Safety Considerations in Cannabinoid-Based Medicine

References

• Allan GM, Ramji J, Perry D, et al. Simplified guideline for prescribing medical cannabinoids in primary care. Can Fam Physician. 2018;64(2):111–120.29449241
   PubMed Web of Science ®Google Scholar
• Cyr C, Arboleda MF, Aggarwal SK, et al. Cannabis in palliative care: current challenges and practical recommendations. Ann Palliat Med. 2018;7(4):463–477. doi:10.21037/apm.2018.06.0430180728
   PubMed Web of Science ®Google Scholar
• Häuser W, Finn DP, Kalso E, et al. European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management. Eur J Pain. 2018;22(9):1547–1564. doi:10.1002/ejp.129730074291
   PubMed Web of Science ®Google Scholar
• Moulin DE, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328–335. doi:10.1155/2014/75469325479151
   PubMed Web of Science ®Google Scholar
• Yadav V, Bever C. Jr, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis. Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(12):1083–1092. doi:10.1212/WNL.000000000000025024663230
   PubMed Web of Science ®Google Scholar
• World Health Organization. WHO expert committee on drug dependence. Critical review. Delta-9-tetrahydrocannabinol; 2018 Available from: https://www.who.int/medicines/access/controlled-substances/THCv1.pdf?ua=1. Accessed 62, 2020..
   Google Scholar
• World Health Organization, Cannabidiol (CBD). Critical review report; 2018 Available from: https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf. Accessed 62, 2020.
   Google Scholar
• ElSohly MA. Chemical constituents of cannabis Grotenhermen F, Russo E, eds. In: Cannabis and Cannabinoids. Pharmacology, Toxicology, and Therapeutic Potential. Binghamton, NY: The Haworth Press; 2002:27–36.
   Google Scholar
• Hanuš LO, Meyer SM, Muñoz E, Taglialatela-Scafati O, Appendino G. Phytocannabinoids: a unified critical inventory. Nat Prod Rep. 2016;33(12):1357–1392. doi:10.1039/c6np00074f27722705
   PubMed Web of Science ®Google Scholar
• Pertwee RG, ed. Handbook of Cannabis. Oxford: Oxford University Press; 2014.
   Google Scholar
• 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(21):2011–2020. doi:10.1056/NEJMoa161161828538134
   PubMed Web of Science ®Google Scholar
• 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):1085–1096. doi:10.1016/S0140-6736(18)30136-329395273
   PubMed Web of Science ®Google Scholar
• Wade DT, 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(4):434–441. doi:10.1191/1352458504ms1082oa15327042
   PubMed Web of Science ®Google Scholar
• Beal JE, Olson R, Lefkowitz L, et al. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage. 1997;14(1):7–14. doi:10.1016/S0885-3924(97)00038-99223837
   PubMed Web of Science ®Google Scholar
• AbbVie Inc. MARINOL (dronabinol) capsules, for oral use. Prescribing Information; 2017 Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf. Accessed 1217, 2019.
   Google Scholar
• Meda Pharmaceuticals Inc. CESAMET - nabilone capsule. Prescribing information; 2015 Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bb582d64-0f51-11df-8a39-0800200c9a66&audience=consumer. Accessed 12, 2020.
   Google Scholar
• National Institute for Health and Care Excellence. Cannabis-based medicinal products. NICE guideline [NG144]; 2019 Available from: https://www.nice.org.uk/guidance/NG144. Accessed 12, 2020.
   Google Scholar
• Bayer Schering Pharma. Sativex oromucosal spray. Summary of product characteristics; 2019 Available from: https://www.medicinesresources.nhs.uk/upload/documents/News/2010/Sativex_UK_SmPC_FINAL.pdf. Accessed 1217, 2019.
   Google Scholar
• Greenwich Biosciences Inc. EPIDIOLEX® (cannabidiol) oral solution, CX. Prescribing information; 2018 Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Accessed 12, 2020.
