**5. Conclusions**

Our results indicate that controlled inhalation of pharmaceutical grade, THC-predominant cannabis flos was associated with a robust improvement in patient-reported pain scores, general mood, anxiety, sleep, and overall HRQoL in a treatment-resistant clinical population. The effect size, which was larger in patients diagnosed with anxiety disorders compared to chronic pain, appeared to be maximal at 3 months and sustained for at least 6 months. Occurrence of side effects was minimal, probably due to the previous experience of participants with cannabis inhalation. This evidence supports the notion that the administration of cannabis flos in a medicalized environment under the supervision of a trained healthcare provider further improves the clinical outcomes of legally prescribed CBMPs when compared to chronic patients self-medicating with illegal cannabis.

**Author Contributions:** Conceptualization, G.M.-S. and M.R.D.B.; methodology, G.M.-S. and M.L.; formal analysis, A.M.; investigation, M.L.; resources, M.L.; data curation, A.M. and M.L.; writing— original draft preparation, G.M.-S.; writing—review and editing, G.M.-S. and M.R.D.B.; visualization, G.M.-S.; supervision, G.M.-S.; project administration, G.M.-S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** According to the National Health Service Health Research Authority, Project Twenty21 is classified as research, and the work was conducted in accordance with the Declaration of Helsinki. However, based on the Medical Research Council decision tools, Research Ethics Committee review and approval is not required.

**Informed Consent Statement:** All subjects involved provided signed informed consent for their data to be used for research purposes.

**Data Availability Statement:** The data presented in this work are available on request from the corresponding author. The data are not publicly available due to privacy and ethical reasons.

**Acknowledgments:** Sofia Antonopoulou created the graphical abstract and her assistance with the edition of the figures is gratefully acknowledged.

**Conflicts of Interest:** G.M.-S. and A.M. are employees of Khiron Life Sciences Corp, a global cannabis company that funded Project T21 and commercializes the CBPM employed in this research, Khiron 20/1. M.R.D.B. is employed by Zerenia Clinics, a subsidiary of Khiron Life Sciences. No other Khiron employee or executive was involved in the design of the work; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The authors declare no other conflict of interest.
