A systematic review of cannabidiol dosing in clinical populations

S Millar

N Stone

Z Bellman

A Yates

T England

S O'Sullivan

^{Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK,}

^{Artelo Biosciences, La Jolla, CA, USA,}

S.A. Millar, Email: moc.liamg@rallimennaeihpos, Email: ku.ca.mahgnitton@limasxts.

^{Corresponding author.}

^{Correspondence}
Sophie A. Millar, Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
Email: moc.liamg@rallimennaeihpos; ku.ca.mahgnitton@limasxts,

Received 2019 Feb 7; Revised 2019 Jun 7; Accepted 2019 Jun 10.

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Abstract

Aims

Cannabidiol (CBD) is a cannabis‐derived medicinal product with potential application in a wide‐variety of contexts; however, its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of CBD in a variety of medical contexts.

Methods

Publications involving administration of CBD alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov.

Results

A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. Twenty‐three studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 and 50 mg/kg/d. Plasma concentrations were not provided in any publication. CBD was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of CBD on reducing seizure frequency or severity (average 15 mg/kg/d within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n = 6–62) assessing diabetes, Crohn's disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/kg/d) were used in these studies.

Conclusion

This review highlights that CBD has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.

Keywords: cannabidiol, cannabinoid, dose, dosing, therapeutics

Abstract

What is already known about this subject

Due to its favourable toxicity and side effect profile, cannabidiol is under increasing investigation in the commercial and medical industry to treat many clinical indications.

What this study adds

This study identifies the wide active dosing range of cannabidiol (<1 to 50 mg/kg/d) within a variety of medical conditions including epilepsy, anxiety and graft‐vs‐host disease.
This review indicates that studies that used higher doses tended to have better therapeutic outcomes compared to lower doses overall.
This study identifies a strong existing need for dose‐ranging clinical studies to be conducted in which plasma concentrations can provide a better indication of the therapeutic range of cannabidiol.

Notes

Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O'Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol. 2019;85:1888–1900. 10.1111/bcp.14038 [PubMed] [CrossRef] [Google Scholar]

