Abstract
There are four main routes of administration of medicinal cannabis: inhalation, the oral route, topical applications and ‘other routes’ (eg. suppositories, intranasal delivery). Each is associated with different onsets of action and durations of action due to their pharmacokinetic profiles. There are some safety issues associated with cannabis. Many of the safety concerns such as associations between cannabis use and conditions such as cannabis use disorder and various mental health conditions that have been raised in the literature relate to recreational smoking of cannabis. Cannabis is associated with a range of negative side effects that are typically dose-dependent, most of which relate to the tetrahydrocannabinol (THC) component. Cannabidiol (CBD) has less serious side effects than THC. In general, CBD has been found to be well tolerated and safe and does not cause addiction. Both CBD and THC can potentially interact with a range of pharmaceuticals because they are metabolised by many of the cytochrome P450 enzymes that metabolise pharmaceuticals. Clinical trials in epilepsy in which high doses of CBD are used in conjunction with typically several anti-epileptic medications have demonstrated that side effects can occur with certain drugs. However, whether drug-cannabis interactions are common in clinical practice has not been well established.
Keywords
- Safety
- Pharmacokinetics
- Delivery methods
- Cannabis
- Tetrahydrocannabinol (THC)
- Cannabidiol (CBD)
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References
Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4:1770–804.
World Health Organization (WHO). World Health Organization Expert Committee on Drug Dependence Pre-Review. Cannabis Plant and Cannabis Resin. Geneva: World Health Organization, 2018a. Available at: https://www.who.int/medicines/access/controlled-substances/ecdd_40_meeting/en/. Accessed 20 Jan 2021.
Lintzeris N, Davis J, Elias N, et al. Medicinal cannabis in Australia 2016: the Cannabis as medicine survey (CAMS-16). Med J Aust. 2018;209(5):211–6.
Sexton M, Cuttler C, Finnell J, Mischley L. A cross-sectional survey of medical cannabis users: patterns of use and perceived efficacy. Cannabis Cannabinoid Res. 2016;1:131–8.
MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Internal Med. 2018;49:12–9.
National Academies of Sciences, Engineering and Medicine. Report. The health effects of Cannabis and cannabinoids. Washington DC: The National Academies Press; 2017.
Van Der Kooy F, Pomahacova B, Verpoorte R. Cannabis smoke condensate II: influence of tobacco on tetrahydrocannabinol levels. Inhal Toxicol. 2009;21(2):87–90.
Zhang LR, Morgenstern H, Greenland S, et al. Cannabis smoking and lung cancer risk: pooled analysis in the international lung cancer consortium. J Cancer. 2015;136(4):894–903.
Wang B, Kovalchuk A, Li D, et al. In search of preventive strategies: novel high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues. Aging (Albany NY). 2020;12(22):22425–4444.
Cobb, Solanki. E-cigarettes, vaping devices, and acute lung injury. Respiratory Care. 2020;65(5):713–8.
Taylor J, Wiens T, Peterson J, et al. Characteristics of e-cigarette, or vaping, products used by patients with associated lung injury and products seized by law enforcement — Minnesota, 2018 and 2019. MMWR Morb Mortal Wkly Rep. 2019a;68:1096–100.
Lewis N. E-cigarette use, or vaping, practices and characteristics among persons with associated lung injury - Utah, April-October 2019. MMWR Morb Mortal Wkly Rep. 2019;68(42):953–6.
Blount BC, Karwowski MP, Morel-Espinosa M, et al. Evaluation of bronchoalveolar lavage fluid from patients in an outbreak of e-cigarette, or vaping, product useassociated lung injury - 10 states, August-October 2019. MMWR Morb Mortal Wkly Rep. 2019;68(45):1040–1.
Tijani AO, Thakur D, Mishra D, et al. Delivering therapeutic cannabinoids via skin: Current state and future perspectives. J Control Release. 2021;334:427–51.
