The Journal of neuroscience : the official journal of the Society for Neuroscience
November 8, 2023
Lindsay P Cameron, Joseph Benetatos, Vern Lewis et al.
88 citations
Serotonergic psychedelics like psilocybin and LSD activate serotonin 5-HT2A receptors in cortical brain regions, altering perception, cognition, and emotions. Their ability to promote neuroplasticity—forming new neural connections and rewiring networks—is thought to underlie therapeutic potential for depression, anxiety, and substance use disorders. These compounds also interact with other serotonin receptor subtypes (5-HT1A, 5-HT2C) and neurotrophin receptors, adding complexity to their effects. Research is exploring nonhallucinogenic derivatives that retain therapeutic benefits without intense psychedelic experiences, potentially reducing adverse reactions. The review also discusses psychedelics as substrates for post-translational protein modification as part of their mechanism.
Molecular psychiatry
September 1, 2023
Kat F Kiilerich, Joe Lorenz, Malthe B Scharff et al.
48 citations
Repeated low doses of psilocybin, similar to human microdosing, were tested in rats. The regimen was well tolerated, causing no signs of anhedonia, anxiety, or altered movement, and did not downregulate or desensitize 5-HT2A receptors. The treatment increased resilience to injection stress, reduced self-grooming (a proxy for compulsive actions), and raised 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
Molecules
April 22, 2021
Paul Cumming, Milan Scheidegger, Dario Dornbierer et al.
45 citations
Hallucinogens such as LSD, psilocybin, and mescaline are being re-evaluated for their psychotherapeutic potential. This narrative review covers in vitro and ex vivo binding studies and molecular imaging using PET or SPECT. Early PET work with [11C]-MBL showed that most specific binding is to serotonin 5-HT2A receptors, but interactions with 5-HT1A receptors and other pathways may contribute to the unique experiences. Other important factors include blood-brain barrier permeability, metabolism, and active metabolites. Only a few PET or SPECT studies of radiolabeled hallucinogens exist, most recently using [11C]Cimbi-36. Hybrid imaging combining PET with fMRI is expected to advance future research.
Frontiers in pharmacology
January 1, 2023
Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen et al.
17 citations
Co-administration of harmine with DMT in rats increased brain DMT levels by inhibiting its metabolism to indole-3-acetic acid, yet no significant occupancy of serotonin 5-HT2A receptors by DMT was detected, even at brain DMT concentrations up to 11.3 µM. Low doses of DMT and/or harmine did not significantly alter brain glucose metabolism as measured by [18F]FDG-PET. These preliminary findings suggest that the role of MAO-A inhibition in potentiating DMT's psychedelic effects may be more complex than previously assumed, and further dose-response studies are needed.
January 5, 2023
Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff et al.
5 citations
preprint
Repeated low doses of psilocybin, a serotonergic psychedelic drug, were given to rats in a regimen that mimics human microdosing. The rats tolerated the doses well, showing no signs of anhedonia, anxiety, or altered movement. The treatment did not downregulate or desensitize the 5-HT2A receptor. It did impart resilience against stress from repeated injections and reduced self-grooming frequency, a proxy for compulsive actions. Additionally, it increased 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
Psychedelic Medicine
February 3, 2026
Anton T. Gregersen, Tobias Whelan, Caroline T. Golden et al.
2 citations
Psilocybin, a serotonergic psychedelic, impaired short-term learning and unlearning speeds in rats performing a three-choice visual reversal learning task, though exploratory analysis suggested possible long-term enhancements in learning dynamics. Only five of sixteen Long-Evans rats (31%) successfully completed all six reversal protocols, demonstrating significant learning and unlearning over time. Computational modeling showed low learning rates with no significant differences between psilocybin and placebo conditions on any parameters. The findings indicate a nuanced effect of psilocybin on cognitive flexibility, with potential relevance for its use in neuropsychiatric disorders, but further research is needed on long-term outcomes.
Frontiers in psychiatry
January 1, 2026
Sivert Drange, Jacob Cohen, Sys Stybe Johansen et al.
