In plain terms

The claim being assessed: Repeated subperceptual LSD microdosing improves depression and anxiety symptoms in adults.

Where the evidence stands: Γ — Plausible mechanism. There is a believable biological story and partial support, but the causal step has not been demonstrated.

What this mechanism does: The evidence reviewed does not show this mechanism causing the outcome. That does not show it has no effect.

Strongest evidence for it: 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.

What decisive evidence would look like

In plain terms, researchers would change the proposed cause, confirm it changed as intended, and measure a meaningful health outcome while checking other explanations. The result should be able to support or count against the claim.

Relative explanatory fit: Alternative ranked ahead

What this review means

Low-dose LSD has real measurable effects, but sustained depression/anxiety relief from repeated microdosing remains unconfirmed beyond expectancy and concurrent care.

Implications for health and treatment: 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.

Limits for individual care: 64 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness. The grade applies to the exact registered claim; stronger findings for narrower subclaims remain separate. No complete-paper audit or blinded calibration is claimed. This educational review does not establish an individual treatment recommendation.

Medical information notice: This review provides general health information, not medical advice. It cannot diagnose a condition or replace an individual discussion with a qualified clinician.

Source checking used bounded original primary abstract passages/status records and selected original partial-body passages. No complete-abstract or complete-paper audit, or independent scientific peer review, is claimed. Detailed access counts and limitations appear in the review.

A low grade is not an accusation. It means the causal work has not been done yet, which is the ordinary state of most actively studied mechanisms in biology.

At a glance

Sub-claims assessed separately

Full assessment

From here the review is written for a technical reader: caps and thresholds, competing models, the independence basis, and the citation ledger.

Sources: 64 primary reports; claims: 69; verified: 69; unverified: 0. Verification is bounded attribution. Access: 3 partial-body and 61 bounded abstract/status examinations. Literature cutoff: 2026-10-13; source examination UTC date: 2026-10-13. No complete-paper audit or blinded calibration claimed. Adversarial review: Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 11 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: Approved as revised.

AT A GLANCE

Low-dose LSD has real measurable effects, but sustained depression/anxiety relief from repeated microdosing remains unconfirmed beyond expectancy and concurrent care.

Deciding experiment: Registered symptomatic-MDD trial of titrated 5–20 microgram base-equivalent LSD twice weekly for 8 weeks versus credible sensory-matched active comparator, with equal contact/co-care and an expectancy-factor manipulation or prespecified sensitivity analyses; follow through withdrawal and relapse.

Belief versus evidence: 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.

Best-supported rival: Measurable low-dose pharmacology without established lasting treatment. Self-blinding 33648632 holds actual condition and guesses in separate analyses, while six-week home LSD 36997080 separates dose-day mood from persistent pre/post change. Open-label diagnosed-MDD 41202873 is the crucial unisolated clinical positive. Different drug mediator perturbation 40707608 does not settle that positive.

COMPETING MECHANISTIC MODELS

Rank 1: Measurable low-dose pharmacology without established lasting treatment (Δ). Low doses produce causal pharmacodynamic changes while persistent clinical benefit remains a separate prediction. Dose/PK32975835, interval-task 30478716 and neural 34613430 contrasts demonstrate real action; six-week 36997080 separates dose-day effects from pre/post null. This descriptive restricted model does not establish why 19 open-label MDD participants improved, nor rule out a future symptomatic benefit.

Rank 2: Different regimens have distinct clinical effects (Δ). Full-dose psychedelic and ketamine treatments have their own comparator-specific evidence and mechanisms. Actual naltrexone perturbation 40707608 narrows an acute ketamine dependency; active-controlled 23982301 and withdrawal 31166571 have clinical positives. Full-dose psilocybin 33852780/41848690 have primary nulls and unblinding concerns; neither positives nor nulls establish LSD microdose equivalence.

Rank 3: Microdose pharmacology improves persistent symptoms (Γ). Repeated low-dose LSD causes sustained depression/anxiety relief. Direct 8-week MDD 41202873 shows substantial persistent symptom decline, supported by real drug action and restricted 48-hour high-BDI 38042914 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 4: Expectancy and allocation recognition explain apparent benefit (Β). Belief and recognized drug effects contribute to symptom reports independently of assigned microdose. 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.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

FULL REVIEW

Registered claim and scope

Repeated subperceptual LSD microdosing improves depression and anxiety symptoms in adults.

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.

Selection: position 18 in the registered editorial traffic-priority list; registration timestamp 2026-10-13T16:06:25.540258+00:00. Ranked editorial traffic priority rather than measured global popularity or a preset verdict. Registered claim assessed against original sources; no independent blinded calibration is claimed.

Evidence and causal interpretation

Rubric fit: 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.

