Psilocybin's effects on obsessive-compulsive behaviors: A systematic review of preclinical and clinical evidence
Psilocybin is a serotonergic psychedelic with growing evidence for efficacy in mood disorders, and its therapeutic potential in obsessive—compulsive disorder (OCD) and related conditions is increasingly recognised but remains understudied. We systematically evaluated clinical and preclinical evidence on psilocybin's effects on obsessive and compulsive behaviours with attention to translational relevance. A systematic search identified 13 eligible studies (4 clinical trials and 9 preclinical investigations examining psilocybin or psilocin on obsessive—compulsive symptoms or behaviours), and reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In clinical studies, single doses of psilocybin led to rapid reductions in obsessive-compulsive symptoms, including in patients with OCD and body dysmorphic disorder. In wild-type mice, psilocybin acutely decreased marble-burying behaviour, although this effect was transient and not observed beyond the first day after administration. In contrast, in SAPAP3 knockout mice—a validated genetic model of compulsive behaviour—a single administration of psilocybin produced robust, enduring reductions in excessive grooming, and these lasting anti-compulsive effects were replicated across independent laboratories and doses. Additionally, chronic hallucinogenic doses of psilocybin did not improve anxiety-like or compulsive-like behaviour in SAPAP3 knockout mice; however, a separate study in Long—Evans rats found that chronic sub-hallucinogenic psilocybin reduced self-grooming and enhanced expression of synaptic markers in the paraventricular thalamus. Together, the evidence suggests that psilocybin transiently reduces obsessive—compulsive symptoms in clinical populations and produces lasting anti-compulsive effects in validated animal models. Future clinical studies should include larger placebo-controlled trials and incorporate neuroimaging to assess psilocybin's impact on fronto-striatal circuitry implicated in OCD pathophysiology.
Introduction
Psilocybin, the psychoactive compound found in some species of fungi, has been long known for its psychedelic properties. Acute ingestion induces physiological and psychological effects, including a transient increase in blood pressure, feelings of euphoria, perceptual disturbances, and altered states of consciousness (1). While the therapeutic applications of psychedelic substances is an emergent field in modern Western medicine, the use of naturally occurring psychedelics for psychological and spiritual benefit has been commonplace in many traditional medicine frameworks for millennia (2).
At present, the strongest empirical data indicating the therapeutic potential of psilocybin has been found in major depressive disorder (MDD). For MDD, there is compelling evidence from double-blind randomized control trials (RCTs) that points to enduring benefits to mood, following even a single dose of psilocybin in a clinical setting [see review of RCTs in Wang et al. (2023) (3)]. Encouragingly, positive results have even been found in patients with treatment-resistant depression (4).
Upon human ingestion, psilocybin is rapidly metabolized to psilocin, which shares a similar chemical structure to endogenous serotonin and is a potent serotonin 5-HT2A receptor agonist (5). While 5-HT2A receptor agonism has been found to underpin the acute psychoactive properties of psilocybin, as well as neuroplastic processes (6), other studies have found 5-HT2A-independent neuroplasticity (7). The activation of neurotrophic pathways and the promotion of cellular and synaptic plasticity may imply some common therapeutic mechanisms between psilocybin and other known antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or ketamine (8).
While there is an established base of evidence supporting the utility of psilocybin in the management of mood disturbances, its therapeutic potential in the treatment of obsessive-compulsive disorders (OCDs) is only beginning to be understood. Arguably, the most well-characterized illness within the obsessive-compulsive and related disorders (OCRD) spectrum is OCD, which affects as many as 2%–3% of the general population throughout their lifetime (9, 10). This illness is characterized by unwanted and distressing thoughts, images, or urges (obsessions), and/or highly repetitive/ritualistic behaviors, such as excessive washing or checking (compulsions) (11). Standard treatment consists of psychological therapy with adjunct pharmacotherapy (usually a high-dose SSRI); however, many patients report incomplete symptom remission (12, 13).
OCD is highly polygenic and environmentally sensitive, making the development and investigation of new pharmacotherapies a challenging endeavor (14). However, convergent lines of evidence suggest dysregulation of the glutamatergic and serotonergic systems in OCD, in both clinical studies and in preclinical models (15–18). Serotonergic genetic candidates include polymorphisms of 5-HT transporter and 5-HT2A receptors (18). Interestingly, while some serotonergic agents such as SSRIs can be effective in treating compulsive behaviors, serotonergic 5-HT1A/1B and 5-HT1A/1D antagonists, such as RU-24969 and sumatriptan, have been found to exacerbate obsessive compulsive–like symptoms in both humans and rodents (19, 20).
Very recently, new evidence has begun to emerge pointing to the therapeutic potential of psilocybin in the treatment of OCRD-spectrum disorders. However, as it will be discussed in detail below, the field is lacking in well-powered high-quality clinical studies, and few attempts have been made to synthesize a consensus of available data. There is a greater weight of evidence in rodent studies, and indeed we have previously asserted that psilocybin could be considered as a lead candidate molecule in preclinical studies of neuropsychiatric disorders, including OCD (22). Notably, there have been recent reports of the efficacy of psilocybin in the most well-characterized animal model of OCD (23–26).
Although previous reviews have examined the therapeutic potential of psilocybin for OCD (27–30), none was conducted systematically. Our review addresses this gap and extends the discussion to psilocybin's therapeutic potential across the full OCRD spectrum.
Here, we will systematically review the available evidence on psilocybin's enduring therapeutic effects on obsessive-compulsive behaviors. By synthesizing preclinical and clinical lines of evidence, we aim to present a current scientific consensus on the utility of psilocybin to treat OCRD spectrum disorders, including OCD, and provide a clear direction for future research.
Results
The search string resulted in the identification of 370 articles on PubMed. An additional updated search was conducted on September 17, which identified another 26 studies. Applying the exclusion criteria resulted in the exclusion of 383 articles, leaving 13 articles to be included in the review (Figure 1 and Figure 2; Table 1). Of these articles, 9 where preclinical and 4 were conducted in clinical populations.
