International Journal of Molecular Sciences
November 16, 2022
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz et al.
60 citations
Psilocybin and the serotonin precursor 5-HTP produce a characteristic head twitch response in mice, which is linked to the human psychedelic experience. This response depends primarily on the 5-HT2A receptor, as blocking it with M100907 reduced twitching. Activating the 5-HT1A receptor with 8-OH-DPAT also suppressed the response, while blocking the 5-HT2C receptor with RS-102221 had a bimodal effect—enhancing twitching at lower doses but reducing it at higher doses. Blocking the trace amine-associated receptor 1 (TAAR1) with EPPTB reduced 5-HTP-induced twitching but not psilocybin-induced twitching. These findings highlight multiple receptor systems that could modulate psychedelic effects and may inform therapeutic applications.
Translational psychiatry
May 10, 2023
Sandeep Singh, Alexander Botvinnik, Orr Shahar et al.
54 citations
Psilocybin reduced marble burying in mice, a behavior used to model obsessive-compulsive disorder, but this effect did not depend on the serotonin 2A or serotonin 1A receptors typically associated with psychedelic effects. The 5-HT1A agonist 8-OH-DPAT also reduced marble burying, and its effect was additive with psilocybin, while the 5-HT1A partial agonist buspirone reduced marble burying without adding to psilocybin's effect. Blocking 5-HT1A receptors with WAY100635 did not attenuate psilocybin's effect. A staggered psilocybin regimen over 3.5 hours had no effect, and the effect of a single injection was not persistent. Co-administration of buspirone blocked psilocybin's head twitch response, a rodent correlate of psychedelic effects, suggesting buspirone might block psychedelic effects without impairing anti-obsessional effects.
Molecular psychiatry
July 1, 2024
Orr Shahar, Alexander Botvinnik, Amit Shwartz et al.
37 citations
Psilocybin-containing mushroom extract (PME) may have stronger and longer-lasting effects on synaptic plasticity than chemically synthesized psilocybin (PSIL) alone. In male mice, both PME and PSIL increased synaptic proteins GAP43 and synaptophysin in brain regions linked to learning and memory, but PME increased more proteins across more brain areas after 11 days. Metabolomic analysis of the frontal cortex revealed a distinct metabolic profile for PME, with a progressive decline in purines associated with oxidative stress from vehicle to PSIL to PME. These findings suggest that other compounds in the mushroom extract contribute to enhanced neuroplasticity, though further research is needed to identify them.
Molecular Psychiatry
October 11, 2024
Michal Brownstien, Michal Lazar, Alexander Botvinnik et al.
23 citations
In mice lacking the SAPAP3 gene, which display excessive self-grooming and anxiety similar to human obsessive-compulsive disorder, a single injection of psilocybin or psychedelic mushroom extract reduced self-grooming by about 15-19% over 21 days, while vehicle-treated mice showed a 119% increase. The effects lasted up to 7 weeks in responsive mice, and non-responsive mice later treated with psilocybin also improved. The mushroom extract was superior for reducing head-body twitches and anxiety. These results support clinical trials of psilocybin for OCD.
Frontiers in Pharmacology
April 18, 2024
Elad Lerer, Alexander Botvinnik, Orr Shahar et al.
14 citations
Psilocybin and a psilocybin-containing mushroom extract, but not the serotonin precursor 5-hydroxytryptophan, increased expression of immediate early genes cfos and egr1 in the somatosensory cortex of male mice. The head twitch response, a behavioral measure, did not correlate with gene expression changes. Blocking the 5-HT2C receptor enhanced psilocybin-induced egr2 expression, but other serotonergic modulators had no effect. These findings suggest that cfos and egr1 expression may be linked to psychedelic effects.
bioRxiv (Cold Spring Harbor Laboratory)
June 29, 2024
Michal Brownstien, Michal Lazar, Alexander Botvinnik et al.
5 citations
preprint
In mice with a genetic deletion that causes excessive self-grooming and anxiety—behaviors resembling aspects of obsessive-compulsive disorder (OCD)—a single dose of psilocybin or psychedelic mushroom extract reduced self-grooming over 21 days, while vehicle-treated mice showed a 118.7% increase. Psilocybin and the extract both decreased self-grooming by about 15–19%, and improvements in secondary measures like twitches and anxiety were also significant. In responsive mice, benefits lasted up to 7 weeks. The extract was superior for alleviating head-body twitches and anxiety. These results support clinical trials of psilocybin for OCD.
bioRxiv (Cold Spring Harbor Laboratory)
July 23, 2022
Orr Shahar, Alexander Botvinnik, Noam Esh-Zuntz et al.
5 citations
preprint
Psilocybin and the serotonin precursor 5-HTP both cause a characteristic head twitch response in mice, a behavior linked to the human psychedelic experience. The head twitch response depends primarily on the 5-HT2A receptor, as blocking this receptor with volanserin reduced the response. Activating the 5-HT1A receptor also reduced head twitching. In contrast, blocking the 5-HT2C receptor had a bimodal effect, enhancing the response at lower doses but reducing it at higher doses. Blocking the trace amine associated receptor 1 (TAAR1) reduced head twitching caused by 5-HTP but not by psilocybin, indicating a differential role for this receptor. These findings identify multiple receptors that could be targeted to modulate the effects of psychedelic compounds in therapeutic settings.
The International Journal of Neuropsychopharmacology
March 29, 2025
Michal Lazar, Michal Brownstien, Alexander Botvinnik et al.