   Google Scholar
• Insys Therapeutics Inc. SYNDROS (dronabinol) oral solution, CX. Prescribing information; 2016 Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205525s000lbl.pdf. Accessed 12, 2020.
   Google Scholar
• Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3(9):771–784. doi:10.1038/nrd149515340387
   PubMed Web of Science ®Google Scholar
• Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462. doi:10.1124/pr.58.3.216968947
   PubMed Web of Science ®Google Scholar
• Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005;168:299–325.
   PubMedGoogle Scholar
• Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20(Suppl 1):10–14. doi:10.1111/j.1365-2826.2008.01671.x18426493
   PubMed Web of Science ®Google Scholar
• Dai E, Zhang L, Ye L, et al. Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B. Int J Infect Dis. 2017;59:124–130. doi:10.1016/j.ijid.2017.03.00828315398
   PubMed Web of Science ®Google Scholar
• Lotersztajn S, Teixeira-Clerc F, Julien B, et al. CB2 receptors as new therapeutic targets for liver diseases. Br J Pharmacol. 2008;153(2):286–289. doi:10.1038/sj.bjp.070751117952109
   PubMed Web of Science ®Google Scholar
• Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–1949. doi:10.1126/science.14709191470919
   PubMed Web of Science ®Google Scholar
• Lynch ME, Ware MA. Cannabinoids for the treatment of chronic non-cancer pain: an updated systematic review of randomized controlled trials. J Neuroimmune Pharmacol. 2015;10(2):293–301. doi:10.1007/s11481-015-9600-625796592
   PubMed Web of Science ®Google Scholar
• Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3:CD012182. doi:10.1002/14651858.CD012182.pub229513392
   PubMed Web of Science ®Google Scholar
• Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use. A systematic review and meta-analysis. JAMA. 2015;313(24):2456–2473. doi:10.1001/jama.2015.635826103030
   PubMed Web of Science ®Google Scholar
• Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ. 2008;178(13):1669–1678. doi:10.1503/cmaj.07117818559804
   PubMed Web of Science ®Google Scholar
• Ware MA, Tawfik VL. Safety issues concerning the medical use of cannabis and cannabinoids. Pain Res Manag. 2005;10(Suppl A):31A–37A. doi:10.1155/2005/312357
   Google Scholar
• Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;370(23):2219–2227. doi:10.1056/NEJMra140230924897085
   PubMed Web of Science ®Google Scholar
• The National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids. The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press; 2017.
   Google Scholar
• Health Canada. Information for Health Care Professionals. Cannabis (marihuana, marijuana) and the cannabinoids. Dried or fresh plant and oil administration by ingestion or other means. Psychoactive agent; 2018 Available from: https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids-eng.pdf. Accessed 12, 2020.