Citation: Psychedelics 2025; 10.61373/pp025i.0044
Citation: Psychedelics 2025; 10.61373/pp025i.0044
| Study | Treatment | Sample Characteristics | Relevant Outcome Measures | Outcome Measures (Results) |
|---|---|---|---|---|
| Clinical Papers | ||||
| Moreno et al. (2006) (31) Open-label trial |
Psilocybin doses were 25 [very low dose (VLD)], 100 [low dose (LD)], 200 [medium dose (MD)], and 300 [high dose (HD)] μg/kg of body weight (orally ingested). LD, MD, and HD were assigned in that order and the VLD was inserted randomly and in a double-blind fashion at any time after the first dose (LD). Testing days were separated by a week. All 9 subjects received LD, 7 of them also received the VLD and MD and 6 of them received all 4 doses. There was no placebo control group. |
n = 9 subjects (7 male, 2 female). Age (mean ± SD) = 40.9 ± 13.2 Subjects were required to have at least one “treatment failure” defined as a lack of significant improvement after an adequate treatment course with a serotonin reuptake inhibitor for at least 12 weeks. Subjects were required to have well tolerated at least one indole-based psychedelic drug. Subjects were required to abstain from use of antidepressants for at least 2 weeks (6 weeks for fluoxetine) before testing. |
The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and a Visual Analogue Scale (VAS) for overall obsessive-compulsive symptom severity was administered immediately before psilocybin ingestion (baseline) and 4, 8, and 24 h postingestion. The hallucinogen rating scale (HRS) was administered at 8 h postingestion. | Marked decreases in OCD symptoms (23% – 100% reduction in YBOCS score) was observed in all subjects during 1 or more sessions. There was no significant effect of dose (p = 0.261) or dose x time interaction (p = 0.515) for YBOCS scores. When all doses were combined, post ingestion YBOCS scores was significantly less than baseline (p = 0.028) (time points range from 4 to 24 h) A similar pattern of results was observed for the VAS. The HRS intensity was dose-dependent (p = 0.017), however, there was no association between HRS intensity and symptom severity. |
| Buot et al. (2023) (36) Retrospective online survey |
Participants needed to have at least one experience taking psilocybin-containing mushrooms. | Participants were included if they had a diagnosis of OCD performed by a health professional, or an OCI-R score greater than 18 or both. 135 participants had reported consuming psilocybin-containing mushrooms. |
Changes in OCD symptoms were assessed using 6 items: negative emotions, obsessions, compulsions/rituals, anxiety, acceptance of condition, and avoidance of possible anxiogenic situations. Each item was scored by moving a cursor on a 100-point scale starting at midpoint (0: no change) and ranging from −100 (Worsening) to + 100 (Improvement). | Individuals who had consumed psilocybin-containing mushrooms had significantly improved OCD symptomatology (p < 0.001). |
| Schneier et al. (2024) (32) Open-label trial |
25 mg dose (oral) of psilocybin was administered to participants. There was no control group. |
n = 12 adults (8 women and 4 men) Age (mean ± SD) = 34.31 ± 8.86 Diagnosed with nondelusional body dysmorphic disorder (BDD) ≥6 months. Required moderate severity (BDD-Y-BOCS ≥24, Clinical Global Impression Severity Scale or CGI ≥4) and nonresponse to at least one adequate trial of SRI, SNRI, or clomipramine at dose equivalent to ≥20 mg/day fluoxetine for ≥2 months. Exclusion criteria included severe depression (Hamilton Rating Scale for Depression score > 20), current suicidality or a suicide attempt within the past year, bipolar disorder, psychotic disorders, active substance use disorder within the past 3 months, use of investigational medication within 3 months, depot antipsychotic within 6 months, or serotonergic medication within 2 weeks (6 weeks for fluoxetine). All participants completed all study assessments through 12 weeks. |
The primary outcome was BDD symptom severity, measured using the clinician-rated BDD-Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (range: 0–48; higher scores = greater severity). Assessments occurred at baseline (day −1), day 0, day 1, and weeks 1, 2, 3, 6, 9, and 12 postdosing. Response was defined as a ≥30% reduction in total score; remission as a score ≤16. | BDD-YBOCS scores decreased significantly over 12 weeks (F1.92, 21.13 = 13.08, p < 0.001, η² = 0.54), with a mean reduction of 13.33 points from baseline at week 12. Scores were significantly lower than baseline at all time points except week 9 (trend-level, p = 0.059). At week 12, 7 participants (58.3%) met response criteria (≥30% BDD-YBOCS reduction or CGI score of 1–2); 4 of these also met remission criteria (BDD-YBOCS ≤16). |
| Pellegrini et al. (2025) (37) Fixed-order double-dose pharmacological challenge (not randomized) |
Participants received two single doses of oral psilocybin administered in a fixed order and separated by at least 4 weeks. The first dose was 1 mg/kg oral psilocybin which served as a very low control dose. The second dose was the active treatment (10 mg/kg, oral), which was administered at least 4 weeks after the first dose. |
n = 19 adult participants 1 participant had to leave the study for personal reasons. The mean age of participants was 38 years and n = 13 were male and n = 6 were female. Participants must have had suffered from OCD for at least 12 months and were of moderate severity. 58% of participants were using medications (SSRIs). 14 participants were psychedelic naïve. Key exclusion criteria included a current or previous diagnosis of psychotic disorder, bipolar disorder or mania, having a first-degree relative with a diagnosed psychotic disorder, a history of serious suicide attempts (requiring hospitalization), or borderline personality disorder. Participants also needed to have stable physical health. |
The primary clinical outcome was the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Y-BOCS was conducted at several time points: 1 day before each dose (baseline 1 and 2), and then 1 week, 2 weeks, and 4 weeks following each dose. The assessor who was blinded to drug treatment. |
Y-BOCS scores significantly decreased over time (p < 0.0001), with the largest reduction at 1-week post-10 mg (β = −3.63, d = 1.12, p < 0.0001). Dose effect was significant at 1 week (β = −4.49, d = 0.82, p = 0.002), trend level at 2 weeks (β = −3.34, d = 0.45, p = 0.06), and nonsignificant by 4 weeks. Compulsions improved more than obsessions at 1 week (β= −2.44, d = 0.74, p = 0.003 vs. β = −1.78, d = 0.50, p = 0.06). |
| Preclinical Papers | ||||
| Sard et al. (2005) (38) Preclinical medicinal chemistry study (SAR) with in vivo testing in a behavioral mouse OCD model. |
All drugs were dissolved in saline (0.9% NaCl) with 1 mg/mL ascorbic acid. Paired testing: each trial involved two mice, one control and one experimental (mice were placed individually in plexiglass boxes). Injection protocol:
Doses of test compound injected:
Analog compounds: Compound 3: 1-methylpsilocin Compound 4: 1-methylpsilocybin Compound 5: 1-butylpsilocin Compound 9: 4-fluoro-N,N-dimethyltryptamine |
Male Swiss–Webster mice, 4–6 weeks old. n = 5–12 per group. Psilocin n = 7 Psilocybin n = 5 Compound 3: n = 12 Compound 4: n = 8 Compound 5: n = 5 Compound 9: n = 5 |
Cumulative hind paw scratches were recorded every 5 min for 30 min post 5-HT injection. Hind paw scratching was an animal behavior relevant to pruritic psychological disorders such as OCD and excursion disorder. |
Psilocin (0.5 mg/kg): ≈ 300 scratches at 15 min vs. control (≈ 400 scratches). **Psilocybin (0.5 mg/kg): ≈ 50 scratches at 15 min; vs. control (≈ 800 scratches). *Compound 3 (5 mg/kg): ≈ 180 scratches at 15 min vs. control (≈ 400 scratches). **Compound 4 (5 mg/kg): ≈ 100 scratches at 15 min; strong inhibition vs. control (∼900 scratches). Compound 5 (5 mg/kg): ≈420 scratches at 15 min; vs. control (≈500 scratches). **Compound 9 (5 mg/kg): ≈100 scratches at 15 min vs. Control (≈900 scratches). Statistical significance: *p < 0.05, **p < 0.01. |
| Matsushima et al. (2009) (39) Preclinical behavioral mouse model study (marble-burying) |
Fluvoxamine, Psilocybin, Psilocin, and Phlebotomus argentipes were tested for effects on marble-burying behavior in mice.
