Efficacy and safety of medical cannabinoids in children: a systematic review and meta-analysis
Park, J. Y. & Wu, L. T. Prevalence, reasons, perceived effects, and correlates of medical marijuana use: A review. Drug. Alcohol. Depend. 177, 1–13. https://doi.org/10.1016/j.drugalcdep.2017.03.009 (2017).
Epidyolex|European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/epidyolex (2021).
Anwar, A., Saleem, S., Patel, U. K., Arumaithurai, K. & Malik, P. Dravet syndrome: An overview. Cureus https://doi.org/10.7759/cureus.5006 (2019).
Asadi-Pooya, A. A. Lennox-Gastaut syndrome: A comprehensive review. Neurol. Sci. 393(39), 403–414 (2017).
Swaminath, A. et al. The role of cannabis in the management of inflammatory bowel disease: a review of clinical, scientific, and regulatory informationcommissioned by the crohn’s and colitis foundation. Inflamm. Bowel Dis. 25, 427–435. https://doi.org/10.1093/ibd/izy319 (2019).
Aran, A., Cassuto, H., Lubotzky, A., Wattad, N. & Hazan, E. Brief report: Cannabidiol-rich cannabis in children with autism spectrum disorder and severe behavioral problems-a retrospective feasibility study. J. Autism Dev. Disord. 49, 1284–1288. https://doi.org/10.1007/s10803-018-3808-2 (2019).
Ben-Zeev, B. Medical cannabis for intractable epilepsy in childhood: A review. Rambam Maimonides Med. J. 11, e0004. https://doi.org/10.5041/RMMJ.10387 (2020).
Tramèr, M. R. et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: Quantitative systematic review. Br. Med. J. 323, 16–21. https://doi.org/10.1136/bmj.323.7303.16 (2001).
Pacher, P., Kogan, N. M. & Mechoulam, R. Beyond THC and endocannabinoids. Annu. Rev. Pharmacol. Toxicol. 60, 637–659. https://doi.org/10.1146/annurev-pharmtox-010818-021441 (2020).
Skrypek, M. M., Bostrom, B. C. & Bendel, A. E. Medical cannabis certification in a large pediatric oncology center. Children 6, 79. https://doi.org/10.3390/children6060079 (2019).
National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. 58,91,97,245 (Washington, DC: The National Academies Press. 2017), DOI: https://doi.org/10.17226/24625.
Bourgeois, F. T. et al. Pediatric versus adult drug trials for conditions with high pediatric disease burden. Pediatrics 130, 285–292. https://doi.org/10.1542/peds.2012-0139 (2012).
Mueller, B. U. et al. Principles of pediatric patient safety: Reducing harm due to medical care. Pediatrics 143, 2. https://doi.org/10.1542/peds.2012-0139 (2019).
Volkow, N. D., Baler, R. D., Compton, W. M. & Weiss, S. R. B. Adverse health effects of marijuana use. N. Engl. J. Med. 370, 2219–2227. https://doi.org/10.1056/NEJMra1402309 (2014).
Kelly, B. F. & Nappe, T. M. Cannabinoid Toxicity. Treasure Island (FL): StatPearls (StatPearls Publishing, 2019). PMID: 29489164.
Martín-Gómez, A., Palacios-Gómez, M. E. & García-Marcos, S. A. Severe intradialytic hypoglycemia associated with marijuana use. Nefrologia. 35, 328–329. https://doi.org/10.1016/j.nefroe.2015.02.001 (2015).
Naji, L. et al. The association between cannabis use and suicidal behavior in patients with psychiatric disorders: an analysis of sex differences. Biol. Sex Differ. 9, 22. https://doi.org/10.1186/s13293-018-0182-x (2018).
Ragazzi, T. C. C., Shuhama, R., Menezes, P. R. & Del-Ben, C. M. Cannabis use as a risk factor for psychotic-like experiences: A systematic review of non-clinical populations evaluated with the Community Assessment of Psychic Experiences. Early Interv. Psychiatry 12, 1013–1023. https://doi.org/10.1111/eip.12693 (2018).
Lev-Ran, S. et al. The association between cannabis use and depression: A systematic review and meta-analysis of longitudinal studies. Psychol. Med. 44, 797–810. https://doi.org/10.1017/S0033291713001438 (2014).
van Gastel, W. A. et al. Change in cannabis use in the general population: A longitudinal study on the impact on psychotic experiences. Schizophr. Res. 157, 266–270. https://doi.org/10.1016/J.SCHRES.2014.04.023 (2014).
Appelboam, A. & Oades, P. J. Coma due to cannabis toxicity in an infant. Eur. J. Emerg. Med. 13, 177–179. https://doi.org/10.1097/01.mej.0000194405.38206.f2 (2006).
Carstairs, S. D., Fujinaka, M. K., Keeney, G. E. & Ly, B. T. Prolonged coma in a child due to hashish ingestion with quantitation of THC metabolites in urine. J. Emerg. Med. 41, 3. https://doi.org/10.1016/j.jemermed.2010.05.032 (2011).