   Google Scholar
• Secades-Villa R, Garcia-Rodriguez O, Jin CJ, Wang S, Blanco C. Probability and predictors of the cannabis gateway effect: a national study. Int J Drug Policy. 2015;26(2):135–142. doi:10.1016/j.drugpo.2014.07.01125168081
   PubMed Web of Science ®Google Scholar
• 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(9):1888–1900. doi:10.1111/bcp.1403831222854
   PubMed Web of Science ®Google Scholar
• MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12–19. doi:10.1016/j.ejim.2018.01.00429307505
   PubMed Web of Science ®Google Scholar
• Schuck RN, Pacanowski M, Kim S, Madabushi R, Zineh I. Use of titration as a therapeutic individualization strategy: An analysis of Food and Drug Administration-approved drugs. Clin Transl Sci. 2019;12(3):236–239. doi:10.1111/cts.1262630791226
   PubMed Web of Science ®Google Scholar
• Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 2018;32(11):1053–1067. doi:10.1007/s40263-018-0578-530374683
   PubMed Web of Science ®Google Scholar
• Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770–1804. doi:10.1002/cbdv.20079015217712819
   PubMed Web of Science ®Google Scholar
• Collin C, Davies P, Mutiboko IK, Ratcliffe S, for the Sativex Spasticity in MS Study Group. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol. 2007;14(3):290–296. doi:10.1111/j.1468-1331.2006.01639.x17355549
   PubMed Web of Science ®Google Scholar
• Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010;32(5):451–459. doi10.1179/016164109X1259051868566020307378
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1056/NEJMoa171463129768152
   PubMed Web of Science ®Google Scholar
• Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler. 2012;18(2):219–228. doi:10.1177/135245851141970021878454
   PubMed Web of Science ®Google Scholar
• Novotna A, Mares J, Ratcliffe S, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011;18(9):1122–1131. doi:10.1111/j.1468-1331.2010.03328.x21362108
   PubMed Web of Science ®Google Scholar
• Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol. 2013;260(1):285–295. doi:10.1007/s00415-012-6634-z22878432
   PubMed Web of Science ®Google Scholar
• Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler. 2006;12(5):639–645. doi:10.1177/135245850507061817086911
   PubMed Web of Science ®Google Scholar
• Ball S, Vickery J, Hobart J, et al. The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Health Technol Assess. 2015;19(12):vii–viii, xxv–xxxi, 1–187. doi:10.3310/hta19120
   Web of Science ®Google Scholar
• Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1–2):169–172. doi:10.1016/s0304-3959(03)00331-214581124
   PubMed Web of Science ®Google Scholar
• Meiri E, Jhangiani H, Vredenburgh JJ, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007;23(3):533–543. doi:10.1185/030079907x16752517355735
   PubMed Web of Science ®Google Scholar
• Pini LA, Guerzoni S, Cainazzo MM, et al. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain. 2012;13(8):677–684. doi:10.1007/s10194-012-0490-123070400
   PubMed Web of Science ®Google Scholar
• Ware MA, Fitzcharles M-A, Joseph L, Shir Y. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110(2):604–610. doi:10.1213/ANE.0b013e3181c76f7020007734
   PubMed Web of Science ®Google Scholar
• Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ. 2008;336(7637):199–201. doi:10.1136/bmj.39429.619653.8018182416
   PubMed Web of Science ®Google Scholar
• Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9(2):164–173. doi:10.1016/j.jpain.2007.09.00217974490
   PubMed Web of Science ®Google Scholar
• Fabre LF, McLendon D. The efficacy and safety of nabilone (a synthetic cannabinoid) in the treatment of anxiety. J Clin Pharmacol. 1981;21(S1):377S–382S. doi:10.1002/j.1552-4604.1981.tb02617.x6117575
   PubMed Web of Science ®Google Scholar
• Schimrigk S, Marziniak M, Neubauer C, Kugler EM, Werner G, Abramov-Sommariva D. Dronabinol is a safe long-term treatment option for neuropathic pain patients. Eur Neurol. 2017;78(5–6):320–329. doi:10.1159/00048108929073592
   PubMed Web of Science ®Google Scholar
• 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):270–278. doi:10.1016/S1474-4422(15)00379-826724101
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1111/epi.1462830582156
   PubMed Web of Science ®Google Scholar
