Generic placeholder image

Current Neuropharmacology

Editor-in-Chief

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

Systematic Review Article

Update on Cannabidiol Clinical Toxicity and Adverse Effects: A Systematic Review

Author(s): Graziella Madeo, Ashita Kapoor, Raffaele Giorgetti, Francesco Paolo Busardò* and Jeremy Carlier

Volume 21, Issue 11, 2023

Published on: 07 April, 2023

Page: [2323 - 2342] Pages: 20

DOI: 10.2174/1570159X21666230322143401

Price: $65

conference banner
Abstract

Background: Compelling evidence from preclinical and clinical studies supports the therapeutic role of cannabidiol (CBD) in several medical disorders. We reviewed the scientific evidence on CBD-related toxicity and adverse events (AEs) in 2019, at the beginning of the spike in clinical studies involving CBD. However, CBD safety remained uncertain.

Objective: With the benefit of hindsight, we aimed to provide an update on CBD-related toxicity and AEs in humans.

Methods: A systematic literature search was conducted following PRISMA guidelines. PubMed, Cochrane, and Embase were accessed in October 2022 to identify clinical studies mentioning CBDrelated toxicity/AEs from February 2019 to September 2022. Study design, population characteristics, CBD doses, treatment duration, co-medications, and AEs were compiled.

Results: A total of 51 reports were included. Most studies investigated CBD efficacy and safety in neurological conditions, such as treatment-resistant epilepsies, although a growing number of studies are focusing on specific psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety. Most studies report mild or moderate severity of AEs. The most common AEs are diarrhea, somnolence, sedation, and upper respiratory disturbances. Few serious AEs have been reported, especially when CBD is co-administered with other classes of drugs, such as clobazam and valproate.

Conclusion: Clinical data suggest that CBD is well tolerated and associated with few serious AEs at therapeutic doses both in children and adults. However, interactions with other medications should be monitored carefully. Additional data are needed to investigate CBD's long-term efficacy and safety, and CBD use in medical conditions other than epilepsy syndromes.

Keywords: Cannabidiol, clinical study, toxicity, adverse event, psychosis, anxiety, treatment-resistant epilepsy.