Paudel KS, Hammell DC, Agu RU, et al. Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers. Drug Dev Ind Pharm. 2010;36(9):1088–97.
Nahtigal I, Blake A, Hand A, et al. The pharmacological properties of Cannabis. J Pain Manag. 2016;9(4):481–91.
Whittle BA, Guy GW, Robson P. Prospects for new cannabis-based prescription medicines. Cannabis Therap HIV/AID. 2012;67:183–206.
Chayasirisobhon S. Mechanisms of action and Pharmacokinetics of Cannabis. Perm J. 2020;25:1–3.
Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Anesthesiology. 1997;86:24–33.
Mechoulam R, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002;42:11–9.
Brown JD, Winterstein AG. Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use. J Clin Med. 2019;8:989.
Jiang R, Yamouri S, Takeda S, et al. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89(5–6):165–70.
Zhornitsky S, Potvin S. Cannabidiol in humans—the quest for therapeutic targets. Pharmaceuticals. 2012;5:529–52.
McGilveray IJ. Pharmacokinetics of cannabinoids. Pain Res Manag. 2005;10(Suppl A):15A–22A.
Ohlsson A, Lindgren JE, Wahlen A, et al. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980;28(3):409–16.
Ohlsson A, Lindgren JE, Wahlén A, et al. Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Mass Spectrom. 1982;9(1):6–10.
Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinetics. 2003;42:327–60.
Goulle J, Saussereau E, Lacroix C. Delta-9tetrahydrocannabinol pharmacokinetics. Ann Pharm Françaises. 2008;66:232–4.
McPartland JM, Russo EB. Cannabis and cannabis extracts: greater than the sum of their parts? J Cannabis Therap. 2001;14:103–32.
Cyr C, Arboleda MF, Aggarwal SK, et al. Cannabis in palliative care: current challenges and practical recommendations. Ann Palliat Med. 2018; https://doi.org/10.21037/apm.2018.06.04.
Wall ME, Sadler BM, Brine D, et al. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther. 1983;34(3):352–63.
Nadulski T, Pragst F, Weinberg G, et al. Randomized, double-blind, placebo controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit. 2005;27:799–810.
Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA. Plasma cannabinoid pharmacokinetics following controlled oral a 9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem. 2011a;57:66–75.
Karschner EL, Darwin WD, McMahon RP, Liu F, Wright S, Goodwin RS, et al. Subjective and physiological effects after controlled Sativex and oral THC administration. Clin Pharmacol Ther. 2011b;89:400–7.
Sharma P, Murthy P, Bharath MMS. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry. 2012;7:149–56.
ElSohly MA, Gula W, Walkera LA. Pharmacokinetics and tolerability of Δ9-THC-hemisuccinate in a suppository formulation as an alternative to capsules for the systemic delivery of Δ9-THC. Med Cannabis Cannabinoids. 2018;1:44–53.
Brenneisen R, Egli A, Elsohly MA et al. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther. 1996;34(10):446–52.
Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol. 1992;16:276–82.
Abramovici H. Information for health care professionals: cannabis (marihuana, marijuana) and the cannabinoids. Health Canada 2013. http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/marihuana/med/infoprof-eng.pdf.
Lemberger L, Axelrod J, Kopin IJ. Metabolism and disposition of delta-9-tetrahydrocannabinol in man. Pharmacol Rev. 1971;23:371–80.
Huestis MA. Pharmacokinetics and metabolism of the plant cannabinoids, delta9- tetrahydrocannabinol, cannabidiol and cannabinol. Handb Exp Pharmacol. 2005:657–90.
Lemberger L, Martz R, Rodda B, et al. Comparative pharmacology of Delta9-tetrahydrocannabinol and its metabolite, 11-OH-Delta9-tetrahydrocannabinol. J Clin Investig. 1973;52:2411–7.
