{
  "$schema_version": "5.3",
  "review_mode": "fresh",
  "claim_restatement": {
    "index_wording": "Repeated subperceptual LSD microdosing improves depression and anxiety symptoms in adults.",
    "entry_form": "claim",
    "gradeable_restatement": "Repeated subperceptual LSD microdosing improves depression and anxiety symptoms in adults.",
    "restatement_required": true,
    "split_into": [],
    "parent_claim": null,
    "scope_qualifiers": [
      {
        "qualifier": "Baseline diagnosis, symptom severity, medication, dose formulation, duration, clinical setting and comparator fixed before outcomes",
        "determinable_before_outcome": true,
        "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.",
        "action": "retained"
      }
    ]
  },
  "hypothesis": {
    "name": "Psychedelic Microdosing and Mental Health",
    "central_claim": "Repeated subperceptual LSD microdosing improves depression and anxiety symptoms in adults.",
    "proposed_mechanism": "Repeated subperceptual LSD microdosing improves depression and anxiety symptoms in adults.",
    "claimed_scope": "Adults with baseline depression/anxiety symptoms measured before treatment; LSD base-equivalent 5–20 micrograms per administration, repeated 4–12 weeks; acute pharmacodynamics, full-dose psychotherapy and ketamine distinguished",
    "claimed_level": [
      "response"
    ],
    "is_conjunctive": false,
    "conjunctive_note": "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint."
  },
  "rubric_routing": {
    "primary_rubric": "07-psychiatry-neuromodulation.md",
    "secondary_rubrics": [],
    "index_notes_applied": [
      "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint."
    ],
    "rubric_fit_note": "Frozen psychiatric rubric 07 governs all scored psychiatric subclaims. Acute drug action is a verified descriptive/experimental finding, distinguished from persistent clinical efficacy. Its literal acute-pharmacodynamic cap and clinical Δ comparator requirements are preserved; no adaptation waives them. SC4 is an untested cross-regimen equivalence claim, not an omnibus grade of full-dose treatment. Dose units use verified LSD base equivalence."
  },
  "subclaim_matrix": {
    "subclaims": [
      {
        "id": "SC1",
        "statement": "LSD microdoses produce measurable pharmacodynamic effects.",
        "subclaim_type": "mechanism",
        "scope": "LSD 5-20 micrograms per administration; repeated schedules and perception measured",
        "claimed_scope": "LSD 5-20 micrograms per administration; repeated schedules and perception measured",
        "governing_rubric": "07-psychiatry-neuromodulation.md",
        "key_evidence_anchor": "Controlled dose and expectancy assessment",
        "hsef_level": "Γ",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Randomized low-dose human LSD exposure demonstrates real acute pharmacodynamic effects, including objective plasma/neural/task measures. That observation is retained explicitly. The frozen psychiatric rubric requires a credible active comparator and preregistered primary outcome for its Δ threshold and applies an acute-pharmacodynamic cap where symptom trajectory is not established. These acute studies do not satisfy that psychiatric therapeutic threshold; SC1 is therefore Γ under rubric 07, rather than receiving a comparator-waiving adaptation. This grade does not deny experimentally induced acute drug action.",
        "rubric_adaptation": "Verified acute causal drug action is described explicitly, while the rubric-specific psychiatric treatment ladder remains Γ until its controlled comparator and symptom-trajectory threshold is met."
      },
      {
        "id": "SC2",
        "statement": "Repeated microdoses improve sustained depression or anxiety symptom trajectories against a credible comparator.",
        "subclaim_type": "sufficiency",
        "scope": "Adults with baseline symptoms measured; 4-12 weeks; subperceptual LSD separated from full-dose treatment",
        "claimed_scope": "Adults with baseline symptoms measured; 4-12 weeks; subperceptual LSD separated from full-dose treatment",
        "governing_rubric": "07-psychiatry-neuromodulation.md",
        "key_evidence_anchor": "Controlled prospective blinded symptom outcomes",
        "hsef_level": "Γ",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Direct eight-week MDD open-label improvement is important positive exploratory support. Consensus additionally identified a real 2026 original conference outcome abstract: a triple-masked LSD versus caffeine MDD trial did not show primary MADRS superiority. That clinical null strengthens the concern about treatment attribution; absent full trial methods and imprecise estimates prevent a definitive zero-effect conclusion. No positive same-scope field-valid therapeutic crossing is verified; Γ remains.",
        "rubric_adaptation": "Measured symptom trajectory is the registered endpoint; do not demand functional recovery for a symptom claim or convert rating scales into functional recovery. Comparator credibility, blinding integrity and baseline symptom scope still bind."
      },
      {
        "id": "SC3",
        "statement": "Effects survive measured expectancy and allocation guessing.",
        "subclaim_type": "mechanism",
        "scope": "Baseline expectancy and participant/rater guesses measured",
        "claimed_scope": "Baseline expectancy and participant/rater guesses measured",
        "governing_rubric": "07-psychiatry-neuromodulation.md",
        "key_evidence_anchor": "Blinding-integrity and active-comparator tests",
        "hsef_level": "Γ",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Baseline-expectancy adjustment can leave dose-day effects, while actual allocation guesses predict or explain several subjective outcomes. These observations do not manipulate expectancy independently, and null clinical comparisons do not become positive drug-efficacy crossings. A restricted psilocybin creativity result survives guess adjustment; it does not prove durable LSD depression benefit beyond expectancy.",
        "rubric_adaptation": "Baseline expectancy, postdose guesses and manipulated expectancy are distinct; covariate adjustment for a posttreatment variable can remove genuine drug information as well as bias."
      },
      {
        "id": "SC4",
        "statement": "Microdosing effects generalize to full-dose psychedelics or ketamine clinical treatments.",
        "subclaim_type": "generalization",
        "scope": "Drug, dose, diagnosis and psychotherapeutic support separated",
        "claimed_scope": "Drug, dose, diagnosis and psychotherapeutic support separated",
        "governing_rubric": "07-psychiatry-neuromodulation.md",
        "key_evidence_anchor": "Direct regimen-specific comparisons",
        "hsef_level": "Α",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Different full-dose psilocybin and ketamine trials have genuine clinical positives, primary nulls and selected mechanistic perturbations. No direct matched comparison shows that subperceptual LSD benefits generalize to those treatment packages. The proposed equivalence is narrative atΑ; this is not a grade of the efficacy of all full-dose or ketamine treatment.",
        "rubric_adaptation": "Compare compound, dose, diagnosis, support and time horizon explicitly; no direct efficacy equivalence is inferred from a shared psychedelic label."
      }
    ],
    "aggregation_rule": "primary-subclaim",
    "aggregation_preregistered": true,
    "aggregation_rationale": "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint.",
    "primary_subclaim_id": "SC2",
    "aggregation_derivation": "Primary-subclaim aggregation returns SC2 Γ. Controlled acute drug action and direct exploratory MDD improvement provide partial support, while a now verified masked clinical conference report is primary-null. Neither healthy nulls nor a single imprecise conference result establish universal inefficacy, and the open-label positive cannot override the clinical comparator. Full-dose and ketamine results retain their actual scopes.",
    "aggregation_alternatives": {
      "weakest_link_would_return": "Α",
      "primary_subclaim_would_return": "Γ",
      "scope_matched_would_return": "Γ",
      "note": "Separate narrow successes do not replace the preregistered full-scope gate."
    },
    "index_rule_deviation": ""
  },
  "competing_models": {
    "models_evaluated": [
      {
        "rank_in_tournament": 1,
        "model_id": "M3",
        "is_nominal": false,
        "name": "Measurable low-dose pharmacology without established lasting treatment",
        "core_claim": "Low doses produce causal pharmacodynamic changes while persistent clinical benefit remains a separate prediction.",
        "explains_what_nominal_does_not": "Low doses produce causal pharmacodynamic changes while persistent clinical benefit remains a separate prediction.",
        "strongest_supporting_evidence": [
          "Dose/PK32975835, interval-task 30478716 and neural 34613430 contrasts demonstrate real action; six-week 36997080 separates dose-day effects from pre/postnull."
        ],
        "strongest_contradictory_evidence": [
          "This descriptive restricted model does not establish why 19 open-label MDD participants improved, nor rule out a future symptomatic benefit."
        ],
        "hsef_level_for_this_model": "Δ",
        "rationale": "Dose/PK32975835, interval-task 30478716 and neural 34613430 contrasts demonstrate real action; six-week 36997080 separates dose-day effects from pre/postnull. This descriptive restricted model does not establish why 19 open-label MDD participants improved, nor rule out a future symptomatic benefit."
      },
      {
        "rank_in_tournament": 2,
        "model_id": "M4",
        "is_nominal": false,
        "name": "Different regimens have distinct clinical effects",
        "core_claim": "Full-dose psychedelic andketamine treatments have their own comparator-specific evidence and mechanisms.",
        "explains_what_nominal_does_not": "Full-dose psychedelic andketamine treatments have their own comparator-specific evidence and mechanisms.",
        "strongest_supporting_evidence": [
          "Actual naltrexone perturbation 40707608 narrows an acute ketamine dependency;active-controlled 23982301 andwithdrawal 31166571 have clinical positives."
        ],
        "strongest_contradictory_evidence": [
          "Full-dose psilocybin 33852780/41848690 have primary nulls and unblinding concerns; neither positives nor nulls establish LSDmicrodose equivalence."
        ],
        "hsef_level_for_this_model": "Δ",
        "rationale": "Actual naltrexone perturbation 40707608 narrows an acute ketamine dependency;active-controlled 23982301 andwithdrawal 31166571 have clinical positives. Full-dose psilocybin 33852780/41848690 have primary nulls and unblinding concerns; neither positives nor nulls establish LSDmicrodose equivalence."
      },
      {
        "rank_in_tournament": 3,
        "model_id": "M1",
        "is_nominal": true,
        "name": "Microdose pharmacology improves persistent symptoms",
        "core_claim": "Repeated low-dose LSD causes sustained depression/anxiety relief.",
        "explains_what_nominal_does_not": "Repeated low-dose LSD causes sustained depression/anxiety relief.",
        "strongest_supporting_evidence": [
          "Direct 8-week MDD41202873 shows substantial persistent symptom decline, supported by real drug action and restricted 48 hour highBDI38042914 positive."
        ],
        "strongest_contradictory_evidence": [
          "Matched open-label clinical improvement lacks a comparator and most continued antidepressants. A verified triple-masked LSD-versus-caffeine MDD conference report is primary-null; healthy controlled findings also lack sustained gains. Its missing full report and imprecision preclude definitive refutation."
        ],
        "hsef_level_for_this_model": "Γ",
        "rationale": "Direct 8-week MDD41202873 shows substantial persistent symptom decline, supported by real drug action and restricted 48 hour highBDI38042914 positive. Matched open-label clinical improvement lacks a comparator and most continued antidepressants. A verified triple-masked LSD-versus-caffeine MDD conference report is primary-null; healthy controlled findings also lack sustained gains. Its missing full report and imprecision preclude definitive refutation."
      },
      {
        "rank_in_tournament": 4,
        "model_id": "M2",
        "is_nominal": false,
        "name": "Expectancy and allocation recognition explain apparent benefit",
        "core_claim": "Belief and recognized drug effects contribute to symptom reports independently of assigned microdose.",
        "explains_what_nominal_does_not": "Belief and recognized drug effects contribute to symptom reports independently of assigned microdose.",
        "strongest_supporting_evidence": [
          "Prospective expectancy and actual guess analyses associate belief with improvement; the newly verified masked MDD conference null narrows the pharmacologic treatment claim."
        ],
        "strongest_contradictory_evidence": [
          "Expectancy was not independently randomized; objectively measured drug effects and creative task 41187880 positive are not erased. All-benefit-is-placebo is not proven."
        ],
        "hsef_level_for_this_model": "Β",
        "rationale": "Prospective expectancy and actual guess analyses associate belief with improvement; the newly verified masked MDD conference null narrows the pharmacologic treatment claim. Expectancy was not independently randomized; objectively measured drug effects and creative task 41187880 positive are not erased. All-benefit-is-placebo is not proven."
      }
    ],
    "tournament_summary": "Descriptive comparison; does not modify the nominal score. Self-blinding 33648632 holds actual condition and guesses in separate analyses, while six-week home LSD36997080 separates dose-day mood from persistent pre/post change. Open-label diagnosed-MDD41202873 is the crucial unisolated clinical positive. Different drug mediator perturbation 40707608 does not settle that positive.",
    "study_separating_rank1_from_rank2": "Self-blinding 33648632 holds actual condition and guesses in separate analyses, while six-week home LSD36997080 separates dose-day mood from persistent pre/post change. Open-label diagnosed-MDD41202873 is the crucial unisolated clinical positive. Different drug mediator perturbation 40707608 does not settle that positive.",
    "nominal_wins_only_by_funding_artifact": false,
    "level_unchanged_by_tournament": true
  },
  "evidence_inventory": [
    {
      "n": 1,
      "pmid": "33648632",
      "title": "Self-blinding citizen science to explore psychedelic microdosing.",
      "citation": "Szigeti B, Kartner L, Blemings A et al. Self-blinding citizen science to explore psychedelic microdosing. eLife. 2021.",
      "doi": "10.7554/eLife.62878",
      "pmcid": "PMC7925122",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33648632/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33648632/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID33648632",
      "access_depth": "full_text_partial",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph7, 1:Materials and methods:paragraph12, 1:Materials and methods:paragraph14, 1:Materials and methods:paragraph16, 1:Materials and methods:paragraph19, 1:Materials and methods:paragraph21, 1:Materials and methods:paragraph23, 2:Results:paragraph0, 2:Results:paragraph3, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph14, 2:Results:paragraph17, 2:Results:paragraph18. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "null",
      "what_it_shows": "In 191 self-blinding citizen participants, psychological outcomes improved over four weeks in both microdose and placebo groups without significant between-group differences; small acute/post-acute differences were explained by blind breaking.",
      "what_it_does_not_show": "Self-supplied drugs and dosing without clinical supervision; mixture of psychedelics and self-selection limit precise LSD exposure and diagnosed-MDD inference. Null differences are not proof of exact equivalence or all benefit being placebo.",
      "confounders_present": [
        "Self-supplied drugs and dosing without clinical supervision; mixture of psychedelics and self-selection limit precise LSD exposure and diagnosed-MDD inference. Null differences are not proof of exact equivalence or all benefit being placebo."
