Striking long-term beneficial effects of single dose psilocybin and psychedelic mushroom extract in the SAPAP3 rodent model of OCD-like excessive self-grooming
Michal Brownstien, Michal Lazar, Alexander Botvinnik, Chloe Shevakh, Karin Blakolmer, Leonard Lerer, Tzuri Lifschytz, Bernard Lerer
Molecular Psychiatry October 11, 2024 DOI: 10.1038/s41380-024-02786-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 50 |
| Population | SAPAP3 knockout mice |
| Interventions | Psilocybin Psychedelic mushroom extract Vehicle control |
| Dose | 4.4 mg/kg |
| Duration | 21-day observation period; up to 7 weeks follow-up for responders |
| Topics | Anxiety Psilocybin |
| Keywords | Placebo Hallucinogen Concomitant Obsessive-compulsive spectrum disorders |
| Citations | 23 |
| Key findings | A single dose of psilocybin or psychedelic mushroom extract significantly reduced excessive self-grooming and anxiety in SAPAP3 knockout mice over 21 days, with effects persisting up to 7 weeks in responders. |
Abstract
Abstract Obsessive compulsive disorder (OCD) is a highly prevalent disorder that causes serious disability. Available treatments leave 40% or more of people with OCD significantly symptomatic. There is an urgent need for novel therapeutic approaches. Mice that carry a homozygous deletion of the SAPAP3 gene (SAPAP3 KO) manifest a phenotype of excessive self-grooming, tic-like head-body twitches and anxiety. These behaviors closely resemble pathological self-grooming behaviors observed in humans in conditions that overlap with OCD. Following a preliminary report that the tryptaminergic psychedelic, psilocybin, may reduce symptoms in patients with OCD, we undertook a randomized controlled trial of psilocybin in 50 SAPAP3 KO mice (28 male, 22 female). Mice that fulfilled inclusion criteria were randomly assigned to a single intraperitoneal injection of psilocybin (4.4 mg/kg), psychedelic mushroom extract (encompassing the same psilocybin dose) or vehicle control and were evaluated after 2, 12, and 21 days by a rater blind to treatment allocation for grooming characteristics, head-body twitches, anxiety, and other behavioral features. Mice treated with vehicle (n = 18) manifested a 118.71 ± 95.96% increase in total self-grooming (the primary outcome measure) over the 21-day observation period. In contrast, total self-grooming decreased by 14.60 ± 17.90% in mice treated with psilocybin (n = 16) and by 19.20 ± 20.05% in mice treated with psychedelic mushroom extract (n = 16) (p = 0.001 for effect of time; p = 0.0001 for time × treatment interaction). Five mice were dropped from the vehicle group because they developed skin lesions; 4 from the psilocybin group and none from the psychedelic mushroom extract group. Secondary outcome measures such as head-body twitches and anxiety all showed a significant improvement over 21 days. Notably, in mice that responded to psilocybin (n = 12) and psychedelic mushroom extract (n = 13), the beneficial effect of a single treatment persisted up to 7 weeks. Mice initially treated with vehicle and non-responsive, showed a clear and lasting therapeutic response when treated with a single dose of psilocybin or psychedelic mushroom extract and followed for a further 3 weeks. While equivalent to psilocybin in overall effect on self-grooming, psychedelic mushroom extract showed superior effects in alleviating head-body twitches and anxiety. These findings strongly justify clinical trials of psilocybin in the treatment of OCD and further studies aimed at elucidating mechanisms that underlie the long-term effects to alleviate excessive self-grooming observed in this study.
Comparable studies
Other preclinical and animal studies on psilocybin for anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats Wistar rats | 2018 | Experimental study | n = 40 |
| Psilocybe cubensis extract potently prevents fear memory recall and freezing behavior in short- but not long-term in a rat model of posttraumatic stress disorder. Male rats | 2024 | Preclinical study | |
| Psilocybin induces acute anxiety and changes in amygdalar phosphopeptides independently from the 5-HT2A receptor Mice | 2024 | Experimental study | |
| Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders Mice and human cellular fractions | 2023 | Experimental study |
Citations in the library
Cited by 24
- Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles. Nature Neuroscience June 1, 2025
- The Emergence of Psilocybin in Psychiatry and Neuroscience Pharmaceuticals April 9, 2025
- Psilocybin reduces grooming in the SAPAP3 knockout mouse model of compulsive behaviour. Neuropharmacology 2025
- Chronic psilocybin administration increases sociability and alters the gut microbiome in male wild-type mice but not in a preclinical model of obsessive-compulsive disorder Neuropharmacology August 21, 2025
- Premorbid characteristics of the SAPAP3 mouse model of obsessive-compulsive disorder: behavior, neuroplasticity, and psilocybin treatment The International Journal of Neuropsychopharmacology March 29, 2025
and 19 more in the library
Cites 10
- Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder The Journal of Clinical Psychiatry November 15, 2006
- Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern‐era clinical studies Acta Psychiatrica Scandinavica October 30, 2020
- Pilot study of single-dose psilocybin for serotonin reuptake inhibitor-resistant body dysmorphic disorder. Journal of Psychiatric Research May 1, 2023
- Effects ofPsilocybe argentipeson Marble-Burying Behavior in Mice Bioscience Biotechnology and Biochemistry August 23, 2009
- Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications International Journal of Molecular Sciences November 16, 2022
and 5 more in the library