Huestis MA, Cone EJ. Urinary excretion half-life of 11-nor-9-carboxy-delta9-tetrahydrocannabinol in humans. Ther Drug Monit. 1998;20:570–6.
Vandevenne M, Vandenbussche H, Verstraete A. Detection time of drugs of abuse in urine. Acta Clin Belg. 2000;55:323–33.
Smith-Kielland A, Skuterud B, Morland J. Urinary excretion of 11-nor-9-carboxy-delta9- tetrahydrocannabinol and cannabinoids in frequent and infrequent drug users. J Anal Toxicol. 1999;23:323–32.
Kelly P, Jones RT. Metabolism of tetrahydrocannabinol in frequent and infrequent marijuana users. J Anal Toxicol. 1992;16:228–35.
Reiter A, Hake J, Meissner C, et al. Time of drug elimination in chronic drug abusers. Case study of 52 patients in a “low-step” detoxification ward. Forensic Sci Int. 2001;119(2):248–53.
Hollister LE, Gillespie HK, Ohlsson A, et al. Do plasma concentrations of Δ-9 tetrahydrocannabinol reflect the degree of intoxication? J Clin Pharmacol. 1981;21:171S–7S.
Spindle TR, Cone EJ, Kuntz D, et al. Urinary Pharmacokinetic profile of cannabinoids following administration of vaporized and oral cannabidiol and vaporized CBD-dominant Cannabis. J Anal Toxicol. 2020;44(2):109–25.
Gable RS. Toward a comparative overview of dependence potential and acute toxicity of psychoactive substances used nonmedically. Am J Drug Alcohol Abuse. 1993;19(3):263–81.
World Health Organization (WHO). World Health Organization Expert Committee on Drug Dependence Pre-Review. Delta-9-Tetrahydrocannabinol. Geneva: World Health Organization, 2018c. Available at: https://www.who.int/medicines/access/controlled-substances/ecdd_40_meeting/en/
Bhaskar A, Bell A, Boivin M et al. Consensus recommendations on dosing and administration of medical cannabis to treat chronic pain: results of a modified Delphi process. J Cannabis Research. 2021;3:22.
Patel RS, Kamil SH, Bachu R, et al. Marijuana use and acute myocardial infarction: a systematic review of published cases in the literature. Trends Cardiovac Med. 2019;S1050-1738(19):30112–4.
De Filippas EM, Sing A, Divakaran S, et al. Cocaine and marijuana use among young adults with myocardial infarction. J Am Coll Cardiol. 2018;71:2540–51.
Frost L, Mostofsky E, Rosenbloom JI, et al. Marijuana use and long-term mortality among survivors of acute myocardial infarction. Am Heart J. 2013;165:170–5.
IOM (Institute of Medicine). Marijuana and medicine: assessing the science base. Washington, DC: National Academy Press; 1999.
Rezkalla S, Kloner RA. Cardiovascular effects of Marijuana. Trends Cardiovasc Med. 2019;29(7):403–7.
Hemachandra D, McKetin R, Cherbuin N, Anstey KJ. Heavy cannabis users at elevated risk of stroke: evidence from a general population survey. Aust N Z J Public Health. 2016;40:226–30.
Jivanji D, Mangosing M, Mahoney SP, et al. Association between Marijuana use and cardiovascular disease in US adults. Cureus. 2020;12(12):e11868. https://doi.org/10.7759/cureus.11868.
Page RL, Allen LA, Kloner RA, et al. Medical Marijuana, recreational cannabis, and cardiovascular health: a scientific statement From the American Heart Association. Circulation. 2020;142:e131–52.
Brown JD. Potential adverse drug events with tetrahydrocannabinol (THC) due to drug–drug interactions. J Clin Med. 2020;9(4):919.
Lim K, See YM, Lee J. A systematic review of the effectiveness of medical cannabis for psychiatric, movement and neurodegenerative disorders. Clin Psychopharmacol Neurosci. 2017;15(4):301–12.