      ],
      "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": []
      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 2,
      "pmid": "32842825",
      "title": "A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers.",
      "citation": "Ramaekers JG, Hutten N, Mason NL et al. A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. Journal of psychopharmacology (Oxford, England). 2021.",
      "doi": "10.1177/0269881120940937",
      "pmcid": "PMC8054163",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32842825/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32842825/",
      "tier": "A",
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      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID32842825",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Twenty-four healthy volunteers received placebo and LSD5/10/20 micrograms;20 micrograms increased cold-pain tolerance and decreased pain/unpleasantness while increasing BP and selected dissociation/anxiety ratings.",
      "what_it_does_not_show": "Single administrations and evoked pain, not 4–12 week depression/anxiety treatment. Acute anxiety can increase; low dose is not necessarily imperceptible.",
      "confounders_present": [
        "Single administrations and evoked pain, not 4–12 week depression/anxiety treatment. Acute anxiety can increase; low dose is not necessarily imperceptible."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      "decisive_test_note": "",
      "shared_components": []
    },
    {
      "n": 3,
      "pmid": "34613430",
      "title": "Low doses of LSD reduce broadband oscillatory power and modulate event-related potentials in healthy adults.",
      "citation": "Murray CH, Tare I, Perry CM et al. Low doses of LSD reduce broadband oscillatory power and modulate event-related potentials in healthy adults. Psychopharmacology. 2022.",
      "doi": "10.1007/s00213-021-05991-9",
      "pmcid": "PMC9847217",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34613430/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34613430/",
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      "opened_on": "2026-10-13",
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      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Twenty-two healthy participants showed dose-related resting EEG power and ERP changes with LSD13/26 micrograms, together with positive mood and anxiety effects; subjective changes did not correlate with EEG.",
      "what_it_does_not_show": "Acute biomarkers and tartrate/base formulation requiring explicit equivalence; no persistent clinical symptom endpoint or mediator manipulation.",
      "confounders_present": [
        "Acute biomarkers and tartrate/base formulation requiring explicit equivalence; no persistent clinical symptom endpoint or mediator manipulation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 4,
      "pmid": "38042914",
      "title": "Greater subjective effects of a low dose of LSD in participants with depressed mood.",
      "citation": "Molla H, Lee R, Tare I et al. Greater subjective effects of a low dose of LSD in participants with depressed mood. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2024.",
      "doi": "10.1038/s41386-023-01772-4",
      "pmcid": "PMC10948752",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38042914/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38042914/",
      "tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "39-person-depressed-mood-LSD-crossover",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Crossover LSD26 micrograms versus placebo in 39 participants found greater acute positive effects and 48-hour BDI decline in 20 participants with high baseline BDI.",
      "what_it_does_not_show": "Dose formulation must distinguish tartrate/base; one dose and 48 hours are not repeated 4–12 week treatment. More pronounced subjective effects threaten blind and high BDI is not a diagnosed-MDD treatment sample.",
      "confounders_present": [
        "Dose formulation must distinguish tartrate/base; one dose and 48 hours are not repeated 4–12 week treatment. More pronounced subjective effects threaten blind and high BDI is not a diagnosed-MDD treatment sample."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 5,
      "pmid": "31331617",
      "title": "Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers.",
      "citation": "Bershad AK, Schepers ST, Bremmer MP et al. Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers. Biological psychiatry. 2019.",
      "doi": "10.1016/j.biopsych.2019.05.019",
      "pmcid": "PMC6814527",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31331617/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31331617/",
      "tier": "A",
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      "relates_to_subclaims": [
        "SC1",
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Twenty healthy adults received 0/6.5/13/26 micrograms in randomized sessions; orderly subjective effects occurred, with vigor increase at highest dose but most mood/cognition unchanged.",
      "what_it_does_not_show": "Single-dose healthy population; no sustained symptomatic cohort endpoint and perceptibility varies by dose.",
      "confounders_present": [
        "Single-dose healthy population; no sustained symptomatic cohort endpoint and perceptibility varies by dose."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 6,
      "pmid": "42322409",
      "title": "Effects of repeated low-dose LSD on neuropsychological functioning in adults with ADHD: a randomized placebo-controlled study.",
      "citation": "Haijen-Bongers ECHM, Hurks PPM, Schepers J et al. Effects of repeated low-dose LSD on neuropsychological functioning in adults with ADHD: a randomized placebo-controlled study. Psychopharmacology. 2026.",
      "doi": "10.1007/s00213-026-07107-7",
      "pmcid": "",
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      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "NCT05200936",
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      "relates_to_subclaims": [
        "SC1",
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      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Secondary NCT05200936 ADHD analysis after six weeks 20 micrograms twice weekly found a time-reproduction effect but no broad cognitive benefit and no corresponding parent clinical symptom benefit.",
      "what_it_does_not_show": "Shares parent 40105807 allocation; ADHD cognition is a diagnosis/endpoint boundary rather than independent depression RCT. Exploratory predictors and one task do not establish general cumulative efficacy.",
      "confounders_present": [
        "Shares parent 40105807 allocation; ADHD cognition is a diagnosis/endpoint boundary rather than independent depression RCT. Exploratory predictors and one task do not establish general cumulative efficacy."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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      "decisive_test_note": "",
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    },
    {
      "n": 7,
      "pmid": "32033922",
      "title": "Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity.",
      "citation": "Bershad AK, Preller KH, Lee R et al. Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity. Biological psychiatry. Cognitive neuroscience and neuroimaging. 2020.",
      "doi": "10.1016/j.bpsc.2019.12.007",
      "pmcid": "PMC7150630",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32033922/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32033922/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID32033922",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Twenty healthy participants showed amygdala connectivity changes after 13 micrograms; positive mood correlated with connectivity amid weak variable mood effects.",
      "what_it_does_not_show": "Single-dose imaging and observational mediator correlation cannot establish sustained therapy or that connectivity is required for benefit.",
      "confounders_present": [
        "Single-dose imaging and observational mediator correlation cannot establish sustained therapy or that connectivity is required for benefit."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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    {
      "n": 8,
      "pmid": "40659913",
      "title": "Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety: a randomized, double-blind, placebo-controlled study.",
      "citation": "Bistue Millón MB, Noguera L, Bruno D et al. Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety: a randomized, double-blind, placebo-controlled study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2025.",
      "doi": "10.1038/s41386-025-02167-3",
      "pmcid": "PMC12436647",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40659913/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40659913/",
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      "source_tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID40659913",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Four-week placebo-controlled sublingual 5-Me O-DMT dose study in symptomatic adults reports pharmacokinetics, EEG modulation and tolerability without formal psychiatric diagnosis.",
      "what_it_does_not_show": "Different compound and formulation, safety-focused Phase I; abstract provides no convincing controlled sustained symptom efficacy estimate or sample size. Promotional therapeutic conclusion exceeds reported outcomes.",
      "confounders_present": [
        "Different compound and formulation, safety-focused Phase I; abstract provides no convincing controlled sustained symptom efficacy estimate or sample size. Promotional therapeutic conclusion exceeds reported outcomes."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "notable_contrasting_statements": []
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      "decisive_test_note": "",
      "shared_components": []
    },
    {
      "n": 9,
      "pmid": "41110634",
      "title": "Cognitive and subjective effects of psilocybin microdosing: Results from two double-blind placebo-controlled longitudinal trials.",
      "citation": "Prochazkova L, Marschall J, Lippelt DP et al. Cognitive and subjective effects of psilocybin microdosing: Results from two double-blind placebo-controlled longitudinal trials. Neuropharmacology. 2026.",
      "doi": "10.1016/j.neuropharm.2025.110722",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41110634/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41110634/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID41110634",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "null",
      "what_it_shows": "Two longitudinal placebo-controlled psilocybin-truffle trials found no corrected cognitive or emotional benefit, while participants reportedly remained effectively blinded.",
      "what_it_does_not_show": "Different drug and dose units; full Methods needed for precise blinding/sample assessment. Healthy/seminaturalistic findings bound general microdosing narratives without proving no diagnosed-MDD LSD benefit.",
      "confounders_present": [
        "Different drug and dose units; full Methods needed for precise blinding/sample assessment. Healthy/seminaturalistic findings bound general microdosing narratives without proving no diagnosed-MDD LSD benefit."
      ],
      "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": []
      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 10,
      "pmid": "38622150",
      "title": "LSD increases sleep duration the night after microdosing.",
      "citation": "Allen N, Jeremiah A, Murphy R et al. LSD increases sleep duration the night after microdosing. Translational psychiatry. 2024.",
      "doi": "10.1038/s41398-024-02900-4",
      "pmcid": "PMC11018829",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38622150/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38622150/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "ACTRN12621000436875",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Eighty healthy men randomized to 10 micrograms LSD every third day for six weeks had 24.3 more tracker-measured sleep minutes on the night after dosing;3231 nights are repeated observations.",
      "what_it_does_not_show": "Same parent trial 36997080; wearable sleep estimate is not polysomnography or depression/anxiety trajectory. Objective effect cannot establish proposed symptom benefit or exclude every expectancy-related behavior.",
      "confounders_present": [
        "Same parent trial 36997080; wearable sleep estimate is not polysomnography or depression/anxiety trajectory. Objective effect cannot establish proposed symptom benefit or exclude every expectancy-related behavior."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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      "decisive_test_note": "",
      "shared_components": []
    },
    {
      "n": 11,
      "pmid": "34915762",
      "title": "Psilocybin microdosing does not affect emotion-related symptoms and processing: A preregistered field and lab-based study.",
      "citation": "Marschall J, Fejer G, Lempe P et al. Psilocybin microdosing does not affect emotion-related symptoms and processing: A preregistered field and lab-based study. Journal of psychopharmacology (Oxford, England). 2022.",
      "doi": "10.1177/02698811211050556",
      "pmcid": "PMC8801668",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34915762/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34915762/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
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      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID34915762",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "null",
      "what_it_shows": "Preregistered three-week psilocybin microdose crossover found no confirmatory depression/anxiety or emotion-processing improvement; both baseline reductions and second-block blind breaking were reported.",
      "what_it_does_not_show": "Different drug and shorter-than-registered duration; no strong clinically depressed sample. Null clinical result is not positive threshold crossing or universal absence.",
      "confounders_present": [
        "Different drug and shorter-than-registered duration; no strong clinically depressed sample. Null clinical result is not positive threshold crossing or universal absence."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "notable_contrasting_statements": []
      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 12,
      "pmid": "36997080",
      "title": "Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.",
      "citation": "Murphy RJ, Sumner R, Evans W et al. Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial. Biological psychiatry. 2023.",
      "doi": "10.1016/j.biopsych.2023.03.013",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36997080/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36997080/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
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      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "ACTRN12621000436875",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Eighty healthy men randomized to 10 micrograms every third day for six weeks had transient dose-day mood/energy positives surviving baseline-expectancy adjustment, but no credible pre/post mood or cognition improvement;four active withdrawals for anxiety.",
      "what_it_does_not_show": "Inactive placebo and dose-day perceptibility remain; adjustment for baseline expectancy does not remove postdose allocation recognition. Healthy men limit clinical/general-sex scope; transient improvement differs from durable symptom treatment.",
      "confounders_present": [
        "Inactive placebo and dose-day perceptibility remain; adjustment for baseline expectancy does not remove postdose allocation recognition. Healthy men limit clinical/general-sex scope; transient improvement differs from durable symptom treatment."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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      },
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      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
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    },
    {
      "n": 13,
      "pmid": "41529826",
      "title": "Reward-related neural activity after low doses of LSD in participants with depressed mood.",
      "citation": "Glazer J, Molla H, Lee R et al. Reward-related neural activity after low doses of LSD in participants with depressed mood. Journal of psychopharmacology (Oxford, England). 2026.",
      "doi": "10.1177/02698811251405686",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41529826/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41529826/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "39-person-depressed-mood-LSD-crossover",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Secondary 39-person 26 microgram crossover report finds reward ERP effects associated with acute mood and 48-hour BDI changes in higher-BDI participants.",
      "what_it_does_not_show": "Shares 38042914 sample; correlation is not mediated causality, tartrate/base formulation and 48 hours is not 4–12 weeks. Reward physiology cannot replace symptom trajectory.",
      "confounders_present": [
        "Shares 38042914 sample; correlation is not mediated causality, tartrate/base formulation and 48 hours is not 4–12 weeks. Reward physiology cannot replace symptom trajectory."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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    },
    {
      "n": 14,
      "pmid": "30478716",
      "title": "The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial.",
      "citation": "Yanakieva S, Polychroni N, Family N et al. The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial. Psychopharmacology. 2019.",
      "doi": "10.1007/s00213-018-5119-x",
      "pmcid": "PMC6591199",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30478716/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30478716/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "ErratumIn: PMID33089876"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID30478716",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Randomized older-adult 5/10/20 microgram LSD study found altered suprasecond interval timing without robust subjective effects; regression suggested independence from marginal drug ratings.",
      "what_it_does_not_show": "Specific acute task, not depression therapy. Attached erratum 33089876 is metadata only until retrieved; no invented correction details or extra original count.",
      "confounders_present": [
        "Specific acute task, not depression therapy. Attached erratum 33089876 is metadata only until retrieved; no invented correction details or extra original count."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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    {
      "n": 15,
      "pmid": "35918311",
      "title": "Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study.",
      "citation": "Cavanna F, Muller S, de la Fuente LA et al. Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study. Translational psychiatry. 2022.",
      "doi": "10.1038/s41398-022-02039-0",
      "pmcid": "PMC9346139",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35918311/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35918311/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "34-person-psilocybin-mushroom-crossover",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2",
        "SC3",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Thirty-four psilocybin-mushroom microdosers had stronger acute subjective effects only when correctly identifying condition and reduced theta EEG, without wellbeing/cognitive benefit and a few impairment changes.",
      "what_it_does_not_show": "Mushroom 0.5 g and acute/short-term design do not equal LSD5–20 micrograms over 4–12 weeks; blind integrity directly limits therapeutic interpretation.",
      "confounders_present": [
        "Mushroom 0.5 g and acute/short-term design do not equal LSD5–20 micrograms over 4–12 weeks; blind integrity directly limits therapeutic interpretation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
        "mentioning_count": 0,
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        "notable_contrasting_statements": []
      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 16,
      "pmid": "41187880",
      "title": "Microdosing psilocybin and its effect on creativity: Lessons learned from three double-blind placebo controlled longitudinal trials.",
      "citation": "Prochazkova L, Marschall J, van Elk M et al. Microdosing psilocybin and its effect on creativity: Lessons learned from three double-blind placebo controlled longitudinal trials. Neuropharmacology. 2026.",
      "doi": "10.1016/j.neuropharm.2025.110732",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41187880/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41187880/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID41187880",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Three psilocybin-truffle trials pooled 171 participants showed a restricted originality/fluency benefit that survived dose-guess adjustment; most other creativity outcomes were null.",
      "what_it_does_not_show": "One of three preregistered; pooled original experiments, not merely a review. Likely overlaps 41110634 trials and must not count as independent allocations; task quality is not depression/anxiety treatment.",
      "confounders_present": [
        "One of three preregistered; pooled original experiments, not merely a review. Likely overlaps 41110634 trials and must not count as independent allocations; task quality is not depression/anxiety treatment."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": [
        "Three original psilocybin-truffle trials pooled; likely includes the two trials reported 41110634. Exact participant overlap not yet fully verified; no independence credit from report count."
