Hexahydrocannabinol: pharmacokinetics, systemic toxicity, and acute behavioral effects in Wistar rats.
Klára Šíchová, Barbara Mallarino, Lucie Janeckova, 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 DOI: 10.1093/ijnp/pyaf041 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male Wistar rats |
| Intervention | Hexahydrocannabinol (HHC) |
| Dose | 1, 5, and 10 mg/kg |
| Keywords | Acute toxicity Behavior Hexahydrocannabinol Pharmacokinetics Rat |
| Citations | 1 |
| Key findings | HHC crosses the blood-brain barrier, exhibits mild toxicity, and induces behavioral effects similar to tetrahydrocannabinol, including reduced movement, increased anxiety, and impaired sensory processing at 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.