A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers
Daniel Perkins · Juliet Butler · Katherine Ong · Tri‑Hung Nguyen · Susan Cox · Barbara Francis ·
Michelle Mcintosh · Brian Lilley
Background : There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties.
Objective : The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal.
Methods : A total of 24 eligible healthy volunteers (aged 18-48 years) were randomised to one of three sequential cohorts (each with six active and two placebo subjects). Cohort 1 received 5 mg/kg CBD or placebo, cohort 2 received 10 mg/kg CBD or placebo (cohort 2), and cohort 3 received 20 mg/kg CBD or placebo. Data relating to adverse events, vital signs, clinical laboratory assessments, 12-lead ECGs, physical examinations and concomitant medications were collected to assess safety and tolerability. Blood samples were collected up to 8 days postdose and plasma was analysed by liquid chromatography and mass spectrometry to assess the pharmacokinetics of the CBD formulation.
Results : CBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (Tmax) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2-3 weeks are needed to fully eliminate CBD.
Conclusions : This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns.
Trial registration : ACTRN12618001424291. Registered August 2018.
Prescribers should be aware of a dose-proportional increase in cannabidiol exposure for doses between 5 and 20 mg/kg when cannabidiol is administered following a high-fat meal.
This new formulation of cannabidiol was generally safe and well tolerated, with the most commonly reported adverse events being headache (17%) and diarrhoea (8%). The formulation is now available in the public domain.
Safety and pharmacokinetic data obtained following a high-fat meal were consistent with data from other studies of purified pharmaceutical-grade cannabidiol, strengthening support for the idea of administering CBD with food to maximize bioavailability.
There is potential for a substantial variation in cannabidiol bioavailability between doses if the fat content of the associated meal varies significantly.
Cannabidiol (CBD) is a major nonpsychoactive cannabinoid derived from the Cannabis plant that has attracted significant interest due to its anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties, as demonstrated in preclinical trials [1–3]. Recent phase III clinical trials of purified cannabidiol have reported that this cannabinoid reduces the frequency of seizures in paediatric patients with Dravet syndrome as well as in paediatric and adult patients with Lennox–Gastaut syndrome [4, 5]. The purified formulation of cannabidiol used in those trials was approved by the United States Food and Drug Administration (FDA) for the treatment of these conditions in 2018. Based on promising other indications such as anxiety, psychosis, autism spectrum disorder, Rett syndrome, Fragile X syndrome and opioid use disorder (amongst others) are underway.
Cannabidiol does not produce a psychoactive “high”. This is due to inverse agonism at CB1 and CB2
receptors—cannabinoid receptors that are members of the G proteincoupled receptor (GPCR) family present throughout the endocannabinoid system. Interactions with multiple other non-endocannabinoid signalling pathways have also been reported, and are still the subject of debate [6, 7]. These include blocking of the equilibrative nucleoside transporter (ENT) , the orphan G protein-coupled receptor GPR55, and the transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) channel [9, 10], in addition to enhancing the activity of the 5-HT1a receptor, the α3 and α1 glycine receptors, peroxisome proliferator-activated receptor γ (PPAR-γ), and the transient receptor potential of ankyrin type 1 (TRPA1) channel . It is suggested that the nonpolar nature of cannabidiol may lead to an interaction mechanism involving the insertion of cannabidiol into the cellular lipid bilayer, thereby impacting membrane fluidity and the functioning of sodium, potassium and calcium channels .
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