Low-dose LSD is not biologically inert. Controlled human studies demonstrate plasma exposure, dose-dependent perception, neural and task effects, and selected acute outcomes. Original35106880 equates13/26micrograms tartrate with10/20micrograms base;40105807 uses29tartrate for20base. Dose formulation must be checked before excluding evidence as outside the registered range. None of these acute findings alone establishes sustained depression or anxiety treatment.

LSDDEP1 is the directly relevant exploratory positive:19MDD participants received an eight-week regimen with6–20microgram titration and had59.5%MADRS decline, sustained up to six months. It merits retention. The uncontrolled open-label design,15participants taking antidepressants and mostly male sample leave expectancy, concurrent care and regression unresolved. One anxiety withdrawal and reassuring small ECG/echo observations do not quantify rare or long-term risks.

Consensus materially improved discovery by finding a real masked clinical outcome report absent from the PubMed candidate set. The September2026 Donegan conference abstract describes eight weeks of titrated LSD versus caffeine in MDD and reports no primary MADRS superiority with active-arm masking. It is a conference outcome abstract; incomplete methods and imprecision prevent treating its null as definitive equivalence.

Eighty healthy men randomized to10micrograms LSD every third day for six weeks had transient dose-day mood positives surviving baseline-expectancy adjustment, but no sustained pre/post mood or cognition improvement;four withdrew for anxiety. The sleep and PK companion papers share that allocation. Healthy-person nulls can involve symptom floor effects and are not direct proof of diagnosed-MDD inefficacy.

The two-center53-person ADHD study provides a diagnosis-specific boundary. Original Methods show supervised20microgram-base dosing twice weekly for six weeks and actual allocation guesses. The clinical primary remained null even using a one-sided.10analysis. After the last dose,21/22active and16/24placebo participants guessed active treatment. Perceptible drug action therefore need not generate clinical superiority.

The self-blinding citizen study used participants’ own varying compounds and doses, randomized capsule schedules and forced guesses. Original Results show191completers and no accumulated between-group benefit. Most acute/post-acute differences disappeared after guess adjustment. Because recognition can itself be caused by pharmacology, conditioning on guesses does not prove that every drug effect is expectancy; it narrows a major competing explanation.

Psilocybin microdosing is companion evidence. Controlled symptom and cognition trials often show nulls, including reported effective masking in later longitudinal work. A pooled original171-person creativity analysis nevertheless found a restricted originality benefit surviving guess adjustment. This positive prevents blanket zero-effect language but does not establish persistent LSD depression relief.

Full-dose psilocybin and ketamine have distinct clinical evidence. COMP36025mg beat1mg at week three, without a supportive sustained week-twelve response contrast; psilocybin-versus-escitalopram andEPISODE have primary nulls despite favorable secondary scales. Ketamine has active-comparator clinical positives and an actual naltrexone perturbation; esketamine withdrawal reduces relapse in prospectively defined maintenance responders. Those results neither validate LSD microdosing nor warrant dismissal of every regimen as placebo.

The official LSDDEP2 registry now lists recruitment Completed, final89participants and actual last data collection3September2025. That number is not the conference analyzed sample. Registry dose range2–20micrograms and caffeine-or-methylphenidate comparator differ from the conference4–20/caffeine description; full reporting or amendments are needed. Protocols and registries verify design/status and earn no completed-outcome primary credit.

Γ is a bounded causal assessment of sustained LSD microdose symptom relief. The direct positive remains exploratory, while a matched masked clinical null is now verified at conference depth. Complete trial reporting, credible comparator integrity and independent symptomatic evidence are the next evidentiary requirements. Corrections attach to their parent reports at the actually examined access depth.

Additional original-source checks outside the primary-report count

Donegan et al. (2026), original conference outcome abstract, DOI10.1093/ijnp/pyag040.021. Status: Original conference outcome report; separately examined, no PMID or full trial publication assumed. Access: Complete original abstract Methods/Results presented; private receipt lsddep2-conference-original-appraisal.json. Triple-masked eight-week LSD versus caffeine MDD primary MADRS comparison was nonsignificant; active-arm masking reported. Complete trial methods, analyzed sample or comparator/rater integrity; definitive equivalence or exact zero effect. This source is not included in the primary-report target or treated as a complete-paper audit.

Official ANZCTR ACTRN12624000128594, LSDDEP2. Status: Registry last updated25October2025; recruitment Completed. Access: Official registration, design, recruitment and enrollment fields examined; private registry receipt. Final recruitment89 and actual last data collection3September2025; prespecified MADRS eight-week endpoint. Analyzed outcome sample or efficacy; registry2–20micrograms/caffeine-or-methylphenidate differs from conference4–20/caffeine. This source is not included in the primary-report target or treated as a complete-paper audit.

HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

Subclaim matrix and aggregation

Preregistered aggregation: primary-subclaim. 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. Sensitivities: weakest-link Α; primary-subclaim Γ; scope-matched Γ.

Decisive-perturbation inventory and causal tally

[1] 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.

[4] 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.

[9] 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.

[11] 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.

[12] 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.

[15] 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.

[16] 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.

[21] 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.

[25] 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.

[32] 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.

[40] 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.

[42] 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.

[45] 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.

[52] 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.

[55] 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.

[61] 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.

[62] 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.

Tally: 0 positive qualifying study units across scoped subclaims; 19 screened discriminating contrast units. These are not independent causal lines or proof of full-claim necessity/sufficiency. 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.

No positive field-valid crossing was verified for the registered causal scope in this bounded audit. Pivotal null or negative tests remain informative; their implications depend on comparator quality, target engagement, power and the registered scope.

Cap audit, precedence and Β/Γ/Δ boundary

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.

Universal six-cap audit: All six universal caps were considered: cell-only inference, unperturbed association, ectopic expression, biomarker-only intervention, forced transfer/seeding, and inherited-to-sporadic scope transfer. Each binds its offered inference; complementary same-scope causal classes are assessed together rather than re-capped in isolation.

Gamma hard-rule audit: Actual low-dose drug effects do not prove persistent symptom therapy. Direct MDD efficacy support remains open-label; naturalistic improvement cannot distinguish expectancy/concurrent care. Inert-placebo with noticeable effects is examined via actual guesses rather than assuming successful blinding from a design label. Full-dose experience correlations are not mediator manipulations.

SC1 cap: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” 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.

SC2 cap: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” 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.

SC3 cap: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” 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.

SC1 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors

Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. 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.

SC2 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors

Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. 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.

SC3 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors

Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. 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.

SC4 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors

Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. 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.

SC1 applied rubric adaptation (distinct from the unchanged literal criterion): 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.

SC2 applied rubric adaptation (distinct from the unchanged literal criterion): 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.

SC3 applied rubric adaptation (distinct from the unchanged literal criterion): Baseline expectancy, postdose guesses and manipulated expectancy are distinct; covariate adjustment for a posttreatment variable can remove genuine drug information as well as bias.

SC4 applied rubric adaptation (distinct from the unchanged literal criterion): Compare compound, dose, diagnosis, support and time horizon explicitly; no direct efficacy equivalence is inferred from a shared psychedelic label.

SC1 literal Γ hard rule: “Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” Applies to the uncontrolled or cell-only positive support class, with ceiling Γ; it does not upgrade that class or describe the whole source set.

SC1 literal Γ hard rule: “Unblinded-rater rule. Outcomes rated by clinicians who delivered the intervention or knew allocation.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” Applies to the uncontrolled or cell-only positive support class, with ceiling Γ; it does not upgrade that class or describe the whole source set.

SC2 literal Γ hard rule: “Unblinded-rater rule. Outcomes rated by clinicians who delivered the intervention or knew allocation.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” Applies to the uncontrolled or cell-only positive support class, with ceiling Γ; it does not upgrade that class or describe the whole source set.

SC3 literal Γ hard rule: “Unblinded-rater rule. Outcomes rated by clinicians who delivered the intervention or knew allocation.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Functional-unblinding rule. Inert-placebo trial of an intervention with unmistakable acute subjective effects — psychedelics, ketamine, entactogens, suprathreshold stimulation, ECT — with no blinding-integrity check reported. Such a trial did not control what it claims to control.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Mediation-by-correlation rule. Candidate mediator correlated with outcome, never manipulated.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Open-label rule. Open-label, single-arm, retrospective, or naturalistic evidence alone. A positive open-label result never crosses Δ, however large.” Applies to the uncontrolled or cell-only positive support class, with ceiling Γ; it does not upgrade that class or describe the whole source set.

SC4 literal Γ hard rule: “Unblinded-rater rule. Outcomes rated by clinicians who delivered the intervention or knew allocation.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Acute-pharmacodynamic rule. Acute molecular, occupancy, or imaging change with no link to symptom trajectory.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Rodent-proxy rule. Forced-swim, tail-suspension, sucrose-preference, or head-twitch alone; head-twitch is pharmacodynamic, not therapeutic.” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

Upward threshold ladder

SC1 Δ: “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. 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.

SC2 Δ: “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. 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.

SC3 Δ: “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. Manipulate or independently balance expectancy while retaining drug exposure, with sensorymatching and actual guesses; demonstrate persistent symptom effects surviving the alternative explanation.

SC4 Δ: “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. 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.

Upper ladder: 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.

Independence: No subclaim reachesΖ. Distinct neural/PK/sleep reports of one trial and multiple scale outcomes share allocation and measurement failures. Replication across drugs or sponsors is not independently convergent evidence for the exactLSDmicrodose symptom proposition.

