Hexahydrocannabinol (HHC): pharmacokinetics, systemic toxicity, and acute behavioural effects in Wistar rats.
Klára Šíchová, Barbara Mallarino, Lucie Janeckova, Petr Palivec, Magdaléna Vágnerová, Čestmír Vejmola, M. Nikolič, Lucie Olejníková, Kristýna Mazochová, Pavel Ryšánek, Martin Šíma, Adam Šafanda, Quang Hiep Bui, Isis Koutrouli, Martin Kuchař, Tomáš Páleníček
October 2, 2024 DOI: 10.22541/au.172786658.80817958/v1 via OpenAlex
Summary
Hexahydrocannabinol (HHC), a psychoactive cannabinoid used as a legal alternative to THC, readily crosses the blood-brain barrier in male Wistar rats. After oral administration, both HHC epimers peaked in blood and brain tissue at two hours. The estimated lethal dose was 1000 mg/kg, classifying HHC as a Category 4 substance with mild toxicity. At the highest dose (10 mg/kg), HHC reduced locomotor activity, increased anxiety, and impaired sensorimotor gating, producing behavioral effects similar to THC-like cannabinoids.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Male Wistar rats |
| Dose | 1, 5, and 10 mg/kg |
| Keywords | Pharmacokinetics Toxicity Pharmacology Internal medicine |
| Key finding | HHC readily crosses the blood-brain barrier, exhibits mild toxicity, and produces behavioral effects similar to THC-like cannabinoids. |
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 (9 R )-HHC and (9 S )-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.