Graphical Abstract
[1]
Zuardi, A.W.; Crippa, J.A.S.; Hallak, J.E.C.; Moreira, F.A.; Guimarães, F.S. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz. J. Med. Biol. Res., 2006, 39(4), 421-429.
[http://dx.doi.org/10.1590/S0100-879X2006000400001] [PMID: 16612464]
[2]
Crippa, J.A.; Guimarães, F.S.; Campos, A.C.; Zuardi, A.W. Translational investigation of the therapeutic potential of cannabidiol (CBD): Toward a new age. Front. Immunol., 2018, 9, 2009.
[http://dx.doi.org/10.3389/fimmu.2018.02009] [PMID: 30298064]
[3]
Ligresti, A.; De Petrocellis, L.; Di Marzo, V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiol. Rev., 2016, 96(4), 1593-1659.
[http://dx.doi.org/10.1152/physrev.00002.2016] [PMID: 27630175]
[4]
Lafaye, G.; Desterke, C.; Marulaz, L.; Benyamina, A. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addict. Biol., 2019, 24(5), 921-934.
[http://dx.doi.org/10.1111/adb.12660] [PMID: 30307084]
[5]
Devane, W.A.; Hanuš, 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 (80-. ), 1992, 258, 1946-1949.
[http://dx.doi.org/10.1126/science.1470919]
[6]
Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.M.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB 1 receptor. Br. J. Pharmacol., 2015, 172(20), 4790-4805.
[http://dx.doi.org/10.1111/bph.13250] [PMID: 26218440]
[7]
Straiker, A.; Dvorakova, M.; Zimmowitch, A.; Mackie, K. Cannabidiol inhibits endocannabinoid signaling in autaptic hippocampal neurons. Mol. Pharmacol., 2018, 94(1), 743-748.
[http://dx.doi.org/10.1124/mol.118.111864] [PMID: 29669714]
[8]
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., 2019, 176(10), 1455-1469.
[http://dx.doi.org/10.1111/bph.14440] [PMID: 29981240]
[9]
Mechoulam, R.; Peters, M.; Murillo-Rodriguez, E.; Hanuš, L.O. Cannabidiol-recent advances. Chem. Biodivers., 2007, 4(8), 1678-1692.
[http://dx.doi.org/10.1002/cbdv.200790147] [PMID: 17712814]
[10]
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., 2017, 49(10), 853-866.
[http://dx.doi.org/10.1093/abbs/gmx073] [PMID: 28981597]
[11]
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, 152, 58-66.
[http://dx.doi.org/10.1016/j.neuropharm.2019.02.004] [PMID: 30738036]
[12]
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(8), 1517-1521.
[http://dx.doi.org/10.1016/j.pnpbp.2009.08.017] [PMID: 19735690]
[13]
Wise, J. European drug agency approves cannabis-based medicine for severe forms of epilepsy. BMJ, 2019, 366, l5708.
[http://dx.doi.org/10.1136/bmj.l5708] [PMID: 31551241]
[14]
Jadoon, K.A.; Ratcliffe, S.H.; Barrett, D.A.; Thomas, E.L.; Stott, C.; Bell, J.D.; O’Sullivan, S.E.; Tan, G.D. 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, 2016, 39(10), 1777-1786.
[http://dx.doi.org/10.2337/dc16-0650] [PMID: 27573936]
[15]
Study to Evaluate the Effect of GWP42003 on Liver Fat Levels in Participants With Fatty Liver Disease. NCT01284634. 2018. Available from: https://clinicaltrials.gov/ct2/show/NCT01284634
[16]
Suraev, A.; Grunstein, R.R.; Marshall, N.S.; D’Rozario, A.L.; Gordon, C.J.; Bartlett, D.J.; Wong, K.; Yee, B.J.; Vandrey, R.; Irwin, C.; Arnold, J.C.; McGregor, I.S.; Hoyos, C.M. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) for chronic insomnia disorder (‘CANSLEEP’ trial): protocol for a randomised, placebo-controlled, double-blinded, proof-of-concept trial. BMJ Open, 2020, 10(5), e034421.
[http://dx.doi.org/10.1136/bmjopen-2019-034421] [PMID: 32430450]
[17]
Cherner, M. CBD for Sleep in People With HIV. NCT05097651. 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT05097651
[18]
McGuire, P.; Robson, P.; Jerzy Cubala, W.; Vasile, D.; Dugald Morrison, P.; Barron, R.; Taylor, A.; Wright, S. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. Am J Psychiatry., 2018, 175(3), 225-231.
[http://dx.doi.org/10.1176/appi.ajp.2017.17030325]
[19]
Köck, P.; Lang, E.; Trulley, V.N.; Dechent, F.; Mercer-Chalmers-Bender, K.; Frei, P.; Huber, C.; Borgwardt, S. Cannabidiol cigarettes as adjunctive treatment for psychotic disorders - a randomized, open-label pilot-study. Front. Psychiatry, 2021, 12, 736822.
