{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Dual-Phase Psilocybin Therapy Hypothesis", "entry_form": "phenomenon", "gradeable_restatement": "Psilocybin works best as psilocybin-assisted psychotherapy: the drug rapidly opens a neurodevelopmental-like window of synaptic plasticity, and formal post-acute psychotherapeutic integration is causally required to consolidate that state into lasting clinical remission.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, baseline disease, diet, dose and timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Dual-Phase Psilocybin Therapy Hypothesis", "central_claim": "Psilocybin works best as psilocybin-assisted psychotherapy: the drug rapidly opens a neurodevelopmental-like window of synaptic plasticity, and formal post-acute psychotherapeutic integration is causally required to consolidate that state into lasting clinical remission.", "proposed_mechanism": "Psilocybin works best as psilocybin-assisted psychotherapy: the drug rapidly opens a neurodevelopmental-like window of synaptic plasticity, and formal post-acute psychotherapeutic integration is causally required to consolidate that state into lasting clinical remission.", "claimed_scope": "human depressive/anxiety clinical remission; cellular/rodent plasticity scored separately", "claimed_level": [ "response" ], "is_conjunctive": true, "conjunctive_note": "The index explicitly prescribes weakest-link; SC2 is distinguishing content. Rubric 07 supersedes the index historical rubric-mismatch note." }, "rubric_routing": { "primary_rubric": "07-psychiatry-neuromodulation.md", "secondary_rubrics": [], "index_notes_applied": [ "The index explicitly prescribes weakest-link; SC2 is distinguishing content. Rubric 07 supersedes the index historical rubric-mismatch note." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Psilocybin induces a transient 5-HT2A- and TrkB/BDNF-dependent window of heightened synaptic plasticity.", "subclaim_type": "mechanism", "scope": "predefined cellular and rodent experimental settings; human inference separate", "claimed_scope": "predefined cellular and rodent experimental settings; human inference separate", "governing_rubric": "07-psychiatry-neuromodulation.md", "key_evidence_anchor": "Receptor blockade and plasticity assays with organismal follow-through", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC1 has directly perturbed cellular/rodent plasticity, including adult targeted receptor deletion and activity manipulation [18–24,30,52]. Exact universal 5HT2A/TrkB dependence differs by paradigm [20,22,24,54]. Rubric 07's preclinical/rodent cap and missing clinical trajectory mediator keep the therapeutic-window interpretation at Γ." }, { "id": "SC2", "statement": "Formal post-acute psychotherapeutic integration is causally required for lasting remission.", "subclaim_type": "necessity", "scope": "human depressive and anxiety disorders studied clinically", "claimed_scope": "human depressive and anxiety disorders studied clinically", "governing_rubric": "07-psychiatry-neuromodulation.md", "key_evidence_anchor": "Randomized component dismantling, equal contact, blinded raters and durable outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC2 remains Γ: positive treatment packages contain support/integration, but no admitted study randomizes removal of formal postacute integration with intact drug exposure, equal contact and masked durable outcomes [1–7,11,14,16,17,43,46,47,50,59,60]. The 2026 CBT pilot is single-arm; MBSR comparison adds PAP to training, not removes integration from psilocybin." }, { "id": "SC3", "statement": "The rodent plasticity window generalizes to human cortex at a duration relevant to integration scheduling.", "subclaim_type": "generalization", "scope": "humans receiving defined clinical doses", "claimed_scope": "humans receiving defined clinical doses", "governing_rubric": "07-psychiatry-neuromodulation.md", "key_evidence_anchor": "Direct human plasticity timing and outcome-relevant intervention", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC3 remains Γ. Human fMRI and cognitive changes are measured, but do not directly establish a cortical synaptic learning-window duration or its required integration schedule [8,34,35,37,38,49,56–58]. Mouse two-week social learning and month-persistent spines are different phenomena [20,30]." }, { "id": "SC4", "statement": "The subjective psychedelic experience is causally required for neuroplastic consolidation.", "subclaim_type": "necessity", "scope": "human clinical treatment", "claimed_scope": "human clinical treatment", "governing_rubric": "07-psychiatry-neuromodulation.md", "key_evidence_anchor": "Experience manipulation with drug exposure intact and durable outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC4 remains Γ: experience-outcome correlations and healthy-human blockade provide plausibility, not a drug-intact human mediator manipulation with durable remission [4,9–12,15,40,44,55,59]. Rodent/congener dissociations constrain universal necessity but cannot establish human dispensability [20,22–24,28,31,51,52,54]." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "The index explicitly prescribes weakest-link; SC2 is distinguishing content. Rubric 07 supersedes the index historical rubric-mismatch note.", "primary_subclaim_id": "SC2", "aggregation_derivation": "The registered weakest-link conjunction returns Γ. All four therapeutic/mechanism clauses remain Γ under rubric 07, though cell/rodent plasticity and some clinical package effects are empirically positive. Primary-SC2 and scope-matched sensitivities also return Γ. The unresolved content is required formal consolidation, not whether the drug ever changes synapses or symptoms.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M4", "is_nominal": false, "name": "Generic plasticity plus environment", "core_claim": "Drug-induced neural susceptibility interacts with activity and environment.", "explains_what_nominal_does_not": "Drug-induced neural susceptibility interacts with activity and environment.", "strongest_supporting_evidence": [ "Activity silencing, social-learning/metaplasticity and structural studies support defined rodent routes [18,20,24,30,36,52]." ], "strongest_contradictory_evidence": [ "No human formal integration necessity or cortical scheduling window is isolated." ], "hsef_level_for_this_model": "Γ", "rationale": "Activity silencing, social-learning/metaplasticity and structural studies support defined rodent routes [18,20,24,30,36,52]. No human formal integration necessity or cortical scheduling window is isolated." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Dose/receptor occupancy", "core_claim": "Dose and receptor exposure explain pharmacodynamic changes and some package response.", "explains_what_nominal_does_not": "Dose and receptor exposure explain pharmacodynamic changes and some package response.", "strongest_supporting_evidence": [ "Randomized dose response and human occupancy/acute antagonist data anchor pharmacology [1,40,55]." ], "strongest_contradictory_evidence": [ "Dose changes experience/expectancy too; receptor engagement is not sufficient proof of lasting therapeutic mediation." ], "hsef_level_for_this_model": "Γ", "rationale": "Randomized dose response and human occupancy/acute antagonist data anchor pharmacology [1,40,55]. Dose changes experience/expectancy too; receptor engagement is not sufficient proof of lasting therapeutic mediation." }, { "rank_in_tournament": 3, "model_id": "M2", "is_nominal": false, "name": "Autonomous pharmacological reset", "core_claim": "A pharmacological change can persist without a required conscious or formal consolidation process.", "explains_what_nominal_does_not": "A pharmacological change can persist without a required conscious or formal consolidation process.", "strongest_supporting_evidence": [ "Persistent mouse synapses and nonhallucinogenic-like congeners provide plausibility [20,23,28,31,51,52,54]." ], "strongest_contradictory_evidence": [ "Human treatment retains support/integration; no isolated autonomous durable-remission experiment." ], "hsef_level_for_this_model": "Γ", "rationale": "Persistent mouse synapses and nonhallucinogenic-like congeners provide plausibility [20,23,28,31,51,52,54]. Human treatment retains support/integration; no isolated autonomous durable-remission experiment." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Expectancy/functional unblinding", "core_claim": "Expectancy, contact and allocation inference contribute to symptoms.", "explains_what_nominal_does_not": "Expectancy, contact and allocation inference contribute to symptoms.", "strongest_supporting_evidence": [ "Placebo improvements, fixed-order ambiguity and unassessed blinding reveal uncontrolled competing influences [17,59]." ], "strongest_contradictory_evidence": [ "These limitations do not establish expectancy as the sole cause; positive drug dose and rodent perturbation findings remain." ], "hsef_level_for_this_model": "Β", "rationale": "Placebo improvements, fixed-order ambiguity and unassessed blinding reveal uncontrolled competing influences [17,59]. These limitations do not establish expectancy as the sole cause; positive drug dose and rodent perturbation findings remain." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Required psychotherapeutic consolidation", "core_claim": "Formal integration is necessary to convert drug-induced plasticity into lasting remission.", "explains_what_nominal_does_not": "Formal integration is necessary to convert drug-induced plasticity into lasting remission.", "strongest_supporting_evidence": [ "Clinical packages and the rodent critical-period theory provide compatible observations [3,4,6,11,30,46,47]." ], "strongest_contradictory_evidence": [ "No human component-removal or mediation-necessity result identifies this distinguishing requirement." ], "hsef_level_for_this_model": "Γ", "rationale": "Clinical packages and the rodent critical-period theory provide compatible observations [3,4,6,11,30,46,47]. No human component-removal or mediation-necessity result identifies this distinguishing requirement." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. With identical drug and supportive safety contact, randomize structured integration versus equal-contact nonintegrative follow-up, balancing allegiance and expectancy; separately manipulate subjective experience while preserving drug exposure and measure durable remission.", "study_separating_rank1_from_rank2": "With identical drug and supportive safety contact, randomize structured integration versus equal-contact nonintegrative follow-up, balancing allegiance and expectancy; separately manipulate subjective experience while preserving drug exposure and measure durable remission.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "36322843", "title": "Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.", "citation": "Goodwin GM, Aaronson ST, Alvarez O et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. The New England journal of medicine. 2022.", "doi": "10.1056/NEJMoa2206443", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36322843/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36322843/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03775200", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "25-mg psilocybin with psychological support improved the week-3 primary depression score versus 1 mg; sustained week-12 response was not supportive.", "what_it_does_not_show": "Dose changes drug exposure and experience together; support was not removed and experience was not selectively manipulated.", "confounders_present": [ "Dose changes drug exposure and experience together; support was not removed and experience was not selectively manipulated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 2, "pmid": "33852780", "title": "Trial of Psilocybin versus Escitalopram for Depression.", "citation": "Carhart-Harris R, Giribaldi B, Watts R et al. Trial of Psilocybin versus Escitalopram for Depression. The New England journal of medicine. 2021.", "doi": "10.1056/NEJMoa2032994", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33852780/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33852780/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03429075", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Psilocybin versus escitalopram with matched support did not differ significantly on the week-6 primary QIDS outcome; several unadjusted secondary outcomes favored psilocybin.", "what_it_does_not_show": "Neither equivalence nor integration necessity follows; drug, experience and daily-treatment schedules differ.", "confounders_present": [ "Neither equivalence nor integration necessity follows; drug, experience and daily-treatment schedules differ." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 3, "pmid": "33146667", "title": "Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.", "citation": "Davis AK, Barrett FS, May DG et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA psychiatry. 2021.", "doi": "10.1001/jamapsychiatry.2020.3285", "pmcid": "PMC7643046", "url": "https://pubmed.ncbi.nlm.nih.gov/33146667/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33146667/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID33566065" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03181529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Immediate psilocybin plus supportive therapy improved MDD symptoms versus delayed treatment.", "what_it_does_not_show": "Waitlist does not control expectancy/contact or remove integration; a linked erratum remains attached.", "confounders_present": [ "Waitlist does not control expectancy/contact or remove integration; a linked erratum remains attached." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 4, "pmid": "27909165", "title": "Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.", "citation": "Griffiths RR, Johnson MW, Carducci MA et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of psychopharmacology (Oxford, England). 2016.", "doi": "10.1177/0269881116675513", "pmcid": "PMC5367557", "url": "https://pubmed.ncbi.nlm.nih.gov/27909165/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27909165/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT00465595", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "High versus low dose with support improved cancer-related distress; experience statistically mediated outcomes.", "what_it_does_not_show": "Statistical mediation and crossover follow-up do not isolate experiential or psychotherapy necessity.", "confounders_present": [ "Statistical mediation and crossover follow-up do not isolate experiential or psychotherapy necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 5, "pmid": "27210031", "title": "Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.", "citation": "Carhart-Harris RL, Bolstridge M, Rucker J et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The lancet. Psychiatry. 2016.", "doi": "10.1016/S2215-0366(16)30065-7", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27210031/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27210031/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "ISRCTN14426797", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Open-label psilocybin with support showed rapid symptom reduction in TRD.", "what_it_does_not_show": "No control group; support preceded, accompanied and followed dosing.", "confounders_present": [ "No control group; support preceded, accompanied and followed dosing." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 6, "pmid": "38359838", "title": "Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin.", "citation": "Rosenblat JD, Meshkat S, Doyle Z et al. Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin. Med (New York, N.Y.). 2024.", "doi": "10.1016/j.medj.2024.01.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38359838/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38359838/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT05029466", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Immediate PAP improved symptoms versus waitlist in complex TRD; flexible repeats were associated with further improvement.", "what_it_does_not_show": "Each dose included preparation and integration; repeat dosing was not randomized independently.", "confounders_present": [ "Each dose included preparation and integration; repeat dosing was not randomized independently." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 7, "pmid": "29119217", "title": "Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.", "citation": "Carhart-Harris RL, Bolstridge M, Day CMJ et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 2018.", "doi": "10.1007/s00213-017-4771-x", "pmcid": "PMC5813086", "url": "https://pubmed.ncbi.nlm.nih.gov/29119217/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29119217/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "ISRCTN14426797-expanded", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "The expanded open-label TRD cohort retained symptom improvement through six months; acute experience predicted early response.", "what_it_does_not_show": "Shares the feasibility programme and lacks controlled long-term or manipulated-experience inference.", "confounders_present": [ "Shares the feasibility programme and lacks controlled long-term or manipulated-experience inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 8, "pmid": "35411074", "title": "Increased global integration in the brain after psilocybin therapy for depression.", "citation": "Daws RE, Timmermann C, Giribaldi B et al. Increased global integration in the brain after psilocybin therapy for depression. Nature medicine. 2022.", "doi": "10.1038/s41591-022-01744-z", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35411074/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35411074/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Imperial-TRD+NCT03429075", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Imaging across two clinical cohorts linked lower network modularity to symptom response.", "what_it_does_not_show": "Brain network integration is not psychotherapy integration or directly measured synaptogenesis; cohorts overlap prior trials.", "confounders_present": [ "Brain network integration is not psychotherapy integration or directly measured synaptogenesis; cohorts overlap prior trials." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 9, "pmid": "35166158", "title": "Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up.", "citation": "Gukasyan N, Davis AK, Barrett FS et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Journal of psychopharmacology (Oxford, England). 2022.", "doi": "10.1177/02698811211073759", "pmcid": "PMC8864328", "url": "https://pubmed.ncbi.nlm.nih.gov/35166158/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35166158/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03181529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "The MDD cohort retained symptom reductions at 12 months; meaning/mystical ratings predicted well-being but not depression improvement.", "what_it_does_not_show": "Follow-up lacks an untreated long-term counterfactual and shares the original delayed-treatment cohort.", "confounders_present": [ "Follow-up lacks an untreated long-term counterfactual and shares the original delayed-treatment cohort." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 10, "pmid": "16826400", "title": "Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance.", "citation": "Griffiths RR, Richards WA, McCann U et al. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006.", "doi": "10.1007/s00213-006-0457-5", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16826400/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16826400/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID16826400", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Psilocybin versus methylphenidate induced marked acute experiences and later meaning/attitude changes in healthy volunteers.", "what_it_does_not_show": "Healthy spiritual outcomes do not establish depression remission or the necessity of subjective experience.", "confounders_present": [ "Healthy spiritual outcomes do not establish depression remission or the necessity of subjective experience." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 11, "pmid": "27909164", "title": "Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.", "citation": "Ross S, Bossis A, Guss J et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of psychopharmacology (Oxford, England). 2016.", "doi": "10.1177/0269881116675512", "pmcid": "PMC5367551", "url": "https://pubmed.ncbi.nlm.nih.gov/27909164/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27909164/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT00957359", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Psilocybin versus niacin within psychotherapy improved cancer-related symptoms before crossover, with later persistence.", "what_it_does_not_show": "Both arms had psychotherapy; observed mystical mediation is not a mediator manipulation.", "confounders_present": [ "Both arms had psychotherapy; observed mystical mediation is not a mediator manipulation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 12, "pmid": "38520045", "title": "Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression.", "citation": "Erritzoe D, Barba T, Spriggs MJ et al. Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression. Journal of psychopharmacology (Oxford, England). 2024.", "doi": "10.1177/02698811241237870", "pmcid": "PMC11102650", "url": "https://pubmed.ncbi.nlm.nih.gov/38520045/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38520045/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03429075", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Post hoc antidepressant discontinuation status predicted smaller clinical response without corresponding experience differences.", "what_it_does_not_show": "Discontinuation was not randomized and continuation was not tested; exploratory association only.", "confounders_present": [ "Discontinuation was not randomized and continuation was not tested; exploratory association only." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 13, "pmid": "36740140", "title": "Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.", "citation": "Goodwin GM, Aaronson ST, Alvarez O et al. Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life. Journal of affective disorders. 2023.", "doi": "10.1016/j.jad.2023.01.108", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36740140/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36740140/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03775200", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "The COMP360 trial follow-up reports favorable exploratory patient-rated function and symptoms at week three.", "what_it_does_not_show": "Same dose trial, not independent replication; functional unblinding and no scaffold removal.", "confounders_present": [ "Same dose trial, not independent replication; functional unblinding and no scaffold removal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 14, "pmid": "41848690", "title": "Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.", "citation": "Mertens LJ, Koslowski M, Betzler F et al. Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial. JAMA psychiatry. 2026.", "doi": "10.1001/jamapsychiatry.2026.0132", "pmcid": "PMC13000742", "url": "https://pubmed.ncbi.nlm.nih.gov/41848690/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41848690/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT04670081", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "The 2026 EPISODE trial missed its primary week-6 response comparison; secondary symptom changes were exploratory.", "what_it_does_not_show": "Adjunct psychotherapy was present; a null package endpoint does not selectively falsify integration necessity.", "confounders_present": [ "Adjunct psychotherapy was present; a null package endpoint does not selectively falsify integration necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 15, "pmid": "34743319", "title": "Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.", "citation": "Becker AM, Holze F, Grandinetti T et al. Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects. Clinical pharmacology and therapeutics. 2022.", "doi": "10.1002/cpt.2487", "pmcid": "PMC9299061", "url": "https://pubmed.ncbi.nlm.nih.gov/34743319/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34743319/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34743319", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Escitalopram pretreatment reduced negative acute effects without changing psilocin exposure or positive mood; circulating BDNF was unchanged.", "what_it_does_not_show": "Healthy acute pharmacodynamics do not measure lasting remission or cortical plasticity.", "confounders_present": [ "Healthy acute pharmacodynamics do not measure lasting remission or cortical plasticity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 16, "pmid": "39636638", "title": "Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial.", "citation": "Back AL, Freeman-Young TK, Morgan L et al. Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial. JAMA network open. 2024.", "doi": "10.1001/jamanetworkopen.2024.49026", "pmcid": "PMC11621983", "url": "https://pubmed.ncbi.nlm.nih.gov/39636638/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39636638/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID39804652", "ErratumIn: PMID40638123" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT05163496", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Psilocybin versus niacin with preparation and three integration visits improved clinician-rated depressive symptoms in frontline clinicians.", "what_it_does_not_show": "Both arms had integration; secondary burnout was not significant, and linked correction details are incompletely examined.", "confounders_present": [ "Both arms had integration; secondary burnout was not significant, and linked correction details are incompletely examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 17, "pmid": "37651119", "title": "Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.", "citation": "Raison CL, Sanacora G, Woolley J et al. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023.", "doi": "10.1001/jama.2023.14530", "pmcid": "PMC10472268", "url": "https://pubmed.ncbi.nlm.nih.gov/37651119/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37651119/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID38277159" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03866174", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Web-Study-Procedures-L469-471, Web-Efficacy-Assessments-L473-477, Web-Limitations-L695-705. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "The MDD trial improved depression and disability with psilocybin versus niacin within identical support.", "what_it_does_not_show": "Methods include four hours of postdose integration; allocation-blinding success was not assessed. It cannot show benefit without integration.", "confounders_present": [ "Methods include four hours of postdose integration; allocation-blinding success was not assessed. It cannot show benefit without integration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 18, "pmid": "41352354", "title": "Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks.", "citation": "Jiang Q, Shao LX, Yao S et al. Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks. Cell. 2026.", "doi": "10.1016/j.cell.2025.11.009", "pmcid": "PMC12695013", "url": "https://pubmed.ncbi.nlm.nih.gov/41352354/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41352354/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID41352354", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [ "M4" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Psilocybin rewired mouse cortical inputs, and silencing presynaptic activity disrupted the pattern.", "what_it_does_not_show": "Activity-dependent mouse rewiring does not identify a human integration window or formal therapy necessity.", "confounders_present": [ "Activity-dependent mouse rewiring does not identify a human integration window or formal therapy necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 19, "pmid": "29898390", "title": "Psychedelics Promote Structural and Functional Neural Plasticity.", "citation": "Ly C, Greb AC, Cameron LP et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell reports. 2018.", "doi": "10.1016/j.celrep.2018.05.022", "pmcid": "PMC6082376", "url": "https://pubmed.ncbi.nlm.nih.gov/29898390/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29898390/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29898390", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell and animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Psychedelics increased neurites/spines and synaptic function with TrkB, mTOR and 5HT2A pathway support.", "what_it_does_not_show": "Drug-class and culture/model plasticity is not a clinical mediator or a universal psilocybin receptor sequence.", "confounders_present": [ "Drug-class and culture/model plasticity is not a clinical mediator or a universal psilocybin receptor sequence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 20, "pmid": "34228959", "title": "Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.", "citation": "Shao LX, Liao C, Gregg I et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021.", "doi": "10.1016/j.neuron.2021.06.008", "pmcid": "PMC8376772", "url": "https://pubmed.ncbi.nlm.nih.gov/34228959/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34228959/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34228959", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: S6. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Psilocybin increased mouse frontal spines persistently; ketanserin abolished head twitch but retained spine-width/formation effects while density significance was lost.", "what_it_does_not_show": "The antagonist was incompletely receptor-blocking; head twitch is not direct consciousness, and month-long spines do not define a month-long learning window.", "confounders_present": [ "The antagonist was incompletely receptor-blocking; head twitch is not direct consciousness, and month-long spines do not define a month-long learning window." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 21, "pmid": "36795823", "title": "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.", "citation": "Vargas MV, Dunlap LE, Dong C et al. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science (New York, N.Y.). 2023.", "doi": "10.1126/science.adf0435", "pmcid": "PMC10108900", "url": "https://pubmed.ncbi.nlm.nih.gov/36795823/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36795823/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36795823", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Molecular/genetic experiments identified intracellular 5HT2A involvement in psychedelic-induced cortical growth.", "what_it_does_not_show": "Cellular receptor-location inference does not identify human therapeutic consolidation.", "confounders_present": [ "Cellular receptor-location inference does not identify human therapeutic consolidation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 22, "pmid": "37280397", "title": "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.", "citation": "Moliner R, Girych M, Brunello CA et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature neuroscience. 2023.", "doi": "10.1038/s41593-023-01316-5", "pmcid": "PMC10244169", "url": "https://pubmed.ncbi.nlm.nih.gov/37280397/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37280397/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37280397", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell and animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "TrkB-binding contrasts linked psychedelic plasticity/behavior to BDNF signaling independent of 5HT2A in the tested paradigms.", "what_it_does_not_show": "Contrasts with receptor-necessity studies require model/assay separation; no demonstrated human experience blockade with remission outcomes.", "confounders_present": [ "Contrasts with receptor-necessity studies require model/assay separation; no demonstrated human experience blockade with remission outcomes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 23, "pmid": "33299186", "title": "A non-hallucinogenic psychedelic analogue with therapeutic potential.", "citation": "Cameron LP, Tombari RJ, Lu J et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021.", "doi": "10.1038/s41586-020-3008-z", "pmcid": "PMC7874389", "url": "https://pubmed.ncbi.nlm.nih.gov/33299186/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33299186/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33299186", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Tabernanthalog promoted rodent neural plasticity and changed drug-seeking and behavioral assays without hallucinogenic-like effects.", "what_it_does_not_show": "A different compound and absent rodent head twitch do not establish subjective-experience dispensability in human psilocybin treatment.", "confounders_present": [ "A different compound and absent rodent head twitch do not establish subjective-experience dispensability in human psilocybin treatment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 24, "pmid": "40175553", "title": "Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.", "citation": "Shao LX, Liao C, Davoudian PA et al. Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors. Nature. 2025.", "doi": "10.1038/s41586-025-08813-6", "pmcid": "PMC12188471", "url": "https://pubmed.ncbi.nlm.nih.gov/40175553/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40175553/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39554087", "ErratumIn: PMID41023408" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40175553", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: S6, S7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Adult local 5HT2A deletion removed specified psilocybin plasticity and stress effects while local deletion left head twitch intact; learned-helplessness control response had a floor-limit caveat.", "what_it_does_not_show": "Cell-type specificity and genotype controls bound inference; rodent stress tests are not human remission and linked correction detail is unexamined.", "confounders_present": [ "Cell-type specificity and genotype controls bound inference; rodent stress tests are not human remission and linked correction detail is unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 25, "pmid": "38680011", "title": "Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice.", "citation": "Zhao X, Du Y, Yao Y et al. Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice. Journal of psychopharmacology (Oxford, England). 2024.", "doi": "10.1177/02698811241249436", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38680011/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38680011/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38680011", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "animal interventional", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Psilocybin improved chronic-corticosterone mouse behavioral proxies alongside plasticity/BDNF-mTOR measures.", "what_it_does_not_show": "Co-occurring molecular changes were not selectively shown necessary for the behavioral effect.", "confounders_present": [ "Co-occurring molecular changes were not selectively shown necessary for the behavioral effect." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 26, "pmid": "40424654", "title": "Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling.", "citation": "Laabi S, LeMmon C, Vogel C et al. Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling. International immunopharmacology. 2025.", "doi": "10.1016/j.intimp.2025.114940", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40424654/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40424654/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40424654", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "cell experimental", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Antagonist contrasts changed microglial TNF and BDNF responses to psilocybin/psilocin.", "what_it_does_not_show": "Inflammation/growth markers in LPS cultures are not cortical synapses or clinical antidepressant mediation.", "confounders_present": [ "Inflammation/growth markers in LPS cultures are not cortical synapses or clinical antidepressant mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 27, "pmid": "36630309", "title": "Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin.", "citation": "Davoudian PA, Shao LX, Kwan AC et al. Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin. ACS chemical neuroscience. 2023.", "doi": "10.1021/acschemneuro.2c00637", "pmcid": "PMC9898239", "url": "https://pubmed.ncbi.nlm.nih.gov/36630309/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36630309/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36630309", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "animal interventional", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Whole-brain cFos mapping identified shared and distinct acute psilocybin/ketamine activation regions.", "what_it_does_not_show": "Immediate early gene activation is not itself structural plasticity, remission or a necessary mediator.", "confounders_present": [ "Immediate early gene activation is not itself structural plasticity, remission or a necessary mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 28, "pmid": "35084960", "title": "Structure-based discovery of nonhallucinogenic psychedelic analogs.", "citation": "Cao D, Yu J, Wang H et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science (New York, N.Y.). 2022.", "doi": "10.1126/science.abl8615", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35084960/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35084960/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35084960", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell and animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Structure-guided 5HT2A analogues showed antidepressant-like mouse activity with attenuated hallucinogenic-like responses.", "what_it_does_not_show": "Biased compounds and behavioral proxies do not settle human experiential necessity.", "confounders_present": [ "Biased compounds and behavioral proxies do not settle human experiential necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 29, "pmid": "32814630", "title": "Differential signaling signatures evoked by DOI versus lisuride stimulation of the 5-HT2A receptor.", "citation": "Banerjee AA, Vaidya VA et al. Differential signaling signatures evoked by DOI versus lisuride stimulation of the 5-HT2A receptor. Biochemical and biophysical research communications. 2020.", "doi": "10.1016/j.bbrc.2020.08.022", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32814630/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32814630/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32814630", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "cell experimental", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "DOI and lisuride produced distinct downstream 5HT2A signaling in engineered cells and neurons.", "what_it_does_not_show": "Signaling efficacy differences do not measure human subjective experience or lasting therapy.", "confounders_present": [ "Signaling efficacy differences do not measure human subjective experience or lasting therapy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 30, "pmid": "37316665", "title": "Psychedelics reopen the social reward learning critical period.", "citation": "Nardou R, Sawyer E, Song YJ et al. Psychedelics reopen the social reward learning critical period. Nature. 2023.", "doi": "10.1038/s41586-023-06204-3", "pmcid": "PMC10284704", "url": "https://pubmed.ncbi.nlm.nih.gov/37316665/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37316665/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37316665", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec3, Sec4, Sec5. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [ "M4" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Psilocybin reopened mouse social reward learning for two weeks but not three; oxytocin metaplasticity and ketanserin contrasts mapped the circuit.", "what_it_does_not_show": "A nucleus-accumbens mouse learning assay is not human cortical synaptogenesis, depression remission or randomized integration scheduling.", "confounders_present": [ "A nucleus-accumbens mouse learning assay is not human cortical synaptogenesis, depression remission or randomized integration scheduling." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 31, "pmid": "36884348", "title": "A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.", "citation": "Lewis V, Bonniwell EM, Lanham JK et al. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell reports. 2023.", "doi": "10.1016/j.celrep.2023.112203", "pmcid": "PMC10112881", "url": "https://pubmed.ncbi.nlm.nih.gov/36884348/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36884348/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36884348", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "2-bromo-LSD promoted culture plasticity and changed chronic-stress behavior without head twitch; a receptor antagonist blocked active coping.", "what_it_does_not_show": "Different compound and rodent behaviors constrain transfer to human psilocybin experience.", "confounders_present": [ "Different compound and rodent behaviors constrain transfer to human psilocybin experience." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 32, "pmid": "36521179", "title": "Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs.", "citation": "Cunningham MJ, Bock HA, Serrano IC et al. Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs. ACS chemical neuroscience. 2023.", "doi": "10.1021/acschemneuro.2c00597", "pmcid": "PMC10147382", "url": "https://pubmed.ncbi.nlm.nih.gov/36521179/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36521179/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36521179", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell and animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "New Ariadne pharmacological profiling and mouse motor rescue mapped a lower-efficacy 5HT2A agonist.", "what_it_does_not_show": "Only the new empirical component is counted; historical clinical anecdotes and PD rescue do not establish psilocybin antidepressant mediation.", "confounders_present": [ "Only the new empirical component is counted; historical clinical anecdotes and PD rescue do not establish psilocybin antidepressant mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 33, "pmid": "17270739", "title": "Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.", "citation": "González-Maeso J, Weisstaub NV, Zhou M et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007.", "doi": "10.1016/j.neuron.2007.01.008", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17270739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17270739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID17270739", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Cortical receptor-expression and signaling contrasts differentiated hallucinogenic from nonhallucinogenic ligands.", "what_it_does_not_show": "Construct/signaling sufficiency is not endogenous human therapeutic necessity.", "confounders_present": [ "Construct/signaling sufficiency is not endogenous human therapeutic necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 34, "pmid": "39020167", "title": "Psilocybin desynchronizes the human brain.", "citation": "Siegel JS, Subramanian S, Perry D et al. Psilocybin desynchronizes the human brain. Nature. 2024.", "doi": "10.1038/s41586-024-07624-5", "pmcid": "PMC11291293", "url": "https://pubmed.ncbi.nlm.nih.gov/39020167/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39020167/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37701731" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39020167", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Precision imaging found acute desynchronization, task modulation and persistent hippocampal-DMN connectivity changes after psilocybin.", "what_it_does_not_show": "Functional connectivity is not directly measured synaptic growth or a tested integration-timing mediator; participants were healthy.", "confounders_present": [ "Functional connectivity is not directly measured synaptic growth or a tested integration-timing mediator; participants were healthy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 35, "pmid": "29030624", "title": "Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.", "citation": "Carhart-Harris RL, Roseman L, Bolstridge M et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific reports. 2017.", "doi": "10.1038/s41598-017-13282-7", "pmcid": "PMC5640601", "url": "https://pubmed.ncbi.nlm.nih.gov/29030624/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29030624/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "ISRCTN14426797-expanded", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "TRD imaging changes correlated with symptoms and predicted early response in an open-label cohort.", "what_it_does_not_show": "Shared cohort and imaging association do not identify a structural plasticity or integration mediator.", "confounders_present": [ "Shared cohort and imaging association do not identify a structural plasticity or integration mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 36, "pmid": "37000971", "title": "Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity.", "citation": "Du Y, Li Y, Zhao X et al. Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity. Chinese medical journal. 