{
  "slug": "psilocybin-therapy",
  "title": "Psilocybin, Cortical Plasticity and Durable Antidepressant Response",
  "claim": "Psilocybin causes a sustained reduction in human depressive symptoms by inducing a temporary increase in cortical plasticity.",
  "update_date": "2026-10-05",
  "search_cutoff": "2026-10-05",
  "framework_for_addendum": "HSEF v5.3 causal distinctions",
  "historical_scorecard_schema": "5.4",
  "regraded": false,
  "status": "curated_local_addendum",
  "full_academic_review_complete": false,
  "summary": "Clinical trials support symptom effects in selected settings, and mouse experiments establish specific receptor/cell dependencies. These findings do not yet show that a temporary rise in human structural plasticity mediates lasting antidepressant benefit; recent null and context-dependent results are central to that distinction.",
  "timeline": [
    {
      "year": "2016",
      "source_id": "P27210031",
      "design": "Open-label depression feasibility study",
      "finding": "Symptoms improved after psilocybin with psychological support.",
      "limit": "Small uncontrolled study cannot separate drug, expectancy, support and natural course.",
      "historical_anchor_only": false
    },
    {
      "year": "2021",
      "source_id": "P33852780",
      "design": "Psilocybin versus escitalopram randomized trial",
      "finding": "The primary depression outcome did not show a significant between-treatment difference.",
      "limit": "Secondary outcomes favoured psilocybin but lacked multiplicity correction; support accompanied treatment.",
      "historical_anchor_only": false
    },
    {
      "year": "2021",
      "source_id": "P34228959",
      "design": "Mouse longitudinal spine imaging",
      "finding": "A single dose increased frontal dendritic-spine measures for weeks.",
      "limit": "Mouse structural change does not establish mediation of human depression relief.",
      "historical_anchor_only": false
    },
    {
      "year": "2022",
      "source_id": "P36322843",
      "design": "Treatment-resistant depression dose trial",
      "finding": "The higher dose improved the short-term primary outcome over low dose.",
      "limit": "Durability and adverse-event findings bound benefit; low-dose control does not guarantee successful blinding.",
      "historical_anchor_only": false
    },
    {
      "year": "2023",
      "source_id": "P37651119",
      "design": "Psilocybin versus niacin MDD randomized trial",
      "finding": "Depressive symptoms and disability improved through the measured follow-up.",
      "limit": "Acute experiential differences and psychological support complicate causal component separation.",
      "historical_anchor_only": false
    },
    {
      "year": "2025",
      "source_id": "P40175553",
      "design": "Mouse cell-type silencing and receptor deletion",
      "finding": "PT-cell activity and targeted 5-HT2A receptors were required for selected lasting effects.",
      "limit": "Blocking a receptor/cell affects multiple processes; it does not isolate structural plasticity as the mediator.",
      "historical_anchor_only": false
    },
    {
      "year": "2025",
      "source_id": "P41224969",
      "design": "Rodent long-term functional/structural comparison",
      "finding": "Enduring behaviour and functional plasticity occurred without detected structural-density changes.",
      "limit": "Species, sampling and measurement sensitivity limit how broadly this structural null applies.",
      "historical_anchor_only": false
    },
    {
      "year": "2026",
      "source_id": "P42138922",
      "design": "Major-depression randomized trial",
      "finding": "Rapid symptom benefit was reported; some late effects were secondary outcomes and anxiety required care in some participants.",
      "limit": "Endpoint hierarchy and follow-up attrition must remain visible in durability claims.",
      "historical_anchor_only": false
    },
    {
      "year": "2026",
      "source_id": "P42457666",
      "design": "Human SV2A PET before/after dosing",
      "finding": "The report found no significant overall synaptic-density increase; setting-related differences were observed.",
      "limit": "Small context-dependent before/after study is not a randomized mediator test or universal absence of plasticity.",
      "historical_anchor_only": false
    }
  ],
  "gaps": [
    {
      "id": "G1",
      "question": "Does structural plasticity mediate human clinical benefit?",
      "source_ids": [
        "P34228959",
        "P40175553",
        "P41224969",
        "P42457666"
      ],
      "alternative": "Functional adaptation or support-related learning may matter without increased synaptic density.",
      "discriminating_test": "Randomized clinical studies with time-ordered orthogonal plasticity measures, functional readouts and symptoms; complement with selective mediator perturbation in models.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G2",
      "question": "Which component is drug action versus expectancy and support?",
      "source_ids": [
        "P27210031",
        "P33852780",
        "P37651119"
      ],
      "alternative": "Acute subjective effects can reveal allocation and modify learning or clinician interactions.",
      "discriminating_test": "Prespecified masking assessment, credible comparators and standardized support; where feasible compare support components while retaining treatment fidelity.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G3",
      "question": "Which receptor/cell dependency translates to humans?",
      "source_ids": [
        "P40175553",
        "P42457666",
        "P34228959"
      ],
      "alternative": "A mouse cell-type dependency may reflect acute excitability rather than the proposed human repair mechanism.",
      "discriminating_test": "Independent model replication with acute versus delayed interventions and human target-engagement measures; separate receptor necessity from mediator necessity.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G4",