[http://dx.doi.org/10.3389/fpsyt.2021.736822] [PMID: 34803760]
[20]
Trauner, D. Trial of Cannabidiol to Treat Severe Behavior Problems in Children With Autism. NCT04517799, 2022. Full Text View - ClinicalTrials Available from: https://clinicaltrials.gov/ct2/show/NCT04517799.
[21]
Tartaglia, N.R.; Sannar, E. CASCADE: CAnnabidiol Study in Children With Autism Spectrum DisordEr. NCT04520685, 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT04520685
[22]
Arout, C.A.; Haney, M.; Herrmann, E.S.; Bedi, G.; Cooper, Z.D. A placebo‐controlled investigation of the analgesic effects, abuse liability, safety and tolerability of a range of oral cannabidiol doses in healthy humans. Br. J. Clin. Pharmacol., 2022, 88(1), 347-355.
[http://dx.doi.org/10.1111/bcp.14973] [PMID: 34223660]
[23]
Zuardi, A.W. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev. Bras. Psiquiatr., 2008, 30(3), 271-280.
[http://dx.doi.org/10.1590/S1516-44462008000300015] [PMID: 18833429]
[24]
Almeida, C.M.O.; Brito, M.M.C.; Bosaipo, N.B.; Pimentel, A.V.; Tumas, V.; Zuardi, A.W.; Crippa, J.A.S.; Hallak, J.E.C.; Eckeli, A.L. Cannabidiol for rapid eye movement sleep behavior disorder. Mov. Disord., 2021, 36(7), 1711-1715.
[http://dx.doi.org/10.1002/mds.28577] [PMID: 33754375]
[25]
Pautex, S.; Bianchi, F.; Daali, Y.; Augsburger, M.; de Saussure, C.; Wampfler, J.; Curtin, F.; Desmeules, J.; Broers, B. Cannabinoids for behavioral symptoms in severe dementia: Safety and feasibility in a long-term pilot observational study in nineteen patients. Front. Aging Neurosci., 2022, 14, 957665.
[http://dx.doi.org/10.3389/fnagi.2022.957665] [PMID: 36247984]
[26]
ISRCTN - ISRCTN87895237: Multi-centre trial of cannabidiol (CBD) for the treatment of Parkinson’s disease psychosis. ISRCTN87895237, 2023. Available from: https://www.isrctn.com/ISRCTN87895237
[27]
Freeman, T.P.; Hindocha, C.; Green, S.F.; Bloomfield, M.A.P. Medicinal use of cannabis based products and cannabinoids. BMJ., 2019, 365, l1141.
[http://dx.doi.org/10.1136/bmj.l1141]
[28]
Huestis, M.A.; Solimini, R.; Pichini, S.; Pacifici, R.; Carlier, J.; Busardò, F.P. Cannabidiol adverse effects and toxicity. Curr. Neuropharmacol., 2019, 17(10), 974-989.
[http://dx.doi.org/10.2174/1570159X17666190603171901] [PMID: 31161980]
[29]
Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; Chou, R.; Glanville, J.; Grimshaw, J.M.; Hróbjartsson, A.; Lalu, M.M.; Li, T.; Loder, E.W.; Mayo-Wilson, E.; McDonald, S.; McGuinness, L.A.; Stewart, L.A.; Thomas, J.; Tricco, A.C.; Welch, V.A.; Whiting, P.; Moher, D. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ, 2021, 372, n71.
[http://dx.doi.org/10.1136/bmj.n71] [PMID: 33782057]
[30]
Metternich, B.; Wagner, K.; Geiger, M.J.; Hirsch, M.; Schulze-Bonhage, A.; Klotz, K.A. Cognitive and behavioral effects of cannabidiol in patients with treatment-resistant epilepsy. Epilepsy Behav., 2021, 114(Pt A), 107558.
[http://dx.doi.org/10.1016/j.yebeh.2020.107558] [PMID: 33246899]
[31]
Laux, L.C.; Bebin, E.M.; Checketts, D.; Chez, M.; Flamini, R.; Marsh, E.D.; Miller, I.; Nichol, K.; Park, Y.; Segal, E.; Seltzer, L.; Szaflarski, J.P.; Thiele, E.A.; Weinstock, A. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Res., 2019, 154, 13-20.
[http://dx.doi.org/10.1016/j.eplepsyres.2019.03.015] [PMID: 31022635]
[32]
Gaston, T.E.; Ampah, S.B.; Martina Bebin, E.; Grayson, L.P.; Cutter, G.R.; Hernando, K.; Szaflarski, J.P. Long-term safety and efficacy of highly purified cannabidiol for treatment refractory epilepsy. Epilepsy Behav., 2021, 117, 107862.
[http://dx.doi.org/10.1016/j.yebeh.2021.107862] [PMID: 33667843]
[33]
Martin, R.C.; Gaston, T.E.; Thompson, M.; Ampah, S.B.; Cutter, G.; Bebin, E.M.; Szaflarski, J.P. Cognitive functioning following long-term cannabidiol use in adults with treatment-resistant epilepsy. Epilepsy Behav., 2019, 97, 105-110.
