{ "$schema_version": "5.4", "review_mode": "red-team synthesis of a fresh review", "review_metadata": { "review_date": "2026-09-28", "reviewer": "Codex (original fresh assessment); Claude (Anthropic) cross-model red team and synthesis", "evidence_base_note": "Targeted primary-literature review through 2026-09-28. Supplied packet treated as methodology and schema. Every reference was re-resolved by PMID/DOI in the red-team pass; access depth is recorded as verified in that pass, which is stricter than the original edition. Company and regulatory documents on the phase 3 program are reported as context and excluded from the graded evidence base under the framework source-tier rule.", "literature_tools_available": true, "literature_tools_note": "Red-team pass used PubMed/PMC E-utilities and Europe PMC REST records, PMC and Europe PMC full-text XML where deposited, publisher abstracts otherwise, ClinicalTrials.gov records for pending work, Crossref for correction notices, and web retrieval for company/regulatory documents cited only as context.", "skill_version": "HSEF v5.4 supplied packet; local HSEF skill 3.0; Research Router and NCBI literature skills", "validator_run": "pass", "validator_warnings_addressed": "Validator 2.2 re-run on the red-team edition; result saved as the package validation file.", "original_review_date": "2026-09-27", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "provenance_header": { "sources_total": 50, "primary_reports_total": 47, "clinical_original_cohorts": 17, "claims_total": 50, "claims_verified": 50, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 47, "full_text_complete": 5, "full_text_partial": 21, "abstract_metadata": 24, "generated_by": "Codex HSEF v5.4 primary-review workflow; red-team synthesis pass by Claude (Anthropic), 2026-09-28", "gate_passed": true, "packet_path": "D:\\HypothesisCritic\\packets\\hsef-v5.4-review-packet-2026-09-27.zip", "packet_sha256": "7e097d3d50d2068f68bdb1cd022df4a045dac46a9f25e51262ec7568e9db11eb", "aggregation_plan": "psilocybin-depression-cortical-plasticity.scope-and-aggregation.md (pre-registered 2026-09-27, unchanged; its rubric-availability sentence is corrected in the red-team log, not in the file)", "verification_limits": "Source-level reported findings were checked at the recorded access depth in the red-team pass; original data were not reanalysed, and structural validation is not independent scientific confirmation. Statistics not verifiable from a primary record at this access depth were removed.", "synthesis_reports_total": 3, "tier_b_sources": 3 }, "claims": [ { "id": "C1", "text": "Feasibility targets were met (60 randomized, 59 of 60 completing the MADRS at all visits); the adjusted between-group MADRS difference was −10.41 points at week 3 (95% CI −14.86 to −5.95; Cohen's d = −1.70) and −12.92 at week 6 (95% CI −17.37 to −8.47; d = −2.11), both secondary outcomes.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Red-team verification: Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C2", "text": "The primary week-6 HAMD-17 response endpoint was not significant: 17.0% with 25 mg, 12.5% with 5 mg and 10.6% with nicotinamide (25 mg vs nicotinamide adjusted OR 1.73, 95% CI 0.53–6.23, P=.19), while the key secondary continuous HAMD-17 difference favoured 25 mg (−4.60, 95% CI −7.01 to −2.18, P<.001).", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Red-team verification: Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C3", "text": "In naturalistic follow-up, HAMD-17 remained below baseline at 6 months (−7.93, 95% CI −9.17 to −6.70) and 12 months (−7.74, 95% CI −9.04 to −6.43) with no significant group differences, while sustained response across groups fell from 28/126 (22.2%) at 6 months to 20/126 (15.9%) at 12 months and antidepressant re-initiation was associated with higher HAMD-17 scores (β=3.79, 95% CI 1.98 to 5.60).", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C4", "text": "Clinician-rated MADRS favoured psilocybin at day 8 (−7.27, 95% CI −12.89 to −1.65, P=.01), day 15 (−11.03, 95% CI −16.65 to −5.42, P<.001) and day 42 (−8.33, 95% CI −13.94 to −2.71, P=.004) but not at day 365 (−3.68, 95% CI −9.30 to 1.94, P=.20); self-rated separation persisted to day 102 (−6.60, 95% CI −13.01 to −0.19, P=.04).", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Red-team verification: Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C5", "text": "The primary day-43 MADRS improvement favoured psilocybin by −12.3 points (95% CI −17.5 to −7.2, P<.001), with a day-8 difference of −12.0 (95% CI −16.6 to −7.4) and a Sheehan Disability Scale difference of −2.31 (95% CI −3.50 to −1.11, P<.001); more participants met sustained response, but not sustained remission, with psilocybin.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C6", "text": "The primary week-3 MADRS change favoured 25 mg over 1 mg by −6.6 points (95% CI −10.2 to −2.9, P<0.001) while 10 mg versus 1 mg was not significant (−2.5, 95% CI −6.2 to 1.2, P=0.18); the trial reports that response and remission at week 3, but not sustained response at week 12, were generally supportive of the primary result.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C7", "text": "In the 52-week observational extension, median time to a prespecified depressive event was 92, 83 and 62 days for the original 25 mg, 10 mg and 1 mg cohorts, with most COMP001 participants having experienced a depressive event by week 12 (25 mg 37/75; 10 mg 38/79; 1 mg 44/75).", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C8", "text": "In an open-label single 25 mg dose added to ongoing SSRI treatment, mean MADRS change at week 3 was −14.9 points (95% CI −20.7 to −9.2), with 8 of 19 participants (42.1%) meeting both response and remission criteria.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C9", "text": "The primary week-6 QIDS-SR-16 change was −8.0±1.0 with psilocybin and −6.0±1.0 with escitalopram, reported as a between-group difference of 2.0 points (95% CI −5.0 to 0.9), P=0.17 — a null on the prespecified primary outcome; response was 70% versus 48% (difference 22 percentage points, 95% CI −3 to 48) and remission 57% versus 28% (28 points, 95% CI 2 to 54).", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C10", "text": "At 6-month naturalistic follow-up both original groups retained self-rated improvement with no sustained between-group advantage; 37 of 59 participants (62.7%) had received additional medication, psychotherapy or psychedelics.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C11", "text": "In the corrected report, 17 of 24 treated participants (71%) met response criteria at week 1 and at week 4 on the blinded GRID-HAMD, with remission in 58% and 54%; the immediate group improved relative to the delayed group at corresponding visits.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Red-team verification: Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C12", "text": "All 24 treated participants completed 12-month follow-up: mean GRID-HAMD fell from 22.8 at baseline to 7.7 at 12 months, with 75% meeting response and 58% remission criteria.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C13", "text": "In the open-label feasibility cohort, QIDS improved by −11.8 points at one week (95% CI −9.15 to −14.35, p=0.002, Hedges' g=3.1) and −9.2 points at three months (95% CI −5.69 to −12.71, p=0.003, g=2) after the 25 mg session.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C14", "text": "In the expanded open-label cohort, nine of nineteen completers met response and four met remission criteria at week 5, with within-cohort effect sizes of about 1.5 at three months and 1.4 at six months; no patient sought conventional antidepressant treatment within five weeks.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C15", "text": "At day 14, MADRS remission occurred in 14 of 26 psilocybin participants (54%) versus 3 of 26 on placebo (P=0.0023), and MADRS response in 15 of 26 versus 4 of 26 (P=0.0034).", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C16", "text": "Before crossover, BDI antidepressant response at seven weeks was 83% in the psilocybin-first arm versus 14% in the niacin-first arm.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C17", "text": "At a mean of 3.2 and 4.5 years, approximately 60–80% of the assessed survivors met criteria for clinically significant antidepressant or anxiolytic response; 15 of the 16 participants still alive took part.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C18", "text": "Five weeks after the first session, clinician-rated depression response was 92% in the high-dose-first group versus 32% in the low-dose-first group; after all participants had received the high dose, the overall six-month response rate was 78%.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C19", "text": "In a within-subject crossover pilot, trait anxiety was significantly reduced at one and three months and BDI-measured mood improvement reached significance at six months, while Profile of Mood States improvement approached but did not reach significance.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C20", "text": "The primary day-28 MADRS improvement favoured psilocybin by −12.00 points (95% CI −17.67 to −6.33, P<.001) in clinicians with persistent depressive symptoms after frontline COVID-19 work.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C21", "text": "After two psilocybin doses combined with twelve CBT sessions over four months, 10 of 16 participants (62.5%) met HAM-D response criteria and 9 of 16 (56.3%) remitted, with improvements maintained three months after treatment (Hedges' g 1.9–2.7 pre-to-post).", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C22", "text": "In a fixed-order within-subject trial, depression and anxiety improved significantly after both placebo and psilocybin with no significant difference between conditions; response was 66.7% and remission 46.7% after psilocybin, within-condition effect sizes were larger after psilocybin (g′ 1.02–2.27) than after placebo (0.65–0.99), and mystical-type experience intensity was not correlated with subsequent antidepressant effect.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C23", "text": "At 6–7 weeks, psilocybin produced greater reductions than niacin in HADS depression (B=−2.49, P=.02, d=1.12), BDI-II (B=−7.56, P=.004) and state anxiety (B=−12.59, P=.005), with benefits described as sustained at 26 weeks.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C24", "text": "A single 1 mg/kg dose increased medial frontal spine density (+7±2% at day 1, +12±3% at day 7) and spine head width (+11±2% at day 1) by raising the formation rate, with about half of new day-1 spines still present at day 7 and 34±10% (females) and 37±12% (males) persisting to day 34, and increased miniature excitatory current frequency at 24 h (P=0.0002); ketanserin pretreatment that abolished head-twitch responses left spine head width (+12±1%, P=0.01), protrusion length and formation rate elevated while the density increase became nonsignificant (+5±2% day 1, +8±2% day 7, P=0.09).", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Red-team verification: Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C25", "text": "A single 1 mg/kg psilocybin dose restored sucrose and female-urine preference after chronic stress and strengthened hippocampal AMPA-receptor responses, and neither effect was prevented by ketanserin pretreatment despite evidence of the antagonist's efficacy.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C26", "text": "One day after a single 0.08 mg/kg intravenous dose, hippocampal SV2A binding was 4.42% higher with unchanged prefrontal binding, and at seven days hippocampal binding was 9.24% and prefrontal binding 6.10% higher, while 5-HT2A density was acutely reduced.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C27", "text": "Pharmacological and genetic manipulations indicate that 5-HT2A receptor activation is required for tryptamine psychedelics to produce antidepressant-like behavioural effects, with psilocybin rescuing corticosterone-induced anhedonia in wild-type but not constitutive 5-HT2A knockout mice.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C28", "text": "Cell-entry, congener and antagonist-localisation experiments indicate that intracellular 5-HT2A receptors mediate psychedelic-induced cortical neuronal growth, explaining why serotonin itself does not engage the same mechanism.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C29", "text": "LSD and psilocin bind TrkB with affinities about 1,000-fold higher than conventional antidepressants at a transmembrane site partly overlapping the antidepressant site, and psychedelic effects on neurotrophic signalling, plasticity and antidepressant-like behaviour in mice depend on TrkB binding and endogenous BDNF signalling while LSD-induced head twitching depends on 5-HT2A.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C30", "text": "A single 0.3 mg/kg dose reinstated adult social reward learning one and two weeks later with closure by three weeks, alongside metaplastic restoration of oxytocin-mediated long-term depression in nucleus accumbens, and the duration of the open state across psychedelics tracked the duration of their acute subjective effects in humans.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C31", "text": "A single 1 mg/kg dose produced anxiolytic- and antidepressant-like effects lasting up to 15 days in a chronic despair model, and psilocybin remained effective in constitutive 5-HT2A knockout mice whereas DOI and the non-hallucinogenic agonist lisuride did not.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C32", "text": "A single 1 mg/kg dose increased spine density in both pyramidal-tract and intratelencephalic frontal cortical neurons, with the elevation still significant at the final imaging session on day 65; silencing pyramidal-tract neurons eliminated psilocybin's effects on stress-related behaviour while silencing intratelencephalic neurons did not, and adult cortical 5-HT2A knockout abolished both the behavioural effects and pyramidal-tract structural remodeling.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C33", "text": "Monosynaptic rabies tracing showed that psilocybin reorganised inputs to frontal cortical pyramidal neurons network-specifically, strengthening perceptual and medial (default-mode homolog) inputs to subcortical-projecting neurons while weakening cortico-cortical recurrent inputs, and silencing retrosplenial cortex during dosing prevented the subsequent retrosplenial input gain.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C34", "text": "In iPSC-derived human cortical neurons, psilocin produced a 5-HT2A-dependent increase in BDNF abundance reproduced across four independent control lines, transcriptomic signatures consistent with priming for plasticity, greater neuronal complexity and synaptic-marker expression, and increased excitability and network activity, with some changes persisting after washout.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C35", "text": "Profiling of 41 psychedelics against 318 human GPCRs, and of LSD against more than 450 human kinases, documented potent activity at nearly every serotonin, dopamine and adrenergic receptor and multiple 5-HT2A transducer pathways correlating with psychedelic-like actions in vivo.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C36", "text": "In adult rats, single doses of psilocybin or of the selective 5-HT2A agonist 25CN-NBOH reduced forced-swim immobility with no decline in effect size for at least three months and changed resting membrane potential, firing rate and synaptic excitation in layer 5 medial prefrontal neurons months later, while spine density, spine classification and pre- and postsynaptic marker gene expression showed no differences from control.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4", "SC5" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C37", "text": "In the preregistered primary analysis (12 of 15 participants with complete arterial input), frontal-cortex SV2A binding rose 2.3% (one-sided p=0.29) and hippocampal binding 3.0% (p=0.33) one week after 0.3 mg/kg psilocybin, with reference-region analyses in all 15 showing −0.03% (p=0.54) and +1.01% (p=0.44); recruitment stopped at a preplanned futility analysis, and exploratory setting analyses showed 5–6% increases in the therapeutic-room subgroup whose own confidence intervals included zero (frontal ΔV_T 1.1 mL/cm³, 95% CI −0.5 to 2.7) with a nominally significant between-setting frontal difference (3.0 mL/cm³, 95% CI 0.4 to 5.5; likelihood-ratio p=0.03) and no significant relation between SV2A change and three-month persisting effects (p>0.37).", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C38", "text": "One month after 25 mg, axial diffusivity fell in prefrontal–striatal (p=0.006) and prefrontal–thalamic (p=0.005) tracts, brain-network modularity decreased relative to baseline (p=0.02) and correlated with well-being change in the 25 mg versus 1 mg contrast (r=−0.4, p=0.04, two-tailed), while a tract-based spatial statistics analysis was null and enduring functional changes were otherwise largely absent; acute EEG entropy predicted one-month well-being with next-day insight as a statistical mediator.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C39", "text": "Reduced resting-state fMRI network modularity after psilocybin correlated with symptom improvement in both an open-label treatment-resistant cohort and the randomized psilocybin-versus-escitalopram cohort, while no network reorganisation was observed after escitalopram.", "carries_number": false, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C40", "text": "Before-and-after imaging in the open-label treatment-resistant cohort found reduced temporal-cortex and amygdala cerebral blood flow whose amygdala component correlated with immediate symptom improvement, increased default-mode connectivity after treatment, and connectivity measures that predicted five-week response, with usable pre- and post-treatment data from 16 of 19 patients and 47% meeting response criteria at five weeks.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C41", "text": "Cognitive flexibility improved for at least four weeks after treatment but was uncorrelated with antidepressant change at every timepoint pairing (all |r| < 0.2, all p > 0.250); anterior cingulate glutamate (t(19)=2.54, p=0.020) and N-acetylaspartate (t(19)=3.05, p=0.007) decreased at one week, and greater increases in anterior-to-posterior cingulate dynamic connectivity were associated with less cognitive improvement.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C42", "text": "Dense precision mapping in seven healthy adults found acute functional-connectivity disruption more than threefold greater than methylphenidate's, driven by desynchronization across spatial scales and strongest in the default-mode network, with whole-brain architecture largely returning to baseline while anterior hippocampus–default-network connectivity remained reduced for about three weeks.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C43", "text": "In eight healthy volunteers, single oral doses of 3–30 mg psilocybin produced dose-related neocortical 5-HT2A receptor occupancy up to 72%, with subjective intensity closely associated with both occupancy and plasma psilocin.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C44", "text": "In twelve healthy volunteers given 25 mg/70 kg, negative affect and amygdala response to facial affect were reduced at one week and returned to baseline by one month while positive affect remained elevated and trait anxiety was reduced, and the number of significant resting-state connections increased at both follow-ups.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C45", "text": "In a double-blind, placebo-controlled, counterbalanced crossover in 28 healthy participants, neither psilocybin (15 or 30 mg) nor LSD (100 or 200 µg) altered plasma BDNF concentrations relative to placebo despite strong subjective and autonomic effects.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C46", "text": "Psilocybin significantly increased peak plasma BDNF relative to baseline under both escitalopram (t22=5.4, P<0.001) and placebo pretreatment (t22=3.6, P=0.002), and escitalopram pretreatment did not alter that increase.", "carries_number": true, "load_bearing_for": [ "SC4", "SC5" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Red-team verification: Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C47", "text": "Pooled across trials, psychedelic-assisted therapy was not more effective than open-label conventional antidepressant treatment, and while blinding status changed within-arm outcomes for conventional antidepressants it did not for psychedelic therapy, consistent with psychedelic trials being effectively open label.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C48", "text": "Control-arm improvement is markedly smaller in psilocybin trials than in SSRI or esketamine trials while active-arm improvement is comparable, indicating that psilocybin's between-group effect sizes are inflated relative to those comparators.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C49", "text": "Pooled randomized evidence shows a significant antidepressant benefit of psilocybin over comparator treatment, with larger effects where depression is secondary to another condition, where outcomes are self-rated, and in participants with previous psychedelic use, at moderate risk of bias throughout.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." }, { "id": "C50", "text": "In freely behaving adult rats, single psilocybin doses (0.3 or 1 mg/kg) unmasked roughly 100 Hz oscillations most pronounced in infralimbic cortex lasting about an hour with decreased firing rates and reduced spike-train complexity, followed by gradually emerging increases in beta and low-gamma local field potential power at one, two and six days after dosing.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Red-team verification: Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "verified_on": "2026-09-28", "note": "Verified as a report at recorded access depth, not independent confirmation of its data or proof of its causal interpretation." } ], "citation_ledger": [ { "n": 1, "citation": "Rucker JJ et al., Nature medicine 2026. Psilocybin-assisted therapy for treatment-resistant major depressive disorder in a public healthcare setting: a randomized controlled trial.", "tier": "A", "kind": "primary", "pmid": "42562964", "pmcid": "PMC13577891", "doi": "10.1038/s41591-026-04541-0", "url": "https://doi.org/10.1038/s41591-026-04541-0", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/42562964/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C1" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "PsiDeR_NHS", "study_ids": [ "PsiDeR_NHS" ], "research_program": null, "access_depth": "full_text_complete", "access_note": "Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 2, "citation": "Mertens LJ et al., JAMA psychiatry 2026. Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.", "tier": "A", "kind": "primary", "pmid": "41848690", "pmcid": "PMC13000742", "doi": "10.1001/jamapsychiatry.2026.0132", "url": "https://doi.org/10.1001/jamapsychiatry.2026.0132", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/41848690/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C2" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "EPISODE_TRD", "study_ids": [ "EPISODE_TRD" ], "research_program": null, "access_depth": "full_text_complete", "access_note": "Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 3, "citation": "Mertens LJ et al., Psychotherapy and psychosomatics 2026. Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression: 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial.", "tier": "A", "kind": "primary", "pmid": "42201843", "pmcid": "PMC13412222", "doi": "10.1159/000552272", "url": "https://doi.org/10.1159/000552272", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/42201843/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C3" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "EPISODE_TRD", "study_ids": [ "EPISODE_TRD" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 4, "citation": "Yngwe H et al., JAMA network open 2026. Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial.", "tier": "A", "kind": "primary", "pmid": "42138922", "pmcid": "PMC13179547", "doi": "10.1001/jamanetworkopen.2026.12589", "url": "https://doi.org/10.1001/jamanetworkopen.2026.12589", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/42138922/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C4" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Sweden_single_dose_MDD", "study_ids": [ "Sweden_single_dose_MDD" ], "research_program": null, "access_depth": "full_text_complete", "access_note": "Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 5, "citation": "Raison CL et al., JAMA 2023. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.", "tier": "A", "kind": "primary", "pmid": "37651119", "pmcid": "PMC10472268", "doi": "10.1001/jama.2023.14530", "url": "https://doi.org/10.1001/jama.2023.14530", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/37651119/", "status_flags": [ "correction_linked" ], "status_detail": "Primary report with linked JAMA correction DOI 10.1001/jama.2024.0828, independently read. Adds an author and corrects a secondary disability-scale CI; primary MADRS estimate unchanged. Bounded status check.", "correction": { "doi": "10.1001/jama.2024.0828", "url": "https://jamanetwork.com/journals/jama/fullarticle/2814577", "effect": "Article corrected 26 January 2024 to add an author to the byline and to correct minor typographical errors (JAMA 2024;331(8):710; PMID 38277159; DOI 10.1001/jama.2024.0828); the primary MADRS estimate is unchanged." }, "carries_claims": [ "C5" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "USONA_MDD_phase2", "study_ids": [ "USONA_MDD_phase2" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 6, "citation": "Goodwin GM et al., The New England journal of medicine 2022. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.", "tier": "A", "kind": "primary", "pmid": "36322843", "pmcid": null, "doi": "10.1056/nejmoa2206443", "url": "https://doi.org/10.1056/nejmoa2206443", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/36322843/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C6" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "COMP001_TRD", "study_ids": [ "COMP001_TRD" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 7, "citation": "Goodwin GM et al., The Journal of clinical psychiatry 2025. Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder.", "tier": "A", "kind": "primary", "pmid": "40047545", "pmcid": null, "doi": "10.4088/jcp.24m15449", "url": "https://doi.org/10.4088/jcp.24m15449", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/40047545/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C7" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "COMP001_TRD + COMP003_SSRI", "study_ids": [ "COMP001_TRD", "COMP003_SSRI" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "abstract_metadata", "verified_by_red_team_on": "2026-09-28" }, { "n": 8, "citation": "Goodwin GM et al., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2023. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication.", "tier": "A", "kind": "primary", "pmid": "37443386", "pmcid": "PMC10425429", "doi": "10.1038/s41386-023-01648-7", "url": "https://doi.org/10.1038/s41386-023-01648-7", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/37443386/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C8" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "COMP003_SSRI", "study_ids": [ "COMP003_SSRI" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 9, "citation": "Carhart-Harris R et al., The New England journal of medicine 2021. Trial of Psilocybin versus Escitalopram for Depression.", "tier": "A", "kind": "primary", "pmid": "33852780", "pmcid": null, "doi": "10.1056/nejmoa2032994", "url": "https://doi.org/10.1056/nejmoa2032994", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/33852780/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C9" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03429075", "study_ids": [ "NCT03429075" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 10, "citation": "Erritzoe D et al., EClinicalMedicine 2024. Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial.", "tier": "A", "kind": "primary", "pmid": "39764567", "pmcid": "PMC11701471", "doi": "10.1016/j.eclinm.2024.102799", "url": "https://doi.org/10.1016/j.eclinm.2024.102799", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/39764567/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C10" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03429075", "study_ids": [ "NCT03429075" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 11, "citation": "Davis AK et al., JAMA psychiatry 2021. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.", "tier": "A", "kind": "primary", "pmid": "33146667", "pmcid": "PMC7643046", "doi": "10.1001/jamapsychiatry.2020.3285", "url": "https://doi.org/10.1001/jamapsychiatry.2020.3285", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/33146667/", "status_flags": [ "correction_linked" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": { "effect": "Article corrected 10 February 2021 for errors in a response rate, effect sizes and confidence intervals (JAMA Psychiatry 2021;78(5):569; PMID 33566065; DOI 10.1001/jamapsychiatry.2020.4714); the values recorded here are the corrected ones. A separate correction notice appears at PMID 33566073 / DOI 10.1001/jamapsychiatry.2020.4638.", "pmid": "33566065", "doi": "10.1001/jamapsychiatry.2020.4714" }, "carries_claims": [ "C11" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03181529", "study_ids": [ "NCT03181529" ], "research_program": null, "access_depth": "full_text_complete", "access_note": "Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 12, "citation": "Gukasyan N et al., Journal of psychopharmacology (Oxford, England) 2022. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up.", "tier": "A", "kind": "primary", "pmid": "35166158", "pmcid": "PMC8864328", "doi": "10.1177/02698811211073759", "url": "https://doi.org/10.1177/02698811211073759", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/35166158/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C12" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03181529", "study_ids": [ "NCT03181529" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 13, "citation": "Carhart-Harris RL et al., The lancet. Psychiatry 2016. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.", "tier": "A", "kind": "primary", "pmid": "27210031", "pmcid": null, "doi": "10.1016/s2215-0366(16)30065-7", "url": "https://doi.org/10.1016/s2215-0366(16)30065-7", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/27210031/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C13" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Imperial_TRD_ISRCTN14426797", "study_ids": [ "Imperial_TRD_ISRCTN14426797" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 14, "citation": "Carhart-Harris RL et al., Psychopharmacology 2018. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.", "tier": "A", "kind": "primary", "pmid": "29119217", "pmcid": "PMC5813086", "doi": "10.1007/s00213-017-4771-x", "url": "https://doi.org/10.1007/s00213-017-4771-x", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/29119217/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C14" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Imperial_TRD_ISRCTN14426797", "study_ids": [ "Imperial_TRD_ISRCTN14426797" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 15, "citation": "von Rotz R et al., EClinicalMedicine 2023. Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial.", "tier": "A", "kind": "primary", "pmid": "36636296", "pmcid": "PMC9830149", "doi": "10.1016/j.eclinm.2022.101809", "url": "https://doi.org/10.1016/j.eclinm.2022.101809", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/36636296/", "status_flags": [ "correction_linked" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false. Linked Corrigendum PMID 36747965 (PMC9898017) read: Figure 2 color coding was corrected/harmonized to blue psilocybin and yellow placebo; numerical findings were not changed.", "correction": { "pmid": "36747965", "doi": "10.1016/j.eclinm.2023.101841", "effect": "Corrigendum harmonising Figure 2 colour labels (blue psilocybin, yellow placebo); numerical findings unchanged (DOI 10.1016/j.eclinm.2023.101841; PMID 36747965)." }, "carries_claims": [ "C15" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Zurich_MDD_single_dose", "study_ids": [ "Zurich_MDD_single_dose" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 16, "citation": "Ross S et al., Journal of psychopharmacology (Oxford, England) 2016. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.", "tier": "A", "kind": "primary", "pmid": "27909164", "pmcid": "PMC5367551", "doi": "10.1177/0269881116675512", "url": "https://doi.org/10.1177/0269881116675512", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/27909164/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C16" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NYU_cancer_psilocybin", "study_ids": [ "NYU_cancer_psilocybin" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 17, "citation": "Agin-Liebes GI et al., Journal of psychopharmacology (Oxford, England) 2020. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.", "tier": "A", "kind": "primary", "pmid": "31916890", "pmcid": null, "doi": "10.1177/0269881119897615", "url": "https://doi.org/10.1177/0269881119897615", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/31916890/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C17" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NYU_cancer_psilocybin", "study_ids": [ "NYU_cancer_psilocybin" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 18, "citation": "Griffiths RR et al., Journal of psychopharmacology (Oxford, England) 2016. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.", "tier": "A", "kind": "primary", "pmid": "27909165", "pmcid": "PMC5367557", "doi": "10.1177/0269881116675513", "url": "https://doi.org/10.1177/0269881116675513", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/27909165/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C18" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "JHU_cancer_psilocybin", "study_ids": [ "JHU_cancer_psilocybin" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 19, "citation": "Grob CS et al., Archives of general psychiatry 2011. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer.", "tier": "A", "kind": "primary", "pmid": "20819978", "pmcid": null, "doi": "10.1001/archgenpsychiatry.2010.116", "url": "https://doi.org/10.1001/archgenpsychiatry.2010.116", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/20819978/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C19" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "UCLA_cancer_pilot", "study_ids": [ "UCLA_cancer_pilot" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 20, "citation": "Back AL et al., JAMA network open 2024. Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial.", "tier": "A", "kind": "primary", "pmid": "39636638", "pmcid": "PMC11621983", "doi": "10.1001/jamanetworkopen.2024.49026", "url": "https://doi.org/10.1001/jamanetworkopen.2024.49026", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/39636638/", "status_flags": [ "correction_linked" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": { "effect": "Two corrections attach to this report: Error in the Byline (DOI 10.1001/jamanetworkopen.2024.59278; PMID 39804652) and Errors in the Author Affiliations (DOI 10.1001/jamanetworkopen.2025.25303; PMID 40638123); numerical results are unaffected.", "pmid": "39804652", "doi": "10.1001/jamanetworkopen.2024.59278", "second_correction_doi": "10.1001/jamanetworkopen.2025.25303", "second_correction_pmid": "40638123" }, "carries_claims": [ "C20" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Clinicians_COVID_MDDsymptoms", "study_ids": [ "Clinicians_COVID_MDDsymptoms" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 21, "citation": "Weintraub MJ et al., Journal of affective disorders 2026. Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trial.", "tier": "A", "kind": "primary", "pmid": "41707717", "pmcid": "PMC13138500", "doi": "10.1016/j.jad.2026.121423", "url": "https://doi.org/10.1016/j.jad.2026.121423", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/41707717/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; current NCBI PMC cloud metadata is_retracted=false.", "correction": null, "carries_claims": [ "C21" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "UCLA_PA_CBT_MDD", "study_ids": [ "UCLA_PA_CBT_MDD" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Primary journal research report.", "access_depth_original": "full_text_complete", "verified_by_red_team_on": "2026-09-28" }, { "n": 22, "citation": "Sloshower J et al., Journal of psychopharmacology (Oxford, England) 2023. Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial.", "tier": "A", "kind": "primary", "pmid": "36938991", "pmcid": null, "doi": "10.1177/02698811231154852", "url": "https://doi.org/10.1177/02698811231154852", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/36938991/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C22" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Yale_fixed_order_MDD", "study_ids": [ "Yale_fixed_order_MDD" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "abstract_metadata", "verified_by_red_team_on": "2026-09-28" }, { "n": 23, "citation": "Ross ML et al., General hospital psychiatry 2025. Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial.", "tier": "A", "kind": "primary", "pmid": "40858059", "pmcid": null, "doi": "10.1016/j.genhosppsych.2025.08.001", "url": "https://doi.org/10.1016/j.genhosppsych.2025.08.001", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/40858059/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; no retraction flag in retrieved PubMed/Europe PMC metadata. This is a bounded status check, not an exhaustive postpublication review.", "correction": null, "carries_claims": [ "C23" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Melbourne_life_threatening_illness", "study_ids": [ "Melbourne_life_threatening_illness" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal research report.", "access_depth_original": "abstract_metadata", "verified_by_red_team_on": "2026-09-28" }, { "n": 24, "citation": "Shao LX et al., Neuron 2021. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.", "tier": "A", "kind": "primary", "pmid": "34228959", "pmcid": "PMC8376772", "doi": "10.1016/j.neuron.2021.06.008", "url": "https://doi.org/10.1016/j.neuron.2021.06.008", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8376772/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C24" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "shao_2021_longitudinal_mouse", "study_ids": [ "shao_2021_longitudinal_mouse" ], "research_program": "Kwan", "access_depth": "full_text_complete", "access_note": "Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "publication_version": "Same Kwan program as Shao 2025 and Jiang 2026: distinct papers, not independent lab replication. PMC contains the NIH author manuscript linked to the final Neuron DOI.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 25, "citation": "Hesselgrave N et al., Proceedings of the National Academy of Sciences of the United States of America 2021. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice.", "tier": "A", "kind": "primary", "pmid": "33850049", "pmcid": "PMC8092378", "doi": "10.1073/pnas.2022489118", "url": "https://doi.org/10.1073/pnas.2022489118", "primary_reading_url": "https://www.pnas.org/doi/full/10.1073/pnas.2022489118", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C25" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "hesselgrave_2021_stressed_mouse", "study_ids": [ "hesselgrave_2021_stressed_mouse" ], "research_program": "Thompson", "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Independent Thompson program. Full publisher methods were successfully read through PNAS; the supplement was not separately read.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 26, "citation": "Raval NR et al., International journal of molecular sciences 2021. A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain.", "tier": "A", "kind": "primary", "pmid": "33467676", "pmcid": "PMC7830000", "doi": "10.3390/ijms22020835", "url": "https://doi.org/10.3390/ijms22020835", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7830000/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C26" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "raval_2021_juvenile_pig", "study_ids": [ "raval_2021_juvenile_pig" ], "research_program": "Knudsen", "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Independent Knudsen program and large-animal assay. Converges on broad cortical-change plausibility, but these are juvenile animals under strict adult-system wording.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 27, "citation": "Cameron LP et al., ACS chemical neuroscience 2023. 5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines.", "tier": "A", "kind": "primary", "pmid": "36630260", "pmcid": "PMC9939288", "doi": "10.1021/acschemneuro.2c00718", "url": "https://doi.org/10.1021/acschemneuro.2c00718", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9939288/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C27" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "cameron_2023_cort_mouse", "study_ids": [ "cameron_2023_cort_mouse" ], "research_program": "Olson", "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Cameron etal 2023, not Jaster. Shares the Olson program with Vargas 2023 and the adjacent Ly 2018 study.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 28, "citation": "Vargas MV et al., Science (New York, N.Y.) 2023. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.", "tier": "A", "kind": "primary", "pmid": "36795823", "pmcid": "PMC10108900", "doi": "10.1126/science.adf0435", "url": "https://doi.org/10.1126/science.adf0435", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10108900/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C28" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "vargas_2023_intracellular_receptor", "study_ids": [ "vargas_2023_intracellular_receptor" ], "research_program": "Olson", "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Shared Olson program with Cameron 2023/Ly 2018. Preserve the distinction between psilocin cultures and engineered serotonin entry in vivo.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 29, "citation": "Moliner R et al., Nature neuroscience 2023. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.", "tier": "A", "kind": "primary", "pmid": "37280397", "pmcid": "PMC10244169", "doi": "10.1038/s41593-023-01316-5", "url": "https://doi.org/10.1038/s41593-023-01316-5", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10244169/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C29" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "moliner_2023_trkb", "study_ids": [ "moliner_2023_trkb" ], "research_program": "Castren", "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Independent Castrén program. The Jain LSD kinase panel is not an exact test of this transmembrane allosteric binding assay.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 30, "citation": "Nardou R et al., Nature 2023. Psychedelics reopen the social reward learning critical period.", "tier": "A", "kind": "primary", "pmid": "37316665", "pmcid": "PMC10284704", "doi": "10.1038/s41586-023-06204-3", "url": "https://doi.org/10.1038/s41586-023-06204-3", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10284704/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C30" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "nardou_2023_social_critical_period", "study_ids": [ "nardou_2023_social_critical_period" ], "research_program": "Dolen", "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Independent Dölen program; strong positive evidence for a bounded learning window with circuit-specific limits.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 31, "citation": "Sekssaoui M et al., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2024. Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?", "tier": "A", "kind": "primary", "pmid": "38212441", "pmcid": "PMC10876623", "doi": "10.1038/s41386-024-01794-6", "url": "https://doi.org/10.1038/s41386-024-01794-6", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10876623/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C31" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "sekssaoui_2024_chronic_despair", "study_ids": [ "sekssaoui_2024_chronic_despair" ], "research_program": "Becamel", "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Independent Montpellier/Bécamel program. Genuine model-specific counterevidence to universal 5-HT2A behavioral necessity.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 32, "citation": "Shao LX et al., Nature 2025. Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.", "tier": "A", "kind": "primary", "pmid": "40175553", "pmcid": "PMC12188471", "doi": "10.1038/s41586-025-08813-6", "url": "https://doi.org/10.1038/s41586-025-08813-6", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12188471/", "status_flags": [ "correction_linked" ], "status_detail": "Correction recorded: PMID41023408, DOI10.1038/s41586-025-09671-y. 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Correction PMID 41023408 changes calcium-figure axis labels from (before−after)/before to (after−before)/before in Fig 3 e,h,k,n and Extended Data 7 b–e; it does not withdraw spine/behavior conclusions. Precursor PMID 39554087 excluded as duplicate.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 33, "citation": "Jiang Q et al., Cell 2026. Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks.", "tier": "A", "kind": "primary", "pmid": "41352354", "pmcid": "PMC12695013", "doi": "10.1016/j.cell.2025.11.009", "url": "https://doi.org/10.1016/j.cell.2025.11.009", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC12695013/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C33" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "jiang_2026_activity_network", "study_ids": [ "jiang_2026_activity_network" ], "research_program": "Kwan", "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "NIHPA accepted author manuscript bearing final Cell 2026 DOI, rather than a precursor preprint. Shares Kwan program; mixed-age methods must not all be labeled adult.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 34, "citation": "Schmidt M et al., eLife 2026. Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons.", "tier": "A", "kind": "primary", "pmid": "41891829", "pmcid": "PMC13030890", "doi": "10.7554/elife.104006", "url": "https://doi.org/10.7554/elife.104006", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13030890/", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C34" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "schmidt_2026_human_ipsc", "study_ids": [ "schmidt_2026_human_ipsc" ], "research_program": "Koch", "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "eLife research article RP104006 as indexed in PMC; peer review is indicated by named reviewing and senior editors. Not used as adult-human causal evidence.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 35, "citation": "Jain MK et al., Neuron 2025. The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.", "tier": "A", "kind": "primary", "pmid": "40683247", "pmcid": null, "doi": "10.1016/j.neuron.2025.06.012", "url": "https://doi.org/10.1016/j.neuron.2025.06.012", "primary_reading_url": "https://www.sciencedirect.com/science/article/pii/S0896627325004702", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C35" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "jain_2025_polypharmacology", "study_ids": [ "jain_2025_polypharmacology" ], "research_program": "Roth", "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Independent Roth/Dror/Shoichet program. Use as an alternative-target constraint, not a direct TrkB-binding refutation.", "access_depth_original": "abstract_metadata", "verified_by_red_team_on": "2026-09-28" }, { "n": 36, "citation": "Kramer HM et al., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2026. Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity.", "tier": "A", "kind": "primary", "pmid": "41224969", "pmcid": "PMC12824308", "doi": "10.1038/s41386-025-02272-3", "url": "https://doi.org/10.1038/s41386-025-02272-3", "primary_reading_url": "https://www.nature.com/articles/s41386-025-02272-3", "status_flags": [ "none_found" ], "status_detail": "No retraction or correction flag in the current Europe PMC MED record; bounded status check, not exhaustive certification.", "correction": null, "carries_claims": [ "C36" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "kramer_2025_2026_enduring_rat", "study_ids": [ "kramer_2025_2026_enduring_rat" ], "research_program": "Nichols", "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Online 2025, journal issue 2026; independent Nichols program. Constrains persistent structural necessity, without disproving an early plasticity mediator.", "access_depth_original": "abstract_metadata", "verified_by_red_team_on": "2026-09-28" }, { "n": 37, "citation": "Johansen A et al., Transl Psychiatry 2026. Psilocybin's effect on human brain synaptic plasticity.", "tier": "A", "kind": "primary", "pmid": "42457666", "pmcid": null, "doi": "10.1038/s41398-026-04285-y", "url": "https://doi.org/10.1038/s41398-026-04285-y", "primary_reading_url": "https://www.nature.com/articles/s41398-026-04285-y_reference.pdf?error=cookies_not_supported&code=a", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C37" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03289949_subproject2b_SV2A_healthy15", "study_ids": [ "NCT03289949_subproject2b_SV2A_healthy15" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Peer-reviewed accepted publisher manuscript in press; predecessor ResearchSquare version excluded from counting and interpretation.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 38, "citation": "Lyons T et al., Nat Commun 2026. Human brain changes after first psilocybin use.", "tier": "A", "kind": "primary", "pmid": "42086570", "pmcid": "PMC13144397", "doi": "10.1038/s41467-026-71962-3", "url": "https://doi.org/10.1038/s41467-026-71962-3", "primary_reading_url": "https://www.nature.com/articles/s41467-026-71962-3", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C38" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Imperial_first_psilocybin_healthy28_fixed_order_Lyons2026", "study_ids": [ "Imperial_first_psilocybin_healthy28_fixed_order_Lyons2026" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Complete EuropePMC XML is saved. Relevant Methods, Results and Discussion were read. The authors describe an exploratory nonclinical study that was not registered as a clinical trial.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 39, "citation": "Daws RE et al., Nat Med 2022. Increased global integration in the brain after psilocybin therapy for depression.", "tier": "A", "kind": "primary", "pmid": "35411074", "pmcid": null, "doi": "10.1038/s41591-022-01744-z", "url": "https://doi.org/10.1038/s41591-022-01744-z", "primary_reading_url": "https://unlimitedsciences.org/wp-content/uploads/2023/10/s41591-022-01744-z-1.pdf", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C39" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Imperial_TRD_ISRCTN14426797 + NCT03429075", "study_ids": [ "Imperial_TRD_ISRCTN14426797", "NCT03429075" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Relevant Methods, Results and Discussion were read in the published 15-page PDF from the UnlimitedSciences mirror. The title, DOI and trial identifiers matched publisher/PubMed metadata. The publisher article page itself supplied a preview.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 40, "citation": "Carhart-Harris RL et al., Sci Rep 2017. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.", "tier": "A", "kind": "primary", "pmid": "29030624", "pmcid": "PMC5640601", "doi": "10.1038/s41598-017-13282-7", "url": "https://doi.org/10.1038/s41598-017-13282-7", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC5640601/", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C40" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "Imperial_TRD_ISRCTN14426797", "study_ids": [ "Imperial_TRD_ISRCTN14426797" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Complete EuropePMC XML is saved. Relevant Methods, Results and Discussion were read.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 41, "citation": "Doss MK et al., Transl Psychiatry 2021. Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder.", "tier": "A", "kind": "primary", "pmid": "34750350", "pmcid": "PMC8575795", "doi": "10.1038/s41398-021-01706-y", "url": "https://doi.org/10.1038/s41398-021-01706-y", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8575795/", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C41" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03181529", "study_ids": [ "NCT03181529" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Complete EuropePMC XML is saved. Relevant Methods, Results and Discussion were read, including the delayed-group design and the null depression–flexibility relation.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 42, "citation": "Siegel JS et al., Nature 2024. Psilocybin desynchronizes the human brain.", "tier": "A", "kind": "primary", "pmid": "39020167", "pmcid": "PMC11291293", "doi": "10.1038/s41586-024-07624-5", "url": "https://doi.org/10.1038/s41586-024-07624-5", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC11291293/", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C42" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT04501653_Siegel2024_healthy7_precision_mapping", "study_ids": [ "NCT04501653_Siegel2024_healthy7_precision_mapping" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Complete EuropePMC XML is saved. Relevant main Methods, Results and Discussion were read.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 43, "citation": "Madsen MK et al., Neuropsychopharmacology 2019. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.", "tier": "A", "kind": "primary", "pmid": "30685771", "pmcid": "PMC6785028", "doi": "10.1038/s41386-019-0324-9", "url": "https://doi.org/10.1038/s41386-019-0324-9", "primary_reading_url": "https://controversiasbarcelona.com/2019/Knudsen2019.pdf", "status_flags": [ "correction_recorded" ], "status_detail": "Published correction exists; figure numbering only. No retraction notice found in retrieved metadata.", "correction": { "pmid": "30846853", "doi": "10.1038/s41386-019-0360-5", "effect": "Figure numbering correction; no reported numerical change." }, "carries_claims": [ "C43" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NRU_Madsen2019_5HT2A_PET_healthy8", "study_ids": [ "NRU_Madsen2019_5HT2A_PET_healthy8" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Relevant Methods, Results and Discussion were read in a seven-page published PDF from a conference mirror. PubMed links correction PMID 30846853: Figures 2 and 3 were misnumbered; captions and content were correct. The indexed primary publisher correction PDF was read. Same NRU research programme as Johansen, but a distinct sample/subproject; participant overlap was not established.