A Multiple‐Dose, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray

Abstract

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain. A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers. The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed. Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day. In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies.

A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans

“…Minimal evidence of plasma accumulation has been reported by chronic dosing studies over 5–9 days (Sellers et al, 2013 ; Stott et al, 2013a ). C max appears to be dose-dependent.…”

“…C max appears to be dose-dependent. A dose of 20 mg/day resulted in a mean C max of 1.5 ng/mL and mean AUC 0−t of 6.1 h × ng/mL while 60 mg/day equated to a mean C max of 4.8 ng/mL and AUC 0−t was 38.9 h × ng/mL (Sellers et al, 2013 ). In another study, C max increased dose-dependently from 0.4 to 1.2 and 2.2 ng/mL following 5, 10, and 20 mg single doses, respectively, and from 0.5 to 1.1 and 3.2 ng/mL, respectively following chronic dosing over 9 consecutive days (Stott et al, 2013a ).…”

“…The mean half-life (t 1/2 ) of CBD was reported as 1.1 and 2.4 h following nebuliser and aerosol administration (20 mg) (Guy and Flint, 2004 ), 1.09 and 1.97 h following single oral administration (10 and 20 mg) (Guy and Flint, 2004 ; Guy and Robson, 2004b ), 2.95 and 3.21 h following 10 mg oral lipid capsules (Atsmon et al, 2017a , b ), between 1.44 and 10.86 h after oromucosal spray administration (5–20 mg) (Guy and Robson, 2004b ; Sellers et al, 2013 ; Stott et al, 2013a , b ; Atsmon et al, 2017b ), 24 h after i.v. infusion, 31 h after smoking (Ohlsson et al, 1986 ), and 2–5 days after chronic oral administration (Consroe et al, 1991 ).…”

Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues

“…In general, 2.5 mg of THC is a threshold dose for patients without previous tolerance to cannabis, 5 mg is a moderate dose, 10 mg a large dose that may be problematic for naïve patients, while 15 mg or more at a time risks psychiatric adverse events (Grotenhermen, 2001 ; Sellers et al, 2013 ).…”

Pain medication and long QT syndrome

“…There is increasing evidence that the cannabinoids can alleviate chronic pain [ 43 ]. In a study performed in healthy volunteers, an oral mucosal spray containing delta-9-tetrahydrocannabinol/cannabidiol had no significant effect on ECG parameters, either in recommended or in supra-therapeutic doses [ 44 ]. In vitro experiments for JWH-030, a new synthetic cannabinoid, demonstrated blocking of the hERG channel and therefore potential QT prolongation [ 45 ].…”