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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Review Article

Cannabidiol Adverse Effects and Toxicity

Author(s): Marilyn A. Huestis, Renata Solimini, Simona Pichini, Roberta Pacifici, Jeremy Carlier and Francesco Paolo Busardò*

Volume 17, Issue 10, 2019

Page: [974 - 989] Pages: 16

DOI: 10.2174/1570159X17666190603171901

Price: $65

Abstract

Background: Currently, there is a great interest in the potential medical use of cannabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid system. Multiple preclinical and clinical studies led to FDA-approval of Epidiolex®, a purified CBD medicine formulated for oral administration for the treatment of infantile refractory epileptic syndromes, by the US Food and Drug Administration in 2018. The World Health Organization considers rescheduling cannabis and cannabinoids. CBD use around the world is expanding for diseases that lack scientific evidence of the drug’s efficacy. Preclinical and clinical studies also report adverse effects (AEs) and toxicity following CBD intake.

Methods: Relevant studies reporting CBD’s AEs or toxicity were identified from PubMed, Cochrane Central, and EMBASE through January 2019. Studies defining CBD’s beneficial effects were included to provide balance in estimating risk/benefit.

Results: CBD is not risk-free. In animals, CBD AEs included developmental toxicity, embryo-fetal mortality, central nervous system inhibition and neurotoxicity, hepatocellular injuries, spermatogenesis reduction, organ weight alterations, male reproductive system alterations, and hypotension, although at doses higher than recommended for human pharmacotherapies. Human CBD studies for epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormalities, diarrhea, fatigue, vomiting, and somnolence.

Conclusion: CBD has proven therapeutic efficacy for serious conditions such as Dravet and Lennox-Gastaut syndromes and is likely to be recommended off label by physicians for other conditions. However, AEs and potential drug-drug interactions must be taken into consideration by clinicians prior to recommending off-label CBD.

Keywords: Cannabidiol, adverse effects, toxicity, animal studies, in vitro studies, in vivo studies, studies in humans.

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[1]
Gaoni, Y.; Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc., 1964, 86, 1646-1647. [http://dx.doi.org/10.1021/ja01062a046].
[2]
Devane, W.A.; Dysarz, F.A., 3rd; Johnson, M.R.; Melvin, L.S.; Howlett, A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol., 1988, 34, 605-613.
[3]
Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature, 1993, 365, 61-65. [http://dx.doi.org/10.1038/365061a0].
[4]
Matsuda, L.A.; Lolait, S.J.; Brownstein, M.J.; Young, A.C.; Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 1990, 346, 561-564. [http://dx.doi.org/10.1038/346561a0].
[5]
Kendall, D.; Alexander, S.P.H. Cannabinoid pharmacology. Adv. Pharmacol., 2017, 80, 1-475.
[6]
Devane, W.A.; Hanus, L.; Breuer, A.; Pertwee, R.G.; Stevenson, L.A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 1992, 258, 1946-1949. [http://dx.doi.org/10.1126/science.1470919].
[7]
Adams, R.; Hunt, M.; Clark, J.H. Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. J. Am. Chem. Soc., 1940, 62, 196-200. [http://dx.doi.org/10.1021/ja01858a058].
[8]
Mechoulam, R.; Shvo, Y. The structure of cannabidiol. Tetrahedron, 1963, 19, 2073-2078. [http://dx.doi.org/10.1016/0040-4020(63)85022-X].
[9]
Campos, A.C.; Ortega, Z.; Palazuelos, J.; Fogaça, M.V.; Aguiar, D.C.; Díaz-Alonso, J.; Ortega-Gutiérrez, S.; Vázquez-Villa, H.; Moreira, F.A.; Guzmán, M.; Galve-Roperh, I.; Guimarães, F.S. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int. J. Neuropsychopharmacol., 2013, 16, 1407-1419. [http://dx.doi.org/10.1017/S1461145712001502].
[10]
Linge, R.; Jiménez-Sánchez, L.; Campa, L.; Pilar-Cuéllar, F.; Vidal, R.; Pazos, A.; Adell, A.; Díaz, Á. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology, 2016, 103, 16-26. [http://dx.doi.org/10.1016/j.neuropharm.2015.12.017].
[11]
Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol., 2015, 172, 4790-4805. [http://dx.doi.org/10.1111/bph.13250].