Notes

References

1. WHO . Cannabidiol (CBD): World Health Organisation Expert Committee on Drug Dependence Thirty‐ninth Meeting. 2017. Available from: . Accessed July 12, 2019.[PubMed]
2. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86‐95. 10.3109/03602532.2013.849268 [] [[PubMed]
3. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) ‐tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737‐753. 10.1111/bph.12944 ] [
4. Campos AC, Fogaca MV, Sonego AB, Guimaraes FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119‐127. 10.1016/j.phrs.2016.01.033 [] [[PubMed]
5. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol (Oxford, England). 2011;25(1):121‐130. 10.1177/0269881110379283 [] [[PubMed]
6. Morgan CJ, Das RK, Joye A, Curran HV, Kamboj SK. Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. Addict Behav. 2013;38(9):2433‐2436. 10.1016/j.addbeh.2013.03.011 [] [[PubMed]
7. Hazekamp A. The trouble with CBD oil. Med Cannabis Cannabinoids. 2018;1(1):65‐72. 10.1159/000489287 [[PubMed]
8. Millar SA, Stone NL, Yates AS, O'Sullivan SE. A systematic review on the pharmacokinetics of Cannabidiol in humans. Front Pharmacol. 2018;9:1365 10.3389/fphar.2018.01365 ] [
9. Walpole SC, Prieto‐Merino D, Edwards P, Cleland J, Stevens G, Roberts I. The weight of nations: an estimation of adult human biomass. BMC Public Health. 2012;12(1):439 10.1186/1471-2458-12-439 ] [
10. Shannon S, Opila‐Lehman J. Effectiveness of Cannabidiol oil for pediatric anxiety and insomnia as part of posttraumatic stress disorder: a case report. Perm J. 2016;20(4):108‐111. 10.7812/tpp/16-005 ] [
11. McGuire P, Robson P, Cubala WJ, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 2018;175(3):225‐231. 10.1176/appi.ajp.2017.17030325 [] [[PubMed]
12. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox‐Gastaut syndrome (GWPCARE4): a randomised, double‐blind, placebo‐controlled phase 3 trial. Lancet. 2018. 10.1016/s0140-6736(18)30136-3 [] [[PubMed]
13. Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on drop seizures in the Lennox‐Gastaut syndrome. N Engl J Med. 2018;378(20):1888‐1897. 10.1056/NEJMoa1714631 [] [[PubMed]
14. Boggs DL, Surti T, Gupta A, et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology (Berl). 2018;235(7):1923‐1932. 10.1007/s00213-018-4885-9 [] [[PubMed]
15. Naftali T, Mechulam R, Marii A, et al. Low‐dose Cannabidiol is safe but not effective in the treatment for Crohn's disease, a randomized controlled trial. Dig Dis Sci. 2017;62(6):1615‐1620. 10.1007/s10620-017-4540-z [] [[PubMed]
16. Devinsky O, Cross JH, Wright S. Trial of Cannabidiol for drug‐resistant seizures in the Dravet syndrome. N Engl J Med. 2017;377(7):699‐700. 10.1056/NEJMc1708349 [] [[PubMed]
17. Jadoon KA, Ratcliffe SH, Barrett DA, et al. 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. 10.2337/dc16-0650 [] [[PubMed]
18. Chagas MH, Zuardi AW, Tumas V, et al. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double‐blind trial. J Psychopharmacol (Oxford, England). 2014;28(11):1088‐1098. 10.1177/0269881114550355 [] [[PubMed]
19. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2(3):e94 10.1038/tp.2012.15 ] [
20. Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment‐naive social phobia patients. Neuropsychopharmacology. 2011;36(6):1219‐1226. 10.1038/npp.2011.6 ] [
21. Tomida I, Azuara‐Blanco A, House H, Flint M, Pertwee RG, Robson PJ. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J Glaucoma. 2006;15(5):349‐353. 10.1097/01.ijg.0000212260.04488.60 [] [[PubMed]
22. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1′ studies. Anaesthesia. 2004;59(5):440‐452. 10.1111/j.1365-2044.2004.03674.x [] [[PubMed]
23. Consroe P, Laguna J, Allender J, et al. Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacol Biochem Behav. 1991;40(3):701‐708. [[PubMed]
24. Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980;21(3):175‐185. [[PubMed]
25. clinicaltrials.gov . Study to Assess the Effect of Cannabidiol on Liver Fat Levels in Subjects With Fatty Liver Disease. Available from: https://clinicaltrials.gov/ct2/show/results/. Accessed July 12, 2019.[PubMed]
26. Rosenberg EC, Louik J, Conway E, Devinsky O, Friedman D. Quality of life in childhood epilepsy in pediatric patients enrolled in a prospective, open‐label clinical study with cannabidiol. Epilepsia. 2017;58(8):e96‐e100. 10.1111/epi.13815 ] [
27. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment‐resistant epilepsy: an open‐label interventional trial. The Lancet Neurology. 2016;15(3):270‐278. 10.1016/s1474-4422(15)00379-8 [] [[PubMed]
28. Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug‐resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57(10):1617‐1624. 10.1111/epi.13499 [] [[PubMed]
29. Yeshurun M, Shpilberg O, Herscovici C, et al. Cannabidiol for the prevention of graft‐versus‐host‐disease after allogeneic hematopoietic cell transplantation: results of a phase II study. Biol Blood Marrow Transplant. 2015;21(10):1770‐1775. 10.1016/j.bbmt.2015.05.018 [] [[PubMed]
30. Hallak JE, Machado‐de‐Sousa JP, Crippa JA, et al. Performance of schizophrenic patients in the Stroop color word test and electrodermal responsiveness after acute administration of cannabidiol (CBD). Revista Brasileira de Psiquiatria (Sao Paulo, Brazil: 1999). 2010;32(1):56‐61. [[PubMed]
31. Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol (Oxford, England). 2009;23(8):979‐983. 10.1177/0269881108096519 [] [[PubMed]
32. Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders. Int J Neurosci. 1986;30(4):277‐282. [[PubMed]
33. Kaplan EH, Offermann EA, Sievers JW, Comi AM. Cannabidiol treatment for refractory seizures in Sturge‐weber syndrome. Pediatr Neurol. 2017;71:18‐23.e2. 10.1016/j.pediatrneurol.2017.02.009 [] [[PubMed]
34. Warren PP, Bebin EM, Nabors LB, Szaflarski JP. The use of cannabidiol for seizure management in patients with brain tumor‐related epilepsy. Neurocase. 2017;23(5–6):287‐291. 10.1080/13554794.2017.1391294 [] [[PubMed]
35. Gofshteyn JS, Wilfong A, Devinsky O, et al. Cannabidiol as a potential treatment for febrile infection‐related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol. 2017;32(1):35‐40. 10.1177/0883073816669450 [] [[PubMed]
36. Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report. Pediatr Neurol. 2015;52(5):544‐547. 10.1016/j.pediatrneurol.2015.02.008 [] [[PubMed]
37. Chagas MH, Eckeli AL, Zuardi AW, et al. Cannabidiol can improve complex sleep‐related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J Clin Pharm Ther. 2014;39(5):564‐566. 10.1111/jcpt.12179 [] [[PubMed]
38. Crippa JA, Hallak JE, Machado‐de‐Sousa JP, et al. Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. J Clin Pharm Ther. 2013;38(2):162‐164. 10.1111/jcpt.12018 [] [[PubMed]
39. Zuardi A, Crippa J, Dursun S, et al. Cannabidiol was ineffective for manic episode of bipolar affective disorder. J Psychopharmacol (Oxford, England). 2010;24(1):135‐137. 10.1177/0269881108096521 [] [[PubMed]
40. Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R. Antipsychotic effect of cannabidiol. J Clin Psychiatry. 1995;56(10):485‐486. [[PubMed]
41. Zuardi AW, Hallak JE, Dursun SM, et al. Cannabidiol monotherapy for treatment‐resistant schizophrenia. J Psychopharmacol (Oxford, England). 2006;20(5):683‐686. 10.1177/0269881106060967 [] [[PubMed]
42. Snider SR, Consroe P. Beneficial and adverse effects of cannabidiol in a Parkinson patient with sinemet‐induced dystonic dyskinesia. Neurology. 1985;35:201. [PubMed]
43. Snider SR, Consroe P. Treatment of Meige's syndrome with cannabidiol. Neurology. 1984;34:147. [PubMed]
44. Paez Espinosa EV, Murad JP, Khasawneh FT. Aspirin: pharmacology and clinical applications. Thrombosis. 2012;2012:173124 10.1155/2012/173124 ] [
45. Derry S, Moore RA. Single dose oral aspirin for acute postoperative pain in adults. Cochrane Database Syst Rev. 2012;(4):Cd002067 10.1002/14651858.CD002067.pub2 ] [
46. Couch DG, Tasker C, Theophilidou E, Lund JN, O'Sullivan SE. Cannabidiol and palmitoylethanolamide are anti‐inflammatory in the acutely inflamed human colon. Clin Sci (London, England: 1979). 2017;131(21):2611‐2626. 10.1042/cs20171288 [] [[PubMed]
47. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245‐259.
48. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet. 1991;337(8746):867‐872. [[PubMed]
49. Zendulka O, Dovrtelova G, Noskova K, et al. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab. 2016;17(3):206‐226. [[PubMed]
50. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586‐1592. 10.1111/epi.13852 [] [[PubMed]