A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans

Sophie A. Millar, Nicole L. Stone, Andrew S. Yates  and Saoirse E. O’Sullivan

Frontiers in  Pharmacology, 26 November 2018

https://doi.org/10.3389/fphar.2018.01365

Background : Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area.

Methods : A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans.

Results : Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2–5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the absolute bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h.

Conclusions : This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Analysis and understanding of properties such as bioavailability and half-life is critical to future therapeutic success, and robust data from a variety of formulations is required.

Keywords : pharmacokinetics, endocannabinoid system, bioavailability, CMAX, TMAX, half life, plasma clearance, volume of distribution

 

INTRODUCTION

The Cannabis sativa plant contains more than a hundred phytocannabinoid compounds, including the non-psychotomimetic compound cannabidiol (CBD) (Izzo et al., 2009). CBD has attracted significant interest due to its anti-inflammatory, anti-oxidative and anti-necrotic protective effects, as well as displaying a favorable safety and tolerability profile in humans (Bergamaschi et al., 2011), making it a promising candidate in many therapeutic avenues including epilepsy, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. GW pharmaceuticals have developed an oral solution of pure CBD
(Epidiolex R ) for the treatment of severe, orphan, early-onset, treatment-resistant epilepsy syndromes, showing significant reductions in seizure frequency compared to placebo in several trials (Devinsky et al., 2017, 2018a; Thiele et al., 2018). Epidiolex  R has recently received US Food and Drug Administration (FDA) approval (GW Pharmaceuticals, 2018). CBD is also being pursued in clinical trials in Parkinson’s disease, Crohn’s disease, society anxiety disorder, and schizophrenia (Crippa et al., 2011; Leweke et al., 2012; Chagas et al., 2014; Naftali et al., 2017), showing promise in these areas. Additionally, CBD is widely used as a popular food supplement in a variety of formats for a range of complaints. It is estimated that the CBD market will grow to $2.1 billion in the US market in consumer sales by 2020 (Hemp Business, 2017).

From previous investigations including animal studies, the oral bioavailability of CBD has been shown to be very low (13–19%) (Mechoulam et al., 2002). It undergoes extensive first pass metabolism and its metabolites are mostly excreted via the kidneys (Huestis, 2007). Plasma and brain concentrations are dose-dependent in animals, and bioavailability is increased with various lipid formulations (Zgair et al., 2016). However, despite the breadth of use of CBD in humans, there is little data on its pharmacokinetics (PK). Analysis and understanding of the PK properties of CBD is critical to its future use as a therapeutic compound in a wide range of clinical settings, particularly regarding dosing regimens and routes of administration. Therefore, the aim of this systematic review was to collate and analyse all available CBD PK data recorded in humans and to highlight gaps in the literature.

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