      ]
    },
    {
      "n": 17,
      "pmid": "31778967",
      "title": "Microdosing psychedelics: Motivations, subjective effects and harm reduction.",
      "citation": "Lea T, Amada N, Jungaberle H et al. Microdosing psychedelics: Motivations, subjective effects and harm reduction. The International journal on drug policy. 2020.",
      "doi": "10.1016/j.drugpo.2019.11.008",
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      "what_it_does_not_show": "Self-selected retrospective attribution, mixed drugs and no controlled allocation; narrative users cannot establish efficacy or dose authenticity. Survey may include 16–17 year-olds outside adult scope.",
      "confounders_present": [
        "Self-selected retrospective attribution, mixed drugs and no controlled allocation; narrative users cannot establish efficacy or dose authenticity. Survey may include 16–17 year-olds outside adult scope."
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      "pmid": "31973684",
      "title": "Psychedelic Microdosing: Prevalence and Subjective Effects.",
      "citation": "Cameron LP, Nazarian A, Olson DE. Psychedelic Microdosing: Prevalence and Subjective Effects. Journal of psychoactive drugs. 2020.",
      "doi": "10.1080/02791072.2020.1718250",
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      "what_it_shows": "Anonymous 2347-person survey included 383 microdosing respondents attributing improved mood/anxiety and cognition to the practice.",
      "what_it_does_not_show": "Self-selected attribution and varying denominator; no verified dose, comparator or symptom trajectory. Report count is not evidence of pharmacologic causality.",
      "confounders_present": [
        "Self-selected attribution and varying denominator; no verified dose, comparator or symptom trajectory. Report count is not evidence of pharmacologic causality."
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      "pmid": "32108529",
      "title": "Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities.",
      "citation": "Rosenbaum D, Weissman C, Anderson T et al. Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities. Journal of psychopharmacology (Oxford, England). 2020.",
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      "what_it_shows": "Reddit 909 respondent survey found typical LSD median 13 micrograms and lower reported anxiety-diagnosis odds among microdosers but higher recent recreational drug use.",
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      "confounders_present": [
        "Cross-sectional diagnosis histories, self-selection and concurrent drug differences; temporal direction and causal reduction unestablished. Mainly young male/White sample limits generalization."
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      "n": 20,
      "pmid": "30726251",
      "title": "A systematic study of microdosing psychedelics.",
      "citation": "Polito V, Stevenson RJ. A systematic study of microdosing psychedelics. PloS one. 2019.",
      "doi": "10.1371/journal.pone.0211023",
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      "direction": "mixed",
      "what_it_shows": "Six-week observational 98 microdoser daily series with 63 paired psychometrics reports depression/stress decline and increased neuroticism; dose-day effects mostly lacked residual following-day benefit.",
      "what_it_does_not_show": "Unblinded mixed-drug naturalistic use; separate 263-person expectation survey does not randomize expectancy in the longitudinal participants. Baseline change/regression cannot establish causal sustained therapy.",
      "confounders_present": [
        "Unblinded mixed-drug naturalistic use; separate 263-person expectation survey does not randomize expectancy in the longitudinal participants. Baseline change/regression cannot establish causal sustained therapy."
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      "pmid": "40105807",
      "title": "Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults: A Randomized Clinical Trial.",
      "citation": "Mueller L, Santos de Jesus J, Schmid Y et al. Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults: A Randomized Clinical Trial. JAMA psychiatry. 2025.",
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    {
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      "pmid": "35676541",
      "title": "Natural language signatures of psilocybin microdosing.",
      "citation": "Sanz C, Cavanna F, Muller S et al. Natural language signatures of psilocybin microdosing. Psychopharmacology. 2022.",
      "doi": "10.1007/s00213-022-06170-0",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/35676541/",
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      "what_it_does_not_show": "Shares 35918311 sample/design; acoustic/semantic condition recognition is pharmacodynamic and may facilitate unblinding, not persistent therapy or externally validated predictor.",
      "confounders_present": [
        "Shares 35918311 sample/design; acoustic/semantic condition recognition is pharmacodynamic and may facilitate unblinding, not persistent therapy or externally validated predictor."
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      "n": 23,
      "pmid": "35694791",
      "title": "Psychedelic Microdosing, Mindfulness, and Anxiety: A Cross-Sectional Mediation Study.",
      "citation": "Hartong V, van Emmerik A. Psychedelic Microdosing, Mindfulness, and Anxiety: A Cross-Sectional Mediation Study. Journal of psychoactive drugs. 2023.",
      "doi": "10.1080/02791072.2022.2080616",
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      "evidence_class": "Weak",
      "system": "human observational",
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      "direction": "mixed",
      "what_it_shows": "497 current/former/naive respondents showed lower trait anxiety associated with microdosing and small statistical mindfulness mediation; associations disappeared after excluding prior macrodose users.",
      "what_it_does_not_show": "Cross-sectional self-selection and 386 prior-macrodose exclusions change comparability/power; disappearance does not prove macrodose causality. Observed mediation cannot establish necessity of mindfulness.",
      "confounders_present": [
        "Cross-sectional self-selection and 386 prior-macrodose exclusions change comparability/power; disappearance does not prove macrodose causality. Observed mediation cannot establish necessity of mindfulness."
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    {
      "n": 24,
      "pmid": "31288862",
      "title": "Psychedelic microdosing benefits and challenges: an empirical codebook.",
      "citation": "Anderson T, Petranker R, Christopher A et al. Psychedelic microdosing benefits and challenges: an empirical codebook. Harm reduction journal. 2019.",
      "doi": "10.1186/s12954-019-0308-4",
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      "what_it_shows": "Qualitative 278 microdoser codebook reports improved mood 26.6%, discomfort 18% and anxiety 6.7%, identifying plausible outcomes and harms.",
      "what_it_does_not_show": "Self-attributed experiences and coded-report proportions are not treatment response or incidence estimates; no blinded comparator and mixed drugs.",
      "confounders_present": [
        "Self-attributed experiences and coded-report proportions are not treatment response or incidence estimates; no blinded comparator and mixed drugs."
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      "n": 25,
      "pmid": "41202873",
      "title": "LSD microdosing in major depressive disorder: results from an open-label trial.",
      "citation": "Daldegan-Bueno D, Donegan CJ, Sumner R et al. LSD microdosing in major depressive disorder: results from an open-label trial. Neuropharmacology. 2026.",
      "doi": "10.1016/j.neuropharm.2025.110762",
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      "n": 26,
      "pmid": "36284231",
      "title": "Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity.",
      "citation": "Glazer J, Murray CH, Nusslock R et al. Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2023.",
      "doi": "10.1038/s41386-022-01479-y",
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      "direction": "supports",
      "what_it_shows": "Eighteen healthy adults showed enhanced reward ERP components after 13/26 micrograms versus placebo, mostly not correlated with subjective effects.",
      "what_it_does_not_show": "Acute neural signal without persistent symptoms;tartrate/base formulation and reward mechanism not manipulated. Does not show that ERP produces clinical recovery.",
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        "Acute neural signal without persistent symptoms;tartrate/base formulation and reward mechanism not manipulated. Does not show that ERP produces clinical recovery."
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      "n": 27,
      "pmid": "31152167",
      "title": "Motives and Side-Effects of Microdosing With Psychedelics Among Users.",
      "citation": "Hutten NRPW, Mason NL, Dolder PC et al. Motives and Side-Effects of Microdosing With Psychedelics Among Users. The international journal of neuropsychopharmacology. 2019.",
      "doi": "10.1093/ijnp/pyz029",
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      "favors_models": [],
      "evidence_class": "Weak",
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      "endogenous": false,
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      "what_it_shows": "1116 current/former microdosers reported performance motives, acute psychological negatives and ineffectiveness as the main stop reason;many did not know dose.",
      "what_it_does_not_show": "Self-selected online sample, no verified compounds and retrospective benefit/AE attribution; neither universal safety nor treatment efficacy established.",
      "confounders_present": [
        "Self-selected online sample, no verified compounds and retrospective benefit/AE attribution; neither universal safety nor treatment efficacy established."
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      "decisive_test_note": "",
      "shared_components": []
    },
    {
      "n": 28,
      "pmid": "30925850",
      "title": "Might Microdosing Psychedelics Be Safe and Beneficial? An Initial Exploration.",
      "citation": "Fadiman J, Korb S. Might Microdosing Psychedelics Be Safe and Beneficial? An Initial Exploration. Journal of psychoactive drugs. 2019.",
      "doi": "10.1080/02791072.2019.1593561",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30925850/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30925850/",
      "tier": "A",
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      "status_flags": [
        "none_found"
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      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID30925850",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human observational",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Descriptive international daily PANAS reports from more than 1000 people suggested mood/work/health improvement with repeated microdosing.",
      "what_it_does_not_show": "Uncontrolled reports and uncertain exposure; strong claim of safety across individuals/conditions exceeds ability to detect rare harms or exclude self-selection/regression. Clinical and nonclinical samples not a blinded diagnosis-specific test.",
      "confounders_present": [
        "Uncontrolled reports and uncertain exposure; strong claim of safety across individuals/conditions exceeds ability to detect rare harms or exclude self-selection/regression. Clinical and nonclinical samples not a blinded diagnosis-specific test."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      "decisive_test_note": "",
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    },
    {
      "n": 29,
      "pmid": "30604183",
      "title": "Microdosing psychedelics: personality, mental health, and creativity differences in microdosers.",
      "citation": "Anderson T, Petranker R, Rosenbaum D et al. Microdosing psychedelics: personality, mental health, and creativity differences in microdosers. Psychopharmacology. 2019.",
      "doi": "10.1007/s00213-018-5106-2",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30604183/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30604183/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID30604183",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human observational",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Preregistered online observational comparison reports lower negative emotionality and greater openness/wisdom/creativity among current/former microdosers.",
      "what_it_does_not_show": "Preregistration does not randomize exposure; pre-existing group differences, prior full doses and concurrent behaviors confound benefits. Personality/task differences are not sustained MDD therapy.",
      "confounders_present": [
        "Preregistration does not randomize exposure; pre-existing group differences, prior full doses and concurrent behaviors confound benefits. Personality/task differences are not sustained MDD therapy."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 30,
      "pmid": "33591231",
      "title": "Microdosing psychedelics: Subjective benefits and challenges, substance testing behavior, and the relevance of intention.",
      "citation": "Petranker R, Anderson T, Maier LJ et al. Microdosing psychedelics: Subjective benefits and challenges, substance testing behavior, and the relevance of intention. Journal of psychopharmacology (Oxford, England). 2022.",
      "doi": "10.1177/0269881120953994",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33591231/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33591231/",
      "tier": "A",
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      "kind": "primary",
      "status_flags": [
        "ErratumIn: PMID37226829"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID33591231",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human observational",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "Global Drug Survey 6753 last-year microdosers report perceived benefits and commonly no challenges;most had not tested substances and approach-intention predicted fewer benefits.",
      "what_it_does_not_show": "Survey selection, attribution and unverifiable exposure; absence of reported challenges is not low clinical risk. Attached correction 37226829 metadata only, no assumed result change or primary credit.",
      "confounders_present": [
        "Survey selection, attribution and unverifiable exposure; absence of reported challenges is not low clinical risk. Attached correction 37226829 metadata only, no assumed result change or primary credit."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 31,
      "pmid": "40051483",
      "title": "Low-Dose LSD Alters Early and Late Event-Related Potentials to Emotional Faces.",
      "citation": "Haggarty C, Molla H, Glazer J et al. Low-Dose LSD Alters Early and Late Event-Related Potentials to Emotional Faces. Psychedelic medicine (New Rochelle, N.Y.). 2024.",
      "doi": "10.1089/psymed.2024.0005",
      "pmcid": "PMC11658383",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40051483/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40051483/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
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      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID40051483",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Thirty-nine healthy adults in 26 microgram crossover showed selective neutral/happy-face ERP attenuation.",
      "what_it_does_not_show": "Acute neural interpretation, dose formulation requiring base-equivalence, not sustained symptom therapy; possible related 39-person depressed-mood cohort requires body verification before independent-line credit.",
      "confounders_present": [
        "Acute neural interpretation, dose formulation requiring base-equivalence, not sustained symptom therapy; possible related 39-person depressed-mood cohort requires body verification before independent-line credit."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      },
      "discriminating_contrast": false,
      "decisive_test_note": "",
      "shared_components": [
        "39-person Chicago 26 microgram crossover resembles related depressed-mood reports; exact overlap unresolved, therefore no independent causal-line credit."
