HHC preclinical safety study reveals results months into sales

Hexahydrocannabinol, also known as HHC, is an altered, semi-synthetic variation of THC isomers. Initially, HHC went up for sale with limited knowledge of its effects on animals. Now, however, the company responsible for producing kilograms of HHC finally revealed the results of a preclinical safety study.

Sales before safety for HHC

Not only was HHC put to market before finalizing any safety studies. The cannabinoid initially hit markets without accredited lab tests. Shortly thereafter, those standards were released and it was revealed the HHC product put to market was a mix of r and s epimers. (1)

Many forms of hydrogenated cannabinoids exist, such as HHC-acid and even fully synthetic variations of hydrogenated THCp. For this reason, it is crucial to know the purity and type of each hydrogenated cannabinoid in the products sold. A mixture of r and s HHC epimers indicates the product is hydrogenated delta-8 THC, likely derived from chemically converted CBD. (2)

Months ago, the COO of the Colorado outfit, Kyle Ray, told this author that ISO 17034 and 17025 certified Certificates of Analysis (COAs) would soon be followed up with preclinical safety studies. The latter work would be done in collaboration with Charles River, explained Ray. Delivering on the promises made back in September of last year, the company released results from a preclinical, in vitro study of HHC on their Linkedin page. 

The test

The study on HHC was preclinical which means it cannot suggest safety in humans, although it provides some evidence for low risk in four specific categories. Hexahydrocannabinol produced by the company was tested for mutagenicity, heart safety, cytotoxicity, and liver damage. (1)

Mutagens are cancer causers

An Ames test was used to study an (r/s) hexahydrocannabinol mixture. The test determines if a substance acts as reverent against a mutation in strains of bacteria such as Salmonella and E. Coli. Controls were also set to assess the role of metabolic activation.

At reasonable doses, HHC was not mutagenic. This result suggests that a mix of hydrogenated THC isomers is likely not carcinogenic. The study, however, did not reveal the results of exceptionally large doses of HHC on the Ames test.

Heart safety with HHC

Molecules of potassium, calcium, and sodium ions, for example, move through channels in your body. This movement of ions induces signals through nerves alongside numerous other biological tasks and functions. THC is known to be intoxicating by activating CB1 receptors and inhibiting calcium currents in the central nervous system — but it also activates potassium ions. (3-5) A later study, however, noted a second bias toward the inhibition of potassium currents by CB1 receptor agonists. (6)

While HHC’s biological mechanisms remain unknown, its viable to deduce any cardiovascular risks. Moreover, many drugs fail by causing cardiac arrhythmias via potassium ion inhibition. According to one of the few preclinical safety studies now available, though, HHC failed to inhibit one critical potassium channel. Failure to do so is good news since it strikes one potential cardiovascular risk as a potential side effect. (1)

Cytotoxicity, liver damage, and where it began

HHC was cytotoxic to connective tissues in the lungs at lower concentrations. Liver damage, however, was a low concern for the hydrogenated cannabinoid. This leads to preliminary evidence that orally ingested HHC is non-toxic. (1) Although, studies on the deeper endocrine system are still lacking.

Dr. Mark Scialdone shared the study and its conclusion on social media. An active key patent on hydrogenated cannabinoids is held by Scialdone. (2) Initially, Professor Roger Adams invented hydrogenated cannabinoids in the late 1940s. (7) Tumours in rodents, following Scialdone’s second patent from 2018, were reduced by HHC as efficiently, if not better than regular cannabinoids. (8)

Let us know in the comments what you think about HHC sales before preclinical safety studies? Should observational trials be performed before pre-clinical assessments on semi-synthetic compounds?

Show your work

• The effect that HHC epimers have on any cannabinoid receptor requires evaluation. (1, 2, 8)
• THC also activates a third receptor, GPR55 which inhibits specific potassium currents. (9)
• It is not known if HHC is chlorogenic like THC.

Sources

1. Colorado Chromatography Labs. 2022. Nonclinical In Vitro Safety Assesment Summary Of Hemp Derived (R/S)-hexahydrocannabinol ((R/S)-HHC). CO.
2. Scialdone. 2017. US9694040B2 2b. Scialdone. 2017. US10071127B2
3. Butler, Helen & Korbonits, Marta. (2009). Cannabinoids for clinicians: The rise and fall of the cannabinoid antagonists. European journal of endocrinology / European Federation of Endocrine Societies. 161. 655-62. 10.1530/EJE-09-0511.
4. Mackie, K., Lai, Y., Westenbroek, R., & Mitchell, R. (1995). Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience, 15(10), 6552–6561.
5. Moss, R., Sachse, F. B., Moreno-Galindo, E. G., Navarro-Polanco, R. A., Tristani-Firouzi, M., & Seemann, G. (2018). Modeling effects of voltage dependent properties of the cardiac muscarinic receptor on human sinus node function. PLoS computational biology, 14(10), e1006438.
6. McAllister, S. D., Griffin, G., Satin, L. S., & Abood, M. E. (1999). Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a xenopus oocyte expression system. The Journal of pharmacology and experimental therapeutics, 291(2), 618–626.
7. Adams. 1942. US 2,419,936
8. Thapa, D., Lee, J. S., Heo, S. W., Lee, Y. R., Kang, K. W., Kwak, M. K., Choi, H. G., & Kim, J. A. (2011). Novel hexahydrocannabinol analogs as potential anti-cancer agents inhibit cell proliferation and tumor angiogenesis. European journal of pharmacology, 650(1), 64–71.
9. McAllister, S. D., Griffin, G., Satin, L. S., & Abood, M. E. (1999). Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a xenopus oocyte expression system. The Journal of pharmacology and experimental therapeutics, 291(2), 618–626.
10. Lauckner, J. E., Jensen, J. B., Chen, H. Y., Lu, H. C., Hille, B., & Mackie, K. (2008). GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proceedings of the National Academy of Sciences of the United States of America, 105(7), 2699–2704.