[http://dx.doi.org/10.1016/j.yebeh.2019.04.044] [PMID: 31220785]
[34]
Herlopian, A.; Hess, E.J.; Barnett, J.; Geffrey, A.L.; Pollack, S.F.; Skirvin, L.; Bruno, P.; Sourbron, J.; Thiele, E.A. Cannabidiol in treatment of refractory epileptic spasms: An open-label study. Epilepsy Behav., 2020, 106, 106988.
[http://dx.doi.org/10.1016/j.yebeh.2020.106988] [PMID: 32169600]
[35]
Nenert, R.; Allendorfer, J.B.; Bebin, E.M.; Gaston, T.E.; Grayson, L.E.; Houston, J.T.; Szaflarski, J.P. Cannabidiol normalizes resting-state functional connectivity in treatment-resistant epilepsy. Epilepsy Behav., 2020, 112, 107297.
[http://dx.doi.org/10.1016/j.yebeh.2020.107297] [PMID: 32745959]
[36]
Thompson, M.D.; Martin, R.C.; Grayson, L.P.; Ampah, S.B.; Cutter, G.; Szaflarski, J.P.; Bebin, E.M. Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy. Epilepsy Behav., 2020, 111, 107299.
[http://dx.doi.org/10.1016/j.yebeh.2020.107299] [PMID: 32759071]
[37]
Scheffer, I.E.; Hulihan, J.; Messenheimer, J.; Ali, S.; Keenan, N.; Griesser, J.; Gutterman, D.L.; Sebree, T.; Sadleir, L.G. Safety and tolerability of transdermal cannabidiol gel in children with developmental and epileptic encephalopathies. JAMA Netw. Open, 2021, 4(9), e2123930.
[http://dx.doi.org/10.1001/jamanetworkopen.2021.23930] [PMID: 34477852]
[38]
Pietrafusa, N.; Ferretti, A.; Trivisano, M.; de Palma, L.; Calabrese, C.; Carfì Pavia, G.; Tondo, I.; Cappelletti, S.; Vigevano, F.; Specchio, N. Purified cannabidiol for treatment of refractory epilepsies in pediatric patients with developmental and epileptic encephalopathy. P ediatr. Drugs, 2019, 214(21), 283-290.
[http://dx.doi.org/10.1007/s40272-019-00341-x]
[39]
Caraballo, R.; Demirdjian, G.; Reyes, G.; Huaman, M.; Gutierrez, R. Effectiveness of cannabidiol in a prospective cohort of children with drug-resistant epileptic encephalopathy in Argentina. Seizure, 2020, 80, 75-80.
[http://dx.doi.org/10.1016/j.seizure.2020.06.005] [PMID: 32544657]
[40]
Patel, A.D.; Mazurkiewicz-Bełdzińska, M.; Chin, R.F.; Gil-Nagel, A.; Gunning, B.; Halford, J.J.; Mitchell, W.; Scott Perry, M.; Thiele, E.A.; Weinstock, A.; Dunayevich, E.; Checketts, D.; Devinsky, O. Long‐term safety and efficacy of add‐on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long‐term open‐label extension trial. Epilepsia, 2021, 62(9), 2228-2239.
[http://dx.doi.org/10.1111/epi.17000] [PMID: 34287833]
[41]
Thiele, E.; Marsh, E.; Mazurkiewicz-Beldzinska, M.; Halford, J.J.; Gunning, B.; Devinsky, O.; Checketts, D.; Roberts, C. Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study. Epilepsia, 2019, 60(3), 419-428.
[http://dx.doi.org/10.1111/epi.14670] [PMID: 30740695]
[42]
Park, Y.D.; Linder, D.F.; Pope, J.; Flamini, J.R.; Moretz, K.; Diamond, M.P.; Long, S.A. Long-term efficacy and safety of cannabidiol (CBD) in children with treatment-resistant epilepsy: Results from a state-based expanded access program. Epilepsy Behav., 2020, 112, 107474.
[http://dx.doi.org/10.1016/j.yebeh.2020.107474] [PMID: 33181893]
[43]
Thiele, E.A.; Bebin, E.M.; Filloux, F.; Kwan, P.; Loftus, R.; Sahebkar, F.; Sparagana, S.; Wheless, J. Long‐term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open‐label extension trial. Epilepsia, 2022, 63(2), 426-439.
[http://dx.doi.org/10.1111/epi.17150] [PMID: 34957550]
[44]
Ebrahimi-Fakhari, D.; Agricola, K.D.; Tudor, C.; Krueger, D.; Franz, D.N. Cannabidiol elevates mechanistic target of rapamycin inhibitor levels in patients with tuberous sclerosis complex. Pediatr. Neurol., 2020, 105, 59-61.
[http://dx.doi.org/10.1016/j.pediatrneurol.2019.11.017] [PMID: 31924480]
[45]
Koo, C.M.; Kim, S.H.; Lee, J.S.; Park, B.J.; Lee, H.K.; Kim, H.D.; Kang, H.C. Cannabidiol for treating lennox-gastaut syndrome and dravet syndrome in Korea. J. Korean Med. Sci., 2020, 35(50), e427.
[http://dx.doi.org/10.3346/jkms.2020.35.e427] [PMID: 33372424]
[46]
