Hexahydrocannabinol: pharmacokinetics, systemic toxicity, and acute behavioral effects in Wistar rats.
Klára Šíchová, Barbara Mallarino, Lucie Janečková, Petr Palivec, Magdaléna Vágnerová, Čestmír Vejmola, Marek Nikolič, Lucie Ladislavová, Kristýna Mazochová, Pavel Ryšánek, Martin Šíma, Adam Šafanda, Bui Quang Hiep, Isis Rita Anzel Koutrouli, Martin Kuchař, Tomáš Páleníček
The international journal of neuropsychopharmacology August 1, 2025 Peer reviewed DOI: 10.1093/ijnp/pyaf041 via PubMed
Summary
Hexahydrocannabinol (HHC) exhibits mild toxicity and alters behavior in male Wistar rats. When administered at a dose of 10 mg/kg, HHC reduced movement, increased anxiety, and impaired sensory processing compared to controls. HHC was found to cross the blood-brain barrier, with peak concentrations observed two hours after administration. The toxicity test classified HHC as a Category 4 substance, with an estimated lethal dose of 1000 mg/kg, indicating the need for careful dosing in potential therapeutic applications.
Study at a glance
| Population | male Wistar rats |
|---|---|
| Key finding | HHC reduces movement, increases anxiety, and impairs sensory processing in male Wistar rats at a dose of 10 mg/kg. |
Abstract
Hexahydrocannabinol (HHC) is a new psychoactive substance known for its mind-altering effects and temporary legal status. It is widely used in parts of the Europe and United Kingdom as a legal alternative to ∆9-tetrahydrocannabinol, yet little research has explored its effects and safety. This study examined how HHC is processed in the body, its toxicity, and its impact on behavior in male Wistar rats. A 1:1 mixture of (9R)-HHC and (9S)-HHC was administered via intragastric gavage at doses of 1, 5, and 10 mg/kg. Behavioral effects were assessed using the open field test and the prepulse inhibition of acoustic startle response. Two hours after the highest dose (10 mg/kg), peak concentrations of HHC were detected in blood and brain tissue. The Organization for Economic Co-operation and Development 423 toxicity test classified HHC as a Category 4 substance, estimating a lethal dose of 1000 mg/kg. Compared to controls (administered by sunflower oil), 10 mg/kg HHC reduced movement, increased anxiety, and impaired sensory processing. Overall, HHC crosses the blood-brain barrier, exhibits mild toxicity, and induces behavioral effects similar to tetrahydrocannabinol. Its dose-dependent anxiogenic properties and impact on information processing highlight the importance of the appropriate dosing in any potential therapeutic use.