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Effects of a single dose of psilocybin on behaviour, brain 5-HT2A receptor occupancy and gene expression in the pig

Lene Lundgaard Donovan, Jens Vilstrup Johansen, Nídia Fernandez Ros, Elham Jaberi, Kristían Línnet, Sys Stybe Johansen, Brice Ozenne, Shohreh Issazadeh‐navikas, Hanne D. Hansen, Gitte M. Knudsen

European Neuropsychopharmacology December 4, 2020 DOI: 10.1016/j.euroneuro.2020.11.013 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Translational animal study Peer reviewed
Population Awake female pigs
Intervention Psilocybin
Dose 0.08 mg/kg
Duration Acute injection, with gene expression measured at 1 day and 1 week post-injection
Topics Psilocybin Serotonin
Keywords Hallucinogen Pharmacology
Citations 45
Key points A single dose of psilocybin in pigs produced acute behavioral changes, 67% 5-HT2A receptor occupancy, and modest changes in gene expression in the prefrontal cortex, with most changes resolving within a week.

Abstract

Psilocybin has in some studies shown promise as treatment of major depressive disorder and psilocybin therapy was in 2019 twice designated as breakthrough therapy by the U.S. Food and Drug Administration (FDA). A very particular feature is that ingestion of just a single dose of psilocybin is associated with lasting changes in personality and mood. The underlying molecular mechanism behind its effect is, however, unknown. In a translational pig model, we here present the effects of a single dose of psilocybin on pig behaviour, receptor occupancy and gene expression in the brain. An acute i.v. injection of 0.08 mg/kg psilocybin to awake female pigs induced characteristic behavioural changes in terms of headshakes, scratching and rubbing, lasting around 20 min. A similar dose was associated with a cerebral 5-HT2A receptor occupancy of 67%, as determined by positron emission tomography, and plasma psilocin levels were comparable to what in humans is associated with an intense psychedelic experience. We found that 19 genes were differentially expressed in prefrontal cortex one day after psilocybin injection, and 3 genes after 1 week. Gene Set Enrichment Analysis demonstrated that multiple immunological pathways were regulated 1 week after psilocybin exposure. This provides a framework for future investigations of the lasting molecular mechanisms induced by a single dose of psilocybin. In the light of an ongoing debate as to whether psilocybin is a safe treatment for depression and other mental illnesses, it is reassuring that our data suggest that any effects on gene expression are very modest.

Comparable studies

Other preclinical and animal studies on serotonin, most cited first.

Study Year Design Participants
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice 2021 Observational cohort
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models 2023 Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study

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Psilocybin Serotonin Depression Psychedelic-assisted therapy