Thiele, E.A.; Bebin, E.M.; Bhathal, H.; Jansen, F.E.; Kotulska, K.; Lawson, J.A.; O’Callaghan, F.J.; Wong, M.; Sahebkar, F.; Checketts, D.; Knappertz, V.; Archer, J.; Arndt, D.H.; Barron, T.; Bebin, E.M.; Bhathal, H.; Cantarín-Extremera, V.; Sanchez-Carpintero, R.; Ciliberto, M.A.; Cock, H.; De Wit, M-C.Y.; Devinsky, O.; Falip, M.; Filloux, F.M.; Fountain, N.B.; Gawlowicz, J.; Greenwood, R.S.; Hamandi, K.; Jansen, F.E.; Joshi, C.; Józwiak, S.; Klein, P.; Kotulska, K.; Kwan, P.; Lawson, J.A.; Lisewski, P.; Miller, I.O.; Morse, R.P.; Mostajelean, A.S.; Nolan, D.A.; O’Brien, T.J.; O’Callaghan, F.J.; Paredes, F.; Perry, M.S.; Ramos, F.J.; Reutens, D.; Roberts, C.M.; Saneto, R.P.; Sharp, G.B.; Saxena, A.; Sparagana, S.P.; Tatachar, P.; Thiele, E.A.; Wheless, J.W.; Wirrell, E.C.; Wong, M.H.; Wong, M.; Wu, J.Y.; Zolnowska, M. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex. JAMA Neurol., 2021, 78(3), 285-292.
[http://dx.doi.org/10.1001/jamaneurol.2020.4607] [PMID: 33346789]
[47]
Devinsky, O.; Nabbout, R.; Miller, I.; Laux, L.; Zolnowska, M.; Wright, S.; Roberts, C. Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial. Epilepsia, 2019, 60(2), 294-302.
[http://dx.doi.org/10.1111/epi.14628] [PMID: 30582156]
[48]
O’Brien, T.J.; Berkovic, S.F.; French, J.A.; Messenheimer, J.A.; Sebree, T.B.; Bonn-Miller, M.O.; Gutterman, D.L.; Wijayath, M.; Patrikios, P.; Reutens, D.; Frasca, J.; Seneviratne, U.; D’Souza, W.; Bergin, P.; Anderson, T.; Rosemergy, I.; Nikpour, A.; Kwan, P.; Asztely, F.; Somerville, E. Adjunctive transdermal cannabidiol for adults with focal epilepsy. JAMA Netw. Open, 2022, 5(7), e2220189.
[http://dx.doi.org/10.1001/jamanetworkopen.2022.20189] [PMID: 35802375]
[49]
VanLandingham, K.E.; Crockett, J.; Taylor, L.; Morrison, G. A phase 2, double‐blind, placebo‐controlled trial to investigate potential drug‐drug interactions between cannabidiol and clobazam. J. Clin. Pharmacol., 2020, 60(10), 1304-1313.
[http://dx.doi.org/10.1002/jcph.1634] [PMID: 32652616]
[50]
Ben-Menachem, E.; Gunning, B.; Arenas Cabrera, C.M.; Van-Landingham, K.; Crockett, J.; Critchley, D.; Wray, L.; Tayo, B.; Morrison, G.; Toledo, M. A phase II randomized trial to explore the potential for pharmacokinetic drug-drug interactions with stiripentol or valproate when combined with cannabidiol in patients with epilepsy. CNS Drugs, 2020, 34(6), 661-672.
[http://dx.doi.org/10.1007/s40263-020-00726-4] [PMID: 32350749]
[51]
Miller, I.; Scheffer, I.E.; Gunning, B.; Sanchez-Carpintero, R.; Gil-Nagel, A.; Perry, M.S.; Saneto, R.P.; Checketts, D.; Dunayevich, E.; Knappertz, V. Dose-ranging effect of adjunctive oral cannabidiol vs. placebo on convulsive seizure frequency in dravet syndrome. JAMA Neurol., 2020, 77(5), 613-621.
[http://dx.doi.org/10.1001/jamaneurol.2020.0073] [PMID: 32119035]
[52]
Scheffer, I.E.; Halford, J.J.; Miller, I.; Nabbout, R.; Sanchez-Carpintero, R.; Shiloh-Malawsky, Y.; Wong, M.; Zolnowska, M.; Checketts, D.; Dunayevich, E.; Devinsky, O. Add‐on cannabidiol in patients with Dravet syndrome: Results of a long‐term open‐label extension trial. Epilepsia, 2021, 62(10), 2505-2517.
[http://dx.doi.org/10.1111/epi.17036] [PMID: 34406656]
[53]
Caraballo, R.; Valenzuela, G.R. Cannabidiol-enriched medical cannabis as add-on therapy in children with treatment-resistant West syndrome: A study of eight patients. Seizure, 2021, 92, 238-243.
[http://dx.doi.org/10.1016/j.seizure.2021.10.002] [PMID: 34624613]
[54]
Heussler, H.; Cohen, J.; Silove, N.; Tich, N.; Bonn-Miller, M.O.; Du, W.; O’Neill, C.; Sebree, T. A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome. J. Neurodev. Disord., 2019, 11(1), 16.
[http://dx.doi.org/10.1186/s11689-019-9277-x] [PMID: 31370779]
[55]
Kuchenbuch, M.; D’Onofrio, G.; Chemaly, N.; Barcia, G.; Teng, T.; Nabbout, R. Add‐on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy. Epilepsia Open, 2020, 5(3), 496-500.
[http://dx.doi.org/10.1002/epi4.12411] [PMID: 32913957]
[56]