Concentration ranges from 0.05–2 g/kg for P. argentipes and 0.025–1.5 g/kg for psilocybin. |
Five-week-old male ICR (Charles River Laboratories Japan) male mice. P. argentipes (n = 10) Psilocybin (n = 10) |
Marble-Burying Test
Locomotor Activity Test measured average total movement over 30 min. |
P. argentipes at 0.05–2 g/kg showed a trend toward inhibiting marble-burying behavior while 0.1–1 g/kg significantly reduced the number of buried marbles (p < 0.05) No significant effect on locomotor activity at any dose (p > 0.05) Inverted bell curve in dose-response relationship (initial reduction in marble-burying, but increase at the highest dose) Reduction in marble-burying was not related to hallucinogenic-like effects or 5-HT2A receptor activation P. argentipes was comparable to fluvoxamine, which also inhibited marble-burying without affecting locomotion. HPLC analysis showed P. argentipes contained 0.024% psilocybin and 0.0008% psilocin Psilocybin at 1.5 mg/kg significantly reduced marble-burying behavior, but P. argentipes was more effective at lower doses Findings suggest anti-OCD effects of P. argentipes are distinct from psilocybin alone, likely due to entourage effects. |
| Odland et al. (2021) (40) Preclinical behavioral mouse model study (marble-burying) |
Psilocybin: 0.5, 1.0, or 2.0 mg/kg, i.p. DOI: 1.0 mg/kg Citalopram: 2.5 mg/kg Antagonists:
Psilocybin was administered 15 min before testing; the other compounds were administered 30 min prior. |
Strain: Female NMRI mice Age: 17–26 weeks Total n = 100 mice Group size per test: Typically, n = 9–10 per group |
Marble-Burying (MB) Test: Used to assess compulsive-like/repetitive digging behavior. Measured marbles buried at 10, 20, and 30 min. Locomotor Activity Test: Assessed whether changes in digging were due to sedation or motor changes. Distance traveled recorded for 45 min. |
Psilocybin (1.0 and 2.0 mg/kg) significantly reduced marble burying at 30 min (p = 0.002) and all doses (0.5, 1.0, 2.0 mg/kg) reduced digging in the first 10 min (p ≤ 0.001). Psilocybin did not affect locomotor activity (p = 0.616), indicating a specific anti-compulsive effect. DOI reduced digging (p < 0.001), an effect blocked by the 5-HT2A antagonist M100907 (p < 0.001), but not by the 5-HT2C antagonist SB242084 (p = 0.312). Citalopram reduced digging (p = 0.005), and this effect was blocked by SB242084 (p = 0.018) but not by M100907 (p = 0.082). Psilocybin's effect on digging was not blocked by either M100907 (p = 0.188) or SB242084 (p = 0.857), suggesting a 5-HT2A/2C-independent mechanism. |
| Singh et al. (2023) (41) Preclinical behavioral mouse model study (marble-burying) |
Mice were administered one or a combination of vehicle, psilocybin (4.4 mg/kg), escitalopram (5.00 mg/kg), 8-hydroxy-dipropylamino-tetralin hydrobromide (8-OH-DPAT; 2.00 mg/kg), M100907 (also known as volinanserin; 2.00 mg/kg), buspirone (5.00 mg/kg) or WAY100635 (2.00 mg/kg) dissolved in saline or DMSO and administered via intraperitoneal injection in a standard volume of 300 μL. The control group received an i.p. injection of vehicle (0.9% saline). Administered 30 min prior to behavioral testing (for the marble-burying test). |
Strain: Male ICR (CD-1) outbred mice. Animal Age: Not provided. n = 6–17 per group Baseline behavioral analysis: Mice underwent a pretest of the MBT (without any drug) at least 1 week prior to the main experiment to identify those that reliably buried more than 15 marbles (the inclusion criterion). |
Marble burying test: Twenty glass marbles were placed in a cage with approximately 4.5 cm of sawdust. Mice were placed in the cage for 30 min. A marble was considered “buried” if two-thirds or more of it was covered. Open-field test: Began immediately after MBT. A 30-min session in a 50 × 50 × 40 cm arena. Locomotion was recorded (total distance traveled, center vs. periphery time) Head twitch response: Measured with a magnetometer approach for 20 min postinjection. |
Marble burying:
Overall, psilocybin's acute reduction of marble burying occurs through yet-unidentified receptors/targets, distinct from the classical 5-HT2A and 5-HT1A pathways that often underlie its psychedelic effects. |
| Kiilerich et al. (2023) (42) Preclinical behavioral rat model study (self-grooming) |
Occupancy study: Doses of psilocybin used were 0.05, 0.20 and 1.0 mg/kg (s.c.) to establish 5-HT2A receptor occupancy and detect overt psychedelic responses (e.g., wet-back shakes). Chosen Microdose: 0.05 mg/kg s.c., repeated every second day for 3 weeks. This dose was chosen because it did not induce wet-back shakes. |
Male Long-Evans rats. Sample size varied by behavior, but the lowest sample size was n = 8 per group. Animal Age: Not provided. |
Occupancy/Wet-Back Shake: Single subcutaneous injections (various psilocybin doses). PET scans with 10 MBq [18F]MHMZ and subsequent wet-back shake counts. Open-Field (OF) and elevated plus maze: The rats were first given a short open-field test (15 min). Then they were placed on a 15-min elevated plus maze. Acoustic startle reflex and open-field behavior: Rats’ startle reflexes are pre-assessed on separate days. On the final test day, they spend 40 min in the open-field, immediately followed by 37 min of PPI (total 80 min), with no injections given that day. Sucrose preference test: Five trials, about 1 week apart. First two trials are baseline, next two during psilocybin or saline regimen, the final trial was 2 days after the last injection. Each trial lasts 2 days. |
Low-dose psilocybin does not induce anxiety in a familiar environment:
Repeated low doses of psilocybin reduces compulsive behavior in a familiar environment:
Repeated low doses of psilocybin does not induce schizophrenic-like behaviors:
Sucrose preference
Repeated low-dose psilocybin did not affect anxiety or exploration in novel environments (open field or elevated plus maze). However, it reduced self-grooming by 48%. No behavioral desensitization observed: rats repeatedly given low-dose psilocybin still showed a full wet-back shake response when later given a high (1 mg/kg) psilocybin dose. No changes in 5-HT2A or 5-HT2C receptor levels in the prefrontal cortex, striatum, or choroid plexus. Psilocybin increased 5-HT7 receptor expression and increased levels of synaptic vesicle protein 2A in the paraventricular nucleus of the thalamus (p = 0.02 and p < 0.0001). |
| Brownstien et al. (2024) (23) Preclinical genetic knockout mouse model |
Psilocybin was administered only once, at a dose of 4.4 mg/kg i.p. 10.15 mg of psychedelic mushroom extract (PME) per 30 g mouse was administered i.p. This dose ensured each mouse received approximately 4.4 mg/kg of psilocybin. The control treatment was saline. 21 days posttreatment, mice whose total self-grooming behavior was decreased by 10% or more did not receive any further treatment and were reassessed 28 and 42 days after treatment. Mice in the saline group whose grooming had worsened by more than 10% but had no skin lesions were assigned to receive either psilocybin or PME. The grooming behavior of these mice was assessed 7 and 21 days after the second injection. |
Baseline behavioral analysis SAPAP3 KO (n = 10) and WT (exact strain not specified) mice (n = 10). Posttreatment Male and Female SAPAP3 KO mice (28 males, 22 females). First injection: Saline (n = 18), PME (n = 16) Psilocybin (n = 16). Second injection: PME (n = 13) and psilocybin (n = 12). Mice were 6–7 months old. KO mice with skin lesions were removed from the study. |
Total self-grooming duration (measured 2, 12, and 21 days posttreatment) Head/body twitch (measured 2, 12, and 21 days posttreatment) Marble-burying test (3 days posttreatment) Open-field test (3 days posttreatment) Elevated plus maze (5 days posttreatment) |
Baseline behavioral results Before treatment, SAPAP3 KO mice exhibited increased grooming and head/body twitches compared to WT mice. SAPAP3 KO did not display significantly different distance traveled in the open-field test. However, they did spend significantly less time in the center (p < 0.0001). KO mice, spent significantly less time on the open arm of the elevated plus maze (p < 0.0001) and buried significantly less marbles in the marble-burying test (p < 0.0001) Post-treatment results Psilocybin and PME significantly reduced grooming duration at 12 and 21 days posttreatment (p < 0.01 and p < 0.0001) compared to saline in SAPAP3 KO mice. Furthermore, in mice who received psilocybin or PME and whose grooming behavior decreased by 10% or more from baseline, were followed up without further treatment at days 28 and 42. PME had a more pronounced effect than psilocybin at 12, 28, and 42 days post-treatment. SAPAP3 KO mice who initially received saline, but did not show an improvement of 10% or more in total grooming scores from baseline received an injection of either psilocybin or PME. Compared to baseline, psilocybin and PME significantly reduced grooming and head/body twitch behavior at 7- and 21 days post-administration (p < 0.001). There was no saline control group. PME significantly increased time spent in the center of the open-field test compared to saline (p < 0.001) and psilocybin (p = 0.002). There was no significant effect on time spent in the periphery. PME significantly increased time spent in the open arm of the elevated plus maze (p = 0.040) compared to saline. There was no significant effect of psilocybin. On the marble-burying test both psilocybin and PME increased the number of marbles buried (p < 0.0001) compared to saline. |
| Gattuso et al. (2024) (24) Preclinical genetic knockout mouse model |
Mice were administered with a single dose of psilocybin 1 mg/kg (i.p.) or a saline control. | 5 to 7 month old male and female wild-type and SAPAP3 KO mice on a C57BL/6J background. Males: n = 12–15 mice per group Females: n = 6–12 mice per group |
Locomotor behavior (conducted for 60 min immediately following injections). Head-twitch behavior (conducted for 15 min immediately following drug administration). Light-dark box (conducted 1, 3, and 8 days after administration) Grooming behavior (conducted 1, 3, and 8 days after administration). |
Psilocybin significantly increased the number of head twitches in both WT and SAPAP3 KO mice (p < 0.0001). Psilocybin increased locomotion in WT (p = 0.0001) but not SAPAP3 KO mice (p = 0.772). Psilocybin significantly reduced compulsive grooming behaviour in male KO mice at 3 (p = 0.010) and 8 days (p = 0.016) after injection. Psilocybin decreased grooming behaviour in both WT and KO female mice (p = 0.033) across time points (1, 3, and 8 days after administration). |
| Lazar et al. (2025) (25) Preclinical genetic knockout mouse model |
Drug: Psilocybin dissolved in 0.9% saline; volume 10 μL/g administered intraperitoneally 48 h before testing. Dose: 4.4 mg/kg (single injection). |
Baseline phenotyping (Study 1, no drug): 141 drug-naive juveniles, 11 weeks old at first test.
