Cannabidiol: pharmacology and therapeutic targets.
Cannabidiol
Cannabis
Human
Marijuana
Medical cannabis
Pharmacokinetics
Journal
Psychopharmacology
ISSN: 1432-2072
Titre abrégé: Psychopharmacology (Berl)
Pays: Germany
ID NLM: 7608025
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
24
07
2020
accepted:
10
11
2020
pubmed:
23
11
2020
medline:
27
2
2021
entrez:
22
11
2020
Statut:
ppublish
Résumé
Cannabidiol (CBD) products lacking regulatory approval are being used to self-treat a myriad of conditions and for their unsubstantiated health benefits. The scientific evidence supporting these claims largely arises not from controlled clinical trials, but from the recognition that CBD has numerous biological targets. Yet, CBD is commonly consumed and often in over-the-counter products that are unapproved and of unknown composition. Epidiolex® is the only product that has undergone rigorous pharmacokinetic assessment and testing in clinical trials; it was approved as a non-scheduled drug by the U.S. Food and Drug Administration for the treatment of intractable childhood-onset seizures. However, studies investigating CBD for other medical conditions are limited in number and often lack the scientific rigor, controls, or sample sizes required to draw clinically meaningful conclusions. Although Epidiolex® is safe for human consumption, recent changes in regulation of commercially available CBD products have resulted in limited quality control and products marketed with unknown CBD bioavailability. Even scientifically rigorous studies have used different sources of CBD and different suspension vehicles for administration, making it difficult to compare results among studies and resolve mixed outcomes. This paper reviews the molecular targets, pharmacokinetics, and safety and abuse liability of CBD; additionally, the extant evidence on its potential therapeutic effects for neurological disorders, pain, inflammation, conditions related to immune function, psychiatric disorders, and substance use are described.
Identifiants
pubmed: 33221931
doi: 10.1007/s00213-020-05712-8
pii: 10.1007/s00213-020-05712-8
pmc: PMC7796924
mid: NIHMS1648940
doi:
Substances chimiques
Cannabidiol
19GBJ60SN5
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
9-28Subventions
Organisme : NIDA NIH HHS
ID : R01 DA045700
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA016718
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA040637
Pays : United States
Organisme : NIDA NIH HHS
ID : DA045700
Pays : United States
Organisme : NIDA NIH HHS
ID : T32 DA035200
Pays : United States
Organisme : NIDA NIH HHS
ID : DA045101
Pays : United States
Organisme : NIDA NIH HHS
ID : DA040637
Pays : United States
Organisme : NIDA NIH HHS
ID : DA016718
Pays : United States
Organisme : NIDA NIH HHS
ID : R21 DA045101
Pays : United States
Références
Alves FH, Crestani CC, Gomes FV, Guimaraes FS, Correa FM, Resstel LB (2010) Cannabidiol injected into the bed nucleus of the stria terminalis modulates baroreflex activity through 5-HT1A receptors. Pharmacol Res 62:228–236. https://doi.org/10.1016/j.phrs.2010.05.003
doi: 10.1016/j.phrs.2010.05.003
pubmed: 20621717
Appiah-Kusi E, Petros N, Wilson R, Colizzi M, Bossong MG, Valmaggia L, Mondelli V, McGuire P, Bhattacharyya S (2020) Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis. Psychopharmacology 237:1121–1130. https://doi.org/10.1007/s00213-019-05442-6
doi: 10.1007/s00213-019-05442-6
pubmed: 31915861
pmcid: 7113209
Arkell TR, Lintzeris N, Kevin RC, Ramaekers JG, Vandrey R, Irwin C, Haber PS, McGregor IS (2019) Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition. Psychopharmacology 236:2713–2724. https://doi.org/10.1007/s00213-019-05246-8
doi: 10.1007/s00213-019-05246-8
pubmed: 31044290
pmcid: 6695367
Atalay S, Jarocka-Karpowicz I, Skrzydlewska E (2019) Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants (Basel) 9. https://doi.org/10.3390/antiox9010021
Azer V et al (2019) Cowen’s collective view of CBD. https://www.cowen.com/insights/cowen-collective-view-of-cbd/ . Accessed 6 Apr 2020
Babalonis S, Haney M, Malcolm RJ, Lofwall MR, Votaw VR, Sparenborg S, Walsh SL (2017) Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers. Drug Alcohol Depend 172:9–13. https://doi.org/10.1016/j.drugalcdep.2016.11.030