3 citations
Mice lacking the SAPAP3 gene (SAPAP3-KO) develop excessive self-grooming at 4–6 months, modeling obsessive-compulsive disorder (OCD). Before that, juvenile (10–13 week) homozygous knockout mice showed anxiety-like behaviors—less time in open field centers and elevated plus maze open arms, fewer marbles buried, and fewer buried Oreos found—compared to wild-type mice. Psilocybin (4.4 mg/kg) did not improve these behaviors. In adult (but not juvenile) male homozygous knockout mice, levels of the synaptic proteins GAP43, synaptophysin, and SV2A increased across multiple brain regions; SV2A also increased in the frontal cortex of adult female homozygotes. These age-dependent protein changes may reflect compensatory plasticity linked to the OCD-like phenotype.
Research Square
July 20, 2023
Orr Shahar, Alexander Botvinnik, Amit Shwartz et al.
3 citations
Psilocybin-containing mushroom extract (PME) produces more potent and prolonged effects on synaptic plasticity in the mouse brain than chemically synthesized psilocybin alone. In male C57Bl/6j mice, both PME and psilocybin triggered similar head twitch responses, but PME increased four synaptic proteins (GAP43, PSD95, synaptophysin, SV2A) across all brain areas studied after 11 days, whereas psilocybin only increased two proteins in the hippocampus and amygdala. Metabolomic analysis of the prefrontal cortex showed a gradient of metabolic changes from vehicle to psilocybin to PME, with declines in purines linked to oxidative stress and energy production. The findings suggest that additional compounds in the mushroom extract may enhance psilocybin's effects on brain plasticity.
Translational Psychiatry
June 13, 2025
Tom Ben-Tal, Ilana Pogodin, Alexander Botvinnik et al.
2 citations
Combining the psychedelic psilocybin with the NMDAR modulators D-serine or D-cycloserine reduced hallucinogenic-like effects and enhanced antipsychotic-like effects in male mice, while also promoting neuroplasticity-related synaptic protein expression. Psilocybin alone increased head twitch response, a surrogate for hallucinogenic effects, which was dose-dependently lowered by either modulator. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic action. The psilocybin-D-serine combination increased GAP43 expression across four brain regions and overall synaptic protein levels in the hippocampus; psilocybin-D-cycloserine elevated PSD95 across all regions. These results suggest that pairing serotonergic psychedelics with NMDAR modulators may improve therapeutic potential by reducing adverse effects and enhancing neuroplasticity.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2022
Sandeep Singh, Alexander Botvinnik, Orr Shahar et al.
1 citation
preprint
In mice, psilocybin reduced marble-burying, a behavior linked to obsessive-compulsive disorder, as effectively as the antidepressant escitalopram. This effect was not blocked by a 5-HT2A antagonist or a 5-HT1A antagonist, indicating neither receptor is essential for psilocybin's anti-obsessional action. The 5-HT1A partial agonist buspirone also reduced marble-burying, but combining buspirone with psilocybin did not enhance the effect. Staggered doses of psilocybin over 3.5 hours had no effect, and the effect of a single injection was not persistent. Importantly, buspirone blocked psilocybin's head-twitch response, a rodent correlate of psychedelic effects, suggesting buspirone could prevent psychedelic effects without interfering with anti-obsessional benefits.
The International Journal of Neuropsychopharmacology
August 1, 2025
Bernard Lerer, T. Tal, Ilana Pogodin et al.
Combining psilocybin with NMDAR modulators D-serine or D-cycloserine may enhance therapeutic benefits while reducing adverse effects. In mice, psilocybin alone increased head twitch response, a proxy for hallucinogenic effects, but co-administration of D-serine or D-cycloserine reduced this response dose-dependently. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic effects, whereas psilocybin alone did not. Additionally, psilocybin with D-serine boosted GAP43 protein expression across four brain regions and overall synaptic protein levels in the hippocampus, while psilocybin with D-cycloserine elevated PSD95 levels across all regions. These results suggest that such combinations could optimize psilocybin's therapeutic potential by mitigating side effects and enhancing neuroplasticity.
The International Journal of Neuropsychopharmacology
August 1, 2025
Bernard Lerer, Michal Brownstien, Mitchell A. Lazar et al.
Psilocybin and a psychedelic mushroom extract reduced compulsive marble burying and excessive self-grooming in mouse models of obsessive-compulsive disorder (OCD). A single dose of psilocybin remained effective for more than 21 days in SAPAP3-knockout mice, which model OCD and Tourette's syndrome. The mushroom extract showed slightly greater efficacy than psilocybin alone. Two novel compounds, one hallucinogenic and one non-hallucinogenic, were also effective in both mouse models. The non-hallucinogenic compound HBL20017 may offer therapeutic benefit for OCD without inducing psychedelic effects.
bioRxiv (Cold Spring Harbor Laboratory)
September 23, 2024
Michal Lazar, Michal Brownstien, Alexander Botvinnik et al.
preprint
Juvenile mice lacking the SAPAP3 gene, a model of obsessive-compulsive disorder (OCD), show anxiety-like behaviors before they develop the excessive self-grooming that mimics OCD compulsions. Compared to normal mice, these knockout mice spent less time in open areas, buried fewer marbles, and found fewer hidden objects. A single dose of psilocybin (4.4 mg/kg) did not reduce these anxiety-like behaviors. In adult but not juvenile male knockout mice, levels of several synaptic proteins (GAP43, synaptophysin, SV2A) were elevated across brain regions, suggesting compensatory plasticity changes that emerge with age. The findings parallel the clinical observation that anxiety often precedes OCD in humans and indicate that psilocybin's therapeutic effects may be age-dependent.