The parent study was a Phase 1, randomized, double-blind, placebo-controlled, multiple-dose trial in 43 healthy participants to assess the safety, tolerability, PK, and PD of Spectrum Yellow oil . The study was conducted in accordance with consensus ethics principles, International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki, and local Australian laws and regulations. The protocol was approved by the Alfred Hospital Ethics Committee (Melbourne, Victoria, Australia). Written informed consent was obtained from each participant before any trial-related procedures were performed.
Spectrum Yellow oil (Tweed Inc., Canopy Growth Corporation, Smiths Falls, ON, Canada) is a cannabis-based product that is currently commercially available in Canada, Australia, United Kingdom, and Cayman Islands. Spectrum Yellow oil was made with supercritical carbon dioxide extracted cannabis resin in medium-chain triglyceride (MCT) oil. Analytical testing of the clinical batch detected 20 mg/mL CBD and 0.9 mg/mL THC, plus a total terpene concentration < 0.05%. Analytical testing of the clinical batch also detected the presence of CBC at a relatively high concentration (1.1 mg/mL), thus prompting the present subanalysis of the CBC time-concentration data. Analytical testing revealed that other cannabinoids were either below the reporting limit (< 0.50 ng/mL) or not detected.
Participants were randomly assigned to one of five groups in a 1:1:1:1:1 ratio: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily (Treatment A); 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily (Treatment B); 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily (Treatment C); 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily (Treatment D); or placebo. Participants were confined to a residential research facility and received study medication twice daily, approximately every 12 h, after a standardized meal (e.g., for breakfast, 2 cups of cereal; 2 slices of toast; 2 servings of butter or margarine; 2 condiments; 250 mL of milk; 1 sugar sachet) for 6 days, plus a single dose in the morning of day 7. PK blood samples included in this analysis were collected prior to the morning dose and 1, 2, 4, 6, 8, and 12 h after the morning dose on day 1; prior to the morning dose and 1, 2, 4, 6, 8, 12, and 16 h after the morning dose on day 7; and 24, 32, 48, 72, 96, and 144 h after the day 7 morning dose. Immediately following collection, blood samples were placed on wet ice and centrifuged, and plasma was immediately frozen at −80 °C until shipment to the bioanalytical laboratory (iC42 Clinical Research and Development, University of Colorado, Aurora, CO, USA) on dry ice. Samples were stored at the bioanalytical laboratory at −80 °C.
CBC plasma concentrations were analyzed using a two-dimensional high-performance liquid chromatography–tandem mass spectrometry assay developed and validated by iC42 Clinical Research and Development , and study samples were analyzed in a CLIA (United States Clinical Laboratory Improvement Amendments)-certified laboratory environment accredited by the College of American Pathologists (Northfield, IL, USA). For details of the analytic method, please see Klawitter et al. . The lower limit of quantification (LLoQ) of CBC was 0.78 ng/mL ; samples with concentrations below the LLoQ were treated as 0 in the analysis. Urinary excretion of CBC was not examined in this pilot study. PK parameters were calculated using non-compartmental analysis (Phoenix WinNonlin version 8.2., Certara, Princeton, NJ, USA). Statistical analysis was carried out using SPSS (version 27.0, IBM, Armonk, NY, USA).