Oral Cannabidiol Does Not Convert to Δ8-THC or Δ9-THC in Humans : A Pharmacokinetic Study in Healthy Subjects, Jose´ Alexandre S. Crippa et al., 2019

Oral Cannabidiol Does Not Convert to Δ8-THC or Δ9-THC in Humans : A Pharmacokinetic Study in Healthy Subjects

Jose´ Alexandre S. Crippa, Antonio Waldo Zuardi, Jaime Eduardo Cecılio Hallak, Bruna Miyazawa,
Sandra Aparecido Bernardo, Carmem Maria Donaduzzi, Silvane Guzzi, Wagner Alex Jann Favreto, Alline Campos, Maria Eugenia C. Queiroz, Francisco S. Guimaraes, Patrıcia Moura da Rosa Zimmermann, Letıcia Mello Rechia, Volnei Jose Tondo Filho, and Liberato Brum Junior

Cannabis and Cannabinoid Research, 2019, Volume X, Number X

DOI: 10.1089/can.2019.0024



Introduction: Recent studies have suggested that cannabidiol (CBD) could interconvert into Delta-8- and Delta-9- tetrahydrocannabinol.

Materials and Methods: Thus, we tested the plasma samples of 120 healthy human subjects (60 male and 60 female), 60 in fasting and the other 60 under normal feeding conditions after acute administration of an oral solution containing CBD 300 mg. To do this, we developed a bioanalytical method to determine CBD and the presence of THC in plasma samples by Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry.

Results: The results showed that THC was not detected in plasma after the administration of CBD, and those study participants did not present psychotomimetic effects.

Conclusions: The findings presented here are consistent with previous evidence suggesting that the oral administration of CBD in a corn oil formulation is a safe route for the administration of the active substance without bioconversion to THC in humans.

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


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 for6,7 and against8–10 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-THC11,12 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).