2023.", "doi": "10.1097/CM9.0000000000002647", "pmcid": "PMC10752473", "url": "https://pubmed.ncbi.nlm.nih.gov/37000971/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37000971/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37000971", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Psilocybin plus extinction training improved mouse fear retrieval/renewal and coincided with hippocampal plasticity measures.", "what_it_does_not_show": "No selective mediation or human integration-necessity test; extinction is not formal postacute psychotherapy.", "confounders_present": [ "No selective mediation or human integration-necessity test; extinction is not formal postacute psychotherapy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 37, "pmid": "34750350", "title": "Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder.", "citation": "Doss MK, Považan M, Rosenberg MD et al. Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Translational psychiatry. 2021.", "doi": "10.1038/s41398-021-01706-y", "pmcid": "PMC8575795", "url": "https://pubmed.ncbi.nlm.nih.gov/34750350/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34750350/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03181529", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Cognitive flexibility improved after treatment, but was not correlated with antidepressant change; larger neural flexibility shifts could predict less improvement.", "what_it_does_not_show": "Shares MDD participants and does not directly measure cortical plasticity or its necessity.", "confounders_present": [ "Shares MDD participants and does not directly measure cortical plasticity or its necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 38, "pmid": "22308440", "title": "Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin.", "citation": "Carhart-Harris RL, Erritzoe D, Williams T et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences of the United States of America. 2012.", "doi": "10.1073/pnas.1119598109", "pmcid": "PMC3277566", "url": "https://pubmed.ncbi.nlm.nih.gov/22308440/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22308440/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID22308440", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Acute human imaging mapped reduced hub activity/connectivity alongside psychedelic effects.", "what_it_does_not_show": "Acute neurovascular/functional signals do not establish synaptogenesis or durable remission.", "confounders_present": [ "Acute neurovascular/functional signals do not establish synaptogenesis or durable remission." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 39, "pmid": "36001306", "title": "Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial.", "citation": "Bogenschutz MP, Ross S, Bhatt S et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA psychiatry. 2022.", "doi": "10.1001/jamapsychiatry.2022.2096", "pmcid": "PMC9403854", "url": "https://pubmed.ncbi.nlm.nih.gov/36001306/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36001306/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID36103174" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT02061293", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Psilocybin plus manualized psychotherapy reduced heavy drinking versus diphenhydramine plus the same psychotherapy.", "what_it_does_not_show": "AUD is outside the registered depressive/anxiety scope; no psychotherapy removal, and linked erratum detail remains unexamined.", "confounders_present": [ "AUD is outside the registered depressive/anxiety scope; no psychotherapy removal, and linked erratum detail remains unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 40, "pmid": "30685771", "title": "Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.", "citation": "Madsen MK, Fisher PM, Burmester D et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2019.", "doi": "10.1038/s41386-019-0324-9", "pmcid": "PMC6785028", "url": "https://pubmed.ncbi.nlm.nih.gov/30685771/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30685771/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID30846853" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30685771", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [ "M3" ], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "PET occupancy and plasma psilocin tracked subjective intensity in healthy adults.", "what_it_does_not_show": "Occupancy-experience correlation does not show experience is necessary for lasting clinical benefit; correction detail not fully examined.", "confounders_present": [ "Occupancy-experience correlation does not show experience is necessary for lasting clinical benefit; correction detail not fully examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 41, "pmid": "29923178", "title": "Effects of psilocybin therapy on personality structure.", "citation": "Erritzoe D, Roseman L, Nour MM et al. Effects of psilocybin therapy on personality structure. Acta psychiatrica Scandinavica. 2018.", "doi": "10.1111/acps.12904", "pmcid": "PMC6220878", "url": "https://pubmed.ncbi.nlm.nih.gov/29923178/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29923178/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "ISRCTN14426797-expanded", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Open-label TRD personality changes and acute insight were associated at follow-up.", "what_it_does_not_show": "Shares the expanded TRD cohort; personality association is not remission mediation.", "confounders_present": [ "Shares the expanded TRD cohort; personality association is not remission mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 42, "pmid": "40683247", "title": "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.", "citation": "Jain MK, Gumpper RH, Slocum ST et al. The polypharmacology of psychedelics reveals multiple targets for potential therapeutics. Neuron. 2025.", "doi": "10.1016/j.neuron.2025.06.012", "pmcid": "PMC13632693", "url": "https://pubmed.ncbi.nlm.nih.gov/40683247/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40683247/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40683247", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell experimental", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "New profiling of 41 psychedelics across 318 GPCRs identified broad receptor actions and multiple 5HT2A transducers.", "what_it_does_not_show": "Polypharmacology constrains unique-target accounts but is not proof of an alternative clinical mediator.", "confounders_present": [ "Polypharmacology constrains unique-target accounts but is not proof of an alternative clinical mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 43, "pmid": "39741440", "title": "Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial.", "citation": "Aaronson ST, van der Vaart A, Miller T et al. Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial. The American journal of psychiatry. 2025.", "doi": "10.1176/appi.ajp.20231063", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39741440/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39741440/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39741440", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "A severe-TRD open-label pilot with three integration sessions reported sustained symptom change and exploratory experience correlations.", "what_it_does_not_show": "No counterfactual or component randomization; PTSD subgroup is exploratory.", "confounders_present": [ "No counterfactual or component randomization; PTSD subgroup is exploratory." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 44, "pmid": "39706482", "title": "The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression.", "citation": "Goodwin GM, Aaronson ST, Alvarez O et al. The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression. Journal of affective disorders. 2025.", "doi": "10.1016/j.jad.2024.12.061", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39706482/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39706482/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID41075579" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03775200", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "COMP360 experience and emotional breakthrough correlated with week-3 response despite overlapping dose experience distributions.", "what_it_does_not_show": "Same dose trial; correlation does not establish causation or measured blinding integrity; correction detail remains incompletely examined.", "confounders_present": [ "Same dose trial; correlation does not establish causation or measured blinding integrity; correction detail remains incompletely examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 45, "pmid": "41039182", "title": "Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain.", "citation": "Hammo A, Wisser S, Cichon J et al. Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain. Nature neuroscience. 2025.", "doi": "10.1038/s41593-025-02068-0", "pmcid": "PMC12586168", "url": "https://pubmed.ncbi.nlm.nih.gov/41039182/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41039182/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID41039182", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Psilocybin/local psilocin improved allodynia and mood-like behaviors in mouse pain models with prefrontal circuit/receptor contrasts.", "what_it_does_not_show": "Partial receptor replication and pain-model behavior are not human depression remission or formal therapy necessity.", "confounders_present": [ "Partial receptor replication and pain-model behavior are not human depression remission or formal therapy necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 46, "pmid": "41707717", "title": "Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trial.", "citation": "Weintraub MJ, Jeffrey JK, Ichinose MC et al. Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trial. Journal of affective disorders. 2026.", "doi": "10.1016/j.jad.2026.121423", "pmcid": "PMC13138500", "url": "https://pubmed.ncbi.nlm.nih.gov/41707717/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41707717/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID41707717", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "The 2026 single-arm CBT programme retained symptom/function gains through follow-up.", "what_it_does_not_show": "All participants received twelve therapy sessions; no randomized CBT or integration counterfactual.", "confounders_present": [ "All participants received twelve therapy sessions; no randomized CBT or integration counterfactual." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 47, "pmid": "40858059", "title": "Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial.", "citation": "Ross ML, Iyer R, Williams ML et al. Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial. General hospital psychiatry. 2025.", "doi": "10.1016/j.genhosppsych.2025.08.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40858059/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40858059/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40858059", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "The 2025 life-threatening-illness trial favored psilocybin over niacin on selected symptom outcomes within psychotherapy.", "what_it_does_not_show": "Both arms had six integration sessions; open-label extension weakens isolated long-term inference.", "confounders_present": [ "Both arms had six integration sessions; open-label extension weakens isolated long-term inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 48, "pmid": "39939591", "title": "Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression.", "citation": "Aboharb F, Davoudian PA, Shao LX et al. Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression. Nature communications. 2025.", "doi": "10.1038/s41467-025-56850-6", "pmcid": "PMC11822132", "url": "https://pubmed.ncbi.nlm.nih.gov/39939591/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39939591/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID38826215" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39939591", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "animal interventional", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Drug-specific cFos patterns classified psychoactive compounds above chance in mice.", "what_it_does_not_show": "A successful drug classifier is not validated plasticity or clinical-mechanism stratification.", "confounders_present": [ "A successful drug classifier is not validated plasticity or clinical-mechanism stratification." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 49, "pmid": "40329640", "title": "Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression.", "citation": "Wall MB, Demetriou L, Giribaldi B et al. Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression. The American journal of psychiatry. 2025.", "doi": "10.1176/appi.ajp.20230751", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40329640/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40329640/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03429075", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Psilocybin and escitalopram differed in emotional BOLD responses with matched preparation/integration.", "what_it_does_not_show": "Same comparative trial; no human structural plasticity or integration removal.", "confounders_present": [ "Same comparative trial; no human structural plasticity or integration removal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 50, "pmid": "40972137", "title": "Psilocybin-assisted group psychotherapy and mindfulness-based stress reduction for frontline healthcare provider COVID-19-related depression and burnout: A randomized controlled trial.", "citation": "Lewis BR, Hendrick J, Byrne K et al. Psilocybin-assisted group psychotherapy and mindfulness-based stress reduction for frontline healthcare provider COVID-19-related depression and burnout: A randomized controlled trial. PLoS medicine. 2025.", "doi": "10.1371/journal.pmed.1004519", "pmcid": "PMC12459851", "url": "https://pubmed.ncbi.nlm.nih.gov/40972137/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40972137/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "UpdateOf: PMID39802794" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT05557643", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "MBSR plus group PAP outperformed MBSR alone on short-term depressive symptoms; the effect waned by six months.", "what_it_does_not_show": "Tests addition of drug plus PAP, not integration removal from drug; contact intensity differed and corrected secondary outcomes were null.", "confounders_present": [ "Tests addition of drug plus PAP, not integration removal from drug; contact intensity differed and corrected secondary outcomes were null." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 51, "pmid": "33915107", "title": "Psychedelic-inspired drug discovery using an engineered biosensor.", "citation": "Dong C, Ly C, Dunlap LE et al. Psychedelic-inspired drug discovery using an engineered biosensor. Cell. 2021.", "doi": "10.1016/j.cell.2021.03.043", "pmcid": "PMC8122087", "url": "https://pubmed.ncbi.nlm.nih.gov/33915107/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33915107/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33915107", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell and animal experimental", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "An engineered biosensor identified a nonhallucinogenic-like analogue with lasting rodent behavioral activity.", "what_it_does_not_show": "New compound discovery is not proof that human psilocybin works without experience or integration.", "confounders_present": [ "New compound discovery is not proof that human psilocybin works without experience or integration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 52, "pmid": "40760185", "title": "The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation.", "citation": "Aarrestad IK, Cameron LP, Fenton EM et al. The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nature neuroscience. 2025.", "doi": "10.1038/s41593-025-02021-1", "pmcid": "PMC12373294", "url": "https://pubmed.ncbi.nlm.nih.gov/40760185/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40760185/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40760185", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [ "M2", "M4" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "TBG required cortical spinogenesis for sustained rodent behavioral effects without the immediate gene/glutamate burst of psychedelics.", "what_it_does_not_show": "Different compound/model; no general human clinical experiential necessity conclusion.", "confounders_present": [ "Different compound/model; no general human clinical experiential necessity conclusion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 53, "pmid": "39764567", "title": "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.", "citation": "Erritzoe D, Barba T, Greenway KT et al. 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. EClinicalMedicine. 2024.", "doi": "10.1016/j.eclinm.2024.102799", "pmcid": "PMC11701471", "url": "https://pubmed.ncbi.nlm.nih.gov/39764567/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39764567/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03429075", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "The escitalopram comparison retained improvement in both arms at six months without significant depression-score separation; secondary function favored psilocybin.", "what_it_does_not_show": "Descriptive follow-up, missingness and additional interventions limit durability attribution.", "confounders_present": [ "Descriptive follow-up, missingness and additional interventions limit durability attribution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 54, "pmid": "33850049", "title": "Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice.", "citation": "Hesselgrave N, Troppoli TA, Wulff AB et al. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences of the United States of America. 2021.", "doi": "10.1073/pnas.2022489118", "pmcid": "PMC8092378", "url": "https://pubmed.ncbi.nlm.nih.gov/33850049/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33850049/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33850049", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [ "M2" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Ketanserin preserved psilocybin's mouse antianhedonic and hippocampal synaptic effects despite blocking its behavioral pharmacodynamic response.", "what_it_does_not_show": "Antagonist/region and rodent proxy limits prevent proof of absence of human consciousness or therapeutic experience necessity.", "confounders_present": [ "Antagonist/region and rodent proxy limits prevent proof of absence of human consciousness or therapeutic experience necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 55, "pmid": "9875725", "title": "Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.", "citation": "Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998.", "doi": "10.1097/00001756-199812010-00024", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9875725/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9875725/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID9875725", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Human ketanserin/risperidone pretreatment blocked acute psychotomimetic effects while haloperidol increased them.", "what_it_does_not_show": "No durable depression outcome; acute blockade is not a therapeutic-mediator necessity experiment.", "confounders_present": [ "No durable depression outcome; acute blockade is not a therapeutic-mediator necessity experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 56, "pmid": "40007438", "title": "Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans.", "citation": "Larsen K, Lindberg U, Ozenne B et al. Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2025.", "doi": "10.1177/0271678X251323364", "pmcid": "PMC11863199", "url": "https://pubmed.ncbi.nlm.nih.gov/40007438/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40007438/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40007438", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Acute psilocybin versus ketanserin altered cerebral blood flow and internal-carotid diameter in healthy volunteers.", "what_it_does_not_show": "Direct drug comparison is not antagonist coadministration with intact psilocybin; vascular effects complicate functional imaging interpretation.", "confounders_present": [ "Direct drug comparison is not antagonist coadministration with intact psilocybin; vascular effects complicate functional imaging interpretation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 57, "pmid": "34246868", "title": "Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience.", "citation": "Madsen MK, Stenbæk DS, Arvidsson A et al. Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2021.", "doi": "10.1016/j.euroneuro.2021.06.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34246868/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34246868/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34246868", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Plasma psilocin and subjective intensity tracked network integrity/segregation during healthy-subject imaging.", "what_it_does_not_show": "Acute correlation does not define cortical learning-window duration or clinical mediation.", "confounders_present": [ "Acute correlation does not define cortical learning-window duration or clinical mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 58, "pmid": "30965131", "title": "Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects.", "citation": "Smigielski L, Scheidegger M, Kometer M et al. Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage. 2019.", "doi": "10.1016/j.neuroimage.2019.04.009", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30965131/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30965131/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30965131", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Psilocybin during a mindfulness retreat changed DMN measures and later psychosocial ratings.", "what_it_does_not_show": "Healthy retreat context, bundled training and observed predictors do not prove depressive integration necessity.", "confounders_present": [ "Healthy retreat context, bundled training and observed predictors do not prove depressive integration necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 59, "pmid": "36938991", "title": "Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial.", "citation": "Sloshower J, Skosnik PD, Safi-Aghdam H et al. Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Journal of psychopharmacology (Oxford, England). 2023.", "doi": "10.1177/02698811231154852", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36938991/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36938991/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36938991", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "A fixed-order placebo then psilocybin therapy study improved both conditions without significant difference; mystical ratings did not predict antidepressant change.", "what_it_does_not_show": "Fixed order, carryover, unequal completion and expectancy limit the negative contrast; metadata RCT label does not override actual design.", "confounders_present": [ "Fixed order, carryover, unequal completion and expectancy limit the negative contrast; metadata RCT label does not override actual design." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 60, "pmid": "38055270", "title": "Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial.", "citation": "Aaronson ST, van der Vaart A, Miller T et al. Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial. JAMA psychiatry. 2024.", "doi": "10.1001/jamapsychiatry.2023.4685", "pmcid": "PMC10701666", "url": "https://pubmed.ncbi.nlm.nih.gov/38055270/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38055270/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38598187" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38055270", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "An open-label bipolar-II depression trial with three integration sessions showed sustained symptoms/function improvement.", "what_it_does_not_show": "No control or component manipulation; distinct diagnosis and linked erratum constrain generalization.", "confounders_present": [ "No control or component manipulation; distinct diagnosis and linked erratum constrain generalization." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } } ], "verification_summary": { "load_bearing_claims_checked": 65, "verified": 65, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.", "specific_trigger": "SC1 has directly perturbed cellular/rodent plasticity, including adult targeted receptor deletion and activity manipulation [18–24,30,52]. Exact universal 5HT2A/TrkB dependence differs by paradigm [20,22,24,54]. Rubric 07's preclinical/rodent cap and missing clinical trajectory mediator keep the therapeutic-window interpretation at Γ.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC2", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.", "specific_trigger": "SC2 remains Γ: positive treatment packages contain support/integration, but no admitted study randomizes removal of formal postacute integration with intact drug exposure, equal contact and masked durable outcomes [1–7,11,14,16,17,43,46,47,50,59,60]. The 2026 CBT pilot is single-arm; MBSR comparison adds PAP to training, not removes integration from psilocybin.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.", "specific_trigger": "SC3 remains Γ. Human fMRI and cognitive changes are measured, but do not directly establish a cortical synaptic learning-window duration or its required integration schedule [8,34,35,37,38,49,56–58]. Mouse two-week social learning and month-persistent spines are different phenomena [20,30].", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.", "specific_trigger": "SC4 remains Γ: experience-outcome correlations and healthy-human blockade provide plausibility, not a drug-intact human mediator manipulation with durable remission [4,9–12,15,40,44,55,59]. Rodent/congener dissociations constrain universal necessity but cannot establish human dispensability [20,22–24,28,31,51,52,54].", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Psilocybin works best as psilocybin-assisted psychotherapy: the drug rapidly opens a neurodevelopmental-like window of synaptic plasticity, and formal post-acute psychotherapeutic integration is causally required to consolidate that state into lasting clinical remission.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Rodent knockout, activity suppression and drug-congener contrasts identify real experimental biology. Rubric 07 requires controlled human mediator/scaffold or credible subjective-effect-matched contrasts for the clinical mechanism. A preclinical success is not silently renamed human integration necessity. Positive package efficacy is retained; no blanket claim that all support is inert is made. Niacin is a side-effect comparator, not an inert placebo, but does not solve subjective matching or component identification.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "at least one of:\n- Active comparator matched for acute subjective effect, blinding integrity measured and reported\n- Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject\n- Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia\n- Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker\n- Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors\n\nRating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.", "qualifying_evidence_present": "unclear", "qualifying_evidence_citation": "PMID34743319, PMID41352354, PMID29898390, PMID34228959, PMID36795823, PMID37280397, PMID33299186, PMID40175553, PMID40424654, PMID35084960, PMID32814630, PMID37316665, PMID36884348, PMID36521179, PMID17270739, PMID37000971, PMID40683247, PMID41039182, PMID33915107, PMID40760185, PMID33850049", "gamma_hard_rules_triggered": [ "Functional-unblinding: low-dose or niacin controls do not automatically match intense subjective effects; Raison explicitly did not assess allocation-blinding success.", "Mediation-by-correlation: mystical/emotional/imaging predictors were not selectively manipulated to test durable human necessity.", "Open-label/waitlist/fixed-order designs leave expectancy, contact, regression and order confounded.", "Acute pharmacodynamics and rodent proxies cannot alone cross the clinical mechanism boundary. Adult genetic receptor deletion narrows mouse biology without identifying human integration." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC1 has directly perturbed cellular/rodent plasticity, including adult targeted receptor deletion and activity manipulation [18–24,30,52]. Exact universal 5HT2A/TrkB dependence differs by paradigm [20,22,24,54]. Rubric 07's preclinical/rodent cap and missing clinical trajectory mediator keep the therapeutic-window interpretation at Γ.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "at least one of:\n- Active comparator matched for acute subjective effect, blinding integrity measured and reported\n- Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject\n- Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia\n- Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker\n- Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors\n\nRating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.", "qualifying_evidence_present": "unclear", "qualifying_evidence_citation": "PMID36322843, PMID33852780, PMID41848690, PMID37000971, PMID36001306, PMID40972137, PMID36938991", "gamma_hard_rules_triggered": [ "Functional-unblinding: low-dose or niacin controls do not automatically match intense subjective effects; Raison explicitly did not assess allocation-blinding success.", "Mediation-by-correlation: mystical/emotional/imaging predictors were not selectively manipulated to test durable human necessity.", "Open-label/waitlist/fixed-order designs leave expectancy, contact, regression and order confounded.", "Acute pharmacodynamics and rodent proxies cannot alone cross the clinical mechanism boundary. Adult genetic receptor deletion narrows mouse biology without identifying human integration." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC2 remains Γ: positive treatment packages contain support/integration, but no admitted study randomizes removal of formal postacute integration with intact drug exposure, equal contact and masked durable outcomes [1–7,11,14,16,17,43,46,47,50,59,60]. The 2026 CBT pilot is single-arm; MBSR comparison adds PAP to training, not removes integration from psilocybin.