{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:35:13Z","timestamp":1790994913304,"version":"4.1.0"},"reference-count":95,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["16\/126\/53"],"award-info":[{"award-number":["16\/126\/53"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Parkinson's UK","award":["G-1901"],"award-info":[{"award-number":["G-1901"]}]},{"name":"Parkinson's UK","award":["G-1901"],"award-info":[{"award-number":["G-1901"]}]},{"name":"National Institute for Health Research Biomedical Research Centre"},{"name":"Maudsley NHS Foundation Trust"},{"DOI":"10.13039\/501100000764","name":"King's College London","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000764","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age \u226550 years.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of \u226550 years for all indications, evaluating the safety\/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 \u00b1 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, <jats:italic>p<\/jats:italic> = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, <jats:italic>p<\/jats:italic> = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness\/light-headedness, and somnolence\/drowsiness. Study limitations include inability to fully exclude data from those &lt;50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>This pooled analysis, using data from RCTs with mean participant age \u226550 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1003524","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T17:23:22Z","timestamp":1617038602000},"page":"e1003524","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":51,"title":["Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis"],"prefix":"10.1371","volume":"18","author":[{"given":"Latha","family":"Velayudhan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"McGoohan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8688-8025","authenticated-orcid":true,"given":"Sagnik","family":"Bhattacharyya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"issue":"3","key":"pmed.1003524.ref001","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/02791072.2013.805976","article-title":"The medicinal use of cannabis and cannabinoids\u2014an international cross-sectional survey on administration forms","volume":"45","author":"A Hazekamp","year":"2013","journal-title":"J Psychoactive Drugs"},{"issue":"6","key":"pmed.1003524.ref002","first-page":"1166","article-title":"The Increasing Use of Cannabis Among Older Americans: A Public Health Crisis or Viable Policy Alternative?","volume":"57","author":"B Kaskie","year":"2017","journal-title":"Gerontologist"},{"issue":"8","key":"pmed.1003524.ref003","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1007\/s00228-013-1503-y","article-title":"The prevalence and incidence of medicinal cannabis on prescription in The Netherlands","volume":"69","author":"A Hazekamp","year":"2013","journal-title":"Eur J Clin Pharmacol"},{"issue":"2","key":"pmed.1003524.ref004","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/sj.bjp.0707442","article-title":"The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin","volume":"153","author":"RG Pertwee","year":"2008","journal-title":"Br J Pharmacol"},{"issue":"4","key":"pmed.1003524.ref005","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1001\/archgenpsychiatry.2009.17","article-title":"Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis","volume":"66","author":"S Bhattacharyya","year":"2009","journal-title":"Arch Gen Psychiatry"},{"key":"pmed.1003524.ref006","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.drugalcdep.2016.11.030","article-title":"Oral cannabidiol does not produce a signal for abuse liability in frequent marijuana smokers","volume":"172","author":"S Babalonis","year":"2017","journal-title":"Drug Alcohol Depend"},{"issue":"7","key":"pmed.1003524.ref007","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.bmc.2015.01.059","article-title":"Cannabidiol (CBD) and its analogs: a review of their effects on inflammation","volume":"23","author":"S Burstein","year":"2015","journal-title":"Bioorg Med Chem"},{"issue":"11","key":"pmed.1003524.ref008","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1001\/jamapsychiatry.2018.2309","article-title":"Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial","volume":"75","author":"S Bhattacharyya","year":"2018","journal-title":"JAMA Psychiatry"},{"issue":"7","key":"pmed.1003524.ref009","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.biopsych.2015.11.018","article-title":"Therapeutic Potential of Cannabinoids in Psychosis","volume":"79","author":"FM Leweke","year":"2016","journal-title":"Biol Psychiatry"},{"issue":"2","key":"pmed.1003524.ref010","first-page":"e78","article-title":"Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms","volume":"64","author":"GM Allan","year":"2018","journal-title":"Can Fam Physician"},{"issue":"16","key":"pmed.1003524.ref011","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1007\/s40265-018-0996-1","article-title":"Medical