      "question": "How durable are benefits and who is harmed or fails to respond?",
      "source_ids": [
        "P36322843",
        "P42138922",
        "P37651119",
        "P33852780"
      ],
      "alternative": "Selected samples, retreatment, added care or dropout can shape follow-up effects.",
      "discriminating_test": "Longer blinded follow-up with predefined relapse, retreatment, co-interventions and adverse-event ascertainment; prespecified subgroup interactions.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    }
  ],
  "source_cards": [
    {
      "id": "P27210031",
      "pmid": "27210031",
      "doi": "10.1016/S2215-0366(16)30065-7",
      "title": "Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27210031/",
      "issue_year": "2016",
      "electronic_date": "2016-05-17",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Clinical Trial",
        "Journal Article"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P33852780",
      "pmid": "33852780",
      "doi": "10.1056/NEJMoa2032994",
      "title": "Trial of Psilocybin versus Escitalopram for Depression.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33852780/",
      "issue_year": "2021",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Clinical Trial, Phase II",
        "Comparative Study",
        "Journal Article",
        "Randomized Controlled Trial",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P34228959",
      "pmid": "34228959",
      "doi": "10.1016/j.neuron.2021.06.008",
      "title": "Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34228959/",
      "issue_year": "2021",
      "electronic_date": "2021-07-05",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, N.I.H., Extramural",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P36322843",
      "pmid": "36322843",
      "doi": "10.1056/NEJMoa2206443",
      "title": "Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36322843/",
      "issue_year": "2022",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Clinical Trial, Phase II",
        "Journal Article",
        "Randomized Controlled Trial",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P37651119",
      "pmid": "37651119",
      "doi": "10.1001/jama.2023.14530",
      "title": "Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37651119/",
      "issue_year": "2023",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [
        {
          "type": "ErratumIn",
          "pmid": "38277159",
          "note": ""
        }
      ],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_partial",
      "complete_paper_examined_in_this_update": false,
      "notice_check_scope": "Linked notice presence was checked in the primary record; its scientific impact was not verified in this update."
    },
    {
      "id": "P40175553",
      "pmid": "40175553",
      "doi": "10.1038/s41586-025-08813-6",
      "title": "Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40175553/",
      "issue_year": "2025",
      "electronic_date": "2025-04-02",
      "access_depth": "full_text_partial",
      "checked_details": "Main P12 and statistical Methods P62: cell-type-specific chemogenetic silencing with control virus/ligand timing, and receptor-knockout structural comparisons. This does not isolate structural plasticity as the human mediator.",
      "publication_types": [
        "Journal Article",
        "Research Support, N.I.H., Extramural"
      ],
      "correction_notices": [
        {
          "type": "ErratumIn",
          "pmid": "41023408",
          "note": ""
        }
      ],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_partial",
      "complete_paper_examined_in_this_update": false,
      "notice_check_scope": "Linked notice presence was checked in the primary record; its scientific impact was not verified in this update."
    },
    {
      "id": "P41224969",
      "pmid": "41224969",
      "doi": "10.1038/s41386-025-02272-3",
      "title": "Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41224969/",
      "issue_year": "2026",
      "electronic_date": "2025-11-13",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P42457666",
      "pmid": "42457666",
      "doi": "10.1038/s41398-026-04285-y",
      "title": "Psilocybin's effect on human brain synaptic plasticity.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42457666/",
      "issue_year": "2026",
      "electronic_date": "2026-07-15",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_partial",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P42138922",
      "pmid": "42138922",
      "doi": "10.1001/jamanetworkopen.2026.12589",
      "title": "Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression: A Randomized Clinical Trial.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42138922/",
      "issue_year": "2026",
      "electronic_date": "2026-05-01",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Randomized Controlled Trial",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    }
  ],
  "access_counts": {
    "full_text_partial": 1,
    "abstract_excerpt_checked": 8,
    "metadata_only": 0
  },
  "browser_messages": 2,
  "targeted_check": {
    "pmid": "40175553",
    "provider_access": "selected primary full-text passages reported by Consensus",
    "independent_primary_body_crosscheck": true,
    "verification_scope": "Main P12 and statistical Methods P62: cell-type-specific chemogenetic silencing with control virus/ligand timing, and receptor-knockout structural comparisons. This does not isolate structural plasticity as the human mediator."
  },
  "editorial_warning": "Primary source 37 reports a nonsignificant overall SV2A result. Positive setting-related comparisons must not replace that overall finding. The 2025 mouse study carries a correction notice.",
  "reading_limit": "This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.",
  "method": "Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected."
}