doi: 10.1016/j.drugalcdep.2016.11.030
pubmed: 28088032
Bergamaschi MM, Queiroz RHC, Chagas MHN, de Oliveira DCG, de Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JEC, Zuardi AW, Crippa JAS (2011) Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 36:1219–1226. https://doi.org/10.1038/npp.2011.6
doi: 10.1038/npp.2011.6
pubmed: 21307846
pmcid: 3079847
Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, Nosarti C, O' Carroll CM, Seal M, Allen P, Mehta MA, Stone JM, Tunstall N, Giampietro V, Kapur S, Murray RM, Zuardi AW, Crippa JA, Atakan Z, McGuire PK (2010) Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–774. https://doi.org/10.1038/npp.2009.184
doi: 10.1038/npp.2009.184
pubmed: 19924114
Bih IC, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ (2015) Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics 12:699–730. https://doi.org/10.1007/s13311-015-0377-3
doi: 10.1007/s13311-015-0377-3
Birnbaum AK, Karanam A, Marino SE, Barkley CM, Remmel RP, Roslawski M, Gramling-Aden M, Leppik IE (2019) Food effect on pharmacokinetics of cannabidiol oral capsules in adult patients with refractory epilepsy. Epilepsia 60:1586–1592. https://doi.org/10.1111/epi.16093
doi: 10.1111/epi.16093
pubmed: 31247132
Bisogno T, Hanuš L, de Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, di Marzo V (2001) 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 134:845–852. https://doi.org/10.1038/sj.bjp.0704327
doi: 10.1038/sj.bjp.0704327
pubmed: 11606325
pmcid: 1573017
Blessing EM, Steenkamp MM, Manzanares J, Marmar CR (2015) Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 12:825–836. https://doi.org/10.1007/s13311-015-0387-1
doi: 10.1007/s13311-015-0387-1
pubmed: 26341731
pmcid: 4604171
Boggs DL, Surti T, Gupta A, Gupta S, Niciu M, Pittman B, Schnakenberg Martin AM, Thurnauer H, Davies A, D’Souza DC, Ranganathan M (2018) The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology 235:1923–1932. https://doi.org/10.1007/s00213-018-4885-9
doi: 10.1007/s00213-018-4885-9
pubmed: 29619533
Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R (2017) Labeling accuracy of cannabidiol extracts sold online. JAMA 318:1708–1709. https://doi.org/10.1001/jama.2017.11909
doi: 10.1001/jama.2017.11909
pubmed: 29114823
pmcid: 5818782
Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA, Seal ML, Fraccaro V, Atakan Z, Martin-Santos R, O'Carroll C, Rubia K, McGuire PK (2008) Neural basis of delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol Psychiatry 64:966–973. https://doi.org/10.1016/j.biopsych.2008.05.011
doi: 10.1016/j.biopsych.2008.05.011
pubmed: 18589404
Brown JD, Winterstein AG (2019) Potential adverse drug events and drug-drug interactions with medical and consumer cannabidiol (CBD) use. J Clin Med 8. https://doi.org/10.3390/jcm8070989
Buchholz HG, Uebbing K, Maus S, Pektor S, Afahaene N, Weyer-Elberich V, Lutz B, Schreckenberger M, Miederer I (2017) Whole-body biodistribution of the cannabinoid type 1 receptor ligand [(18)F]MK-9470 in the rat. Nucl Med Biol 52:63–69. https://doi.org/10.1016/j.nucmedbio.2017.06.003
doi: 10.1016/j.nucmedbio.2017.06.003
pubmed: 28648984
Burstein S (2015) Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorg Med Chem 23:1377–1385. https://doi.org/10.1016/j.bmc.2015.01.059
doi: 10.1016/j.bmc.2015.01.059
pubmed: 25703248
Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (2012) Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond Ser B Biol Sci 367:3364–3378. https://doi.org/10.1098/rstb.2011.0389
doi: 10.1098/rstb.2011.0389
Cannabidiol (CBD) Critical Review Report (2018) World Health Organization. Expert Committee on Drug Dependence, Geneva
Capano A, Weaver R, Burkman E (2020) Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med 132:56–61. https://doi.org/10.1080/00325481.2019.1685298
doi: 10.1080/00325481.2019.1685298
pubmed: 31711352
Chagas MH et al (2014) Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol (Oxford, England) 28:1088–1098. https://doi.org/10.1177/0269881114550355
doi: 10.1177/0269881114550355
Chesney E, Oliver D, Green A, Sovi S, Wilson J, Englund A, Freeman TP, McGuire P (2020) Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology 45:1799–1806. https://doi.org/10.1038/s41386-020-0667-2
doi: 10.1038/s41386-020-0667-2
