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Hexahydrocannabinol (HHC): pharmacokinetics, systemic toxicity, and acute behavioural effects in Wistar rats.
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  • Klára Šíchová,
  • Barbara Mallarino,
  • Lucie Janečková,
  • Petr Palivec,
  • Magdaléna Vágnerová,
  • Čestmír Vejmola,
  • Marek Nikolič,
  • Lucie Olejníková-Ladislavová,
  • Kristýna Mazochová,
  • Pavel Ryšánek,
  • Martin Šíma,
  • Adam Šafanda,
  • Quang Hiep Bui,
  • Isis Koutrouli,
  • Martin Kuchař,
  • Tomáš Páleníček
Klára Šíchová
Psychedelic Research Centre, National Institute of Mental Health

Corresponding Author:klara.sichova@nudz.cz

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Barbara Mallarino
Psychedelic Research Centre, National Institute of Mental Health
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Lucie Janečková
Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague
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Petr Palivec
Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague
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Magdaléna Vágnerová
Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague
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Čestmír Vejmola
Psychedelic Research Centre, National Institute of Mental Health
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Marek Nikolič
Psychedelic Research Centre, National Institute of Mental Health
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Lucie Olejníková-Ladislavová
Psychedelic Research Centre, National Institute of Mental Health
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Kristýna Mazochová
Psychedelic Research Centre, National Institute of Mental Health
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Pavel Ryšánek
Institute of Pharmacology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague
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Martin Šíma
Institute of Pharmacology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague
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Adam Šafanda
Institute of Pathology, 1st Faculty of Medicine, Charles University
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Quang Hiep Bui
Institute of Pathology, 1st Faculty of Medicine, Charles University
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Isis Koutrouli
Psychedelic Research Centre, National Institute of Mental Health
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Martin Kuchař
Psychedelic Research Centre, National Institute of Mental Health
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Tomáš Páleníček
Psychedelic Research Centre, National Institute of Mental Health
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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.