A Single Centre, Placebo-Controlled, Four Period, Crossover, Tolerability Study Assessing, Pharmacodynamic Effects, Pharmacokinetic Characteristics and Cognitive Profiles of a Single Dose of Three Formulations of Cannabis Based Medicine Extracts (CBMEs) (GWPD9901), Plus a Two Period Tolerability Study Comparing Pharmacodynamic Effects and Pharmacokinetic Characteristics of a Single Dose of a Cannabis Based Medicine Extract Given via Two Administration Routes (GWPD9901 EXT) (2004)

SUMMARY This study was the first study of GW's CBME in man. It was performed in six healthy subjects, employing test treatments consisting of CBD:THC sublingual drops (GW-1011-01): 5 mg Δ9-tetrahydrocannabinol (THC) + 5 mg cannabidiol (CBD) per ml of glycerol:ethanol (Eth):propylene glycol (PG) (4:4:2), with peppermint flavouring, High CBD sublingual drops (GW-3009-01): 5 mg CBD per ml of glycerol: Eth:PG (4:4:2), with peppermint flavouring, High THC sublingual drops (GW-2009-01): 5 mg THC per ml of glycerol:Eth:PG (4:4:2), with peppermint flavouring, placebo sublingual drops (GW-4003-01): glycerol: Eth:PG (4:4:2), with peppermint flavouring, aerosol (GW-1009-01): 5 mg CBD + 5 mg THC per ml formulated in propellant:Eth (80:20), and nebuliser (GW-1012-01): 10 mg CBD + 10 mg THC per ml of cremophor (Crem) (0.4):PG (1.5):macrogol (1):dodecanol (0.8):H2O (7.4), and placebo nebuliser (administered to subjects 005 and 006 instead of the active nebuliser test treatment): Crem (0.4):PG (1.5):macrogol (1):dodecanol (0.8):H2O (7.4). Periods 1, 5 and 6 were open label, Periods 2 to 4 double blind. The study was a partially randomised crossover using single doses of THC and/or CBD or placebo. The study drug was administered as sublingual drops according to a pre-determined randomisation scheme in Periods 1 to 4. In Period 5, CBD:THC was administered as a sublingual aerosol and in Period 6 CBD:THC was administered as an inhalation via a nebuliser. There was a six-day washout between each dose. Primary objectives of the study were to make a preliminary evaluation of the tolerability of cannabis based medicine extracts at single dose in comparison to placebo in order to provide guidance for dosage in future studies; GWPD9901 EXT: was designed to compare the effect of method of administration (sublingually via an aerosol) or the route (inhalation) on the cannabis based medicine extract containing THC and CBD in a ratio of 1:1 in terms of subjective assessment of well-being, in vivo pharmacokinetic characteristics over 12 h, the adverse event (AE) profile and measurement of vital signs and conjunctival reddening over 12 h. Secondary objectives were to compare the effects of the four preparations in terms of cognitive assessment, subjective assessment of well-being in vivo pharmacokinetic characteristics over 12 h, the AE profile and measurement of vital signs and conjunctival reddening over 12 h. The methodology was a six single dose, partially randomised, six-way cross-over study. In Period 1, all subjects received CBD:THC drops. In Periods 2–4, High THC drops, High CBD drops and placebo drops were administered, double blind and fully randomised. In Period 5, all subjects received the aerosol test treatment and in Period 6, all subjects received the nebuliser test treatment. Each subject received five single doses of a maximum of 20 mg CBD, 20 mg CBD + 20 mg THC and 20 mg THC on five separate occasions and a placebo dose on one occasion. The duration of the study was six weeks. Following administration of CBD:THC (Sativex) sublingual drops, mean concentrations of CBD, THC and 11-hydroxy-THC were above the Lower Limit of Quantification (LLOQ) by 45 min post-dose. Plasma concentrations of THC were at least double those of CBD before both decreased below the LLOQ by 360 min and 480 min post-dose, respectively. When High CBD sublingual drops were administered, plasma levels of CBD were generally similar to those measured after CBD:THC sublingual drops. High THC resulted in marginally earlier detection of mean concentrations of both THC and 11-hydroxy-THC and a slightly earlier decline than for CBD:THC sublingual plasma concentrations. Following administration of CBD:THC via the pressurised aerosol, mean quantifiable levels of CBD and THC were detected marginally earlier than for the CBD:THC sublingual drops and declined below the LLOQ marginally later. Plasma concentrations of THC, 11-hydroxy-THC and CBD following administration via the aerosol were lower than after administration of the sublingual drops. Following administration of CBD:THC via the nebuliser, mean plasma levels of both CBD and THC increased rapidly (within 5 min) to levels much higher than measured following administration of the sublingual drops and were maintained until around 120 min post-dose before declining rapidly. Levels of 11-hydroxy-THC were very low compared with those after sublingual dosing. There were no statistically significant differences in the pharmacokinetics of THC or CBD between CBD:THC sublingual drops and High THC, High CBD or pressurised aerosol. With the exception of a single statistically significant difference in AUC0-∞ for 11-hydroxy-THC following administration of the High THC compared with CBD:THC sublingual drops there were no significant differences in the PK of 11-hydroxy-THC either. Dosing with the inhaled nebuliser produced marked differences in the pharmacokinetics of CBD and THC compared with CBD:THC sub-lingual dosing. Peak concentration was greater and much earlier although only Cmax of CBD and Tmax of THC were statistically significantly different. Peak concentration and AUCs of 11-hydroxy-THC were statistically significantly less, reflecting reduced early metabolism of THC by this route. No consistent statistically significant differences were noted between the pharmacokinetic parameters of High CBD, High THC and the aerosol when compared to the CBD:THC sublingual drops. However, the nebuliser resulted in a rapid absorption of CBD and THC and higher peak plasma levels but a reduction in the metabolism of THC to 11-hydroxy-THC. Subjects experienced a reduction in wakefulness, feeling of well-being, mood, production of saliva and increased hunger and unpleasant effect following administration of each test treatment and placebo. The maximum mean changes in wakefulness, feeling of well-being, mood and production of saliva were reported 3 h post-dose following administration of CBD:THC sublingual drops. Similar trends were also reported following administration of placebo and therefore it is suggested that the effects reported may not be entirely due to active test treatments. The greatest mean incidence of unpleasant effects was reported earlier than for any other effect and following administration of the nebuliser test treatment. The sublingual test treatments were best liked and the nebuliser test treatment was least liked. All of the subjects (100%) reported coughing and three subjects (50%) reported a sore throat following dosing with the nebuliser. The sublingual test treatments were well tolerated by all subjects. All six subjects experienced at least two AEs during the study, but there were no deaths, serious adverse events (SAEs) or other significant AEs. The commonest AEs were tachycardia, conjunctival hyperaemia and abnormal dreams. The small variations in individual subject laboratory parameters and urinalyses and in the mean laboratory parameters did not suggest any patterns or trends. The mean values of all the vital signs showed no patterns or trends either and no differences from placebo. ECGs at both screening and post-study were normal for all subjects. In conclusion, each sublingual test treatment was well tolerated by all subjects. The inhaled test treatment was not well tolerated and resulted in adverse effects.