Cannabimimetic and discriminative stimulus effects of hexahydrocannabinols in mice

Abstract

BACKGROUND: 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.

AIMS: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.