*3.1. Participants*

A total of 344 patients registered in T21 satisfied the inclusion criteria of (i) having PROMS questionnaires correctly recorded at the initial appointment (t = 0) and, at the least, at the 3-month follow up (t = 3), and (ii) receiving a prescription for KHIRON 20/1

at t = 0. Of those, 140 participants had also reported PROMS at the 6-month follow up (t = 6). Participants enrolled in T21 between August 2020 and June 2022. Demographics and clinical characteristics of the patient cohort are depicted in Table 1. Coherent with the overall patient population of T21, three out of four participants were adult males (77.6%), with an average age of 38.4 ± 10.4 years old. A majority of them were diagnosed with a chronic painful condition (50.8%) or an anxiety-related disorder (25.3%). Other minor qualifying diagnosis were Attention Deficit Hyperactivity Disorder (ADHD) (6.98%), Post Traumatic Stress Disorder (PTSD) (6.1%) or insomnia (2.9%). As required by law, all patients had trialed at the least two standard therapeutic options to treat their condition before accessing medicinal cannabis. Of note, only 16 participants were naïve to cannabis when commencing the T21 process. A vast majority of patients (95.6%) had previously utilized illicitly acquired cannabis, and 3 out of 4 of those consuming cannabis did so with the intention of treating their primary diagnosed condition. Most participants elected to administer CBPM once a day (58.7%).



*3.2. General Health Outcome Measures*

3.2.1. Health Related Quality of Life (HRQoL)

Inhalation of THC-predominant cannabis flos was associated with a marked improvement both in general health and in health-related quality of life (HRQoL) after 3 months, expressed as the VAS score (Figure 2A, T = 8.80; *p* < 0.001) and the sum of ratings for the 5 dimensions of the EuroQol (Figure 2B T = 10.3; *p* < 0.001), respectively. A similar degree of improvement was reported by participants at the 6-month follow up (Figure 3A,B), which is suggestive of (i) the maximal effect of the treatment being already achieved at the 3-month timepoint which was maintained but not further improved at 6 months, and (ii) no overt tolerance to the treatment developing after 6 months of daily administration. As shown in Table 2, participants diagnosed with chronic pain reported lower baseline levels of HRQoL compared to those diagnosed with anxiety disorders. However, no significant differences in the degree of improvement captured by the EQ-5D were found between these two groups at the 3-month follow up. On the contrary, patients diagnosed with

anxiety-related disorders did report a larger improvement in general health compared to chronic pain patients (mean difference 12.4 vs. 6.98; *p* < 0.05), as captured by the VAS of the EuroQoL questionnaire.

**Figure 2.** Improvement of general health outcome measures at the 3-month follow-up. Analysis of PROMS shows how the inhalation of KHIRON 20/1 was associated with a marked improvement in self-reported health related QoL (N = 344) measured as (**A**) the scoring of the VAS of the EQ5D, and (**B**) the sum of the 5 dimensions of the EQ5D questionnaire. (**C**) General mood/ clinical depression assessed with the PHQ-9 scale (N = 339) was markedly improved. This effect was mainly driven by patients diagnosed with anxiety-related disorders (Table 2). (**D**) Quality of sleep assessed with the Pittsburgh Sleep Quality Index (N = 344) was improved by the treatment with inhaled chemotype 1 cannabis flos. \*\*\* *p* < 0.001.

**Figure 3.** Comparative improvement of general health outcome measures at 3- and 6-month followup. Analysis of outcome measures reported by patients that completed the validated questionnaires both at 3- and at 6-month follow-up visits (N = 140). Improvements associated with the inhalation of KHIRON 20/1 in (**A**,**B**) HRQoL, (**C**) General mood/ clinical depression, and (**D**) quality of sleep were maximal at 3 months and maintained, although not further increased, at the 6-month follow-up. \*\*\* *p* < 0.001.


**Table 2.** Comparative analysis on the influence of the two main participants sub-populations by primary indication, chronic painful conditions, and anxiety-related disorders, over the general PROMS: HRQoL, mood/depression and sleep quality. \* *p* < 0.05; \*\* *p* < 0.01.