Use of Cannabinoids","volume":"78","author":"AI Fraguas-S\u00e1nchez","year":"2018","journal-title":"Drugs"},{"key":"pmed.1003524.ref012","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.arr.2014.01.007","article-title":"Efficacy and safety of medical cannabinoids in older subjects: a systematic review","volume":"14","author":"GA van den Elsen","year":"2014","journal-title":"Ageing Res Rev"},{"issue":"6","key":"pmed.1003524.ref013","doi-asserted-by":"crossref","first-page":"341","DOI":"10.4140\/TCP.n.2017.341","article-title":"Marijuana Use in the Elderly: Implications and Considerations","volume":"32","author":"TD Mahvan","year":"2017","journal-title":"Consult Pharm"},{"issue":"10","key":"pmed.1003524.ref014","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.jamda.2015.03.015","article-title":"The Mortality Risk of Conventional Antipsychotics in Elderly Patients: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials","volume":"16","author":"TA Hulshof","year":"2015","journal-title":"J Am Med Dir Assoc"},{"issue":"3","key":"pmed.1003524.ref015","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/npp.2009.184","article-title":"Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology","volume":"35","author":"S Bhattacharyya","year":"2010","journal-title":"Neuropsychopharmacology"},{"issue":"24","key":"pmed.1003524.ref016","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1001\/jama.2015.6358","article-title":"Cannabinoids for Medical Use: A Systematic Review and Meta-analysis","volume":"313","author":"PF Whiting","year":"2015","journal-title":"Jama"},{"issue":"13","key":"pmed.1003524.ref017","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1503\/cmaj.071178","article-title":"Adverse effects of medical cannabinoids: a systematic review","volume":"178","author":"T Wang","year":"2008","journal-title":"Cmaj"},{"issue":"13","key":"pmed.1003524.ref018","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.2174\/13816128113199990434","article-title":"Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review","volume":"20","author":"L Velayudhan","year":"2014","journal-title":"Curr Pharm Des"},{"issue":"1","key":"pmed.1003524.ref019","article-title":"Cannabinoids in the Older Person: A Literature Review","volume":"5","author":"W Beedham","year":"2020","journal-title":"Geriatrics (Basel)"},{"key":"pmed.1003524.ref020","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.maturitas.2018.10.010","article-title":"Medical cannabis use in older patients: Update on medical knowledge","volume":"118","author":"O Beauchet","year":"2018","journal-title":"Maturitas"},{"key":"pmed.1003524.ref021","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ejim.2018.01.019","article-title":"Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly","volume":"49","author":"R Abuhasira","year":"2018","journal-title":"Eur J Intern Med"},{"key":"pmed.1003524.ref022","first-page":"1","article-title":"Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis","volume":"2020","author":"A O\u2019Neill","journal-title":"Psychol Med"},{"issue":"1","key":"pmed.1003524.ref023","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1177\/0269881110379283","article-title":"Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report","volume":"25","author":"JA Crippa","year":"2011","journal-title":"J Psychopharmacol"},{"issue":"4","key":"pmed.1003524.ref024","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1007\/s00213-019-05442-6","article-title":"Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis","volume":"237","author":"E Appiah-Kusi","year":"2020","journal-title":"Psychopharmacology (Berl)"},{"issue":"S1","key":"pmed.1003524.ref025","doi-asserted-by":"crossref","first-page":"58s","DOI":"10.1002\/j.1552-4604.2002.tb06004.x","article-title":"Cardiovascular system effects of marijuana","volume":"42","author":"RT Jones","year":"2002","journal-title":"J Clin Pharmacol"},{"issue":"12","key":"pmed.1003524.ref026","doi-asserted-by":"crossref","first-page":"e93760","DOI":"10.1172\/jci.insight.93760","article-title":"A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study","volume":"2","author":"KA Jadoon","year":"2017","journal-title":"JCI insight"},{"issue":"1","key":"pmed.1003524.ref027","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/0269881112460109","article-title":"Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment","volume":"27","author":"A Englund","year":"2013","journal-title":"J Psychopharmacol"},{"issue":"3","key":"pmed.1003524.ref028","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.euroneuro.2014.11.014","article-title":"Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users","volume":"25","author":"C Hindocha","year":"2015","journal-title":"Eur Neuropsychopharmacol"},{"issue":"7","key":"pmed.1003524.ref029","doi-asserted-by":"crossref","first-page":"e1000097","DOI":"10.1371\/journal.pmed.1000097","article-title":"Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement","volume":"6","author":"D