Bonkowsky, J. L., Sarco, D. & Pomeroy, S. L. Ataxia and shaking in a 2-year-old girl: Acute marijuana intoxication presenting as seizure. Pediatr. Emerg. Care. 21, 527–528. https://doi.org/10.1097/01.pec.0000173349.38024.33 (2005).
Richards, J. R., Smith, N. E. & Moulin, A. K. Unintentional cannabis ingestion in children: A systematic review. J. Pediatr. 190, 142–152. https://doi.org/10.1016/j.jpeds.2017.07.005 (2017).
Corsi, D. J. et al. Maternal cannabis use in pregnancy and child neurodevelopmental outcomes. Nat. Med. 26, 1536–1540. https://doi.org/10.1038/s41591-020-1002-5 (2020).
Sadhana, D., Kathleen, M. & Jonathan, D. K. Marijuana and the pediatric population. Pediatrics https://doi.org/10.1542/peds.2019-2629 (2020).
Wong, S. S. & Wilens, T. E. Medical cannabinoids in children and adolescents: A systematic review. Pediatrics 140, 5. https://doi.org/10.1542/peds.2017-1818 (2017).
Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. N. Engl. J. Med. 376, 2011–2020. https://doi.org/10.1056/NEJMoa1611618 (2017).
Porcari, G. S., Fu, C., Doll, E. D., Carter, E. G. & Carson, R. P. Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center. Epilepsy Behav. 80, 240–246. https://doi.org/10.1016/j.yebeh.2018.01.026 (2018).
Devinsky, O. et al. Effect of cannabidiol on drop seizures in the lennox-gastaut syndrome. N. Engl. J. Med. 378, 1888–1897. https://doi.org/10.1056/NEJMoa1714631 (2018).
Lattanzi, S. et al. Efficacy and safety of cannabidiol in epilepsy: A systematic review and meta-analysis. Drugs 78, 1791–1804. https://doi.org/10.1007/s40265-018-0992-5 (2018).
de Carvalho, R. R., Almeida, K. J., da Silva, L. L., de Melo Mendes, C. M. & Bor-Seng-Shu, E. Efficacy and adverse event profile of cannabidiol and medicinal cannabis for treatment-resistant epilepsy: Systematic review and meta-analysis. Epilepsy Behav. 102, 106635. https://doi.org/10.1016/j.yebeh.2019.106635 (2020).
Liberati, A. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339, b2700. https://doi.org/10.1136/bmj.b2700 (2009).
Ouzzani, M., Hammady, H., Fedorowicz, Z. & Elmagarmid, A. Rayyan-a web and mobile app for systematic reviews. Syst. Rev. 5(210), 1. https://doi.org/10.1186/s13643-016-0384-4 (2016).
Sterne, J. A. et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355, i4919. https://doi.org/10.1136/bmj.i4919 (2016).
Higgins, J. P. T. et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343, i7829. https://doi.org/10.1136/bmj.d5928 (2011).
Busner, J. & Targum, S. D. The clinical global impressions scale: Applying a research tool in clinical practice. Psychiat. Edgmont 4(7), 28–37 (2007).
European Medicines Agency. Important medical event terms list (MedDRA version 23.0, updated). https://www.ema.europa.eu/en/documents/other/important-medical-event-terms-list-version-meddra-version-221_en.xls (2020).
Viechtbauer, W. Conducting meta-analyses in R with the metafor. J. Stat. Softw. 36, 1–48. https://doi.org/10.18637/jss.v036.i03 (2010).
Balduzzi, S., Rücker, G. & Schwarzer, G. How to perform a meta-analysis with R: A practical tutorial. Evid. Based. Ment. Health 22, 153–160. https://doi.org/10.1136/ebmental-2019-300117 (2019).
Rücker, G., Krahn, U., König, J., Efthimiou, O. & Schwarzer, G. Package ‘netmeta’ title network meta-analysis using frequentist methods. Epidemiol. Health https://doi.org/10.1007/978-3-319-21416 (2020).
McGrath, S., Zhao, X., Steele, R. & Benedetti, A. Package ‘metamedian’ Title Meta-Analysis of Medians. (2020). https://doi.org/10.1002/sim.8013.
Copenhagen Trial Unit. Trial Sequential Analysis Viewer. (2016).
Wetterslev, J., Thorlund, K., Brok, J. & Gluud, C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med. Res. Methodol. 91(9), 1–12. https://doi.org/10.1186/1471-2288-9-86 (2009).
Borenstein, M., Hedges, L., Higgins, J., Rothstein, H. & Biostat Englewood, N.J. Comprehensive Meta-Analysis 3. (2013).
Dean, A.G., Sullivan, K.M., Soe, M.M. OpenEpi: Open source epidemiologic statistics for public health, Version. www.OpenEpi.com, updated 2013/04/06, accessed 2021/10/16.
Page, M. J. et al. Epidemiology and reporting characteristics of systematic reviews of biomedical research: A cross-sectional study. PLOS Med. 13, e1002028. https://doi.org/10.1371/journal.pmed.1002028 (2016).
Chan, S. G., Correia, A. J. & MecLeod, M. S. Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: A double-blind, crossover trial. Pediatrics 79(6), 946–952 (1987).
Dalzell, A. M., Bartlett, H. & Lilleyman, J. S. Nabilone: An alternative antiemetic for cancer chemotherapy. Arch. Dis. Child. 61, 502–505. https://doi.org/10.1136/adc.61.5.502 (1986).
Miller, I. et al. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in dravet syndrome: A randomized clinical trial. JAMA Neurol. 77, 613–621. https://doi.org/10.1001/jamaneurol.2020.0073 (2020).
Fairhurst, C., Kumar, R., Checketts, D., Tayo, B. & Turner, S. Efficacy and safety of nabiximols cannabinoid medicine for paediatric spasticity in cerebral palsy or traumatic brain injury: a randomized controlled trial. Dev. Med. Child Neurol. 62, 1031–1039. https://doi.org/10.1111/dmcn.14548 (2020).
Efron, D. et al. A pilot randomised placebo-controlled trial of cannabidiol to reduce severe behavioural problems in children and adolescents with intellectual disability. Br. J. Clin. Pharmacol. 87, 436–446. https://doi.org/10.1111/bcp.14399 (2021).
Aran, A. et al. Cannabinoid treatment for autism: A proof-of-concept randomized trial. Mol. Autism 12, 1–11. https://doi.org/10.1186/S13229-021-00420-2 (2021).
Devinsky, O. et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 90, e1204–e1211. https://doi.org/10.1212/WNL.0000000000005254 (2018).
Chesney, E. et al. Adverse effects of cannabidiol: A systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology 45, 1799–1806. https://doi.org/10.1038/s41386-020-0667-2 (2020).
Malyshevskaya, O. et al. Natural (∆ 9 -THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB 1 receptor. Sci. Rep. 2017(7), 1–8. https://doi.org/10.1038/s41598-017-10447-2 (2017).
FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy. FDA https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms (2018).
Ruggiero, A. et al. Acute chemotherapy-induced nausea and vomiting in children with cancer: Still waiting for a common consensus on treatment. J. Int. Med. Res. 46, 2149–2156. https://doi.org/10.1177/0300060518765324 (2018).
NICE. Cannabis-based medicinal products: [A] Evidence review for intractable nausea and vomiting NICE guideline NG144 Evidence review underpinning recommendations 1.1.1 and 1.1.2 in the NICE guideline. (2019).
Huestis, M. A. et al. Cannabidiol adverse effects and toxicity. Curr. Neuropharmacol. 17, 974–989. https://doi.org/10.2174/1570159×17666190603171901 (2019).
Stockings, E. et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J. Neurol. Neurosurg. Psychiat. 89, 741–753. https://doi.org/10.1136/JNNP-2017-317168 (2018).
Wiley, J. L. et al. CB1 cannabinoid receptor-mediated modulation of food intake in mice. Br. J. Pharmacol. 145, 293. https://doi.org/10.1038/SJ.BJP.0706157 (2005).
Jankowska, B. I., Jankowski, M. M. & Swiergiel, A. H. Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci. Lett. 490, 82–84. https://doi.org/10.1016/J.NEULET.2010.12.031 (2011).
Skluzacek, J. V., Watts, K. P., Parsy, O., Wical, B. & Camfield, P. Dravet syndrome and parent associations: The IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia 52, 95–101. https://doi.org/10.1111/j.1528-1167.2011.03012.x (2011).
Bandini, L. G. et al. Changes in food selectivity in children with autism spectrum disorder. J. Autism Dev. Disord. 47, 439–446. https://doi.org/10.1007/s10803-016-2963-6 (2017).
Di Marzo, V. & Piscitelli, F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics 12, 692. https://doi.org/10.1007/s13311-015-0374-6 (2015).
Zou, S. & Kumar, U. Cannabinoid receptors and the endocannabinoid system: Signaling and function in the central nervous system. Int. J. Mol. Sci. 1, 9. https://doi.org/10.3390/ijms19030833 (2018).
Netzahualcoyotzi, C., Rodríguez-Serrano, L. M., Chávez-Hernández, M. E. & Buenrostro-Jáuregui, M. H. Early consumption of cannabinoids: From adult neurogenesis to behavior. Int. J. Mol. Sci. 22, 7450. https://doi.org/10.3390/ijms22147450 (2021).
Solowij, N. et al. Therapeutic effects of prolonged cannabidiol treatment on psychological symptoms and cognitive function in regular cannabis users: A pragmatic open-label clinical trial. Cannabis Cannabinoid. Res. 3, 21–34. https://doi.org/10.1089/can.2017.004 (2018).
Osborne, A. L., Solowij, N. & Weston-Green, K. A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia. Neurosci. Biobehav. Rev. 72, 310–324. https://doi.org/10.1016/j.neubiorev.2016.11.012 (2017).
Sidik, K. & Jonkman, J. N. A comparison of heterogeneity variance estimators in combining results of studies. Stat. Med. 26, 1964–1981 (2007).