{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T13:09:15Z","timestamp":1781010555938,"version":"3.54.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T00:00:00Z","timestamp":1665705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medlab Clinical"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>This pilot study aimed to assess the safety, tolerability, pharmacokinetics and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesic. The study was a non-blinded single arm 2 stage study. Stage I was a single escalating dose (n = 5) [2.5 mg \u03949-THC and 2.5 mg CBD) versus a 3-fold escalated dose. Stage II was an up-titrated dose in patients with advanced cancers and intractable pain (n = 25). During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of \u03949-THC than CBD (AUC from 2.5 mg each of \u03949-THC and CBD, was 1.71 ng mL.h<jats:sup>\u22121<\/jats:sup>(1.1, 6.6) and 0.65 ng mL.h<jats:sup>\u22121<\/jats:sup>(0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastases, had the highest mean pain score improvement from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients. The water-soluble cannabis-based medicine provided acceptable bioavailability for \u03949-THC\/CBD, appeared safe and tolerable in advanced incurable cancers with uncontrolled pain with preliminary evidence of analgesic efficacy.<\/jats:p>","DOI":"10.1371\/journal.pone.0270543","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T17:49:29Z","timestamp":1665769769000},"page":"e0270543","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Pilot clinical and pharmacokinetic study of \u03949-Tetrahydrocannabinol (THC)\/Cannabidiol (CBD) nanoparticle oro-buccal spray in patients with advanced cancer experiencing uncontrolled pain"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5817-1222","authenticated-orcid":true,"given":"Stephen","family":"Clarke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda E.","family":"Butcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"McLachlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy D.","family":"Henson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Rutolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0090-7895","authenticated-orcid":true,"given":"Sean","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7490-9298","authenticated-orcid":true,"given":"Luis","family":"Vitetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,10,14]]},"reference":[{"issue":"2","key":"pone.0270543.ref001","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1377\/hlthaff.2018.05266","article-title":"Qualifying Conditions Of Medical Cannabis License Holders In The United States","volume":"38","author":"KF Boehnke","year":"2019","journal-title":"Health Aff (Millwood)"},{"key":"pone.0270543.ref002","first-page":"Cd012182","article-title":"Cannabis-based medicines for chronic neuropathic pain in adults","volume":"3","author":"M Mucke","year":"2018","journal-title":"The Cochrane database of systematic reviews"},{"issue":"6","key":"pone.0270543.ref003","doi-asserted-by":"crossref","first-page":"E755","DOI":"10.36076\/ppj.20.5.E755","article-title":"Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"20","author":"J Aviram","year":"2017","journal-title":"Pain Physician"},{"issue":"4","key":"pone.0270543.ref004","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1037\/pha0000281","article-title":"Effects of cannabinoid administration for pain: A meta-analysis and meta-regression","volume":"27","author":"JA Yanes","year":"2019","journal-title":"Exp Clin Psychopharmacol"},{"issue":"2","key":"pone.0270543.ref005","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jpain.2012.10.009","article-title":"Low-dose vaporized cannabis significantly improves neuropathic pain","volume":"14","author":"B Wilsey","year":"2013","journal-title":"J Pain"},{"issue":"14","key":"pone.0270543.ref006","doi-asserted-by":"crossref","first-page":"E694","DOI":"10.1503\/cmaj.091414","article-title":"Smoked cannabis for chronic neuropathic pain: a randomized controlled trial","volume":"182","author":"MA Ware","year":"2010","journal-title":"Cmaj"},{"issue":"3","key":"pone.0270543.ref007","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/npp.2008.120","article-title":"Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial","volume":"34","author":"RJ Ellis","year":"2009","journal-title":"Neuropsychopharmacology"},{"issue":"10","key":"pone.0270543.ref008","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1080\/10826084.2017.1416408","article-title":"Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain","volume":"53","author":"NL Sohler","year":"2018","journal-title":"Subst Use Misuse"},{"issue":"7","key":"pone.0270543.ref009","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1212\/01.wnl.0000253187.66183.9c","article-title":"Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial","volume":"68","author":"DI Abrams","year":"2007","journal-title":"Neurology"},{"key":"pone.0270543.ref010","unstructured":"National Academies of Sciences E, Medicine, Health, Medicine D, Board on Population H, Public Health P, et al. The National Academies Collection: Reports funded by National Institutes of Health. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington (DC): National Academies Press (US) 2017 by the National Academy of Sciences. All rights reserved."},{"issue":"1","key":"pone.0270543.ref011","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1136\/bmjspcare-2019-002032","article-title":"Cannabinoids for adult cancer-related pain: systematic review and meta-analysis","volume":"10","author":"EG Boland","year":"2020","journal-title":"BMJ Support Palliat Care"},{"issue":"11","key":"pone.0270543.ref012","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1093\/pm\/pnz227","article-title":"Cannabis and Pain","volume":"20","author":"EB Russo","year":"2019","journal-title":"Pain Med"},{"issue":"5","key":"pone.0270543.ref013","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/jat\/16.5.276","article-title":"Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana","volume":"16","author":"MA Huestis","year":"1992","journal-title":"J Anal Toxicol"},{"issue":"7","key":"pone.0270543.ref014","doi-asserted-by":"crossref","DOI":"10.3390\/jcm8070989","article-title":"Potential Adverse Drug Events and Drug-Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use","volume":"8","author":"JD Brown","year":"2019","journal-title":"J Clin Med"},{"issue":"10","key":"pone.0270543.ref015","doi-asserted-by":"crossref","DOI":"10.3390\/molecules23102478","article-title":"Cannabinoid Delivery Systems for Pain and Inflammation Treatment","volume":"23","author":"N Bruni","year":"2018","journal-title":"Molecules (Basel, Switzerland)"},{"issue":"1","key":"pone.0270543.ref016","doi-asserted-by":"crossref","DOI":"10.3390\/jfb9010012","article-title":"Route and Type of Formulation Administered Influences the Absorption and Disposition of Vitamin B(12) Levels in Serum","volume":"9","author":"L Vitetta","year":"2018","journal-title":"J Funct Biomater"},{"key":"pone.0270543.ref017","article-title":"A pilot safety, tolerability and pharmacokinetic study of an oro-buccal administered cannabidiol-dominant anti-inflammatory formulation in healthy individuals: a randomized placebo-controlled single-blinded study","author":"L Vitetta","year":"2021","journal-title":"Inflammopharmacology"},{"key":"pone.0270543.ref018","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jclinepi.2019.09.028","article-title":"Thresholds for clinical importance were defined for the European Organisation for Research and Treatment of Cancer Computer Adaptive Testing Core-an adaptive measure of core quality of life domains in oncology clinical practice and research","volume":"117","author":"JM Giesinger","year":"2020","journal-title":"J Clin Epidemiol"},{"issue":"7","key":"pone.0270543.ref019","doi-asserted-by":"crossref","DOI":"10.3390\/cancers9070073","article-title":"Quality-of-Life (QOL) during Screening for Phase 1 Trial Studies in Patients with Advanced Solid Tumors and Its Impact on Risk for Serious Adverse Events","volume":"9","author":"S Anwar","year":"2017","journal-title":"Cancers (Basel)"},{"issue":"2","key":"pone.0270543.ref020","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/intqhc\/mzi021","article-title":"The JCAHO patient safety event taxonomy: a standardized terminology and classification schema for near misses and adverse events","volume":"17","author":"A Chang","year":"2005","journal-title":"Int J Qual Health Care"},{"issue":"4","key":"pone.0270543.ref021","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00228-012-1393-4","article-title":"A phase I study to assess the effect of food on the single dose bioavailability of the THC\/CBD oromucosal spray","volume":"69","author":"CG Stott","year":"2013","journal-title":"Eur J Clin Pharmacol"},{"key":"pone.0270543.ref022","volume-title":"Statistical Analysis: A Computer Oriented Approach","author":"AA Afifi","year":"1979","edition":"2"},{"key":"pone.0270543.ref023","unstructured":"Frayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, et al. The EORTC QLQ-30 scoring manual (3rd edition). Brussels: European Organisation for Research and Treatment of Cancer, 2001."