Moher","year":"2009","journal-title":"PLoS Med"},{"issue":"7650","key":"pmed.1003524.ref030","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: an emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"GH Guyatt","year":"2008","journal-title":"Bmj"},{"issue":"4","key":"pmed.1003524.ref031","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.jclinepi.2010.07.015","article-title":"GRADE guidelines: 3. Rating the quality of evidence","volume":"64","author":"H Balshem","year":"2011","journal-title":"J Clin Epidemiol"},{"issue":"1","key":"pmed.1003524.ref032","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1093\/ije\/31.1.140","article-title":"Meta-analyses involving cross-over trials: methodological issues","volume":"31","author":"DR Elbourne","year":"2002","journal-title":"International Journal of Epidemiology"},{"issue":"6","key":"pmed.1003524.ref033","doi-asserted-by":"crossref","first-page":"604","DOI":"10.3102\/1076998615606099","article-title":"Small-Sample Adjustments for Tests of Moderators and Model Fit Using Robust Variance Estimation in Meta-Regression","volume":"40","author":"E Tipton","year":"2015","journal-title":"Journal of Educational and Behavioral Statistics"},{"issue":"4","key":"pmed.1003524.ref034","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1080\/07350015.2016.1247004","article-title":"Small-Sample Methods for Cluster-Robust Variance Estimation and Hypothesis Testing in Fixed Effects Models","volume":"36","author":"JE Pustejovsky","year":"2018","journal-title":"Journal of Business & Economic Statistics"},{"issue":"23","key":"pmed.1003524.ref035","doi-asserted-by":"crossref","first-page":"4081","DOI":"10.1002\/sim.2502","article-title":"Improved hypothesis testing for coefficients in generalized estimating equations with small samples of clusters","volume":"25","author":"DF McCaffrey","year":"2006","journal-title":"Stat Med"},{"issue":"7109","key":"pmed.1003524.ref036","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"M Egger","year":"1997","journal-title":"Bmj"},{"issue":"449","key":"pmed.1003524.ref037","first-page":"89","article-title":"A Nonparametric \u201cTrim and Fill\u201d Method of Accounting for Publication Bias in Meta-Analysis","volume":"95","author":"S Duval","year":"2000","journal-title":"Journal of the American Statistical Association"},{"issue":"3","key":"pmed.1003524.ref038","doi-asserted-by":"crossref","first-page":"48","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting Meta-Analyses in R with the metafor Package","volume":"36","author":"W Viechtbauer","year":"2010","journal-title":"Journal of Statistical Software"},{"issue":"9","key":"pmed.1003524.ref039","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/(SICI)1099-1166(199709)12:9<913::AID-GPS663>3.0.CO;2-D","article-title":"Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer\u2019s disease","volume":"12","author":"L Volicer","year":"1997","journal-title":"Int J Geriatr Psychiatry"},{"issue":"9","key":"pmed.1003524.ref040","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/j.euroneuro.2014.06.007","article-title":"Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial","volume":"24","author":"AI Ahmed","year":"2014","journal-title":"Eur Neuropsychopharmacol"},{"issue":"2","key":"pmed.1003524.ref041","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/JCP.0b013e31820e861c","article-title":"Randomized, controlled crossover trial of dronabinol, 2.5 mg, for agitation in 2 patients with dementia","volume":"31","author":"S Walther","year":"2011","journal-title":"J Clin Psychopharmacol"},{"issue":"2","key":"pmed.1003524.ref042","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1177\/1479972310391283","article-title":"Cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety","volume":"8","author":"EE Pickering","year":"2011","journal-title":"Chron Respir Dis"},{"issue":"6","key":"pmed.1003524.ref043","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/0885-3924(91)90026-Z","article-title":"Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting","volume":"6","author":"M Lane","year":"1991","journal-title":"J Pain Symptom Manage"},{"issue":"11","key":"pmed.1003524.ref044","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.1212\/WNL.57.11.2108","article-title":"Cannabinoids reduce levodopa-induced dyskinesia in Parkinson\u2019s disease: a pilot study","volume":"57","author":"KA Sieradzan","year":"2001","journal-title":"Neurology"},{"issue":"2","key":"pmed.1003524.ref045","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1200\/JCO.2002.20.2.567","article-title":"Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study","volume":"20","author":"A Jatoi","year":"2002","journal-title":"J Clin Oncol"},{"issue":"9395","key":"pmed.1003524.ref046","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1016\/S0140-6736(03)14738-1","article-title":"Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial","volume":"362","author":"J