Drug experiment (Study 2): 64 juveniles, 12 weeks at dosing.
|
Testing schedule: starting 48 h post-injection, mice were run over consecutive days in this order:
Only these tasks were repeated because they showed clear genotype effects in Study 1. Downstream molecular work – on day 13 after dosing, brains from a VEH subset (11 KO, 13 WT mice) were harvested for synaptic‑protein Western blots; psilocybin‑treated brains were not analyzed. |
Results from Study 2 Psilocybin effect: 4.4 mg kg i.p. produced no main or interaction effect on any behavioral endpoint (three-way ANOVA, all p > 0.05). Hypoactivity persists: SAPAP3-KO mice traveled far less than WT in the open field (F = 156.0, p < 0.0001). Anxiety-like profile: KO mice spent less time/entries on open arms of the elevated plus maze (time F = 50.97, p < 0.0001; entries F = 24.4, p < 0.0001) and showed reduced center exploration (F = 11.37, p = 0.0013). Molecular findings (adult cohort): male KO mice showed higher GAP43 (p = 0.001), synaptophysin (p = 0.003) and SV2A (p < 0.0001) across brain regions; females showed only SV2A elevation in the frontal cortex (p = 0.01). Reduced burrowing/compulsion: KO mice buried fewer marbles than WT (F = 116.2, p < 0.0001). Enhanced social dominance: KO mice won more tube-test contests (F = 18.70, p < 0.0001). Blunted food-seeking: KO mice located the buried Oreo in only 25–50% of cases, whereas WT mice succeeded in 87.5%–100% of cases; all genotype differences were statistically significant (χ² = 5.33–8.73, p < 0.05–0.01). Sex factor: no main or interaction effects of sex on any measure (all p > 0.05). |
| Gattuso et al. (2025) (26) Preclinical genetic knockout mouse model |
Mice received psilocybin dissolved in water via oral gavage (10 mL/kg, pH ∼7), with vehicle-treated controls receiving water alone. Two doses were tested (0.1 mg/kg and 1 mg/kg), administered 5 days per week for 5 weeks. A final dose was delivered 24 h prior to culling. Note: The first oral gavage was conducted on day 0. |
4 to 7 months old male and female WT and SAPAP3 KO mice on a C57BL/6J background. Males: n = 6–8 mice per group. Females: n = 7–11 mice per group. |
Locomotor behavior (day 0 and day 10) Head-twitch response (day 0 and day 10) Social interaction test (days 21 – 25) Light-dark box (day 28) Pre-pulse Inhibition (day 29) Gut transit time (day 30) Porsolt swim test (day 32) Gut microbiome 16sRNA sequencing (day 28). Locomotor behavior and head-twitch response was conducted for 15 and 30 min respectively, 30 min after oral gavage. All other behaviors were conducted approximately 24 h after the last dose. |
Locomotor activity: Psilocybin (1 mg/kg) increased locomotion acutely in WT mice (p < 0.001) and across all groups after repeated dosing (p = 0.002). Head-twitch response Both 0.1 and 1 mg/kg psilocybin increased head-twitches in males and females (p < 0.0001) in a dose-dependent manner. There was no time x treatment effects (p = 0.311). Three-chamber test: SAPAP3 KO mice displayed reduced sociability/social novelty (p < 0.0001 and p = 0.015); psilocybin (1 mg/kg) increased sociability in male WT mice (p = 0.009). Light-dark box: SAPAP3 KO mice showed anxiety-like behavior (reduced light duration) (p < 0.0001) unaffected by psilocybin 0.1 or 1 mg/kg (p = 0.872 and p > 0.999). Grooming behavior: SAPAP3 KO mice exhibited compulsive-like grooming (p < 0.0001), with no significant effect of psilocybin 0.1 or 1 mg/kg (p = 0.978 and p = 0.803). Pre-pulse inhibition: Psilocybin 0.1 and 1 mg/kg did not alter pre-pulse inhibition (p = 0.622, p = 0.895); however, 1 mg/kg reduced acoustic startle response in male mice (p = 0.017). There was no genotype effect (p = 0.680). Gut-transit time: Psilocybin dose-dependently increased gut transit time (p = 0.034 and p = 0.003). No genotype differences (p = 0.382). Porsolt Swim Test (PST): No genotype differences in immobility (p = 0.116); psilocybin had no effect (p = 0.726). Gut microbiome: There was no genotype or treatment effect on alpha or beta diversity. However, at the species level, psilocybin decreased the abundance of several Lactobacillus and Alistipes species only in male wild-type mice. |
Discussion
Therapeutic efficacy across studies
Psilocybin administration in clinical populations
When synthesizing the papers included in this review, a consistent theme emerges: psilocybin is capable of reducing obsessive and compulsive symptoms in clinical and compulsive-like behavior in preclinical studies. For instance, Moreno et al. (2006) (31) found that at a range of doses (25–300 μg /kg, oral), psilocybin significantly decreased obsessive and compulsive symptoms between 4 and 24 h compared to baseline in patients with treatment-resistant OCD. The reduction in obsessive and compulsive symptoms was comparable. In another pilot study, Schneier et al. (2024) (32) found that a single dose of 25 mg of psilocybin (oral) significantly decreased obsessive and compulsive symptoms related to body dysmorphic disorder at 1, 2, 3, 6, and 12 weeks after administration compared to baseline, with a large effect size. This study was conducted in patients with body dysmorphic disorder (BDD) which is classified by the American Psychiatric Association within the cluster OCRD recognizing its similarity to other disorders with repetitive and ritualistic elements (11). In addition to BDD, this cluster of disorders includes OCD, trichotillomania (hair pulling disorder), hoarding disorder, and dematillomania (skin pricking disorder). It has been argued that this clustering of disorders reflects a common underlying construct of maladaptive harm avoidance juxtaposed with the subjective feeling of “sensory incompleteness” (33).
BDD is defined by distressing preoccupation such as mirror checking and gazing, disproportionate grooming, modification or camouflaging of appearance, and mentally comparing appearance to that of others (11). Thus, BDD is related to OCD both behaviorally and neurobiologically and is often comorbid (34) and has been referred to as a disorder of “obsession with perfection” (35). Thus, psilocybin's reduction in obsessions and compulsions related to BDD, highlights psilocybin's transtherapeutic potential for disorders across the OCRD spectrum.
Furthermore, Buot et al. (2023) (36) found that participants who had consumed psilocybin-containing mushrooms had a significant reduction in their OCD symptomatology. Although in their subsequent analysis they combined the results of participants who had consumed lysergic acid diethylamide (LSD) and psilocybin-containing mushrooms, they found that approximately 30% of users found a persistence in effects for more than 3 months. Interestingly, users who reported consuming psilocybin-containing mushrooms (or LSD) on more than one occasion had a stronger improvement in OCD symptoms [47% (n = 42) reported an intake frequency of at most three times a year, 14% (n = 13) reported once a month and 16% (n = 14) at least once a week].
