Pilot study of single-dose psilocybin for serotonin reuptake inhibitor-resistant body dysmorphic disorder

Body dysmorphic disorder (BDD) is characterised by preoccupation with perceived defects in appearance, and is associated with obsessive thoughts, compulsive behaviours, anxiety, social withdrawal, depression and a high rate of suicide attempts. Schneier and colleagues note that only selective serotonin reuptake inhibitors (or clomipramine) and disorder-specific cognitive behavioural therapy have demonstrated efficacy in randomised controlled trials, leaving a substantial unmet need for novel treatments. Psilocybin, a 5-HT2A/5-HT1A partial agonist, has shown growing evidence of efficacy in mood disorders and preliminary findings in obsessive–compulsive and substance-use disorders; mechanistically, it may reduce rigid thinking and alter bodily self-awareness, features relevant to BDD. A single case report also suggested possible benefit in BDD after unsupervised psilocybin use, motivating further investigation. This study aimed to pilot the feasibility, tolerability, safety and preliminary efficacy of a single 25 mg oral dose of psilocybin given with manualised psychological support in adults with non‑delusional BDD who had previously failed at least one serotonin reuptake inhibitor (SRI) trial. The investigators designed an open‑label proof‑of‑concept trial with 12 weeks of follow‑up to assess symptom change on the BDD‑YBOCS and a range of secondary clinical and safety measures, to determine whether controlled studies are warranted.

The study was an open‑label trial enrolling 12 adults with DSM‑5 non‑delusional BDD between March 2021 and April 2022. Participants were identified through online notices; after telephone screening a study psychiatrist used a comprehensive psychiatric interview, the BDD module of the Structured Clinical Interview for DSM‑5 and the MINI 7.0.2 to confirm diagnoses. Key inclusion criteria were age 18–55, principal non‑delusional BDD for more than six months with at least moderate severity (BDD‑YBOCS total >24 and Clinical Global Impression‑Severity >4), and prior nonresponse or intolerance to an SRI/SNRI or clomipramine at approximately fluoxetine >20 mg/day for more than two months. Absence of delusionality was operationalised as Brown Assessment of Beliefs Scale (BABS) 6‑item total <18. Major exclusion criteria included current moderate‑severe major depressive episode (HRSD‑17 >20), recent suicidality, bipolar or psychotic disorders, recent substance use disorders or positive urine drug screen, significant medical illness, seizure history, recent serotonergic medication, pregnancy or inadequate contraception, and current CBT. Participants were required to continue non‑CBT psychotherapy after dosing to support integration. Treatment comprised four weekly preparatory sessions with two psychotherapists trained in manualised supportive procedures used in psilocybin depression studies, covering psychoeducation and relaxation techniques. On dosing day, participants received five 5 mg capsules (COMP360 synthetic psilocybin; total 25 mg) orally at 09:00 in a room configured for psychedelic administration. Two therapists provided support during a 7–8 hour session while participants used eyeshades and a music programme aimed at inward focus. A psychiatrist assessed safety after at least seven hours and participants were discharged with a companion. Debriefing visits with the therapists occurred at one day and one week post‑dosing. Resting‑state fMRI was performed one day before and one day after dosing but those results are to be reported separately. Assessments were conducted at baseline (one day pre‑dosing), end of dosing day (day 0), day 1, and at 1, 2, 3, 6, 9 and 12 weeks post‑dosing; some secondary measures were collected at a subset of visits. Clinician ratings were done in person at baseline, day 0, day 1 and week 3 by a single study psychiatrist (FS), and by telephone at other points. The primary efficacy outcome was the Yale‑Brown Obsessive Compulsive Scale Modified for BDD (BDD‑YBOCS). Additional clinician‑ and self‑rated secondary outcomes included conviction of belief, affect measures, depression, psychological insight and disability; safety monitoring included adverse events, labs, vitals and urine toxicology. Statistical analyses used repeated‑measures ANOVAs across baseline to week 12 with Greenhouse‑Geisser corrections and Bonferroni‑corrected post hoc pairwise comparisons in SPSS v23; a paired t‑test compared HRSD scores from baseline to week 12. Raters, participants and statisticians were unmasked to treatment.

