Over the course of the past year, there has been a heated scientific debate, weather cannabidiol (CBD) converts into Δ9-tertrahydocannabinol (THC) in our bodies. It has been known for decades, that CBD can convert to THC in gastric fluid; the question was does this happen in humans, when taking oral CBD preparations. This is a particularly important topic, as more and more people are using CBD products and if true, could have economic and legal repercussions. In this article, I try to find an answer to this very relevant question
Simulated gastric fluid converts CBD into the psychoactive components Δ9-THC and Δ8-THC
The debate was initiated by a study done by Merrick et al., where they exposed CBD to simulated gastric fluid, to evaluate the potential formation of psychoactive cannabinoids. The reasoning behind these experiments was, that several studies with CBD on pediatric epilepsy, showed somnolence as the major side effect. Somnolence is also one of the main side effects of THC, hence the hypothesis that when taken orally, CBD could convert into THC and cause the somnolence.
They also added “Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored.” and comes into context, when we look at what projects, the authors are currently working on. (1)
Yes, but not in humans
Soon after, a rebuttal by Grotenhermen, Russo and Zuardi, three prominent scientists with decades of experience on therapeutic use of cannabis, was published in the same journal, disputing the allegations that this could happen in humans. If CBD did convert to THC in our bodies, it would be logical that we would feel some of the typical psychotropic effects of the latter. Also the main metabolites of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and carboxy-THC (THC-COOH), should be detected in body fluids.
Citing several clinical studies, where patients were given high doses of CBD, they did not find evidence that this happens in vivo. Their conclusion was “The overall available scientific data, and the serum level data suggests that oral administration of CBD is a safe and easy way to use CBD, even at high doses, in a therapeutic context with no indication of human bioconversion of CBD to THC”. (2).
Are you sure?
I did not take for a reply to the rebuttal. Bone-Miller eta al. addressed the argument against conversion of CBD to THC and its clinical implications in humans. By citing and interpreting several studies they concluded that “The current evidence indicates that gastric conversion of CBD to THC has been relatively consistently observed across multiple studies over the past half century; however, the circumstances in which this happens, and the subsequent clinical consequences, remain uncertain.” Regarding human clinical implications, they wrote “it is imperative that we continue to explore this issue among larger (particularly human) samples through a priori studies of potential side effects, including prospective evaluation of symptoms commonly associated with THC that employ validated instruments”. (3)
A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans
This was the title of the reply by Nahler et al. to the conclusions and interpretations of Merrick et al. and Bone-Miller et al. The main focus was to “clarify a number of serious misinterpretations in the above mentioned articles and reinforce the arguments published recently”. Their main issues were:
- A transformation of CBD to THC in the stomach should demonstrate the presence of typical metabolites of THC in blood and urine
- Simulated gastric fluid does not reflect in vivo conditions
- A transformation of CBD to THC is likely to cause typical effects of THC
They concluded “both publications, that of Merrick et al. and Bonn-Miller et al., are unfortunately misleading in many aspects. Over 40 years of research on CBD does not suggest a conversion of CBD to delta9-THC and/or other cannabinoids in vivo after oral administration. Such transformation occurs under artificial conditions, but is without any relevance for an oral therapy with CBD.” (4)
What about recent animal studies? Could they give us an insight into the truth?
Pigs might fly, but they don’t convert CBD into THC
In a study done by Wray et al., they administered oral doses of 15 mg/kg of CBD, twice per day, to minipigs and analyzed the plasma levels of CBD, THC and 11-OH-THC. The also measured concentrations of the same cannabinoids in GI tract content samples. In both cases, they did not detect any levels of THC or its major first pass metabolite.
They concluded that “when dosed orally in a sesame oil formulation to give CBD plasma exposures similar to those known to be clinically relevant in patients, CBD does not convert to THC in the minipig”. Regarding the limitations of this study they suggested that “supplementary research in human subjects with the measurement of 11-COOH-THC and Δ8-THC, in addition to validated in silico modeling may be required to confirm the hypothesis supported by our results that the conversion of CBD to THC does not occur in vivo.” (5)
I smell a rat
Two studies, by two different groups, one Czech and one Italian, published at approximately the same time (November 2017), had conflicting results. Both studies were done on rats and measured the levels of cannabinoids, after oral administration of CBD.
