A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans, Gerhard Nahler et al., 2017

A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans

Gerhard Nahler, Franjo Grotenhermen, Antonio Waldo Zuardi, and Jose´ A.S. Crippa3

Cannabis and Cannabinoid Research, 2017, 2, 1, 81-86

DOI: 10.1089/can.2017.0009


Cannabidiol (CBD), a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. Under acidic conditions, CBD can be transformed to delta9 tetrahydro-cannabinol (THC) and other cannabinoids. It has been argued that this may occur also after oral administration in humans. However, the experimental conversion of CBD to THC and delta8-THC in simulated gastric fluid (SGF) is a highly artificial approach that deviates significantly from physiological conditions in the stomach; therefore, SGF does not allow an extrapolation to in vivo conditions. Unsurprisingly, the conversion of oral CBD to THC and its metabolites has not been observed to occur in vivo, even after high doses of oral CBD. In addition, the typical spectrum of side effects of THC, or of the very similar synthetic cannabinoid nabilone, as listed in the official Summary of Product Characteristics (e.g., dizziness, euphoria/high, thinking abnormal/concentration difficulties, nausea, tachycardia) has not been observed after treatment with CBD in double-blind, randomized, controlled clinical trials. In conclusion, the conversion of CBD to THC in SGF seems to be an in vitro artifact.

Keywords : cannabidiol; delta9-tetrahydrocannabinol; acid-catalyzed cyclization; degradation; isomerization; gastric fluid



Two recent publications of Merrick et al.1 and Bonn- Miller et al.2 have caused much confusion and uncertainty whether oral cannabidiol (CBD) is safe and whether subjects who are treated with CBD run the risk of positive workplace tests on delta9-tetrahydrocannabinol (delta9- THC, in short THC) with the respective consequences. In this article, we would like to clarify a number of serious misinterpretations in the abovementioned articles and reinforce the arguments published recently.3

CBD and THC have a very similar chemical structure. Despite this similarity, they differ widely in their properties. CBD shows insufficient binding to the cannabinoid receptors, particularly to CB1, which is involved in psychotomimetic effects. As toCB1, CBDis considered to be a negative allosteric modulator, which means, it modifies this receptor in such a way that the binding of classical agonists such as anandamide (AEA), THC, or nabilone is dramatically reduced.4 This effect is utilized also by Sativex to reduce some side effects of THC. Given that CBD is not a CB1 agonist, it is free from psychotomimetic properties and lacks cannabis-like intoxicating effects. This has been confirmed repeatedly by studies performed in the last four decades.

CBD, particularly in solution, is not fully stable; it needs to be stored at temperatures below 8°C and protected from light. Under acidic conditions, CBD can be converted (isomerized) to THC and other cannabinoids. Therapeutically used CBD can be either plant derived, which is (-) trans CBD (purity >99.5%, CBD, e.g., of GW, United Kingdom or of BSPG, United Kingdom), or synthetic; the purity of marketed products is around 98% to 99% according to respective websites. Byproducts of plant-derived CBD are (-)cannabinoids, as the plant makes only one isomere, whereas impurities of synthetic CBD arise from remaining starting material and products formed during the synthesis. Traces of THC in less-purified CBD products cannot be excluded, but are unlikely of concern.

Based on in vitro conditions in simulated gastric fluid (SGF), it has been argued that this conversion of CBD to THC may also occur after oral administration. 1,5 Such chemical transformations would not occur by other routes of administration, such as parenteral applications, particularly by inhalation, rectal, or transdermal application. In the following, the physiologic relevance of this in vitro transformation is discussed.