• Szaflarski JP, Bebin EM, Comi AM, et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59(8):1540–1548. doi:10.1111/epi.1447729998598
   PubMed Web of Science ®Google Scholar
• 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):419–428. doi:10.1111/epi.1467030740695
   PubMed Web of Science ®Google Scholar
• De Gregorio D, McLaughlin RJ, Posa L, et al. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain. 2019;160(1):136–150. doi:10.1097/j.pain.000000000000138630157131
   PubMed Web of Science ®Google Scholar
• Ware MA, Wang T, Shapiro S, Collet J-P, for the COMPASS study team. Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). J Pain. 2015;16(12):1233–1242. doi:10.1016/j.jpain.2015.07.01426385201
   PubMed Web of Science ®Google Scholar
• Abuhasira R, Schleider LB, Mechoulam R, Novack V. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. Eur J Intern Med. 2018;49:44–50. doi:10.1016/j.ejim.2018.01.01929398248
   PubMed Web of Science ®Google Scholar
• Etges T, Karolia K, Grint T, et al. An observational postmarketing safety registry of patients in the UK, Germany, and Switzerland who have been prescribed Sativex® (THC:CBD, nabiximols) oromucosal spray. Ther Clin Risk Manag. 2016;12:1667–1675. doi:10.2147/TCRM.S11501427956834
   PubMed Web of Science ®Google Scholar
• Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):37. doi:10.1186/s10194-018-0862-229797104
   PubMed Web of Science ®Google Scholar
• Park J-Y, Wu L-T. Prevalence, reasons, perceived effects, and correlates of medical marijuana use: A review. Drug Alcohol Depend. 2017;177:1–13. doi:10.1016/j.drugalcdep.2017.03.00928549263
   PubMed Web of Science ®Google Scholar
• Russo EB. Cannabis and pain. Pain Med. 2019;20(11):2083–2085. doi:10.1093/pm/pnz22731529092
   PubMed Web of Science ®Google Scholar
• Jank R, Gallee A, Boeckle M, Fiegl S, Pieh C. Chronic pain and sleep disorders in primary care. Pain Res Treat. 2017;2017:9081802. doi:10.1155/2017/908180229410915
   PubMed Web of Science ®Google Scholar
• Office for National Statistics. Deaths related to drug poisoning, England and Wales; 2019 Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/deathsrelatedtodrugpoisoningenglandandwalesreferencetable. Accessed 32, 2020.
   Google Scholar
• Marel C, Sunderland M, Mills KL, Slade T, Teesson M, Chapman C. Conditional probabilities of substance use disorders and associated risk factors: Progression from first use to use disorder on alcohol, cannabis, stimulants, sedatives and opioids. Drug Alcohol Depend. 2019;194:136–142. doi:10.1016/j.drugalcdep.2018.10.01030439610
   PubMed Web of Science ®Google Scholar
• Bonn-Miller MO, Pollack CV, Jr., Casarett D, et al. Priority considerations for medicinal cannabis-related research. Cannabis Cannabinoid Res. 2019;4(3):139–157. doi:10.1089/can.2019.004531579832
   PubMedGoogle Scholar
• Canadian Pharmacists Association. CPhA monograph. Cannabis. Compendium of Pharmaceuticals and Specialties; 2018.
   Google Scholar
• Antoniou T, Bodkin J, Ho JM. Drug interactions with cannabinoids. CMAJ. 2020;192(9):E206. doi:10.1503/cmaj.19109732122975
   PubMed Web of Science ®Google Scholar
• Zendulka O, Dovrtělová G, Nosková K, et al. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab. 2016;17(3):206–226. doi:10.2174/138920021766615121014205126651971
   PubMed Web of Science ®Google Scholar
• Brown JD, Winterstein AG. Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use. J Clin Med. 2019;8(7):989. doi:10.3390/jcm8070989
   PubMed Web of Science ®Google Scholar
• Alsherbiny MA, Li CG. Medicinal cannabis—potential drug interactions. Medicines (Basel). 2018;6(1):3. doi:10.3390/medicines6010003
   Google Scholar
• Taha T, Meiri D, Talhamy S, Wollner M, Peer A, Bar-Sela G. Cannabis impacts tumor response rate to nivolumab in patients with advanced malignancies. Oncologist. 2019;24(4):549–554. doi:10.1634/theoncologist.2018-038330670598
   PubMed Web of Science ®Google Scholar
• Wong SS, Wilens TE. Medical cannabinoids in children and adolescents: A systematic review. Pediatrics. 2017;140(5):e20171818. doi:10.1542/peds.2017-181829061872
   PubMed Web of Science ®Google Scholar
• Canadian Pharmacists Association. CPhA monograph. Opioids. Compendium of Pharmaceuticals and Specialties. 2018.
