283:16124–34.
75. Russo EB, et al. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 2005;30:1037–43.
76. Russo EB, Marcu J. Cannabis pharmacology: The usual suspects and a few promising leads. Adv Pharmacol 2017;80:67–134.
77. Scuderi C, Steardo L, Esposito G. Cannabidiol promotes amyloid precursor protein ubiquitination and reduction of beta amyloid expression in SHSY5YAPP+ cells through PPARgamma involvement. Phytother Res 2014;28:1007–13.
78. Sonego AB, et al. Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice. Behav Brain Res 2016;309:22–8.
79. Sonego AB, et al. Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARgamma receptors. Brain Behav Immun 2018;74:241–51.
80. Sugiura T, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 1995;215:89–97.
81. Sylantyev S, et al. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci U S A 2013;110:5193–8.
82. Turner SE, et al. Molecular pharmacology of phytocannabinoids. Prog Chem Org Nat Prod 2017;103:61–101.
83. Varvel SA, et al. Delta9-tetrahydrocannbinol accounts for the antinociceptive, hypothermic, and cataleptic effects of marijuana in mice. J Pharmacol Exp Ther 2005;314:329–37.
84. Vilela LR, et al. Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: Pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels. Epilepsy Beh 2017;75:29–35.
85. Williams CM, Rogers PJ, Kirkham TC. Hyperphagia in pre-fed rats following oral delta9-THC. Physiol Behav 1998;65:343–6.
86. Xiong W, et al. A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. J Neurosci 2012;32:5200–8.
87. Yamauchi T, et al. Tetrahydrocannabinolic acid, a genuine substance of tetrahydrocannabinol. Chem Pharm Bull (Tokyo) 1967;15:1075–6.
88. Zimmer A, et al. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci U S A 1999;96:5780–5.
Dr. Cathrin Rohleder, Brain and Mind Centre, The University of Sydney, 94 Mallett Street, Camperdown, NSW, 2006, E-Mail: firstname.lastname@example.org
Dr. Juliane K Müller, Klinik für Psychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Frankfurt, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main