      ]
    },
    {
      "n": 32,
      "pmid": "35106880",
      "title": "Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study.",
      "citation": "de Wit H, Molla HM, Bershad A et al. Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study. Addiction biology. 2022.",
      "doi": "10.1111/adb.13143",
      "pmcid": "PMC9731343",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35106880/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35106880/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
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      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID35106880",
      "access_depth": "full_text_partial",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:MATERIALS AND METHODS:paragraph0, 1:MATERIALS AND METHODS:paragraph1, 1:MATERIALS AND METHODS:paragraph3, 1:MATERIALS AND METHODS:paragraph4, 1:MATERIALS AND METHODS:paragraph5, 1:MATERIALS AND METHODS:paragraph6, 1:MATERIALS AND METHODS:paragraph8, 1:MATERIALS AND METHODS:paragraph9, 2:RESULTS:paragraph1, 2:RESULTS:paragraph2, 2:RESULTS:paragraph4, 2:RESULTS:paragraph7, 2:RESULTS:paragraph14, 2:RESULTS:paragraph16, 2:RESULTS:paragraph17. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Fifty-six healthy adults randomized to placebo 13 or 26 micrograms for four doses at 3–4 day intervals showed subjective effects at 26 but no mood/cognition or drug-free residual benefit.",
      "what_it_does_not_show": "Original Methods verify 13/26 micrograms tartrate equals 10/20 base, within dose range; about two-week limited administrations and healthy subjects remain boundaries; does not definitively refute 8-week MDD therapy. Inert placebo with perceptibility demands blinding check.",
      "confounders_present": [
        "Original Methods verify 13/26 micrograms tartrate equals 10/20 base, within dose range; about two-week limited administrations and healthy subjects remain boundaries; does not definitively refute 8-week MDD therapy. Inert placebo with perceptibility demands blinding check."
      ],
      "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": []
      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 33,
      "pmid": "29537989",
      "title": "Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats.",
      "citation": "Horsley RR, Páleníček T, Kolin J et al. Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats. Behavioural pharmacology. 2018.",
      "doi": "10.1097/FBP.0000000000000394",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29537989/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29537989/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID29537989",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "animal model",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Forty male rats intermittently dosed with low psilocin/ketamine had modest/borderline elevated-plus-maze effects tending mildly anxiogenic 48 hours later.",
      "what_it_does_not_show": "Different compounds and rodent anxiety proxy;multiple pairwise testing and small groups. Does not establish human LSD harm or clinical inefficacy.",
      "confounders_present": [
        "Different compounds and rodent anxiety proxy;multiple pairwise testing and small groups. Does not establish human LSD harm or clinical inefficacy."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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    },
    {
      "n": 34,
      "pmid": "40251818",
      "title": "Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.",
      "citation": "Morse JD, Jeong SH, Murphy RJ et al. Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers. Journal of psychopharmacology (Oxford, England). 2025.",
      "doi": "10.1177/02698811251330747",
      "pmcid": "PMC12371133",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40251818/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40251818/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "ACTRN12621000436875",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Eighty-man 10 microgram trial provides plasma PK and small HR/feel-effect responses, no peripheral BDNF alteration;four anxiety withdrawals, two with lower CYP2 D6 activity.",
      "what_it_does_not_show": "Same 36997080 parent;qualitative genotype observation not prospective predictive validation. Peripheral BDNFnull does not deny central plasticity;PK is not clinical efficacy.",
      "confounders_present": [
        "Same 36997080 parent;qualitative genotype observation not prospective predictive validation. Peripheral BDNFnull does not deny central plasticity;PK is not clinical efficacy."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    {
      "n": 35,
      "pmid": "39024488",
      "title": "[Psilocybin fungi microdose treatment in major depressive disorder: a case report].",
      "citation": "Zarankin M, Pellegrini MS, Zenteno F. [Psilocybin fungi microdose treatment in major depressive disorder: a case report]. Vertex (Buenos Aires, Argentina). 2024.",
      "doi": "10.53680/vertex.v35i164.544",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39024488/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39024488/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID39024488",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "Single 19-year-old MDD case reports remission during seven-month psilocybin microdosing accompaniment and conventional-drug withdrawal.",
      "what_it_does_not_show": "One uncontrolled case, different compound and concomitant advice;cannot establish dose-specific therapy, safe medication discontinuation or general response.",
      "confounders_present": [
        "One uncontrolled case, different compound and concomitant advice;cannot establish dose-specific therapy, safe medication discontinuation or general response."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    {
      "n": 36,
      "pmid": "30357434",
      "title": "Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting.",
      "citation": "Prochazkova L, Lippelt DP, Colzato LS et al. Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting. Psychopharmacology. 2018.",
      "doi": "10.1007/s00213-018-5049-7",
      "pmcid": "PMC6267140",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30357434/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30357434/",
      "tier": "A",
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      "kind": "primary",
      "status_flags": [
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      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID30357434",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Nonblinded truffle microdose event shows before/after convergent/divergent task improvement with fluid intelligence unchanged;alkaloids subsequently quantified.",
      "what_it_does_not_show": "No placebo, practice/expectancy effects or clinical symptoms;creativity mechanism speculation does not establish therapeutic efficacy.",
      "confounders_present": [
        "No placebo, practice/expectancy effects or clinical symptoms;creativity mechanism speculation does not establish therapeutic efficacy."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    {
      "n": 37,
      "pmid": "36918852",
      "title": "Experiences of microdosing psychedelics in an attempt to support wellbeing and mental health.",
      "citation": "Ryan RS, Copello A, Fox AP. Experiences of microdosing psychedelics in an attempt to support wellbeing and mental health. BMC psychiatry. 2023.",
      "doi": "10.1186/s12888-023-04628-9",
      "pmcid": "PMC10012542",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36918852/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36918852/",
      "tier": "A",
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      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID36918852",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human observational",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Thirteen anonymous qualitative interviews describe purposeful microdosing and perceived mental-health/cognitive/social benefits.",
      "what_it_does_not_show": "Experiential meaning informs hypotheses but lacks comparator/exposure verification;interpretative themes are not causal evidence or response prevalence.",
      "confounders_present": [
        "Experiential meaning informs hypotheses but lacks comparator/exposure verification;interpretative themes are not causal evidence or response prevalence."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 38,
      "pmid": "39009578",
      "title": "Inter-individual variability in neural response to low doses of LSD.",
      "citation": "Hutten NRPW, Quaedflieg CWEM, Mason NL et al. Inter-individual variability in neural response to low doses of LSD. Translational psychiatry. 2024.",
      "doi": "10.1038/s41398-024-03013-8",
      "pmcid": "PMC11251148",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39009578/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39009578/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID39009578",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Fifty-three healthy participants received 15 micrograms or placebo four times over two weeks;EEG/attention effects and some one-week persistence were baseline-state dependent, while LTPinduction was blunted.",
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      "confounders_present": [
        "Neural adaptation and exploratory moderation are not clinical 4–12 week symptom benefit;subgroup selection must precede outcome, and not all markers improve."
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      "verification": "verified",
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      "pmid": "41789300",
      "title": "Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice.",
      "citation": "Effinger DP, Schalk SS, King JL et al. Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice. ACS pharmacology & translational science. 2025.",
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      "endogenous": false,
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      "what_it_shows": "Chronic low-dose LSD mice showed no detected ventricular/valvular remodeling while serotonin/fenfluramine positive controls had cardiac changes;receptor affinity/potency compared across species.",
      "what_it_does_not_show": "Useful positive-controlled preclinical safety boundary, not rare or years-long human safety. No evidence of remodeling does not establish absence;no clinical depression endpoint.",
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        "Useful positive-controlled preclinical safety boundary, not rare or years-long human safety. No evidence of remodeling does not establish absence;no clinical depression endpoint."
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      "pmid": "33479342",
      "title": "Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing.",
      "citation": "Kaertner LS, Steinborn MB, Kettner H et al. Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing. Scientific reports. 2021.",
      "doi": "10.1038/s41598-021-81446-7",
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      "confounders_present": [
        "No randomized expectancy or treatment;association supports competing explanation but does not prove every pharmacologic effect is placebo. Attrition and mixed exposure constrain interpretation."
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    {
      "n": 41,
      "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",
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      "favors_models": [],
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      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Eleven-site 104 MDD trial 25 mg psilocybin versus 100 mg niacin with support found central MADRSdifference−12.3 atday 43 and disability improvement;more overall/severe AE but no serious treatment-emergent AE.",
      "what_it_does_not_show": "Niacin is side-effect active but not necessarily subjective-experience matched;blinding labels are not reported integrity. Full-dose scaffold differs from LSDmicrodosing. Attached 38277159 correction metadata only.",
      "confounders_present": [
        "Niacin is side-effect active but not necessarily subjective-experience matched;blinding labels are not reported integrity. Full-dose scaffold differs from LSDmicrodosing. Attached 38277159 correction metadata only."
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      "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.",
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      "relates_to_subclaims": [
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      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "EPISODE144 randomized TRDpatients 25 mg versus 5 mg/nicotinamide primaryweek 6 HAMDresponse 17%/12.5%/10.6% failed first hierarchicalcomparison P.19;secondary scale changes exploratory,serious reactions included HPPD.",
      "what_it_does_not_show": "Primary failure cannot be recast as positive crossing from secondarymeans;different full-dose psychotherapy regimen. Trial is inconclusive, not proof zero effect or all full-dose inefficacy.",
      "confounders_present": [
        "Primary failure cannot be recast as positive crossing from secondarymeans;different full-dose psychotherapy regimen. Trial is inconclusive, not proof zero effect or all full-dose inefficacy."
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      "verification": "verified",
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    {
      "n": 43,
      "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/",
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      "favors_models": [],
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      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "COMP360233 TRDparticipants 25/10/1 mg with support showed week 3 patient-reported symptom/function improvements strongest 25 mg.",
      "what_it_does_not_show": "Exploratory secondary outcomes, no active experience-matched comparator and acknowledged functional unblinding. Same allocation as 39706482/39427449;full-dose results cannot validate LSDmicrodose.",
      "confounders_present": [
        "Exploratory secondary outcomes, no active experience-matched comparator and acknowledged functional unblinding. Same allocation as 39706482/39427449;full-dose results cannot validate LSDmicrodose."
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    {
      "n": 44,
      "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",
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      "system": "human interventional",
      "decisive_perturbation": false,
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      "what_it_shows": "Thirty-five life-threatening-illness patients 25 mg psilocybin versusniacin with psychotherapy had 6–7 week depression/anxiety advantages and 26 week persistence.",
      "what_it_does_not_show": "Smallsingle-site and lateropenlabel/allactive extension lose randomizedlongtermcontrast;niacin mismatch andoneanxietywithdrawal. Distinct disease/support scope, not LSDmicrodose efficacy.",
      "confounders_present": [
        "Smallsingle-site and lateropenlabel/allactive extension lose randomizedlongtermcontrast;niacin mismatch andoneanxietywithdrawal. Distinct disease/support scope, not LSDmicrodose efficacy."
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      "verification": "verified",
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      "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",
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      "opened": true,
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      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
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      "endogenous": true,
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      "what_it_shows": "Fifty-nine MDDpatients two 25 mg psilocybin versusescitalopram with 1 mg sessions/support had nonsignificant primary QIDSdifference P.17, while uncorrectedsecondary outcomes favoredpsilocybin.",
      "what_it_does_not_show": "Head-to-head not placebo;smallimpreciseprimaryresult neither establishes equivalence norpsilocybin superiority. Functionalunblinding/supportdrugpackages notisolated.",
      "confounders_present": [
        "Head-to-head not placebo;smallimpreciseprimaryresult neither establishes equivalence norpsilocybin superiority. Functionalunblinding/supportdrugpackages notisolated."
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    {
      "n": 46,
      "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",
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      "opened": true,
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      "study_id": "NCT03181529",
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      "relates_to_subclaims": [
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      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human interventional",
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      "direction": "supports",
      "what_it_shows": "Twenty-seven MDDpatients immediate versuswaitlist two 20/30 mg-per 70 kg psilocybin sessions with 11 hourssupport showedlargeweeks 1/4 scale improvement in 24 completers.",
      "what_it_does_not_show": "Waitlist doesn’tmatchcontact/expectancy, outcomeawareintervention andevaluablepopulation;full-dose package distinct. Correction 33566065 attachedmetadataonly.",
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      "n": 47,
      "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",
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      "evidence_class": "Weak",
      "system": "human interventional",
      "decisive_perturbation": false,
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      "what_it_shows": "Thirtycomplex TRD/MDD/bipolar IIpatients randomizedimmediate versuswaitlist 25 mgwithpsychotherapy showedweek 2 MADRSbenefit;additionaldoses associatedwithfurtherdecline.",
      "what_it_does_not_show": "Unmatchedwaitlist andeventualactive dosing don’tisolatepharmacologyorcausalrepeat-doseincrement;safety/scopeunderpowered. Not LSDmicrodosegeneralization.",
      "confounders_present": [
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      "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.",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/27909165/",
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      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
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      "what_it_shows": "Fifty-onecancer-distresspatients high 22/30 mg versus 1/3 mg-per 70 kg crossover psilocybin showedpersistentclinician/self/community-ratedmoodbenefits andexperience-outcomemediation.",
      "what_it_does_not_show": "Lowdosecomparator maynotmatchacuteexperience;statisticalmysticalmediationnotmanipulation ornecessity. Crossover/alltreatedfollowup andcancerscaffold limittransfer.",
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      "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.",
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      "citation": "Daly EJ, Trivedi MH, Janik A et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA psychiatry. 2019.",
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      "title": "The impact of antidepressant discontinuation prior to treatment with psilocybin for treatment-resistant depression.",
      "citation": "Marwood L, Croal M, Mistry S et al. The impact of antidepressant discontinuation prior to treatment with psilocybin for treatment-resistant depression. Journal of psychiatric research. 2024.",
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        "Discontinuationgroupnotrandomized;cannotgeneralizeallwithdrawalregimensorconcomitantdrugs. Sameparentallocation,notnewreplication orvalidatation LSDwithongoingantidepressants."