pubmed: 32268347
pmcid: 7608221
Chung H, Fierro A, Pessoa-Mahana CD (2019) Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: an in silico study. PLoS One 14:e0220025. https://doi.org/10.1371/journal.pone.0220025
doi: 10.1371/journal.pone.0220025
pubmed: 31335889
pmcid: 6650144
Consroe P, Carlini EA, Zwicker AP, Lacerda LA (1979) Interaction of cannabidiol and alcohol in humans. Psychopharmacology 66:45–50. https://doi.org/10.1007/bf00431988
doi: 10.1007/bf00431988
pubmed: 120541
Consroe P, Kennedy K, Schram K (1991a) Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans. Pharmacol Biochem Behav 40:517–522. https://doi.org/10.1016/0091-3057(91)90357-8
doi: 10.1016/0091-3057(91)90357-8
pubmed: 1666917
Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, Kennedy K, Schram K (1991b) Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol Biochem Behav 40:701–708. https://doi.org/10.1016/0091-3057(91)90386-g
doi: 10.1016/0091-3057(91)90386-g
pubmed: 1839644
Corroon J, MacKay D, Dolphin W (2020) Labeling of cannabidiol products: a public health perspective. Cannabis Cannabinoid Res. https://doi.org/10.1089/can.2019.0101
Couch DG, Tasker C, Theophilidou E, Lund JN, O'Sullivan SE (2017) Cannabidiol and palmitoylethanolamide are anti-inflammatory in the acutely inflamed human colon. Clin Sci (Lond) 131:2611–2626. https://doi.org/10.1042/cs20171288
doi: 10.1042/cs20171288
Couch DG, Cook H, Ortori C, Barrett D, Lund JN, O’Sullivan SE (2019) Palmitoylethanolamide and cannabidiol prevent inflammation-induced hyperpermeability of the human gut in vitro and in vivo—a randomized, placebo-controlled, double-blind controlled trial. Inflamm Bowel Dis 25:1006–1018
doi: 10.1093/ibd/izz017
Crippa JA et al (2011) Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol (Oxford, England) 25:121–130. https://doi.org/10.1177/0269881110379283
doi: 10.1177/0269881110379283
Crippa JAS et al (2019) Oral cannabidiol does not convert to Δ8-THC or Δ9-THC in humans: a pharmacokinetic study in healthy subjects. Cannabis Cannabinoid Res 0:null. https://doi.org/10.1089/can.2019.0024
doi: 10.1089/can.2019.0024
Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Sanvito WL, Lander N, Mechoulam R (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21:175–185. https://doi.org/10.1159/000137430
doi: 10.1159/000137430
pubmed: 7413719
De Petrocellis L et al (2011) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163:1479–1494. https://doi.org/10.1111/j.1476-5381.2010.01166.x
doi: 10.1111/j.1476-5381.2010.01166.x
pubmed: 21175579
pmcid: 3165957
Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D (2014) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55:791–802. https://doi.org/10.1111/epi.12631
doi: 10.1111/epi.12631
pubmed: 24854329
pmcid: 4707667
Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR (2016) Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 15:270–278. https://doi.org/10.1016/s1474-4422(15)00379-8
doi: 10.1016/s1474-4422(15)00379-8
pubmed: 26724101
Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S, Cannabidiol in Dravet Syndrome Study Group (2017) Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 376:2011–2020. https://doi.org/10.1056/NEJMoa1611618
doi: 10.1056/NEJMoa1611618
pubmed: 28538134
Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham K, Zuberi SM, GWPCARE3 Study Group (2018a) Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med 378:1888–1897. https://doi.org/10.1056/NEJMoa1714631
doi: 10.1056/NEJMoa1714631
pubmed: 29768152
Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K, On behalf of the GWPCARE1 Part A Study Group (2018b) Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 90:e1204–e1211. https://doi.org/10.1212/wnl.0000000000005254
doi: 10.1212/wnl.0000000000005254
pubmed: 29540584
pmcid: 5890607
Elsaid S, Kloiber S, Le Foll B (2019) Effects of cannabidiol (CBD) in neuropsychiatric disorders: a review of pre-clinical and clinical findings. Prog Mol Biol Transl Sci 167:25–75. https://doi.org/10.1016/bs.pmbts.2019.06.005
doi: 10.1016/bs.pmbts.2019.06.005
pubmed: 31601406
Englund A et al (2013) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol (Oxford, England) 27:19–27. https://doi.org/10.1177/0269881112460109
doi: 10.1177/0269881112460109
