HHC safety study shows potentially low-risk months after sale

Hexahydrocannabinol, also known as HHC, is an altered, semi-synthetic variant of THC isomers. Originally, HHC was put up for sale with limited knowledge of its effects on animals. Now, however, the company responsible for manufacturing Kilograms of HHC has finally unveiled the results of a preclinical safety study.

Sale before security for HHC

Not only was HHC launched before safety studies were completed. The cannabinoid initially hit the market without accredited laboratory testing. Shortly thereafter, these standards were published and it was revealed that the HHC product being marketed was a mixture of r- and s-epimers. (1)

There are many forms of hydrogenated cannabinoids, such as HHC acid and even fully synthetic variations of hydrogenated THCp. Because of this, it is crucial to know the purity and nature of each hydrogenated cannabinoid in the products being sold. A mix of r- and s-HHC epimers indicates that the product is hydrogenated delta-8 THC, likely derived from chemically converted CBD. (2)

Months ago, the company’s COO in Colorado, Kyle Ray, informed this author that ISO 17034 and 17025 certified Certificates of Analysis (COAs) would soon be followed by preclinical safety studies. The latter would be done in partnership with Charles River, Ray explained. The company has published on its Linkedin page the results of an in vitro preclinical study on HHC that was done in September last year.

The exam

The HHC study was preclinical, meaning it cannot suggest safety in humans, although it does provide some evidence of low risk in four specific categories. The hexahydrocannabinol manufactured by the company has been tested for mutagenicity, cardiac safety, cytotoxicity and liver damage. (1)

Mutagens cause cancer

An Ames test was used to test a (r/s) hexahydrocannabinol mixture. The test determines whether a substance works respectfully against a mutation in bacterial strains such as Salmonella and E. Coli. Controls were also set to assess the role of metabolic activation.

At appropriate doses, HHC was not mutagenic. This result suggests that a mixture of hydrogenated THC isomers is unlikely to be carcinogenic. However, the study did not reveal the results of abnormally high doses of HHC in the Ames test.

Cardiac safety with HHC

For example, molecules of potassium, calcium, and sodium ions move through channels in your body. This movement of ions induces signals through nerves, among numerous other biological tasks and functions. THC is known for intoxicating effects by activating CB1 receptors and inhibiting calcium currents in the central nervous system—but it also activates potassium ions. (3-5) However, a later study found a secondary propensity for inhibition of potassium currents by CB1 receptor agonists. (6)

CB1 agonists down-regulate calcium and up-regulate potassium ions. (Butler and Korbonits).

While the biological mechanisms of HHC remain unknown, it is possible to deduce cardiovascular risks. In addition, many drugs fail by causing cardiac arrhythmias via inhibition of potassium ions. However, according to one of the few preclinical safety studies now available, HHC failed to inhibit a critical potassium channel. If you don’t, that’s good news as it poses potential cardiovascular risk as a potential side effect. (1)

Cytotoxicity, Liver Damage and Where It Started

At lower concentrations, HHC was cytotoxic to connective tissue in the lungs. However, liver damage was of minor importance for the hydrogenated cannabinoid. This leads to preliminary evidence that orally ingested HHC is not toxic. (1) However, studies on the deeper endocrine system are still lacking.

dr Mark Scialdone shared the study and its conclusions on social media. Scialdone holds an active key patent for hydrogenated cannabinoids. (2) Professor Roger Adams originally invented hydrogenated cannabinoids in the late 1940s. (7) HHC reduced tumors in rodents as efficiently, if not better than regular cannabinoids, according to Scialdone’s second patent in 2018. (8th)

Let us know in the comments what you think about HHC sales ahead of pre-clinical safety studies? Should observational studies be conducted before preclinical evaluations of semi-synthetic compounds?

Show your work

• The effect that HHC epimers have on each cannabinoid receptor needs to be evaluated. (1, 2, 8)
• THC also activates a third receptor, GPR55, that inhibits specific potassium currents. (9)
• It is not known whether HHC, like THC, is chlorogenic.

Sources

1. Colorado Chromatography Laboratories. 2022. Summary of the in vitro non-clinical safety assessment of hemp-derived (R/S)-hexahydrocannabinol ((R/S)-HHC). CO
2. Scialdone. 2017. US9694040B2 2 B. Scialdone. 2017. US10071127B2
3. Butler, Helen & Korbonits, Marta. (2009). Cannabinoids for Clinicians: The Rise and Fall of 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 inward rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptors. The Journal of Neuroscience: the official journal of the Society for Neuroscience, 15(10), 6552-6561.
5. Moss, R., Sachse, FB, Moreno-Galindo, EG, Navarro-Polanco, RA, 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 SD, Griffin G, Satin LS & Abood ME (1999). Cannabinoid receptors can activate and inhibit G protein-coupled inward rectifying potassium channels in a Xenopus oocyte expression system. The Journal of Pharmacology and Experimental Therapeutics, 291(2), 618-626.
7. adams 1942. U.S. 2,419,936
8. Thapa D, Lee JS, Heo SW, Lee YR, Kang KW, Kwak MK, Choi HG, & Kim JA (2011). Novel hexahydrocannabinol analogues as potential anticancer agents inhibit cell proliferation and tumor angiogenesis. European Journal of Pharmacology, 650(1), 64-71.
9. McAllister SD, Griffin G, Satin LS & Abood ME (1999). Cannabinoid receptors can activate and inhibit G protein-coupled inward rectifying potassium channels in a Xenopus oocyte expression system. The Journal of Pharmacology and Experimental Therapeutics, 291(2), 618-626.
10. Lauckner JE, Jensen JB, Chen HY, Lu HC, 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.