   Google Scholar
• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. DSM-5™. Arlington, VA: American Psychiatric Publishing; 2013.
   Google Scholar
• Adamson SJ, Kay-Lambkin FJ, Baker AL, et al. An improved brief measure of cannabis misuse: the Cannabis Use Disorders Identification Test-Revised (CUDIT-R). Drug Alcohol Depend. 2010;110(1–2):137–143. doi:10.1016/j.drugalcdep.2010.02.01720347232
   PubMed Web of Science ®Google Scholar
• Skinner HA. The drug abuse screening test. Addict Behav. 1982;7(4):363–371. doi:10.1016/0306-4603(82)90005-37183189
   PubMed Web of Science ®Google Scholar
• Copeland WE, Hill S, Costello EJ, Shanahan L. Cannabis use and disorder from childhood to adulthood in a longitudinal community sample with American Indians. J Am Acad Child Adolesc Psychiatry. 2017;56(2):124–132.e2. doi:10.1016/j.jaac.2016.11.00628117058
   PubMed Web of Science ®Google Scholar
• Degenhardt L, Ferrari AJ, Calabria B, et al. The global epidemiology and contribution of cannabis use and dependence to the global burden of disease: results from the GBD 2010 study. PLoS One. 2013;8(10):e76635. doi:10.1371/journal.pone.007663524204649
   PubMed Web of Science ®Google Scholar
• Ware MA, St Arnaud-Trempe E. The abuse potential of the synthetic cannabinoid nabilone. Addiction. 2010;105(3):494–503. doi:10.1111/j.1360-0443.2009.02776.x20402993
   PubMed Web of Science ®Google Scholar
• Lintzeris N, Bhardwaj A, Mills L, et al. Nabiximols for the treatment of cannabis dependence. A randomized clinical trial. JAMA Intern Med. 2019;179(9):1242–1253. doi:10.1001/jamainternmed.2019.1993
   Web of Science ®Google Scholar
• Wiese B, Wilson-Poe AR. Emerging evidence for cannabis’ role in opioid use disorder. Cannabis Cannabinoid Res. 2018;3(1):179–189. doi:10.1089/can.2018.002230221197
   PubMedGoogle Scholar
• Hoggart B, Ratcliffe S, Ehler E, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. J Neurol. 2015;262(1):27–40. doi:10.1007/s00415-014-7502-925270679
   PubMed Web of Science ®Google Scholar
• Lachenmeier DW, Rehm J. Comparative risk assessment of alcohol, tobacco, cannabis and other illicit drugs using the margin of exposure approach. Sci Rep. 2015;5:8126. doi:10.1038/srep0812625634572
   PubMed Web of Science ®Google Scholar
• Li W, Gunja N. Illicit drug overdose. Prevalence and acute management. Aust Fam Physician. 2013;42(7):481–485.23826601
   PubMedGoogle Scholar
• Cao D, Srisuma S, Bronstein AC, Hoyte CO. Characterization of edible marijuana product exposures reported to United States poison centers. Clin Toxicol (Phila). 2016;54(9):840–846. doi:10.1080/15563650.2016.120976127418198
   PubMed Web of Science ®Google Scholar
• Moreira FA, Aguiar DC, Guimarães FS. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(8):1466–1471. doi:10.1016/j.pnpbp.2006.06.00416876926
   PubMed Web of Science ®Google Scholar
• Pisanti S, Malfitano AM, Ciaglia E, et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol Ther. 2017;175:133–150. doi:10.1016/j.pharmthera.2017.02.04128232276
   PubMed Web of Science ®Google Scholar
• Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3364–3378. doi:10.1098/rstb.2011.038923108553
   PubMed Web of Science ®Google Scholar
• Micale V, Di Marzo V, Sulcova A, Wotjak CT, Drago F. Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther. 2013;138(1):18–37. doi:10.1016/j.pharmthera.2012.12.00223261685
   PubMed Web of Science ®Google Scholar
• Onaivi ES, Green MR, Martin BR. Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther. 1990;253(3):1002–1009.2162942
   PubMed Web of Science ®Google Scholar