FDA (2019) Warning letters and test results for cannabidiol-related products
FDA (2020a) FDA approves new indication for drug containing an active ingredient derived from cannabis to treat seizures in rare genetic disease
FDA (2020b) FDA warns companies illegally selling CBD products to treat medical conditions, opioid addiction
Fitzcharles MA, Clauw DJ, Hauser W (2020) A cautious hope for cannabidiol (CBD) in rheumatology care. Arthritis Care Res. https://doi.org/10.1002/acr.24176
Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, Seal M, Surguladze SA, O’Carrol C, Atakan Z, Zuardi AW, McGuire PK (2009) Distinct effects of Δ9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry 66:95–105. https://doi.org/10.1001/archgenpsychiatry.2008.519
doi: 10.1001/archgenpsychiatry.2008.519
pubmed: 19124693
Galaj E, Bi GH, Yang HJ, Xi ZX (2019) Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-TH1A and TRPV1 receptor mechanisms. Neuropharmacology:107740. https://doi.org/10.1016/j.neuropharm.2019.107740
Galiazzo G, Giancola F, Stanzani A, Fracassi F, Bernardini C, Forni M, Pietra M, Chiocchetti R (2018) Localization of cannabinoid receptors CB1, CB2, GPR55, and PPARalpha in the canine gastrointestinal tract. Histochem Cell Biol 150:187–205. https://doi.org/10.1007/s00418-018-1684-7
doi: 10.1007/s00418-018-1684-7
pubmed: 29882158
Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61
doi: 10.1111/j.1432-1033.1995.tb20780.x
Geffrey AL, Pollack SF, Bruno PL, Thiele EA (2015) Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 56:1246–1251. https://doi.org/10.1111/epi.13060
doi: 10.1111/epi.13060
pubmed: 26114620
Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, Laux L, Marsh ED (2017) Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol 32:35–40. https://doi.org/10.1177/0883073816669450
doi: 10.1177/0883073816669450
pubmed: 27655472
Gomes FV, Resstel LB, Guimaraes FS (2011) The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 213:465–473. https://doi.org/10.1007/s00213-010-2036-z
doi: 10.1007/s00213-010-2036-z
pubmed: 20945065
Gomes FV, Reis DG, Alves FH, Correa FM, Guimaraes FS, Resstel LB (2012) Cannabidiol injected into the bed nucleus of the stria terminalis reduces the expression of contextual fear conditioning via 5-HT1A receptors. J Psychopharmacol (Oxford, England) 26:104–113. https://doi.org/10.1177/0269881110389095
doi: 10.1177/0269881110389095
Gomes FV, Alves FH, Guimaraes FS, Correa FM, Resstel LB, Crestani CC (2013) Cannabidiol administration into the bed nucleus of the stria terminalis alters cardiovascular responses induced by acute restraint stress through 5-HT(1)A receptor. Eur Neuropsychopharmacol 23:1096–1104. https://doi.org/10.1016/j.euroneuro.2012.09.007
doi: 10.1016/j.euroneuro.2012.09.007
pubmed: 23041353
Gray RA, Whalley BJ (2020) The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord 22:10–15. https://doi.org/10.1684/epd.2020.1135
doi: 10.1684/epd.2020.1135
pubmed: 32053110
Guy GW, Flint ME (2004) A single centre, placebo-controlled, four period, crossover, tolerability study assessing, pharmacodynamic effects, pharmacokinetic characteristics and cognitive profiles of a single dose of three formulations of cannabis based medicine extracts (CBMEs) (GWPD9901), plus a two period tolerability study comparing pharmacodynamic effects and pharmacokinetic characteristics of a single dose of a cannabis based medicine extract given via two administration routes (GWPD9901 EXT). J Cannabis Ther 3:35–77. https://doi.org/10.1300/J175v03n03_03
doi: 10.1300/J175v03n03_03
Hallak JE et al (2010) Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD). Braz J Psychiatry 32:56–61. https://doi.org/10.1590/s1516-44462010000100011
doi: 10.1590/s1516-44462010000100011
pubmed: 20339735
Haney M, Malcolm RJ, Babalonis S, Nuzzo PA, Cooper ZD, Bedi G, Gray KM, McRae-Clark A, Lofwall MR, Sparenborg S, Walsh SL (2016) Oral cannabidiol does not alter the subjective, reinforcing or cardiovascular effects of smoked cannabis. Neuropsychopharmacology 41:1974–1982. https://doi.org/10.1038/npp.2015.367
doi: 10.1038/npp.2015.367
pubmed: 26708108
pmcid: 4908634
Hartmann A, Lisboa SF, Sonego AB, Coutinho D, Gomes FV, Guimaraes FS (2019) Cannabidiol attenuates aggressive behavior induced by social isolation in mice: involvement of 5-HT1A and CB1 receptors. Prog Neuro-Psychopharmacol Biol Psychiatry 94:109637. https://doi.org/10.1016/j.pnpbp.2019.109637