Finally, the most recent clinical study is by Pellegrini et al. (2025) enrolled 19 adults with moderate-to-severe OCD who received two single oral doses of psilocybin (1 mg followed by 10 mg, separated by at least 4 weeks) in a fixed-order design. Psilocybin produced a rapid reduction in OCD symptoms, with the 10 mg dose leading to the strongest improvement, particularly in compulsive symptoms. However, these effects were transient, diminishing after 1 week and no longer evident by 4 weeks.
Methodological limitations of included clinical studies
Although these preliminary findings are encouraging, there are several methodological limitations, which warrants cautious consideration when interpreting these results. First, a major limitation of Moreno et al. (2006) (31) was the lack of a placebo control group; thus, it is impossible to delineate how much of the reduction in obsessive and compulsive symptoms was due to true treatment effects. Furthermore, this study contained a very small samples size of only 9 patients and had limited longitudinal data (the last time point was only 24 h post-administration). Additionally, this patient population was resistant to at least one prior treatment and, therefore, these results may not be able to be extrapolated to clinical populations who respond to frontline pharmacotherapy. Similarly, the study by Schneier et al. (2024) (32) also featured a very low sample size of only 12 patients; however, they did report large effect sizes (which is independent of sample size). Although, due to the absence of a placebo control group, how much of this effect size is due to placebo and expectancy effects cannot be determined. Finally, while Buot et al. (2023) (36) was a retrospective online survey, and therefore not limited by low statistical power, there are numerous other limitations associated with this study design. In a similar fashion to Moreno et al. (2006) (31) and Schneier et al. (2024) (32), a lack of a placebo control group limits interpretability of the results. Web-based surveys are also subject to bias in participant selection. For instance, participants who had more favorable experiences with psilocybin may have been more likely to complete the survey. Additionally, precise dose and duration of effects cannot be determined in this experimental design.
Although the results from Pellegrini et al. (2025) (37) are timely and help propel the knowledge base forward, the results should be interpreted with caution due to several important limitations. The study included only 19 participants, restricting statistical power and generalizability. The fixed-order design (1 mg always preceding 10 mg) introduced potential biases, and despite a 4-week washout, carry-over effects cannot be excluded. Blinding was imperfect, as nearly all participants correctly identified the 10 mg dose, raising the possibility of expectancy-driven influences. The use of 1 mg psilocybin as an active control also posed challenges, as it is unclear whether this lower dose was clinically inert and therefore may have been an unsatisfactory placebo. Moreover, the absence of a significant dose × time interaction on Y-BOCS scores indicates that the observed 1-week dose effect should be interpreted cautiously. An additional limitation was the moderate treatment dose, which was not compared to a higher therapeutic dose (20–30 mg) routinely used in clinical trials for depression (3).
Psilocybin administration in preclinical studies
Well-designed preclinical psychedelic studies are advantageous as they are completely devoid of expectancy and placebo effects (22). This is crucial, as even well-designed clinical psychedelic trials that contain a double-blinded placebo control group can be confounded by placebo, as individuals and researchers often know if they received the placebo or the active drug treatment due to the strong perceptual alteration that occur after ingestion of the psychedelic (43). Additionally, in clinical trials such as Schneier et al. (2024) (32) and Pellegrini et al. (2025) (37), there was substantial psychological support that accompanied psilocybin administration which may have had additional and unique psychological effects (44). Thus, preclinical literature assessing psilocybin administration on obsessive and compulsive-like behaviors may reveal the “true” biological effects of psilocybin devoid of expectancy and placebo effects. Furthermore, recent reviews, highlight the translatability of mouse models relevant to obsessive and compulsive disorder (specifically the SAPAP3 KO mouse model), where molecular and circuit level mechanisms can be investigated (14, 22).
The marble-burying test (MBT) is a test that exploits rodents spontaneous digging behavior, where a greater number of marbles buried, reflects meaningless repetitive behavior that is characteristic of OCD. Furthermore, frontline pharmacological treatments for OCD such as SSRIs, often decrease marble-burying behavior (45). Using the MBT as a measure of compulsive-like behavior, Matsushima et al. (2009) (39) found that psilocybin containing mushrooms (Phlebotomus argentipes) at a dose of 0.1–1 g/kg acutely reduced the number of marbles buried in the MBT in 5-week-old male ICR mice. Similarly, psilocybin (1.5 mg/kg, oral) significantly reduced marble burying behavior but to a lesser degree then P. argentipes, especially at lower doses. Odland et al. (2021) (40) found that psilocybin (1 and 2 mg/kg, i.p.) significantly reduced marble-burying behavior (MBT was conducted 15 min after injection) in female NMRI mice, which was not mediated by activation of the 5-HT2A and 5-HT2C receptors. This effect was aligned with findings in a different mouse strain, sex and dose, where Singh et al. (2023) (41) administered a single dose of psilocybin (4.4 mg/kg, i.p.) 30 min before the MBT in male wild-type (WT) ICR mice and found that psilocybin acutely decreased marble burying compared to vehicle; however, this effect did not persist until day 7. This acute reduction in marble-burying behavior was independent of the 5-HT2A and 5-HT1A receptor.
However, it is important to note that the MBT has been critiqued as a model of compulsive-like behavior with concerns around its predictive and construct validity (45). Additionally, all of these studies utilized WT mice only (rather than a mouse model of OCD such as SAPAP3 KO mice) which complicates interpretation as psilocybin's effect may not be anti-compulsive but could be a more generalized effect. For instance, in WT mice, marble burying is also related to exploratory behavior, thus, a psilocybin effect in WT mice may not be purely anti-compulsive but may indicate, anxiolysis or reduced motivation. However, overcoming these limitations, Brownstien et al. (2024) (23) and Gattuso et al. (2024) (24) investigated how acute psilocybin administration alters compulsive grooming behavior in the SAPAP3 KO mouse model. The SAPAP3 KO mouse model is arguably the most well-validated animal model of OCD (46). SAPAP3 KO mice lack the SAPAP3 protein, a postsynaptic protein, involved in the regulating and trafficking of excitatory neurotransmitter receptors and highly expressed in the striatum. The human ortholog of SAPAP3 (DLGAP3) has been implicated in patients with OCD (47) and pathological grooming (48) and mice display cortico-striatal dysfunction that recapitulates the circuit-level abnormalities observed in humans (49, 50). Furthermore, these mice display a repetitive and harmful excessive grooming phenotype which if left untreated will cause skin lesions (51). Thus, the excessive grooming is compulsive because, despite the behavior causing self-harm, the mice cannot stop. Additionally, these mice also display excessive anxiety-like behavior and tic-like behavior which respond to frontline pharmacological treatments relevant to OCD and OCRD (51, 52).
Both Brownstien et al. (2024) (23) and Gattuso et al. (2024) (24) found that psilocybin (4.4 and 1 mg/kg, i.p., respectively) led to enduring reductions (between 1 and 7 weeks postinjection) in excessive grooming behavior in SAPAP3 KO mice. These data suggest that psilocybin has anti-compulsive effects that are independent of placebo. Furthermore, the reliability of the findings that psilocybin can lead to enduring reductions in compulsive-like behavior is strengthened by independent labs using different doses and time points (53). Whereas Brownstien et al. (2024) (23) and Gattuso et al. (2024) (24) did not assess the immediate effects of psilocybin on excessive grooming behavior, Sard et al. (2005) (38) demonstrated that psilocybin (0.5 mg/kg, i.p.) rapidly reduced 5-HT–induced scratching behavior in Swiss-Webster mice and, importantly, provided novel structure–activity relationship insights into the anti-compulsive potential of psilocybin analogues. The study identified 1-methylpsilocin as a selective 5-HT2C agonist with minimal 5-HT2A activity and an inverse agonist profile at 5-HT2B, suggesting both therapeutic relevance and an improved safety profile. Its phosphate prodrug, 1-methylpsilocybin, showed strong in vivo efficacy in the scratching model, comparable to psilocybin itself, indicating the translational value of prodrug approaches. Similarly, 4-fluoro-N,N-dimethyltryptamine produced robust antiscratching effects, possibly due to enhanced blood–brain barrier penetration despite only modest in vitro 5-HT2C activity. By contrast, compounds with bulkier substitutions (e.g., N-butylpsilocin) were largely inactive, underscoring the importance of structural constraints at the 1-position for 5-HT2C selectivity. Collectively, these findings highlight that psilocybin's anticompulsive effects may be mediated via 5-HT2C receptor activity and that rational modification of its structure could yield compounds with greater selectivity and potentially superior therapeutic profiles for OCD and related disorders.