Whiting PF, Wolff RF, Deshepande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313:2456–73.
Appelboam A, Oades PJ. Coma due to cannabis toxicity in an infant. Eur J Emerg Med. 2006;13(3):177–9.
Carstairs SD, Fujinaka MK, Keeney GE, Ly BT. Prolonged coma in a child due to hashish ingestion with quantitation of thc metabolites in urine. J Emerg Med. 2011;41(3):e69–71.
Piontek D, Kraus L, Legleye S, Buhringer G. The validity of DSM‐IV cannabis abuse and dependence criteria in adolescents and the value of additional cannabis use indicators. Addiction. 2011;106(6):1137–45.
Leung J, Chan GCK, Hide L, Hall WD. What is the prevalence and risk of cannabis use disorders among people who use cannabis? a systematic review and meta-analysis. Addict Behav. 2020;109:106479.
Lintzeris N, Bhardwaj A, Mills L, et al. Nabiximols for the treatment of cannabis dependence: a randomized clinical trial. JAMA. 2019;179(9):1242–53.
Friedrich J, Khatib D, Parsa K, et al. The grass isn’t always greener: the effects of cannabis on embryological development. BMC Pharmacol Toxicol. 2016;17:45.
Grant KS, Petroff R, Isoherranen N, et al. Cannabis use during pregnancy: pharmacokinetics and effects on child development. Pharmacol Ther. 2018;182:133–51.
Dahl RE, Scher MS, Williamson DE, et al. A longitudinal study of prenatal marijuana use: effects on sleep and arousal at age 3 years. Arch Pediatr Adolesc Med. 1995; https://doi.org/10.1001/archpedi.1995.02170140027004.
Winiger EA, Hewitt JK. Prenatal cannabis exposure and sleep outcomes in children 9-10 years of age in the adolescent brain cognitive development SM study. Sleep Health. 2020; https://doi.org/10.1016/j.sleh.2020.05.006. Accessed 20 Jan 2021.
Corsi DJ, Donelle J, Sucha E, et al. Maternal cannabis use in pregnancy and child neurodevelopmental outcomes. Nat Med. 2020; https://doi.org/10.1038/s41591-020-1002-5.
Hayes JS, Lampart R, Dreher MC, Morgan L. Five year follow up of rural Jamaican children whose mothers used marijuana during pregnancy. West Indian Med J. 1991;40(3):120–3.
Dubois S, Mullen N, Weaver B, Bedard M. The combined effects of alcohol and cannabis on driving: impact on crash risk. Forensic Sci Int. 2015;248:94–100.
Price JW. Marijuana and workplace safety: an examination of urine drug tests. J Addict Dis. 2014;33(1):24–7.
Zhang JC, Carnide N, Holness L, Cram P. Cannabis use and work-related injuries: a cross-sectional analysis. Occup Med (Lond). 2020;70(8):570–7.
Bernerth JB, Walker HJ. Altered states or much to do about nothing? A study of when Cannabis is used in relation to the impact it has on performance. Business Manag INK. 2020;45(4):459–78.
Biasutti WR, Leffers KSH, Callaghan RC. Systematic review of Cannabis use and risk of occupational injury. Subst Use Misuse. 2020;55(11):1733–45.
Malone DDT, Hill MN, Rubino T. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. 2010;160(3):511–22.
Ames F. A clinical and metabolic study of acute intoxication with Cannabis sativa and its role in the model psychoses. J Ment Sci. 1958;104:972–99.
Chopra GS, Smith JW. Psychotic reactions following cannabis use in East Indians. Arch Gen Psychiatry. 1974;30:24–7.
Spencer DJ. Cannabis induced psychosis. Br J Addiction. 1970;65:369–72.
Hall W, Degenhardt L, Teesson M. Cannabis use and psychotic disorders: an update. Drug Alcohol Rev. 2004;23:433–43.
Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. Lancet. 1987;2:1483–6.
Zammit S, Allebeck P, Andreasson S, et al. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002;325:1199.
Gage SH, Jones HJ, Burgess S, et al. Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study. Psychol Med. 2017;47:971–80.
Minichino A, Senior M, Brondino N, et al. Measuring disturbance of the endocannabinoid system in psychosis. JAMA Psychiat. 2019; https://doi.org/10.1001/jamapsychiatry.2019.0970.
Davis C, Bhattacharyya S. Cannabidiol as a potential treatment for psychosis. Ther Adv Psychopharmacol. 2019;9:1–16.
Dickens AM, Borgan F, Laurikainen H, et al. Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis. Schizophrenia. 2020;6:21.
Lee TTY, Gorzalka BB. Timing is everything: evidence for a role of corticolimbic endocannabinoids in modulating hypothalamic–pituitary–adrenal axis activity across developmental periods. Neuroscience. 2012;204:17–30.
Muller N, WEidinger E, Leitner B, Schwartz MJ. The role of inflammation in schizophrenia. Front Neurosci. 2015;9:372.
Grinspoon L, Bakalar JB. Marihuana, the forbidden medicine, revised edition. New Haven, CT: Yale University Press, 1997, in: McPartland JM, Russo E. Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? Cannabis Therapeutics. 2001;14:103–32.
McPartland JM, Russo E. Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? The Haworth Press; 2001. Available at: http://cannabismed.org/data/pdf/2001-03-04-7.pdf
McPartland JM, Duncan M, Di Marzo V, Pertwee R. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Brit J Pharmacol. 2015;172:737–53.
Ranganathan M, D’Souza DC. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology. 2006;188(4):425–44.
Walter C, Oertel BG. Felden Lisa et al. Effects of oral Δ9-tetrahydrocannabinol on the cerebral processing of olfactory input in healthy non-addicted subjects. Eur J Clin Pharmacol. 2017;73(12):1579–87.
Sorensen CJ, DeSanto K, Borgelt L, et al. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment- a systematic review. J Med Toxicol. 2017;13:71–87.
D’Souza DC, Perry E, MacDougall L, et al. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004;29(8):1558–72.
Morrison PD, Zois Z, McKeown DA, et al. The acute effects of synthetic intravenous Delta9-tetrahydrocannabinol on psychosis, mood and cognitive functioning. Psychol Med. 2009;39(10):1607–16.
Hart CL, van Gorp W, Haney M, et al. Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology. 2001;25(5):757–65.
World Health Organization (WHO). World Health Organization Expert Committee on Drug Dependence. Cannabidiol (CBD) Critical Review Report. Expert Committee on Drug Dependence Fortieth Meeting Geneva, 4–7 June 2018. World Health Organization (WHO), 2018b. Available at URL: https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf. Accessed 20 Jan 2021.
Black N, Stockings E, Campbell G, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2019; https://doi.org/10.1016/S2215-0366(19)30401-8.
Kocis PT, Vrana KE. Delta-9-Tetrahydrocannabinol and cannabidiol drug-drug interactions. Med Cannabis Cannabinoids. 2020;1 https://doi.org/10.1159/000507998.
Sultan SR, Millar SA, O’Sullivan SE, England TJ. A systematic review and meta-analysis of the in vivo haemodynamic effects of Δ9-Tetrahydrocannabinol. Pharmaceuticals. 2018;11(1):13.
Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther. 1975;18(3):287–97.
Kayser RR, Haney M, Raskin M, Arout C, Simpson HB. Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: a human laboratory study. Depress Anxiety. 2020; https://doi.org/10.1002/da.23032.da.23032.
Abuhasira R, Haviv YS, Leiba M, et al. Cannabis is associated with blood pressure reduction in older adults – a 24-hours ambulatory blood pressure monitoring study. Eur J Internal Med. 2021; https://doi.org/10.1016/j.ejim.2021.01.005.