doi: 10.1016/j.pnpbp.2019.109637
Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583
doi: 10.1523/JNEUROSCI.11-02-00563.1991
Hess EJ, Moody KA, Geffrey AL, Pollack SF, Skirvin LA, Bruno PL, Paolini JL, Thiele EA (2016) Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 57:1617–1624. https://doi.org/10.1111/epi.13499
doi: 10.1111/epi.13499
pubmed: 27696387
Highlights of Prescribing Information (2018) https://www.epidiolex.com/sites/default/files/pdfs/EPIDIOLEX_Full_Prescribing_Information_04_16_2020.pdf . Accessed 21 May 2020
Hindocha C et al (2018) Cannabidiol reverses attentional bias to cigarette cues in a human experimental model of tobacco withdrawal. Addiction 113:1696–1705. https://doi.org/10.1111/add.14243
doi: 10.1111/add.14243
pmcid: 6099309
Hundal H et al (2018) The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group. J Psychopharmacol (Oxford, England) 32:276–282. https://doi.org/10.1177/0269881117737400
doi: 10.1177/0269881117737400
Hurd YL et al (2019) Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: a double-blind randomized placebo-controlled trial. Am J Psychiatry 176:911–922. https://doi.org/10.1176/appi.ajp.2019.18101191
doi: 10.1176/appi.ajp.2019.18101191
pubmed: 31109198
Iannotti FA et al (2014) 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 5:1131–1141. https://doi.org/10.1021/cn5000524
doi: 10.1021/cn5000524
pubmed: 25029033
Iannotti FA et al (2019) Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice. Br J Pharmacol 176:1568–1584. https://doi.org/10.1111/bph.14460
doi: 10.1111/bph.14460
pubmed: 30074247
Irving PM et al (2018) A randomized, double-blind, placebo-controlled, parallel-group, pilot study of cannabidiol-rich botanical extract in the symptomatic treatment of ulcerative colitis. Inflamm Bowel Dis 24:714–724. https://doi.org/10.1093/ibd/izy002
doi: 10.1093/ibd/izy002
pubmed: 29538683
Jadoon KA et al (2016) Efficacy and safety of cannabidiol and tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel group pilot study. Diabetes Care 39:1777–1786. https://doi.org/10.2337/dc16-0650
doi: 10.2337/dc16-0650
pubmed: 27573936
Jadoon KA, Tan GD, O'Sullivan SE (2017) A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight 2. https://doi.org/10.1172/jci.insight.93760
Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA (1974) Cannabidiol interferes with the effects of delta 9 - tetrahydrocannabinol in man. Eur J Pharmacol 28:172–177. https://doi.org/10.1016/0014-2999(74)90129-0
doi: 10.1016/0014-2999(74)90129-0
pubmed: 4609777
Kossakowski R, Schlicker E, Toczek M, Weresa J, Malinowska B (2019) Cannabidiol affects the Bezold-Jarisch reflex via TRPV1 and 5-HT3 receptors and has peripheral sympathomimetic effects in spontaneously hypertensive and normotensive rats. Front Pharmacol 10(500). https://doi.org/10.3389/fphar.2019.00500
Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172:4790–4805. https://doi.org/10.1111/bph.13250
doi: 10.1111/bph.13250
pubmed: 26218440
pmcid: 4621983
Lazarini-Lopes W, Do Val-da Silva RA, da Silva-Junior RMP, Leite JP, Garcia-Cairasco N (2020) The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: from behavior and mechanisms to clinical insights. Neurosci Biobehav Rev 111:166–182. https://doi.org/10.1016/j.neubiorev.2020.01.014
doi: 10.1016/j.neubiorev.2020.01.014
pubmed: 31954723
Lee JLC, Bertoglio LJ, Guimarães FS, Stevenson CW (2017) Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. Br J Pharmacol 174:3242–3256. https://doi.org/10.1111/bph.13724
doi: 10.1111/bph.13724
pubmed: 28268256
pmcid: 5595771
Leweke FM et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2:e94. https://doi.org/10.1038/tp.2012.15
doi: 10.1038/tp.2012.15
pubmed: 22832859
pmcid: 3316151
Li H et al (2020) Overview of cannabidiol (CBD) and its analogues: structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer’s disease. Eur J Med Chem 192:112163. https://doi.org/10.1016/j.ejmech.2020.112163
doi: 10.1016/j.ejmech.2020.112163
pubmed: 32109623
Liebling JP, Clarkson NJ, Gibbs BW, Yates AS, O'Sullivan SE (2020) An analysis of over-the-counter cannabidiol products in the United Kingdom. Cannabis Cannabinoid Res. https://doi.org/10.1089/can.2019.0078