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "at least one of:\n- Active comparator matched for acute subjective effect, blinding integrity measured and reported\n- Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject\n- Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia\n- Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker\n- Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors\n\nRating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.", "qualifying_evidence_present": "unclear", "qualifying_evidence_citation": "PMID41352354, PMID34228959, PMID37316665, PMID39020167, PMID40007438", "gamma_hard_rules_triggered": [ "Functional-unblinding: low-dose or niacin controls do not automatically match intense subjective effects; Raison explicitly did not assess allocation-blinding success.", "Mediation-by-correlation: mystical/emotional/imaging predictors were not selectively manipulated to test durable human necessity.", "Open-label/waitlist/fixed-order designs leave expectancy, contact, regression and order confounded.", "Acute pharmacodynamics and rodent proxies cannot alone cross the clinical mechanism boundary. Adult genetic receptor deletion narrows mouse biology without identifying human integration." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC3 remains Γ. Human fMRI and cognitive changes are measured, but do not directly establish a cortical synaptic learning-window duration or its required integration schedule [8,34,35,37,38,49,56–58]. Mouse two-week social learning and month-persistent spines are different phenomena [20,30].", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "at least one of:\n- Active comparator matched for acute subjective effect, blinding integrity measured and reported\n- Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject\n- Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia\n- Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker\n- Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors\n\nRating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.", "qualifying_evidence_present": "unclear", "qualifying_evidence_citation": "PMID36322843, PMID33852780, PMID16826400, PMID34743319, PMID34228959, PMID37280397, PMID33299186, PMID40175553, PMID35084960, PMID32814630, PMID36884348, PMID36521179, PMID17270739, PMID39020167, PMID40683247, PMID33915107, PMID40760185, PMID33850049, PMID9875725, PMID36938991", "gamma_hard_rules_triggered": [ "Functional-unblinding: low-dose or niacin controls do not automatically match intense subjective effects; Raison explicitly did not assess allocation-blinding success.", "Mediation-by-correlation: mystical/emotional/imaging predictors were not selectively manipulated to test durable human necessity.", "Open-label/waitlist/fixed-order designs leave expectancy, contact, regression and order confounded.", "Acute pharmacodynamics and rodent proxies cannot alone cross the clinical mechanism boundary. Adult genetic receptor deletion narrows mouse biology without identifying human integration." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC4 remains Γ: experience-outcome correlations and healthy-human blockade provide plausibility, not a drug-intact human mediator manipulation with durable remission [4,9–12,15,40,44,55,59]. Rodent/congener dissociations constrain universal necessity but cannot establish human dispensability [20,22–24,28,31,51,52,54].", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "satisfied": "no", "supporting_evidence": [ "[15] Escitalopram pretreatment reduced negative acute effects without changing psilocin exposure or positive mood; circulating BDNF was unchanged.", "[18] Psilocybin rewired mouse cortical inputs, and silencing presynaptic activity disrupted the pattern.", "[19] Psychedelics increased neurites/spines and synaptic function with TrkB, mTOR and 5HT2A pathway support.", "[20] Psilocybin increased mouse frontal spines persistently; ketanserin abolished head twitch but retained spine-width/formation effects while density significance was lost.", "[21] Molecular/genetic experiments identified intracellular 5HT2A involvement in psychedelic-induced cortical growth.", "[22] TrkB-binding contrasts linked psychedelic plasticity/behavior to BDNF signaling independent of 5HT2A in the tested paradigms.", "[23] Tabernanthalog promoted rodent neural plasticity and changed drug-seeking and behavioral assays without hallucinogenic-like effects.", "[24] Adult local 5HT2A deletion removed specified psilocybin plasticity and stress effects while local deletion left head twitch intact; learned-helplessness control response had a floor-limit caveat.", "[26] Antagonist contrasts changed microglial TNF and BDNF responses to psilocybin/psilocin.", "[28] Structure-guided 5HT2A analogues showed antidepressant-like mouse activity with attenuated hallucinogenic-like responses.", "[29] DOI and lisuride produced distinct downstream 5HT2A signaling in engineered cells and neurons.", "[30] Psilocybin reopened mouse social reward learning for two weeks but not three; oxytocin metaplasticity and ketanserin contrasts mapped the circuit.", "[31] 2-bromo-LSD promoted culture plasticity and changed chronic-stress behavior without head twitch; a receptor antagonist blocked active coping.", "[32] New Ariadne pharmacological profiling and mouse motor rescue mapped a lower-efficacy 5HT2A agonist.", "[33] Cortical receptor-expression and signaling contrasts differentiated hallucinogenic from nonhallucinogenic ligands.", "[36] Psilocybin plus extinction training improved mouse fear retrieval/renewal and coincided with hippocampal plasticity measures.", "[42] New profiling of 41 psychedelics across 318 GPCRs identified broad receptor actions and multiple 5HT2A transducers.", "[45] Psilocybin/local psilocin improved allodynia and mood-like behaviors in mouse pain models with prefrontal circuit/receptor contrasts.", "[51] An engineered biosensor identified a nonhallucinogenic-like analogue with lasting rodent behavioral activity.", "[52] TBG required cortical spinogenesis for sustained rodent behavioral effects without the immediate gene/glutamate burst of psychedelics.", "[54] Ketanserin preserved psilocybin's mouse antianhedonic and hippocampal synaptic effects despite blocking its behavioral pharmacodynamic response." ], "what_would_cross_it": "For Δ in therapeutic-window interpretation, a human mediator perturbation must link plasticity change to a preregistered clinical trajectory with credible exposure/comparator controls." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "satisfied": "no", "supporting_evidence": [ "[1] 25-mg psilocybin with psychological support improved the week-3 primary depression score versus 1 mg; sustained week-12 response was not supportive.", "[2] Psilocybin versus escitalopram with matched support did not differ significantly on the week-6 primary QIDS outcome; several unadjusted secondary outcomes favored psilocybin.", "[14] The 2026 EPISODE trial missed its primary week-6 response comparison; secondary symptom changes were exploratory.", "[36] Psilocybin plus extinction training improved mouse fear retrieval/renewal and coincided with hippocampal plasticity measures.", "[39] Psilocybin plus manualized psychotherapy reduced heavy drinking versus diphenhydramine plus the same psychotherapy.", "[50] MBSR plus group PAP outperformed MBSR alone on short-term depressive symptoms; the effect waned by six months.", "[59] A fixed-order placebo then psilocybin therapy study improved both conditions without significant difference; mystical ratings did not predict antidepressant change." ], "what_would_cross_it": "Randomize scaffold removal or integration components with intact psilocybin, equal safety/contact, masked raters, fidelity and durable remission; demonstrate loss and rescue of the alleged required component." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "satisfied": "no", "supporting_evidence": [ "[18] Psilocybin rewired mouse cortical inputs, and silencing presynaptic activity disrupted the pattern.", "[20] Psilocybin increased mouse frontal spines persistently; ketanserin abolished head twitch but retained spine-width/formation effects while density significance was lost.", "[30] Psilocybin reopened mouse social reward learning for two weeks but not three; oxytocin metaplasticity and ketanserin contrasts mapped the circuit.", "[34] Precision imaging found acute desynchronization, task modulation and persistent hippocampal-DMN connectivity changes after psilocybin.", "[56] Acute psilocybin versus ketanserin altered cerebral blood flow and internal-carotid diameter in healthy volunteers." ], "what_would_cross_it": "Directly validate human plasticity duration and randomize experience/learning timing to establish outcome-relevant consolidation; network imaging alone is insufficient." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.", "satisfied": "no", "supporting_evidence": [ "[1] 25-mg psilocybin with psychological support improved the week-3 primary depression score versus 1 mg; sustained week-12 response was not supportive.", "[2] Psilocybin versus escitalopram with matched support did not differ significantly on the week-6 primary QIDS outcome; several unadjusted secondary outcomes favored psilocybin.", "[10] Psilocybin versus methylphenidate induced marked acute experiences and later meaning/attitude changes in healthy volunteers.", "[15] Escitalopram pretreatment reduced negative acute effects without changing psilocin exposure or positive mood; circulating BDNF was unchanged.", "[20] Psilocybin increased mouse frontal spines persistently; ketanserin abolished head twitch but retained spine-width/formation effects while density significance was lost.", "[22] TrkB-binding contrasts linked psychedelic plasticity/behavior to BDNF signaling independent of 5HT2A in the tested paradigms.", "[23] Tabernanthalog promoted rodent neural plasticity and changed drug-seeking and behavioral assays without hallucinogenic-like effects.", "[24] Adult local 5HT2A deletion removed specified psilocybin plasticity and stress effects while local deletion left head twitch intact; learned-helplessness control response had a floor-limit caveat.", "[28] Structure-guided 5HT2A analogues showed antidepressant-like mouse activity with attenuated hallucinogenic-like responses.", "[29] DOI and lisuride produced distinct downstream 5HT2A signaling in engineered cells and neurons.", "[31] 2-bromo-LSD promoted culture plasticity and changed chronic-stress behavior without head twitch; a receptor antagonist blocked active coping.", "[32] New Ariadne pharmacological profiling and mouse motor rescue mapped a lower-efficacy 5HT2A agonist.", "[33] Cortical receptor-expression and signaling contrasts differentiated hallucinogenic from nonhallucinogenic ligands.", "[34] Precision imaging found acute desynchronization, task modulation and persistent hippocampal-DMN connectivity changes after psilocybin.", "[42] New profiling of 41 psychedelics across 318 GPCRs identified broad receptor actions and multiple 5HT2A transducers.", "[51] An engineered biosensor identified a nonhallucinogenic-like analogue with lasting rodent behavioral activity.", "[52] TBG required cortical spinogenesis for sustained rodent behavioral effects without the immediate gene/glutamate burst of psychedelics.", "[54] Ketanserin preserved psilocybin's mouse antianhedonic and hippocampal synaptic effects despite blocking its behavioral pharmacodynamic response.", "[55] Human ketanserin/risperidone pretreatment blocked acute psychotomimetic effects while haloperidol increased them.", "[59] A fixed-order placebo then psilocybin therapy study improved both conditions without significant difference; mystical ratings did not predict antidepressant change." ], "what_would_cross_it": "Keep drug exposure intact while blocking experience or dosing under anesthesia with matched anesthesia/support controls, and measure preregistered durable symptoms/remission rather than acute biomarkers." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Escitalopram comparison missed its primary between-group endpoint [2].", "EPISODE missed its prespecified primary response comparison [14].", "Meaning/mystical ratings did not predict depression change in the 12-month MDD follow-up [9].", "Fixed-order placebo and psilocybin changes did not significantly differ; mystical ratings were not predictive [59].", "Mouse antagonist/genetic dependence differed by circuit, blockade and assay [20,22,24,54]." ], "note": "Baseline diagnosis, severity, species, cortical/accumbens region, dose, learning assay and support protocol are identifiable before outcome. Responders and posthoc mystical subgroups do not define scope. Actual knockout controls and incomplete pharmacological blockade preserve distinctions instead of forcing one universal pathway." }, "falsification_patterns_met": [ { "subclaim_id": "SC4", "pattern": "Blocking the acute experience, or dosing under anaesthesia, leaves the effect intact", "evidence": "Mouse head-twitch-blocking antagonist contrasts preserve some structural/synaptic/behavioral effects [20,54]. This is a rodent proxy, not a completed human experience-removal result.", "downgrade_applied": false }, { "subclaim_id": "SC4", "pattern": "A non-subjective congener reproduces the therapeutic effect", "evidence": "Nonhallucinogenic-like compounds reproduce specified rodent plasticity and behavioral effects [23,28,31,51,52]. Clinical human subjective status and remission transfer are not established.", "downgrade_applied": false }, { "subclaim_id": "SC2", "pattern": "Multi-site replication with blinded central raters fails to reproduce a single-site effect", "evidence": "EPISODE's primary null challenges uniform package efficacy [14], but does not selectively remove integration and cannot falsify its necessity by itself.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "subclaim_id": "SC2", "pitfall": "13. Therapeutic effect misread as mechanistic proof", "where": "Successful drug-plus-support is not integration necessity." }, { "subclaim_id": "SC3", "pitfall": "16. Untested generalization confused with mapped boundaries", "where": "Mouse social-learning metaplasticity, persistent spines and human cortical duration are separate outcomes." }, { "subclaim_id": "SC2", "pitfall": "22. Scope fitted to the result", "where": "Post-treatment mystical responders cannot supply predeclared integration requirement." }, { "subclaim_id": "SC4", "pitfall": "21. A universal cap re-applied to a convergent evidence set", "where": "Model dissociations are retained as a set; no independent full-scope human necessity chain is present to re-cap." } ], "causal_tally_audit": { "tally_claimed_by_document": 31, "tally_after_audit": 31, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "No listed discriminator is a completed human integration-removal necessity experiment.", "Drug dose, receptor blockade and congeners are not interchangeable with selective experiential manipulation.", "Primary reports can share clinical cohorts; neither follow-up nor a preprint version adds independent replication." ] }, "steelman": { "case_one_rung_higher": "The strongest Δ case combines randomized drug-package benefit, long follow-up, experience associations and directly manipulated mouse plasticity. The missing identifying experiment is human component dismantling or drug-intact mediator removal with durable outcomes. The package can work while the claimed required consolidation mechanism remains untested.", "case_one_rung_lower": "The strongest Β case stresses that formal integration itself is merely co-delivered and its human causal benefit not isolated. It understates experimentally causal model plasticity, environment/activity dependence and pharmacological human acute perturbations supporting a mechanistically plausible bridge. Γ retains that support without treating it as clinical necessity.", "which_rejected": "Reject Δ because no scope-matched human integration/experience mediator-removal result identifies the dependency. Reject Β for the conjunction because mechanistic support extends beyond association; avoid scoring the easier acute clause as the whole hypothesis.