**6. Conclusions**

Taken together, our findings sugges<sup>t</sup> that much additional work is needed to understand safety and tolerability in PLWH. Transaminitis in 2/5 participants in the CBD-only group suggests that more work is required to elucidate the best dosages of CBD in this population. Pharmacokinetic studies in this regard could be helpful. We sugges<sup>t</sup> that PLWH should undergo a hepatological screening, ideally with transient elastography or, if unavailable, with simple fibrosis biomarkers like fibrosis-4 score, prior to initiating cannabinoid-based medicine, particularly formulations with high CBD dose, and they should be closely monitored to detect any rise of transaminases reflecting potential hepatotoxicity. Work is also required to better understand the potential benefits and harms of cannabinoids in chronic liver diseases and particularly in the context of HIV. As we recently reviewed [69], the liver contains both CB1 and CB2 receptors and the consequences of administering compounds which target these receptors must be understood. While future studies in PLWH should use a lower maximum dose of CBD, the optimal dose to avoid hepatotoxicity while leveraging anti-inflammatory and immunomodulatory properties of cannabinoids are unknown. Future studies may wish to examine the potential of these compounds to improve specific conditions, such as fatty liver disease, in PLWH. Work is currently ongoing to address whether the treatments in this study had any impact on immune activation, inflammatory markers, HIV reservoir size or gu<sup>t</sup> microbiome, the ultimately goal being a reduction in HIV-associated comorbidities driven by chronic inflammation. Given the small sample size and lack of blinding or use of placebo, we remain cautious in our conclusions regarding the therapeutic benefits until more data is available.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/biomedicines10123168/s1, Figure S1. Frequency of responses of the EuroQoL-5D (EQ-5D) questionnaire for the quality-of-life assessment during the 12 weeks of treatment. Figure S2. Frequency of responses of the World Health Organization Quality of Life—HIV Brief (WHOQOL-HIV BREF) questionnaire for general quality of life and general health state during the study visits. Figure S3. Total mood disturbance (TMD) score from the Profile of Mood States) (POMS) questionnaire during the study. Table S1. List of exclusion criteria. Table S2. World Health Organization (WHO) Toxicity Scale Grading for Adverse Events. Table S3. Hematological parameters (excel attachment). Table S4. Biochemistry parameters (excel attachment). Table S5. HIV immunological and virological parameters.

**Author Contributions:** Conceptualization: C.T.C. and M.-A.J.; Participant recruitment and data acquisition: F.B., C.V., L.D.B., N.P., B.L., M.K., M.-J.B., J.C., J.S. (Jason Szabo) J.-P.R., R.T. and E.H.; Methodology, C.T.C., M.-A.J., J.N., J.S. (Joel Singer), T.L., S.M., E.M. and A.V.; Software: J.N., J.S. (Joel Singer) and T.L.; Validation: J.N., J.S. (Joel Singer) and T.L.; Formal Analysis, R.-S.M.B., M.-A.J., C.T.C., J.S. (Joel Singer) and T.L.; Investigation: C.T.C., G.S., M.K., L.D.B., N.P. and M.K.; Resources: C.T.C., M.-A.J., J.N. and D.N.; Data Curation: R.-S.M.B. and C.T.C.; Writing—Original Draft Preparation, R.-S.M.B. and C.T.C.; Writing—Review and Editing, all authors; Supervision, C.T.C., M.-A.J., J.N. and S.S.; Project Administration, C.T.C., J.N., D.N. and M.-A.J.; Funding Acquisition, C.T.C. and M.-A.J.; Manuscript approval: all authors. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work has been supported by a team gran<sup>t</sup> from the Canadian Institutes of Health Research (CIHR) (# CC1-177334), CIHR Canadian HIV Trials Network and the Lotte & John Hecht Memorial Foundation. Tilray provided study capsules as an in-kind service but did not provide study funding. R.-S.M.B. is supported by a CIHR postdoctoral fellowship. G.S. holds a FRSQ-S Chercheur Boursier Clinicien Senior career award (#296306). M.-A.J. holds the tier 2 CIHR Canada Research Chair in Immuno-Virology. C.T.C. is a recipient of an FRQ-S Junior 2 Chercheur Boursier Clinicien career award.

**Institutional Review Board Statement:** This study was approved by the McGill University Health Centre (#2018-4336) and conducted in conformity with the Declaration of Helsinki.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** Anonymized data may be available upon reasonable request of the author and the CTN.

**Acknowledgments:** We thank the participants for their participation in this study. We also thank the staff at the CTN, including Nisha Shewaramani and Elisa Lau (database managers), and Jayamarx Jayaraman (study monitoring) and all CVIS/MUHC research and clinical staff, including Hansi Peiris, Carolina Berini, Sebastien Landry, Benoit Lemire, Jasmine Mian, Kathleen Normandin, Claude Cyr, Yulia Alexandrova, Erik Pavey and Tara Mabanga. We are grateful to the Tilray staff, including Philippe Lucas, Catherine Jacobson and Gosia Grzyb, as well as to Carolyn Baglole and the Research Centre for Cannabis at McGill University.

**Conflicts of Interest:** G.S. has acted as speaker for Merck, Gilead, Abbvie, Pfizer, Novonordisk, served as an advisory board member for Merck, Novartis, Pfizer, Gilead and Intercept and has received unrestricted research funding from Theratecnologies. C.T.C. has served on advisory boards for Viiv Healthcare and Gilead, and received gran<sup>t</sup> support from Merck, Gilead, Viiv and Tilray Inc. She has also received travel support to attend conferences from Gilead and Viiv Healthcare.