Zajicek","year":"2003","journal-title":"The Lancet"},{"issue":"7460","key":"pmed.1003524.ref047","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1136\/bmj.38149.566979.AE","article-title":"Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial","volume":"329","author":"KB Svendsen","year":"2004","journal-title":"Bmj"},{"issue":"12","key":"pmed.1003524.ref048","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1136\/jnnp.2005.070136","article-title":"Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up","volume":"76","author":"JP Zajicek","year":"2005","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"21","key":"pmed.1003524.ref049","doi-asserted-by":"crossref","first-page":"3394","DOI":"10.1200\/JCO.2005.05.1847","article-title":"Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group","volume":"24","author":"F Strasser","year":"2006","journal-title":"J Clin Oncol"},{"issue":"5","key":"pmed.1003524.ref050","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1097\/01.ijg.0000212260.04488.60","article-title":"Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study","volume":"15","author":"I Tomida","year":"2006","journal-title":"J Glaucoma"},{"issue":"3","key":"pmed.1003524.ref051","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1185\/030079907X167525","article-title":"Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting","volume":"23","author":"E Meiri","year":"2007","journal-title":"Curr Med Res Opin"},{"issue":"15","key":"pmed.1003524.ref052","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1002\/mds.22809","article-title":"A pilot study using nabilone for symptomatic treatment in Huntington\u2019s disease","volume":"24","author":"A Curtis","year":"2009","journal-title":"Mov Disord"},{"issue":"2","key":"pmed.1003524.ref053","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jpainsymman.2009.06.008","article-title":"Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain","volume":"39","author":"JR Johnson","year":"2010","journal-title":"J Pain Symptom Manage"},{"issue":"2","key":"pmed.1003524.ref054","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1213\/ANE.0b013e3181c76f70","article-title":"The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial","volume":"110","author":"MA Ware","year":"2010","journal-title":"Anesth Analg"},{"issue":"10","key":"pmed.1003524.ref055","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1136\/jnnp.2009.200642","article-title":"Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial","volume":"81","author":"M Weber","year":"2010","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"9","key":"pmed.1003524.ref056","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1093\/annonc\/mdq727","article-title":"Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial","volume":"22","author":"TD Brisbois","year":"2011","journal-title":"Ann Oncol"},{"issue":"2","key":"pmed.1003524.ref057","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.baga.2011.04.002","article-title":"Cannabinoid, CB1 agonists in cervical dystonia: Failure in a phase IIa randomized controlled trial","volume":"1","author":"C Zadikoff","year":"2011","journal-title":"Basal Ganglia"},{"issue":"10","key":"pmed.1003524.ref058","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1016\/j.pain.2012.06.024","article-title":"An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain","volume":"153","author":"C Toth","year":"2012","journal-title":"Pain"},{"issue":"9","key":"pmed.1003524.ref059","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S1474-4422(13)70159-5","article-title":"Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial","volume":"12","author":"J Zajicek","year":"2013","journal-title":"Lancet Neurol"},{"issue":"14","key":"pmed.1003524.ref060","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1007\/s00213-015-3889-y","article-title":"Safety, pharmacodynamics, and pharmacokinetics of multiple oral doses of delta-9-tetrahydrocannabinol in older persons with dementia","volume":"232","author":"AI Ahmed","year":"2015","journal-title":"Psychopharmacology (Berl)"},{"issue":"23","key":"pmed.1003524.ref061","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1212\/WNL.0000000000001675","article-title":"Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial","volume":"84","author":"GA van den Elsen","year":"2015","journal-title":"Neurology"},{"issue":"3","key":"pmed.1003524.ref062","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/bcp.12811","article-title":"Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability","volume":"81","author":"M de Vries","year":"2016","journal-title":"Br J Clin Pharmacol"},{"issue":"9","key":"pmed.1003524.ref063","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/j.clinthera.2017.01.016","article-title":"Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Delta9-tetrahydrocannabinol in Patients WithProgressive Multiple Sclerosis","volume":"40","author":"G van