Wheless, J.W.; Dlugos, D.; Miller, I. Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy. CNS Drugs, 123AD, 33.
[http://dx.doi.org/10.1007/s40263-019-00624-4] [PMID: 31049885]
[57]
Freeman, T.P.; Hindocha, C.; Baio, G.; Shaban, N.D.C.; Thomas, E.M.; Astbury, D.; Freeman, A.M.; Lees, R.; Craft, S.; Morrison, P.D.; Bloomfield, M.A.P.; O’Ryan, D.; Kinghorn, J.; Morgan, C.J.A.; Mofeez, A.; Curran, H.V. Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial. Lancet Psychiatry, 2020, 7(10), 865-874.
[http://dx.doi.org/10.1016/S2215-0366(20)30290-X] [PMID: 32735782]
[58]
Kwee, C.M.B.; Baas, J.M.P.; van der Flier, F.E.; Groenink, L.; Duits, P.; Eikelenboom, M.; van der Veen, D.C.; Moerbeek, M.; Batelaan, N.M.; van Balkom, A.J.L.M.; Cath, D.C. Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial. Eur. Neuropsychopharmacol., 2022, 59, 58-67.
[http://dx.doi.org/10.1016/j.euroneuro.2022.04.003] [PMID: 35561538]
[59]
Efron, D.; Freeman, J.L.; Cranswick, N.; Payne, J.M.; Mulraney, M.; Prakash, C.; Lee, K.J.; Taylor, K.; Williams, K. A pilot randomised placebo‐controlled trial of cannabidiol to reduce severe behavioural problems in children and adolescents with intellectual disability. Br. J. Clin. Pharmacol., 2021, 87(2), 436-446.
[http://dx.doi.org/10.1111/bcp.14399] [PMID: 32478863]
[60]
Hurd, Y.L.; Spriggs, S.; Alishayev, J.; Winkel, G.; Gurgov, K.; Kudrich, C.; Oprescu, A.M.; Salsitz, E. 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, 2019, 176(11), 911-922.
[http://dx.doi.org/10.1176/appi.ajp.2019.18101191] [PMID: 31109198]
[61]
Meneses-Gaya, C.; Crippa, J.A.; Hallak, J.E.; Miguel, A.Q.; Laranjeira, R.; Bressan, R.A.; Zuardi, A.W.; Lacerda, A.L. Cannabidiol for the treatment of crack-cocaine craving: An exploratory double-blind study. Br. J. Psychiatry, 2021, 43(5), 467-476.
[http://dx.doi.org/10.1590/1516-4446-2020-1416] [PMID: 33146345]
[62]
Crippa, J.A.S.; Pacheco, J.C.; Zuardi, A.W.; Guimarães, F.S.; Campos, A.C.; Osório, F.L.; Loureiro, S.R.; dos Santos, R.G.; Souza, J.D.S.; Ushirohira, J.M.; Ferreira, R.R.; Mancini Costa, K.C.; Scomparin, D.S.; Scarante, F.F.; Pires-Dos-Santos, I.; Mechoulam, R.; Kapczinski, F.; Fonseca, B.A.L.; Esposito, D.L.A.; Passos, A.D.C.; Dal Fabbro, A.L.; Bellissimo-Rodrigues, F.; Arruda, E.; Scarpelini, S.; Andraus, M.H.; Nather, Junior, J.C.; Wada, D.T.; Koenigkam-Santos, M.; Santos, A.C.; Busatto Filho, G.; Hallak, J.E.C. Cannabidiol for COVID-19 patients with mild to moderate symptoms (CANDIDATE Study): A randomized, double-blind, placebo-controlled clinical trial. Cannabis Cannabinoid Res., 2022, 7(5), 658-669.
[http://dx.doi.org/10.1089/can.2021.0093] [PMID: 34619044]
[63]
Berger, M.; Li, E.; Rice, S.; Davey, C.G.; Ratheesh, A.; Adams, S.; Jackson, H.; Hetrick, S.; Parker, A.; Spelman, T.; Kevin, R.; McGregor, I.S.; McGorry, P.; Amminger, G.P. Cannabidiol for treatment-resistant anxiety disorders in young people. J. Clin. Psychiatry, 2022, 83(5), 21m14130.
[http://dx.doi.org/10.4088/JCP.21m14130] [PMID: 35921510]
[64]
Suzuki, J.; Martin, B.; Prostko, S.; Chai, P.R.; Weiss, R.D. Cannabidiol effect on cue-induced craving for individuals with opioid use disorder treated with buprenorphine: A small proof-of-concept open-label study. Integr. Med. Res., 2022, 1(1), 157-163.
[http://dx.doi.org/10.1089/imr.2022.0070] [PMID: 36105269]
[65]
Elms, L.; Shannon, S.; Hughes, S.; Lewis, N. Cannabidiol in the treatment of post-traumatic stress disorder: A case series. J. Altern. Complement. Med., 2019, 25(4), 392-397.
[http://dx.doi.org/10.1089/acm.2018.0437] [PMID: 30543451]
[66]
Crippa, J.A.S.; Zuardi, A.W.; Guimarães, F.S.; Campos, A.C.; de Lima Osório, F.; Loureiro, S.R.; dos Santos, R.G.; Souza, J.D.S.; Ushirohira, J.M.; Pacheco, J.C.; Ferreira, R.R.; Mancini Costa, K.C.; Scomparin, D.S.; Scarante, F.F.; Pires-Dos-Santos, I.; Mechoulam, R.; Kapczinski, F.; Fonseca, B.A.L.; Esposito, D.L.A.; Pereira-Lima, K.; Sen, S.; Andraus, M.H.; Hallak, J.E.C.; Litcanov, D.C.; Rodrigues, L.; Alves, T.F.; Coutinho, B.M. Efficacy and safety of cannabidiol plus standard care vs. standard care alone for the treatment of emotional exhaustion and burnout among frontline health care workers during the COVID-19 pandemic. JAMA Netw. Open, 2021, 4(8), e2120603.
