631. PSILOCYBIN AND KETANSERIN VS RTMS IN TREATMENT-RESISTANT DEPRESSION: ENHANCING TOLERABILITY BY MITIGATING PSYCHEDELIC EFFECTS
The International Journal of Neuropsychopharmacology – August 01, 2025
Source: OpenAlex
Summary
Psilocybin, a potent hallucinogen, shows remarkable efficacy in medicine, achieving up to 70% remission in treatment-resistant depression. Its psychedelic effects, however, can complicate psychology studies. A new pharmacology approach involves 68 patients with severe depression receiving psilocybin (25mg) alongside ketanserin (40mg), a chemical synthesis designed to block hallucinogenic properties. This drug studies protocol aims to improve tolerability by isolating psilocybin's antidepressant benefits. Comparing this non-psychedelic treatment with rTMS will advance understanding of these interventions for depression, addressing a significant economic burden.
Abstract
Abstract Background Among the innovative treatments investigated for depression, psilocybin appears to play an extremely promising role, with several studies showing remission rates up to 70% in patients with treatment-resistant depression (TRD) treated with protocols involving a single or double dose administration [1,2]. Psilocybin is a psychedelic compound belonging to the tryptamine class, known for its hallucinogenic properties related to its action of partial agonist on serotonin receptors, specifically the 5-HT2A receptors. Recent preclinical studies suggest that the psychedelic and antidepressant actions of psilocybin may be independent, with the former related to direct action on 5-HT2A receptors, and the latter induced by modulation of TRKβ receptors [3]. Removing psilocybin's psychedelic effects with 5-HT2A receptor antagonists (i.e ketanserin) would reduce bias of suggestion, due to the so called “mystical experience”, enabling more reliable studies and improving its clinical feasibility. Aims & Objectives The primary aim is to compare the effectiveness of non-psychedelic psilocybin and rTMS, two treatment strategies that have recently shown promise in treatment-resistant depression. Method We will recruit 68 TRD patients, who will be randomly assigned to 2 groups: PSILO Group: Patients will receive one capsule of psilocybin (25 mg) on day 1 (T1) and one capsule of psilocybin (25 mg) on day 22 (T4). Both administrations will be preceded (1.5 hours) by two ketanserin tablets (20 mg each) to minimize the psychedelic effects. In addition, these patients will receive sham arTMS from day 4 (T2) to day 9 (T3). TMS Group: Patients will undergo an accelerated and personalized arTMS protocol, using intermittent theta-burst stimulation (iTBS), guided by fMRI for five consecutive days (from day 4, T2, to day 9, T3), with placebo doses of psilocybin and ketanserin on day 1 and on day 22. At baseline (T0) and on day 60 (T5) patients will undergo a battery of psychometric tests, an EEG recording and a fMRI. Results Study design: Discussion & Conclusions By co-administering ketanserin, psilocybin can be “cleaned” of its psychedelic effects, thereby reducing bias, enabling more reliable comparative studies, and greatly increasing its feasibility in clinical settings. A comparison with rTMS would represent a valid non-pharmacological option, given its promising results in treatment-resistant depression.