Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

Abstract

Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF).Methods: Materials included synthetic CBD, Δ8-THC, and Δ9-THC. Linearity was demonstrated for each component over the concentration range used in this study. CBD was spiked into media containing 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatography with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid.Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degradation followed first-order kinetics at a rate constant of −0.031 min−1 (R2=0.9933). The major products formed were Δ9-THC and Δ8-THC with less significant levels of other related cannabinoids. CBD in physiological buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral analysis, mass identification, and retention time of Δ9-THC and Δ8-THC in the SGF samples against authentic reference standards.Conclusions: SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored.

Unique treatment potential of cannabidiol for the prevention of relapse to drug use: preclinical proof of principle

“…Drugs CBD was administered transdermally to enhance translational relevance regarding future therapeutic applications. The clinical potential of CBD when administered orally is constrained to some extent by low (~6%) bioavailability [28] and potential for conversion into psychoactive cannabinoids in gastric fluid [29]. However, we have identified the transdermal route of administration as an effective delivery method that eliminates both these limitations and produces stable and sustained plasma CBD levels [26,30].…”

Cannabis use during pregnancy: Pharmacokinetics and effects on child development

“…Specific strains of cannabis may also produce high levels of a second phyto-CB, cannabidiol (CBD), often referred to as non-psychoactive. Although not associated with cannabis-induced euphoria or intoxication (Grotenhermen et al, 2017), CBD exposure is psychoactive and affects several brain functions and behaviors, including neuronal activity, seizure incidence and social interactions (Renard et al, 2017a; Todd and Arnold, 2016). Accordingly, CBD has been linked to influencing a wide range of clinical outcomes such as epilepsy and neuropsychiatric disorders.…”

Cannabinoid glycosides:In vitroproduction of a new class of cannabinoids with improved physicochemical properties

“…shown that orally administered CBD may degrade into the psychoactive THC in simulated gastric fluids containing 1% SDS (Watanabe 2007, Merrick 2016. More recently, these in vitro results have been called into question as there is no in vivo evidence to support these claims (Russo 2017, Vitality Bio unpublished results).…”