      ],
      "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": []
      },
      "discriminating_contrast": false,
      "decisive_test_note": "",
      "shared_components": [
        "Posthoc nonrandomized discontinuation strata withinCOMP360 parent."
      ]
    },
    {
      "n": 60,
      "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": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID34743319",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3",
        "SC4"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Healthy-subjectescitaloprampretreatment crossoverretainedpositive 25 mgpsilocybinmoodwhileattenuatinganxiety/negativecardiovascularresponses;PKunchangedandperipheral BDNFnull.",
      "what_it_does_not_show": "Two-week SSRIpretreatment andacutehealthyfull-doseoutcomenot MDDtreatmentorlongtermmedicationcombination. Experience-qualitymanipulationdoesnotprovenecessityorabsenceofneuroplasticity.",
      "confounders_present": [
        "Two-week SSRIpretreatment andacutehealthyfull-doseoutcomenot MDDtreatmentorlongtermmedicationcombination. Experience-qualitymanipulationdoesnotprovenecessityorabsenceofneuroplasticity."
      ],
      "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": []
      },
      "discriminating_contrast": false,
      "decisive_test_note": "",
      "shared_components": []
    },
    {
      "n": 61,
      "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": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "NCT03775200",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed",
      "what_it_shows": "COMP360 233 TRD patients randomized 25/10/1 mg psilocybin with support had week 3 MADRS difference −6.6 for 25 versus 1 mg;10 mg contrast nonsignificant and sustained week 12 response not supportive.",
      "what_it_does_not_show": "Low-dose control does not ensure experience matching; acute adverse events common and suicidal/self-injury events in all arms. Full-dose primary signal retained without validating LSD microdosing; shared secondary reports grouped.",
      "confounders_present": [
        "Low-dose control does not ensure experience matching; acute adverse events common and suicidal/self-injury events in all arms. Full-dose primary signal retained without validating LSD microdosing; shared secondary reports grouped."
      ],
      "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": []
      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 62,
      "pmid": "32975835",
      "title": "Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants.",
      "citation": "Holze F, Liechti ME, Hutten NRPW et al. Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants. Clinical pharmacology and therapeutics. 2021.",
      "doi": "10.1002/cpt.2057",
      "pmcid": "PMC7984326",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32975835/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32975835/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID32975835",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Twenty-three healthy participants received LSD base 5/10/20 micrograms versusplacebo;PKscaled with dose,5 micrograms subjective-null while 10/20 produced perceptibleeffects and 20 also bad-drug ratings.",
      "what_it_does_not_show": "Acute healthy crossover not persistent therapy;definesdose-dependent perception rather than universal subperceptual threshold. PK/subjectivitynot independently demonstrated clinical mechanism.",
      "confounders_present": [
        "Acute healthy crossover not persistent therapy;definesdose-dependent perception rather than universal subperceptual threshold. PK/subjectivitynot independently demonstrated clinical mechanism."
      ],
      "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": []
      },
      "discriminating_contrast": true,
      "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.",
      "shared_components": []
    },
    {
      "n": 63,
      "pmid": "33860175",
      "title": "Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers.",
      "citation": "Hutten NRPW, Mason NL, Dolder PC et al. Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers. ACS pharmacology & translational science. 2021.",
      "doi": "10.1021/acsptsci.0c00099",
      "pmcid": "PMC8033605",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33860175/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33860175/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID33860175",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "supports",
      "what_it_shows": "Placebo-controlled within-subject 5/10/20 microgram LSD study found selected plasma BDNF rises at 4/6 hours.",
      "what_it_does_not_show": "Circulating BDNFnot direct synaptic plasticity or symptom mediation;time/dose pattern and null 40251818 show marker not uniformly positive. Potential overlap with low-dose healthy studies limits independent causal-line credit.",
      "confounders_present": [
        "Circulating BDNFnot direct synaptic plasticity or symptom mediation;time/dose pattern and null 40251818 show marker not uniformly positive. Potential overlap with low-dose healthy studies limits independent causal-line credit."
      ],
      "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": []
      },
      "discriminating_contrast": false,
      "decisive_test_note": "",
      "shared_components": [
        "Acute low-dose Maastricht blood study may reuse participants from associated PK/pain/neural reports. Separate assays cannot multiply independent causal classes."
      ]
    },
    {
      "n": 64,
      "pmid": "41073618",
      "title": "Daily self-assessment within a regimen of microdosing indicates enhanced psychological functioning on microdosing days relative to non-microdosing days.",
      "citation": "St Pierre M, Argento E, Cates J et al. Daily self-assessment within a regimen of microdosing indicates enhanced psychological functioning on microdosing days relative to non-microdosing days. Psychopharmacology. 2026.",
      "doi": "10.1007/s00213-025-06913-9",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41073618/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41073618/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-13",
      "status_checked_on": "2026-10-13",
      "study_id": "PMID41073618",
      "access_depth": "abstract_metadata",
      "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human observational",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Prospective 1435-adult naturalistic survey found higher self-rated wellbeing/productivity/connectedness/focus on microdosing days versus nondosingdays;previousmacrodoses modifiedcreativity.",
      "what_it_does_not_show": "Within-person unblinded dose scheduling doesnotrandomizeexposure/expectancy;daychanges are not persistent 4–12 weekdepression therapy anddifferent denominators reflectmissingdomainresponses.",
      "confounders_present": [
        "Within-person unblinded dose scheduling doesnotrandomizeexposure/expectancy;daychanges are not persistent 4–12 weekdepression therapy anddifferent denominators reflectmissingdomainresponses."
      ],
      "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": []
      },
      "discriminating_contrast": false,
      "decisive_test_note": "",
      "shared_components": []
    }
  ],
  "verification_summary": {
    "load_bearing_claims_checked": 69,
    "verified": 69,
    "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": "**Open-label rule.** Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.",
      "specific_trigger": "Randomized low-dose human LSD exposure demonstrates real acute pharmacodynamic effects, including objective plasma/neural/task measures. That observation is retained explicitly. The frozen psychiatric rubric requires a credible active comparator and preregistered primary outcome for its Δ threshold and applies an acute-pharmacodynamic cap where symptom trajectory is not established. These acute studies do not satisfy that psychiatric therapeutic threshold; SC1 is therefore Γ under rubric 07, rather than receiving a comparator-waiving adaptation. This grade does not deny experimentally induced acute drug action.",
      "resulting_ceiling": "Γ"
    },
    {
      "subclaim_id": "SC2",
      "cap": "Γ",
      "cap_source": "rubric",
      "triggered": true,
      "trigger_text_quoted": "**Open-label rule.** Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.",
      "specific_trigger": "Direct eight-week MDD open-label improvement is important positive exploratory support. Consensus additionally identified a real 2026 original conference outcome abstract: a triple-masked LSD versus caffeine MDD trial did not show primary MADRS superiority. That clinical null strengthens the concern about treatment attribution; absent full trial methods and imprecise estimates prevent a definitive zero-effect conclusion. No positive same-scope field-valid therapeutic crossing is verified; Γ remains.",
      "resulting_ceiling": "Γ"
    },
    {
      "subclaim_id": "SC3",
      "cap": "Γ",
      "cap_source": "rubric",
      "triggered": true,
      "trigger_text_quoted": "**Mediation-by-correlation rule.** Candidate mediator correlated with outcome, never manipulated.",
      "specific_trigger": "Baseline-expectancy adjustment can leave dose-day effects, while actual allocation guesses predict or explain several subjective outcomes. These observations do not manipulate expectancy independently, and null clinical comparisons do not become positive drug-efficacy crossings. A restricted psilocybin creativity result survives guess adjustment; it does not prove durable LSD depression benefit beyond expectancy.",
      "resulting_ceiling": "Γ"
    }
  ],
  "cap_precedence_resolutions": [
    {
      "collision": "Perturbation in a defined setting versus broader inference",
      "subclaim_scope_cap_binds_on": "Repeated subperceptual LSD microdosing improves depression and anxiety symptoms in adults.",
      "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope",
      "resolution": "The literal psychiatric rubric is retained. Measurable acute drug action is not a clinical therapeutic crossing. Open-label matched-MDD support cannot be promoted by acute assays, healthy participants or different full-dose compounds; controlled clinical nulls are not positive causal crossings.",
      "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": "no",
      "qualifying_evidence_citation": "",
      "gamma_hard_rules_triggered": [
        "Literal rubric-07 acute-pharmacodynamic rule and psychiatric Δ comparator requirement bind the scored inference. Measurable drug effects remain verified findings."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "Randomized low-dose human LSD exposure demonstrates real acute pharmacodynamic effects, including objective plasma/neural/task measures. That observation is retained explicitly. The frozen psychiatric rubric requires a credible active comparator and preregistered primary outcome for its Δ threshold and applies an acute-pharmacodynamic cap where symptom trajectory is not established. These acute studies do not satisfy that psychiatric therapeutic threshold; SC1 is therefore Γ under rubric 07, rather than receiving a comparator-waiving adaptation. This grade does not deny experimentally induced acute drug action.",
      "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": "no",
      "qualifying_evidence_citation": "",
      "gamma_hard_rules_triggered": [
        "Direct matched MDD result 41202873 triggers open-label rule; no same-regimen active-comparator symptomatic positive verified."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "Direct eight-week MDD open-label improvement is important positive exploratory support. Consensus additionally identified a real 2026 original conference outcome abstract: a triple-masked LSD versus caffeine MDD trial did not show primary MADRS superiority. That clinical null strengthens the concern about treatment attribution; absent full trial methods and imprecise estimates prevent a definitive zero-effect conclusion. No positive same-scope field-valid therapeutic crossing is verified; Γ remains.",
      "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": "no",
      "qualifying_evidence_citation": "",
      "gamma_hard_rules_triggered": [
        "Observed expectancy/guess mediation is not manipulated expectancy; base-expectancy-adjusted acute effect does not establish durable relief."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "Baseline-expectancy adjustment can leave dose-day effects, while actual allocation guesses predict or explain several subjective outcomes. These observations do not manipulate expectancy independently, and null clinical comparisons do not become positive drug-efficacy crossings. A restricted psilocybin creativity result survives guess adjustment; it does not prove durable LSD depression benefit beyond expectancy.",
      "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": "no",
      "qualifying_evidence_citation": "",
      "gamma_hard_rules_triggered": [
        "No direct regimen-equivalence experiment; distinct actual clinical results do not qualify this narrative generalization."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "Different full-dose psilocybin and ketamine trials have genuine clinical positives, primary nulls and selected mechanistic perturbations. No direct matched comparison shows that subperceptual LSD benefits generalize to those treatment packages. The proposed equivalence is narrative atΑ; this is not a grade of the efficacy of all full-dose or ketamine treatment.",
      "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": [],
      "what_would_cross_it": "For higher mechanistic attribution, establish low-dose target specificity and link to prespecified relevant trajectories through an independently controlled manipulation rather than marker change alone."
    },
    {
      "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": [],
      "what_would_cross_it": "A prospectively registered4–12week symptomatic-LSD trial with base-equivalent dose, matched active comparator, actual participant/rater guess-confidence measures, clinically meaningful symptom contrast and adequate followup; independent corroboration required for higher rungs."
    },
    {
      "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": [],
      "what_would_cross_it": "Manipulate or independently balance expectancy while retaining drug exposure, with sensorymatching and actual guesses; demonstrate persistent symptom effects surviving the alternative explanation."
    },
    {
      "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": [],
      "what_would_cross_it": "Direct preregistered comparison of exact microdose versus full-dose/ketamine packages on equal baseline diagnosis, care/contact and time horizons, with appropriate blinding and benefit-harm interpretation."
    }
  ],
  "generalization_check": {
    "generalization_tested": "yes",
    "context_boundary_mapped": "yes",
    "internal_negative_controls": "Healthy six-week 10 microgram LSD had no enduring pre/post mood benefit despite transient dose-day effects; ADHD clinical primary null despite perceptible 20 microgram effects; psilocybin micro symptom trials have controlled nulls. PlasmaBDNF is positive in one acute report and null in another, not uniformly validated plasticity. A directly symptomatic masked LSD-versus-caffeine conference outcome report now supplies a primary clinical null, at conference abstract access depth.",
    "note": "Tested acute, healthy, ADHD, psilocybin and clinical MDD comparator findings are explicitly scoped. The clinical masked conference null does not imply that no person or untested regimen could benefit. No verified positive context-specific MDD microdose causal effect is mapped across adults. Full-dose and ketamine clinical experiments are separate."