Van Den Elsen GAH, Ahmed AIA, Verkes RJ, et al. Tetrahydrocannabinol in behavioral disturbances in dementia: a crossover randomized controlled trial. Am J Geriatr Psychiatry. 2015a;23:1214–24.
Van Den Elsen GAH, Ahmed AIA, Verkes R-J, et al. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: a randomized controlled trial. Neurology. 2015b;84:2338–46.
Ahmed AIA, van den Elsen GAH, Colbers A, et al. Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial. Eur Neuropsychopharmacol. 2014;24:1475–82.
Sidney S. Cardiovascular consequences of Marijuana use. J Clin Pharmacol. 2002;42(11 Suppl):64S–70S.
Robbe H. Marijuana’s impairing effects on driving are moderate when taken alone but severe when combined with alcohol. Human Psychopharmacol. 1998;13(S2):S70–8.
Downey LA, King R, Papafotiou K, Swann P, Ogden E, Boorman M, Stough C. The effects of cannabis and alcohol on simulated driving: Influences of dose and experience. Accid Anal Prev. 2013;50:879–86.
Ramaekers JG, Robbe HWJ, O’Hanlon JF. Marijuana, alcohol and actual driving performance. Hum Psychopharmacol. 2000;15:551–8.
Ronen A, Chassidim HS, Gershon P, et al. The effect of alcohol, THC and their combination on perceived effects, willingness to drive and performance of driving and non-driving tasks. Accid Anal Prev. 2010;42:1855–65.
Hartman RL, Brown TL, Milavetz G, et al. Cannabis effects on driving longitudinal control with and without alcohol. J Appl Toxicol. 2016;36(11):1418–29.
Vigil JM, Stith SS, Adams IM, Reeve AP. Associations between medical cannabis and prescription opioid use in chronic pain patients: a preliminary cohort study. PLoS One. 2017;12(11):e0187795.
Grotenhermen F, Russo E, Zuardi AW. Even high doses of oral cannabidiol do not cause THC-like effects in humans: comment on Merrick et al. Cannabis Cannabinoid Res. 2016;1(1):102–12.
Gulbransen G, Xu W, Arroll B. Cannabidiol prescription in clinical practice: an audit on the first 400 patients in New Zealand. BJGP Open. 2020;4(1):bjgpopen20X101010.
Crippa JA, Zuardi AW, Hallak JEC, et al. Oral Cannabidiol does not convert to Δ 8-THC or Δ 9-THC in humans: a pharmacokinetic study in healthy subjects. Cannabis Cannabinoid Res. 2020;5(1):89–98.
Consroe P, Kennedy K, Schram K. Assays of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans. Pharmacol Biochem Behav. 1991;40:517–22.
Rosenkrantz H, Fleischman RW, Grant RJ. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicol Appl Pharmacol. 1981;58(1):118–31.
Dash R, Ali C, Jahan I, et al. Emerging potential of cannabidiol in reversing proteinopathies. Ageing Res Rev. 2020; https://doi.org/10.1016/j.arr.2020.101209.
Scuderi C, Filippis DD, Iuvone T, et al. Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders. Phytother Res. 2009;23(5):597–602.
Ewing LE, Skinner CM, Quick CM, et al. Hepatoxicity of a cannabidiol-rich cannabis extract in the mouse model. Molecules. 2019;24:1694. https://doi.org/10.3390/molecules24091694.
EPIDIOLEX® (cannabidiol) oral solution, CV Initial U.S. Approval: 2018. Prescribing Information Revised 12/2018. Available at: https://www.epidiolex.com/sites/default/files/EPIDIOLEX_Full_Prescribing_Information.pdf. Accessed 12 Feb 2019.
Thiele E, Marsh E, Mazurkiewicz‐Beldzinska M, et al. Cannabidiol in patients with Lennox‐Gastaut syndrome: Interim analysis of an open‐label extension study. Epilepsia. 2019;60(3):419–28.
