*2.1. Design*

We analyzed clinical data collected prospectively between August 2020 and June 2022 to investigate the clinical outcomes associated with the inhalation of THC-predominant flos for therapeutic purposes in a legal and medically supervised setting. Participants were patients registered in Project Twenty21 (T21), the first UK multi-center registry seeking to develop a body of real-world evidence (RWE) to inform on the effectiveness and safety of medical cannabis. Full information relating to T21 procedures is outlined elsewhere [23,25]. In brief, patients receiving CBPMs for a variety of conditions are entered into the registry by invitation and monitored for data collection as part of their standard of care. According to UK regulations, individuals must have an established diagnosis and have failed to respond to at least two treatment options to legally receive CBPMs. Patients provided consent (following Good Clinical Practice guidelines) to the collection of their medical history, past and current treatments, plus a series of symptomatic assessments based on standardized and comprehensively validated self-report questionnaires. Prescribing physicians partnering with T21 use a product formulary that includes a wide range of CBPMs including oral extracts and flos of differing CBD and THC ratios. To date, THC-predominant flos remains the most prescribed CBPM in the project [23]. To reduce the inherent variability associated with the chemical composition of cannabis dried flowers, we decided to include in our data review only those patients receiving at their initial appointment a prescription for KHIRON 20/1, the most frequently prescribed THC-predominant flos in T21. Additional inclusion criterion was that participants had completed health-related quality of life (HRQoL) questionnaires both at the initial appointment (baseline) and at the subsequent 3-month follow up.