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Randomize baseline-defined depressed/anxious participants receiving the same psilocybin dose and preparation to formal postacute integration versus equal-contact supportive follow-up, with balanced allegiance, explicit protocol/fidelity, participant/rater allocation guesses and masked central assessments at six and twelve months. Add a prespecified early-versus-delayed integration contrast and a separately controlled drug-intact experience-removal study to distinguish timing, therapy and subjective mechanisms." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 4 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The registered weakest-link conjunction returns Γ. All four therapeutic/mechanism clauses remain Γ under rubric 07, though cell/rodent plasticity and some clinical package effects are empirically positive. Primary-SC2 and scope-matched sensitivities also return Γ. The unresolved content is required formal consolidation, not whether the drug ever changes synapses or symptoms." }, "role_of_mechanism": { "classification": "epiphenomenon", "derivation_step_matched": "2", "derivation": "For the nominal human formal-integration-to-remission dependency: acute dosing/support precedes remission, so a purely outcome-produced label is not established (step 1). No examined result demonstrates an isolated causal dependency of remission on formal postacute integration, or the reverse; its co-delivery with successful drug packages matches step 2 at this identification level. This provisional evidence-role label does not demonstrate integration is useless and does not deny causal mouse plasticity. Because the procedure stops at step 2, a proven necessary permissive-factor role is not inferred from the theory.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Completed activity-dependent network rewiring [18], adult cell-type receptor deletion [24], nonhallucinogenic spinogenesis [52] and CBT feasibility [46] programmes are concrete artifacts. The anesthesia paper discovered by SciSpace/Consensus is a proposal, not a verified running trial or completed result.", "justification": "Completed activity-dependent network rewiring [18], adult cell-type receptor deletion [24], nonhallucinogenic spinogenesis [52] and CBT feasibility [46] programmes are concrete artifacts. The anesthesia paper discovered by SciSpace/Consensus is a proposal, not a verified running trial or completed result." }, "stability": { "value": "Stable", "trigger": "No specifically verified pending integration-dismantling or drug-intact human experience-removal trial result identified in this bounded search. Proposals and completed efficacy trials are not pending triggers.", "justification": "No specifically verified pending integration-dismantling or drug-intact human experience-removal trial result identified in this bounded search. Proposals and completed efficacy trials are not pending triggers." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Randomize baseline-defined depressed/anxious participants receiving the same psilocybin dose and preparation to formal postacute integration versus equal-contact supportive follow-up, with balanced allegiance, explicit protocol/fidelity, participant/rater allocation guesses and masked central assessments at six and twelve months. Add a prespecified early-versus-delayed integration contrast and a separately controlled drug-intact experience-removal study to distinguish timing, therapy and subjective mechanisms.", "readout": "Durable remission/relapse and independently assessed function, with validated plasticity measures as distinct mechanistic endpoints", "critical_control": "Equal drug exposure, safety support and contact; measured expectancy/alliance and masking integrity; fidelity; co-interventions and multiplicity", "supporting_result": "Selective loss of durable remission when formal integration is removed or outside the validated window, with benefit restored by component rescue", "falsifying_result": "Preserved durable remission under credible scaffold removal, with a prespecified adequately powered equivalence/noninferiority boundary" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Is formal integration beneficial, necessary, or one of several sufficient learning environments?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Does a mouse social-learning critical period have a comparable human cortical clinical window?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Which receptor/TrkB effects generalize across region, dose and assay?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Does subjective experience independently mediate benefit when exposure and support are held intact?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "What net durable functional benefit survives expectancy, co-intervention and masking assessment?", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-04", "reviewer": "Codex", "evidence_base_note": "60 primary reports; cutoff 2026-10-04; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/PMC; SciSpace and authenticated Consensus discovery; primary-source verification. No API credential handled.", "skill_version": "5.3", "validator_run": "Archived validator run; receipt and logs accompany this pair.", "validator_warnings_addressed": "Claim-form warning is justified: the popularity-list topic is explicitly restated as a causal proposition. The steelman specifies the missing experiment.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Blinding-integrity-reported subjective-effect comparators, drug-intact mediator manipulation, discontinuation/rechallenge, component dismantling and a plausible exposure genetic instrument are eligible equivalents. None of the admitted results identifies formal integration necessity or its human synaptic timing. Sponsor/site multiplicity and shared-cohort analyses do not supply independent failure-mode exclusion for the full mechanism." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Blinding-integrity-reported subjective-effect comparators, drug-intact mediator manipulation, discontinuation/rechallenge, component dismantling and a plausible exposure genetic instrument are eligible equivalents. None of the admitted results identifies formal integration necessity or its human synaptic timing. Sponsor/site multiplicity and shared-cohort analyses do not supply independent failure-mode exclusion for the full mechanism." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Blinding-integrity-reported subjective-effect comparators, drug-intact mediator manipulation, discontinuation/rechallenge, component dismantling and a plausible exposure genetic instrument are eligible equivalents. None of the admitted results identifies formal integration necessity or its human synaptic timing. Sponsor/site multiplicity and shared-cohort analyses do not supply independent failure-mode exclusion for the full mechanism." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Blinding-integrity-reported subjective-effect comparators, drug-intact mediator manipulation, discontinuation/rechallenge, component dismantling and a plausible exposure genetic instrument are eligible equivalents. None of the admitted results identifies formal integration necessity or its human synaptic timing. Sponsor/site multiplicity and shared-cohort analyses do not supply independent failure-mode exclusion for the full mechanism." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Blinding-integrity-reported subjective-effect comparators, drug-intact mediator manipulation, discontinuation/rechallenge, component dismantling and a plausible exposure genetic instrument are eligible equivalents. None of the admitted results identifies formal integration necessity or its human synaptic timing. Sponsor/site multiplicity and shared-cohort analyses do not supply independent failure-mode exclusion for the full mechanism." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 60, "claims_total": 65, "claims_verified": 65, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 60, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "25-mg psilocybin with psychological support improved the week-3 primary depression score versus 1 mg; sustained week-12 response was not supportive. Dose changes drug exposure and experience together; support was not removed and experience was not selectively manipulated.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C2", "text": "Psilocybin versus escitalopram with matched support did not differ significantly on the week-6 primary QIDS outcome; several unadjusted secondary outcomes favored psilocybin. Neither equivalence nor integration necessity follows; drug, experience and daily-treatment schedules differ.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C3", "text": "Immediate psilocybin plus supportive therapy improved MDD symptoms versus delayed treatment. Waitlist does not control expectancy/contact or remove integration; a linked erratum remains attached.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C4", "text": "High versus low dose with support improved cancer-related distress; experience statistically mediated outcomes. Statistical mediation and crossover follow-up do not isolate experiential or psychotherapy necessity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C5", "text": "Open-label psilocybin with support showed rapid symptom reduction in TRD. No control group; support preceded, accompanied and followed dosing.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C6", "text": "Immediate PAP improved symptoms versus waitlist in complex TRD; flexible repeats were associated with further improvement. Each dose included preparation and integration; repeat dosing was not randomized independently.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C7", "text": "The expanded open-label TRD cohort retained symptom improvement through six months; acute experience predicted early response. Shares the feasibility programme and lacks controlled long-term or manipulated-experience inference.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C8", "text": "Imaging across two clinical cohorts linked lower network modularity to symptom response. Brain network integration is not psychotherapy integration or directly measured synaptogenesis; cohorts overlap prior trials.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C9", "text": "The MDD cohort retained symptom reductions at 12 months; meaning/mystical ratings predicted well-being but not depression improvement. Follow-up lacks an untreated long-term counterfactual and shares the original delayed-treatment cohort.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C10", "text": "Psilocybin versus methylphenidate induced marked acute experiences and later meaning/attitude changes in healthy volunteers. Healthy spiritual outcomes do not establish depression remission or the necessity of subjective experience.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C11", "text": "Psilocybin versus niacin within psychotherapy improved cancer-related symptoms before crossover, with later persistence. Both arms had psychotherapy; observed mystical mediation is not a mediator manipulation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C12", "text": "Post hoc antidepressant discontinuation status predicted smaller clinical response without corresponding experience differences. Discontinuation was not randomized and continuation was not tested; exploratory association only.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C13", "text": "The COMP360 trial follow-up reports favorable exploratory patient-rated function and symptoms at week three. Same dose trial, not independent replication; functional unblinding and no scaffold removal.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C14", "text": "The 2026 EPISODE trial missed its primary week-6 response comparison; secondary symptom changes were exploratory. Adjunct psychotherapy was present; a null package endpoint does not selectively falsify integration necessity.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C15", "text": "Escitalopram pretreatment reduced negative acute effects without changing psilocin exposure or positive mood; circulating BDNF was unchanged. Healthy acute pharmacodynamics do not measure lasting remission or cortical plasticity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C16", "text": "Psilocybin versus niacin with preparation and three integration visits improved clinician-rated depressive symptoms in frontline clinicians. Both arms had integration; secondary burnout was not significant, and linked correction details are incompletely examined.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C17", "text": "The MDD trial improved depression and disability with psilocybin versus niacin within identical support. Methods include four hours of postdose integration; allocation-blinding success was not assessed. It cannot show benefit without integration.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Web-Study-Procedures-L469-471, Web-Efficacy-Assessments-L473-477, Web-Limitations-L695-705. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C18", "text": "Psilocybin rewired mouse cortical inputs, and silencing presynaptic activity disrupted the pattern. Activity-dependent mouse rewiring does not identify a human integration window or formal therapy necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C19", "text": "Psychedelics increased neurites/spines and synaptic function with TrkB, mTOR and 5HT2A pathway support. Drug-class and culture/model plasticity is not a clinical mediator or a universal psilocybin receptor sequence.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C20", "text": "Psilocybin increased mouse frontal spines persistently; ketanserin abolished head twitch but retained spine-width/formation effects while density significance was lost. The antagonist was incompletely receptor-blocking; head twitch is not direct consciousness, and month-long spines do not define a month-long learning window.