Ligresti A et al (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318:1375–1387. https://doi.org/10.1124/jpet.106.105247
doi: 10.1124/jpet.106.105247
pubmed: 16728591
Linares IM, Zuardi AW, Pereira LC, Queiroz RH, Mechoulam R, Guimarães FS, Crippa JA (2019) Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry 41:9–14
doi: 10.1590/1516-4446-2017-0015
Madden K, Tanco K, Bruera E (2020) Clinically significant drug-drug interaction between methadone and cannabidiol. Pediatrics 145. https://doi.org/10.1542/peds.2019-3256
Manini AF et al (2015) Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med 9:204–210. https://doi.org/10.1097/adm.0000000000000118
doi: 10.1097/adm.0000000000000118
pubmed: 25748562
pmcid: 4449284
Martin-Santos R et al (2012) Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des 18:4966–4979. https://doi.org/10.2174/138161212802884780
doi: 10.2174/138161212802884780
pubmed: 22716148
Massi P et al (2008) 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem 104:1091–1100. https://doi.org/10.1111/j.1471-4159.2007.05073.x
doi: 10.1111/j.1471-4159.2007.05073.x
pubmed: 18028339
McGuire P et al (2018) Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry 175:225–231. https://doi.org/10.1176/appi.ajp.2017.17030325
doi: 10.1176/appi.ajp.2017.17030325
pubmed: 29241357
McPartland JM, Duncan M, Di Marzo V, Pertwee RG (2015) Are cannabidiol and delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 172:737–753. https://doi.org/10.1111/bph.12944
doi: 10.1111/bph.12944
pubmed: 25257544
pmcid: 4301686
Millar SA, Stone NL, Yates AS, O'Sullivan SE (2018) A systematic review on the pharmacokinetics of cannabidiol in humans. Front Pharmacol 9:1365
doi: 10.3389/fphar.2018.01365
Morelli MB et al (2014) The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential vanilloid type-2. Int J Cancer 134:2534–2546. https://doi.org/10.1002/ijc.28591
doi: 10.1002/ijc.28591
pubmed: 24293211
Morgan CJ, Das RK, Joye A, Curran HV, Kamboj SK (2013) Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. Addict Behav 38:2433–2436. https://doi.org/10.1016/j.addbeh.2013.03.011
doi: 10.1016/j.addbeh.2013.03.011
pubmed: 23685330
Morgan CJA, Freeman TP, Hindocha C, Schafer G, Gardner C, Curran HV (2018) Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function. Transl Psychiatry 8:181. https://doi.org/10.1038/s41398-018-0191-x
doi: 10.1038/s41398-018-0191-x
pubmed: 30185793
pmcid: 6125482
Nabissi M, Morelli MB, Santoni M, Santoni G (2013) Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34:48–57. https://doi.org/10.1093/carcin/bgs328
doi: 10.1093/carcin/bgs328
pubmed: 23079154
Nabissi M et al (2015) Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner. Int J Cancer 137:1855–1869. https://doi.org/10.1002/ijc.29573
doi: 10.1002/ijc.29573
pubmed: 25903924
Naftali T et al (2017) Low-dose cannabidiol is safe but not effective in the treatment for Crohn’s disease, a randomized controlled trial. Dig Dis Sci 62:1615–1620. https://doi.org/10.1007/s10620-017-4540-z
doi: 10.1007/s10620-017-4540-z
pubmed: 28349233
Nichols JM, Kaplan BLF (2020) Immune responses regulated by cannabidiol. Cannabis Cannabinoid Res 5:12–31. https://doi.org/10.1089/can.2018.0073
doi: 10.1089/can.2018.0073
pubmed: 32322673
pmcid: 7173676
Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmons S, Sansom C (2004) Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia 59:440–452. https://doi.org/10.1111/j.1365-2044.2004.03674.x
doi: 10.1111/j.1365-2044.2004.03674.x
pubmed: 15096238
Nunez E et al (2004) Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 53:208–213. https://doi.org/10.1002/syn.20050
doi: 10.1002/syn.20050
pubmed: 15266552
Ohlsson A, Lindgren JE, Andersson S, Agurell S, Gillespie H, Hollister LE (1986) Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration. Biomed Environ Mass Spectrom 13:77–83. https://doi.org/10.1002/bms.1200130206
doi: 10.1002/bms.1200130206
pubmed: 2937482
Petrosino S, Verde R, Vaia M, Allara M, Iuvone T, Di Marzo V (2018) Anti-inflammatory properties of cannabidiol, a nonpsychotropic cannabinoid, in experimental allergic contact dermatitis. J Pharmacol Exp Ther 365:652–663. https://doi.org/10.1124/jpet.117.244368
doi: 10.1124/jpet.117.244368