  },
  "falsification_patterns_met": [
    {
      "pattern": "Outcome tracks guessed allocation or disappears after guess adjustment",
      "evidence": "33648632 self-blinding subjective outcomes; posttreatment adjustment is informative but not definitive proof all benefit is expectancy.",
      "downgrade_applied": false
    },
    {
      "pattern": "Effect fails to separate from a credible active comparator",
      "evidence": "Original Donegan2026 conference outcome abstract reports no primary MADRS superiority over caffeine; precision and full trial/reporting details remain unresolved.",
      "downgrade_applied": false
    }
  ],
  "pitfalls_flagged": [
    {
      "pitfall": "Confirmation by biomarker",
      "where": "EEG, connectivity, rewardERPs, sleep and bloodBDNF are treated as proof of sustained depression/anxiety therapy."
    },
    {
      "pitfall": "Mechanism conflation",
      "where": "LSDbase/tartrate, psilocybin mushroom mass,5-MeO-DMT, full-dose psychotherapy andNMDA-antagonist treatment are interchanged."
    },
    {
      "pitfall": "Missing-control interpretation",
      "where": "Open-label MDD baseline decline becomes a drug-placebo contrast or blind labels become verified integrity."
    },
    {
      "pitfall": "Negative field-valid perturbation read as a crossed threshold",
      "where": "Healthy/ADHD/micro-psilocybin nulls are counted as positive clinical causal support."
    },
    {
      "pitfall": "Replication confused with reproduction",
      "where": "Sleep/PK/primary mood reports of one 80-persontrial andCOMP360 secondary reports are counted as independent studies."
    },
    {
      "pitfall": "Selective generalization",
      "where": "Healthy acute effects, one symptomatic open-label sample, or full-dose clinical efficacy are projected onto all adults/regimens."
    }
  ],
  "causal_tally_audit": {
    "tally_claimed_by_document": 0,
    "tally_after_audit": 0,
    "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.",
    "screened_discriminating_contrasts": 19,
    "items_rejected": [
      "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.",
      "No positive same-scope symptomaticLSD4–12 week credible-active-comparator causal unit is claimed.",
      "Actual acutepharmacodynamics and other-drugclinicalbenefits are preserved within their scopes.",
      "Protocols, comments and corrections earn no original outcome credit; repeatedtrialreports grouped.",
      "Negative designs do not become positive crossings andall-benefit-is-placebo is not established."
    ]
  },
  "steelman": {
    "case_one_rung_higher": "One rung above Δ: directly matched eight-week MDD exploratory improvement and real controlled drug action support a possible pharmacological effect, while healthy-person floor effects can obscure symptom changes. A full matched clinical trial could still find a clinically meaningful effect. The already reported masked clinical null makes this argument less persuasive; its imprecision is not a positive result.",
    "case_one_rung_lower": "One rung belowΒ: the persistent microdose symptom proposition currently rests on uncontrolled self-selection and baseline decline; controlled healthy and related-drug symptom studies often do not reproduce it. A strict endpoint-only reading could classify that evidence as association.",
    "which_rejected": "Δ is not granted because no positive matched clinical perturbation was verified: the open-label improvement lacks causal isolation and the masked conference clinical result is null. Β understates the partial experimental pharmacology and directly relevant exploratory treatment rationale. Γ preserves the clinical positive and null without implying equivalence, zero benefit in every context, or a positive crossing from a negative design.",
    "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Registered symptomatic-MDD trial of titrated 5–20 microgram base-equivalentLSD twiceweekly for 8 weeks versus credible sensory-matched active comparator, with equalcontact/co-care and an expectancy-factor manipulation or prespecified sensitivity analyses; follow throughwithdrawal and relapse."
  },
  "final_score": {
    "hsef_level": "Γ",
    "hsef_descriptor": "Mechanistically plausible, partial system support",
    "confidence": "Moderate",
    "confidence_rationale": "64 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.",
    "rests_on_non_peer_reviewed_work": false,
    "rationale": "Primary-subclaim aggregation returns SC2 Γ. Controlled acute drug action and direct exploratory MDD improvement provide partial support, while a now verified masked clinical conference report is primary-null. Neither healthy nulls nor a single imprecise conference result establish universal inefficacy, and the open-label positive cannot override the clinical comparator. Full-dose and ketamine results retain their actual scopes."
  },
  "role_of_mechanism": {
    "classification": "epiphenomenon",
    "derivation_step_matched": 2,
    "derivation": "For persistent depression/anxiety reduction, causal dependency on repeated LSD microdosing is not established in either direction. This framework role describes the current clinical evidence state, not absence of acute biological action. Drug-responsive EEG/PK/task effects have a different endpoint scope.",
    "tournament_used_as_tiebreaker": false,
    "note": "Derived from causal direction, not tournament rank."
  },
  "extended_scoring_MSD": {
    "momentum": {
      "value": "Mechanistic only",
      "artifact": "Official ANZCTR ACTRN12624000128594, examined13October2026, lists recruitment Completed, final89participants and actual last data collection3September2025. An original September2026 IJNP conference abstract reports the clinical primary null and masking data; a complete outcome paper/analysis and comparator details were not examined. The publication protocol is superseded as a status source. No currently recruiting clinical trial is asserted from the older protocol.",
      "justification": "Official ANZCTR ACTRN12624000128594, examined13October2026, lists recruitment Completed, final89participants and actual last data collection3September2025. An original September2026 IJNP conference abstract reports the clinical primary null and masking data; a complete outcome paper/analysis and comparator details were not examined. The publication protocol is superseded as a status source. No currently recruiting clinical trial is asserted from the older protocol."
    },
    "stability": {
      "value": "Stable",
      "trigger": "A full outcome publication from the completed registered trial, with analyzed sample, missing-data handling, all-arm/rater masking and complete clinical estimates, could refine the grade or confidence. Its verified conference primary null already informs this review; it is not mislabeled pending clinical data.",
      "justification": "A full outcome publication from the completed registered trial, with analyzed sample, missing-data handling, all-arm/rater masking and complete clinical estimates, could refine the grade or confidence. Its verified conference primary null already informs this review; it is not mislabeled pending clinical data."
    },
    "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": "none assigned",
    "prior_confidence": null,
    "prior_source": null,
    "derived_before_consulting_prior": true,
    "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": "Registered symptomatic-MDD trial of titrated 5–20 microgram base-equivalentLSD twiceweekly for 8 weeks versus credible sensory-matched active comparator, with equalcontact/co-care and an expectancy-factor manipulation or prespecified sensitivity analyses; follow throughwithdrawal and relapse.",
      "readout": "Prespecified blinded-rater and self-rated depression/anxiety trajectories and clinically meaningful response, plus function and adverse effects separately; dose-day changes,EEG,PK,BDNF andsleep secondary",
      "critical_control": "Measure baseline expectations, participant/rater guess andconfidence repeatedly, drug purity/base equivalence, concurrent antidepressants/contact, dose-specific perception and adherence; avoid posthoc responder eligibility and distinguish adjusted posttreatment guesses from randomizedexpectancy",
      "supporting_result": "A sustained clinically importantbetween-arm contrast survives credible sensory matching, raters remainmasked, and independentdesign narrows expectancy/co-care; a prespecified diagnosis/severity boundary is mapped",
      "falsifying_result": "Adequatelyprecise unchanged symptoms despite drugtarget engagement, or outcomes primarily follow experimentallymanipulated belief rather than drug; an acute marker-positive but trajectory-null result doesnot crossSC2"
    }
  ],
  "knowledge_gaps": [
    {
      "name": "Gap 1",
      "statement": "Complete outcome-paper methods, analyzed sample, missing-data handling, dose distribution and comparator/rater masking for the completed LSDDEP2 trial; additional independent symptomatic trials and anxiety-specific estimates.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 2",
      "statement": "Dose/base-tartrate normalization and individual perceptibility measured before declaring a regimen subperceptual.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 3",
      "statement": "Independent expectancy manipulation and safe interpretation of postdose allocation-guess adjustment.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 4",
      "statement": "Clinical relevance of reward/connectivity/EEG/BDNF signals rather than assumed plasticity-mediated therapy.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 5",
      "statement": "Longerterm, uncommon and cardiovascular harms; small trial echo/mouse nulls do not quantify rarehuman risk.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 6",
      "statement": "Regimen-specific comparative efficacy, support intensity and function without transferring full-dose/ketamine positives ornulls.",
      "relevance": "Limits mechanism identification or scope."
    }
  ],
  "review_metadata": {
    "review_date": "2026-10-13",
    "reviewer": "Codex",
    "evidence_base_note": "64 primary reports; literature cutoff 2026-10-13; source examination UTC date 2026-10-13; bounded critical review, not exhaustive systematic review.",
    "literature_tools_available": true,
    "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite monthly limit was reached earlier in this session; no new Scite query or incoming citation-context audit is claimed for these cases. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review.",
    "skill_version": "5.3",
    "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.",
    "validator_warnings_addressed": "No warnings.",
    "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs."
  },
  "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": "These topic families were selected from an editorial traffic-priority list. Selection was visible; no blind calibration or predetermined clinical verdict was preregistered."
  },
  "upper_ladder_check": {
    "final_level_below_zeta": true,
    "equivalents_considered": [
      {
        "kind": "mendelian_randomization",
        "available": false,
        "why_not_sufficient": "Blinding-integrity-reported randomized designs, drug withdrawal/rechallenge and mediator manipulations were considered. Actual low-dose nulls and guessed-allocation associations do not establish persistent symptom efficacy; ketaminewithdrawal andnaltrexone perturbations have different drugscope. No valid LSDclinical genetic instrument or same-scope independent causal set was verified. A completed registered MDD active-comparator clinical trial now has a separately verified conference primary-null report, not a qualifying positive causal crossing; complete outcome reporting remains required."
      },
      {
        "kind": "natural_experiment",
        "available": false,
        "why_not_sufficient": "Blinding-integrity-reported randomized designs, drug withdrawal/rechallenge and mediator manipulations were considered. Actual low-dose nulls and guessed-allocation associations do not establish persistent symptom efficacy; ketaminewithdrawal andnaltrexone perturbations have different drugscope. No valid LSDclinical genetic instrument or same-scope independent causal set was verified. A completed registered MDD active-comparator clinical trial now has a separately verified conference primary-null report, not a qualifying positive causal crossing; complete outcome reporting remains required."
      },
      {
        "kind": "dose_response_across_populations",
        "available": false,
        "why_not_sufficient": "Blinding-integrity-reported randomized designs, drug withdrawal/rechallenge and mediator manipulations were considered. Actual low-dose nulls and guessed-allocation associations do not establish persistent symptom efficacy; ketaminewithdrawal andnaltrexone perturbations have different drugscope. No valid LSDclinical genetic instrument or same-scope independent causal set was verified. A completed registered MDD active-comparator clinical trial now has a separately verified conference primary-null report, not a qualifying positive causal crossing; complete outcome reporting remains required."
      },
      {
        "kind": "withdrawal_rechallenge",
        "available": true,
        "why_not_sufficient": "Blinding-integrity-reported randomized designs, drug withdrawal/rechallenge and mediator manipulations were considered. Actual low-dose nulls and guessed-allocation associations do not establish persistent symptom efficacy; ketaminewithdrawal andnaltrexone perturbations have different drugscope. No valid LSDclinical genetic instrument or same-scope independent causal set was verified. A completed registered MDD active-comparator clinical trial now has a separately verified conference primary-null report, not a qualifying positive causal crossing; complete outcome reporting remains required."
      },
      {
        "kind": "therapeutic_perturbation_hard_endpoint",
        "available": false,
        "why_not_sufficient": "Blinding-integrity-reported randomized designs, drug withdrawal/rechallenge and mediator manipulations were considered. Actual low-dose nulls and guessed-allocation associations do not establish persistent symptom efficacy; ketaminewithdrawal andnaltrexone perturbations have different drugscope. No valid LSDclinical genetic instrument or same-scope independent causal set was verified. A completed registered MDD active-comparator clinical trial now has a separately verified conference primary-null report, not a qualifying positive causal crossing; complete outcome reporting remains required."