[12]
McPartland, J.M.; Duncan, M.; Di Marzo, V.; Pertwee, R.G. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br. J. Pharmacol., 2015, 172, 737-753. [http://dx.doi.org/10.1111/bph.12944].
[13]
Tham, M.; Yilmaz, O.; Alaverdashvili, M.; Kelly, M.E.M.; Denovan-Wright, E.M.; Laprairie, R.B. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br. J. Pharmacol., 2018. [http://dx.doi.org/10.1111/bph.14440].
[14]
Straiker, A.; Dvorakova, M.; Zimmowitch, A.; Mackie, K. Cannabidiol inhibits endocannabinoids signaling in autaptic hippocampal neurons. Mol. Pharmacol., 2018, 94, 743-748. [http://dx.doi.org/10.1124/mol.118.111864].
[15]
Mechoulam, R.; Peters, M.; Murillo-Rodriguez, E.; Hanus, L.O. Cannabidiol-recent advances. Chem. Biodivers., 2007, 4, 1678-1692. [http://dx.doi.org/10.1002/cbdv.200790147].
[16]
Vallée, A.; Lecarpentier, Y.; Guillevin, R.; Vallée, J.N. Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim. Biophys. Sin. (Shanghai), 2017, 49, 853-866. [http://dx.doi.org/10.1093/abbs/gmx073].
[17]
Campos, A.C.; Guimarães, F.S. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2009, 33, 1517-1521. [http://dx.doi.org/10.1016/j.pnpbp.2009.08.017].
[18]
Franco, R.; Villa, M.; Morales, P.; Reyes-Resina, I.; Gutiérrez-Rodríguez, A.; Jiménez, J.; Jagerovic, N.; Martínez-Orgado, J.; Navarro, G. Increased expression of cannabinoid CB2 and serotonin 5-HT1A heteroreceptor complexes in a model of newborn hypoxic-ischemic brain damage. Neuropharmacology, 2019. [http://dx.doi.org/10.1016/j.neuropharm.2019.02.004].
[19]
Greenwich Biosciences Epidiolex, full prescribing information., https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf (Accessed 12 March, 2019).
[20]
Paton, W.D.M.; Pertwee, R.G. Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Br. J. Pharmacol., 1972, 44, 250-261. [http://dx.doi.org/10.1111/j.1476-5381.1972.tb07261.x].
[21]
Devinsky, O.; Cilio, M.R.; Cross, H.; Fernandez-Ruiz, J.; French, J.; Hill, C.; Katz, R.; Di Marzo, V.; Jutras-Aswad, D.; Notcutt, W.G.; Martinez-Orgado, J.; Robson, P.J.; Rohrback, B.G.; Thiele, E.; Whalley, B.; Friedman, D. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 2014, 55, 791-802. [http://dx.doi.org/10.1111/epi.12631].
[22]
Pertwee, R.G. Cannabinoid pharmacology: the first 66 years. Br. J. Pharmacol., 2006, 147(Suppl. 1), S163-S171. [http://dx.doi.org/10.1038/sj.bjp.0706406].
[23]
Zuardi, A.W. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Br. J. Psychiatry, 2008, 30, 271-280. [http://dx.doi.org/10.1590/S1516-44462008000300015].
[24]
The National Academies of Sciences Engineering, Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research., Washington, DC The National Academies Press. 2017. (Accessed 12 March, 2019).
[25]
Cunha, J.M.; Carlini, E.A.; Pereira, A.E.; Ramos, O.L.; Pimentel, C.; Gagliardi, R.; Santivo, W.L.; Lander, N.; Mechoulam, R. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology, 1980, 21, 175-185. [http://dx.doi.org/10.1159/000137430].
[26]
Lattanzi, S.; Brigo, F.; Trinka, E.; Zaccara, G.; Cagnetti, C.; Del Giovane, C.; Silvestrini, M. Efficacy and safety of cannabidiol in epilepsy: a systematic review and meta-analysis. Drugs, 2018, 78, 1791-1804. [http://dx.doi.org/10.1007/s40265-018-0992-5].
[27]
US Food and Drug Administration (FDA). FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy., FDA News Release, June 25. 2018. Available at:https://www.fda.gov/newsevents/newsroom/ pressannouncements/ucm611046.htm (Accessed 12 March, 2019).
[28]
Zuardi, A.W.; Guimarães, F.S.; Moreira, A.C. Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers. Braz. J. Med. Biol. Res., 1993, 26, 213-217. [http://dx.doi.org/10.1177/0269881106060967].