pubmed: 29632236
Pisanti S et al (2017) Cannabidiol: state of the art and new challenges for therapeutic applications. Pharmacol Ther 175:133–150. https://doi.org/10.1016/j.pharmthera.2017.02.041
doi: 10.1016/j.pharmthera.2017.02.041
pubmed: 28232276
Poklis JL, Mulder HA, Peace MR (2019) The unexpected identification of the cannabimimetic, 5F-ADB, and dextromethorphan in commercially available cannabidiol e-liquids. Forensic Sci Int 294:e25–e27. https://doi.org/10.1016/j.forsciint.2018.10.019
doi: 10.1016/j.forsciint.2018.10.019
pubmed: 30442388
Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 28:6231–6238. https://doi.org/10.1523/jneurosci.0504-08.2008
doi: 10.1523/jneurosci.0504-08.2008
pubmed: 18550765
pmcid: 6670541
Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimaraes FS (2009) 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156:181–188. https://doi.org/10.1111/j.1476-5381.2008.00046.x
doi: 10.1111/j.1476-5381.2008.00046.x
pubmed: 19133999
pmcid: 2697769
Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043. https://doi.org/10.1007/s11064-005-6978-1
doi: 10.1007/s11064-005-6978-1
pubmed: 16258853
Sartim AG, Guimaraes FS, Joca SR (2016) Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex—possible involvement of 5-HT1A and CB1 receptors. Behav Brain Res 303:218–227. https://doi.org/10.1016/j.bbr.2016.01.033
doi: 10.1016/j.bbr.2016.01.033
pubmed: 26801828
Schier AR, Ribeiro NP, Silva AC, Hallak JE, Crippa JA, Nardi AE, Zuardi AW (2012) Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Braz J Psychiatry 34(Suppl 1):S104–S110. https://doi.org/10.1590/s1516-44462012000500008
doi: 10.1590/s1516-44462012000500008
pubmed: 22729452
Schoedel KA et al (2018) Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: a randomized, double-blind, controlled trial. Epilepsy Behav 88:162–171. https://doi.org/10.1016/j.yebeh.2018.07.027
doi: 10.1016/j.yebeh.2018.07.027
pubmed: 30286443
Soares VP, Campos AC (2017) Evidences for the anti-panic actions of cannabidiol. Curr Neuropharmacol 15:291–299. https://doi.org/10.2174/1570159x14666160509123955
doi: 10.2174/1570159x14666160509123955
pubmed: 27157263
pmcid: 5412699
Soares VP, Campos AC, Bortoli VC, Zangrossi H Jr, Guimaraes FS, Zuardi AW (2010) Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behav Brain Res 213:225–229. https://doi.org/10.1016/j.bbr.2010.05.004
doi: 10.1016/j.bbr.2010.05.004
Solowij N et al (2019) A randomised controlled trial of vaporised Delta(9)-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects. Eur Arch Psychiatry Clin Neurosci 269:17–35. https://doi.org/10.1007/s00406-019-00978-2
doi: 10.1007/s00406-019-00978-2
pubmed: 30661105
Sonego AB, Gomes FV, Del Bel EA, Guimaraes FS (2016) Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice. Behav Brain Res 309:22–28. https://doi.org/10.1016/j.bbr.2016.04.042
doi: 10.1016/j.bbr.2016.04.042
pubmed: 27131780
Spindle TR et al (2020a) Pharmacodynamic effects of vaporized and oral cannabidiol (CBD) and vaporized CBD-dominant cannabis in infrequent cannabis users. Drug Alcohol Depend:107937. https://doi.org/10.1016/j.drugalcdep.2020.107937
Spindle TR, Cone EJ, Kuntz D, Mitchell JM, Bigelow GE, Flegel R, Vandrey R (2020b) Urinary pharmacokinetic profile of cannabinoids following administration of vaporized and oral cannabidiol and vaporized CBD-dominant cannabis. J Anal Toxicol 44:109–125. https://doi.org/10.1093/jat/bkz080
doi: 10.1093/jat/bkz080
pubmed: 31682266
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
doi: 10.3109/03602532.2013.849268
pubmed: 24160757
Sultan SR, O'Sullivan SE, England TJ (2020) The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: a randomised controlled trial. Br J Clin Pharmacol. https://doi.org/10.1111/bcp.14225
Szaflarski JP et al (2018) Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav 87:131–136. https://doi.org/10.1016/j.yebeh.2018.07.020
doi: 10.1016/j.yebeh.2018.07.020
pubmed: 30100226
Taylor L, Gidal B, Blakey G, Tayo B, Morrison G (2018) A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs 32:1053–1067. https://doi.org/10.1007/s40263-018-0578-5
doi: 10.1007/s40263-018-0578-5
pubmed: 30374683
pmcid: 6223703