      }
    ],
    "convergence_present": false,
    "cap_reapplied_to_convergent_set": false
  },
  "provenance_header": {
    "sources_total": 64,
    "claims_total": 69,
    "claims_verified": 69,
    "claims_unverified": 0,
    "claims_contradicted": 0,
    "tier_a_sources": 64,
    "generated_by": "Codex; HSEF v5.3",
    "gate_passed": true
  },
  "claims": [
    {
      "id": "C1",
      "text": "In 191 self-blinding citizen participants, psychological outcomes improved over four weeks in both microdose and placebo groups without significant between-group differences; small acute/post-acute differences were explained by blind breaking. Self-supplied drugs and dosing without clinical supervision; mixture of psychedelics and self-selection limit precise LSD exposure and diagnosed-MDD inference. Null differences are not proof of exact equivalence or all benefit being placebo.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        1
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph7, 1:Materials and methods:paragraph12, 1:Materials and methods:paragraph14, 1:Materials and methods:paragraph16, 1:Materials and methods:paragraph19, 1:Materials and methods:paragraph21, 1:Materials and methods:paragraph23, 2:Results:paragraph0, 2:Results:paragraph3, 2:Results:paragraph6, 2:Results:paragraph8, 2:Results:paragraph14, 2:Results:paragraph17, 2:Results:paragraph18. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C2",
      "text": "Twenty-four healthy volunteers received placebo and LSD5/10/20 micrograms;20 micrograms increased cold-pain tolerance and decreased pain/unpleasantness while increasing BP and selected dissociation/anxiety ratings. Single administrations and evoked pain, not 4–12 week depression/anxiety treatment. Acute anxiety can increase; low dose is not necessarily imperceptible.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        2
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C3",
      "text": "Twenty-two healthy participants showed dose-related resting EEG power and ERP changes with LSD13/26 micrograms, together with positive mood and anxiety effects; subjective changes did not correlate with EEG. Acute biomarkers and tartrate/base formulation requiring explicit equivalence; no persistent clinical symptom endpoint or mediator manipulation.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        3
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C4",
      "text": "Crossover LSD26 micrograms versus placebo in 39 participants found greater acute positive effects and 48-hour BDI decline in 20 participants with high baseline BDI. Dose formulation must distinguish tartrate/base; one dose and 48 hours are not repeated 4–12 week treatment. More pronounced subjective effects threaten blind and high BDI is not a diagnosed-MDD treatment sample.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "source_ns": [
        4
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C5",
      "text": "Twenty healthy adults received 0/6.5/13/26 micrograms in randomized sessions; orderly subjective effects occurred, with vigor increase at highest dose but most mood/cognition unchanged. Single-dose healthy population; no sustained symptomatic cohort endpoint and perceptibility varies by dose.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        5
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C6",
      "text": "Secondary NCT05200936 ADHD analysis after six weeks 20 micrograms twice weekly found a time-reproduction effect but no broad cognitive benefit and no corresponding parent clinical symptom benefit. Shares parent 40105807 allocation; ADHD cognition is a diagnosis/endpoint boundary rather than independent depression RCT. Exploratory predictors and one task do not establish general cumulative efficacy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        6
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C7",
      "text": "Twenty healthy participants showed amygdala connectivity changes after 13 micrograms; positive mood correlated with connectivity amid weak variable mood effects. Single-dose imaging and observational mediator correlation cannot establish sustained therapy or that connectivity is required for benefit.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        7
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C8",
      "text": "Four-week placebo-controlled sublingual 5-Me O-DMT dose study in symptomatic adults reports pharmacokinetics, EEG modulation and tolerability without formal psychiatric diagnosis. Different compound and formulation, safety-focused Phase I; abstract provides no convincing controlled sustained symptom efficacy estimate or sample size. Promotional therapeutic conclusion exceeds reported outcomes.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC4"
      ],
      "source_ns": [
        8
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C9",
      "text": "Two longitudinal placebo-controlled psilocybin-truffle trials found no corrected cognitive or emotional benefit, while participants reportedly remained effectively blinded. Different drug and dose units; full Methods needed for precise blinding/sample assessment. Healthy/seminaturalistic findings bound general microdosing narratives without proving no diagnosed-MDD LSD benefit.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3",
        "SC4"
      ],
      "source_ns": [
        9
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C10",
      "text": "Eighty healthy men randomized to 10 micrograms LSD every third day for six weeks had 24.3 more tracker-measured sleep minutes on the night after dosing;3231 nights are repeated observations. Same parent trial 36997080; wearable sleep estimate is not polysomnography or depression/anxiety trajectory. Objective effect cannot establish proposed symptom benefit or exclude every expectancy-related behavior.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        10
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C11",
      "text": "Preregistered three-week psilocybin microdose crossover found no confirmatory depression/anxiety or emotion-processing improvement; both baseline reductions and second-block blind breaking were reported. Different drug and shorter-than-registered duration; no strong clinically depressed sample. Null clinical result is not positive threshold crossing or universal absence.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3",
        "SC4"
      ],
      "source_ns": [
        11
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C12",
      "text": "Eighty healthy men randomized to 10 micrograms every third day for six weeks had transient dose-day mood/energy positives surviving baseline-expectancy adjustment, but no credible pre/post mood or cognition improvement;four active withdrawals for anxiety. Inactive placebo and dose-day perceptibility remain; adjustment for baseline expectancy does not remove postdose allocation recognition. Healthy men limit clinical/general-sex scope; transient improvement differs from durable symptom treatment.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "source_ns": [
        12
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C13",
      "text": "Secondary 39-person 26 microgram crossover report finds reward ERP effects associated with acute mood and 48-hour BDI changes in higher-BDI participants. Shares 38042914 sample; correlation is not mediated causality, tartrate/base formulation and 48 hours is not 4–12 weeks. Reward physiology cannot replace symptom trajectory.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        13
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C14",
      "text": "Randomized older-adult 5/10/20 microgram LSD study found altered suprasecond interval timing without robust subjective effects; regression suggested independence from marginal drug ratings. Specific acute task, not depression therapy. Attached erratum 33089876 is metadata only until retrieved; no invented correction details or extra original count.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        14
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C15",
      "text": "Thirty-four psilocybin-mushroom microdosers had stronger acute subjective effects only when correctly identifying condition and reduced theta EEG, without wellbeing/cognitive benefit and a few impairment changes. Mushroom 0.5 g and acute/short-term design do not equal LSD5–20 micrograms over 4–12 weeks; blind integrity directly limits therapeutic interpretation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2",
        "SC3",
        "SC4"
      ],
      "source_ns": [
        15
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C16",
      "text": "Three psilocybin-truffle trials pooled 171 participants showed a restricted originality/fluency benefit that survived dose-guess adjustment; most other creativity outcomes were null. One of three preregistered; pooled original experiments, not merely a review. Likely overlaps 41110634 trials and must not count as independent allocations; task quality is not depression/anxiety treatment.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC3",
        "SC4"
      ],
      "source_ns": [
        16
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C17",
      "text": "International 525 current-microdoser survey reports mental-health motivations, perceived mood/anxiety benefits, stronger-than-expected effects and anxiety adverse experiences. Self-selected retrospective attribution, mixed drugs and no controlled allocation; narrative users cannot establish efficacy or dose authenticity. Survey may include 16–17 year-olds outside adult scope.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        17
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C18",
      "text": "Anonymous 2347-person survey included 383 microdosing respondents attributing improved mood/anxiety and cognition to the practice. Self-selected attribution and varying denominator; no verified dose, comparator or symptom trajectory. Report count is not evidence of pharmacologic causality.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        18
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C19",
      "text": "Reddit 909 respondent survey found typical LSD median 13 micrograms and lower reported anxiety-diagnosis odds among microdosers but higher recent recreational drug use. Cross-sectional diagnosis histories, self-selection and concurrent drug differences; temporal direction and causal reduction unestablished. Mainly young male/White sample limits generalization.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        19
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C20",
      "text": "Six-week observational 98 microdoser daily series with 63 paired psychometrics reports depression/stress decline and increased neuroticism; dose-day effects mostly lacked residual following-day benefit. Unblinded mixed-drug naturalistic use; separate 263-person expectation survey does not randomize expectancy in the longitudinal participants. Baseline change/regression cannot establish causal sustained therapy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        20
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C21",
      "text": "Two-center 53-adult ADHD trial randomized 20 micrograms twice weekly for six weeks;AISRS improved 7.1 active versus 8.9 placebo with no between-group benefit. ADHD is a prespecified diagnosis boundary, not direct MDD treatment. Selected psychiatric exclusions and short supervised follow-up constrain safety;42322409 is a secondary analysis rather than replication.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "source_ns": [
        21
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph3, 1:Methods:paragraph7, 1:Methods:paragraph8, 1:Methods:paragraph12, 2:Results:paragraph4, 2:Results:paragraph10, 2:Results:paragraph11, 2:Results:paragraph12, 2:Results:paragraph14. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C22",
      "text": "Thirty-four psilocybin participants showed speech-feature changes and cross-validated condition discrimination after 0.5 g mushrooms. Shares 35918311 sample/design; acoustic/semantic condition recognition is pharmacodynamic and may facilitate unblinding, not persistent therapy or externally validated predictor.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC3",
        "SC4"
      ],
      "source_ns": [
        22
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C23",
      "text": "497 current/former/naive respondents showed lower trait anxiety associated with microdosing and small statistical mindfulness mediation; associations disappeared after excluding prior macrodose users. Cross-sectional self-selection and 386 prior-macrodose exclusions change comparability/power; disappearance does not prove macrodose causality. Observed mediation cannot establish necessity of mindfulness.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        23
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C24",
      "text": "Qualitative 278 microdoser codebook reports improved mood 26.6%, discomfort 18% and anxiety 6.7%, identifying plausible outcomes and harms. Self-attributed experiences and coded-report proportions are not treatment response or incidence estimates; no blinded comparator and mixed drugs.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        24
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C25",
      "text": "Nineteen MDD participants received 16 doses over eight weeks, initially 8 then 6–20 micrograms twice weekly;MADRS fell 59.5% with sustained six-month improvement;one withdrew for anxiety, no serious/severe AE or observed ECG/echo change. Direct dose/duration/diagnosis match and important positive, but open-label/no comparator,15 on antidepressants and small mostly-male sample. Regression, care and expectancy unresolved; short small echo null cannot establish long-term valvular safety.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "source_ns": [
        25
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C26",
      "text": "Eighteen healthy adults showed enhanced reward ERP components after 13/26 micrograms versus placebo, mostly not correlated with subjective effects. Acute neural signal without persistent symptoms;tartrate/base formulation and reward mechanism not manipulated. Does not show that ERP produces clinical recovery.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        26
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C27",
      "text": "1116 current/former microdosers reported performance motives, acute psychological negatives and ineffectiveness as the main stop reason;many did not know dose. Self-selected online sample, no verified compounds and retrospective benefit/AE attribution; neither universal safety nor treatment efficacy established.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        27
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C28",
      "text": "Descriptive international daily PANAS reports from more than 1000 people suggested mood/work/health improvement with repeated microdosing. Uncontrolled reports and uncertain exposure; strong claim of safety across individuals/conditions exceeds ability to detect rare harms or exclude self-selection/regression. Clinical and nonclinical samples not a blinded diagnosis-specific test.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        28
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C29",
      "text": "Preregistered online observational comparison reports lower negative emotionality and greater openness/wisdom/creativity among current/former microdosers. Preregistration does not randomize exposure; pre-existing group differences, prior full doses and concurrent behaviors confound benefits. Personality/task differences are not sustained MDD therapy.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        29
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C30",
      "text": "Global Drug Survey 6753 last-year microdosers report perceived benefits and commonly no challenges;most had not tested substances and approach-intention predicted fewer benefits. Survey selection, attribution and unverifiable exposure; absence of reported challenges is not low clinical risk. Attached correction 37226829 metadata only, no assumed result change or primary credit.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        30
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C31",
      "text": "Thirty-nine healthy adults in 26 microgram crossover showed selective neutral/happy-face ERP attenuation. Acute neural interpretation, dose formulation requiring base-equivalence, not sustained symptom therapy; possible related 39-person depressed-mood cohort requires body verification before independent-line credit.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        31
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C32",
      "text": "Fifty-six healthy adults randomized to placebo 13 or 26 micrograms for four doses at 3–4 day intervals showed subjective effects at 26 but no mood/cognition or drug-free residual benefit. Original Methods verify 13/26 micrograms tartrate equals 10/20 base, within dose range; about two-week limited administrations and healthy subjects remain boundaries; does not definitively refute 8-week MDD therapy. Inert placebo with perceptibility demands blinding check.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2",
        "SC3"
      ],
      "source_ns": [
        32
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:MATERIALS AND METHODS:paragraph0, 1:MATERIALS AND METHODS:paragraph1, 1:MATERIALS AND METHODS:paragraph3, 1:MATERIALS AND METHODS:paragraph4, 1:MATERIALS AND METHODS:paragraph5, 1:MATERIALS AND METHODS:paragraph6, 1:MATERIALS AND METHODS:paragraph8, 1:MATERIALS AND METHODS:paragraph9, 2:RESULTS:paragraph1, 2:RESULTS:paragraph2, 2:RESULTS:paragraph4, 2:RESULTS:paragraph7, 2:RESULTS:paragraph14, 2:RESULTS:paragraph16, 2:RESULTS:paragraph17. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C33",
      "text": "Forty male rats intermittently dosed with low psilocin/ketamine had modest/borderline elevated-plus-maze effects tending mildly anxiogenic 48 hours later. Different compounds and rodent anxiety proxy;multiple pairwise testing and small groups. Does not establish human LSD harm or clinical inefficacy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2",
        "SC4"
      ],
      "source_ns": [
        33
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C34",
      "text": "Eighty-man 10 microgram trial provides plasma PK and small HR/feel-effect responses, no peripheral BDNF alteration;four anxiety withdrawals, two with lower CYP2 D6 activity. Same 36997080 parent;qualitative genotype observation not prospective predictive validation. Peripheral BDNFnull does not deny central plasticity;PK is not clinical efficacy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        34
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C35",
      "text": "Single 19-year-old MDD case reports remission during seven-month psilocybin microdosing accompaniment and conventional-drug withdrawal. One uncontrolled case, different compound and concomitant advice;cannot establish dose-specific therapy, safe medication discontinuation or general response.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC4"
