Cannabimimetic and discriminative stimulus effects of hexahydrocannabinols in mice

Hexahydrocannabinol (HHC) recently appeared on the recreational drug market and is often sold as a legal replacement for Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Users primarily consume HHC for recreational purposes, but adverse effects have been reported. Given the scant literature on HHC, additional research is needed to better understand its effects.

The present study sought to determine whether 9(R)-hexahydrocannabinol [9(R)-HHC] and 9(S)-hexahydrocannabinol [9(S)-HHC] are psychoactive cannabinoids that share behavioral effects with Δ⁹-THC.

Adult male mice were administered 9(R)-HHC, 9(S)-HHC, or Δ⁹-THC and tested in the tetrad battery to examine cannabimimetic effects (i.e., locomotor suppression, antinociception, hypothermia, and catalepsy). Separate mice were trained to discriminate Δ⁹-THC from the vehicle in drug discrimination and subsequently tested with 9(R)-HHC and 9(S)-HHC.

Δ⁹-THC and 9(R)-HHC produced cannabimimetic effects in all tetrad measures, and 9(R)-HHC fully substituted for Δ⁹-THC in drug discrimination. Δ⁹-THC and 9(R)-HHC showed similar potency across measures, except that 9(R)-HHC produced more hypothermia than Δ⁹-THC. By contrast, 9(S)-HHC only produced cannabimimetic effects in two tetrad measures, was less potent than Δ⁹-THC, and only partially substituted for Δ⁹-THC in drug discrimination.

9(R)-HHC is likely to possess abuse liability in humans, whereas 9(S)-HHC may produce weak Δ⁹-THC-like psychoactivity in humans. The differences in the pharmacology between the two HHC epimers may lead to a range of effects in human users depending on the ratio of the epimers consumed.