• Childs E, Lutz JA, de Wit H. Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug Alcohol Depend. 2017;177:136–144. doi:10.1016/j.drugalcdep.2017.03.03028599212
   PubMed Web of Science ®Google Scholar
• Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of ∆9-tetrahydrocannabinol in man. Eur J Pharmacol. 1974;28(1):172–177. doi:10.1016/0014-2999(74)90129-04609777
   PubMed Web of Science ®Google Scholar
• Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19–27. doi:10.1177/026988111246010923042808
   PubMed Web of Science ®Google Scholar
• Solowij N, Broyd S, Greenwood LM, et al. A randomised controlled trial of vaporised ∆9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects. Eur Arch Psychiatry Clin Neurosci. 2019;269(1):17–35. doi:10.1007/s00406-019-00978-230661105
   PubMed Web of Science ®Google Scholar
• Scott JC, Slomiak ST, Jones JD, Rosen AFG, Moore TM, Gur RC. Association of cannabis with cognitive functioning in adolescents and young adults: a systematic review and meta-analysis. JAMA Psychiatry. 2018;75(6):585–595. doi:10.1001/jamapsychiatry.2018.033529710074
   PubMed Web of Science ®Google Scholar
• Meier MH, Schriber RA, Beardslee J, Hanson J, Pardini D. Associations between adolescent cannabis use frequency and adult brain structure: A prospective study of boys followed to adulthood. Drug Alcohol Depend. 2019;202:191–199. doi:10.1016/j.drugalcdep.2019.05.01231357120
   PubMed Web of Science ®Google Scholar
• Rogeberg O, Elvik R. The effects of cannabis intoxication on motor vehicle collision revisited and revised. Addiction. 2016;111(8):1348–1359. doi:10.1111/add.1334726878835
   PubMed Web of Science ®Google Scholar
• Neavyn MJ, Blohm E, Babu KM, Bird SB. Medical marijuana and driving: a review. J Med Toxicol. 2014;10(3):269–279. doi:10.1007/s13181-014-0393-424648180
   PubMedGoogle Scholar
• Dahlgren MK, Sagar KA, Smith RT, Lambros AM, Kuppe MK, Gruber SA. Recreational cannabis use impairs driving performance in the absence of acute intoxication. Drug Alcohol Depend. 2020;208:107771. doi:10.1016/j.drugalcdep.2019.10777131952821
   PubMed Web of Science ®Google Scholar
• Zhang LR, Morgenstern H, Greenland S, et al. Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium. Int J Cancer. 2015;136(4):894–903. doi:10.1002/ijc.2903624947688
   PubMed Web of Science ®Google Scholar
• Reis JP, Auer R, Bancks MP, et al. Cumulative lifetime marijuana use and incident cardiovascular disease in middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Am J Public Health. 2017;107(4):601–606. doi:10.2105/AJPH.2017.30365428207342
   PubMed Web of Science ®Google Scholar
• Kalla A, Krishnamoorthy P, Gopalakrishnan A, Garg J, Figueredo V. Cannabis use predicts risks of heart failure and cerebrovascular accidents: results from the national inpatient sample. J Am Coll Cardiol. 2017;69(Suppl)(11):1784. doi:10.1016/S0735-1097(17)35173-2
   Web of Science ®Google Scholar
• Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation. 2001;103(23):2805–2809. doi:10.1161/01.cir.103.23.280511401936
   PubMed Web of Science ®Google Scholar
• Rezkalla SH, Sharma P, Kloner RA. Coronary no-flow and ventricular tachycardia associated with habitual marijuana use. Ann Emerg Med. 2003;42(3):365–369. doi:10.1016/s0196-0644(03)00426-812944889
   PubMed Web of Science ®Google Scholar
• Astley SJ, Little RE. Maternal marijuana use during lactation and infant development at one year. Neurotoxicol Teratol. 1990;12(2):161–168. doi:10.1016/0892-0362(90)90129-z2333069
   PubMed Web of Science ®Google Scholar
• Briggs GG, Freeman RK, Towers CV, Forinash AB. Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Eleventh Edition. Philadelphia, PA: Wolters Kluwer; 2017.