Interestingly, Brownstien et al. (2024) (23) found that psilocybin and psychedelic mushroom extract (PME) increased marble-burying behavior in SAPAP3 KO mice and KO mice had reduced marble burying compared to WT mice at baseline, supporting concerns surrounding the validity of this behavioral test for compulsive-like behavior (45). The authors contend that psilocybin and PME increased marble burying in SAPAP3 KO mice because these animals display abnormally low baseline marble burying due to heightened anxiety. They argue that by reducing anxiety, the treatments restored normal exploratory and digging behaviors, making the increase in marble burying a reflection of behavioral normalization rather than enhanced compulsivity. However, in Brownstein et al. (2024) (23), only PME (and not psilocybin) significantly altered anxiety-related measures, whereas both compounds significantly increased marble burying. Thus, we contend that excessive grooming in SAPAP3 KO mice may monopolize the behavioral repertoire and suppress other behaviors, including digging. By reducing pathological grooming, psilocybin and PME may have reallocated behavioral capacity, thereby enabling mice to engage in more typical exploratory and digging activity.
Interestingly, psilocybin did not alter marble-burying behavior in younger SAPAP3 KO mice which have less severe compulsive grooming behavior (25). Notably, Brownstien et al. (2024) (23) reported that psilocybin and PME produced long-term reductions in head and body twitches, behaviors proposed to model tic-like activity in SAPAP3 KO mice (52). These findings suggest that psilocybin could hold therapeutic potential for Tourette syndrome, a disorder also marked by compulsive features, thereby supporting its broader applicability across the OCRD spectrum. Interestingly, psilocybin did not attenuate the excessive anxiety-like phenotype in SAPAP3 KO mice (23, 24), but PME did (23), possibly due to entourage effects.
The majority of preclinical studies reviewed here used only one dose of psilocybin administration; however, both Kiilerich et al. (2023) (42) and Gattuso et al. (2025) (26) assessed the effects of chronic psilocybin administration on compulsive-like behavior. Kiilerich et al. (2023) found that male Long-Evans rats that received psilocybin (0.05 mg/kg, s.c.) every second day for 3 weeks had significantly reduced self-grooming behavior the second day after the last psilocybin dose. Importantly, this dose of psilocybin (0.05 mg/kg, s.c.) did not induce any hallucinogenic-like behavior. Interestingly, the researchers also found that chronic low-dose psilocybin increased the expression of the 5-HT7 receptor and the synaptic vesicle protein 2A (SV2A: a proposed marker for synaptic density) in the paraventricular thalamus. As 5-HT7 receptors and SV2A are located presynaptically, this suggests that chronic low-dose psilocybin is increasing synaptic input into the paraventricular thalamus compared to control. Due to the reasons mentioned above (i.e., less parsimonious findings when using WT rodents), Gattuso et al. (2025) (26) decided to investigate the effects of chronic administration of psilocybin 0.1 mg/kg and 1 mg/kg in SAPAP3 KO mice. They found that 20 doses of psilocybin 0.1 mg/kg and 1 mg/kg (oral) did not ameliorate the excessive anxiety or grooming phenotype in SAPAP3 KO mice. The absence of an effect was unlikely due to tolerance as the head twitch response did not diminish after chronic compared to acute administration. Additionally, 20 doses of psilocybin 1 mg/kg did not significantly alter the gut microbiome of SAPAP3 KO animals.
Methodological limitations of included preclinical studies
One key caveat in modelling OCD and OCRD preclinically, is the inability to assess effects on obsessional behaviors in rodents because obsessions are defined as intrusive, unwanted, and repetitive thoughts or urges, which inherently require subjective reporting and internal experience. Animals cannot communicate internal thought processes or mental experiences, so obsessions cannot be directly measured or reliably inferred in rodents.
In contrast, compulsions are overt, observable, repetitive behaviors intended to alleviate distress or anxiety associated with obsessions. Such behaviors (e.g., excessive grooming, repetitive checking, or stereotyped patterns) can be objectively quantified and analyzed in rodents.
Therefore, preclinical mouse models focus primarily on compulsive-like behaviors, as these behaviors provide a measurable and operationally defined endpoint that can be consistently observed, quantified, and experimentally manipulated. However, according to current diagnostic criteria (although rare), it is possible for individuals to be diagnosed with having only obsessional or compulsive behavior (rather than both) (11) and so clinical studies are needed to assess psilocybin's effect on obsessions.
Synthesizing clinical and preclinical findings
Overall, the evidence suggests that psilocybin administration has the potential for reducing obsessive symptoms and compulsive behaviors and is relevant to a variety of neuropsychiatric disorders across the OCRD spectrum. Of the disorders across the OCRD spectrum, psilocybin has been most thoroughly investigated for OCD. Preclinical evidence suggests that psilocybin exhibits anti-compulsive effects that are independent of placebo and expectancy effects. These effects can be both rapid (38, 40, 41) and enduring (23, 24). However, the exact mechanisms by which psilocybin reduced compulsive behavior have been underexplored. For instance, both Brownstien et al. (2024) (23) and Gattuso et al. (2024) (24) did not assess which receptors could be mediating the reduction in compulsive-like behavior in SAPAP3 KO mice. Such findings could provide critical evidence to support or refute the hypothesis that these serotonergic receptors are directly involved in the anti-compulsive-like effects of psilocybin especially as studies have found that psilocybin can reduce rodent marble-burying independently of 5-HT1A, 5-HT2A, and 5-HT2C receptor activation (40, 41). Figure 3 indicates that psilocybin's therapeutic effects in animal models relevant to OCRD has consistently been shown to be independent of the 5-HT2A receptor; however, future well-designed experiments are needed.
Citation: Psychedelics 2025; 10.61373/pp025i.0044
As hallucinogenic-like behavior in rodents and psychedelic experiences in humans is mediated by the 5-HT2A receptor (54, 55) follow-up receptor antagonism studies could elucidate if the hallucinogenic experience is necessary for the anti-compulsive effects of psilocybin. Additionally, preclinical evidence from Kiilerich et al. (2023) (42) suggests that repeated subhallucinogenic dosing may have beneficial effects on compulsive-like behavior. Thus, future studies should continue to investigate whether pretreatment with a highly selective 5-HT2A antagonist such as MDL-100,907 (Volinanserin) abolishes the anti-compulsive effect of a single hallucinogenic dose of psilocybin in a mouse model of OCD and whether nonhallucinogenic psychedelic analogs can reduce compulsive-like behavior. If further preclinical evidence suggests that psilocybin can retain its anticompulsive effects at the preclinical level independent of 5-HT2A receptor activation, then it would be logical to conduct similar studies in clinical populations. If a reduction in obsessive and compulsive symptoms is independent of the psychedelic experience, this treatment would be more scalable as there would be a reduced need for clinical supervisions and, therefore, less financial barriers, improved safety and tolerability, and better patient acceptance and adherence as some individuals may prefer treatments without an intense psychedelic experience due to personal, cultural, or psychological reservation.
Although further research is needed to explore different chronic dosing paradigms, the findings of Gattuso et al. (2025) (26) suggest that acute psilocybin administration may have greater therapeutic efficacy for compulsive-like behavior. Moreover, since psilocybin did not alter the gut microbiome in the SAPAP3 KO mouse model, future studies could investigate the use of probiotics as an adjunctive treatment to enhance psilocybin's anti-compulsive effects, particularly given evidence that probiotics can reduce obsessive-compulsive–like behaviors (56).
