Safety and Tolerability of Oral Cannabinoids in People Living with HIV on Long-Term ART: A Randomized, Open-Label, Interventional Pilot Clinical Trial (CTNPT 028)

Abstract

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed.

Methods: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0-2 scores).

Results: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate.

Conclusions: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

Keywords: HIV; cannabidiol (CBD); cannabinoids; chronic liver diseases; pilot clinical trial; quality of life; tetrahydrocannabinol (THC).

Figure 1

Schedule of visits and procedures. Screening: Up to 4 weeks prior to randomization, during the screening visit, study staff explained the study to the participants and obtained written informed consent prior to initiating any study procedures. Study staff assessed the participant’s eligibility by assessing the inclusion and exclusion criteria. Study staff collected the medical history and concomitant medications of the study participants and they underwent a complete physical exam. Blood was collected for hematology, blood chemistry, HIV RNA load and CD4 and CD8 T cells counts. A urine pregnancy test was performed for female participants. Cannabis Use Disorder Identification Test-Revised (CUDIT-R), Drug Use Disorder Identification Test (DUDIT) and Alcohol Use Disorder Identification Test (AUDIT) questionnaires were administrated to the participants and they underwent testing for Hepatitis B and C and syphilis infections. They also underwent urine screen for cannabinoids use. Baseline 1: Up to 3 weeks before the randomization, study staff confirmed eligibility of the candidate and reviewed their medical history. Participants then underwent a second cannabinoids screening test, if his/her initial screen was positive, and answered the CUDIT-R questionnaire in order to identify any problematic cannabis use. The participants underwent a targeted physical exam and blood and semen (from male) were collected to quantify the HIV reservoir size in circulating PBMC from blood and in the semen. Nasal swab and stool specimens were collected from study participants. Antiretroviral Therapy (ART) compliance, alcohol intake and concomitant medication were reviewed by the study staff. Baseline 2 (week 0: Initiation of treatment): Participants confirmed their willingness to participate in the study and eligibility was confirmed, before participants were randomized to either arm 1 or arm 2. Blood was collected from participants. Participants underwent a targeted physical exam. Participants also completed the World Health Organization Quality of Life—HIV Brief Scale (WHOQOLHIV-BREF), Euro-Qol-5Dimension (EQ-5D) questionnaire, and Profile of MoodStates (POMS) questionnaires before receiving a one week supply of the study medication. Follow-up visits (visit 3–8; week 1 to 10): During the follow-up visits, participants underwent a physical examination, and blood was collected to assess the biological study measures. Study drug and ART compliance was assessed. Adverse effects (AEs) were recorded. Pregnancy test was performed on urine of female participants. The participants completed the WHOQOLHIV-BREF, EQ-5D, and POMS questionnaires (Visit 6) and received the study medication until their next visit. End of the treatment (Visit 9; week 12): At Visit 9, participants underwent a physical examination, and blood was collected to assess the biological study measures. Nasal swab and stool specimens were collected from all study participants and semen was collected from male participants. AEs were recorded. A pregnancy test was performed on urine of female participants. Participants then completed the WHOQOLHIV-BREF, EQ-5D, and POMS questionnaires. Final study visit (Visit 10; week 14): At the final visit, participants underwent a physical examination, and blood was collected to assess the biological study measures. AEs were recorded and ART compliance was assessed. A pregnancy test was performed on urine of female participants.

Figure 2

Allocation of participants enrolled in the study (n = 10). Distribution of study participants randomized to arm 1 (TN-TC11M2; THC:CBD) or arm 2 (TN-C200M2; CBD-only), to the study.

Figure 3

Daily dosage of CBD-only and THC/CBD combination during the 12 weeks of treatment. (A) THC/CBD arm: In arm 1 (THC/CBD), two participants were able to reach the maximum daily dose of the study drugs (15 mg THC/15 mg CBD), but only one remained at this dose until the end of the treatment, the other participant reduced his dosing to 10 mg THC/10 mg CBD per day because of the occurrence of AEs (somnolence). Two other participants from arm 1 reached the daily dose 10 mg THC/10 mg CBD, but after 3 weeks of treatment, they reduced their dosing because of the occurrence of AEs, one participant experienced cognitive impairment (#102109), while the other had somnolence, fatigue, difficulty concentrating, nightmares and paranoid thoughts (#102101). One remained at 5 mg THC/5 mg CBD per day and the other one who had multiple AEs reduced his daily dose to 2.5 mg THC/2.5 mg CBD after 5 weeks of treatment. A participant (#102110) from arm 1 who first reduced his daily dosing from 5 mg THC/5 mg CBD after 3 weeks of treatment to 2.5 mg THC:2.5 mg CBD, finally increased his dosing from 2.5 mg THC/2.5 mg CBD per day to reach 7.5 mg THC/7.5 mg CBD per day until the end of treatment. (B) CBD arm: 3 participants reached the maximum daily dose of 800 mg CBD after 4 weeks of treatment, but two of them experienced AEs (transient transaminitis for #102107) and SAE (hepatitis with persistent elevated transaminases and worsened diabetes type 2, for #102108) and the treatment was permanently discontinued 1 and 2 weeks after, and they were withdrawn from the study. The other participant who reached the maximum daily dose of 800 mg remained on this daily dose until the end of the study. Finally, two participants from arm 2 gradually increased their daily dosing to reach dose of 400 mg of CBD per day and remained in this range until the end of the study medication.

Figure 4

Dynamics of liver enzymes of participant #102107 and #102108 from arm 2 (TN-C200M2: CBD only), during cannabinoid uptake. Evolution of liver enzyme blood levels in (A). participant #102107 and (B). participant #102108 during the up-titration of CBD dose from the starting of CBD medication to the cessation of the treatment.