Objective: Cannabidiol (CBD) has been approved by the US Food and DrugAdministration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a +/− mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a +/− mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA) A receptors to investigate the activity of GABA A receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a +/− mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABA A receptor activation.

Background Cannabidiol (CBD) has demonstrated anti-inflammatory, analgesic, anxiolytic and neuroprotective effects that have the potential to benefit athletes. This pilot study investigated the effects of acute, oral CBD treatment on physiological and psychological responses to aerobic exercise to determine its practical utility within the sporting context. Methods On two occasions, nine endurance-trained males (mean ± SD V̇O2max: 57.4 ± 4.0 mL·min−1·kg−1) ran for 60 min at a fixed intensity (70% V̇O2max) (RUN 1) before completing an incremental run to exhaustion (RUN 2). Participants received CBD (300 mg; oral) or placebo 1.5 h before exercise in a randomised, double-blind design. Respiratory gases (V̇O2), respiratory exchange ratio (RER), heart rate (HR), blood glucose (BG) and lactate (BL) concentrations, and ratings of perceived exertion (RPE) and pleasure–displeasure were measured at three timepoints (T1–3) during RUN 1. V̇O2max, RERmax, HRmax and time to exhaustion (TTE) were recorded during RUN 2. Venous blood was drawn at Baseline, Pre- and Post-RUN 1, Post-RUN 2 and 1 h Post-RUN 2. Data were synthesised using Cohen’s dz effect sizes and 85% confidence intervals (CIs). Effects were considered worthy of further investigation if the 85% CI included ± 0.5 but not zero. Results CBD appeared to increase V̇O2 (T2: + 38 ± 48 mL·min−1, dz: 0.25–1.35), ratings of pleasure (T1: + 0.7 ± 0.9, dz: 0.22–1.32; T2: + 0.8 ± 1.1, dz: 0.17–1.25) and BL (T2: + 3.3 ± 6.4 mmol·L−1, dz: > 0.00–1.03) during RUN 1 compared to placebo. No differences in HR, RPE, BG or RER were observed between treatments. CBD appeared to increase V̇O2max (+ 119 ± 206 mL·min−1, dz: 0.06–1.10) and RERmax (+ 0.04 ± 0.05 dz: 0.24–1.34) during RUN 2 compared to placebo. No differences in TTE or HRmax were observed between treatments. Exercise increased serum interleukin (IL)-6, IL-1β, tumour necrosis factor-α, lipopolysaccharide and myoglobin concentrations (i.e. Baseline vs. Post-RUN 1, Post-RUN 2 and/or 1-h Post-RUN 2, p’s < 0.05). However, the changes were small, making it difficult to reliably evaluate the effect of CBD, where an effect appeared to be present. Plasma concentrations of the endogenous cannabinoid, anandamide (AEA), increased Post-RUN 1 and Post-RUN 2, relative to Baseline and Pre-RUN 1 (p’s < 0.05). CBD appeared to reduce AEA concentrations Post-RUN 2, compared to placebo (− 0.95 ± 0.64 pmol·mL−1, dz: − 2.19, − 0.79). Conclusion CBD appears to alter some key physiological and psychological responses to aerobic exercise without impairing performance. Larger studies are required to confirm and better understand these preliminary findings. Trial Registration This investigation was approved by the Sydney Local Health District’s Human Research Ethics Committee (2020/ETH00226) and registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12620000941965).

Background and Purpose: Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties.Experimental Approach: We used the Scn1a +/À mouse model of Dravet syndrome to investigate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia-induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a +/À mice and in electroshock seizure models. Pharmacological effects of CBGA were surveyed across multiple drug targets.

Background: Cannabidiol (CBD), a major cannabinoid of Cannabis sativa, is widely consumed in prescription and non-prescription products. While CBD is generally considered ‘non-intoxicating’, its effects on safety-sensitive tasks are still under scrutiny. Aim: We investigated the effects of CBD on driving performance. Methods: Healthy adults ( n = 17) completed four treatment sessions involving the oral administration of a placebo, or 15, 300 or 1500 mg CBD in a randomised, double-blind, crossover design. Simulated driving performance was assessed between ~45–75 and ~210–240 min post-treatment (Drives 1 and 2) using a two-part scenario with ‘standard’ and ‘car following’ (CF) components. The primary outcome was standard deviation of lateral position (SDLP), a well-established measure of vehicular control. Cognitive function, subjective experiences and plasma CBD concentrations were also measured. Non-inferiority analyses tested the hypothesis that CBD would not increase SDLP by more than a margin equivalent to a 0.05% blood alcohol concentration (Cohen’s dz = 0.50). Results: Non-inferiority was established during the standard component of Drive 1 and CF component of Drive 2 on all CBD treatments and during the standard component of Drive 2 on the 15 and 1500 mg treatments (95% CIs < 0.5). The remaining comparisons to placebo were inconclusive (the 95% CIs included 0 and 0.50). No dose of CBD impaired cognition or induced feelings of intoxication ( ps > 0.05). CBD was unexpectedly found to persist in plasma for prolonged periods of time (e.g. >4 weeks at 1500 mg). Conclusion: Acute, oral CBD treatment does not appear to induce feelings of intoxication and is unlikely to impair cognitive function or driving performance (Registration: ACTRN12619001552178).

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