[29]
Zuardi, A.W.; Crippa, J.A.; Hallak, J.E.; Moreira, F.A.; Guimarães, F.S. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz. J. Med. Biol. Res., 2006, 39, 421-429. [http://dx.doi.org/S0100-879X2006000400001].
[30]
Fusar-Poli, P.; Crippa, J.A.; Bhattacharyya, S.; Borgwardt, S.J.; Allen, P.; Martin-Santos, R.; Seal, M.; Surguladze, S.A.; O’Carrol, C.; Atakan, Z.; Zuardi, A.W.; McGuire, P.K. Distinct effects of delta9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch. Gen. Psychiatry, 2009, 66, 95-105. [http://dx.doi.org/10.1001/archgenpsychiatry.2008.519].
[31]
Fusar-Poli, P.; Allen, P.; Bhattacharyya, S.; Crippa, J.A.; Mechelli, A.; Borgwardt, S.; Martin-Santos, R.; Seal, M.L.; O’Carrol, C.; Atakan, Z.; Zuardi, A.W.; McGuire, P. Modulation of effective connectivity during emotional processing by Delta9-tetrahydrocannabinol and cannabidiol. Int. J. Neuropsychopharmacol., 2010, 13, 421-432. [http://dx.doi.org/10.1017/S1461145709990617].
[32]
Bhattacharyya, S.; Morrison, P.D.; Fusar-Poli, P.; Martin-Santos, R.; Borgwardt, S.; Winton-Brown, T.; Nosarti, C.; O’Carroll, C.M.; Seal, M.; Allen, P.; Mehta, M.A.; Stone, J.M.; Tunstall, N.; Giampietro, V.; Kapur, S.; Murray, R.M.; Zuardi, A.W.; Crippa, J.A.; Atakan, Z.; McGuire, P.K. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 2010, 35, 764-774. [http://dx.doi.org/10.1038/npp.2009.184].
[33]
Englund, A.; Morrison, P.D.; Nottage, J.; Hague, D.; Kane, F.; Bonaccorso, S.; Stone, J.M.; Reichenberg, A.; Brenneisen, R.; Holt, D.; Feilding, A.; Walker, L.; Murray, R.M.; Kapur, S. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J. Psychopharmacol., 2013, 27, 19-27. [http://dx.doi.org/10.1177/0269881112460109].
[34]
Hindocha, C.; Freeman, T.P.; Schafer, G.; Gardener, C.; Das, R.K.; Morgan, C.J.; Curran, H.V. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur. Neuropsychopharmacol., 2015, 25, 325-334. [http://dx.doi.org/10.1016/j.euroneuro.2014.11.014].
[35]
McGuire, P.; Robson, P.; Cubala, W.J.; Vasile, D.; Morrison, P.D.; Barron, R.; Taylor, A.; Wright, S. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am. J. Psychiatry, 2018, 175, 225-231. [http://dx.doi.org/10.1176/appi.ajp.2017.17030325].
[36]
Schiavon, A.P.; Bonato, J.M.; Milani, H.; Guimarães, F.S. Weffort, de Oliveira R.M. Influence of single and repeated cannabidiol administration on emotional behaviour and markers of cell proliferation and neurogenesis in non-stressed mice. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2016, 64, 27-34. [http://dx.doi.org/10.1016/j.pnpbp.2015.06.017].
[37]
Hallak, J.E.; Machado-de-Sousa, J.P.; Crippa, J.A.; Sanches, R.F.; Trzesniak, C.; Chaves, C.; Bernardo, S.A.; Regalo, S.C.; Zuardi, A.W. Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD). Br. J. Psychiatry, 2010, 32, 56-61. [http://dx.doi.org/10.1590/S1516-44462010000100011].
[38]
Leweke, F.M.; Piomelli, D.; Pahlisch, F.; Muhl, D.; Gerth, C.W.; Hoyer, C.; Klosterköter, J.; Hellmich, M.; Koethe, D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry, 2012, 2e94 [http://dx.doi.org/10.1038/tp.2012.15].
[39]
Hundal, H.; Lister, R.; Evans, N.; Antley, A.; Englund, A.; Murray, R.M.; Freeman, D.; Morrison, P.D. The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group. J. Psychopharmacol., 2018, 32, 276-282. [http://dx.doi.org/10.1177/0269881117737400].
