**1. Introduction**

People living with HIV (PLWH) experience persistent immune activation and systemic inflammation [1–4]. These processes, in turn, drive development and progression of non-Acquired Immune Deficiency Syndrome (AIDS)-related comorbidities such as cardiovascular diseases, metabolic and neurological disorders, malignancies, and liver fibrosis [1–4]. By attenuating chronic inflammation, one may slow the progression of chronic diseases [5–8].

Historically, cannabis was used by PLWH to alleviate AIDS-related symptoms such as nausea, anorexia and depression [9]. During the modern antiretroviral treatment (ART) era, cannabis use remains common amongs<sup>t</sup> PLWH for both recreational and medicinal reasons, including chronic pain, anxiety and depression [9–13]. The primary phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), possess anti-inflammatory and anti-fibrotic properties, as demonstrated in vitro [14–18] and in vivo during animal [19–22] and human observational studies [23–25]. Therefore, cannabinoids might be a potential therapeutic strategy to reduce chronic inflammation in PLWH on ART.

Due to successful advocacy during the early days of the HIV/AIDS epidemic, medical cannabis first became legalized in Canada in 2001 [26]. However, cannabinoid-based medicines (CBM) have not gone through the traditional drug development and formal drug approval process, and formal nonclinical pharmacokinetic and toxicology information are lacking [7]. Consequently, there remains an important lack of safety data for cannabisbased medicines in PLWH in the modern ART era [7]. Moreover, with legalization of recreational cannabis in Canada [27], it is now easier to obtain cannabinoids which may not have been thoroughly evaluated for safety and tolerability [28,29]. Before conducting large scale clinical trials to evaluate the efficacy of CBM for diverse comorbidities and symptomatology experienced by PLWH, a pivotal step will be to determine the safety, tolerability and feasibility, of using oral cannabinoids in this population. Here, we report on the safety and tolerability of oral cannabinoids in PLWH in a randomized, open-label, interventional pilot study. A THC:CBD combination arm was selected as both compounds have therapeutic properties and may function synergistically [30–34]. Furthermore, the use of CBD tends to improve THC tolerability when combined [30–34]. A CBD-only arm was also selected, in part, to observe the effects of CBD monotherapy in addition to feasibility reasons (i.e., capsules availability). Feasibility and effects on immune cell profiles, inflammatory markers, HIV reservoir size and gu<sup>t</sup> microbiome will be reported in separate manuscripts.