},{"issue":"12","key":"pone.0270543.ref024","article-title":"Short-Term Medical Cannabis Treatment Regimens Produced Beneficial Effects among Palliative Cancer Patients","volume":"13","author":"J Aviram","year":"2020","journal-title":"Pharmaceuticals (Basel, Switzerland)"},{"issue":"2","key":"pone.0270543.ref025","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":"J Pain Symptom Manage"},{"issue":"24","key":"pone.0270543.ref026","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":"12","key":"pone.0270543.ref027","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1097\/AJP.0000000000000364","article-title":"The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study","volume":"32","author":"S Haroutounian","year":"2016","journal-title":"Clin J Pain"},{"issue":"1","key":"pone.0270543.ref028","doi-asserted-by":"crossref","DOI":"10.1186\/s42238-019-0013-x","article-title":"Overbaked: assessing and predicting acute adverse reactions to Cannabis","volume":"2","author":"EM LaFrance","year":"2020","journal-title":"Journal of Cannabis Research"},{"issue":"1","key":"pone.0270543.ref029","doi-asserted-by":"crossref","first-page":"7","DOI":"10.11607\/ofph.1274","article-title":"The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review","volume":"29","author":"DG Boychuk","year":"2015","journal-title":"J Oral Facial Pain Headache"},{"issue":"2","key":"pone.0270543.ref030","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1002\/jcsm.12273","article-title":"Systematic review and meta-analysis of cannabinoids in palliative medicine","volume":"9","author":"M Mucke","year":"2018","journal-title":"J Cachexia Sarcopenia Muscle"},{"issue":"Suppl 2","key":"pone.0270543.ref031","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.21037\/apm.2017.08.05","article-title":"A selective review of medical cannabis in cancer pain management","volume":"6","author":"A Blake","year":"2017","journal-title":"Ann Palliat Med"},{"issue":"5","key":"pone.0270543.ref032","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/s00482-019-0373-3","article-title":"Efficacy, tolerability and safety of cannabis-based medicines for cancer pain: A systematic review with meta-analysis of randomised controlled trials","volume":"33","author":"W Hauser","year":"2019","journal-title":"Schmerz"},{"issue":"3","key":"pone.0270543.ref033","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":"Br J Pain"},{"issue":"9","key":"pone.0270543.ref034","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1136\/jnnp-2015-312591","article-title":"Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity","volume":"87","author":"F Patti","year":"2016","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"9","key":"pone.0270543.ref035","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1212\/WNL.58.9.1404","article-title":"Safety, tolerability, and efficacy of orally administered cannabinoids in MS","volume":"58","author":"J Killestein","year":"2002","journal-title":"Neurology"},{"issue":"1","key":"pone.0270543.ref036","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.coph.2009.09.009","article-title":"Cannabinoid-opioid interactions during neuropathic pain and analgesia","volume":"10","author":"I Bushlin","year":"2010","journal-title":"Curr Opin Pharmacol"},{"issue":"2","key":"pone.0270543.ref037","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S0091-3057(98)00012-4","article-title":"The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol","volume":"60","author":"FL Smith","year":"1998","journal-title":"Pharmacol Biochem Behav"},{"issue":"1","key":"pone.0270543.ref038","first-page":"10","article-title":"Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice","volume":"262","author":"SP Welch","year":"1992","journal-title":"J Pharmacol Exp Ther"},{"issue":"1\u20133","key":"pone.0270543.ref039","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":"3","key":"pone.0270543.ref040","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":"5","key":"pone.0270543.ref041","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"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0270543","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,5]],"date-time":"2024-10-05T20:48:56Z","timestamp":1728161336000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0270543"}},"subtitle":[],"editor":[{"given":"Rizaldy Taslim","family":"Pinzon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,10,14]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0270543","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,14]]}}}