The Italian group orally administered a single high dose of CBD (50 mg/kg) and then measured the levels of cannabinoids and their metabolites, at 3 and 6 hours after administration. Using an in-house developed, highly sensitive and selective LC–MS/MS method, they did not find any THC or it’s metabolites in the blood. (7)
The study by the Czech group was more extensive, but they also gave the rats a single dose of CBD (10mg/kg) and then measured the level of cannabinoids and their metabolites in the blood, as well as in the brain tissue, 0.5, 1, 2, 4, 8 and 24h after administration. Using an in-house validated and certified GC–MS method, they found THC in the blood, ranging from 2.0 to 68.6 ng/ml, but not in the brain tissue.
They did an additional experiment with a higher dose of CBD (60 mg/kg) on 2 rats, and also found THC in the serum as well as in the brain tissue. Another interesting finding is that they also found THC in the serum after subcutaneous administration of CBD (10 mg/kg), but did not find any when CBD (20mg) was delivered via inhalation. (6)
Follow the money
When we interpret findings of published studies, we have to be careful, especially if they are funded by institutions, that have a financial gain in a certain outcome. So it is always good to check out who is funding the study and what their bias toward a positive outcome might be.
The studies by Merrick eta al. and Bonn-Miller et al. were funded by Zynerba Pharmaceuticals and the authors are also employees or paid consultants, of the same company. Zynerba Pharmaceuticals is currently developing a CBD gel and as stated on their website is the “First and only pharmaceutically-produced CBD formulated as a permeation-enhanced gel being developed for neuropsychiatric disorders including fragile x syndrome, adult refractory focal epilepsy and developmental and epileptic encephalopathies.” and has been granted Orphan Drug designation for the use of CBD as treatment of patients with fragile x syndrome, by the FDA.(8)
All the authors from the Wray eta al. study are employees of GW Research Ltd. GW Pharmacuticals is developing Epidiolex which is “GW’s lead cannabinoid product candidate and is a proprietary oral solution of pure plant-derived cannabidiol” and is doing clinical trials for use in “severe, orphan, early-onset, treatment-resistant epilepsy syndromes including Dravet syndrome, Lennox-Gastaut syndrome, Tuberous Sclerosis Complex and Infantile Spasms”.(9)
One can see how the results of the studies, could have important financial and other implications for these pharmaceutical companies, which are also both publicly traded companies.
It seems that we will need further studies, that can efficiently detect and accurately measure, the presence of THC and its metabolites, in patients who take CBD medications, to have a definitive answer.
We must also take into account that the presence of THC, in blood and brain tissue, was achieved at “doses several times higher compared to those typically used by humans” as quoted by Hložek et al.
As mentioned earlier, the implications of this phenomena are not therapeutic, as such low quantities of THC do not have a negative effect, I would argue quite the opposite. The main concern is what legal implications it could have, on workplace and roadside drug tests, as well as in countries, that still have archaic zero-tolerance THC laws.
1. Merrick, John & Lane, Brian & Sebree, Terri & Yaksh, Tony & O’Neill, Carol & Banks, Stan. (2016). Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid. Cannabis and Cannabinoid Research. 1. 102-112.
2. Grotenhermen Franjo, Russo Ethan, and Zuardi Antonio Waldo. Cannabis and Cannabinoid Research. January 2017, 2(1): 1-4.
3. Bonn-Miller Marcel O., Banks Stan L., and Sebree Terri. Cannabis and Cannabinoid Research. January 2017, 2(1): 5-7.
4. Nahler G, Grotenhermen F, Zuardi AW, Crippa JAS. A Conversion of Oral Cannabidiol to Delta9-Tetrahydrocannabinol Seems Not to Occur in Humans. Cannabis and Cannabinoid Research. 2017;2(1):81-86.
5. Wray L, Stott C, Jones N, Wright S (2017) Cannabidiol does not convert to Δ9-tetrahydrocannabinol in an in vivo animal model, Cannabis and Cannabinoid Research 2:1, 282–287
6. Hložek, T., et al. Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. European Neuropsychopharmacology, Volume 27, Issue 12, December 2017, Pages 1223-1237
7. Federica Palazzoli, T., et al. Development of a simple and sensitive liquid chromatography triple quadrupole mass spectrometry (LC–MS/MS) method for the determination of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and its metabolites in rat whole blood after oral administration of a single high dose of CBD. Journal of Pharmaceutical and Biomedical Analysis, Volume 150, 20 February 2018, Pages 25–32
8. Zynerba Pharmaceuticals http://zynerba.com
9. GW Pharmaceuticals https://www.gwpharm.com