Recruitment yielded 198 inquiries, 37 psychiatric assessments and 12 eligible participants (8 women, 4 men). Comorbid diagnoses included major depressive disorder (n=4), ADHD (n=2), PTSD (n=1) and generalised anxiety disorder (n=1). Two participants were taking stimulant medications. Participants' primary appearance concerns most commonly involved face/nose/ears (n=6) or hair/head (n=3). During follow‑up, two participants discontinued their non‑study psychotherapy, and one began an SRI at week 4 because of increased social stressors; for categorical analyses that participant was counted as a non‑responder after week 4, and a sensitivity analysis carrying forward week 3 scores did not change primary significance. All 12 participants completed dosing and all scheduled follow‑up visits, providing complete outcome data. The BDD‑YBOCS total score showed a significant change over 12 weeks (repeated‑measures ANOVA: F(1.92,21.13) = 13.08, p < 0.001) with a large effect size (partial eta squared = 0.54). Pairwise testing indicated BDD‑YBOCS scores were significantly lower than baseline at each timepoint except week 9, which was at trend level (p = 0.059). There were no significant differences between timepoints from week 1 to week 12, indicating maintenance of the early improvement. At week 12 the mean change from baseline was reported as −13.33 (95% CI −3.43 to −23.23). Using a response threshold of >30% reduction in BDD‑YBOCS (and equivalently CGI‑Improvement of 1 or 2), seven of 12 participants (58.33%) were responders at week 12. Seven participants demonstrated >30% decrease sustained at every follow‑up, and four of those met sustained remission criteria (BDD‑YBOCS <16 at every follow‑up). Secondary clinician‑rated and self‑report measures of BDD symptom components, conviction of belief, negative affect, depression, psychological insight and disability showed significant improvement over 12 weeks; positive affect did not show a significant change. No serious adverse events or suicidal ideation were reported, and there were no clinically significant changes in laboratory values or vital signs. Mild adverse effects beginning and resolving within two days occurred in 11 participants: fatigue (n=5), headache (n=3), nausea (n=2), somnolence (n=1), lightheadedness (n=1), insomnia (n=1) and a sensation of spaciness (n=1). Other intercurrent illnesses included one case each of mild COVID‑19 and pneumonia. One participant experienced possibly drug‑related events persisting or arising beyond the first week: transient low libido for two weeks, brief mood disturbances in weeks 2–3, and four brief visual hallucination episodes (5–45 minutes) occurring in weeks 3 and 7; the participant retained insight and reported only mild disturbance. The investigators note that resting‑state fMRI findings will be reported separately.

Schneier and colleagues interpret these results as preliminary support that a single 25 mg dose of psilocybin given with psychological support is feasible, tolerable, safe and may produce clinically meaningful reductions in BDD symptoms in adults whose disorder had been unresponsive to at least one prior SRI trial. Feasibility was indicated by successful recruitment and completion of all study procedures despite restrictive eligibility criteria; tolerability and safety were evidenced by completion of all visits and absence of persistent or serious adverse events in this small sample. The authors highlight robust improvement on the primary outcome (BDD‑YBOCS) that emerged early and was largely maintained through 12 weeks, with concordant improvements on several secondary measures including conviction of belief, depression, negative affect, psychological insight and disability. They note that some participants reported reduced distress despite little change in the content of appearance beliefs, and that reductions in BABS scores suggest increased insight may have contributed to clinical improvement. The observed week 12 response rate of 58.3% is lower than uncontrolled SRI trials in BDD (reported at 70–80%), but those studies did not focus on an SRI‑resistant sample; direct comparisons are therefore limited. Key limitations acknowledged by the investigators include the uncontrolled, open‑label design, which leaves room for nonspecific effects such as expectancy; a small sample with limited socioeconomic diversity; and the concomitant, naturalistic psychotherapy that may have contributed to outcomes. Additionally, most participants had not necessarily received guideline‑recommended full courses (>12 weeks at maximum dose) of SRIs or a full course of BDD‑specific CBT before enrolment, limiting interpretation about treatment‑refractory status. Safety monitoring did not systematically capture non‑serious experiences during the dosing session unless they persisted to the session end. The occurrence of transient visual hallucinations up to week 7 in one participant raises the possibility of rare perceptual sequelae and underlines the importance of careful screening and provision of psychological support. The authors conclude that these preliminary findings justify controlled trials to more rigorously evaluate efficacy, durability and safety of psilocybin in BDD.