[40]
Beale, C.; Broyd, S.J.; Chye, Y.; Suo, C.; Schira, M.; Galettis, P.; Martin, J.H.; Yücel, M.; Solowij, N. Prolonged cannabidiol treatment effects on hippocampal subfield volumes in current cannabis users. Cannabis Cannabinoid Res., 2018, 3, 94-107. [http://dx.doi.org/10.1089/can.2017.0047].
[41]
Solowij, N.; Broyd, S.J.; Beale, C.; Prick, J.A.; Greenwood, L.M.; van Hell, H.; Suo, C.; Galettis, P.; Pai, N.; Fu, S.; Croft, R.J.; Martin, J.H.; Yücel, M. Therapeutic effects of prolonged cannabidiol treatment on psychological symptoms and cognitive function in regular cannabis users: a pragmatic open-label clinical trial. Cannabis Cannabinoid Res., 2018, 3, 21-34. [http://dx.doi.org/10.1089/can.2017.0043].
[42]
Yücel, M.; Lorenzetti, V.; Suo, C.; Zalesky, A.; Fornito, A.; Takagi, M.J.; Lubman, D.I.; Solowij, N. Hippocampal harms, protection and recovery following regular cannabis use. Transl. Psychiatry, 2016, 6e710 [http://dx.doi.org/doi: 10.1038/tp.2015.201].
[43]
Chagas, M.H.; Zuardi, A.W.; Tumas, V.; Pena-Pereira, M.A.; Sobreira, E.T.; Bergamaschi, M.M.; dos Santos, A.C.; Texeira, A.L.; Hallak, J.E.; Crippa, J.A. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J. Psychopharmacol., 2014, 28, 1088-1098. [http://dx.doi.org/10.1177/0269881114550355].
[44]
Cheng, D.; Spiro, A.S.; Jenner, A.M.; Garner, B.; Karl, T. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J. Alzheimers Dis., 2014, 42, 1383-1396. [http://dx.doi.org/10.3233/JAD-140921].
[45]
Wade, D.T.; Makela, P.; Robson, P.; House, H.; Bateman, C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult. Scler., 2004, 10, 434-441. [http://dx.doi.org/10.1191/1352458504ms1082oa].
[46]
Urits, I.; Borchart, M.; Hasegawa, M.; Kochanski, J.; Orhurhu, V.; Viswanath, O. An update of current cannabis-based pharmaceuticals in pain medicine. Pain Ther., 2019. [http://dx.doi.org/10.1007/s40122-019-0114-4].
[47]
Aviello, G.; Romano, B.; Borrelli, F.; Capasso, R.; Gallo, L.; Piscitelli, F.; Di Marzo, V.; Izzo, A.A. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J. Mol. Med. (Berl.), 2012, 90, 925-934. [http://dx.doi.org/10.1007/s00109-011-0856-x].
[48]
De Petrocellis, L.; Ligresti, A.; Schiano Moriello, A.; Iappelli, M.; Verde, R.; Stott, C.G.; Cristino, L.; Orlando, P.; Di Marzo, V. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br. J. Pharmacol., 2013, 168, 79-102. [http://dx.doi.org/10.1111/j.1476-5381.2012.02027.x].
[49]
Ivanov, V.N.; Wu, J.; Wang, T.J.C.; Hei, T.K. Inhibition of ATM kinase upregulates levels of cell death induced by cannabidiol and γ-irradiation in human glioblastoma cells. Oncotarget, 2019, 10, 825-846. [http://dx.doi.org/10.18632/oncotarget.26582].
[50]
Babalonis, S.; Haney, M.; Malcolm, R.J.; Lofwall, M.R.; Votaw, V.R.; Sparenborg, S.; Walsh, S.L. Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers. Drug Alcohol Depend., 2017, 172, 9-13. [http://dx.doi.org/10.1016/j.drugalcdep.2016.11.030].
[51]
Schoedel, K.A.; Szeto, I.; Setnik, B.; Sellers, E.M.; Levy-Cooperman, N.; Mills, C.; Etges, T.; Sommerville, K. Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial. Epilepsy Behav., 2018, 88, 162-171. [http://dx.doi.org/10.1016/j.yebeh.2018.07.027].
[52]
Shannon, S.; Opila-Lehman, J. Cannabidiol oil for decreasing addictive use of marijuana: a case report. Integr. Med. (Encinitas), 2015, 14, 31-35. [http://dx.doi.org/10.1111/jcpt.12018].
[53]
Crippa, J.A.; Hallak, J.E.; Machado-de-Sousa, J.P.; Queiroz, R.H.; Bergamaschi, M.; Chagas, M.H.; Zuardi, A.W. Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. J. Clin. Pharm. Ther., 2013, 38, 162-164. [http://dx.doi.org/10.1111/jcpt.12018].
[54]
Mayor, S. WHO proposes rescheduling cannabis to allow medical applications. BMJ, 2019, 364, I574. [http://dx.doi.org/10.1136/bmj.l574].
[55]
World Health Organization (WHO). World Health Organization. Essential medicines and health products: forty-first meeting of the Expert Committee on Drug Dependence. 24 Sep 2018.https://www.who.int/medicines/access/controlled-substances/en (Accessed 12 March, 2019).
[56]
US Drug Enforcement Administration (DEA).Schedules of controlled substances: Placement in schedule V of certain FDA-approved drugs containing cannabidiol; corresponding change to permit requirements. Final order. Fed. Regist., 2018, 83, 48950-48953.
[57]
Bergamaschi, M.M.; Queiroz, R.H.; Zuardi, A.W.; Crippa, J.A. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr. Drug Saf., 2011, 6, 237-249. [http://dx.doi.org/10.2174/157488611798280924].
[58]
Iffland, K.; Grotenhermen, F. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis Cannabinoid Res., 2017, 2, 139-154. [http://dx.doi.org/10.1089/can.2016.0034].
[59]
Mato, S.; Victoria Sánchez-Gómez, M.; Matute, C. Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. Glia, 2010, 58, 1739-1747. [http://dx.doi.org/10.1002/glia.21044].
[60]
Schönhofen, P.; de Medeiros, L.M.; Bristot, I.J.; Lopes, F.M.; De Bastiani, M.A.; Kapczinski, F.; Crippa, J.A.; Castro, M.A.; Parsons, R.B.; Klamt, F. Cannabidiol exposure during neuronal differentiation sensitizes cells against redox-active neurotoxins. Mol. Neurobiol., 2015, 52, 26-37. [http://dx.doi.org/10.1007/s12035-014-8843-1].
[61]
Rosenkrantz, H.; Fleischman, R.W.; Grant, R.J. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicol. Appl. Pharmacol., 1981, 58, 118-131. [http://dx.doi.org/10.1016/0041-008X(81)90122-8].
[62]
Guinguis, R.; Ruiz, M.I.; Rada, G. Is cannabidiol an effective treatment for schizophrenia? Medwave, 2017, 17e7010 [http://dx.doi.org/10.5867/medwave.2017.07.7010].
[63]
Garberg, H.T.; Solberg, R.; Barlinn, J.; Martinez-Orgado, J.; Løberg, E.M.; Saugstad, O.D. High-dose cannabidiol induced hypotension after global hypoxia-ischemia in piglets. Neonatology, 2017, 112, 143-149. [http://dx.doi.org/10.1159/000471786].
[64]
Barata, L.; Arruza, L.; Rodríguez, M.J.; Aleo, E.; Vierge, E.; Criado, E.; Sobrino, E.; Vargas, C.; Ceprián, M.; Gutiérrez-Rodrígez, A.; Hind, W.; Martínez-Orgado, J. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. Neuropharmacology, 2019, 146, 1-11. [http://dx.doi.org/10.1016/j.neuropharm.2018.11.020].
[65]
Thiele, E.A.; Marsh, E.D.; French, J.A.; Mazurkiewicz-Beldzinska, M.; Benbadis, S.R.; Joshi, C.; Lyons, P.D.; Taylor, A.; Roberts, C.; Sommerville, K. GWPCARE4 Study Group.Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet, 2018, 391, 1085-1096. [http://dx.doi.org/10.1016/S0140-6736(18)30136-3].
[66]
Szaflarski, J.P.; Bebin, E.M.; Comi, A.M.; Patel, A.D.; Joshi, C.; Checketts, D.; Beal, J.C.; Laux, L.C.; De Boer, L.M.; Wong, M.H.; Lopez, M.; Devinsky, O.; Lyons, P.D.; Zentil, P.P.; Wechsler, R. CBD EAP study group Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia, 2018, 59, 1540-1548. [http://dx.doi.org/10.1111/epi.14477].
[67]
Hussain, S.A.; Zhou, R.; Jacobson, C.; Weng, J.; Cheng, E.; Lay, J.; Hung, P.; Lerner, J.T.; Sankar, R. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: a potential role for infantile spasms and Lennox-Gastaut syndrome. Epilepsy Behav., 2015, 47, 138-141. [http://dx.doi.org/10.1016/j.yebeh.2015.04.009].
[68]
Porter, B.E.; Jacobson, C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav., 2013, 29, 574-577. [http://dx.doi.org/10.1016/j.yebeh.2013.08.037].
[69]
Tzadok, M.; Uliel-Siboni, S.; Linder, I.; Kramer, U.; Epstein, O.; Menascu, S.; Nissenkorn, A.; Yosef, O.B.; Hyman, E.; Granot, D.; Dor, M.; Lerman-Sagie, T.; Ben-Zeev, B. CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure, 2016, 35, 41-44. [http://dx.doi.org/10.1016/j.seizure.2016.01.004].
[70]
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, N.S.; Wilson, C.A.; Patel, A.; Cilio, M.R. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol., 2016, 15, 270-278. [http://dx.doi.org/10.1016/S1474-4422(15)00379-8].
[71]
Devinsky, O.; Cross, J.H.; Laux, L.; Marsh, E.; Miller, I.; Nabbout, R.; Scheffer, I.E.; Thiele, E.A.; Wright, S. Cannabidiol in Dravet Syndrome Study Group.Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med., 2017, 376, 2011-2020. [http://dx.doi.org/10.1056/NEJMoa1611618].
[72]
Koo, C.M.; Kang, H.C. Could cannabidiol be a treatment option for intractable childhood and adolescent epilepsy? J. Epilepsy Res., 2017, 7, 16-20. [http://dx.doi.org/10.14581/jer.17003].
[73]
Neale, M. Efficacy and safety of cannabis for treating children with refractory epilepsy. Nurs. Child. Young People, 2017, 29, 32-37. [http://dx.doi.org/10.7748/ncyp.2017.e907].
[74]
Devinsky, O.; Patel, A.D.; Thiele, E.A.; Wong, M.H.; Appleton, R.; Harden, C.L.; Greenwood, S.; Morrison, G.; Sommerville, K. GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology, 2018, 90, e1204-e1211. [http://dx.doi.org/10.1212/WNL.0000000000005254].
[75]
Devinsky, O.; Patel, A.D.; Cross, J.H.; Villanueva, V.; Wirrell, E.C.; Privitera, M.; Greenwood, S.M.; Roberts, C.; Checketts, D.; VanLandingham, K.E.; Zuberi, S.M. GWPCARE3 Study Group.Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N. Engl. J. Med., 2018, 378, 1888-1897. [http://dx.doi.org/10.1056/NEJMoa1714631].
[76]
Crippa, J.A.; Zuardi, A.W.; Garrido, G.E.; Wichert-Ana, L.; Guarnieri, R.; Ferrari, L.; Azevedo-Marques, P.M.; Hallak, J.E.; McGuire, P.K.; Filho, B.G. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology, 2004, 29, 417-426. [http://dx.doi.org/10.1038/sj.npp.1300340].
[77]
Resstel, L.B.; Joca, S.R.; Moreira, F.A.; Corrêa, F.M.; Guimarães, F.S. Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav. Brain Res., 2006, 172, 294-298. [http://dx.doi.org/10.1016/j.bbr.2006.05.016].
[78]
Moreira, F.A.; Aguiar, D.C.; Guimarães, F.S. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2006, 30, 1466-1471. [http://dx.doi.org/10.1016/j.pnpbp.2006.06.004].
[79]
ElBatsh, M.M.; Assareh, N.; Marsden, C.A.; Kendall, D.A. Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology (Berl.), 2012, 221, 239-247. [http://dx.doi.org/10.1007/s00213-011-2566-z].
[80]
Khoury, J.M.; Neves, M.C.L.D.; Roque, M.A.V.; Queiroz, D.A.B.; Corrêa de Freitas, A.A.; de Fátima, Â.; Moreira, F.A.; Garcia, F.D. Is there a role for cannabidiol in psychiatry? World J. Biol. Psychiatry, 2017, 20, 1-16. [http://dx.doi.org/10.1080/15622975.2017.1285049].
[81]
Karniol, I.G.; Shirakawa, I.; Kasinski, N.; Pfeferman, A.; Carlini, E.A. Cannabidiol interferes with the effects of delta 9 - tetrahydrocannabinol in man. Eur. J. Pharmacol., 1974, 28, 172-177. [http://dx.doi.org/10.1016/0014-2999(74)90129-0].