      ],
      "source_ns": [
        35
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C36",
      "text": "Nonblinded truffle microdose event shows before/after convergent/divergent task improvement with fluid intelligence unchanged;alkaloids subsequently quantified. No placebo, practice/expectancy effects or clinical symptoms;creativity mechanism speculation does not establish therapeutic efficacy.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3",
        "SC4"
      ],
      "source_ns": [
        36
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C37",
      "text": "Thirteen anonymous qualitative interviews describe purposeful microdosing and perceived mental-health/cognitive/social benefits. Experiential meaning informs hypotheses but lacks comparator/exposure verification;interpretative themes are not causal evidence or response prevalence.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        37
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C38",
      "text": "Fifty-three healthy participants received 15 micrograms or placebo four times over two weeks;EEG/attention effects and some one-week persistence were baseline-state dependent, while LTPinduction was blunted. Neural adaptation and exploratory moderation are not clinical 4–12 week symptom benefit;subgroup selection must precede outcome, and not all markers improve.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        38
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C39",
      "text": "Chronic low-dose LSD mice showed no detected ventricular/valvular remodeling while serotonin/fenfluramine positive controls had cardiac changes;receptor affinity/potency compared across species. Useful positive-controlled preclinical safety boundary, not rare or years-long human safety. No evidence of remodeling does not establish absence;no clinical depression endpoint.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        39
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C40",
      "text": "Prospective naturalistic four-week study 81 endpoint completers reports symptom/wellbeing improvement and baseline positive expectancy predicting wellbeing gains. No randomized expectancy or treatment;association supports competing explanation but does not prove every pharmacologic effect is placebo. Attrition and mixed exposure constrain interpretation.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        40
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C41",
      "text": "Eleven-site 104 MDD trial 25 mg psilocybin versus 100 mg niacin with support found central MADRSdifference−12.3 atday 43 and disability improvement;more overall/severe AE but no serious treatment-emergent AE. Niacin is side-effect active but not necessarily subjective-experience matched;blinding labels are not reported integrity. Full-dose scaffold differs from LSDmicrodosing. Attached 38277159 correction metadata only.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        41
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C42",
      "text": "EPISODE144 randomized TRDpatients 25 mg versus 5 mg/nicotinamide primaryweek 6 HAMDresponse 17%/12.5%/10.6% failed first hierarchicalcomparison P.19;secondary scale changes exploratory,serious reactions included HPPD. Primary failure cannot be recast as positive crossing from secondarymeans;different full-dose psychotherapy regimen. Trial is inconclusive, not proof zero effect or all full-dose inefficacy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        42
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C43",
      "text": "COMP360233 TRDparticipants 25/10/1 mg with support showed week 3 patient-reported symptom/function improvements strongest 25 mg. Exploratory secondary outcomes, no active experience-matched comparator and acknowledged functional unblinding. Same allocation as 39706482/39427449;full-dose results cannot validate LSDmicrodose.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        43
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C44",
      "text": "Thirty-five life-threatening-illness patients 25 mg psilocybin versusniacin with psychotherapy had 6–7 week depression/anxiety advantages and 26 week persistence. Smallsingle-site and lateropenlabel/allactive extension lose randomizedlongtermcontrast;niacin mismatch andoneanxietywithdrawal. Distinct disease/support scope, not LSDmicrodose efficacy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        44
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C45",
      "text": "Fifty-nine MDDpatients two 25 mg psilocybin versusescitalopram with 1 mg sessions/support had nonsignificant primary QIDSdifference P.17, while uncorrectedsecondary outcomes favoredpsilocybin. Head-to-head not placebo;smallimpreciseprimaryresult neither establishes equivalence norpsilocybin superiority. Functionalunblinding/supportdrugpackages notisolated.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        45
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C46",
      "text": "Twenty-seven MDDpatients immediate versuswaitlist two 20/30 mg-per 70 kg psilocybin sessions with 11 hourssupport showedlargeweeks 1/4 scale improvement in 24 completers. Waitlist doesn’tmatchcontact/expectancy, outcomeawareintervention andevaluablepopulation;full-dose package distinct. Correction 33566065 attachedmetadataonly.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        46
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C47",
      "text": "Thirtycomplex TRD/MDD/bipolar IIpatients randomizedimmediate versuswaitlist 25 mgwithpsychotherapy showedweek 2 MADRSbenefit;additionaldoses associatedwithfurtherdecline. Unmatchedwaitlist andeventualactive dosing don’tisolatepharmacologyorcausalrepeat-doseincrement;safety/scopeunderpowered. Not LSDmicrodosegeneralization.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        47
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C48",
      "text": "Fifty-onecancer-distresspatients high 22/30 mg versus 1/3 mg-per 70 kg crossover psilocybin showedpersistentclinician/self/community-ratedmoodbenefits andexperience-outcomemediation. Lowdosecomparator maynotmatchacuteexperience;statisticalmysticalmediationnotmanipulation ornecessity. Crossover/alltreatedfollowup andcancerscaffold limittransfer.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3",
        "SC4"
      ],
      "source_ns": [
        48
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C49",
      "text": "Same 33146667 parent 24 completers showedlarge 12 monthdepressionscaledecline,response 75%/remission 58%;mysticalmeaning predictedwellbeingbutnotdepression improvement. Longtermalltreatedobservations have nocontemporaneousrandomizedcontrol;notnewindependenttrial orproofmysticalexperiencecausestherapy. No serious AEsinsmallsampleisnotuniversalsafety.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3",
        "SC4"
      ],
      "source_ns": [
        49
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C50",
      "text": "Twenty-ninecancer-distresspatients 0.3 mg/kg psilocybin versusniacinwithpsychotherapy hadpre-crossover 7 weeksymptompositivesandsustainedalltreatedfollowup. Experience-matching/blindingintegrity notconfirmedfromabstract;statisticalmediationnotnecessarycausalexperience. Distinctfull-doseoncologycontextcannotvalidate LSDmicrodose.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3",
        "SC4"
      ],
      "source_ns": [
        50
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C51",
      "text": "Two-site 73 TRDpatients ketamine versusmidazolam produced 24 hour MADRSdifference 7.95 points and 64%versus 28%response. Active psychoactive comparator important but integrity/sensorymatch notverifiedfromabstract;single-day effectnot 4–12 week LSDtherapy andketamine mechanism notsame serotonergicmicrodose.",
      "carries_number": true,
      "load_bearing_for": [
        "SC4"
      ],
      "source_ns": [
        51
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C52",
      "text": "Twenty-six MDD crossover participants receivingnaltrexone beforeketamine hadattenuatedglutamate/glutamine response andday 1 MADRSreduction versusplacebopretreatment. Actualmediator perturbation narrower opioid-dependency evidence,notexperience-removal orproofonlyopioidmechanism;acuteoutcomeandpotentialnaltrexonedirecteffects requirecontrols. Differentdrugcannotqualify LSDclinicalclaim.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3",
        "SC4"
      ],
      "source_ns": [
        52
      ],
      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C53",
      "text": "676 TRDpatients randomizedesketamine versusquetiapine augmentation withblindraters hadweek 8 remission 27.1%versus 17.6% andmaintainednonrelapse advantage. Openlabelparticipants,ongoing SSRI/SNRI anddifferingdrugpackages;notcleanexpectancy separation ormicrodosegeneralization. Sponsor-linkedtrialnotindependent mechanisticclass.",
      "carries_number": true,
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C54",
      "text": "Five-site 403 randomizednonpsychotic TRDpatients ketamine versus ECT metprespecifiednoninferiority for 3 weekself-ratedresponse;memorydeclinegreater ECT. Openlabel with 38 predosingwithdrawals anddifferenttreateddenominators;noninferiority doesn'tproveuniversal superiority/equivalence orseparatepackageexpectancy. Not LSDregimen efficacy.",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C55",
      "text": "297 stableesketamineresponders/remitters randomizedcontinuation versuswithdrawal whileoralantidepressantcontinued showedlowerrelapse;remitters 26.7%versus 45.3%. Field-validwithdrawal withinprespecifiedmaintenancescope,notallnewpatients;dissociationimbalance threatensblind andwithdrawaleffects needconsideration. Responder-definedtrialeligibility isdeclaredprospectively,notposthocscopeforscoring LSD.",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C56",
      "text": "Twenty-five TRD crossoverpatients ketamine 0.5/1 mg/kg versusfentanyl hadgreater 24 hourdepression/anxietyresponses withsome 7 daypersistence. Activecontrolbutsmall,carryoverandexperiencematching unresolvedfromabstract;similarantidepressanteffectacrossdoses despitegradedsideeffects. Differentdrug short horizon not LSDmicrodose.",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C57",
      "text": "Eighty MDDpatients ketamine versusmidazolam showed 24 hoursuicidalideationdifference 4.96 points and 55%versus 30%response. Suicidalideationscaleisnotattempt/death prevention;6 weekpersistencefolloweduncontrolledoptimizedpharmacotherapy. Statisticaldepressionmediationnotnecessity anddifferentdrug/scope.",
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      "verification": "verified",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C58",
      "text": "COMP360233 trialsecondaryanalysis reportsdose-relatedexperiencesandspecificweek 3 MADRSexperiencecorrelations withoverlapacrossdoses. Experienceobservednotrandomizedmediator;overlapdoesn'tmeasureallocationguessintegrity orprovecausation. Same 36740140/39427449 allocation;correction 41075579 metadataonly.",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C59",
      "text": "Posthoc COMP360233 analysis foundantidepressantdiscontinuationnotassociatedwithworseningscreeningsymptomsorcompromisedpsilocybineffects. Discontinuationgroupnotrandomized;cannotgeneralizeallwithdrawalregimensorconcomitantdrugs. Sameparentallocation,notnewreplication orvalidatation LSDwithongoingantidepressants.",
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      "verification": "verified",
      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C60",
      "text": "Healthy-subjectescitaloprampretreatment crossoverretainedpositive 25 mgpsilocybinmoodwhileattenuatinganxiety/negativecardiovascularresponses;PKunchangedandperipheral BDNFnull. Two-week SSRIpretreatment andacutehealthyfull-doseoutcomenot MDDtreatmentorlongtermmedicationcombination. Experience-qualitymanipulationdoesnotprovenecessityorabsenceofneuroplasticity.",
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      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C61",
      "text": "COMP360 233 TRD patients randomized 25/10/1 mg psilocybin with support had week 3 MADRS difference −6.6 for 25 versus 1 mg;10 mg contrast nonsignificant and sustained week 12 response not supportive. Low-dose control does not ensure experience matching; acute adverse events common and suicidal/self-injury events in all arms. Full-dose primary signal retained without validating LSD microdosing; shared secondary reports grouped.",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C62",
      "text": "Twenty-three healthy participants received LSD base 5/10/20 micrograms versusplacebo;PKscaled with dose,5 micrograms subjective-null while 10/20 produced perceptibleeffects and 20 also bad-drug ratings. Acute healthy crossover not persistent therapy;definesdose-dependent perception rather than universal subperceptual threshold. PK/subjectivitynot independently demonstrated clinical mechanism.",
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      "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C63",
      "text": "Placebo-controlled within-subject 5/10/20 microgram LSD study found selected plasma BDNF rises at 4/6 hours. Circulating BDNFnot direct synaptic plasticity or symptom mediation;time/dose pattern and null 40251818 show marker not uniformly positive. Potential overlap with low-dose healthy studies limits independent causal-line credit.",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "C64",
      "text": "Prospective 1435-adult naturalistic survey found higher self-rated wellbeing/productivity/connectedness/focus on microdosing days versus nondosingdays;previousmacrodoses modifiedcreativity. Within-person unblinded dose scheduling doesnotrandomizeexposure/expectancy;daychanges are not persistent 4–12 weekdepression therapy anddifferent denominators reflectmissingdomainresponses.",
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      "verified_on": "2026-10-13",
      "note": ""
    },
    {
      "id": "CSC1",
      "text": "Randomized low-dose human LSD exposure demonstrates real acute pharmacodynamic effects, including objective plasma/neural/task measures. That observation is retained explicitly. The frozen psychiatric rubric requires a credible active comparator and preregistered primary outcome for its Δ threshold and applies an acute-pharmacodynamic cap where symptom trajectory is not established. These acute studies do not satisfy that psychiatric therapeutic threshold; SC1 is therefore Γ under rubric 07, rather than receiving a comparator-waiving adaptation. This grade does not deny experimentally induced acute drug action.",
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    {
      "id": "CSC2",
      "text": "Direct eight-week MDD open-label improvement is important positive exploratory support. Consensus additionally identified a real 2026 original conference outcome abstract: a triple-masked LSD versus caffeine MDD trial did not show primary MADRS superiority. That clinical null strengthens the concern about treatment attribution; absent full trial methods and imprecise estimates prevent a definitive zero-effect conclusion. No positive same-scope field-valid therapeutic crossing is verified; Γ remains.",
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      "verified_on": "2026-10-13",
      "note": ""
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    {
      "id": "CSC3",
      "text": "Baseline-expectancy adjustment can leave dose-day effects, while actual allocation guesses predict or explain several subjective outcomes. These observations do not manipulate expectancy independently, and null clinical comparisons do not become positive drug-efficacy crossings. A restricted psilocybin creativity result survives guess adjustment; it does not prove durable LSD depression benefit beyond expectancy.",
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    },
    {
      "id": "CSC4",
      "text": "Different full-dose psilocybin and ketamine trials have genuine clinical positives, primary nulls and selected mechanistic perturbations. No direct matched comparison shows that subperceptual LSD benefits generalize to those treatment packages. The proposed equivalence is narrative atΑ; this is not a grade of the efficacy of all full-dose or ketamine treatment.",
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      "note": ""
    },
    {
      "id": "CH",
      "text": "Low-dose LSD has real measurable effects, but sustained depression/anxiety relief from repeated microdosing remains unconfirmed beyond expectancy and concurrent care.",
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      "citation": "Molla H, Lee R, Tare I et al. Greater subjective effects of a low dose of LSD in participants with depressed mood. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2024.",
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    {
      "n": 5,
      "citation": "Bershad AK, Schepers ST, Bremmer MP et al. Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers. Biological psychiatry. 2019.",
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    },
    {
      "n": 6,
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      "carries_claims": [
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        "CSC1",
        "CSC2"
      ]
    },
    {
      "n": 7,
      "citation": "Bershad AK, Preller KH, Lee R et al. Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity. Biological psychiatry. Cognitive neuroscience and neuroimaging. 2020.",
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        "C7",
        "CSC1"
      ]
    },
    {
      "n": 8,
      "citation": "Bistue Millón MB, Noguera L, Bruno D et al. Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety: a randomized, double-blind, placebo-controlled study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2025.",
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      "n": 11,
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      "citation": "Hutten NRPW, Mason NL, Dolder PC et al. Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers. ACS pharmacology & translational science. 2021.",
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        "consensus_aspect": "Psilocybin symptom null and actual duration",
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        "consensus_aspect": "Later restricted positive prevents blanket zero-effect claims",
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        "access_depth": "abstract_metadata",
        "consensus_aspect": "Full-dose clinical results cannot become microdose proof",
        "result_comparison": "Consensus appropriately separates full-dose and ketamine treatment. Actual COMP360 primary25mg contrast is positive at three weeks but sustained week-twelve response is not supportive; full-dose33852780 and41848690 have primary nulls despite secondary positives. These exact outcomes are more informative than a broad class efficacy claim and cannot establish low-doseLSD generalization.",
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    "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them."
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}