Title : A large Australian longitudinal cohort registry demonstrates sustained safety and efficacy of oral medicinal cannabis for at least two years. Introduction :  Oral medicinal cannabis (MC) has been increasingly prescribed for a wide range of clinical conditions since 2016.  Despite an exponential rise in prescriptions and publications, high quality clinical efficacy and safety studies are lacking. The outcomes of a large Australian clinical electronic registry cohort are presented. Methods : A prospective cannabis-naïve patient cohort prescribed oral MC participated in an ongoing longitudinal registry at a network of specialised clinics.  Patient MC dose, safety and validated outcome data were collected regularly over two years and analysed. Results : 3,961 patients (mean age 56.07 years [SD 19.08], 51.0% female) with multimorbidity (mean diagnoses 5.14 [SD 4.08]). and polypharmacy (mean 6.26 medications [SD 4.61]). Clinical indications were for; chronic pain (71.9%) psychiatric (15.4%), neurological (2.1%), and other diagnoses (10.7%). Median total oral daily dose was 10mg for Δ9-tetrahydrocannabinol (THC) and 22.5mg for cannabidiol (CBD). A stable dose was observed for over two years. Treatment related adverse events (37.3%) were mild (dry mouth 79.9%), dose-related (sedation/dizziness, 68.2%) with fewer than 2% (n=23) experiencing severe and only two serious adverse events. Highly significant improvements across all outcomes were sustained for over two years, including: clinical global impression (CGI-E, +39%: CGI-I, +52%; p<0.001), pain interference and severity (BPI, 26.1% and 22.2%; p<0.001), mental health (DASS-21, depression 24.5%, anxiety 25.5%, stress 27.7%; p<0.001), insomnia (ISI, 35.0%; p<0.001), and health status (RAND SF36: Physical function, 34.4%: Emotional well-being, 37.3%; p<0.001). Mean number of concomitant medications did not significantly change over 2 years. Conclusions : Oral MC was demonstrated to be safe and well-tolerated for a sustained period in a large complex cohort of cannabis-naïve, multimorbid patients with polypharmacy. There was highly significant improvement across all clinical outcomes over two years. Results are subject to limitations of real world data for causation and generalisability. Future high quality randomised controlled trials are awaited.

I have read the journal's policy and the authors of this manuscript have the following competing interests: All authors of this manuscript and the analysis are employees of Emyria Pty Ltd, a public company that owns specialist medical clinics, Emerald Clinical Network, AV is the only author who is a clinician prescribing for patients in the clinic. This uncontrolled cohort real-world analysis presents observed data and all data have been included across the entire cohort. Emerald Clinical Network does not have any affiliation with the MC producers and clinicians at the Emerald Clinical Network are independent contractors that choose for whom, when and what to prescribe for patients referred to the clinic. Clinicians are not provided inducement or instruction to prescribe any brand or formulation of Medicinal cannabis product.

Yes. All authors of this manuscript and the analysis are employees of Emyria Pty Ltd, a public company that owns specialist medical clinics, Emerald Clinical Network, AV is the only author who is a clinician prescribing for patients in the clinic. This uncontrolled cohort real-world analysis presents observed data and all data have been included across the entire cohort. Emerald Clinical Network does not have any affiliation with the MC producers and clinicians at the Emerald Clinical Network are independent contractors that choose for whom, when and what to prescribe for patients referred to the clinic. Clinicians are not provided inducement or instruction to prescribe any specific brand, type or formulation of Medicinal cannabis product.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines All assessments were performed as part of routine quality assurance clinical care adhering to relevant Therapeutic Goods Administration standards for an unapproved therapeutic good, good medical practice, therapeutic guideline requirements, and informed consent. The data registry, utilisation and analysis were reviewed by the Australian National Health and Medical Research Council certified Bellberry Human Research Ethics Committee HREC 29th May 2020 who determined the quality assurance analysis exempt from ethical review due to their being no foreseeable risks of participant inconvenience or discomfort. The National Statement is Australias national guidance for ensuring compliance with the Declaration of Helsinki as revised in 2013 and our independent advice outlined that we were compliant with both

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

The data underlying the results presented in the study are available from Palantir Foundry. Access to personal health information will not be permitted except as de-identified aggregated data to avoid re-identification

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