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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:[email protected]

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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.
29 Sep 2024Submitted to British Journal of Pharmacology
02 Oct 2024Submission Checks Completed
02 Oct 2024Assigned to Editor
02 Oct 2024Review(s) Completed, Editorial Evaluation Pending
07 Oct 2024Reviewer(s) Assigned