Hexahydrocannabinol (HHC): pharmacokinetics, systemic toxicity, and
acute behavioural effects in Wistar rats.
Abstract
Background and purpose: Hexahydrocannabinol (HHC) is a novel
psychoactive substance that has gained attention due to its psychotropic
effects and temporary legal status. It is widely abused in several EU
and US countries, where it serves as a legal and easily accessible
alternative to ∆9-tetrahydrocannabinol
(∆9-THC). Despite its widespread use, few studies have
examined its in vivo effects and safety profile.
Experimental approach: This study investigated the
pharmacokinetics, systemic toxicity, and acute behavioural effects of
HHC in male Wistar rats. A mixture of (9R)-HHC and
(9S)-HHC epimers (in a 1:1 ratio) was administered via
intragastric gavage at doses of 1, 5, and 10 mg/kg. Behavioural effects
were assessed using the Open field test and the Prepulse inhibition of
acoustic startle response. Key results: Two hours after 10
mg/kg administration, concentrations of both HHC epimers peaked in blood
serum and brain tissue. According to the OECD 423 toxicity test, HHC was
classified as a Category 4 substance, with an estimated lethal dose of
1000 mg/kg. Compared to the control group (administered sunflower oil),
the highest dose (10 mg/kg) led to reduced locomotor activity, increased
anxiety, and impaired sensorimotor gating. Conclusions &
Implications: HHC readily crosses the blood-brain barrier, exhibits
mild toxicity, and produces behavioural effects similar to THC-like
cannabinoids.