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: S6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C21", "text": "Molecular/genetic experiments identified intracellular 5HT2A involvement in psychedelic-induced cortical growth. Cellular receptor-location inference does not identify human therapeutic consolidation.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C22", "text": "TrkB-binding contrasts linked psychedelic plasticity/behavior to BDNF signaling independent of 5HT2A in the tested paradigms. Contrasts with receptor-necessity studies require model/assay separation; no demonstrated human experience blockade with remission outcomes.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C23", "text": "Tabernanthalog promoted rodent neural plasticity and changed drug-seeking and behavioral assays without hallucinogenic-like effects. A different compound and absent rodent head twitch do not establish subjective-experience dispensability in human psilocybin treatment.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C24", "text": "Adult local 5HT2A deletion removed specified psilocybin plasticity and stress effects while local deletion left head twitch intact; learned-helplessness control response had a floor-limit caveat. Cell-type specificity and genotype controls bound inference; rodent stress tests are not human remission and linked correction detail is unexamined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: S6, S7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C25", "text": "Psilocybin improved chronic-corticosterone mouse behavioral proxies alongside plasticity/BDNF-mTOR measures. Co-occurring molecular changes were not selectively shown necessary for the behavioral effect.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C26", "text": "Antagonist contrasts changed microglial TNF and BDNF responses to psilocybin/psilocin. Inflammation/growth markers in LPS cultures are not cortical synapses or clinical antidepressant mediation.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C27", "text": "Whole-brain cFos mapping identified shared and distinct acute psilocybin/ketamine activation regions. Immediate early gene activation is not itself structural plasticity, remission or a necessary mediator.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C28", "text": "Structure-guided 5HT2A analogues showed antidepressant-like mouse activity with attenuated hallucinogenic-like responses. Biased compounds and behavioral proxies do not settle human experiential necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C29", "text": "DOI and lisuride produced distinct downstream 5HT2A signaling in engineered cells and neurons. Signaling efficacy differences do not measure human subjective experience or lasting therapy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C30", "text": "Psilocybin reopened mouse social reward learning for two weeks but not three; oxytocin metaplasticity and ketanserin contrasts mapped the circuit. A nucleus-accumbens mouse learning assay is not human cortical synaptogenesis, depression remission or randomized integration scheduling.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec3, Sec4, Sec5. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C31", "text": "2-bromo-LSD promoted culture plasticity and changed chronic-stress behavior without head twitch; a receptor antagonist blocked active coping. Different compound and rodent behaviors constrain transfer to human psilocybin experience.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C32", "text": "New Ariadne pharmacological profiling and mouse motor rescue mapped a lower-efficacy 5HT2A agonist. Only the new empirical component is counted; historical clinical anecdotes and PD rescue do not establish psilocybin antidepressant mediation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C33", "text": "Cortical receptor-expression and signaling contrasts differentiated hallucinogenic from nonhallucinogenic ligands. Construct/signaling sufficiency is not endogenous human therapeutic necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C34", "text": "Precision imaging found acute desynchronization, task modulation and persistent hippocampal-DMN connectivity changes after psilocybin. Functional connectivity is not directly measured synaptic growth or a tested integration-timing mediator; participants were healthy.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C35", "text": "TRD imaging changes correlated with symptoms and predicted early response in an open-label cohort. Shared cohort and imaging association do not identify a structural plasticity or integration mediator.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C36", "text": "Psilocybin plus extinction training improved mouse fear retrieval/renewal and coincided with hippocampal plasticity measures. No selective mediation or human integration-necessity test; extinction is not formal postacute psychotherapy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C37", "text": "Cognitive flexibility improved after treatment, but was not correlated with antidepressant change; larger neural flexibility shifts could predict less improvement. Shares MDD participants and does not directly measure cortical plasticity or its necessity.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C38", "text": "Acute human imaging mapped reduced hub activity/connectivity alongside psychedelic effects. Acute neurovascular/functional signals do not establish synaptogenesis or durable remission.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C39", "text": "Psilocybin plus manualized psychotherapy reduced heavy drinking versus diphenhydramine plus the same psychotherapy. AUD is outside the registered depressive/anxiety scope; no psychotherapy removal, and linked erratum detail remains unexamined.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C40", "text": "PET occupancy and plasma psilocin tracked subjective intensity in healthy adults. Occupancy-experience correlation does not show experience is necessary for lasting clinical benefit; correction detail not fully examined.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C41", "text": "Open-label TRD personality changes and acute insight were associated at follow-up. Shares the expanded TRD cohort; personality association is not remission mediation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C42", "text": "New profiling of 41 psychedelics across 318 GPCRs identified broad receptor actions and multiple 5HT2A transducers. Polypharmacology constrains unique-target accounts but is not proof of an alternative clinical mediator.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C43", "text": "A severe-TRD open-label pilot with three integration sessions reported sustained symptom change and exploratory experience correlations. No counterfactual or component randomization; PTSD subgroup is exploratory.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C44", "text": "COMP360 experience and emotional breakthrough correlated with week-3 response despite overlapping dose experience distributions. Same dose trial; correlation does not establish causation or measured blinding integrity; correction detail remains incompletely examined.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C45", "text": "Psilocybin/local psilocin improved allodynia and mood-like behaviors in mouse pain models with prefrontal circuit/receptor contrasts. Partial receptor replication and pain-model behavior are not human depression remission or formal therapy necessity.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C46", "text": "The 2026 single-arm CBT programme retained symptom/function gains through follow-up. All participants received twelve therapy sessions; no randomized CBT or integration counterfactual.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C47", "text": "The 2025 life-threatening-illness trial favored psilocybin over niacin on selected symptom outcomes within psychotherapy. Both arms had six integration sessions; open-label extension weakens isolated long-term inference.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C48", "text": "Drug-specific cFos patterns classified psychoactive compounds above chance in mice. A successful drug classifier is not validated plasticity or clinical-mechanism stratification.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C49", "text": "Psilocybin and escitalopram differed in emotional BOLD responses with matched preparation/integration. Same comparative trial; no human structural plasticity or integration removal.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C50", "text": "MBSR plus group PAP outperformed MBSR alone on short-term depressive symptoms; the effect waned by six months. Tests addition of drug plus PAP, not integration removal from drug; contact intensity differed and corrected secondary outcomes were null.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C51", "text": "An engineered biosensor identified a nonhallucinogenic-like analogue with lasting rodent behavioral activity. New compound discovery is not proof that human psilocybin works without experience or integration.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C52", "text": "TBG required cortical spinogenesis for sustained rodent behavioral effects without the immediate gene/glutamate burst of psychedelics. Different compound/model; no general human clinical experiential necessity conclusion.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C53", "text": "The escitalopram comparison retained improvement in both arms at six months without significant depression-score separation; secondary function favored psilocybin. Descriptive follow-up, missingness and additional interventions limit durability attribution.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C54", "text": "Ketanserin preserved psilocybin's mouse antianhedonic and hippocampal synaptic effects despite blocking its behavioral pharmacodynamic response. Antagonist/region and rodent proxy limits prevent proof of absence of human consciousness or therapeutic experience necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C55", "text": "Human ketanserin/risperidone pretreatment blocked acute psychotomimetic effects while haloperidol increased them. No durable depression outcome; acute blockade is not a therapeutic-mediator necessity experiment.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C56", "text": "Acute psilocybin versus ketanserin altered cerebral blood flow and internal-carotid diameter in healthy volunteers. Direct drug comparison is not antagonist coadministration with intact psilocybin; vascular effects complicate functional imaging interpretation.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C57", "text": "Plasma psilocin and subjective intensity tracked network integrity/segregation during healthy-subject imaging. Acute correlation does not define cortical learning-window duration or clinical mediation.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C58", "text": "Psilocybin during a mindfulness retreat changed DMN measures and later psychosocial ratings. Healthy retreat context, bundled training and observed predictors do not prove depressive integration necessity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C59", "text": "A fixed-order placebo then psilocybin therapy study improved both conditions without significant difference; mystical ratings did not predict antidepressant change. Fixed order, carryover, unequal completion and expectancy limit the negative contrast; metadata RCT label does not override actual design.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C60", "text": "An open-label bipolar-II depression trial with three integration sessions showed sustained symptoms/function improvement. No control or component manipulation; distinct diagnosis and linked erratum constrain generalization.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC1", "text": "SC1 has directly perturbed cellular/rodent plasticity, including adult targeted receptor deletion and activity manipulation [18–24,30,52]. Exact universal 5HT2A/TrkB dependence differs by paradigm [20,22,24,54]. Rubric 07's preclinical/rodent cap and missing clinical trajectory mediator keep the therapeutic-window interpretation at Γ.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 15, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 36, 42, 45, 48, 51, 52, 54 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC2", "text": "SC2 remains Γ: positive treatment packages contain support/integration, but no admitted study randomizes removal of formal postacute integration with intact drug exposure, equal contact and masked durable outcomes [1–7,11,14,16,17,43,46,47,50,59,60]. The 2026 CBT pilot is single-arm; MBSR comparison adds PAP to training, not removes integration from psilocybin.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 14, 16, 17, 36, 39, 41, 43, 46, 47, 49, 50, 53, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC3", "text": "SC3 remains Γ. Human fMRI and cognitive changes are measured, but do not directly establish a cortical synaptic learning-window duration or its required integration schedule [8,34,35,37,38,49,56–58]. Mouse two-week social learning and month-persistent spines are different phenomena [20,30].", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 8, 18, 20, 30, 34, 35, 37, 38, 49, 56, 57, 58 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC4", "text": "SC4 remains Γ: experience-outcome correlations and healthy-human blockade provide plausibility, not a drug-intact human mediator manipulation with durable remission [4,9–12,15,40,44,55,59]. Rodent/congener dissociations constrain universal necessity but cannot establish human dispensability [20,22–24,28,31,51,52,54].", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 4, 7, 9, 10, 11, 12, 15, 20, 22, 23, 24, 28, 29, 31, 32, 33, 34, 38, 40, 41, 42, 43, 44, 51, 52, 54, 55, 57, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CH", "text": "Psilocybin changes experimental synapses and can improve clinical treatment-package outcomes. Required formal integration and required subjective experience remain mechanistically plausible but unisolated (Γ).", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 20, 24, 30, 17, 14, 46, 59 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-04", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Goodwin GM, Aaronson ST, Alvarez O et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. The New England journal of medicine. 2022.", "tier": "A", "kind": "rct", "pmid": "36322843", "doi": "10.1056/NEJMoa2206443", "url": "https://pubmed.ncbi.nlm.nih.gov/36322843/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03775200", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC2", "CSC4" ] }, { "n": 2, "citation": "Carhart-Harris R, Giribaldi B, Watts R et al. Trial of Psilocybin versus Escitalopram for Depression. The New England journal of medicine. 2021.", "tier": "A", "kind": "rct", "pmid": "33852780", "doi": "10.1056/NEJMoa2032994", "url": "https://pubmed.ncbi.nlm.nih.gov/33852780/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03429075", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC2", "CSC4" ] }, { "n": 3, "citation": "Davis AK, Barrett FS, May DG et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. 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