[http://dx.doi.org/10.1001/jamanetworkopen.2021.20603] [PMID: 34387679]
[67]
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(2), 250-261.
[http://dx.doi.org/10.1111/j.1476-5381.1972.tb07261.x] [PMID: 4668592]
[68]
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(6), 791-802.
[http://dx.doi.org/10.1111/epi.12631] [PMID: 24854329]
[69]
Pertwee, R.G. Cannabinoid pharmacology: the first 66 years. Br. J. Pharmacol., 2006, 147(S1)(Suppl. 1), S163-S171.
[http://dx.doi.org/10.1038/sj.bjp.0706406] [PMID: 16402100]
[70]
Abbotts, K.S.S.; Ewell, T.R.; Butterklee, H.M.; Bomar, M.C.; Akagi, N.; Dooley, G.P.; Bell, C. Cannabidiol and cannabidiol metabolites: Pharmacokinetics, interaction with food, and influence on liver function. Nutrients, 2022, 14(10), 2152.
[http://dx.doi.org/10.3390/nu14102152] [PMID: 35631293]
[71]
Crockett, J.; Critchley, D.; Tayo, B.; Berwaerts, J.; Morrison, G. A phase 1, randomized, pharmacokinetic trial of the effect of different meal compositions, whole milk, and alcohol on cannabidiol exposure and safety in healthy subjects. Epilepsia, 2020, 61(2), 267-277.
[http://dx.doi.org/10.1111/epi.16419] [PMID: 32012251]
[72]
Hosseini, A.; McLachlan, A.J.; Lickliter, J.D. A phase I trial of the safety, tolerability and pharmacokinetics of cannabidiol administered as single‐dose oil solution and single and multiple doses of a sublingual wafer in healthy volunteers. Br. J. Clin. Pharmacol., 2021, 87(4), 2070-2077.
[http://dx.doi.org/10.1111/bcp.14617] [PMID: 33075170]
[73]
Perkins, D.; Butler, J.; Ong, K.; Nguyen, T.H.; Cox, S.; Francis, B.; Mcintosh, M.; Lilley, B. A Phase 1, randomised, placebo-controlled, dose escalation study to investigate the safety, tolerability and pharmacokinetics of cannabidiol in fed healthy volunteers. Eur. J. Drug Metab. Pharmacokinet., 2020, 45(5), 575-586.
[http://dx.doi.org/10.1007/s13318-020-00624-6] [PMID: 32409982]
[74]
Taylor, L.; Crockett, J.; Tayo, B.; Checketts, D.; Sommerville, K. Abrupt withdrawal of cannabidiol (CBD): A randomized trial. Epilepsy Behav., 2020, 104(Pt A), 106938.
[http://dx.doi.org/10.1016/j.yebeh.2020.106938] [PMID: 32036242]
[75]
Thai, C.; Tayo, B.; Critchley, D. A phase 1 open‐label, fixed‐sequence pharmacokinetic drug interaction trial to investigate the effect of cannabidiol on the cyp1a2 probe caffeine in healthy subjects. Clin. Pharmacol. Drug Dev., 2021, 10(11), 1279-1289.
[http://dx.doi.org/10.1002/cpdd.950] [PMID: 33951339]
[76]
Watkins, P.B.; Church, R.J.; Li, J.; Knappertz, V. Cannabidiol and abnormal liver chemistries in healthy adults: Results of a phase i clinical trial. Clin. Pharmacol. Ther., 2021, 109(5), 1224-1231.
[http://dx.doi.org/10.1002/cpt.2071] [PMID: 33022751]
[77]
Morrison, G.; Crockett, J.; Blakey, G.; Sommerville, K. A phase 1, open‐label, pharmacokinetic trial to investigate possible drug‐drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects. Clin. Pharmacol. Drug Dev., 2019, 8(8), 1009-1031.
[http://dx.doi.org/10.1002/cpdd.665] [PMID: 30791225]
[78]
Taylor, L.; Crockett, J.; Tayo, B.; Morrison, G. 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., 2019, 59(8), 1110-1119.
[http://dx.doi.org/10.1002/jcph.1412] [PMID: 30921490]
[79]
Tayo, B.; Taylor, L.; Sahebkar, F.; Morrison, G. A phase i, open-label, parallel-group, single-dose trial of the pharmacokinetics, safety, and tolerability of cannabidiol in subjects with mild to severe renal impairment. Clin. Pharmacokinet., 2020, 59(6), 747-755.
[http://dx.doi.org/10.1007/s40262-019-00841-6] [PMID: 31802404]
[80]