[82]
Bornheim, L.M.; Kim, K.Y.; Li, J.; Perotti, B.Y.; Benet, L.Z. Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab. Dispos., 1995, 23, 825-831.
[83]
Jones, G.; Pertwee, R.G. A metabolic interaction in vivo between cannabidiol and 1 –tetrahydrocannabinol. Br. J. Pharmacol., 1972, 45, 375-377. [http://dx.doi.org/10.1111/j.1476-5381.1972.tb08092.x].
[84]
Paton, W.D.; Pertwee, R.G. Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Br. J. Pharmacol., 1972, 44, 250-261. [http://dx.doi.org/10.1111/j.1476-5381.1972.tb07261.x].
[85]
Bornheim, L.M.; Everhart, E.T.; Li, J.; Correia, M.A. Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol. Biochem. Pharmacol., 1994, 48, 161-171. [http://dx.doi.org/10.1016/0006-2952(94)90236-4].
[86]
Narimatsu, S.; Watanabe, K.; Matsunaga, T.; Yamamoto, I.; Imaoka, S.; Funae, Y.; Yoshimura, H. Inhibition of hepatic microsomal cytochrome P450 by cannabidiol in adult male rats. Chem. Pharm. Bull. (Tokyo), 1990, 38, 1365-1368. [http://dx.doi.org/10.1248/cpb.38.1365].
[87]
Bornheim, L.M.; Correia, M.A. Selective inactivation of mouse liver cytochrome P-4501IIA by cannabidiol. Mol. Pharmacol., 1990, 38, 319-326.
[88]
Bornheim, L.M.; Correia, M.A. Purification and characterization of the major hepatic cannabinoid hydroxyiase in the mouse: A possible member of the cytochrome P-450IIC subfamily. Mol. Pharmacol., 1991, 40, 228-234.
[89]
Bornheim, L.M.; Lasker, J.M.; Raucy, J.L. Human hepatic microsomal metabolism of delta 1-tetrahydrocannabinol. Drug Metab. Dispos., 1992, 2, 241-246.
[90]
Jaeger, W.; Benet, L.Z.; Bornheim, L.M. Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes. Xenobiotica, 1996, 26, 275-284. [http://dx.doi.org/10.3109/00498259609046707].
[91]
Guengerich, F.P. Human cytochrome P450 enzymes In: Cytochrome P450: structure, mechanism, and biochemistry; Ortiz de Montellano, P.R., Ed.; Plenum Press: New York,. , 1995; pp. 473-535.
[92]
Bornheim, L.M. In:Biochemistry and physiology of substance abuse; Watson, R.R., Ed.; CRC Press: Boca Raton, 1989, pp. 21-35.
[93]
Bornheim, L.M.; Kim, Y.K.; Chen, B.; Correia, M.A. The Effect of Cannabidiol on Mouse Hepatic Microsomal Cytochrome P450- Dependent Anandamide Metabolism. Biochem. Biophys. Res. Commun., 1993, 197, 740-746. [http://dx.doi.org/10.1006/bbrc.1993.2541].
[94]
Karschner, E.L.; Darwin, W.D.; Goodwin, R.S.; Wright, S.; Huestis, M.A. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin. Chem., 2011, 57, 66-75. [http://dx.doi.org/10.1373/clinchem.2010.152439].
[95]
Karschner, E.L.; Darwin, W.D.; McMahon, R.P.; Liu, F.; Wright, S.; Goodwin, R.S.; Huestis, M.A. Subjective and physiological effects after controlled Sativex and oral THC administration. Clin. Pharmacol. Ther., 2011, 89, 400-407. [http://dx.doi.org/10.1038/clpt.2010.318].
[96]
Hložek, T.; Uttl, L.; Kadeřábek, L.; Balíková, M.; Lhotková, E.; Horsley, R.R.; Nováková, P.; Šíchová, K.; Štefková, K.; Tylš, F.; Kuchař, M.; Páleníček, T. Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. Eur. Neuropsychopharmacol., 2017, 27, 1223-1237. [http://dx.doi.org/10.1016/j.euroneuro.2017.10.037].
[97]
Yang, Y.T.; Szaflarski, J.P. The us food and drug administration’s authorization of the first cannabis-derived pharmaceutical: Are we out of the haze? JAMA Neurol., 2018, 76(2), 135-136. [http://dx.doi.org/10.1001/jamaneurol.2018.3550].
[98]
Reich, R.; Laufer, N.; Lewysohn, O.; Cordova, T.; Ayalon, D.; Tsafriri, A. In vitro effects of cannabinoids on follicular function in the rat. Biol. Reprod., 1982, 27, 223-231.
[http://dx.doi.org/10.1095/ biolreprod27.1.223]
[99]
Watanabe, K.; Motoya, E.; Matsuzawa, N.; Funahashi, T.; Kimura, T.; Matsunaga, T.; Arizono, K.; Yamamoto, I. Marijuana extracts possess the effects like the endocrine disrupting chemicals. Toxicology, 2005, 206, 471-478. [http://dx.doi.org/10.1016/j.tox.2004.08.005].
[100]
Rosenkrantz, H.; Hayden, D.W. Acute and subacute inhalation toxicity of Turkish marihuana, cannabichromene, and cannabidiol in rats. Toxicol. Appl. Pharmacol., 1979, 48, 375-386. [http://dx.doi.org/10.1016/0041-008X(79)90421-6].
[101]
Schuel, H.; Schuel, R.; Zimmerman, A.M.; Zimmerman, S. Cannabinoids reduce fertility of sea urchin sperm. Biochem. Cell Biol., 1987, 65, 130-136. [http://dx.doi.org/10.1139/o87-018].
[102]
Schuel, H.; Berkery, D.; Schuel, R.; Chang, M.C.; Zimmerman, A.M.; Zimmerman, S. Reduction of the fertilizing capacity of sea urchin sperm by cannabinoids derived from marihuana. I. Inhibition of the acrosome reaction induced by egg jelly. Mol. Reprod. Dev., 1991, 29, 51-59. [http://dx.doi.org/10.1002/mrd.1080290109].
[103]
Center for Drug Evaluation and Research. Non-clinical reviews. US FDA Report 2018.https://www.accessdata.fda.gov/drugsatfda_ docs/nda/2018/210365Orig1s000PharmR.pdf (Accessed 12 March, 2019).
[104]
Carvalho, R.K.; Santos, M.L.; Souza, M.R.; Rocha, T.L.; Guimarães, F.S.; Anselmo-Franci, J.A.; Mazaro-Costa, R. Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice. J. Appl. Toxicol., 2018, 38, 1215-1223. [http://dx.doi.org/10.1002/jat.3631].
[105]
Srivastava, M.D.; Srivastava, B.I.; Brouhard, B. Delta 9-tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology, 1998, 40, 179-185. [http://dx.doi.org/10.1016/S0162-3109(98)00041-1].
[106]
Wu, H.Y.; Chu, R.M.; Wang, C.C.; Lee, C.Y.; Lin, S.H.; Jan, T.R. Cannabidiol-induced apoptosis in primary lymphocytes is associated with oxidative stress-dependent activation of caspase-8. Toxicol. Appl. Pharmacol., 2008, 226, 260-270. [http://dx.doi.org/10.1016/j.taap.2007.09.012].
[107]
Lee, C.Y.; Wey, S.P.; Liao, M.H.; Hsu, W.L.; Wu, H.Y.; Jan, T.R. A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells. Int. Immunopharmacol., 2008, 8, 732-740. [http://dx.doi.org/10.1016/j.intimp.2008.01.018].
[108]
Holland, M.L.; Lau, D.T.; Allen, J.D.; Arnold, J.C. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids. Br. J. Pharmacol., 2007, 152, 815-824. [http://dx.doi.org/10.1038/sj.bjp.0707467].
[109]
Holland, M.L.; Panetta, J.A.; Hoskins, J.M.; Bebawy, M.; Roufogalis, B.D.; Allen, J.D.; Arnold, J.C. The effects of cannabinoids on P-glycoprotein transport and expression in multidrug resistant cells. Biochem. Pharmacol., 2006, 71, 1146-1154. [http://dx.doi.org/10.1016/j.bcp.2005.12.033].
[110]
Holland, M.L.; Allen, J.D.; Arnold, J.C. Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur. J. Pharmacol., 2008, 591, 128-131. [http://dx.doi.org/10.1016/j.ejphar.2008.06.079].
[111]
Ujváry, I.; Hanuš, L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res., 2016, 1, 90-101. [http://dx.doi.org/10.1089/can.2015.0012].
[112]
Stott, C.; White, L.; Wright, S.; Wilbraham, D.; Guy, G. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus, 2013, 2, 236. [http://dx.doi.org/10.1186/2193-1801-2-236].

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