Psilocybin's effect on neuroplasticity relevant to OCRD
There is a relative paucity of studies directly investigating the cellular mechanisms by which psilocybin exerts therapeutic effects in animal models of OCRDs (Figure 3; Table 1). Addressing this gap is critical for developing targeted therapeutics. We hypothesize that psilocybin's long-term benefits in reducing compulsive-like behavior are mediated through its ability to induce rapid and sustained alterations in neuronal morphology and synaptic signaling. Below, we outline evidence for psilocybin-induced neuroplasticity across molecular, cellular, synaptic, and behavioral levels, highlighting their potential translational relevance for OCD.
Molecular level
Moliner et al. (2023) reported that psilocybin's neuroplastic effects may involve positive allosteric modulation of TrkB signalling, independent of 5-HT2A receptor activation, suggesting an alternative mechanism through which psychedelics might enhance cortical plasticity. However, these findings have not yet been independently replicated, and subsequent evidence has called this mechanism into question. Jain et al. (2025) (57) directly tested whether classical psychedelics, including psilocin and LSD, interact with TrkB using a live-cell reporter assay and found no evidence of agonist or allosteric modulation of TrkB. Taken together, while TrkB involvement remains an intriguing possibility, the precise nature of psilocin's interaction with TrkB remains unclear, and further research is needed to determine whether psychedelic-induced plasticity occurs through direct modulation of TrkB signaling or via distinct molecular pathways.
In the mouse cortex, psilocybin-evoked c-Fos expression was strongly correlated with endogenous Grin2a and Grin2b (58). As SAPAP3 KO mice exhibit altered NMDA receptor subunit expression and function in the striatum compared to WT mice (51), it is possible that psilocybin's downstream interactions with glutamatergic signaling could normalize NMDA receptor function. Testing this empirically and determining whether such normalization translates into reduced compulsive behaviors, represents an exciting future direction.
Preclinical studies demonstrate that psilocybin induces rapid, region-specific transcriptional changes consistent with enhanced neuroplasticity. Jefsen et al. (2021) (59) showed that acute psilocybin robustly upregulated immediate early genes (e.g., c-Fos, Junb, and Nr4a1) and plasticity-related transcripts (e.g., Sgk1 and Psd-95) in the prefrontal cortex, with more modest effects in the hippocampus. Similarly, Fadhunsi et al. (60) found widespread acute transcriptional alterations in the prefrontal cortex, including regulation of BDNF, Negr1, and neuroplastin, but no persistent changes at 4 weeks. Together, these findings highlight psilocybin's capacity to rapidly engage molecular programs of plasticity, particularly in the prefrontal cortex—a key node in the corticostriatal circuits implicated in OCRDs. By transiently reshaping these molecular pathways, psilocybin may facilitate long-term normalization of dysregulated frontostriatal connectivity that underlies compulsive symptomatology.
Cellular level
At the cellular level, psilocybin promotes neuronal proliferation, differentiation, and maturation (72, 73). These processes support long-term circuit remodeling, potentially reversing cellular plasticity deficits observed in OCD models. For example, SAPAP3 KO mice, which display striatal plasticity impairments (45–47), may be particularly responsive to psilocybin's neuroplastic effects.
Synaptic level
Psilocybin induces dendritic plasticity, including increased spine density in the medial prefrontal cortex (73, 74). Jefsen et al. (2021) (59) found that psilocybin increased the expression of PSD-95 in the rat prefrontal cortex which is a postsynaptic scaffolding protein which is crucial for synaptic plasticity and excitatory neurotransmission (75).
Shao et al. 2021 (74) demonstrated that psilocybin not only increases dendritic spine density but also enhances excitatory neurotransmission in layer 5 pyramidal neurons of the medial frontal cortex, as reflected by elevated miniature excitatory postsynaptic current frequency and a trend toward increased amplitude. These electrophysiological findings provide functional evidence of psilocybin-induced synaptic plasticity, complementing structural spine remodeling.
Together, these synaptic modifications may underpin lasting improvements in compulsive behavior. Experimentally, this could be probed by measuring prefrontal and striatal expression of PSD-95, synaptophysin, and BDNF following psilocybin treatment in SAPAP3 KO mice, linking synaptic changes to behavioral outcomes. To determine whether psilocybin's effects on dendritic spine growth causally mediate reductions in compulsive-like behavior, future studies could employ spine-specific photoablation approaches (e.g., (76)), enabling selective elimination of newly formed spines while assessing behavioral outcomes.
Behavioral level
At the behavioral level, the observation that psilocybin produces enduring reductions in compulsive-like behavior for up to 1–7 weeks after a single dose (23, 24) suggests that it may induce long-lasting structural changes in the brain. However, this possibility requires empirical verification using a well-validated mouse model of compulsive-like behavior. Based on the findings of this systematic review, we hypothesize that psilocybin normalizes aberrant striatal plasticity through coordinated molecular, cellular, and synaptic mechanisms, thereby restoring balanced corticostriatal circuit function and promoting sustained therapeutic effects (Figure 4).
Citation: Psychedelics 2025; 10.61373/pp025i.0044
Future clinical directions
Future clinical research should prioritize randomized, placebo-controlled trials with sufficient sample sizes to determine psilocybin's true efficacy in OCD and related disorders. Furthermore, we encourage the use of psychedelic-naïve participants and an active placebo control, such as niacin or methylphenidate, which can produce somatic symptoms such as tingling and euphoria, respectively, which could be confused with the somatic symptoms of psychedelics (particularly in psychedelic-naïve participants). Additionally, the studies should compare different dosing strategies—single high doses versus repeated low doses—and examine psilocybin's neural effects in patients with OCD using functional neuroimaging. Neuroimaging studies in healthy participants have demonstrated that psilocybin acutely influences brain regions implicated in OCD pathophysiology. For example, functional magnetic resonance imaging (fMRI) revealed that healthy controls administered psilocybin exhibited acute reductions in blood oxygen level-dependent signal and cerebral blood flow within fronto-temporo-parietal areas and key connectivity hubs, including the thalamus, putamen (striatum), and midline cortex (anterior and posterior cingulate cortices) (77). Notably, these regions show hyperactivity in patients with OCD (78).
Furthermore, future studies could systematically investigate the synergistic effects of combining psilocybin treatment with structured psychotherapy, particularly exposure and response prevention (ERP), for patients with OCD. Although current clinical trials already incorporate psychotherapeutic support, controlled comparisons could clarify how psilocybin may enhance cognitive flexibility and engagement with therapeutic tasks, potentially accelerating treatment gains (32, 79). Structured integration of psilocybin with ERP in clinical protocols could harness both biological and psychological mechanisms.
Addressing some of these future directions, Ching et al. (2023) (80) have published a study protocol assessing the clinical and neural effects of a single dose of psilocybin in patients with OCD in a randomized, double-blind placebo-controlled trial (using the active control – niacin). The researchers are using fMRI to assess how psilocybin alters fronto-striatal circuitry in patients with OCD and if normalization of this circuitry is associated with reductions in OCD symptomatology. The study is more well powered than Pellegrini et al. (2025) (37) with a plan to enroll 36 participants. The studies end point will be assessing symptoms and neural changes 48 h after the last dose. This study is an exciting future direction that will further elucidate the potential role of psilocybin treatment for patients with OCD. We encourage additional studies to assess the enduring effects of psilocybin on OCD symptomatology and neural changes from 1 to 12 months based on the sustained therapeutic effects of psilocybin in preclinical animal models of OCD and psilocybin's long-lasting effect in other patient populations (81–83).
It is important to note out of the 9 preclinical studies, only 2 studies (24, 26) comprehensively analyzed sex as an important biological variable. Out of the 3 clinical studies, merely one study (36) was powered enough to investigate sex differences, which found minimal sex differences.
In alignment with Shadani et al. (2024) (84) we strongly encourage future researchers to consider sex as an important biological variable in psilocybin research, to develop more targeted interventions, especially since Gattuso et al. (2024, 2025) (24, 26, 85) has found sex-specific responses to psilocybin.