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):392–7.
Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in anxiety and sleep: a large case series. Perm J. 2019;23:18–041.
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. 2019b;59(8):1110–9.
Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270–8.
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. ACCP. 2019;8(8):1009–31.
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;391(10125):1085–96.
Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug‐resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–20.
Devinsky O, Nabbout R, Miller I, et al. Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial. Epilepsia. 2019;60(2):294–302.
Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56(8):1246–51.
Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586–92.
Consroe P, Carlini EA, Zwicker AP, Lacerda LA. Interaction of cannabidiol and alcohol in humans. Psychopharmacol (Berl). 1979;66(1):45–50.
Liput DL, Hammell DC, Stinchcomb AL, Nixon K. Transdermal delivery of cannabidiol attenuates binge alcohol-induced neurodegeneration in a rodent model of an alcohol use disorder. Pharmacol Biochem Behav. 2013;111:120–7.
Sultan SR, O’Sullivan SE, England TJ. 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. 2020;86(6):1125–38.
Sultan SR, Millar SA, England TJ, O’Sullivan SEA. Systematic review and meta-analysis of the Haemodynamic effects of cannabidiol. Front Pharmacol. 2017;8:81.
Jadoon KA, Tan GD, O’Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017;2(12):e93760.
Pamplona FA, da Silva LR, Coan AC, et al. Potential clinical benefits of CBD-rich cannabis extracts over purified CBD in treatment-resistant epilepsy: observational data meta-analysis. Front Neurol. 2018;9:759.
Bergamaschi MM, Queiroz RH, Zuardi AW, et al. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6:237–49.
Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metabol Rev. 2014:46(1). https://doi-org.ezproxy.uws.edu.au/10.3109/03602532.2013.849268.
Tanaka E. Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes. J Clin Pharm Therap. 1998;23:403–16.
White CM. A review of human studies assessing cannabidiol’s (CBD) therapeutic actions and potential. J Clin Pharmacol. 2019;00(0):1–12.
Qian Y, Gurley BJ, Markowitz JS. The potential for pharmacokinetic interactions between cannabis products and conventional medications. J Clin Psychopharmacol. 2019a;39(5):462–71.
Qian Y, Wang X, Markowitz JS. In vitro inhibition of carboxylesterase 1 by major cannabinoids and selected metabolites. Drug Metab Dispos. 2019b;47:465–72.
Bland TM, Haining RL, Tracy TS, et al. CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin. Biochem Pharmacol. 2005;70:1096–103.
Yamaori S, Koeda K, Kushihara M, et al. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet. 2012;27:294–300.
Roth MD, Marques-Magallanes JA, Yuan M, et al. Induction and regulation of the carcinogen-metabolizing enzyme CYP1A1 by marijuana smoke and delta (9)-tetrahydrocannabinol. Am J Respir Cell Mol Biol. 2001;24:339–44.
Yamaori S, Kushihara M, Yamamoto I, et al. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem Pharmacol. 2010;79:1691–8.
Sachse-Seeboth C, Pfeil J, Sehrt D, et al. Interindividual variation in the pharmacokinetics of delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin Pharmacol Ther. 2009;85:273–6.
Wang B, Wang J, Huang SQ, et al. Genetic polymorphism of the human cytochrome P450 2C9 gene and its clinical significance. Curr Drug Metab. 2009;10(7):781–834.
Grayson L, Vines B, Nichol K, et al. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. 2018;9:10–1.
Nuutinen T. Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus. Eur J Med Chem. 2018;157:198–228.
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O’Brien, K., Blair, P. (2021). Routes of Administration, Pharmacokinetics and Safety of Medicinal Cannabis. In: Medicinal Cannabis and CBD in Mental Healthcare. Springer, Cham. https://doi.org/10.1007/978-3-030-78559-8_11
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