   Google Scholar
• Conner SN, Bedell V, Lipsey K, Macones GA, Cahill AG, Tuuli MG. Maternal marijuana use and adverse neonatal outcomes: Asystematic review and meta-analysis. Obstet Gynecol. 2016;128(4):713–723. doi:10.1097/AOG.000000000000164927607879
   PubMed Web of Science ®Google Scholar
• Volkow ND, Han B, Compton WM, McCance-Katz EF. Self-reported medical and nonmedical cannabis use among pregnant women in the United States. JAMA. 2019;322(2):167–169. doi:10.1001/jama.2019.798231211824
   PubMed Web of Science ®Google Scholar
• Westfall RE, Janssen PA, Lucas P, Capler R. Survey of medicinal cannabis use among childbearing women: patterns of its use in pregnancy and retroactive self-assessment of its efficacy against ‘morning sickness’. Complement Ther Clin Pract. 2006;12(1):27–33. doi:10.1016/j.ctcp.2005.09.00616401527
   PubMedGoogle Scholar
• Badowski S, Smith G. Cannabis use during pregnancy and postpartum. Can Fam Physician. 2020;66(2):98–103.32060189
   PubMed Web of Science ®Google Scholar
• Gurney J, Shaw C, Stanley J, Signal V, Sarfati D. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer. 2015;15:897. doi:10.1186/s12885-015-1905-626560314
   PubMed Web of Science ®Google Scholar
• Gorzalka BB, Hill MN, Chang SCH. Male–female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function. Horm Behav. 2010;58(1):91–99. doi:10.1016/j.yhbeh.2009.08.00919733173
   PubMed Web of Science ®Google Scholar
• Gundersen TD, Jørgensen N, Andersson A-M, et al. Association between use of marijuana and male reproductive hormones and semen quality: a study among 1,215 healthy young men. Am J Epidemiol. 2015;182(6):473–481. doi:10.1093/aje/kwv13526283092
   PubMed Web of Science ®Google Scholar
• Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844–851. doi:10.1038/clpt.2011.18822048225
   PubMed Web of Science ®Google Scholar
• Haroutounian S, Ratz Y, Ginosar Y, et al. The effect of medicinal cannabis on pain and quality-of-life outcomes in chronic pain: a prospective open-label study. Clin J Pain. 2016;32(12):1036–1043. doi:10.1097/AJP.000000000000036426889611
   PubMed Web of Science ®Google Scholar
• Reiman A, Welty M, Solomon P. Cannabis as a substitute for opioid-based pain medication: patient self-report. Cannabis Cannabinoid Res. 2017;2(1):160–166. doi:10.1089/can.2017.001228861516
   PubMedGoogle Scholar
• Wen H, Hockenberry JM. Association of medical and adult-use marijuana laws with opioid prescribing for Medicaid enrollees. JAMA Intern Med. 2018;178(5):673–679. doi:10.1001/jamainternmed.2018.100729610827
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1371/journal.pone.018779529145417
   PubMed Web of Science ®Google Scholar
• Purcell C, Davis A, Moolman N, Taylor SM. Reduction of benzodiazepine use in patients prescribed medical cannabis. Cannabis Cannabinoid Res. 2019;4(3):214–218. doi:10.1089/can.2018.002031559336
   PubMedGoogle Scholar