1 citation
In identical twins discordant for obsessive-compulsive disorder, the affected twin self-administered low doses of psilocybin (1–5 mg every third day) while the unaffected twin did not. The affected twin reported notable reductions in OCD symptoms, improved emotional regulation, and better well-being. However, cognitive flexibility, measured with a set-shift task, remained impaired compared to the unaffected twin. Low-dose psilocybin may alleviate some OCD symptoms but does not fully address underlying cognitive deficits.
December 30, 2024
Sivert Drange, Jacob Cohen, Sys Stybe Johansen et al.
1 citation
preprint
In a pair of identical twins where one had obsessive-compulsive disorder and the other did not, the affected twin self-administered low, non-psychedelic doses of psilocybin. After the regimen, the affected twin reported a notable reduction in OCD symptoms, improved emotional regulation, and greater well-being. However, cognitive flexibility deficits—the ability to shift thinking—remained compared to the unaffected twin. This suggests that microdosing psilocybin may help relieve some OCD symptoms but does not fully address underlying cognitive impairments. Larger, longer studies are needed to understand how these low doses work and their potential as a treatment.
May 28, 2024
Frederik Gudmundsen, Julia Czurylo, Camilla Trang Vo et al.
1 citation
preprint
Three serotonergic psychedelics—psilocybin, LSD, and 2C-B—produce distinct acute and long-term changes in rat brain metabolic activity and connectivity. Psilocybin uniquely alters connectivity between cortical regions including the orbitofrontal, medial prefrontal, and insula cortex, as well as with the dorsal striatum, thalamus, and hippocampus. LSD and 2C-B share more similar effects, centered on acute inhibition of the anterior cingulate cortex, increased activity and connectivity between the amygdala and hypothalamus, and heightened activity in dopamine-rich regions of the ventral tegmental area and substantia nigra. These distinct neural patterns may guide which psychedelic drug could be most beneficial for specific neuropsychiatric disorders.
Open Access CRIS of the University of Bern
February 9, 2026
Mikael Palner, Elisabeth Kolesnik, Christina Baun et al.
The mammalian brain may contain an endogenous pool of the psychedelic N,N-dimethyltryptamine (DMT), possibly acting as a co-transmitter with serotonin. In rats, inhibiting monoamine oxidase with pargyline did not make endogenous DMT detectable, while probenecid slightly elevated the acidic metabolite 3-indoleacetic acid (3-IAA), suggesting formation from tryptamine, especially in the striatum. After administering DMT plus harmine, peak brain DMT occurred at 45 minutes and peak 3-IAA at 60 minutes, with nearly complete washout by 210 minutes. Escitalopram did not alter exogenous DMT or 3-IAA disposition, and dihydrotetrabenazine slightly increased 3-IAA in some regions. The results do not support an endogenous DMT pool or retention of exogenous DMT in serotonin terminals.
Neuropharmacology
February 9, 2026
Mikael Palner, Elisabeth Kolesnik, Christina Baun et al.
The study tested whether the psychedelic compound N,N-dimethyltryptamine (DMT) exists naturally in the mammalian brain and acts as a co-transmitter with serotonin. In rats, blocking monoamine oxidase with pargyline did not allow detection of endogenous DMT, while blocking acidic metabolite transport with probenecid slightly elevated the DMT metabolite 3-indoleacetic acid, likely from tryptamine. Exogenous DMT was rapidly taken up and cleared from the brain, with peak concentrations at 45 minutes and near-complete washout by 210 minutes. Blocking serotonin reuptake or vesicular monoamine transporters did not alter DMT levels. The results do not support the hypothesis that DMT is an endogenous co-transmitter with serotonin.
February 27, 2025
Anton T. Gregersen, Tobias P. Whelan, Caroline T. Golden et al.
preprint
In a visual reversal learning task with rats, psilocybin temporarily impaired the speed of learning and unlearning, but exploratory analyses suggested possible long-term improvements in learning dynamics. Five out of sixteen rats completed all six reversal protocols, showing significant decreases in sessions needed to meet learning criteria and in reaction time over successive reversals. Computational modeling revealed low learning rates overall, with no significant differences between psilocybin and placebo on any modeled parameter. The findings indicate a nuanced, time-dependent effect of psilocybin on cognitive flexibility, with short-term impairment and hints of later enhancement, warranting further study of long-term outcomes.