A Phase I, Double Blind, Three-Way Crossover Study to Assess the Pharmacokinetic Profile of Cannabis Based Medicine Extract (CBME) Administered Sublingually in Variant Cannabinoid Ratios in Normal Healthy Male Volunteers (GWPK0215) (2004)

SUMMARY Primary objectives of this study were to assess the pharmacokinetic characteristics of CBME when administered sublingually in different ratios, to determine if the pharmacokinetic profiles of THC and its metabolite 11-hydroxy-THC are different when administered sublingually in different formulations, and to characterise the pharmacokinetic profile of CBD when administered with THC in equal amounts. Secondary objectives were to determine if there was a correlation between intoxication levels and plasma concentrations of THC and/or its metabolite 11-hydroxy-THC, and to assess safety and tolerability of CBME when administered sublingually. Methodology employed a double-blind, randomised, three-way crossover study of placebo, High THC and CBD:THC administered sublingually as a liquid spray. Twenty-four subjects were planned, dosed, completed the study and were analysed. Test products were Δ9-tetrahydrocannabinol (THC, formulated as 25 mg THC per ml) with or without cannabidiol (CBD) (formulated as 25 mg CBD + 25 mg THC per ml) formulated in ethanol (Eth):propylene glycol (PG) with peppermint (ppmt) flavouring or matching placebo, administered with a 100 μl pump. Each subject received one single dose of 10 mg THC and one single dose of 10 mg CBD + 10 mg THC plus a single dose of placebo in a randomised manner on three separate occasions. The washout period was six days between each dose. Placebo was Eth:PG in a 50:50 ratio with ppmt flavouring, administered with a 100 μl actuator pump. Mean plasma concentrations show that following administration of both High THC and CBD:THC formulations CBD and or THC was detectable in plasma in measurable concentrations 15–30 minutes after dosing, although individual subjects showed quite wide variability, 15 to 135 minutes, to appearance measurable concentrations. At all time points up to 180 minutes after dosing mean concentrations of THC were greater following the High THC formulation than CBD:THC. Concentrations of THC were also greater than corresponding concentrations of CBD following the CBD:THC treatment. There were no statistically significant differences in mean Cmax, t1/2, AUC0-t and AUC0-∞of both THC and 11-hydroxy-THC between the High THC and CBD:THC formulations. THC Tmax was statistically significantly later following CBD:THC than High THC (p = 0.014) and this was the only statistically significant difference in pharmacokinetic parameters between the treatments. The AUC values (AUC0-t and AUC0-∞) for THC show an approximate 8 to 10-fold difference between the lowest and highest subject values while the difference for CBD was approximately 3.5 to 4-fold. Differences in Cmax were 20 to 30 fold for THC and approximately 14-fold for CBD. Intra-subject differences in values for THC between treatments were smaller though differences in Cmax of up to 5-fold and 3-fold in AUC (AUC0-t and AUC0-∞) were observed. Other than a single isolated significant difference in Tmax there were no significant differences in pharmacokinetic parameters between the CBD:THC and High THC formulations. The bioavailability of THC appears to be greater than that of CBD. Mean intoxication scores on both CBME treatments were very low throughout the observation period. The majority of subjects scored zero for the majority of assessment points and there were few scores greater than three on the Box Scale 11 (BS-11). Recorded intoxication scores do not seem to show a direct relationship to plasma concentrations of THC and/or 11-hydroxy-THC either within or between subjects. The time of intoxication scores in individual subjects do not seem to relate consistently with the timing of increases in plasma concentrations or maximal concentrations of THC or 11-hydroxy-THC. Neither is there an apparent relationship between subjects reporting intoxication and those with the highest plasma levels of THC or 11-hydroxy-THC. No subjects withdrew from the study as a result of adverse events and both active and the placebo test treatments were well tolerated. The treatment with the least number of treatment related adverse events was placebo. High THC and CBD:THC had a greater number of subjects who experienced intoxication type adverse events and application site type reactions. The most common overall adverse event experienced was throat irritation, followed by dizziness, somnolence, oral paraesthesia and then headache. All the events were mild and only two events needed any treatment. There were no clinically significant changes from baseline for haematology, biochemistry, vital signs or ECGs. There was wide inter- and intra-subject variability in pharmacokinetic parameters with up to 10-fold differences in THC AUC between subjects and even greater differences in Cmax. Results suggest that there are no overall statistically significant differences between the pharmacokinetic parameters of High THC and CBD:THC other than a delay in Tmax. Considering the wide inter- and intra-subject variability in pharmacokinetic parameters including Tmax this is unlikely to be clinically important in a medication that is self titrated by the patient.