The findings that psilocybin had therapeutic effects in SAPAP3 KO mice (23, 24), a mouse model relevant not just to OCD but across the OCRD spectrum (52), coupled with the promising improvement in BDD symptoms following psilocybin (32), suggests that future research should also expand to include disorders with overlapping neurobiological features, such as trichotillomania, dermatilomania, and hoarding disorder, where compulsivity is a core element (11).
Finally, preclinical evidence suggests that mushroom extract containing psilocybin may yield superior efficacy when compared to isolated psilocybin (23, 39) for behaviors relevant to OCD, most likely due to entourage effects through additional biologically active compounds such as baeocystin and norbaeocystin. Administering psilocybin-containing mushrooms to patients with OCD and related disorders and comparing effects to isolated psilocybin would be an exciting and worthwhile avenue of investigation.
Conclusions
This comprehensive review highlights psilocybin as a promising therapeutic candidate for OCD and related disorders. Across clinical and preclinical studies, psilocybin has demonstrated the capacity to reduce obsessive symptoms and compulsive behaviors, with both rapid (clinical) and enduring (preclinical) effects. While early clinical trials are constrained by small sample sizes and methodological limitations, converging evidence from animal models—particularly those employing the SAPAP3 KO mice—indicates robust anti-compulsive effects that are independent of placebo or expectancy influences.
Mechanistically, emerging data suggest that psilocybin may exert its long-term therapeutic effects (in other disorders, but also presumably OCD) through the induction of neuroplasticity. Notably, some neuroplastic effects appear to be independent of hallucinogenic-like behavior, raising the possibility that non-hallucinogenic psychedelic analogs or subperceptual dosing regimens may retain therapeutic efficacy while enhancing scalability and patient acceptability.
Future research should focus on well-powered, placebo-controlled clinical trials, detailed mechanistic studies in validated animal models, and investigations into the role of sex, symptom dimensions, and dosing paradigms. Given the consistency of findings across models and the transdiagnostic relevance of compulsivity, psilocybin-based interventions may offer a novel and scalable approach for treating OCRDs. For instance, Gattuso et al. (2024) (24) found that administration of psilocybin 1 mg/kg reduced compulsive grooming, with effects persisting for up to 8 days in male KO mice but proving more transient in female KO mice which aligns with clinical data from Pellegrini et al. (2025) (37). Pellegrini et al. (2025) (37) reported that a single 10 mg dose of psilocy—binapproximately comparable to the dose used in our study—led to a significant reduction in OCD symptomatology, primarily driven by compulsions, with effects most sustained in males at four weeks. This cross-species convergence adds further credence for the use of screening potential novel therapeutics for compulsive behavior using the SAPAP3 KO mouse model.
This review has systematically synthesized the existing scientific literature, critically identified current limitations and gaps, and provided informed guidance for future research directions—thereby advancing the development of effective and scalable therapeutic interventions for individuals suffering from OCD and related disorders.
Methods
The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (21) for transparent and comprehensive reporting and was in alignment with previously published systematic reviews (22, 86). J.J.G. conducted an electronic search on the PubMed database on March 21, 2025 using the following search string: (psilocybin OR psilocin OR “magic mushrooms” OR psychedelic OR psychedelics) AND (“obsessive compulsive disorder” OR OCD OR compulsive OR compulsion OR compulsions OR obsessive OR obsession OR obsessions OR “obsessive-compulsive” OR compulsive-like). A second search was conducted on September 17, 2025, during the peer-review process.
Articles were excluded by J.J.G. or B.B., if they were not an original article (i.e., reviews, book chapters, editorials, study protocol, and conference abstracts), were not in English, did not administer psilocybin, psilocin or psilocybin containing mushrooms, were not peer reviewed (i.e., preprints) or did not assess obsessive and/or compulsive behavior. The primary variables extracted where the main outcomes measures related to behavioral testing (and molecular and neural mechanisms where appropriate) (Table 1). Furthermore, descriptive statistics such as sample size, age, sex and dose were included where possible.
Author contributions
J.J.G. conducted the systematic review and wrote the manuscript and generated Figures 1 and 3. B.B. helped with the systematic search, Table 1 and generated Figures 2 and 4. C.W. helped with writing on the manuscript. K.H. helped with Table 1. T.R. and A.J.H. helped with supervision, manuscript revision and funding.
Funding sources
A.J.H. has been supported by a Principal Research Fellowship, Project Grants and an Ideas Grant from the National Health and Medical Research Council (NHMRC). T.R. has been supported by a NHMRC Boosting Dementia Research Leadership Fellowship and currently holds a Ronald Philip Griffiths Fellowship from the University of Melbourne. The Florey Institute of Neuroscience and Mental Health acknowledges the support from the Victorian Government's Operational Infrastructure Support Grant. J.J.G. is supported by Medicine, Dentistry and Health Sciences (MDHS) Faculty graduate research scholarships.
Author disclosures
The authors have no conflict of interests.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram (21) for study selection.
Cross-study heat map of psilocybin's behavioral and mechanistic effects in obsessive-compulsive related animal models and patients. Rows list the 13 primary studies reviewed (4 clinical at top, 9 preclinical beneath, ordered chronologically). Columns display seven endpoints that recur across ≥ 3 papers. It is important to note that effect magnitudes vary widely across species and paradigms.
Cross-study heat map of mechanistic endpoints assessed following psilocybin administration. Rows list the 13 primary studies reviewed (4 clinical at top, 9 preclinical beneath, ordered chronologically. Blue shading indicates that the receptor or mechanism was implicated in mediating or being associated with psilocybin's effects, purple shading indicates that it was not involved or associated, and gray shading indicates that the endpoint was not assessed.
Synaptic structure and function in WT, SAPAP3 KO, and psilocybin-treated SAPAP3 KO mice. (A) Wild-type (WT) mice: At the presynaptic terminal, action potentials open voltage gated calcium channels (VGCCs), allowing Ca²⁺ influx. Calcium binds to synaptotagmin, triggering vesicle fusion and the release of brain-derived neurotrophic factor (BDNF) and glutamate into the synaptic cleft. Glutamate activates postsynaptic AMPA and NMDA receptors (AMPAR and NMDAR). AMPAR-mediated Na⁺ influx depolarizes the dendritic spine, relieving the Mg²⁺ block on NMDAR's and allowing Ca²⁺ entry. These receptors are anchored by the postsynaptic scaffold composed of PSD-95, SAPAP3, Shank, and Homer proteins which play a crucial role in synaptic plasticity (61, 62). BDNF bind to TrkB receptors, activating CaMKII and supporting synaptic plasticity (63, 64). mGluR5 modulates additional metabotropic signaling (65). (B) SAPAP3 knockout (KO) mice (untreated): There is no direct evidence that BDNF release is reduced in SAPAP3 KO mice, but changes to the postsynaptic structure may affect how BDNF signals through its receptor, TrkB. Without SAPAP3, the scaffold that holds key receptors like AMPARs and NMDARs together becomes unstable due to the poor receptor anchoring (51, 66). This increases mGluR5 activity and weakens AMPAR signaling (66, 67). As a result, this could lead to impaired synaptic plasticity and behavior (66–69). (C) Psilocybin treated SAPAP3 KO mice: Psilocybin normalizes presynaptic Ca²⁺ influx and restores glutamate release via synaptotagmin-dependent exocytosis (70). In the synaptic cleft, psilocin may bind directly to TrkB dimers, stabilizing them in a conformation that enhances responsiveness to endogenous BDNF, however, evidence is mixed (Jain et al. (2025) (57). Psilocin also accesses both surface and intracellular 5-HT2A receptor pools. 5-HT2A receptors mediate hallucinogenic responses (70) and contribute to structural plasticity (6). Despite this, psilocybin-induced plasticity may occurs independently of the 5-HT2A receptor via direct TrkB activation (7). Postsynaptically, TrkB signaling re-engages CaMKII and promotes AMPAR trafficking, potentially rescuing aspects of the disrupted postsynaptic scaffold and potentially mediating long-term therapeutic behavioral outcomes (7, 23, 24, 71). Created in https://BioRender.com
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#These authors contributed equally.
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