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 44, "citation": "Barrett FS et al., Sci Rep 2020. Emotions and brain function are altered up to one month after a single high dose of psilocybin.", "tier": "A", "kind": "primary", "pmid": "32042038", "pmcid": "PMC7010702", "doi": "10.1038/s41598-020-59282-y", "url": "https://doi.org/10.1038/s41598-020-59282-y", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7010702/", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C44" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT02971605_Barrett2020_healthy12", "study_ids": [ "NCT02971605_Barrett2020_healthy12" ], "research_program": null, "access_depth": "abstract_metadata", "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Complete EuropePMC XML is saved. Relevant main Methods, Results and Discussion were read.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 45, "citation": "Holze F et al., Neuropsychopharmacology 2022. Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects.", "tier": "A", "kind": "primary", "pmid": "35217796", "pmcid": "PMC9018810", "doi": "10.1038/s41386-022-01297-2", "url": "https://doi.org/10.1038/s41386-022-01297-2", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9018810/", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C45" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03604744_Holze2022_healthy28", "study_ids": [ "NCT03604744_Holze2022_healthy28" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Complete EuropePMC XML is saved. Relevant main Methods, Results and Discussion were read; the null plasma BDNF result is explicit.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 46, "citation": "Becker AM et al., Clin Pharmacol Ther 2022. Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.", "tier": "A", "kind": "primary", "pmid": "34743319", "pmcid": "PMC9299061", "doi": "10.1002/cpt.2487", "url": "https://doi.org/10.1002/cpt.2487", "primary_reading_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC9299061/", "status_flags": [ "none_found" ], "status_detail": "No retraction notice found in retrieved PubMed/EuropePMC/publisher publication metadata; targeted status screen only, not exhaustive integrity guarantee.", "correction": null, "carries_claims": [ "C46" ], "opened": true, "opened_on": "2026-09-27", "status_checked_on": "2026-09-28", "study_id": "NCT03912974_Becker2022_healthy23_SSRIpretreatment", "study_ids": [ "NCT03912974_Becker2022_healthy23_SSRIpretreatment" ], "research_program": null, "access_depth": "full_text_partial", "access_note": "Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "publication_version": "Complete EuropePMC XML is saved. Relevant main Methods, Results and Discussion were read. The Discussion explicitly acknowledges the absence of a placebo control for the BDNF rise.", "access_depth_original": "full_text_partial", "verified_by_red_team_on": "2026-09-28" }, { "n": 47, "citation": "Williams ZJ et al., JAMA psychiatry 2026;83(5):461-468. Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis.", "tier": "B", "kind": "systematic_review_meta_analysis", "pmid": "41848744", "pmcid": "PMC13000746", "doi": "10.1001/jamapsychiatry.2025.4809", "url": "https://doi.org/10.1001/jamapsychiatry.2025.4809", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/41848744/", "status_flags": [ "none_found" ], "status_detail": "Peer-reviewed systematic review and meta-analysis; screened for retraction and correction notices with none found.", "correction": null, "carries_claims": [ "C47" ], "opened": true, "opened_on": "2026-09-28", "status_checked_on": "2026-09-28", "study_id": "williams_2026_equal_unblinding", "study_ids": [ "williams_2026_equal_unblinding" ], "research_program": null, "access_depth": "abstract_metadata", "access_depth_original": null, "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal report.", "verified_by_red_team_on": "2026-09-28", "added_by": "red-team synthesis 2026-09-28" }, { "n": 48, "citation": "Hieronymus F et al., JAMA network open 2025;8(7):e2524119. Control Group Outcomes in Trials of Psilocybin, SSRIs, or Esketamine for Depression: A Meta-Analysis.", "tier": "B", "kind": "meta_analysis", "pmid": "40736734", "pmcid": "PMC12311713", "doi": "10.1001/jamanetworkopen.2025.24119", "url": "https://doi.org/10.1001/jamanetworkopen.2025.24119", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/40736734/", "status_flags": [ "none_found" ], "status_detail": "Peer-reviewed meta-analysis; screened for retraction and correction notices with none found.", "correction": null, "carries_claims": [ "C48" ], "opened": true, "opened_on": "2026-09-28", "status_checked_on": "2026-09-28", "study_id": "hieronymus_2025_control_arms", "study_ids": [ "hieronymus_2025_control_arms" ], "research_program": null, "access_depth": "abstract_metadata", "access_depth_original": null, "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal report.", "verified_by_red_team_on": "2026-09-28", "added_by": "red-team synthesis 2026-09-28" }, { "n": 49, "citation": "Metaxa AM, Clarke M. BMJ 2024;385:e078084. Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis.", "tier": "B", "kind": "systematic_review_meta_analysis", "pmid": "38692686", "pmcid": "PMC11062320", "doi": "10.1136/bmj-2023-078084", "url": "https://doi.org/10.1136/bmj-2023-078084", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/38692686/", "status_flags": [ "none_found" ], "status_detail": "Peer-reviewed systematic review and meta-analysis; screened for retraction and correction notices with none found.", "correction": null, "carries_claims": [ "C49" ], "opened": true, "opened_on": "2026-09-28", "status_checked_on": "2026-09-28", "study_id": "metaxa_2024_meta", "study_ids": [ "metaxa_2024_meta" ], "research_program": null, "access_depth": "abstract_metadata", "access_depth_original": null, "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal report.", "verified_by_red_team_on": "2026-09-28", "added_by": "red-team synthesis 2026-09-28" }, { "n": 50, "citation": "Purple RJ et al., Molecular psychiatry 2025;30(12):5889-5900. Short- and long-term modulation of rat prefrontal cortical activity following single doses of psilocybin.", "tier": "A", "kind": "primary", "pmid": "40858779", "pmcid": "PMC12602310", "doi": "10.1038/s41380-025-03182-y", "url": "https://doi.org/10.1038/s41380-025-03182-y", "primary_reading_url": "https://pubmed.ncbi.nlm.nih.gov/40858779/", "status_flags": [ "none_found" ], "status_detail": "Primary research report; screened for retraction and correction notices with none found.", "correction": null, "carries_claims": [ "C50" ], "opened": true, "opened_on": "2026-09-28", "status_checked_on": "2026-09-28", "study_id": "purple_2025_rat_neuropixels", "study_ids": [ "purple_2025_rat_neuropixels" ], "research_program": null, "access_depth": "abstract_metadata", "access_depth_original": null, "access_note": "Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "publication_version": "Primary journal report.", "verified_by_red_team_on": "2026-09-28", "added_by": "red-team synthesis 2026-09-28" } ], "claim_restatement": { "index_wording": "Psilocybin dual-phase (drug plus integration therapy)", "entry_form": "conjunction", "user_wording": "Psilocybin produces durable reduction in depressive symptoms through a drug-induced period of enhanced cortical plasticity.", "gradeable_restatement": "Psilocybin causes a sustained reduction in human depressive symptoms by inducing a temporary increase in cortical plasticity.", "restatement_required": false, "split_into": [ "SC1", "SC2", "SC3", "SC4", "SC5" ], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "human depressive symptoms", "determinable_before_outcome": true, "determined_from": "baseline clinical status and species", "action": "retained" }, { "qualifier": "supervised clinical protocol", "determinable_before_outcome": true, "determined_from": "assigned intervention and setting", "action": "retained as an evidence boundary" }, { "qualifier": "adult experimental systems", "determinable_before_outcome": true, "determined_from": "species, age, receptor/cell manipulation", "action": "supporting subclaim scope only" } ], "durability_benchmark": "Twelve weeks prespecified as the main analytical benchmark; six weeks, six months and twelve months reported separately. Not a universal clinical definition." }, "hypothesis": { "name": "Psilocybin, durable antidepressant response and cortical plasticity — red-team synthesis edition", "central_claim": "Psilocybin causes a sustained reduction in human depressive symptoms by inducing a temporary increase in cortical plasticity.", "proposed_mechanism": "Transient enhancement of cortical inducibility/remodeling carries later depressive-symptom benefit.", "claimed_scope": "disease-class", "claimed_level": [ "response" ], "is_conjunctive": true, "conjunctive_note": "Clinical benefit, its persistence, a temporary cortical-plasticity interval, and mediation by that interval are distinct propositions. Human mediator contribution has not been isolated." }, "lay_summary": { "paragraphs": [ "The hypothesis says psilocybin briefly makes the brain's outer layer more able to change, and that this period of change produces lasting relief from depression.", "Several randomized studies support symptom relief for weeks after supervised treatment, while two large trials missed their main target and long-term advantages are less certain. Almost everyone in these trials can tell whether they received psilocybin, and pooled analyses suggest that matters. Mouse experiments directly observe changes in cortical connections and identify the cells and receptor needed for them; human measurements are indirect and mixed, and one human imaging study found no overall increase in a synaptic marker a week after treatment.", "The complete explanation is Γ, with Moderate confidence: plausible, with real experimental support in other systems, but no reviewed human study shows that a temporary period of increased brain plasticity is what carries the sustained antidepressant effect." ], "grade_restated_faithfully": true, "claims_referenced": [ "C5", "C6", "C24", "C32", "C37", "C47", "C48" ], "jargon_glossed": [ "cortex: the brain outer layer", "plasticity: capacity for change" ], "no_practical_advice": true, "written_for": "general reader, no field background" }, "is_calibration_entry": false, "rubric_routing": { "primary_rubric": "references/evidence-rubrics/07-psychiatry-neuromodulation.md", "secondary_rubrics": [ "references/hsef-framework.md (universal ladder, caps and cap precedence)" ], "index_notes_applied": [ "The hypothesis index assigns 01-neurodegeneration as an acknowledged v3-era mismatch and directs the universal constraints; rubric 07 was added in v4.0 precisely for this class of hypothesis and its scope names 'psilocybin dual-phase models ... rapid-plasticity antidepressant models'.", "Nearest dual-phase index entry is stronger than the user sentence: psychotherapy necessity and subjective-experience necessity are not imported.", "Weakest-link was selected in the saved scope plan before scores; primary-SC5 and scope-matched alternatives are reported and all three return the same letter." ], "rubric_fit_note": "Corrected in the red-team pass. The original edition recorded that no psychiatry-specific rubric existed in the packet and applied the universal framework alone; 07-psychiatry-neuromodulation.md is present and governs. Its comparator principle, Γ hard rules (functional unblinding, mediation by correlation, open label, unblinded rater, acute pharmacodynamics, rodent proxies), Δ design list and upper-ladder equivalents are applied here. Neurodegeneration pathology, seeding and progression requirements are not applied. Routing did not move the overall letter.", "routing_correction": "Rubric 07 substituted for universal-only routing on 2026-09-28 (finding RT-01); the pre-registered aggregation rule and subclaim set were left unchanged." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "A supervised psilocybin-containing protocol causes post-acute reduction of depressive symptoms.", "subclaim_type": "sufficiency", "governing_rubric": "07-psychiatry-neuromodulation.md (primary); universal hsef-framework.md caps and cap precedence", "claimed_scope": "Clinical response in prospectively defined adult depression settings; preparation and support included. Protocol-assignment scope, not drug-specific pharmacological attribution.", "scope": "Clinical response in prospectively defined adult depression settings; preparation and support included. Protocol-assignment scope, not drug-specific pharmacological attribution.", "key_evidence_anchor": "Randomized supported-protocol contrast with a prespecified clinical symptom endpoint.", "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "governing_cap_or_threshold": "Rubric 07 Ε: causal support restricted to a defined context, including with the accompanying psychotherapeutic scaffold", "rationale": "Repeated positive randomized symptom contrasts with null and population boundaries establish causality for assignment to the supported protocol in defined contexts. Component-specific attribution remains unresolved, and rubric 07's functional-unblinding rule caps the drug-specific pharmacological inference at Γ: the positive trials either report no blinding-integrity check or report near-ceiling allocation guessing, and two 2025-2026 syntheses show psychedelic therapy performing no better than open-label antidepressant treatment and psilocybin-trial control arms improving far less than SSRI or esketamine control arms." }, { "id": "SC2", "statement": "Depressive-symptom reduction persists approximately twelve weeks after treatment.", "subclaim_type": "generalization", "governing_rubric": "07-psychiatry-neuromodulation.md (primary); universal hsef-framework.md caps and cap precedence", "claimed_scope": "Human symptom persistence around twelve weeks; six-month and twelve-month endpoints assessed separately.", "scope": "Human symptom persistence around twelve weeks; six-month and twelve-month endpoints assessed separately.", "key_evidence_anchor": "Maintained active-control clinical contrast at twelve weeks with rescue treatment and missingness handled prospectively.", "hsef_level": "Δ", "hsef_descriptor": "First field-valid causal perturbation crossed", "confidence": "Low", "governing_cap_or_threshold": "Universal Δ: First field-valid causal perturbation crossed", "rationale": "Exploratory randomized self-report separation to about three months in a 35-person trial is the only maintained randomized signal at the benchmark; it shortens to day 72 when censoring at antidepressant initiation, the largest peer-reviewed trial did not confirm sustained response at week 12, and rubric 07's open-label rule prevents the observational extensions from crossing Δ however large they are." }, { "id": "SC3", "statement": "Psilocybin induces cortical structural or functional plasticity in adult experimental systems.", "subclaim_type": "mechanism", "governing_rubric": "07-psychiatry-neuromodulation.md (primary); universal hsef-framework.md caps and cap precedence", "claimed_scope": "Direct adult rodent cortical response; juvenile pig and human developmental culture data are supporting bridges.", "scope": "Direct adult rodent cortical response; juvenile pig and human developmental culture data are supporting bridges.", "key_evidence_anchor": "Adult in-vivo cortical measurement under randomized drug and selective receptor/cell perturbation.", "hsef_level": "Ε", "hsef_descriptor": "Context-specific causality established", "confidence": "Moderate", "governing_cap_or_threshold": "Universal Ε: Context-specific causality established", "rationale": "Direct longitudinal spine imaging, slice physiology and adult cell-type and receptor interventions show a bounded experimental cortical response. The strongest direct adult structural work shares one laboratory program and technique, so it is one causal line; two independent adult-rat reports support persistent functional change, one of them explicitly without persistent structural excess." }, { "id": "SC4", "statement": "Psilocybin induces a temporary period of enhanced cortical plasticity in humans.", "subclaim_type": "mechanism", "governing_rubric": "07-psychiatry-neuromodulation.md (primary); universal hsef-framework.md caps and cap precedence", "claimed_scope": "Living human cortical inducibility, with measured opening and closure times.", "scope": "Living human cortical inducibility, with measured opening and closure times.", "key_evidence_anchor": "Positive validated cortical inducibility time course in living humans, under a randomized drug/control contrast.", "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "governing_cap_or_threshold": "Universal Γ: Mechanistically plausible, partial system support", "rationale": "Target engagement and persisting proxies do not measure a temporary increase in cortical inducibility; the one preregistered human synaptic-marker test was null overall and stopped for futility, and a targeted search of the human literature and trial registries found no completed psilocybin study using a validated inducibility assay. Rubric 07's acute-pharmacodynamic rule governs the occupancy and acute-imaging evidence." }, { "id": "SC5", "statement": "That cortical-plasticity period causally mediates sustained human depressive-symptom reduction.", "subclaim_type": "mechanism", "governing_rubric": "07-psychiatry-neuromodulation.md (primary); universal hsef-framework.md caps and cap precedence", "claimed_scope": "The full human drug → cortical-plasticity interval → sustained symptom-response pathway.", "scope": "The full human drug → cortical-plasticity interval → sustained symptom-response pathway.", "key_evidence_anchor": "Human mediator perturbation, timing instrument or natural experiment with justified exclusion restrictions and sustained symptoms.", "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "governing_cap_or_threshold": "Universal Γ: Mechanistically plausible, partial system support", "rationale": "No reviewed human experiment, valid instrument or sufficiently selective contrast establishes this mediator contribution; every human mediation analysis in the set is a correlated-but-unmanipulated mediator, which is rubric 07's mediation-by-correlation rule." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "The sentence is a conjunction requiring sustained human benefit plus an induced cortical-plasticity period and causal mediation; the least supported required link governs.", "primary_subclaim_id": "SC5", "aggregation_derivation": "Ε, Δ, Ε, Γ, Γ → Γ.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "All declared rules return Γ for the full mediated claim. Protocol-level clinical efficacy alone reaches Ε and answers a narrower question; drug-specific pharmacological efficacy at that same scope is itself Γ-capped by rubric 07's functional-unblinding rule. A six-week durability definition would not resolve SC4 or SC5." }, "index_rule_deviation": "User scope excludes the indexed psychotherapy/experience necessity clauses; weakest-link retained for the actual clinical-plasticity conjunction." }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M1", "is_nominal": false, "name": "Context-dependent treatment response with unresolved mediators (including expectancy)", "core_claim": "Assignment to a supported psilocybin protocol reduces symptoms in some clinical contexts through an unresolved combination of pharmacological, experiential and learning processes.", "explains_what_nominal_does_not": "Allows clinical benefit without treating a human cortical plasticity interval as already demonstrated.", "strongest_supporting_evidence": [ "Raison controlled day-43 result [5]", "Goodwin controlled week-3 result [6]", "Psychedelic therapy no better than open-label antidepressant treatment [47]", "Control-arm underperformance in psilocybin trials [48]" ], "strongest_contradictory_evidence": [ "EPISODE primary response null and escitalopram-comparator primary inconclusive [2, 9]" ], "hsef_level_for_this_model": "Ε", "rationale": "Ε attaches to the observable bounded protocol-response claim. Two 2025-2026 syntheses give the expectancy component positive content rather than leaving it a caveat, without showing that the whole effect is expectancy; EPISODE's own stratified description suggests week-6 outcomes did not track unblinding status. It remains a model of unresolved mediators, not a rival molecular mechanism proven by exclusion." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": true, "name": "Temporary enhanced cortical plasticity mediates durable benefit", "core_claim": "A drug-induced interval of increased cortical capacity for change carries sustained human depressive-symptom improvement.", "explains_what_nominal_does_not": "Nominal model; predicts a positive measured window and symptom dependence on intervention during that window.", "strongest_supporting_evidence": [ "Direct mouse cortical growth and cell/receptor interventions [24, 32]", "Clinical brain-function associations [39, 40]" ], "strongest_contradictory_evidence": [ "Overall human one-week SV2A null [37]", "Cognitive-flexibility/depression dissociation [41]" ], "hsef_level_for_this_model": "Γ", "rationale": "Drug-to-cortex effects are causal in defined experimental systems. The temporary human window and its symptom-mediating role have not crossed Δ; the contrary human assays constrain specific predictions, without disproving all functional plasticity." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Persistent circuit-function adaptation without persistent structural excess", "core_claim": "Lasting changes in circuit function contribute to clinical improvement without requiring a demonstrated extended interval of structural growth.", "explains_what_nominal_does_not": "Accommodates persistence of electrophysiology or connectivity when late structural markers are unchanged.", "strongest_supporting_evidence": [ "Human network measurements [42, 39]", "Independent adult-rat report of persisting function with a late spine and marker null [36]", "Independent adult-rat cortical electrophysiology days after dosing [50]" ], "strongest_contradictory_evidence": [ "No selective human circuit-mediator contrast; some fMRI arm/dose contrasts null [39, 38]" ], "hsef_level_for_this_model": "Γ", "rationale": "Human causal mediation remains unresolved, but the model now rests on two independent adult-rat reports rather than one access-limited abstract. It partly overlaps M2 when plasticity is defined broadly; the ranking is provisional and did not determine the letter." } ], "tournament_summary": "M1 is most directly supported at protocol-response scope. M2 remains a plausible mediated explanation; M3 is a partly overlapping functional route. M2/M3 relative ranking is provisional, not an exclusion result.", "study_separating_rank1_from_rank2": "Human drug/control trial with a measured cortical-inducibility window and an independently randomized timing/mediator contrast with justified exclusion restrictions.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "citation": "Rucker JJ et al., Nature medicine 2026. Psilocybin-assisted therapy for treatment-resistant major depressive disorder in a public healthcare setting: a randomized controlled trial.", "source_pointer": "PMID 42562964; DOI 10.1038/s41591-026-04541-0; ref 1", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized parallel feasibility trial: one 25 mg psilocybin dose versus inactive placebo, both with preparation and integration support.", "n": 60, "duration": "3 and 6 weeks", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "Feasibility targets were met (60 randomized, 59 of 60 completing the MADRS at all visits); the adjusted between-group MADRS difference was −10.41 points at week 3 (95% CI −14.86 to −5.95; Cohen's d = −1.70) and −12.92 at week 6 (95% CI −17.37 to −8.47; d = −2.11), both secondary outcomes.", "what_it_does_not_show": "Primary outcomes were recruitment, retention and MADRS variance, not confirmatory efficacy; efficacy estimates are preliminary secondary outcomes. Blinding was not upheld — 13/13 psilocybin and 7/10 placebo participants guessed correctly — and the authors attribute part of the between-group difference to expectancy. Follow-up ended at 6 weeks; no 12-week controlled endpoint and no plasticity measurement.", "confounders_present": [ "Primary outcomes were recruitment, retention and MADRS variance, not confirmatory efficacy; efficacy estimates are preliminary secondary outcomes. Blinding was not upheld — 13/13 psilocybin and 7/10 placebo participants guessed correctly — and the authors attribute part of the between-group difference to expectancy. Follow-up ended at 6 weeks; no 12-week controlled endpoint and no plasticity measurement." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "PsiDeR_NHS", "study_ids": [ "PsiDeR_NHS" ], "access_depth": "full_text_complete" }, { "citation": "Mertens LJ et al., JAMA psychiatry 2026. Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.", "source_pointer": "PMID 41848690; DOI 10.1001/jamapsychiatry.2026.0132; ref 2", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized triple-arm first-period comparison of 25 mg, 5 mg psilocybin, and nicotinamide 100 mg with psychological support; a second session occurred at week 6.", "n": 144, "duration": "Primary 6 weeks; study 12 weeks", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "mixed", "what_it_shows": "The primary week-6 HAMD-17 response endpoint was not significant: 17.0% with 25 mg, 12.5% with 5 mg and 10.6% with nicotinamide (25 mg vs nicotinamide adjusted OR 1.73, 95% CI 0.53–6.23, P=.19), while the key secondary continuous HAMD-17 difference favoured 25 mg (−4.60, 95% CI −7.01 to −2.18, P<.001).", "what_it_does_not_show": "144 randomized, 143 dosed, 142 in the primary analysis. Confirmatory fixed-order testing stopped at the primary endpoint, so all later comparisons are exploratory. All groups received at least one 25 mg dose by week 12. Functional unblinding was substantial (86% of participants correctly identified 25 mg); raters' guesses and participants' expectations were not assessed, although the trial's own stratified description suggests unblinding of dose 1 played a negligible role in week-6 outcomes. No cortical plasticity measurement.", "confounders_present": [ "144 randomized, 143 dosed, 142 in the primary analysis. Confirmatory fixed-order testing stopped at the primary endpoint, so all later comparisons are exploratory. All groups received at least one 25 mg dose by week 12. Functional unblinding was substantial (86% of participants correctly identified 25 mg); raters' guesses and participants' expectations were not assessed, although the trial's own stratified description suggests unblinding of dose 1 played a negligible role in week-6 outcomes. No cortical plasticity measurement." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "EPISODE_TRD", "study_ids": [ "EPISODE_TRD" ], "access_depth": "full_text_complete" }, { "citation": "Mertens LJ et al., Psychotherapy and psychosomatics 2026. Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression: 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial.", "source_pointer": "PMID 42201843; DOI 10.1159/000552272; ref 3", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "actual_system": "human clinical", "design": "Naturalistic 6- and 12-month follow-up of EPISODE; all groups had received at least one 25 mg dose.", "n": 126, "duration": "6 and 12 months", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "In naturalistic follow-up, HAMD-17 remained below baseline at 6 months (−7.93, 95% CI −9.17 to −6.70) and 12 months (−7.74, 95% CI −9.04 to −6.43) with no significant group differences, while sustained response across groups fell from 28/126 (22.2%) at 6 months to 20/126 (15.9%) at 12 months and antidepressant re-initiation was associated with higher HAMD-17 scores (β=3.79, 95% CI 1.98 to 5.60).", "what_it_does_not_show": "126 of 144 randomized participants contributed at least one follow-up visit and no untreated randomized comparison remained; all groups had received 25 mg psilocybin at least once. Group sustained-response totals are sums across the four randomized groups. Observed persistence cannot identify a drug-specific durable effect or a plasticity mediator, and a positive open-label result never crosses Δ.", "confounders_present": [ "126 of 144 randomized participants contributed at least one follow-up visit and no untreated randomized comparison remained; all groups had received 25 mg psilocybin at least once. Group sustained-response totals are sums across the four randomized groups. Observed persistence cannot identify a drug-specific durable effect or a plasticity mediator, and a positive open-label result never crosses Δ." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "EPISODE_TRD", "study_ids": [ "EPISODE_TRD" ], "access_depth": "full_text_partial" }, { "citation": "Yngwe H et al., JAMA network open 2026. Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial.", "source_pointer": "PMID 42138922; DOI 10.1001/jamanetworkopen.2026.12589; ref 4", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized parallel trial: 25 mg psilocybin versus niacin 100 mg with matched psychological support in recurrent MDD.", "n": 35, "duration": "Day 8 primary; day 42, repeated self-report to day 365, and clinician day 365 secondary", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "Clinician-rated MADRS favoured psilocybin at day 8 (−7.27, 95% CI −12.89 to −1.65, P=.01), day 15 (−11.03, 95% CI −16.65 to −5.42, P<.001) and day 42 (−8.33, 95% CI −13.94 to −2.71, P=.004) but not at day 365 (−3.68, 95% CI −9.30 to 1.94, P=.20); self-rated separation persisted to day 102 (−6.60, 95% CI −13.01 to −0.19, P=.04).", "what_it_does_not_show": "17 versus 18 randomized. The self-report separation is exploratory and shortened to day 72 when censoring at antidepressant initiation. Blinding failed at both ends: the blinded rater correctly guessed 12/17 psilocybin and 15/17 niacin allocations at day 8, and at day 365 16/17 psilocybin and 16/16 niacin participants guessed correctly. Small trial not powered for secondary year outcomes; rescue treatment occurred in both arms; cortical plasticity was not measured.", "confounders_present": [ "17 versus 18 randomized. The self-report separation is exploratory and shortened to day 72 when censoring at antidepressant initiation. Blinding failed at both ends: the blinded rater correctly guessed 12/17 psilocybin and 15/17 niacin allocations at day 8, and at day 365 16/17 psilocybin and 16/16 niacin participants guessed correctly. Small trial not powered for secondary year outcomes; rescue treatment occurred in both arms; cortical plasticity was not measured." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Sweden_single_dose_MDD", "study_ids": [ "Sweden_single_dose_MDD" ], "access_depth": "full_text_complete" }, { "citation": "Raison CL et al., JAMA 2023. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.", "source_pointer": "PMID 37651119; DOI 10.1001/jama.2023.14530; ref 5", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Multicenter randomized parallel trial: single 25 mg psilocybin versus niacin 100 mg, with matched psychological support and independent remote central raters.", "n": 104, "duration": "Primary day 43 (6 weeks)", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "The primary day-43 MADRS improvement favoured psilocybin by −12.3 points (95% CI −17.5 to −7.2, P<.001), with a day-8 difference of −12.0 (95% CI −16.6 to −7.4) and a Sheehan Disability Scale difference of −2.31 (95% CI −3.50 to −1.11, P<.001); more participants met sustained response, but not sustained remission, with psilocybin.", "what_it_does_not_show": "51 versus 53 randomized; independent central blinded raters reduced assessment bias, but no blinding-integrity check was reported, which triggers the psychiatry rubric's functional-unblinding rule for the drug-specific inference. Loss to follow-up was unequal. The PubMed Central deposit for this article carries front matter and abstract rather than the results tables, so participant-level sustained-response counts were not audited in this pass. No 12-week endpoint and no plasticity measurement.", "confounders_present": [ "51 versus 53 randomized; independent central blinded raters reduced assessment bias, but no blinding-integrity check was reported, which triggers the psychiatry rubric's functional-unblinding rule for the drug-specific inference. Loss to follow-up was unequal. The PubMed Central deposit for this article carries front matter and abstract rather than the results tables, so participant-level sustained-response counts were not audited in this pass. No 12-week endpoint and no plasticity measurement." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "USONA_MDD_phase2", "study_ids": [ "USONA_MDD_phase2" ], "access_depth": "full_text_partial" }, { "citation": "Goodwin GM et al., The New England journal of medicine 2022. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.", "source_pointer": "PMID 36322843; DOI 10.1056/nejmoa2206443; ref 6", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized parallel dose comparison: single 25 mg, 10 mg, or 1 mg psilocybin with psychological support.", "n": 233, "duration": "Primary 3 weeks; sustained response through 12 weeks", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "The primary week-3 MADRS change favoured 25 mg over 1 mg by −6.6 points (95% CI −10.2 to −2.9, P<0.001) while 10 mg versus 1 mg was not significant (−2.5, 95% CI −6.2 to 1.2, P=0.18); the trial reports that response and remission at week 3, but not sustained response at week 12, were generally supportive of the primary result.", "what_it_does_not_show": "79/75/79 participants per arm. Confirmatory hierarchy stopped at the nonsignificant 10 mg comparison, so sustained response and remission were not confirmed by multiplicity-controlled testing. Blinding integrity was not tested and functional unblinding is likely. New depression treatment increased after week 3. No cortical plasticity mediator. Access in this pass was the publisher abstract (no PubMed Central deposit), so participant-level sustained-response counts and the odds ratio reported in the original edition were not verifiable and have been removed.", "confounders_present": [ "79/75/79 participants per arm. Confirmatory hierarchy stopped at the nonsignificant 10 mg comparison, so sustained response and remission were not confirmed by multiplicity-controlled testing. Blinding integrity was not tested and functional unblinding is likely. New depression treatment increased after week 3. No cortical plasticity mediator. Access in this pass was the publisher abstract (no PubMed Central deposit), so participant-level sustained-response counts and the odds ratio reported in the original edition were not verifiable and have been removed." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "COMP001_TRD", "study_ids": [ "COMP001_TRD" ], "access_depth": "abstract_metadata" }, { "citation": "Goodwin GM et al., The Journal of clinical psychiatry 2025. Results From a Long-Term Observational Follow-Up Study of a Single Dose of Psilocybin for a Treatment-Resistant Episode of Major Depressive Disorder.", "source_pointer": "PMID 40047545; DOI 10.4088/jcp.24m15449; ref 7", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "actual_system": "human clinical", "design": "COMP004 observational extension of two earlier psilocybin trials, not an independent randomized efficacy trial.", "n": 66, "duration": "Up to 52 weeks from original dose", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "In the 52-week observational extension, median time to a prespecified depressive event was 92, 83 and 62 days for the original 25 mg, 10 mg and 1 mg cohorts, with most COMP001 participants having experienced a depressive event by week 12 (25 mg 37/75; 10 mg 38/79; 1 mg 44/75).", "what_it_does_not_show": "Only 58 COMP001 and 8 COMP003 participants entered the extension. Selection, censoring and post-trial treatment limit causal durability, and abstract-only access cannot audit the estimand or attrition analysis. Not an independent replication and not confirmed one-year remission; an observational extension cannot cross Δ.", "confounders_present": [ "Only 58 COMP001 and 8 COMP003 participants entered the extension. Selection, censoring and post-trial treatment limit causal durability, and abstract-only access cannot audit the estimand or attrition analysis. Not an independent replication and not confirmed one-year remission; an observational extension cannot cross Δ." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "COMP001_TRD + COMP003_SSRI", "study_ids": [ "COMP001_TRD", "COMP003_SSRI" ], "access_depth": "abstract_metadata" }, { "citation": "Goodwin GM et al., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2023. Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication.", "source_pointer": "PMID 37443386; DOI 10.1038/s41386-023-01648-7; ref 8", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Open-label single 25 mg dose adjunctive to ongoing SSRI in TRD, with preparation and integration support.", "n": 19, "duration": "3 weeks", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "In an open-label single 25 mg dose added to ongoing SSRI treatment, mean MADRS change at week 3 was −14.9 points (95% CI −20.7 to −9.2), with 8 of 19 participants (42.1%) meeting both response and remission criteria.", "what_it_does_not_show": "Uncontrolled descriptive study; two escitalopram doses were increased during the study; no formal sample-size calculation or missing-data imputation. Cannot distinguish psilocybin, support, expectation and concurrent medication; too short for durability and no plasticity measurement. The psychiatry rubric's open-label rule caps this evidence at Γ.", "confounders_present": [ "Uncontrolled descriptive study; two escitalopram doses were increased during the study; no formal sample-size calculation or missing-data imputation. Cannot distinguish psilocybin, support, expectation and concurrent medication; too short for durability and no plasticity measurement. The psychiatry rubric's open-label rule caps this evidence at Γ." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "COMP003_SSRI", "study_ids": [ "COMP003_SSRI" ], "access_depth": "full_text_partial" }, { "citation": "Carhart-Harris R et al., The New England journal of medicine 2021. Trial of Psilocybin versus Escitalopram for Depression.", "source_pointer": "PMID 33852780; DOI 10.1056/nejmoa2032994; ref 9", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized parallel active-comparator trial: two 25 mg psilocybin sessions plus daily placebo versus two 1 mg sessions plus escitalopram, with matched support.", "n": 59, "duration": "6 weeks", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "mixed", "what_it_shows": "The primary week-6 QIDS-SR-16 change was −8.0±1.0 with psilocybin and −6.0±1.0 with escitalopram, reported as a between-group difference of 2.0 points (95% CI −5.0 to 0.9), P=0.17 — a null on the prespecified primary outcome; response was 70% versus 48% (difference 22 percentage points, 95% CI −3 to 48) and remission 57% versus 28% (28 points, 95% CI 2 to 54).", "what_it_does_not_show": "30/29 randomized. Favourable secondary endpoints were not adjusted for multiplicity and remain exploratory; this was not an equivalence or noninferiority trial. Most participants self-referred and preferred psilocybin; blinding effectiveness was not measured. No plasticity mediator was tested. Access in this pass was the publisher abstract (no PubMed Central deposit).", "confounders_present": [ "30/29 randomized. Favourable secondary endpoints were not adjusted for multiplicity and remain exploratory; this was not an equivalence or noninferiority trial. Most participants self-referred and preferred psilocybin; blinding effectiveness was not measured. No plasticity mediator was tested. Access in this pass was the publisher abstract (no PubMed Central deposit)." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03429075", "study_ids": [ "NCT03429075" ], "access_depth": "abstract_metadata" }, { "citation": "Erritzoe D et al., EClinicalMedicine 2024. Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial.", "source_pointer": "PMID 39764567; DOI 10.1016/j.eclinm.2024.102799; ref 10", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "actual_system": "human clinical", "design": "Naturalistic 6-month follow-up of psilocybin versus escitalopram randomized cohort.", "n": 59, "duration": "Monthly follow-up to 6 months after 6-week trial", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "At 6-month naturalistic follow-up both original groups retained self-rated improvement with no sustained between-group advantage; 37 of 59 participants (62.7%) had received additional medication, psychotherapy or psychedelics.", "what_it_does_not_show": "Average missing data across follow-up visits was 13% in the psilocybin arm and 26% in the escitalopram arm, reaching 38% for escitalopram at 6 months; escitalopram continuation was optional and usual care was reported retrospectively. Underpowered for causal comparison; no new cohort and no human plasticity mediation test.", "confounders_present": [ "Average missing data across follow-up visits was 13% in the psilocybin arm and 26% in the escitalopram arm, reaching 38% for escitalopram at 6 months; escitalopram continuation was optional and usual care was reported retrospectively. Underpowered for causal comparison; no new cohort and no human plasticity mediation test." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03429075", "study_ids": [ "NCT03429075" ], "access_depth": "full_text_partial" }, { "citation": "Davis AK et al., JAMA psychiatry 2021. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.", "source_pointer": "PMID 33146667; DOI 10.1001/jamapsychiatry.2020.3285; ref 11", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized immediate versus delayed treatment waitlist; two psilocybin sessions (20 then 30 mg/70 kg) with psychological support.", "n": 27, "duration": "Controlled approximately 1 and 4 weeks after second dose", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "In the corrected report, 17 of 24 treated participants (71%) met response criteria at week 1 and at week 4 on the blinded GRID-HAMD, with remission in 58% and 54%; the immediate group improved relative to the delayed group at corresponding visits.", "what_it_does_not_show": "A waitlist comparison controls spontaneous change incompletely and does not control expectation, attention or functional unblinding. 27 were randomized and the main report used 24 completers (13 immediate, 11 delayed). No active placebo, no maintained untreated long-term group and no cortical plasticity measure.", "confounders_present": [ "A waitlist comparison controls spontaneous change incompletely and does not control expectation, attention or functional unblinding. 27 were randomized and the main report used 24 completers (13 immediate, 11 delayed). No active placebo, no maintained untreated long-term group and no cortical plasticity measure." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03181529", "study_ids": [ "NCT03181529" ], "access_depth": "full_text_complete" }, { "citation": "Gukasyan N et al., Journal of psychopharmacology (Oxford, England) 2022. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up.", "source_pointer": "PMID 35166158; DOI 10.1177/02698811211073759; ref 12", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "actual_system": "human clinical", "design": "Prospective long-term follow-up of the same 24 treated participants from the randomized waitlist trial.", "n": 24, "duration": "1, 3, 6, and 12 months", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "All 24 treated participants completed 12-month follow-up: mean GRID-HAMD fell from 22.8 at baseline to 7.7 at 12 months, with 75% meeting response and 58% remission criteria.", "what_it_does_not_show": "All participants had received psilocybin and no untreated control remained; 8 of 24 (33%) began an antidepressant during follow-up and facilitator contact continued at assessments. Observed long-term improvement does not prove a durable drug effect or mediation by cortical plasticity.", "confounders_present": [ "All participants had received psilocybin and no untreated control remained; 8 of 24 (33%) began an antidepressant during follow-up and facilitator contact continued at assessments. Observed long-term improvement does not prove a durable drug effect or mediation by cortical plasticity." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03181529", "study_ids": [ "NCT03181529" ], "access_depth": "full_text_partial" }, { "citation": "Carhart-Harris RL et al., The lancet. Psychiatry 2016. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.", "source_pointer": "PMID 27210031; DOI 10.1016/s2215-0366(16)30065-7; ref 13", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Open-label feasibility trial: 10 mg then 25 mg psilocybin one week apart with support.", "n": 12, "duration": "1 week primary preliminary efficacy; 3 months follow-up", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "In the open-label feasibility cohort, QIDS improved by −11.8 points at one week (95% CI −9.15 to −14.35, p=0.002, Hedges' g=3.1) and −9.2 points at three months (95% CI −5.69 to −12.71, p=0.003, g=2) after the 25 mg session.", "what_it_does_not_show": "Twelve patients, no randomized comparator and mostly self-referral; feasibility was the primary aim and efficacy preliminary. The original twelve were subsequently included in the expanded twenty-person report, so these are not independent cohorts. Access in this pass was the publisher abstract.", "confounders_present": [ "Twelve patients, no randomized comparator and mostly self-referral; feasibility was the primary aim and efficacy preliminary. The original twelve were subsequently included in the expanded twenty-person report, so these are not independent cohorts. Access in this pass was the publisher abstract." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Imperial_TRD_ISRCTN14426797", "study_ids": [ "Imperial_TRD_ISRCTN14426797" ], "access_depth": "abstract_metadata" }, { "citation": "Carhart-Harris RL et al., Psychopharmacology 2018. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.", "source_pointer": "PMID 29119217; DOI 10.1007/s00213-017-4771-x; ref 14", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "actual_system": "human clinical", "design": "Expanded open-label TRD cohort and six-month follow-up, including the original twelve.", "n": 20, "duration": "5 weeks; 3 and 6 months", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "In the expanded open-label cohort, nine of nineteen completers met response and four met remission criteria at week 5, with within-cohort effect sizes of about 1.5 at three months and 1.4 at six months; no patient sought conventional antidepressant treatment within five weeks.", "what_it_does_not_show": "No control arm and no independent replication of the initial cohort; additional treatment and non-study psilocybin use during later follow-up limit attribution of six-month persistence. Plasticity was discussed as a hypothesis, not measured.", "confounders_present": [ "No control arm and no independent replication of the initial cohort; additional treatment and non-study psilocybin use during later follow-up limit attribution of six-month persistence. Plasticity was discussed as a hypothesis, not measured." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Imperial_TRD_ISRCTN14426797", "study_ids": [ "Imperial_TRD_ISRCTN14426797" ], "access_depth": "full_text_partial" }, { "citation": "von Rotz R et al., EClinicalMedicine 2023. Single-dose psilocybin-assisted therapy in major depressive disorder: A placebo-controlled, double-blind, randomised clinical trial.", "source_pointer": "PMID 36636296; DOI 10.1016/j.eclinm.2022.101809; ref 15", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized placebo-controlled trial: one 0.215 mg/kg psilocybin dose versus mannitol with 11 hours of support.", "n": 52, "duration": "14 days primary endpoint", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "At day 14, MADRS remission occurred in 14 of 26 psilocybin participants (54%) versus 3 of 26 on placebo (P=0.0023), and MADRS response in 15 of 26 versus 4 of 26 (P=0.0034).", "what_it_does_not_show": "Two-week follow-up does not test 12-week durability. Expectancy and blinding integrity were not assessed; a study-involved assessor and a homogeneous sample leave bias and generalizability limits. Within-arm change must not be reported as a between-arm difference. The linked Figure 2 colour correction was reviewed.", "confounders_present": [ "Two-week follow-up does not test 12-week durability. Expectancy and blinding integrity were not assessed; a study-involved assessor and a homogeneous sample leave bias and generalizability limits. Within-arm change must not be reported as a between-arm difference. The linked Figure 2 colour correction was reviewed." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Zurich_MDD_single_dose", "study_ids": [ "Zurich_MDD_single_dose" ], "access_depth": "full_text_partial" }, { "citation": "Ross S et al., Journal of psychopharmacology (Oxford, England) 2016. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.", "source_pointer": "PMID 27909164; DOI 10.1177/0269881116675512; ref 16", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized 7-week crossover: single 0.3 mg/kg psilocybin versus niacin 250 mg, both with psychotherapy.", "n": 29, "duration": "Controlled to 7 weeks; uncontrolled 6.5-month postcrossover endpoint", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "Before crossover, BDI antidepressant response at seven weeks was 83% in the psilocybin-first arm versus 14% in the niacin-first arm.", "what_it_does_not_show": "About 90% had adjustment disorder, so this is cancer-related psychiatric distress rather than a general MDD population; 29 patients were randomized. All received psilocybin after crossover, so later response has no untreated comparison. Subjective-experience mediation was observational, not experimental, and not cortical plasticity; functional unblinding is likely.", "confounders_present": [ "About 90% had adjustment disorder, so this is cancer-related psychiatric distress rather than a general MDD population; 29 patients were randomized. All received psilocybin after crossover, so later response has no untreated comparison. Subjective-experience mediation was observational, not experimental, and not cortical plasticity; functional unblinding is likely." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NYU_cancer_psilocybin", "study_ids": [ "NYU_cancer_psilocybin" ], "access_depth": "full_text_partial" }, { "citation": "Agin-Liebes GI et al., Journal of psychopharmacology (Oxford, England) 2020. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer.", "source_pointer": "PMID 31916890; DOI 10.1177/0269881119897615; ref 17", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "actual_system": "human clinical", "design": "Survivor long-term follow-up of the NYU cancer crossover trial.", "n": 15, "duration": "Mean 3.2 years (15) and 4.5 years (14)", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "At a mean of 3.2 and 4.5 years, approximately 60–80% of the assessed survivors met criteria for clinically significant antidepressant or anxiolytic response; 15 of the 16 participants still alive took part.", "what_it_does_not_show": "Survivor selection from the original 29, mostly adjustment disorder, small homogeneous group, self-report and no control after week 7; some participants had received psychotherapy or psychotropic medication in the interval. Neurobiological explanations were explicitly speculative and no cortical plasticity mediator was measured. The range reported in the original edition (57–79% across HADS-D and BDI) could not be verified at this pass's access depth.", "confounders_present": [ "Survivor selection from the original 29, mostly adjustment disorder, small homogeneous group, self-report and no control after week 7; some participants had received psychotherapy or psychotropic medication in the interval. Neurobiological explanations were explicitly speculative and no cortical plasticity mediator was measured. The range reported in the original edition (57–79% across HADS-D and BDI) could not be verified at this pass's access depth." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NYU_cancer_psilocybin", "study_ids": [ "NYU_cancer_psilocybin" ], "access_depth": "abstract_metadata" }, { "citation": "Griffiths RR et al., Journal of psychopharmacology (Oxford, England) 2016. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.", "source_pointer": "PMID 27909165; DOI 10.1177/0269881116675513; ref 18", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized dose-sequence crossover: high 22/30 mg per 70 kg versus low 1/3 mg per 70 kg psilocybin with support.", "n": 51, "duration": "Controlled 5 weeks; combined 6-month follow-up", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "Five weeks after the first session, clinician-rated depression response was 92% in the high-dose-first group versus 32% in the low-dose-first group; after all participants had received the high dose, the overall six-month response rate was 78%.", "what_it_does_not_show": "56 randomized and 51 received at least one session; mixed cancer-associated mood and anxiety diagnoses with only about 35% meeting MDD criteria. No untreated comparison remained at six months and some participants began antidepressant or anxiolytic treatment. Dose guessing was strongly separated, and reported mystical-experience mediation is neither experimental proof nor cortical plasticity mediation.", "confounders_present": [ "56 randomized and 51 received at least one session; mixed cancer-associated mood and anxiety diagnoses with only about 35% meeting MDD criteria. No untreated comparison remained at six months and some participants began antidepressant or anxiolytic treatment. Dose guessing was strongly separated, and reported mystical-experience mediation is neither experimental proof nor cortical plasticity mediation." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "JHU_cancer_psilocybin", "study_ids": [ "JHU_cancer_psilocybin" ], "access_depth": "full_text_partial" }, { "citation": "Grob CS et al., Archives of general psychiatry 2011. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer.", "source_pointer": "PMID 20819978; DOI 10.1001/archgenpsychiatry.2010.116; ref 19", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Within-subject randomized crossover pilot: 0.2 mg/kg psilocybin versus niacin 250 mg.", "n": 12, "duration": "Controlled acute/two-week assessments; combined follow-up to 6 months", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "mixed", "what_it_shows": "In a within-subject crossover pilot, trait anxiety was significantly reduced at one and three months and BDI-measured mood improvement reached significance at six months, while Profile of Mood States improvement approached but did not reach significance.", "what_it_does_not_show": "Twelve adults with advanced-cancer anxiety rather than a primary MDD trial; follow-up data were collected unblinded and later timepoints were uncontrolled with incomplete retention. No cortical plasticity measurement. The drug-by-time and six-month p values quoted in the original edition were not verifiable at this pass's access depth and have been removed.", "confounders_present": [ "Twelve adults with advanced-cancer anxiety rather than a primary MDD trial; follow-up data were collected unblinded and later timepoints were uncontrolled with incomplete retention. No cortical plasticity measurement. The drug-by-time and six-month p values quoted in the original edition were not verifiable at this pass's access depth and have been removed." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "UCLA_cancer_pilot", "study_ids": [ "UCLA_cancer_pilot" ], "access_depth": "abstract_metadata" }, { "citation": "Back AL et al., JAMA network open 2024. Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial.", "source_pointer": "PMID 39636638; DOI 10.1001/jamanetworkopen.2024.49026; ref 20", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized parallel trial in clinicians with persistent depression symptoms after frontline COVID work: 25 mg versus niacin 100 mg and matched support.", "n": 30, "duration": "Primary day 28; optional crossover then 6-month within-arm follow-up", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "The primary day-28 MADRS improvement favoured psilocybin by −12.00 points (95% CI −17.67 to −6.33, P<.001) in clinicians with persistent depressive symptoms after frontline COVID-19 work.", "what_it_does_not_show": "A formal MDD diagnosis was not required. Blinding failed completely: immediately after swallowing the capsule no participant claimed to know their allocation, but by the end of the session 100% said they knew and all were correct. Niacin participants were offered crossover after day 28, so six-month change is uncontrolled; work roles changed for most participants over follow-up; no cortical plasticity measure.", "confounders_present": [ "A formal MDD diagnosis was not required. Blinding failed completely: immediately after swallowing the capsule no participant claimed to know their allocation, but by the end of the session 100% said they knew and all were correct. Niacin participants were offered crossover after day 28, so six-month change is uncontrolled; work roles changed for most participants over follow-up; no cortical plasticity measure." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Clinicians_COVID_MDDsymptoms", "study_ids": [ "Clinicians_COVID_MDDsymptoms" ], "access_depth": "full_text_partial" }, { "citation": "Weintraub MJ et al., Journal of affective disorders 2026. Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trial.", "source_pointer": "PMID 41707717; DOI 10.1016/j.jad.2026.121423; ref 21", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Open-label two-dose psilocybin (10 then 25 mg) plus twelve CBT sessions delivered over four months.", "n": 16, "duration": "Four-month treatment plus three-month posttreatment follow-up", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "After two psilocybin doses combined with twelve CBT sessions over four months, 10 of 16 participants (62.5%) met HAM-D response criteria and 9 of 16 (56.3%) remitted, with improvements maintained three months after treatment (Hedges' g 1.9–2.7 pre-to-post).", "what_it_does_not_show": "No comparator and no factorial separation of CBT from drug; CBT continued for months, so durability does not represent an autonomous drug effect. Self-selection and unblinded delivery. Cannot establish the necessity of psychotherapy or a drug-induced cortical plasticity period.", "confounders_present": [ "No comparator and no factorial separation of CBT from drug; CBT continued for months, so durability does not represent an autonomous drug effect. Self-selection and unblinded delivery. Cannot establish the necessity of psychotherapy or a drug-induced cortical plasticity period." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "UCLA_PA_CBT_MDD", "study_ids": [ "UCLA_PA_CBT_MDD" ], "access_depth": "full_text_partial" }, { "citation": "Sloshower J et al., Journal of psychopharmacology (Oxford, England) 2023. Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial.", "source_pointer": "PMID 36938991; DOI 10.1177/02698811231154852; ref 22", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Fixed-order within-subject placebo then 0.3 mg/kg psilocybin, embedded in manualized psychotherapy.", "n": 19, "duration": "Sixteen-week study; reported effects lasting about two months", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "mixed", "what_it_shows": "In a fixed-order within-subject trial, depression and anxiety improved significantly after both placebo and psilocybin with no significant difference between conditions; response was 66.7% and remission 46.7% after psilocybin, within-condition effect sizes were larger after psilocybin (g′ 1.02–2.27) than after placebo (0.65–0.99), and mystical-type experience intensity was not correlated with subsequent antidepressant effect.", "what_it_does_not_show": "Nineteen received placebo and fifteen psilocybin; fixed order confounds drug with time, therapy exposure and expectancy. Abstract-only access prevents a full methods and attrition audit. This is not a randomized parallel null trial and not a plasticity intervention.", "confounders_present": [ "Nineteen received placebo and fifteen psilocybin; fixed order confounds drug with time, therapy exposure and expectancy. Abstract-only access prevents a full methods and attrition audit. This is not a randomized parallel null trial and not a plasticity intervention." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Yale_fixed_order_MDD", "study_ids": [ "Yale_fixed_order_MDD" ], "access_depth": "abstract_metadata" }, { "citation": "Ross ML et al., General hospital psychiatry 2025. Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial.", "source_pointer": "PMID 40858059; DOI 10.1016/j.genhosppsych.2025.08.001; ref 23", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "human clinical", "design": "Randomized trial: single 25 mg psilocybin versus niacin 100 mg with preparation and integration, followed by open-label psilocybin for all.", "n": 35, "duration": "Controlled primary 6–7 weeks; postcrossover follow-up to 26 weeks", "molecule": "psilocybin", "decisive_perturbation": true, "decisive_for_scope": "SC1 supported protocol response", "endogenous": true, "direction": "supports", "what_it_shows": "At 6–7 weeks, psilocybin produced greater reductions than niacin in HADS depression (B=−2.49, P=.02, d=1.12), BDI-II (B=−7.56, P=.004) and state anxiety (B=−12.59, P=.005), with benefits described as sustained at 26 weeks.", "what_it_does_not_show": "Seventeen versus eighteen randomized in life-threatening illness, so not a general MDD trial; all participants received open-label psilocybin after the double-blind endpoint, so the 26-week data are not placebo-controlled. Full text unavailable in this pass, so protocol and attrition detail remain abstract-level; no plasticity measurement.", "confounders_present": [ "Seventeen versus eighteen randomized in life-threatening illness, so not a general MDD trial; all participants received open-label psilocybin after the double-blind endpoint, so the 26-week data are not placebo-controlled. Full text unavailable in this pass, so protocol and attrition detail remain abstract-level; no plasticity measurement." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Melbourne_life_threatening_illness", "study_ids": [ "Melbourne_life_threatening_illness" ], "access_depth": "abstract_metadata" }, { "citation": "Shao LX et al., Neuron 2021. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.", "source_pointer": "PMID 34228959; DOI 10.1016/j.neuron.2021.06.008; ref 24", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "Young adult male and female mice; medial frontal Cg 1/M 2 layer 5/6 apical tufts.", "design": "Single psilocybin 1 mg/kg i.p.; longitudinal two-photon imaging, acute-slice miniature excitatory currents, learned helplessness, ketanserin pretreatment.", "n": "Imaging: 1,820 spines on 161 dendrites in 12 mice (6 male, 6 female); day 34 persistence subset 4 mice. Learned helplessness: 68 mice.", "duration": "Formation increased principally early; density measured days 1–7; some new spines survived to day 34.", "molecule": "Psilocybin in vivo", "decisive_perturbation": true, "decisive_for_scope": "SC3 experimental cortical response", "endogenous": true, "direction": "supports", "what_it_shows": "A single 1 mg/kg dose increased medial frontal spine density (+7±2% at day 1, +12±3% at day 7) and spine head width (+11±2% at day 1) by raising the formation rate, with about half of new day-1 spines still present at day 7 and 34±10% (females) and 37±12% (males) persisting to day 34, and increased miniature excitatory current frequency at 24 h (P=0.0002); ketanserin pretreatment that abolished head-twitch responses left spine head width (+12±1%, P=0.01), protrusion length and formation rate elevated while the density increase became nonsignificant (+5±2% day 1, +8±2% day 7, P=0.09).", "what_it_does_not_show": "Survival of formed spines does not define the length of enhanced inducibility. Learned-helplessness improvement was significant within subjects (P=0.004) but the treatment main effect was P=0.09. The ketanserin dose blocks only about 30% of rodent cortical 5-HT2A receptors, so the experiment shows that a partial knockdown sufficient to remove head-twitch does not remove remodeling — not that remodeling is 5-HT2A-independent. No selective spine manipulation established mediation, and human symptoms were not studied.", "confounders_present": [ "Survival of formed spines does not define the length of enhanced inducibility. Learned-helplessness improvement was significant within subjects (P=0.004) but the treatment main effect was P=0.09. The ketanserin dose blocks only about 30% of rodent cortical 5-HT2A receptors, so the experiment shows that a partial knockdown sufficient to remove head-twitch does not remove remodeling — not that remodeling is 5-HT2A-independent. No selective spine manipulation established mediation, and human symptoms were not studied." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Full primary article read in the red-team pass (open-access or PubMed Central deposit); supplementary appendices not exhaustively audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "shao_2021_longitudinal_mouse", "study_ids": [ "shao_2021_longitudinal_mouse" ], "access_depth": "full_text_complete" }, { "citation": "Hesselgrave N et al., Proceedings of the National Academy of Sciences of the United States of America 2021. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice.", "source_pointer": "PMID 33850049; DOI 10.1073/pnas.2022489118; ref 25", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "8 wk male C57BL/6J mice after 10–14 d chronic multimodal stress; hippocampal temporoammonic→CA 1 synapses.", "design": "Single psilocybin 1 mg/kg i.p.; sucrose and female-urine preference 24–48 h; ex-vivo field AMPA/NMDA and fiber-volley-normalized responses.", "n": "Sucrose/field-physiology groups: vehicle 12, ketanserin 6–7, psilocybin 13, combination 7. Female-urine subset 4–6/group; separate forced-swim cohort 20 male and 20 female.", "duration": "Hedonic and hippocampal synaptic effects 24–48 h; no forced-swim benefit at days 1,3,7 in unstressed mice.", "molecule": "Psilocybin in vivo", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "supports", "what_it_shows": "A single 1 mg/kg psilocybin dose restored sucrose and female-urine preference after chronic stress and strengthened hippocampal AMPA-receptor responses, and neither effect was prevented by ketanserin pretreatment despite evidence of the antagonist's efficacy.", "what_it_does_not_show": "Hippocampal strengthening is not cortical spinogenesis, and correlation with sucrose preference does not establish synaptic mediation. Effects beyond 48 h and in stressed females were not established. Ketanserin blockade in rodents is partial, so receptor-independence is not demonstrated.", "confounders_present": [ "Hippocampal strengthening is not cortical spinogenesis, and correlation with sucrose preference does not establish synaptic mediation. Effects beyond 48 h and in stressed females were not established. Ketanserin blockade in rodents is partial, so receptor-independence is not demonstrated." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "hesselgrave_2021_stressed_mouse", "study_ids": [ "hesselgrave_2021_stressed_mouse" ], "access_depth": "abstract_metadata" }, { "citation": "Raval NR et al., International journal of molecular sciences 2021. A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain.", "source_pointer": "PMID 33467676; DOI 10.3390/ijms22020835; ref 26", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "24 healthy female juvenile Danish pigs (~9 wk, 20 kg); prefrontal cortex and hippocampus.", "design": "Single 0.08 mg/kg IV psilocybin or saline; ex-vivo [3 H]UCB-J SV2A and 5-HT2A autoradiography at 1 d and 7 d.", "n": "24 pigs;6 biological animals/treatment/timepoint;3 technical tissue sections/region/animal.", "duration": "Day 1 and day 7 after dosing.", "molecule": "Psilocybin in vivo", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "supports", "what_it_shows": "One day after a single 0.08 mg/kg intravenous dose, hippocampal SV2A binding was 4.42% higher with unchanged prefrontal binding, and at seven days hippocampal binding was 9.24% and prefrontal binding 6.10% higher, while 5-HT2A density was acutely reduced.", "what_it_does_not_show": "SV2A ligand binding is a presynaptic protein surrogate rather than a synapse count, and this was ex vivo autoradiography rather than in vivo PET. Twenty-four juvenile female pigs; no behavioural or disease outcome; juvenile age and intravenous exposure limit adult-human scope.", "confounders_present": [ "SV2A ligand binding is a presynaptic protein surrogate rather than a synapse count, and this was ex vivo autoradiography rather than in vivo PET. Twenty-four juvenile female pigs; no behavioural or disease outcome; juvenile age and intravenous exposure limit adult-human scope." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "raval_2021_juvenile_pig", "study_ids": [ "raval_2021_juvenile_pig" ], "access_depth": "abstract_metadata" }, { "citation": "Cameron LP et al., ACS chemical neuroscience 2023. 5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines.", "source_pointer": "PMID 36630260; DOI 10.1021/acschemneuro.2c00718; ref 27", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "Male and female 129S6/SvEv WT and constitutive 5-HT2A knockout mice, aged 13–20 wk; corticosterone-induced anhedonia.", "design": "Corticosterone 20 mg/kg daily 10 d, single psilocybin 10 mg/kg i.p., sucrose preference 24 h later; separate 5-MeO-DMT culture, forced-swim and electrophysiology experiments.", "n": "Group sizes vary; exact psilocybin sucrose-preference n was not stated in the textual figure caption and was not reconstructed from plotted points.", "duration": "Psilocybin sucrose preference at 24 h; separate 5-MeO-DMT behavioral studies at 24 h and 7 d.", "molecule": "Psilocybin 10 mg/kg in the hedonic-behavior arm;5-MeO-DMT in most plasticity/pharmacologic experiments.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "supports", "what_it_shows": "Pharmacological and genetic manipulations indicate that 5-HT2A receptor activation is required for tryptamine psychedelics to produce antidepressant-like behavioural effects, with psilocybin rescuing corticosterone-induced anhedonia in wild-type but not constitutive 5-HT2A knockout mice.", "what_it_does_not_show": "Plasticity was not measured in the psilocybin sucrose-preference arm and most spine and pharmacological experiments concern 5-MeO-DMT. Constitutive deletion permits developmental compensation, and strain, dose and endocrine model differ from the chronic-stress studies. This does not isolate cortical plasticity mediation.", "confounders_present": [ "Plasticity was not measured in the psilocybin sucrose-preference arm and most spine and pharmacological experiments concern 5-MeO-DMT. Constitutive deletion permits developmental compensation, and strain, dose and endocrine model differ from the chronic-stress studies. This does not isolate cortical plasticity mediation." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "cameron_2023_cort_mouse", "study_ids": [ "cameron_2023_cort_mouse" ], "access_depth": "abstract_metadata" }, { "citation": "Vargas MV et al., Science (New York, N.Y.) 2023. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.", "source_pointer": "PMID 36795823; DOI 10.1126/science.adf0435; ref 28", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "in vitro and animal model", "actual_system": "Rat embryonic cortical neurons, HEK receptor-localization preparations, and engineered mouse SERT-overexpression experiments.", "design": "Permeability, congener and electroporation experiments; antagonist localization; native receptor imaging with knockout validation; separate serotonin entry experiments in vivo.", "n": "Culture and animal n vary; complete main text read, but supplementary methods and all group-level denominators were not audited.", "duration": "Culture growth at 24 h; separate mouse spine and forced-swim endpoints at 24 h after the serotonin-releasing manipulation.", "molecule": "Psilocin 1µM and congeners in culture; the in-vivo causal arm primarily manipulated serotonin entry via SERT, rather than dosing psilocybin.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "supports", "what_it_shows": "Cell-entry, congener and antagonist-localisation experiments indicate that intracellular 5-HT2A receptors mediate psychedelic-induced cortical neuronal growth, explaining why serotonin itself does not engage the same mechanism.", "what_it_does_not_show": "The in vivo proof-of-principle uses engineered serotonin transport and is not durable psilocybin antidepressant mediation. Intracellular signalling versus receptor trafficking remains unresolved, and developmental culture systems constrain translation.", "confounders_present": [ "The in vivo proof-of-principle uses engineered serotonin transport and is not durable psilocybin antidepressant mediation. Intracellular signalling versus receptor trafficking remains unresolved, and developmental culture systems constrain translation." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "vargas_2023_intracellular_receptor", "study_ids": [ "vargas_2023_intracellular_receptor" ], "access_depth": "abstract_metadata" }, { "citation": "Moliner R et al., Nature neuroscience 2023. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.", "source_pointer": "PMID 37280397; DOI 10.1038/s41593-023-01316-5; ref 29", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "in vitro and animal model", "actual_system": "HEK full-length TrkB preparations, primary rodent cortical neurons, and TrkB.Y433F heterozygous mice.", "design": "Radioligand competition, microscale thermophoresis, transmembrane-domain mutations/NMR, cortical neurite/spine assays; separate LSD behavior and ocular plasticity in mice.", "n": "Reported psilocin competition Ki 6.73±3.05 nM; biological n varies by assay; main figures and relevant binding/cellular/animal methods read.", "duration": "Psilocin culture spines 24 h and dendrites 72 h; separate LSD behavior 7 d and fear extinction 4 wk.", "molecule": "Psilocin and LSD in binding/cultures; in-vivo behavioral and visual-plasticity experiments predominantly LSD.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "supports", "what_it_shows": "LSD and psilocin bind TrkB with affinities about 1,000-fold higher than conventional antidepressants at a transmembrane site partly overlapping the antidepressant site, and psychedelic effects on neurotrophic signalling, plasticity and antidepressant-like behaviour in mice depend on TrkB binding and endogenous BDNF signalling while LSD-induced head twitching depends on 5-HT2A.", "what_it_does_not_show": "The in vivo genotype dissociation and prolonged behavioural benefits concern LSD, so psilocybin-specific evidence here is binding and cell-level. The direct-binding model needs assay-comparable independent replication; generic TrkB inhibition alone does not establish direct binding. No mediated clinical pathway in depressed humans.", "confounders_present": [ "The in vivo genotype dissociation and prolonged behavioural benefits concern LSD, so psilocybin-specific evidence here is binding and cell-level. The direct-binding model needs assay-comparable independent replication; generic TrkB inhibition alone does not establish direct binding. No mediated clinical pathway in depressed humans." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "moliner_2023_trkb", "study_ids": [ "moliner_2023_trkb" ], "access_depth": "full_text_partial" }, { "citation": "Nardou R et al., Nature 2023. Psychedelics reopen the social reward learning critical period.", "source_pointer": "PMID 37316665; DOI 10.1038/s41586-023-06204-3; ref 30", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "Adult male C57BL/6J mice (~P 96–98); social reward learning, nucleus accumbens and medial prefrontal slices.", "design": "Single psilocybin 0.3 mg/kg i.p.; timed social conditioned-place learning; oxytocin-LTD metaplasticity and baseline miniature-current slice recordings.", "n": "At 48 h: psilocybin 15/saline 17; psilocybin at 1 wk 17,2 wk 22,3 wk 16. Each mouse was used for one behavioral timepoint.", "duration": "Social reward critical period open at 48 h,1 wk and 2 wk; closed by 3 wk.", "molecule": "Psilocybin, with separate LSD, MDMA, ketamine and ibogaine arms.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "supports", "what_it_shows": "A single 0.3 mg/kg dose reinstated adult social reward learning one and two weeks later with closure by three weeks, alongside metaplastic restoration of oxytocin-mediated long-term depression in nucleus accumbens, and the duration of the open state across psychedelics tracked the duration of their acute subjective effects in humans.", "what_it_does_not_show": "This concerns social reward learning and accumbens metaplasticity, not depressive symptoms or a cortical antidepressant window; baseline medial prefrontal and accumbens miniature currents were unchanged at 48 h. The extracellular-matrix and transcriptomic convergence experiments did not include psilocybin.", "confounders_present": [ "This concerns social reward learning and accumbens metaplasticity, not depressive symptoms or a cortical antidepressant window; baseline medial prefrontal and accumbens miniature currents were unchanged at 48 h. The extracellular-matrix and transcriptomic convergence experiments did not include psilocybin." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "nardou_2023_social_critical_period", "study_ids": [ "nardou_2023_social_critical_period" ], "access_depth": "full_text_partial" }, { "citation": "Sekssaoui M et al., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2024. Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?", "source_pointer": "PMID 38212441; DOI 10.1038/s41386-024-01794-6; ref 31", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "Adult male and female C57BL/6J WT and constitutive 5-HT2A knockout mice; five-day chronic despair paradigm.", "design": "Single psilocybin 1 mg/kg i.p.; novelty-suppressed feeding, sucrose preference and forced swim 2–15 d later; DOI/lisuride comparisons and receptor antagonists.", "n": "WT psilocybin 20; knockout psilocybin 24; knockout vehicle 17–19 depending on endpoint; other groups vary.", "duration": "Sequential behavioral assessments 2–15 d; each outcome has its own postdose timing.", "molecule": "Psilocybin in vivo; separate DOI and lisuride comparisons.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "A single 1 mg/kg dose produced anxiolytic- and antidepressant-like effects lasting up to 15 days in a chronic despair model, and psilocybin remained effective in constitutive 5-HT2A knockout mice whereas DOI and the non-hallucinogenic agonist lisuride did not.", "what_it_does_not_show": "No neural plasticity measure and no selective plasticity intervention. Differences in model, strain and constitutive versus adult regional deletion can reconcile these results with the adult conditional-knockout findings. This does not establish universal receptor dispensability or human antidepressant mediation.", "confounders_present": [ "No neural plasticity measure and no selective plasticity intervention. Differences in model, strain and constitutive versus adult regional deletion can reconcile these results with the adult conditional-knockout findings. This does not establish universal receptor dispensability or human antidepressant mediation." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "sekssaoui_2024_chronic_despair", "study_ids": [ "sekssaoui_2024_chronic_despair" ], "access_depth": "abstract_metadata" }, { "citation": "Shao LX et al., Nature 2025. Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.", "source_pointer": "PMID 40175553; DOI 10.1038/s41586-025-08813-6; ref 32", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "Adult male and female mice; medial frontal PT versus IT pyramidal neurons; adult local corticalHtr2a deletion.", "design": "Psilocybin 1 mg/kg i.p.; cell-type imaging, acute activity, PT/IT chemogenetic silencing, adult viral receptor deletion, stress behaviors.", "n": "Approximately 1,040–1,147 spines/group on 69–85 dendrites in 8–9 mice; behavioral n varies.", "duration": "Spine density increased at day 1 and remained elevated through day 65; behavior tested mainly at 24 h and in fear-extinction protocols.", "molecule": "Psilocybin in vivo", "decisive_perturbation": true, "decisive_for_scope": "SC3 experimental cortical response", "endogenous": true, "direction": "supports", "what_it_shows": "A single 1 mg/kg dose increased spine density in both pyramidal-tract and intratelencephalic frontal cortical neurons, with the elevation still significant at the final imaging session on day 65; silencing pyramidal-tract neurons eliminated psilocybin's effects on stress-related behaviour while silencing intratelencephalic neurons did not, and adult cortical 5-HT2A knockout abolished both the behavioural effects and pyramidal-tract structural remodeling.", "what_it_does_not_show": "Receptor deletion and cell silencing affect several downstream pathways, so blocking both spines and behaviour does not selectively establish spine mediation. The structural cell-type-specific knockout and the broader local behavioural knockout are distinct manipulations, and the receptor-control learned-helplessness arm had a floor effect the authors flag. Sixty-five-day spine persistence is not a 65-day inducibility window.", "confounders_present": [ "Receptor deletion and cell silencing affect several downstream pathways, so blocking both spines and behaviour does not selectively establish spine mediation. The structural cell-type-specific knockout and the broader local behavioural knockout are distinct manipulations, and the receptor-control learned-helplessness arm had a floor effect the authors flag. Sixty-five-day spine persistence is not a 65-day inducibility window." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "shao_2025_pyramidal_cells", "study_ids": [ "shao_2025_pyramidal_cells" ], "access_depth": "full_text_partial" }, { "citation": "Jiang Q et al., Cell 2026. Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks.", "source_pointer": "PMID 41352354; DOI 10.1016/j.cell.2025.11.009; ref 33", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "Male and female mice: tracing/Neuropixels at 2–3 months; imaging at 5–7 wk; PT/IT medial frontal systems.", "design": "Psilocybin 1 mg/kg i.p.; brainwide rabies input fractions, bouton/spine imaging, pathway-specific slice EPSCs, retrosplenial chemogenetic activity block.", "n": "PT tracing 9 drug/8 saline; IT 8/8; imaging 8 drug/7 saline; chemogenetic 3–4/group; slice physiology 4–7 mice/group.", "duration": "Imaging days 1/3; rabies injected day 1 and tissue collected 8 d after drug.", "molecule": "Psilocybin in vivo", "decisive_perturbation": true, "decisive_for_scope": "SC3 experimental cortical response", "endogenous": true, "direction": "supports", "what_it_shows": "Monosynaptic rabies tracing showed that psilocybin reorganised inputs to frontal cortical pyramidal neurons network-specifically, strengthening perceptual and medial (default-mode homolog) inputs to subcortical-projecting neurons while weakening cortico-cortical recurrent inputs, and silencing retrosplenial cortex during dosing prevented the subsequent retrosplenial input gain.", "what_it_does_not_show": "Rabies input fractions are not direct synapse counts and can depend on tracing efficiency and activity, although bouton and slice-physiology validation narrows these biases in selected pathways. No depression behaviour and no rewiring-to-symptom mediation was tested, and the coexistence of gains and losses precludes a blanket strengthening model. Same laboratory program as the adult spine-imaging work.", "confounders_present": [ "Rabies input fractions are not direct synapse counts and can depend on tracing efficiency and activity, although bouton and slice-physiology validation narrows these biases in selected pathways. No depression behaviour and no rewiring-to-symptom mediation was tested, and the coexistence of gains and losses precludes a blanket strengthening model. Same laboratory program as the adult spine-imaging work." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "jiang_2026_activity_network", "study_ids": [ "jiang_2026_activity_network" ], "access_depth": "full_text_partial" }, { "citation": "Schmidt M et al., eLife 2026. Psilocin fosters neuroplasticity in iPSC-derived human cortical neurons.", "source_pointer": "PMID 41891829; DOI 10.7554/elife.104006; ref 34", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "in vitro", "actual_system": "Human iPSC-derived dorsal forebrain/cortical neurons differentiated>40 d;2–4 donor lines; electrophysiology included mouse astrocyte co-culture.", "design": "10µM psilocin 10 min trigger or 24/96 h exposure; BDNF/AKT/TrkB, transcriptomics, Sholl neurites, synaptic-marker colocalization and electrophysiology after washout.", "n": "BDNF in 4 donor lines; transcriptomics in 2 genetic backgrounds; other assays 2–3 lines and multiple differentiation batches. Numerous neurons/neurites are nested observations.", "duration": "Brief-trigger BDNF/neurites 24–48 h; functional changes at 7 d;96 h exposure followed by 6 d washout for some synaptic findings.", "molecule": "Psilocin in human cell culture; no treated human participants.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": false, "direction": "supports", "what_it_shows": "In iPSC-derived human cortical neurons, psilocin produced a 5-HT2A-dependent increase in BDNF abundance reproduced across four independent control lines, transcriptomic signatures consistent with priming for plasticity, greater neuronal complexity and synaptic-marker expression, and increased excitability and network activity, with some changes persisting after washout.", "what_it_does_not_show": "Developmental cultures with few donor lines are not adult living cortex; 10 µM psilocin and prolonged exposure match clinical exposure poorly, and the strongest late synaptic findings used the longest dosing. Cells and neurites are not independent donors. No depressive symptoms or clinical mediation were measured, and in vitro evidence alone cannot exceed Γ.", "confounders_present": [ "Developmental cultures with few donor lines are not adult living cortex; 10 µM psilocin and prolonged exposure match clinical exposure poorly, and the strongest late synaptic findings used the longest dosing. Cells and neurites are not independent donors. No depressive symptoms or clinical mediation were measured, and in vitro evidence alone cannot exceed Γ." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "schmidt_2026_human_ipsc", "study_ids": [ "schmidt_2026_human_ipsc" ], "access_depth": "full_text_partial" }, { "citation": "Jain MK et al., Neuron 2025. The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.", "source_pointer": "PMID 40683247; DOI 10.1016/j.neuron.2025.06.012; ref 35", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "in vitro and animal model", "actual_system": "Human GPCR expression and kinase profiling assays.", "design": "41 psychedelics profiled across 318 GPCRs; LSD against 450 human protein kinases; structure-guided target profiling.", "n": "41 ligands,318 GPCR targets,450 kinase targets; assay-level replication/methods unavailable for audit.", "duration": "Acute in-vitro target assays.", "molecule": "Multiple psychedelics; LSD, rather than psilocin, in the kinase screen.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "Profiling of 41 psychedelics against 318 human GPCRs, and of LSD against more than 450 human kinases, documented potent activity at nearly every serotonin, dopamine and adrenergic receptor and multiple 5-HT2A transducer pathways correlating with psychedelic-like actions in vivo.", "what_it_does_not_show": "Full primary methods were not read. The claim that the kinase panel showed no potent LSD–TrkB interaction could not be verified at this access depth and is not used as counter-evidence; in any case a kinase-domain panel is not an assay-comparable test of a proposed transmembrane allosteric interaction with full-length TrkB. No antidepressant mediator or clinical plasticity window was tested.", "confounders_present": [ "Full primary methods were not read. The claim that the kinase panel showed no potent LSD–TrkB interaction could not be verified at this access depth and is not used as counter-evidence; in any case a kinase-domain panel is not an assay-comparable test of a proposed transmembrane allosteric interaction with full-length TrkB. No antidepressant mediator or clinical plasticity window was tested." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "jain_2025_polypharmacology", "study_ids": [ "jain_2025_polypharmacology" ], "access_depth": "abstract_metadata" }, { "citation": "Kramer HM et al., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2026. Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity.", "source_pointer": "PMID 41224969; DOI 10.1038/s41386-025-02272-3; ref 36", "relates_to_subclaims": [ "SC3", "SC4", "SC5" ], "favors_models": [ "M3" ], "evidence_class": "Weak", "system": "animal model", "actual_system": "Rat model and medial prefrontal layer 5 neurons; exact strain, age and sex not verified from full methods.", "design": "Single psilocybin or 25CN-NBOH; serial forced swim; late ex-vivo electrophysiology, spine density/classification and synaptic-marker genes.", "n": "Full group-level n unavailable in the accessed abstract; not inferred.", "duration": "Behavior and functional changes to 3 months; structural endpoint at 12 weeks.", "molecule": "Psilocybin plus a separate 25CN-NBOH comparison.", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "In adult rats, single doses of psilocybin or of the selective 5-HT2A agonist 25CN-NBOH reduced forced-swim immobility with no decline in effect size for at least three months and changed resting membrane potential, firing rate and synaptic excitation in layer 5 medial prefrontal neurons months later, while spine density, spine classification and pre- and postsynaptic marker gene expression showed no differences from control.", "what_it_does_not_show": "A late structural null does not establish that early transient spinogenesis was unnecessary, and functional plasticity remains compatible with the broad hypothesis. Forced-swim immobility is a coping proxy, not human MDD, and the rubric treats it as weak evidence on its own. Lack of full methods limits the independence audit; the publisher does not release full text for download.", "confounders_present": [ "A late structural null does not establish that early transient spinogenesis was unnecessary, and functional plasticity remains compatible with the broad hypothesis. Forced-swim immobility is a coping proxy, not human MDD, and the rubric treats it as weak evidence on its own. Lack of full methods limits the independence audit; the publisher does not release full text for download." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "kramer_2025_2026_enduring_rat", "study_ids": [ "kramer_2025_2026_enduring_rat" ], "access_depth": "abstract_metadata" }, { "citation": "Johansen A et al., Transl Psychiatry 2026. Psilocybin's effect on human brain synaptic plasticity.", "source_pointer": "PMID 42457666; DOI 10.1038/s41398-026-04285-y; ref 37", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Moderate", "system": "human interventional", "actual_system": "Healthy humans; in vivo PET SV2A presynaptic marker", "design": "Preregistered open-label single-arm study with a group-sequential futility rule; dosing environments changed sequentially and were not randomized.", "n": "15 participants; 12 with complete arterial-input data for the primary VT analysis; 15 for BPND analyses.", "duration": "PET one week after a single 0.3 mg/kg dose; subjective persisting effects at three months.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "null", "what_it_shows": "In the preregistered primary analysis (12 of 15 participants with complete arterial input), frontal-cortex SV2A binding rose 2.3% (one-sided p=0.29) and hippocampal binding 3.0% (p=0.33) one week after 0.3 mg/kg psilocybin, with reference-region analyses in all 15 showing −0.03% (p=0.54) and +1.01% (p=0.44); recruitment stopped at a preplanned futility analysis, and exploratory setting analyses showed 5–6% increases in the therapeutic-room subgroup whose own confidence intervals included zero (frontal ΔV_T 1.1 mL/cm³, 95% CI −0.5 to 2.7) with a nominally significant between-setting frontal difference (3.0 mL/cm³, 95% CI 0.4 to 5.5; likelihood-ratio p=0.03) and no significant relation between SV2A change and three-month persisting effects (p>0.37).", "what_it_does_not_show": "Open-label single-arm design with no placebo and possible test–retest bias; healthy participants rather than depressed patients; one post-dose timepoint cannot exclude an earlier transient change; dosing setting was assigned sequentially (participants 1–5 in the scanner, 6–15 in the room) rather than randomly, and exploratory thresholds were not prespecified. SV2A binding is a presynaptic protein marker, not a measure of cortical inducibility. Statistics were verified against the openly available author version of the same study, with a version check against the published record.", "confounders_present": [ "Open-label single-arm design with no placebo and possible test–retest bias; healthy participants rather than depressed patients; one post-dose timepoint cannot exclude an earlier transient change; dosing setting was assigned sequentially (participants 1–5 in the scanner, 6–15 in the room) rather than randomly, and exploratory thresholds were not prespecified. SV2A binding is a presynaptic protein marker, not a measure of cortical inducibility. Statistics were verified against the openly available author version of the same study, with a version check against the published record." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03289949_subproject2b_SV2A_healthy15", "study_ids": [ "NCT03289949_subproject2b_SV2A_healthy15" ], "access_depth": "full_text_partial" }, { "citation": "Lyons T et al., Nat Commun 2026. Human brain changes after first psilocybin use.", "source_pointer": "PMID 42086570; DOI 10.1038/s41467-026-71962-3; ref 38", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Healthy psychedelic-naive humans; EEG, fMRI and diffusion MRI.", "design": "Exploratory single-blind repeated-measures study in fixed order: all 1 mg sessions preceded the 25 mg sessions; doses were not randomized or counterbalanced.", "n": "28 participants; 25 in the main paired diffusion MRI analyses.", "duration": "EEG at one, two and 4.5 hours; fMRI, diffusion MRI and psychological outcomes one month after each dose.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "One month after 25 mg, axial diffusivity fell in prefrontal–striatal (p=0.006) and prefrontal–thalamic (p=0.005) tracts, brain-network modularity decreased relative to baseline (p=0.02) and correlated with well-being change in the 25 mg versus 1 mg contrast (r=−0.4, p=0.04, two-tailed), while a tract-based spatial statistics analysis was null and enduring functional changes were otherwise largely absent; acute EEG entropy predicted one-month well-being with next-day insight as a statistical mediator.", "what_it_does_not_show": "Exploratory single-blind fixed-order design in 28 psychedelic-naive healthy participants, with all 1 mg sessions preceding 25 mg, so practice, habituation and expectation cannot be excluded — as the authors state. Axial diffusivity has several possible biological determinants. Statistical mediation of well-being by insight is not a selective test of cortical plasticity carrying durable relief of depression.", "confounders_present": [ "Exploratory single-blind fixed-order design in 28 psychedelic-naive healthy participants, with all 1 mg sessions preceding 25 mg, so practice, habituation and expectation cannot be excluded — as the authors state. Axial diffusivity has several possible biological determinants. Statistical mediation of well-being by insight is not a selective test of cortical plasticity carrying durable relief of depression." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Imperial_first_psilocybin_healthy28_fixed_order_Lyons2026", "study_ids": [ "Imperial_first_psilocybin_healthy28_fixed_order_Lyons2026" ], "access_depth": "full_text_partial" }, { "citation": "Daws RE et al., Nat Med 2022. Increased global integration in the brain after psilocybin therapy for depression.", "source_pointer": "PMID 35411074; DOI 10.1038/s41591-022-01744-z; ref 39", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Humans with treatment-resistant depression or MDD; resting-state fMRI.", "design": "Secondary analyses of two existing trials: an open-label TRD trial and the randomized psilocybin versus escitalopram MDD trial.", "n": "16 in the TRD imaging sample; 22 psilocybin and 21 escitalopram participants in the RCT imaging sample, from 59 originally randomized.", "duration": "TRD fMRI one day after 25 mg, with symptoms followed to six months; RCT fMRI three weeks after the second dose, at the six-week treatment endpoint.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "Reduced resting-state fMRI network modularity after psilocybin correlated with symptom improvement in both an open-label treatment-resistant cohort and the randomized psilocybin-versus-escitalopram cohort, while no network reorganisation was observed after escitalopram.", "what_it_does_not_show": "Secondary analyses of two existing trials whose cohorts overlap the 2016/2018 clinical reports, the 2017 imaging report and the 2021 randomized trial, so these are not independent efficacy replications. The inference rests on within-arm change and change–symptom correlation; no significant psilocybin-versus-escitalopram interaction for modularity is reported, and the specific interaction statistic quoted in the original edition could not be verified from a primary record at this pass's access depth and has been removed. Modularity is not a synaptic measure and nothing was manipulated.", "confounders_present": [ "Secondary analyses of two existing trials whose cohorts overlap the 2016/2018 clinical reports, the 2017 imaging report and the 2021 randomized trial, so these are not independent efficacy replications. The inference rests on within-arm change and change–symptom correlation; no significant psilocybin-versus-escitalopram interaction for modularity is reported, and the specific interaction statistic quoted in the original edition could not be verified from a primary record at this pass's access depth and has been removed. Modularity is not a synaptic measure and nothing was manipulated." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Imperial_TRD_ISRCTN14426797 + NCT03429075", "study_ids": [ "Imperial_TRD_ISRCTN14426797", "NCT03429075" ], "access_depth": "abstract_metadata" }, { "citation": "Carhart-Harris RL et al., Sci Rep 2017. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.", "source_pointer": "PMID 29030624; DOI 10.1038/s41598-017-13282-7; ref 40", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Humans with TRD; arterial-spin-labeling cerebral blood flow and BOLD fMRI.", "design": "Open-label imaging analysis before and after psilocybin with support; 10 mg then 25 mg seven days apart.", "n": "19 scanned; 16 retained for ASL and 15 for BOLD analyses.", "duration": "fMRI one day after 25 mg; symptom outcome at five weeks.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "Before-and-after imaging in the open-label treatment-resistant cohort found reduced temporal-cortex and amygdala cerebral blood flow whose amygdala component correlated with immediate symptom improvement, increased default-mode connectivity after treatment, and connectivity measures that predicted five-week response, with usable pre- and post-treatment data from 16 of 19 patients and 47% meeting response criteria at five weeks.", "what_it_does_not_show": "Open-label design in the same cohort as the 2016/2018 clinical reports and the 2022 modularity analysis, so not an independent line. Network-function correlations; synaptic plasticity was neither measured nor manipulated.", "confounders_present": [ "Open-label design in the same cohort as the 2016/2018 clinical reports and the 2022 modularity analysis, so not an independent line. Network-function correlations; synaptic plasticity was neither measured nor manipulated." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "Imperial_TRD_ISRCTN14426797", "study_ids": [ "Imperial_TRD_ISRCTN14426797" ], "access_depth": "abstract_metadata" }, { "citation": "Doss MK et al., Transl Psychiatry 2021. Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder.", "source_pointer": "PMID 34750350; DOI 10.1038/s41398-021-01706-y; ref 41", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Humans with MDD; cognitive set shifting, fMRI dynamics and magnetic-resonance spectroscopy.", "design": "Secondary mechanistic analysis of an immediate versus delayed treatment study. Neuroimaging used an open-label before–after design.", "n": "24 patients, with measure-specific missing data; 22 completed the cognitive test analyses.", "duration": "One and four weeks after the second session; doses were 20 then 30 mg/70 kg.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "Cognitive flexibility improved for at least four weeks after treatment but was uncorrelated with antidepressant change at every timepoint pairing (all |r| < 0.2, all p > 0.250); anterior cingulate glutamate (t(19)=2.54, p=0.020) and N-acetylaspartate (t(19)=3.05, p=0.007) decreased at one week, and greater increases in anterior-to-posterior cingulate dynamic connectivity were associated with less cognitive improvement.", "what_it_does_not_show": "Secondary mechanistic analysis of the immediate-versus-delayed trial with an open-label before–after neuroimaging design in 24 patients, so not an independent clinical trial. The dissociation constrains the assumption that measured flexibility carries antidepressant benefit; it does not show that plasticity is irrelevant.", "confounders_present": [ "Secondary mechanistic analysis of the immediate-versus-delayed trial with an open-label before–after neuroimaging design in 24 patients, so not an independent clinical trial. The dissociation constrains the assumption that measured flexibility carries antidepressant benefit; it does not show that plasticity is irrelevant." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03181529", "study_ids": [ "NCT03181529" ], "access_depth": "full_text_partial" }, { "citation": "Siegel JS et al., Nature 2024. Psilocybin desynchronizes the human brain.", "source_pointer": "PMID 39020167; DOI 10.1038/s41586-024-07624-5; ref 42", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Healthy humans; dense resting-state and task fMRI.", "design": "Randomized crossover of 25 mg psilocybin versus 40 mg methylphenidate with dense imaging; four participants received an open-label repeat session 6–12 months later.", "n": "Seven initial participants; six in persistent-effect analyses; four in the repeat-session analysis.", "duration": "About 18 MRI visits per person; post-dose assessment over 1–21 days; repeat session at 6–12 months.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "Dense precision mapping in seven healthy adults found acute functional-connectivity disruption more than threefold greater than methylphenidate's, driven by desynchronization across spatial scales and strongest in the default-mode network, with whole-brain architecture largely returning to baseline while anterior hippocampus–default-network connectivity remained reduced for about three weeks.", "what_it_does_not_show": "Participants were healthy and no antidepressant endpoint was measured; the authors state explicitly that the proposed antidepressant mechanism requires studies in patients. Roughly 18 scans per participant increase within-person precision, not the number of independent participants.", "confounders_present": [ "Participants were healthy and no antidepressant endpoint was measured; the authors state explicitly that the proposed antidepressant mechanism requires studies in patients. Roughly 18 scans per participant increase within-person precision, not the number of independent participants." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT04501653_Siegel2024_healthy7_precision_mapping", "study_ids": [ "NCT04501653_Siegel2024_healthy7_precision_mapping" ], "access_depth": "abstract_metadata" }, { "citation": "Madsen MK et al., Neuropsychopharmacology 2019. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.", "source_pointer": "PMID 30685771; DOI 10.1038/s41386-019-0324-9; ref 43", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Healthy humans; PET serotonin 2A receptor occupancy and plasma psilocin.", "design": "Dose-variable single-arm PET study: baseline then 3–30 mg psilocybin. Five of eight participants had a second scan later during drug exposure.", "n": "Eight participants; five with two occupancy scans.", "duration": "Acute PET beginning about one hour and about 344 minutes after dosing.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "In eight healthy volunteers, single oral doses of 3–30 mg psilocybin produced dose-related neocortical 5-HT2A receptor occupancy up to 72%, with subjective intensity closely associated with both occupancy and plasma psilocin.", "what_it_does_not_show": "No placebo control and doses varied across participants. This verifies human target engagement for the psychedelic state; it does not measure plasticity, enduring efficacy or mediation, and the rubric's acute-pharmacodynamic rule applies.", "confounders_present": [ "No placebo control and doses varied across participants. This verifies human target engagement for the psychedelic state; it does not measure plasticity, enduring efficacy or mediation, and the rubric's acute-pharmacodynamic rule applies." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NRU_Madsen2019_5HT2A_PET_healthy8", "study_ids": [ "NRU_Madsen2019_5HT2A_PET_healthy8" ], "access_depth": "abstract_metadata" }, { "citation": "Barrett FS et al., Sci Rep 2020. Emotions and brain function are altered up to one month after a single high dose of psilocybin.", "source_pointer": "PMID 32042038; DOI 10.1038/s41598-020-59282-y; ref 44", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Healthy humans; affect, fMRI emotional tasks and functional connectivity.", "design": "Open-label longitudinal pilot with a single 25 mg/70 kg dose.", "n": "12 participants.", "duration": "One week and one month after dosing.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "In twelve healthy volunteers given 25 mg/70 kg, negative affect and amygdala response to facial affect were reduced at one week and returned to baseline by one month while positive affect remained elevated and trait anxiety was reduced, and the number of significant resting-state connections increased at both follow-ups.", "what_it_does_not_show": "Small selected healthy cohort with an open-label before–after design rather than MDD patients. These are nonuniform functional changes rather than direct plasticity measurement or evidence of mediation.", "confounders_present": [ "Small selected healthy cohort with an open-label before–after design rather than MDD patients. These are nonuniform functional changes rather than direct plasticity measurement or evidence of mediation." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT02971605_Barrett2020_healthy12", "study_ids": [ "NCT02971605_Barrett2020_healthy12" ], "access_depth": "abstract_metadata" }, { "citation": "Holze F et al., Neuropsychopharmacology 2022. Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects.", "source_pointer": "PMID 35217796; DOI 10.1038/s41386-022-01297-2; ref 45", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Healthy humans; plasma BDNF and psychedelic pharmacology.", "design": "Randomized double-blind placebo-controlled counterbalanced crossover with five conditions: LSD 100/200 micrograms, psilocybin 15/30 mg, and placebo.", "n": "28 participants.", "duration": "Plasma BDNF at 4, 6 and 12 hours after each session; at least ten days between sessions.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "null", "what_it_shows": "In a double-blind, placebo-controlled, counterbalanced crossover in 28 healthy participants, neither psilocybin (15 or 30 mg) nor LSD (100 or 200 µg) altered plasma BDNF concentrations relative to placebo despite strong subjective and autonomic effects.", "what_it_does_not_show": "Peripheral plasma BDNF is not brain BDNF and not a synaptic measurement. Healthy participants, acute timepoints only, no depressive endpoint.", "confounders_present": [ "Peripheral plasma BDNF is not brain BDNF and not a synaptic measurement. Healthy participants, acute timepoints only, no depressive endpoint." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03604744_Holze2022_healthy28", "study_ids": [ "NCT03604744_Holze2022_healthy28" ], "access_depth": "full_text_partial" }, { "citation": "Becker AM et al., Clin Pharmacol Ther 2022. Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.", "source_pointer": "PMID 34743319; DOI 10.1002/cpt.2487; ref 46", "relates_to_subclaims": [ "SC4", "SC5" ], "favors_models": [ "M2", "M3" ], "evidence_class": "Weak", "system": "human interventional", "actual_system": "Healthy humans; plasma BDNF and acute psilocybin response.", "design": "Randomized double-blind counterbalanced crossover of escitalopram versus placebo pretreatment; both conditions received 25 mg psilocybin.", "n": "23 completers.", "duration": "Fourteen days of pretreatment; post-dose plasma BDNF at four and seven hours and at peak.", "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": "none for the exact human mediated claim", "endogenous": true, "direction": "mixed", "what_it_shows": "Psilocybin significantly increased peak plasma BDNF relative to baseline under both escitalopram (t22=5.4, P<0.001) and placebo pretreatment (t22=3.6, P=0.002), and escitalopram pretreatment did not alter that increase.", "what_it_does_not_show": "Both conditions received 25 mg psilocybin, so a pretreatment placebo is not a psilocybin placebo and this is not controlled evidence that psilocybin raises BDNF; it contrasts with the placebo-controlled null in the LSD/psilocybin crossover. Healthy participants; peripheral marker only.", "confounders_present": [ "Both conditions received 25 mg psilocybin, so a pretreatment placebo is not a psilocybin placebo and this is not controlled evidence that psilocybin raises BDNF; it contrasts with the placebo-controlled null in the LSD/psilocybin crossover. Healthy participants; peripheral marker only." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Relevant primary Methods/Results/Discussion read in the red-team pass; not every experiment or supplement separately audited.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "NCT03912974_Becker2022_healthy23_SSRIpretreatment", "study_ids": [ "NCT03912974_Becker2022_healthy23_SSRIpretreatment" ], "access_depth": "full_text_partial" }, { "citation": "Williams ZJ et al., JAMA psychiatry 2026;83(5):461-468. Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis.", "source_pointer": "PMID 41848744; DOI 10.1001/jamapsychiatry.2025.4809; ref 47", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "synthesis of human interventional trials", "actual_system": "synthesis of human interventional trials", "design": "systematic review meta analysis", "n": null, "duration": null, "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": null, "endogenous": false, "direction": "contradicts", "what_it_shows": "Comparing psychedelic-assisted therapy with open-label antidepressant treatment, the analysis found no advantage for psychedelic therapy (estimated difference 0.3 favouring open-label antidepressants, 95% CI −1.39 to 1.98, P=.73; 8 psychedelic trials, 249 patients versus 16 open-label antidepressant trials, 7,921 patients), while open-label antidepressant treatment outperformed blinded antidepressant treatment (1.3, 95% CI 0.07 to 2.51, P=.04) with no equivalent difference for psychedelic therapy (0.67, 95% CI −3.08 to 1.73, P=.58).", "what_it_does_not_show": "A Tier B synthesis of within-arm effects across non-randomised comparisons; it frames the inference and does not carry a primary experimental result. Indirect comparison cannot establish that psilocybin's effect is expectancy alone, and the psychedelic dataset is small. No plasticity measurement.", "confounders_present": [ "A Tier B synthesis of within-arm effects across non-randomised comparisons; it frames the inference and does not carry a primary experimental result. Indirect comparison cannot establish that psilocybin's effect is expectancy alone, and the psychedelic dataset is small. No plasticity measurement." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "B", "study_id": "williams_2026_equal_unblinding", "study_ids": [ "williams_2026_equal_unblinding" ], "access_depth": "abstract_metadata", "added_by": "red-team synthesis 2026-09-28" }, { "citation": "Hieronymus F et al., JAMA network open 2025;8(7):e2524119. Control Group Outcomes in Trials of Psilocybin, SSRIs, or Esketamine for Depression: A Meta-Analysis.", "source_pointer": "PMID 40736734; DOI 10.1001/jamanetworkopen.2025.24119; ref 48", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "synthesis of human interventional trials", "actual_system": "synthesis of human interventional trials", "design": "meta analysis", "n": null, "duration": null, "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": null, "endogenous": false, "direction": "contradicts", "what_it_shows": "Across 17 trials, pre-to-post standardized mean change in control arms was 0.50 (SEM 0.15) in psilocybin trials versus 1.00 (0.08) in SSRI and 1.12 (0.17) in esketamine trials, with study population a significant moderator of control-arm change (QM 10.4, P=.005) and of between-group differences (QM 10.7, P=.005) but not of active-arm change (QM 1.21, P=.55); control-arm response rates were 14 and 23 percentage points lower than in SSRI and esketamine trials.", "what_it_does_not_show": "A Tier B synthesis across heterogeneous populations and eras; control-arm differences could also reflect population, era or trial-conduct differences rather than expectancy alone. It does not measure plasticity and does not quantify how much of the psilocybin effect is expectancy.", "confounders_present": [ "A Tier B synthesis across heterogeneous populations and eras; control-arm differences could also reflect population, era or trial-conduct differences rather than expectancy alone. It does not measure plasticity and does not quantify how much of the psilocybin effect is expectancy." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "B", "study_id": "hieronymus_2025_control_arms", "study_ids": [ "hieronymus_2025_control_arms" ], "access_depth": "abstract_metadata", "added_by": "red-team synthesis 2026-09-28" }, { "citation": "Metaxa AM, Clarke M. BMJ 2024;385:e078084. Efficacy of psilocybin for treating symptoms of depression: systematic review and meta-analysis.", "source_pointer": "PMID 38692686; DOI 10.1136/bmj-2023-078084; ref 49", "relates_to_subclaims": [ "SC1" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "synthesis of human interventional trials", "actual_system": "synthesis of human interventional trials", "design": "systematic review meta analysis", "n": null, "duration": null, "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": null, "endogenous": false, "direction": "contradicts", "what_it_shows": "Meta-analysis of 436 participants from seven of nine included randomized trials found a significant benefit of psilocybin on change in depression scores (Hedges' g=0.66, 95% CI 0.46 to 0.86, P<0.001), with larger effects for secondary depression and for self-report scales (both 0.88, 95% CI 0.42 to 1.33) and metaregression coefficients of 0.13 (95% CI 0.02 to 0.23) for older age and 6.00 (95% CI 2.48 to 9.53) for previous psychedelic use; all studies carried moderate risk of bias and certainty was graded moderate.", "what_it_does_not_show": "A Tier B synthesis that frames the effect size and its moderators rather than carrying a primary experimental result; the moderator analyses are exploratory, and the review predates the 2026 trials and the phase 3 program. No plasticity measurement.", "confounders_present": [ "A Tier B synthesis that frames the effect size and its moderators rather than carrying a primary experimental result; the moderator analyses are exploratory, and the review predates the 2026 trials and the phase 3 program. No plasticity measurement." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "B", "study_id": "metaxa_2024_meta", "study_ids": [ "metaxa_2024_meta" ], "access_depth": "abstract_metadata", "added_by": "red-team synthesis 2026-09-28" }, { "citation": "Purple RJ et al., Molecular psychiatry 2025;30(12):5889-5900. Short- and long-term modulation of rat prefrontal cortical activity following single doses of psilocybin.", "source_pointer": "PMID 40858779; DOI 10.1038/s41380-025-03182-y; ref 50", "relates_to_subclaims": [ "SC3" ], "favors_models": [ "M3", "M2" ], "evidence_class": "Moderate", "system": "animal model", "actual_system": "animal model", "design": "primary", "n": null, "duration": null, "molecule": "psilocybin", "decisive_perturbation": false, "decisive_for_scope": null, "endogenous": true, "direction": "supports", "what_it_shows": "In freely behaving adult rats, single psilocybin doses (0.3 or 1 mg/kg) unmasked roughly 100 Hz oscillations most pronounced in infralimbic cortex lasting about an hour with decreased net firing rates and reduced spike-train complexity, and local field potentials at one, two and six days showed gradually emerging increases in beta and low-gamma power.", "what_it_does_not_show": "Electrophysiological changes in rat prefrontal cortex are not a measure of inducibility and were not linked to a depressive endpoint or to human symptoms; acute effects were state-dependent (more prominent at rest than during task performance). Access in this pass was the publisher abstract, so the full methods were not audited. Independent of the mouse imaging program, which is why it is retained as a distinct line.", "confounders_present": [ "Electrophysiological changes in rat prefrontal cortex are not a measure of inducibility and were not linked to a depressive endpoint or to human symptoms; acute effects were state-dependent (more prominent at rest than during task performance). Access in this pass was the publisher abstract, so the full methods were not audited. Independent of the mouse imaging program, which is why it is retained as a distinct line." ], "verification": "verified", "verification_note": "Red-team verified 2026-09-28. Verified in the red-team pass at publisher abstract, PubMed/Europe PMC record and metadata level; full Methods were not available for audit.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "source_tier": "A", "study_id": "purple_2025_rat_neuropixels", "study_ids": [ "purple_2025_rat_neuropixels" ], "access_depth": "abstract_metadata", "added_by": "red-team synthesis 2026-09-28" } ], "verification_summary": { "load_bearing_claims_checked": 50, "verified": 50, "unverified": 0, "contradicted": 0, "note": "One registered reported finding per source. Every PMID and DOI was re-resolved in the red-team pass and matched on title, first author, year and journal; load-bearing numerics were re-checked against full text where deposited and against publisher abstracts otherwise. Statistics that could not be verified from a primary record at this pass's access depth were removed rather than repeated. Verification means source attribution, reported result and stated scope at the recorded access depth, not raw-data reproducibility or causal proof." }, "factual_issues_found": [ { "quoted_text": "Additional author and a 95% CI for the secondary Sheehan Disability Scale mean difference corrected; primary MADRS estimate unchanged.", "quoted_text_location": "Original edition, reference 5 correction note and factual_issues_found entry", "problem": "The correction was mischaracterised: no Sheehan-interval correction is documented.", "source_says": "The article's own correction note reads that it \"was corrected on January 26, 2024, to add an author to the byline and correct minor typographical errors\"; the notice is titled \"Error in Byline\".", "source_pointer": "JAMA 2024;331(8):710; PMID 38277159; DOI 10.1001/jama.2024.0828; parent PMID 37651119", "affects_score": false, "action": "corrected-in-this-edition", "finding_id": "RT-06" }, { "quoted_text": "Relevant corrections are linked in the ledger.", "quoted_text_location": "Original edition, Reviewer notes and provenance", "problem": "Two journal corrections were not recorded, one of them on a paper whose corrected numbers the review cites.", "source_says": "The 2021 waitlist trial carries \"Errors in Response Rate, Effect Sizes, and Confidence Intervals\" (article corrected 10 February 2021); the 2024 clinician trial carries byline and author-affiliation corrections.", "source_pointer": "DOI 10.1001/jamapsychiatry.2020.4714 (PMID 33566065); DOI 10.1001/jamanetworkopen.2024.59278 (PMID 39804652); DOI 10.1001/jamanetworkopen.2025.25303 (PMID 40638123)", "affects_score": false, "action": "corrections-attached-to-parent-rows", "finding_id": "RT-05" }, { "quoted_text": "the treatment-arm × scan interaction was nonsignificant (P=.107)", "quoted_text_location": "Original edition, section 5 and reference 39 row", "problem": "Specific inferential statistics were carried for paywalled records that this pass could not verify from a primary source.", "source_says": "The abstract reports within-arm modularity change and change-symptom correlation and states that no network changes were observed after escitalopram; it reports no interaction statistic. The same applies to the sustained-response counts and odds ratio attributed to the 2022 dose-comparison trial, the drug-by-time and six-month p values attributed to the 2011 pilot, and the 57-79% response range attributed to the 4.5-year cancer follow-up.", "source_pointer": "PMIDs 35411074, 36322843, 20819978, 31916890", "affects_score": false, "action": "unverifiable-statistics-removed-and-access-depth-restated", "finding_id": "RT-07" }, { "quoted_text": "An identified retracted rat-activity paper is excluded.", "quoted_text_location": "Original edition, Reviewer notes and provenance", "problem": "An unidentified exclusion cannot be audited, and the systematic screen found no retractions anywhere in the set.", "source_says": "Screening all fifty records against PubMed and Europe PMC comment/correction links on 2026-09-28 returned no retractions and no expressions of concern; six records carry errata.", "source_pointer": "Europe PMC commentCorrectionList for all ledger PMIDs, checked 2026-09-28", "affects_score": false, "action": "statement-removed-and-screen-result-recorded", "finding_id": "RT-08" }, { "quoted_text": "publisher text reports no potent LSD interactions in a 450-human-kinase panel, including TrkB", "quoted_text_location": "Original edition, reference 35 row and section 4", "problem": "A directional negative result was attributed to a paper whose abstract does not report it, and it was used to weigh against a competing mechanism.", "source_says": "The abstract states that 41 psychedelics were profiled against 318 human GPCRs and LSD against more than 450 human kinases, and reports potent activity at nearly every serotonin, dopamine and adrenergic receptor; the kinase-panel outcome is not stated.", "source_pointer": "PMID 40683247; DOI 10.1016/j.neuron.2025.06.012", "affects_score": false, "action": "claim-restated-to-verifiable-content", "finding_id": "RT-14" }, { "quoted_text": "No psychiatry-specific rubric exists in this packet.", "quoted_text_location": "Pre-registered scope and aggregation file, 2026-09-27", "problem": "The packet contains 07-psychiatry-neuromodulation.md, which governs this hypothesis class.", "source_says": "The rubric's scope names psilocybin dual-phase models and rapid-plasticity antidepressant models, and the framework changelog records that it was added in v4.0 because a psychedelic-therapy hypothesis had been scored under the neurodegeneration rubric.", "source_pointer": "references/evidence-rubrics/07-psychiatry-neuromodulation.md; SKILL.md Step 5; CHANGELOG v4.0", "affects_score": false, "action": "routing-corrected-in-this-edition; pre-registered aggregation rule and subclaim set left unchanged and the error logged rather than edited", "finding_id": "RT-01" } ], "cap_rules_applied": [ { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Biomarker change without functional/phenotypic change caps at Γ.", "specific_trigger": "Human structural, protein and connectivity markers do not by themselves show a temporary cortical-inducibility interval linked to symptom benefit.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "07-psychiatry-neuromodulation.md", "triggered": true, "trigger_text_quoted": "Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.", "specific_trigger": "Receptor occupancy and acute desynchronization are offered as plasticity evidence but are not linked to a symptom trajectory.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC5", "cap": "Γ", "cap_source": "07-psychiatry-neuromodulation.md", "triggered": true, "trigger_text_quoted": "Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.", "specific_trigger": "Modularity, EEG entropy and insight, cognitive flexibility and SV2A change are correlated with outcome or with each other; none was manipulated in humans.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC5", "cap": "Β", "cap_source": "universal", "triggered": false, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β.", "specific_trigger": "SC5 is supported by experimental partial-system evidence as well as human association, so the Β ceiling binds the isolated associational inference class and is not re-applied to the convergent set (framework pitfall 21).", "resulting_ceiling": "Β", "ceiling_scope_note": "Binds the isolated associational inference class only; not re-applied to the convergent set." }, { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "universal", "triggered": false, "trigger_text_quoted": "In vitro evidence alone cannot exceed Γ.", "specific_trigger": "SC1 is not offered on in vitro evidence; the cellular inference component is capped separately under component_cap_rules.", "resulting_ceiling": "Γ" } ], "component_cap_rules": [ { "inference_class": "Human iPSC culture → living human cortical inducibility", "related_subclaim": "SC4", "cap": "Γ", "triggered": true, "trigger_text_quoted": "In vitro evidence alone cannot exceed Γ." }, { "inference_class": "Human imaging–symptom association alone → causal mediation", "related_subclaim": "SC5", "cap": "Β", "triggered": true, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β." }, { "inference_class": "Randomized protocol-assignment benefit → drug-specific pharmacological effect", "related_subclaim": "SC1", "cap": "Γ", "triggered": true, "trigger_text_quoted": "Inert-placebo trial of an agent with unmistakable acute effects (see Γ cap)" }, { "inference_class": "Adult mouse cortical receptor/cell dependency → human symptom mediation", "related_subclaim": "SC5", "cap": "Γ", "triggered": true, "trigger_text_quoted": "A perturbation crosses a threshold within the system it was actually run in." }, { "inference_class": "Inert-placebo or sub-perceptual-dose randomized trial without a blinding-integrity check → drug-specific antidepressant effect", "related_subclaim": "SC1", "cap": "Γ", "triggered": true, "trigger_text_quoted": "Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.", "note": "Binds the drug-specific pharmacological inference, not the protocol-assignment claim scored at Ε; recorded as a component cap so that a component ceiling is not mistaken for a subclaim-wide ceiling." }, { "inference_class": "Open-label extension or naturalistic follow-up → controlled durability", "related_subclaim": "SC2", "cap": "Γ", "triggered": true, "trigger_text_quoted": "Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.", "note": "Binds the long-term open-label evidence class; SC2 remains Δ on the maintained randomized self-report contrast alone." }, { "inference_class": "Rodent behavioural-despair endpoints → therapeutic antidepressant claim", "related_subclaim": "SC3", "cap": "Γ", "triggered": true, "trigger_text_quoted": "Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.", "note": "Binds the rodent behavioural evidence class; SC3 remains Ε on the direct adult cortical measurements and their perturbations." } ], "cap_precedence_resolutions": [ { "collision": "Rubric 07 Δ designs versus universal caps on the same trials", "subclaim_scope_cap_binds_on": "SC1 drug-specific attribution, and SC4/SC5 at human mediator scope", "subclaim_scope_threshold_binds_on": "SC1 protocol-assignment response; SC2 the maintained randomized twelve-week signal; SC3 the adult experimental cortical response", "resolution": "A perturbation crosses a threshold within the system it was actually run in; a universal cap governs the inference from that system to the claimed scope. Randomized assignment crosses the threshold for the protocol it randomized; it does not allocate credit to cortical plasticity, and rubric 07 caps the drug-specific reading of trials without blinding-integrity data.", "note": "Recorded, not resolved silently. No blanket pharmacological-intervention cap." }, { "collision": "Association-only Β ceiling versus convergent Γ mechanism assessment", "subclaim_scope_cap_binds_on": "The isolated human imaging–symptom association", "subclaim_scope_threshold_binds_on": "Experimental cortical and molecular evidence supporting partial-system plausibility", "resolution": "The Β cap binds the associational inference class; combined experimentally supported mechanistic plausibility may reach Γ. It is not applied to the entire convergent set.", "note": "Framework pitfall 21; source linkage preserved so component caps do not erase stronger evidence." }, { "collision": "Rubric 07 threshold list versus the rubric's own Moderate-evidence class for partially matched comparators", "subclaim_scope_cap_binds_on": "Niacin, nicotinamide and 1 mg psilocybin comparators read as subjective-effect-matched", "subclaim_scope_threshold_binds_on": "SC1 and SC2 as randomized contrasts within their own designs", "resolution": "The rubric classes side-effect-only placebo and sub-perceptual dose as partially matched (Moderate) rather than Strong, so these trials support context-specific causality for the protocol without satisfying the Δ design list for a drug-specific or mediator claim.", "note": "This is why SC1 sits at Ε on protocol scope while the mediated claim remains Γ." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "Rubric 07 Δ: Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "5, 6, 15, 4", "gamma_hard_rules_triggered": [ "Functional-unblinding rule fires on the drug-specific inference; protocol-assignment response is unaffected." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Repeated positive randomized symptom contrasts with null and population boundaries; component-specific attribution remains unresolved.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "Rubric 07 Δ: Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "4, 6", "gamma_hard_rules_triggered": [ "Open-label rule fires on the extensions and naturalistic follow-ups that carry most of the long-term narrative." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Exploratory randomized self-report signal around three months; rescue-sensitive loss of separation and unconfirmed sustained-response endpoint limit causal durability.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "Rubric 07 Δ: Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "24, 32, 33", "gamma_hard_rules_triggered": [ "Rodent-proxy rule fires on the behavioural endpoints; the direct cortical measurements and adult perturbations are unaffected." ], "disease_phenotype_relevance": "no", "perturbation_result_positive": "yes", "perturbation_result_note": "Direct longitudinal spines, physiology and cell/receptor interventions show a bounded experimental cortical response; strongest direct adult structural work shares a program.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "Rubric 07 Δ: Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "37, 38, 42, 41", "gamma_hard_rules_triggered": [ "Acute-pharmacodynamic rule; biomarker-without-phenotype cap; negative field-valid perturbation does not cross Δ (framework pitfall 17)." ], "disease_phenotype_relevance": "no", "perturbation_result_positive": "no", "perturbation_result_note": "Target engagement and persisting proxies do not measure a temporary increase in inducibility; overall one-week SV2A test was null.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "Rubric 07 Δ: Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "39, 41, 32, 37", "gamma_hard_rules_triggered": [ "Mediation-by-correlation rule; cross-system mechanistic plausibility does not establish the human mediator." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "No reviewed human experiment, valid instrument or sufficiently selective contrast establishes this mediator contribution.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "At least one endogenous in vivo (or equivalent human interventional / natural-experiment) perturbation shows the mechanism contributes causally to the claimed phenotype.", "satisfied": "yes", "supporting_evidence": [ "5", "6", "15", "4" ], "what_would_cross_it": "Crossed within the specified scope, with limits stated." }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "The mechanism is causally operative in a defined context, subtype, stage, or model — but generalization to the full claimed scope fails.", "satisfied": "yes", "supporting_evidence": [ "5", "6", "15", "4" ], "what_would_cross_it": "Crossed with population/model and endpoint limits mapped." }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Replication across at least two relevant systems, with major alternative models narrowed but not excluded.", "satisfied": "no", "supporting_evidence": [ "5", "6", "15", "4" ], "what_would_cross_it": "A distinct causal line with a different systematic-error basis, resolving component/expectancy alternatives." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "At least one endogenous in vivo (or equivalent human interventional / natural-experiment) perturbation shows the mechanism contributes causally to the claimed phenotype.", "satisfied": "yes", "supporting_evidence": [ "4", "6" ], "what_would_cross_it": "Crossed within the specified scope, with limits stated." }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "The mechanism is causally operative in a defined context, subtype, stage, or model — but generalization to the full claimed scope fails.", "satisfied": "no", "supporting_evidence": [ "4", "6" ], "what_would_cross_it": "Replicate maintained twelve-week clinician-rated benefit and map a prespecified context boundary with rescue treatment handled prospectively." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "At least one endogenous in vivo (or equivalent human interventional / natural-experiment) perturbation shows the mechanism contributes causally to the claimed phenotype.", "satisfied": "yes", "supporting_evidence": [ "24", "32", "33" ], "what_would_cross_it": "Crossed within the specified scope, with limits stated." }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "The mechanism is causally operative in a defined context, subtype, stage, or model — but generalization to the full claimed scope fails.", "satisfied": "yes", "supporting_evidence": [ "24", "32", "33" ], "what_would_cross_it": "Crossed with population/model and endpoint limits mapped." }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Replication across at least two relevant systems, with major alternative models narrowed but not excluded.", "satisfied": "no", "supporting_evidence": [ "24", "32", "33" ], "what_would_cross_it": "Assay-comparable direct adult cortical replication across independent programs, with molecule, age and methodological biases separated." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "At least one endogenous in vivo (or equivalent human interventional / natural-experiment) perturbation shows the mechanism contributes causally to the claimed phenotype.", "satisfied": "no", "supporting_evidence": [ "37", "38", "42", "41" ], "what_would_cross_it": "Positive validated cortical inducibility time course in living humans, under a randomized drug/control contrast." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "At least one endogenous in vivo (or equivalent human interventional / natural-experiment) perturbation shows the mechanism contributes causally to the claimed phenotype.", "satisfied": "no", "supporting_evidence": [ "39", "41", "32", "37" ], "what_would_cross_it": "Human mediator perturbation, timing instrument or natural experiment with justified exclusion restrictions and sustained symptoms." }, { "subclaim_id": "SC4", "threshold": "Δ (rubric 07)", "requirement_quoted": "Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia", "satisfied": "no", "supporting_evidence": [ "37", "38", "42" ], "what_would_cross_it": "A human study measuring cortical inducibility before and after psilocybin given with and without 5-HT2A blockade, with prespecified plasticity and symptom endpoints; two such trials are recruiting (NCT06512220, NCT07490353) and neither has results." }, { "subclaim_id": "SC1", "threshold": "Δ (rubric 07)", "requirement_quoted": "Active comparator matched for acute subjective effect, blinding integrity measured and reported", "satisfied": "no", "supporting_evidence": [ "5", "6", "4", "2", "47", "48" ], "what_would_cross_it": "A randomized trial whose comparator reproduces the acute subjective effects, with allocation guessing and confidence measured in participants and raters; niacin, nicotinamide and 1 mg psilocybin are partially matched comparators under the rubric." }, { "subclaim_id": "SC1", "threshold": "Ζ (rubric 07)", "requirement_quoted": "Independent multi-site replication by sponsor-independent teams, pre-registered, without outcome switching; blinding-integrity reporting in each replicating trial; one result narrowing the mechanism against expectancy", "satisfied": "no", "supporting_evidence": [ "5", "2", "4", "47" ], "what_would_cross_it": "Sponsor-independent multi-site replication with blinding integrity reported in each trial, plus one result narrowing the mechanism against expectancy (mediator manipulation, blinded dose-response adjusted for allocation guessing, or a non-subjective congener)." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Clinical primary-positive and primary-null contrasts differ in population, comparator and endpoint; they bound protocol response, not a universal drug response.", "Mouse PT/IT and receptor manipulations map cell/receptor contexts; constitutive knockout behavior differs across stress models.", "Healthy human SV2A null and dose/arm fMRI nulls constrain specific marker predictions without excluding all forms of plasticity." ], "note": "Mapped bounded contexts support Ε for SC1/SC3. Generalization of a temporary human cortical window and its clinical mediation is not established." }, "falsification_patterns_met": [ { "subclaim_id": "SC4", "pattern": "Predicted marker does not move at the tested interval", "evidence": "Overall one-week human SV2A null that stopped for futility; 37", "downgrade_applied": true, "scope_limit": "Healthy volunteers, one protein marker and one timepoint; not all functional plasticity." }, { "subclaim_id": "SC5", "pattern": "Candidate proxy improvement dissociates from depressive improvement", "evidence": "Cognitive-flexibility change uncorrelated with symptom change (all |r| < 0.2, p > 0.250); 41", "downgrade_applied": true, "scope_limit": "This cognitive measure does not exhaust cortical plasticity." }, { "subclaim_id": "SC2", "pattern": "Long-term treatment advantage not confirmed", "evidence": "Sustained response at week 12 not confirmed in the largest peer-reviewed trial; no significant one-year clinician-rated advantage in the Swedish trial; 6, 4", "downgrade_applied": true, "scope_limit": "Restricts a broad durability claim; not proof of no benefit in any individual." }, { "subclaim_id": "SC1", "pattern": "Allocation guessing is near-perfect and outcome tracks guessed allocation (rubric 07)", "evidence": "Guessing near-perfect wherever measured (86%, 13/13, 100%, 70.6-94.1%); psychedelic therapy no better than open-label antidepressant treatment and psilocybin control arms improving far less than SSRI/esketamine control arms; 2, 1, 20, 4, 47, 48", "downgrade_applied": false, "scope_limit": "Half-met: the guessing half is established; whether outcome tracks guessed allocation is contested, and EPISODE's own stratified description suggests it did not at week 6. Caps the drug-specific inference rather than the protocol-response level." }, { "subclaim_id": "SC5", "pattern": "Blocking the acute experience, or dosing under anaesthesia, leaves the effect intact (rubric 07)", "evidence": "Tested only in rodents and with mixed results: ketanserin pretreatment left most structural measures and hippocampal synaptic effects intact, while adult cortical receptor knockout abolished both behaviour and remodeling; 24, 25, 32, 31", "downgrade_applied": false, "scope_limit": "Rodent evidence cannot settle the human pattern; the two recruiting antagonist trials are the relevant test." }, { "subclaim_id": "SC3", "pattern": "No late persistent excess spine density despite reported function", "evidence": "Independent adult-rat report of persisting behaviour and physiology with no spine-density, spine-classification or synaptic-marker differences at twelve weeks; 36", "downgrade_applied": false, "scope_limit": "Compatible with earlier transient remodeling; functional plasticity remains, and this is why M3 is retained." } ], "pitfalls_flagged": [ { "subclaim_id": "SC5", "pitfall": "Therapeutic benefit substituted for mechanism proof", "where": "Clinical randomization does not randomize the mediator." }, { "subclaim_id": "SC4", "pitfall": "Persistent state substituted for temporary enhanced capacity", "where": "Day-65 spine density and multi-week connectivity changes do not measure an inducibility window." }, { "subclaim_id": "SC5", "pitfall": "Shared upstream receptor intervention treated as selective mediator interruption", "where": "Adult receptor deletion and cell silencing can affect parallel routes." }, { "subclaim_id": "SC2", "pitfall": "Post-crossover and observational persistence treated as controlled durability", "where": "Long follow-ups permit additional care and reuse treated cohorts; rubric 07 open-label rule." }, { "subclaim_id": "SC4", "pitfall": "Within-arm or subgroup significance treated as between-arm primary evidence", "where": "No significant arm x scan interaction for modularity; Johansen overall null with a nonrandom setting contrast; Lyons fixed order." }, { "subclaim_id": "SC3", "pitfall": "Species, age and molecule labels collapsed", "where": "Juvenile pigs, developmental cultures, LSD animal outcomes and psilocin cell assays have different scopes." }, { "subclaim_id": "SC5", "pitfall": "\"Neuroplasticity\" used as an unfalsifiable bridge from acute molecule to distant outcome (rubric 07)", "where": "The hypothesis is only testable once \"plasticity\" is operationalised as measured inducibility with onset and closure." }, { "subclaim_id": "SC3", "pitfall": "Rodent behavioural-despair assays treated as models of human depression (rubric 07)", "where": "Forced-swim, sucrose-preference and head-twitch endpoints carry the rodent antidepressant narrative." }, { "subclaim_id": "SC1", "pitfall": "Conjunctive claims scored on their easier clause (rubric 07)", "where": "Efficacy evidence must not be read as evidence for the through-plasticity clause; weakest-link aggregation is what prevents it." }, { "subclaim_id": "SC3", "pitfall": "Replication confused with reproduction", "where": "The direct adult structural imaging line and its perturbations share one laboratory program and technique." } ], "causal_tally_audit": { "tally_claimed_by_document": 0, "tally_after_audit": 0, "scope_of_tally": "Complete human experimentally established cortical-plasticity interval and causal contribution to sustained depressive-symptom relief.", "items_rejected": [ "Positive clinical trials demonstrate supported protocol effects, not cortical mediator selection.", "Adult mouse receptor/cell manipulation crosses its actual experimental scope and can affect parallel pathways.", "Human network, BDNF, cognitive and SV2A findings do not identify a selective human mediator.", "Statistical mediation in healthy well-being or clinical experience ratings is not equivalent to experimental identification of cortical plasticity mediation." ] }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "blinding_integrity_reported_randomized_trial (rubric 07)", "available": true, "why_not_sufficient": "Available and sometimes positive on the primary endpoint, but the comparators are not matched for acute subjective effects and measured guessing is near-ceiling, so these trials do not separate the drug from its package, and none measures the plasticity mediator." }, { "kind": "discontinuation_and_rechallenge (rubric 07)", "available": false, "why_not_sufficient": "Not applicable to a single-dose intervention whose proposed mediator is a transient window; no human on/off design for the plasticity process exists." }, { "kind": "genetic_instrument (rubric 07)", "available": false, "why_not_sufficient": "No plausible instrument for drug-induced cortical inducibility was identified; candidate receptor or BDNF variants do not isolate the proposed interval." }, { "kind": "therapeutic_perturbation_clinical_endpoint", "available": true, "why_not_sufficient": "Multiple randomized symptom contrasts establish response in some contexts; none independently changes cortical plasticity." }, { "kind": "selective_adult_genetic_intervention", "available": true, "why_not_sufficient": "Adult mouse cortical receptor deletion and cell silencing establish experimental dependencies with parallel downstream routes, not human spine-mediated durable response." }, { "kind": "dose_response", "available": true, "why_not_sufficient": "Blinded dose-response exists (25/10/1 mg) but has not been adjusted for allocation guessing, and dose–symptom contrasts do not isolate a mediator; the phase 3 dose-response data are not peer reviewed." }, { "kind": "non_subjective_congener", "available": false, "why_not_sufficient": "No non-hallucinogenic congener has been shown to reproduce the antidepressant effect in humans; this remains one of the rubric's named discriminating tests." }, { "kind": "mediator_manipulation_with_intervention_intact", "available": false, "why_not_sufficient": "Two human trials of psilocybin with and without a 5-HT2A/D2 antagonist are recruiting (NCT06512220, NCT07490353); neither has results, and the first is a feasibility study with twelve participants." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false, "note": "Experimental remodeling, molecular interventions and clinical response converge on a plausible mechanism. The missing connection is human interval identification and mediator manipulation. Necessity AND sufficiency is not demanded for the next Δ contribution threshold." }, "steelman": { "case_one_rung_higher": "A Δ case triangulates randomized post-acute benefit in several populations, direct adult cortical remodeling with cell-type and receptor specificity, an adult-mouse demonstration that the behavioural effect requires cortical 5-HT2A receptors and pyramidal-tract neurons, a measured two-week reopening of a learning-sensitive state in adult mice, verified human target engagement, and human imaging changes that correlate with symptom improvement. The hypothesis names a molecule, receptor, cell type, time course and measurable readout, and each has been confirmed somewhere.", "case_one_rung_lower": "A Β case notes that human mediator attribution is entirely correlational, proxy results are mixed or null, two well-powered primary endpoints were missed, and pooled analyses are consistent with a large expectancy contribution.", "which_rejected": "Δ is rejected for the complete human mediated claim because rubric 07's Δ design list is unsatisfied: no acute-effect-matched comparator with measured blinding integrity, no mediator manipulation with the drug intact, no human challenge experiment with a symptom trajectory outcome. Β is rejected because adult cell-type-restricted receptor deletion in living cortex is a causal perturbation, not an association.", "blocking_cap_threshold_or_missing_experiment": "The first unmet threshold is rubric 07 Δ for SC4 and SC5: a positive human cortical-inducibility interval and a sufficiently selective causal test that it contributes to sustained symptom benefit. The mediation-by-correlation and functional-unblinding hard rules are what hold the present evidence at Γ." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Substantial multi-modal primary literature, independently replicated across clinical and experimental lines, supports the distinction between efficacy and mechanism. Human measurement is heterogeneous, mediator identification is absent, and the largest randomized datasets are not yet peer reviewed and carry no part of the grade. This is evidence-density confidence, not a probability that the hypothesis is true, and not a statement about this reviewer's access depth, which is recorded separately.", "rests_on_non_peer_reviewed_work": false, "rationale": "SC1 protocol-level clinical response and SC3 adult experimental cortical effects reach Ε; approximately twelve-week persistence is a qualified Δ. The temporary human cortical-plasticity interval and its causal contribution to sustained symptoms each remain Γ under rubric 07's acute-pharmacodynamic and mediation-by-correlation rules. Weakest-link therefore returns Γ. The red-team pass changed neither the overall letter nor any subclaim level.", "non_peer_reviewed_note": "Company and regulatory documents describing the phase 3 program (COMP005, COMP006) are reported as context only. Under the framework source-tier rule they are inadmissible as evidence items, hold no ledger row, and carry no part of the grade or confidence band." }, "role_of_mechanism": { "classification": "epiphenomenon", "derivation_step_matched": 2, "derivation": "At the claimed human clinical scope, causal dependency has not been demonstrated in either direction between the proposed cortical-plasticity period and durable symptom change, so the framework's derivation stops at step 2, co-occurrence. This is an evidence-status label, not proof that the process is biologically inactive; in adult mouse cortex dependency on 5-HT2A receptors and pyramidal-tract neurons has been demonstrated and is scored separately as SC3.", "claimed_scope": "Human cortical-plasticity interval as mediator of sustained depressive response", "plain_language_role": "Causal role unestablished", "tournament_used_as_tiebreaker": false }, "extended_scoring_MSD": { "momentum": { "value": "Decisive work underway", "artifact": "SYNVEST (ClinicalTrials.gov NCT06512220, Centre for Addiction and Mental Health, recruiting since 2025-04-21, n=12, primary completion 2027-04): 25 mg psilocybin with and without risperidone 1 mg in treatment-resistant depression, with [18F]SynVesT-1 SV2A PET before and four weeks after dosing, TMS-EEG cortical-plasticity measures, diffusion MRI and MADRS. NCT07490353 (Medical University of Vienna, recruiting since 2025-11-01, n=85, primary completion 2028-05): psilocybin with and without risperidone 1 mg in depression with anhedonia plus healthy controls, with fMRI complexity measures, BDNF and clinician- and self-rated depression scales. NCT05601648, an earlier SV2A study inside a psilocybin depression trial, was withdrawn with zero enrolment. Ongoing mechanistic artifacts: adult cell-type and receptor manipulations, activity-dependent rewiring, human iPSC cortical neurons, human SV2A PET, and independent adult-rat electrophysiology.", "justification": "Two registered human trials administer the drug with and without 5-HT2A/D2 antagonism while measuring plasticity and symptoms, which is rubric 07's \"mediator manipulation with the intervention intact\" and could cross Δ for SC4/SC5. Corrected from the original edition, which recorded that no such study was under way; both trials are small and neither has results." }, "stability": { "value": "Uncertain", "trigger": "Upward: a positive adequately powered human inducibility or blockade result linking a measured plasticity interval to sustained symptoms (NCT06512220, NCT07490353 or a successor); peer-reviewed publication of the phase 3 program with blinding-integrity and durability analyses. Downward: adequately powered nulls in those designs, or peer-reviewed confirmation of the phase 3 program's modest week-six effects and re-treatment-dependent durability.", "justification": "Named triggers point in both directions, which is the definition of Uncertain; general efficacy programs alone do not decide the plasticity attribution." }, "divergence": { "implied_level": null, "implied_level_basis": "Primary reports differ in molecular route and in the strength of their mechanistic framing, and recent human authors explicitly qualify the translation. No systematic field-consensus estimate or single defensible implied HSEF grade exists for this exact human mediated sentence.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "Report the disagreement and measurement limits without manufacturing an arithmetic overstatement gap. Read literally as settled human causation the sentence would overstate what has been demonstrated; read as a mechanistic candidate with strong animal support it is fairly stated." }, "calibration_note": "M/S/D are reviewer judgments at the exact claim scope and do not alter level or confidence." }, "proposed_decisive_experiments": [ { "name": "Post-acute selective plasticity-effector interruption and rescue in adult animals", "experiment": "Interrupt a validated growth/functional-plasticity effector after acute psilocybin exposure, with an independent rescue and laboratory replication.", "readout": "Direct cortical spine formation and physiology, multiple sustained stress-related behavioral endpoints, motor function and general learning.", "critical_control": "Preserved drug exposure and acute cortical activity, selectivity of effector interruption, animal-level replication and blinded analysis.", "falsifying_result": "Sustained behavior intact despite verified loss of the specified plasticity process.", "supporting_result": "Selective loss and rescue of plasticity and sustained behavior within the defined model." }, { "name": "Human cortical-inducibility time course plus randomized temporal learning contrast", "experiment": "Randomize a prospectively defined depressed population to psilocybin or credible active control under matched support; independently randomize equivalent learning within a measured candidate window or later.", "readout": "Validated cortical inducibility/excitability assay plus complementary imaging over hours/days/weeks; clinician-rated symptoms at six/twelve weeks and six months.", "critical_control": "Drug×timing interaction, justified exclusion restrictions, blinding guesses, participant-level analysis, multiplicity, attrition, treatment-policy and rescue-sensitive estimands.", "falsifying_result": "Verified window without sustained symptom advantage attributable to its timing/mediator contrast.", "supporting_result": "Prespecified replicated drug×timing interaction supported by measured inducibility and selective mediation assumptions; timing alone is insufficient." }, { "name": "Human mediator manipulation with the drug left in place, at adequate power", "experiment": "Randomize depressed participants to psilocybin with and without 5-HT2A antagonist pretreatment (or conditions that suppress the acute experience), with randomized order and setting, a preregistered plasticity readout and a prespecified sustained symptom endpoint, powered for the mediation contrast rather than for feasibility.", "readout": "Validated cortical inducibility measure plus a static synaptic marker, with clinician-rated symptoms at six and twelve weeks and six months.", "critical_control": "Measured allocation guessing and expectancy in participants and raters; drug exposure verified; randomized rather than sequential assignment of setting and order.", "falsifying_result": "Sustained symptom benefit preserved when the plasticity response is verifiably blocked, or a verified plasticity interval with no related symptom advantage.", "supporting_result": "Blockade that removes both the measured plasticity response and the sustained symptom benefit, with exposure and support held constant." } ], "knowledge_gaps": [ { "name": "Human window", "statement": "Opening/closure times and existence of increased cortical inducibility in depressed humans.", "relevance": "Persistence of a state is not increased capacity for future change." }, { "name": "Mediator identity", "statement": "Structural growth versus functional adaptation versus learning sensitivity.", "relevance": "Assay and intervention must measure the same proposed process." }, { "name": "Causal contribution", "statement": "Whether the proposed period carries sustained symptom benefit independent of exposure, experience, support and later care.", "relevance": "The missing Δ for the full mechanism." }, { "name": "Antecedent boundaries", "statement": "Baseline clinical, medication, receptor, cell and circuit conditions predicting reproducibility.", "relevance": "Scope must be known before outcome." }, { "name": "Long-term attribution", "statement": "Initial-treatment contribution after twelve weeks, six months and twelve months under subsequent care.", "relevance": "Defines what durable treatment response means causally." }, { "name": "Comparator adequacy", "statement": "How much measured benefit survives a comparator matched for acute subjective effects, and what an acceptable comparator in this field would be.", "relevance": "Rubric 07 treats the comparator, not the intervention, as the hard part of the field." }, { "name": "Setting effects", "statement": "Whether the dosing-environment difference reported in exploratory human synaptic-marker imaging survives randomization.", "relevance": "Setting was assigned sequentially, so the interaction is a hypothesis about context, not a demonstrated moderator." } ], "change_record": { "applies": true, "prior_level": "Γ", "prior_confidence": "Moderate", "new_level": "Γ", "direction": "held", "what_moved_it": "Level held; sub-claim, confidence, routing and evidence changes are itemised in the red-team change log.", "itemised_changes": [ { "field": "rubric_routing", "before": "universal framework only; \"no psychiatry-specific rubric exists in this packet\"", "after": "07-psychiatry-neuromodulation.md primary, universal caps secondary", "reason": "RT-01", "level_effect": "none" }, { "field": "cap_rules_applied / component_cap_rules / boundary_check_BGD / thresholds_tested", "before": "universal caps only", "after": "rubric 07 hard rules and Δ design list added and quoted", "reason": "RT-01", "level_effect": "none" }, { "field": "citation_ledger / claims / evidence_inventory", "before": "46 sources, 46 claims", "after": "50 sources, 50 claims; four peer-reviewed additions", "reason": "RT-02, RT-03, RT-10", "level_effect": "none" }, { "field": "access depth", "before": "18 complete / 23 partial / 5 abstract as recorded 2026-09-27", "after": "re-derived as verified in the red-team pass, with access_depth_original retained on every row", "reason": "RT-12", "level_effect": "none" }, { "field": "extended_scoring_MSD.momentum", "before": "Mechanistic only", "after": "Decisive work underway", "reason": "RT-09", "level_effect": "none" }, { "field": "extended_scoring_MSD.stability", "before": "Stable", "after": "Uncertain", "reason": "RT-09", "level_effect": "none" }, { "field": "final_score", "before": "Γ / Moderate", "after": "Γ / Moderate", "reason": "no finding required a grade movement", "level_effect": "none" } ] }, "redteam_synthesis": { "date": "2026-09-28", "red_team_model": "Claude (Anthropic), cross-model red team; authoring model(s) differed", "inputs": [ "psilocybin-depression-cortical-plasticity.review.md", "psilocybin-depression-cortical-plasticity.scorecard.json", "psilocybin-depression-cortical-plasticity.source-access.csv", "psilocybin-depression-cortical-plasticity.scope-and-aggregation.md", "psilocybin-depression-cortical-plasticity.validation.txt", "psilocybin-depression-cortical-plasticity.README.md", "SHA256SUMS.txt" ], "mode": "single-version red team", "external_red_team_document": null, "findings_total": 16, "findings_accepted": 14, "findings_partially_accepted": 1, "findings_rejected": 1, "score_before": { "level": "Γ", "confidence": "Moderate", "subclaims": { "SC1": "Ε", "SC2": "Δ", "SC3": "Ε", "SC4": "Γ", "SC5": "Γ" } }, "score_after": { "level": "Γ", "confidence": "Moderate", "subclaims": { "SC1": "Ε", "SC2": "Δ", "SC3": "Ε", "SC4": "Γ", "SC5": "Γ" } }, "grade_changed": false, "grade_change_rationale": "Both directions were tested and rejected on the evidence. Δ fails because rubric 07's Δ design list is unsatisfied for the mediated claim: no acute-effect-matched comparator with measured blinding integrity, no human mediator manipulation with the drug intact, and the one preregistered human synaptic-marker test was null. Β fails because adult, cell-type-restricted receptor deletion in living mouse cortex is a causal perturbation rather than an association, which is what rubric 07 and the universal ladder define Γ to cover. The corrections made instead were to routing, caps, omissions, citation integrity and the M/S/D artifacts.", "citations_checked": 50, "citations_corrected": 9, "citations_removed": 0, "citations_added": 4, "non_admissible_context_reported": [ "Compass Pathways COMP005 and COMP006 phase 3 topline results (company investor releases 2026-02-17 and 2026-07-06/07, SEC 8-K exhibit 2026-07-07, 52-week Part C topline 2026-09); Tier C under the framework, reported in prose, excluded from the ledger and from the grade" ], "pending_work_named": [ "NCT06512220 (SYNVEST)", "NCT07490353", "NCT05601648 (withdrawn)" ], "audit_trail": "redteam/REDTEAM_REPORT.md; redteam/SYNTHESIS_CHANGE_LOG.md" }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [], "grade_changed": false, "score_before": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Substantial multi-modal primary literature with many full texts read supports the distinction between efficacy and mechanism. Human measurement is heterogeneous, mediator identification is absent, several records remain access-limited, and the largest randomized datasets are not yet peer reviewed and carry no part of the grade. This is evidence-density confidence, not a probability that the hypothesis is true.", "rests_on_non_peer_reviewed_work": false, "rationale": "SC1 protocol-level clinical response and SC3 adult experimental cortical effects reach Ε; approximately twelve-week persistence is a qualified Δ. The temporary human cortical-plasticity interval and its causal contribution to sustained symptoms each remain Γ under rubric 07's acute-pharmacodynamic and mediation-by-correlation rules. Weakest-link therefore returns Γ. The red-team pass changed neither the overall letter nor any subclaim level.", "non_peer_reviewed_note": "Company and regulatory documents describing the phase 3 program (COMP005, COMP006) are reported as context only. Under the framework source-tier rule they are inadmissible as evidence items, hold no ledger row, and carry no part of the grade or confidence band." }, "score_after": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Substantial multi-modal primary literature with many full texts read supports the distinction between efficacy and mechanism. Human measurement is heterogeneous, mediator identification is absent, several records remain access-limited, and the largest randomized datasets are not yet peer reviewed and carry no part of the grade. This is evidence-density confidence, not a probability that the hypothesis is true.", "rests_on_non_peer_reviewed_work": false, "rationale": "SC1 protocol-level clinical response and SC3 adult experimental cortical effects reach Ε; approximately twelve-week persistence is a qualified Δ. The temporary human cortical-plasticity interval and its causal contribution to sustained symptoms each remain Γ under rubric 07's acute-pharmacodynamic and mediation-by-correlation rules. Weakest-link therefore returns Γ. The red-team pass changed neither the overall letter nor any subclaim level.", "non_peer_reviewed_note": "Company and regulatory documents describing the phase 3 program (COMP005, COMP006) are reported as context only. Under the framework source-tier rule they are inadmissible as evidence items, hold no ledger row, and carry no part of the grade or confidence band." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\prepublication-enrichment-2026-10-05\\website-series\\psilocybin-therapy\\consensus-browser-links.json", "sha256": "9686b2a0d79918a7ae19ca2af42d6e2ff168dc06155c03e3135ad472dd2337b3" }, { "path": "deliverables\\prepublication-enrichment-2026-10-05\\website-series\\psilocybin-therapy\\consensus-browser.txt", "sha256": "f0af0c5d83f9c40c29c389c96dd332cf0cc8e0224123038e62b46d2d75722085" }, { "path": "deliverables\\prepublication-enrichment-2026-10-05\\website-series\\psilocybin-therapy\\consensus-targeted-check.txt", "sha256": "62dfee4403421884c433180bdfe53cbacecd36d92e3379c622d6b5cf79d91c14" } ], "limitations": "This verifies documented historical use and links the record to the final edition. It adds no primary-source, full-text, independence or verification credit. Original access remains limited to the source-specific record.", "existing_primary_reconciliation": { "slug": "psilocybin-therapy", "consensus_used": true, "rawproof": [ "deliverables/prepublication-enrichment-2026-10-05/website-series/psilocybin-therapy/consensus-browser.txt", "deliverables/prepublication-enrichment-2026-10-05/website-series/psilocybin-therapy/consensus-targeted-check.txt", "deliverables/prepublication-enrichment-2026-10-05/website-series/psilocybin-therapy/consensus-browser-links.json" ], "reconciliation_existing": "Yes; 9 primary identifiers; selected mechanistic Methods/Results passage and caveat about overall nonsignificant SV2A result; correction notice flagged.", "primary_sources_matched": [ "27210031", "33852780", "34228959", "36322843", "37651119", "40175553", "41224969", "42138922", "42457666" ], "limitations": "Do not transfer separate psilocybin-dual-phase run; selected mechanistic check does not establish human mediation; 2025 mouse study has correction notice." } } }