Taylor L, Crockett J, Tayo B, Morrison G (2019) A phase 1, open-label, parallel-group, single-dose trial of the pharmacokinetics and safety of cannabidiol (CBD) in subjects with mild to severe hepatic impairment. J Clin Pharmacol 59:1110–1119. https://doi.org/10.1002/jcph.1412
doi: 10.1002/jcph.1412
pubmed: 30921490
pmcid: 6618279
Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB (2019) Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol 176:1455–1469. https://doi.org/10.1111/bph.14440
doi: 10.1111/bph.14440
pubmed: 29981240
Thiele EA et al (2018) Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 391:1085–1096. https://doi.org/10.1016/s0140-6736(18)30136-3
doi: 10.1016/s0140-6736(18)30136-3
pubmed: 29395273
Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee RG, Robson PJ (2006) Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J Glaucoma 15:349–353. https://doi.org/10.1097/01.ijg.0000212260.04488.60
doi: 10.1097/01.ijg.0000212260.04488.60
pubmed: 16988594
Turna J, Syan SK, Frey BN, Rush B, Costello MJ, Weiss M, MacKillop J (2019) Cannabidiol as a novel candidate alcohol use disorder pharmacotherapy: a systematic review. Alcohol Clin Exp Res 43:550–563. https://doi.org/10.1111/acer.13964
doi: 10.1111/acer.13964
pubmed: 30698831
pmcid: 6910215
van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, van Velzen M (2019) An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain 160:860–869. https://doi.org/10.1097/j.pain.0000000000001464
doi: 10.1097/j.pain.0000000000001464
pubmed: 30585986
Van Sickle MD et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332. https://doi.org/10.1126/science.1115740
doi: 10.1126/science.1115740
pubmed: 16224028
Vilela LR et al (2017) Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels. Epilepsy Behav 75:29–35. https://doi.org/10.1016/j.yebeh.2017.07.014
doi: 10.1016/j.yebeh.2017.07.014
pubmed: 28821005
Wade DT, Robson P, House H, Makela P, Aram J (2003) A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil 17:21–29. https://doi.org/10.1191/0269215503cr581oa
doi: 10.1191/0269215503cr581oa
pubmed: 12617376
Wheless JW et al (2019) Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy. CNS Drugs 33:593–604. https://doi.org/10.1007/s40263-019-00624-4
doi: 10.1007/s40263-019-00624-4
pubmed: 31049885
pmcid: 6534520
Wiemer-Kruel A, Stiller B, Bast T (2019) Cannabidiol interacts significantly with everolimus—report of a patient with tuberous sclerosis complex. Neuropediatrics 50:400–403. https://doi.org/10.1055/s-0039-1695786
doi: 10.1055/s-0039-1695786
pubmed: 31539915
Xu DH, Cullen BD, Tang M, Fang Y (2020) The effectiveness of topical cannabidiol oil in symptomatic relief of peripheral neuropathy of the lower extremities. Curr Pharm Biotechnol 21:390–402. https://doi.org/10.2174/1389201020666191202111534
doi: 10.2174/1389201020666191202111534
pubmed: 31793418
Yang KH, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M (2010) The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J Pharmacol Exp Ther 333:547–554. https://doi.org/10.1124/jpet.109.162594
doi: 10.1124/jpet.109.162594
pubmed: 20160007
pmcid: 2872948
Yeshurun M et al (2015) Cannabidiol for the prevention of graft-versus-host-disease after allogeneic hematopoietic cell transplantation: results of a phase II study. Biol Blood Marrow Transplant 21:1770–1775. https://doi.org/10.1016/j.bbmt.2015.05.018
doi: 10.1016/j.bbmt.2015.05.018
pubmed: 26033282
Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 159:122–128. https://doi.org/10.1111/j.1476-5381.2009.00521.x
doi: 10.1111/j.1476-5381.2009.00521.x
pubmed: 20002102
Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138:103–141. https://doi.org/10.1016/j.pharmthera.2012.12.007
doi: 10.1016/j.pharmthera.2012.12.007
pubmed: 23333322
Zuardi AW, Cosme RA, Graeff FG, Guimarães FS (1993) Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 7:82–88. https://doi.org/10.1177/026988119300700112
doi: 10.1177/026988119300700112
pubmed: 22290374
Zuardi AW et al (2009) Cannabidiol for the treatment of psychosis in Parkinson’s disease. J Psychopharmacol (Oxford, England) 23:979–983. https://doi.org/10.1177/0269881108096519
doi: 10.1177/0269881108096519
Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JEC, Guimarães FS, Crippa JAS (2017) Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol 8. https://doi.org/10.3389/fphar.2017.00259