Keywords : cannabidiol; delta-8-tetrahydrocannabinol; delta-9-tetrahydrocannabinol; interconversion; pharmacokinetics; protein precipitation; UHPLC-ESI-MS/MS

Introduction

Cannabis sativa (cannabis) contains more than 100 compounds with similar chemical structures, known as phytocannabinoids. The main psychoactive compound in cannabis is Delta-9-tetrahydrocannabinol (Δ⁹-THC), responsible for most of the usual psychotomimetic effects linked to the use of the plant. Another major phytocannabinoid present in cannabis is cannabidiol (CBD), a compound that does not produce the typical subjective effects of cannabis induced by Δ⁹-THC. CBD was shown to have a wide range of pharmacological properties of great therapeutic interest such as anxiolytic, antiepileptic, and neuroprotective actions, among others, without causing significant adverse effects.^1–3 Interestingly, although CBD and Δ⁹-THC show entirely different clinical and central actions, they share very similar chemical structures.

A recent study demonstrated that CBD could convert to Δ⁹-THC in an acidic medium in vitro that simulates gastric fluid. This led the authors to conclude that oral treatment with CBD could expose patients to the risk of ingesting significant levels of THC.⁴ A comment to this article contested the clinical relevance in its conclusion based on available clinical data that showed no effects characteristic of THC in subjects after the ingestion of CBD, even at high doses.⁵ These articles initiated a scientific controversy that generated more publications since then, with reports presenting animal data arguing for^6,7 and against^8–10 the risk of CBD conversion into Δ⁹-THC after oral ingestion. In humans, the only two studies that provided data regarding the conversion of CBD into Δ⁹-THC^11,12 did not detect Δ⁹-THC in the plasma samples of any of the patients included.

While definitive conclusions remain to be reached, this scientific debate may have significant clinical and practical implications. Preliminary pre-clinical and more extensive clinical trials have shown that orally-administered CBD has antiseizure properties, particularly in children with treatment-resistant epilepsies such as Lennox-Gastaut and Dravet syndrome.^13,14 Since it is well known that chronic exposure to Δ⁹-THC has long-lasting harmful effects, such as the onset of severe psychiatric disorders and cognitive impairment, the possible conversion of CBD into Δ⁹-THC raises important safety concerns, particularly in the developing brain of children and adolescents.¹⁵ Therefore, to contribute to the elucidation of the controversy about the conversion of oral CBD to THC, we investigated the pharmacokinetics of a single dose of CBD administered to a large sample of healthy human volunteers (male and female).

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