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 C_max increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. C_max is increased during fed states and in lipid formulations. T_max 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.

Cannabinoids act at two classical cannabinoid receptors (CB₁ and CB₂), a 7TM orphan receptor and the transmitter‐gated channel transient receptor potential vanilloid type‐1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator‐activated receptors (PPARs, with three subtypes α, β (δ) and γ), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPARα. Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPARα. Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti‐inflammatory properties mediated by PPARα. Other endocannabinoids that activate PPARα include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPARγ; anandamide and 2‐arachidonoylglycerol have anti‐inflammatory properties mediated by PPARγ. Similarly, ajulemic acid, a structural analogue of a metabolite of Δ⁹‐tetrahydrocannabinol (THC), causes anti‐inflammatory effects in vivo through PPARγ. THC also activates PPARγ, leading to a time‐dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPARγ include N‐arachidonoyl‐dopamine, HU210, WIN55212‐2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPARδ. In this newly emerging area, a number of research questions remain unanswered; for example, why do cannabinoids activate some isoforms and not others? How much of the chronic effects of cannabinoids are through activation of nuclear receptors? And importantly, do cannabinoids confer the same neuro‐ and cardioprotective benefits as other PPARα and PPARγ agonists? This review will summarize the published literature implicating cannabinoid‐mediated PPAR effects and discuss the implications thereof.British Journal of Pharmacology (2007) 152, 576–582; doi:10.1038/sj.bjp.0707423; published online 20 August 2007

OBJECTIVE Cannabidiol (CBD) and Δ⁹-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of these compounds in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and tolerability end points were also evaluated. RESULTS Compared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference [ETD] = −1.2 mmol/L; P < 0.05) and improved pancreatic β-cell function (HOMA2 β-cell function [ETD = −44.51 points; P < 0.01]), adiponectin (ETD = −5.9 × 10⁶ pg/mL; P < 0.01), and apolipoprotein A (ETD = −6.02 μmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (−898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated. CONCLUSIONS THCV could represent a new therapeutic agent in glycemic control in subjects with type 2 diabetes.

Structural alterations and breakdown of the blood brain barrier (BBB) is often a primary or secondary consequence of disease, resulting in brain oedema and the transport of unwanted substances into the brain. It is critical that effective in vitro models are developed to model the in vivo environment to aid in clinically relevant research, especially regarding drug screening and permeability studies. Our novel model uses only primary human cells and includes four of the key cells of the BBB: astrocytes, pericytes, brain microvascular endothelial cells (HBMEC) and neurons. We show that using a larger membrane pore size (3.0 μM) there is an improved connection between the endothelial cells, astrocytes and pericytes. Compared to a two and three cell model, we show that when neurons are added to HBMECs, astrocytes and pericytes, BBB integrity was more sensitive to oxygen-glucose deprivation evidenced by increased permeability and markers of cell damage. Our data also show that a four cell model responds faster to the barrier tightening effects of glucocorticoid dexamethasone, when compared to a two cell and three cell model. These data highlight the important role that neurons play in response to ischaemia, particularly how they contribute to BBB maintenance and breakdown. We consider that this model is more representative of the interactions at the neurovascular unit than other transwell models and is a useful method to study BBB physiology.

Aims Cannabidiol (CBD) is a cannabis‐derived medicinal product with potential application in a wide‐variety of contexts; however, its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of CBD in a variety of medical contexts. Methods Publications involving administration of CBD alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov. Results A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. Twenty‐three studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 and 50 mg/kg/d. Plasma concentrations were not provided in any publication. CBD was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of CBD on reducing seizure frequency or severity (average 15 mg/kg/d within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n = 6–62) assessing diabetes, Crohn's disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/kg/d) were used in these studies. Conclusion This review highlights that CBD has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.