Amerongen","year":"2018","journal-title":"Clin Ther"},{"issue":"1","key":"pmed.1003524.ref064","doi-asserted-by":"crossref","DOI":"10.1093\/sleep\/zsx184","article-title":"Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea","volume":"41","author":"DW Carley","year":"2018","journal-title":"Sleep"},{"issue":"11","key":"pmed.1003524.ref065","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.jagp.2019.05.002","article-title":"Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer\u2019s Disease","volume":"27","author":"N Herrmann","year":"2019","journal-title":"Am J Geriatr Psychiatry"},{"issue":"12","key":"pmed.1003524.ref066","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.jagp.2015.07.011","article-title":"Tetrahydrocannabinol in Behavioral Disturbances in Dementia: A Crossover Randomized Controlled Trial","volume":"23","author":"GAH van den Elsen","year":"2015","journal-title":"Am J Geriatr Psychiatry"},{"issue":"4","key":"pmed.1003524.ref067","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/ana.25864","article-title":"Non-Motor Symptoms in Parkinson\u2019s Disease are Reduced by Nabilone","volume":"88","author":"M Peball","year":"2020","journal-title":"Ann Neurol"},{"issue":"7","key":"pmed.1003524.ref068","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1212\/01.WNL.0000140288.48796.8E","article-title":"Cannabis for dyskinesia in Parkison disease: A randomized double-blind crossover study","volume":"63","author":"CB Carroll","year":"2004","journal-title":"Neurology"},{"issue":"4","key":"pmed.1003524.ref069","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1191\/1352458504ms1048oa","article-title":"Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study","volume":"10","author":"C Vaney","year":"2004","journal-title":"Mult Scler"},{"issue":"4","key":"pmed.1003524.ref070","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1191\/1352458504ms1082oa","article-title":"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","volume":"10","author":"DT Wade","year":"2004","journal-title":"Mult Scler"},{"issue":"1","key":"pmed.1003524.ref071","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1093\/rheumatology\/kei183","article-title":"Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis","volume":"45","author":"DR Blake","year":"2006","journal-title":"Rheumatology (Oxford)"},{"issue":"1\u20133","key":"pmed.1003524.ref072","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.pain.2007.08.028","article-title":"Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial","volume":"133","author":"TJ Nurmikko","year":"2007","journal-title":"Pain"},{"issue":"5","key":"pmed.1003524.ref073","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1111\/j.1365-2125.2010.03743.x","article-title":"Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting","volume":"70","author":"M Duran","year":"2010","journal-title":"Br J Clin Pharmacol"},{"issue":"2","key":"pmed.1003524.ref074","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jpainsymman.2009.06.008","article-title":"Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain","volume":"39","author":"JR Johnson","year":"2010","journal-title":"Journal of Pain & Symptom Management"},{"issue":"2","key":"pmed.1003524.ref075","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1177\/1352458511419700","article-title":"A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex(R) (nabiximols)","volume":"18","author":"W Notcutt","year":"2012","journal-title":"Mult Scler"},{"issue":"5","key":"pmed.1003524.ref076","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.jpain.2012.01.003","article-title":"Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial","volume":"13","author":"RK Portenoy","year":"2012","journal-title":"J Pain"},{"issue":"11","key":"pmed.1003524.ref077","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1136\/jnnp-2012-302468","article-title":"Multiple sclerosis and extract of cannabis: results of the MUSEC trial","volume":"83","author":"JP Zajicek","year":"2012","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"1","key":"pmed.1003524.ref078","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.jpainsymman.2013.02.018","article-title":"A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain","volume":"47","author":"ME Lynch","year":"2014","journal-title":"J Pain Symptom Manage"},{"issue":"7","key":"pmed.1003524.ref079","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/j.1532-2149.2013.00445.x","article-title":"A double-blind, randomized, placebo-controlled, parallel group study of THC\/CBD spray in peripheral neuropathic pain treatment","volume":"18","author":"M Serpell","year":"2014","journal-title":"Eur J Pain"},{"issue":"10","key":"pmed.1003524.ref080","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.2337\/dc16-0650","article-title":"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","volume":"39","author":"KA Jadoon","year":"2016","journal-title":"Diabetes