Alaia, M.J.; Hurley, E.T.; Vasavada, K.; Markus, D.H.; Britton, B.; Gonzalez-Lomas, G.; Rokito, A.S.; Jazrawi, L.M.; Kaplan, K. Buccally absorbed cannabidiol shows significantly superior pain control and improved satisfaction immediately after arthroscopic rotator cuff repair: A placebo-controlled, double-blinded, randomized trial. Am. J. Sports Med., 2022, 50(11), 3056-3063.
[http://dx.doi.org/10.1177/03635465221109573] [PMID: 35905305]
[81]
Vela, J.; Dreyer, L.; Petersen, K.K.; Arendt-Nielsen, L.; Duch, K.S.; Kristensen, S. Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: A randomized, double-blind, placebo-controlled trial. Pain, 2022, 163(6), 1206-1214.
[http://dx.doi.org/10.1097/j.pain.0000000000002466] [PMID: 34510141]
[82]
Heineman, J.T.; Forster, G.L.; Stephens, K.L.; Cottler, P.S.; Timko, M.P.; DeGeorge, B.R., Jr A randomized controlled trial of topical cannabidiol for the treatment of thumb basal joint arthritis. J. Hand Surg. Am., 2022, 47(7), 611-620.
[http://dx.doi.org/10.1016/j.jhsa.2022.03.002] [PMID: 35637038]
[83]
Devinsky, O.; Thiele, E.A.; Wright, S.; Checketts, D.; Morrison, G.; Dunayevich, E.; Knappertz, V. Cannabidiol efficacy independent of clobazam: Meta‐analysis of four randomized controlled trials. Acta Neurol. Scand., 2020, 142(6), 531-540.
[http://dx.doi.org/10.1111/ane.13305] [PMID: 32592183]
[84]
Gunning, B.; Mazurkiewicz-Bełdzińska, M.; Chin, R.F.M.; Bhathal, H.; Nortvedt, C.; Dunayevich, E.; Checketts, D. Cannabidiol in conjunction with clobazam: Analysis of four randomized controlled trials. Acta Neurol. Scand., 2021, 143(2), 154-163.
[http://dx.doi.org/10.1111/ane.13351] [PMID: 32969022]
[85]
Dos Santos, R.G.; Guimarães, F.S.; Crippa, J.A.S.; Hallak, J.E.C.; Rossi, G.N.; Rocha, J.M.; Zuardi, A.W. Serious adverse effects of cannabidiol (CBD): A review of randomized controlled trials. Expert Opin. Drug Metab. Toxicol., 2020, 16(6), 517-526.
[http://dx.doi.org/10.1080/17425255.2020.1754793] [PMID: 32271618]
[86]
Chesney, E.; Oliver, D.; Green, A.; Sovi, S.; Wilson, J.; Englund, A.; Freeman, T.P.; McGuire, P. Adverse effects of cannabidiol: A systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology, 2020, 45(11), 1799-1806.
[http://dx.doi.org/10.1038/s41386-020-0667-2] [PMID: 32268347]
[87]
Malaca, S.; Gottardi, M.; Pigliasco, F.; Barco, S.; Cafaro, A.; Amadori, E.; Riva, A.; Marcenaro, M.; Striano, P.; Cangemi, G.; Pacifici, R.; Pichini, S.; Busardò, F.P. UHPLC-MS/MS Analysis of cannabidiol and its metabolites in serum of patients with resistant epilepsy treated with CBD formulations. Pharmaceuticals, 2021, 14(7), 630.
[http://dx.doi.org/10.3390/ph14070630] [PMID: 34209666]
[88]
Pérez-Acevedo, A.; Busardò, F.; Pacifici, R.; Mannocchi, G.; Gottardi, M.; Poyatos, L.; Papaseit, E.; Pérez-Mañá, C.; Martin, S.; Di Trana, A.; Pichini, S.; Farré, M. Disposition of cannabidiol metabolites in serum and urine from healthy individuals treated with pharmaceutical preparations of medical cannabis. Pharmaceuticals, 2020, 13(12), 459.
[http://dx.doi.org/10.3390/ph13120459] [PMID: 33322849]
[89]
Brunetti, P.; Pichini, S.; Pacifici, R.; Busardò, F.P.; del Rio, A. Herbal preparations of medical cannabis: A vademecum for prescribing doctors. Medicina, 2020, 56(5), 237.
[http://dx.doi.org/10.3390/medicina56050237] [PMID: 32429074]
[90]
Marchei, E.; Tittarelli, R.; Pellegrini, M.; Rotolo, M.C.; Pacifici, R.; Pichini, S. Is “light cannabis” really light? Determination of cannabinoids content in commercial products. Clin. Chem. Lab. Med. (CCLM), 2020, 58(9), e175-e177.
[http://dx.doi.org/10.1515/cclm-2020-0040] [PMID: 32229657]
[91]
Pichini, S.; Mannocchi, G.; Berretta, P.; Zaami, S.; Pirani, F.; Pacifici, R.; Busardò, F.P. Δ9-Tetrahydrocannabinol and cannabidiol time courses in the sera of “Light Cannabis” smokers: Discriminating light cannabis use from illegal and medical cannabis use. Ther. Drug Monit., 2020, 42(1), 151-156.
[http://dx.doi.org/10.1097/FTD.0000000000000683] [PMID: 31389860]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy