Gerhard Nahler M.D., Ph.D. General Manager Clinical Investigation Support GmbH
Franjo Grotenhermen M.D. Principle Nova-Institut GmbH
Antonio Waldo Zuardi Ph.D. Vice Director Ribeirão Preto Medical School,, University of São Paulo
José A.S. Crippa M.D., Ph.D. University of São Paulo Ribeirão Preto

Although CBD Can Be Transformed to THC Under Acidic Conditions, the Conversion of Oral CBD Doesn’t Occur In Vivo

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 above-mentioned 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 to CB1, CBD is 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.


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-tetrahydrocannabinol (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.

SGF Does Not Reflect In Vivo Conditions

Merrick et al.1 used an in vitro model with an SGF to study the conversion of CBD to delta-9THC and delta8-THC. This SGF was highly artificial; synthetic CBD (99% purity) was dissolved in methanol and an aliquot diluted. The final SGF contained 1% sodium dodecyl sulfate and 0.2% methanol, with a pH of 1. There is no mention of the addition of electrolytes or gastric enzymes; overall test conditions deviate also from the U.S. Pharmacopoeia. In this assay, CBD degraded about 85% after 60 min and greater than 98% at 120 min, mainly to delta9-THC and delta8-THC. Although the authors had cited a similar in vitro investigation by Watanabe et al.,5 they did not discuss a striking discrepancy between these and their own results.

Watanabe et al.5 incubated CBD of herbal origin (purity not stated) in modified artificial gastric juice without pepsin, but containing NaCl (2 mg/mL, pH 1.2) at 37°C. Even after 20 h, the conversion rates for THC, cannabinol, 9alpha-hydroxyhexahydrocannabinol [9α-OH-HHC], and 8-OH-iso-HHC from CBD were only 2.9%, 1.1%, 1.4%, and 10.0%, respectively. This is a much lower conversion rate and strongly suggests that the composition of SGF and other test conditions has a major impact on the degradation of CBD.

The traditional medium to simulate gastric conditions in the fasted state has been SGF of the U.S. Pharmacopeial Convention (USP). This medium contains hydrochloric acid and sodium chloride, as well as pepsin and water, and has a pH of 1.2. Most often, it is prepared by dissolving 2.0 g of sodium chloride and 3.2 g of purified pepsin (derived from porcine stomach mucosa, with an activity of 800–2500 U per mg of protein) in 7.0 mL of hydrochloric acid and water up to 1000 mL. However, it must be stressed that even this SGF significantly deviates from physiologic conditions. Most studies of gastric pH indicate that the across-the-board average gastric pH usually lies in the range 1.5–1.9.6 To note, standard SGF is used to test the dissolution/disintegration of oral medications; it has not been developed to study chemical transformations. In fact, physiologic gastric juice is a very complex fluid with a pH around 1.5 to 1.9 to 3.5 (more acidic after a meal), and which contains a number of proteins to improve digestion, notably gastricsin, pepsin, trypsin (1 and 2), gastric lipase, gastric amylase, gelatinase, and mucin-glycoproteins, in addition to inorganic substances such as potassium, sodium, and calcium.7 Gastric transit time, although varying, is in the order of 2.5 to 3 h (for 50% of stomach contents emptied).

It is reminded that cannabinoids demonstrate significant protein binding; this could also protect CBD to some extent from a chemical transformation.8

As to the in vivo relevance of CBD degradation to THC and other cannabinoids, Watanabe et al.5 comment that “In biological systems, there have been no reports on the conversion of CBD to delta9-THC.” We agree, despite intensive research, we are also unaware of any in vivo conversion of CBD to THC. In vivo, CBD undergoes extensive hydroxylation at multiple sites and further oxidations result in complex metabolic profiles; altogether, some 100 CBD metabolites have been identified.9 Compared to THC, the metabolism of CBD is unusually complex with considerable species variability.

The entire article and its references are available at Cannabis and Cannabinoid Research.

Cannabis and Cannabinoid Research, published by Mary Ann Liebert, Inc., a peer-reviewed journal, is dedicated to the scientific, medical, and psychosocial exploration of clinical cannabis, cannabinoids, and the endocannabinoid system. The above article was first published in the June 2017 issue of Cannabis and Cannabinoid Research with the title “A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans”. The views expressed here are those of the authors and are not necessarily those of Cannabis and Cannabinoid Research, Mary Ann Liebert, Inc., publishers, or their affiliates. No endorsement of any entity or technology is implied.


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