Care"},{"issue":"3","key":"pmed.1003524.ref081","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1177\/2049463717710042","article-title":"Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies","volume":"11","author":"MT Fallon","year":"2017","journal-title":"British journal of pain"},{"issue":"2","key":"pmed.1003524.ref082","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jpainsymman.2017.09.001","article-title":"Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain","volume":"55","author":"AH Lichtman","year":"2018","journal-title":"Journal of Pain and Symptom Management"},{"issue":"2","key":"pmed.1003524.ref083","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1080\/00207454.2018.1481066","article-title":"Sativex\u00ae as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial","volume":"129","author":"J Markov\u00e0","year":"2019","journal-title":"International Journal of Neuroscience"},{"issue":"2","key":"pmed.1003524.ref084","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S1474-4422(18)30406-X","article-title":"Safety and efficacy of nabiximols on spasticity symptoms in patients with motor neuron disease (CANALS): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial","volume":"18","author":"N Riva","year":"2019","journal-title":"Lancet Neurol"},{"issue":"3","key":"pmed.1003524.ref085","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/0091-3057(91)90386-G","article-title":"Controlled clinical trial of cannabidiol in Huntington\u2019s disease","volume":"40","author":"P Consroe","year":"1991","journal-title":"Pharmacol Biochem Behav"},{"issue":"1","key":"pmed.1003524.ref086","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1089\/can.2016.0034","article-title":"An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies","volume":"2","author":"K Iffland","year":"2017","journal-title":"Cannabis Cannabinoid Res"},{"issue":"12","key":"pmed.1003524.ref087","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S2215-0366(19)30401-8","article-title":"Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis","volume":"6","author":"N Black","year":"2019","journal-title":"Lancet Psychiatry"},{"issue":"9","key":"pmed.1003524.ref088","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1023\/A:1007636531965","article-title":"Risk factors in falls among the elderly according to extrinsic and intrinsic precipitating causes","volume":"16","author":"A Bueno-Cavanillas","year":"2000","journal-title":"Eur J Epidemiol"},{"issue":"3","key":"pmed.1003524.ref089","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.cger.2017.03.002","article-title":"Falls in the Aging Population","volume":"33","author":"KSF Khow","year":"2017","journal-title":"Clin Geriatr Med"},{"issue":"11","key":"pmed.1003524.ref090","doi-asserted-by":"crossref","DOI":"10.3390\/jcm8111819","article-title":"Medical Cannabis for Older Patients-Treatment Protocol and Initial Results","volume":"8","author":"R Abuhasira","year":"2019","journal-title":"J Clin Med"},{"issue":"1","key":"pmed.1003524.ref091","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0197-2456(95)00134-4","article-title":"Assessing the quality of reports of randomized clinical trials: is blinding necessary?","volume":"17","author":"AR Jadad","year":"1996","journal-title":"Control Clin Trials"},{"issue":"9836","key":"pmed.1003524.ref092","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0140-6736(12)60240-2","article-title":"Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study","volume":"380","author":"K Barnett","year":"2012","journal-title":"Lancet"},{"issue":"12","key":"pmed.1003524.ref093","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1080\/14740338.2018.1546841","article-title":"An update on the clinical consequences of polypharmacy in older adults: a narrative review","volume":"17","author":"JW Wastesson","year":"2018","journal-title":"Expert Opin Drug Saf"},{"issue":"1","key":"pmed.1003524.ref094","doi-asserted-by":"crossref","first-page":"e1919325","DOI":"10.1001\/jamanetworkopen.2019.19325","article-title":"Limitations of Meta-analyses of Studies With High Heterogeneity","volume":"3","author":"PB Imrey","year":"2020","journal-title":"JAMA Netw Open"},{"issue":"Pt B","key":"pmed.1003524.ref095","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.arr.2015.07.006","article-title":"Pharmacotherapy in the ageing patient: The impact of age per se (A review)","volume":"24","author":"S Singh","year":"2015","journal-title":"Ageing Res Rev"}],"container-title":["PLOS Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003524","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T17:25:07Z","timestamp":1617038707000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pmed.1003524"}},"subtitle":[],"editor":[{"given":"Alexander C.","family":"Tsai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":95,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pmed.1003524","relation":{},"ISSN":["1549-1676"],"issn-type":[{"value":"1549-1676","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]}}}