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.
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.
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.
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.