Cannabis alternative 9(R)-HHC may be as potent as THC, study in mice suggests

A new study published in the Journal of Psychopharmacology shows that a specific type of hexahydrocannabinol, known as 9(R)-HHC, produces behavioral and psychoactive effects in mice that closely resemble those of delta-9-tetrahydrocannabinol—the main psychoactive component in cannabis. The researchers also found that another form, 9(S)-HHC, produces far weaker effects, suggesting that different types of HHC may have very different effects on users.

Hexahydrocannabinol, or HHC, is a synthetic cannabinoid that has appeared in recent years in hemp-derived products sold online and in stores. It is often marketed as a legal alternative to marijuana, especially in regions where cannabis remains illegal. While tetrahydrocannabinol, or THC, has been extensively studied and is regulated in many places, far less is known about HHC—including its effects on the brain, its potential for abuse, or its safety in humans.

HHC is not a single compound but a group of related molecules. Two common forms, or epimers, of HHC are 9(R)-HHC and 9(S)-HHC. These epimers are mirror-image versions of each other, meaning they have the same atoms but are arranged differently in space. This subtle difference in structure can lead to very different effects in the body. The goal of the study was to determine whether each of these two forms of HHC produces the same kinds of behavioral effects seen with THC.

To find out, researchers from RTI International and the U.S. Drug Enforcement Administration conducted a series of behavioral experiments in male mice. One set of experiments used what is known as the cannabinoid tetrad test, a method that measures four classic effects of cannabinoids in rodents: reduced movement, decreased sensitivity to pain, lowered body temperature, and catalepsy, which is a type of rigid immobility. These effects are considered indicators that a compound is activating cannabinoid receptors in the brain.

Another set of experiments tested whether the mice could recognize the effects of the different compounds. In this part of the study, mice were trained to distinguish between injections of THC and injections of a neutral solution. The animals learned to nose-poke in different areas of a test chamber depending on which compound they had received. Once the mice had learned this discrimination, the researchers tested whether they would respond to the HHC compounds as if they were THC. If they did, it would suggest the animals perceived HHC as producing similar psychoactive effects.

In the tetrad tests, both THC and 9(R)-HHC produced strong and consistent effects across all four measures. Mice that received either compound moved less, showed reduced sensitivity to pain, had lower body temperatures, and spent more time in a rigid posture. These results suggest that 9(R)-HHC engages cannabinoid receptors in the brain in a manner similar to THC.

In contrast, 9(S)-HHC produced only two of the four effects. It lowered body temperature and increased immobility, but did not reliably reduce movement or block pain. It also required higher doses to produce any effects at all, indicating it was much less potent than either THC or 9(R)-HHC.

The drug discrimination experiments told a similar story. Mice trained to recognize THC responded to 9(R)-HHC as if it were the same drug, but only at moderate to high doses. This suggests that 9(R)-HHC has similar psychoactive properties and could potentially be misused in the same way as THC. The 9(S)-HHC compound, by contrast, only partially substituted for THC, and only at high doses. Even then, the mice showed decreased motivation and signs of toxicity, including lethargy and significant drops in response rate.

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The results suggest that 9(R)-HHC has a high potential to mimic the psychoactive and behavioral effects of THC in humans, while 9(S)-HHC may be less likely to do so—unless taken in large amounts. Notably, the mice given very high doses of 9(R)-HHC sometimes experienced seizures, tremors, and muscle stiffness, and half of the animals exposed to the highest dose died several days after testing. Although the exact cause of death is unknown, the researchers noted that delayed lethality is unusual in cannabinoid studies.

The study also highlights how differences in chemical structure can lead to large differences in how a compound behaves in the brain. While 9(R)-HHC and 9(S)-HHC are nearly identical in terms of their atomic composition, only the 9(R) version showed clear signs of psychoactivity across all tests. This suggests that the ratio of these epimers in consumer HHC products could have a strong impact on how those products affect users. Prior analyses of commercial products have found wide variation in this ratio, ranging from less than one part 9(R)-HHC for every five parts 9(S)-HHC, to more than two parts 9(R) for every one part 9(S).

Although the study was conducted in mice, the findings raise important questions about the use and regulation of HHC products in humans. Since 9(R)-HHC behaves much like THC, it may have similar risks—including the potential for abuse, negative cognitive or psychiatric effects, and physical side effects such as hypothermia and lethargy. The authors note that additional studies are needed to evaluate these risks in humans.

The researchers also point out several limitations. The experiments only included male mice, so it is unknown whether female animals or humans would show the same responses. The study did not assess whether the compounds produce tolerance or withdrawal symptoms with repeated use, although early surveys suggest that HHC products may trigger more withdrawal symptoms than THC. The findings also cannot speak to long-term safety, as only single doses were used.

Future research will need to explore the effects of repeated exposure, possible dependence, sex differences, and other health risks related to HHC use. Studies in humans will also be needed to determine whether the psychoactive effects observed in mice translate to the human experience.

The study, “Cannabimimetic and discriminative stimulus effects of hexahydrocannabinols in mice,” Julie A. Marusich, Cassandra Prioleau, and Luli R. Akinfiresoye.