Falsification and pitfalls

Outcome tracks guessed allocation or disappears after guess adjustment. 33648632 self-blinding subjective outcomes; posttreatment adjustment is informative but not definitive proof all benefit is expectancy. Additional downgrade: False.

Effect fails to separate from a credible active comparator. Original Donegan2026 conference outcome abstract reports no primary MADRS superiority over caffeine; precision and full trial/reporting details remain unresolved. Additional downgrade: False.

Confirmation by biomarker. EEG, connectivity, rewardERPs, sleep and bloodBDNF are treated as proof of sustained depression/anxiety therapy.

Mechanism conflation. LSDbase/tartrate, psilocybin mushroom mass,5-MeO-DMT, full-dose psychotherapy andNMDA-antagonist treatment are interchanged.

Missing-control interpretation. Open-label MDD baseline decline becomes a drug-placebo contrast or blind labels become verified integrity.

Negative field-valid perturbation read as a crossed threshold. Healthy/ADHD/micro-psilocybin nulls are counted as positive clinical causal support.

Replication confused with reproduction. Sleep/PK/primary mood reports of one 80-persontrial andCOMP360 secondary reports are counted as independent studies.

Selective generalization. Healthy acute effects, one symptomatic open-label sample, or full-dose clinical efficacy are projected onto all adults/regimens.

Adversarial steelman: above, then below

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.

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.

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.

Final score, causal direction and M/S/D

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.

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.

Momentum: Mechanistic only. 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: Stable. 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: Contested. No manufactured field consensus or arithmetic gap. These dimensions do not change level or confidence.

PROPOSED DECISIVE EXPERIMENTS

Registered symptomatic-MDD trial of titrated 5–20 microgram base-equivalent LSD twice weekly for 8 weeks versus credible sensory-matched active comparator, with equal contact/co-care and an expectancy-factor manipulation or prespecified sensitivity analyses; follow through withdrawal 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. Controls: 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: 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: 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

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.

Dose/base-tartrate normalization and individual perceptibility measured before declaring a regimen subperceptual.

Independent expectancy manipulation and safe interpretation of postdose allocation-guess adjustment.

Clinical relevance of reward/connectivity/EEG/BDNF signals rather than assumed plasticity-mediated therapy.

Longerterm, uncommon and cardiovascular harms; small trial echo/mouse nulls do not quantify rarehuman risk.

Regimen-specific comparative efficacy, support intensity and function without transferring full-dose/ketamine positives ornulls.

REVIEWER NOTES

Sixty-four original peer-reviewed reports were examined via complete abstract/status presentation, plus selected original Methods/Results from three papers. Forty-three concern microdose exposure, mechanism, symptoms, expectancy or safety;twenty-one are explicit full-dose/ketamine comparator reports. One original conference outcome abstract and the official registry were examined separately, without count padding or fabricated PMID. Legitimate secondary reports are grouped by study. Two protocols earn no completed-outcome primary credit. No exhaustive full-paper/supplement audit, fresh blind calibration, independent scientific peer review or rendered video is claimed.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

Consensus and original-source reconciliation

Consensus accurately retains the19-person open-label MDD result and identifies a masked caffeine-comparator result. The latter was independently verified in the original September2026 Donegan conference abstract, DOI10.1093/ijnp/pyag040.021, rather than accepted from synthesis. It reports primary MADRS nonsuperiority and active-arm masking; it is not a complete trial publication or definitive equivalence. The open-label positive remains exploratory, while the separately receipted clinical null narrows its causal attribution. Original PMID41202873.

Consensus labels13/26micrograms as low doses. Original text explicitly states these are LSD tartrate equivalent to10/20micrograms base, fitting the registered base range. Original Methods use water placebo and a possible-drug-category cover story with end-session guesses; actual Results show no residual mood improvement. A26-number label alone cannot justify excluding this study, and a design label cannot guarantee successful masking. Original PMID35106880.

Consensus accurately distinguishes dose-day mood elevations from no baseline-to-six-week questionnaire/cognitive change in80healthy men. Four anxiety withdrawals are important. Baseline-expectancy-adjusted acute effects do not automatically control postdose recognition or establish diagnosed-MDD treatment. The same-trial sleep and PK reports are grouped rather than counted as independent clinical replication. Original PMID36997080.

Consensus describes the self-blinding result as decisive on expectancy. Original Methods confirm participant-sourced uncontrolled substances/doses, randomized capsule schedules and forced guesses; Results show no accumulated benefit and loss of most acute/post-acute contrasts after guess adjustment. Recognition is a posttreatment variable and may carry genuine pharmacologic information, so this supports an expectancy alternative without proving all benefit is placebo. Original PMID33648632.

Consensus correctly reports baseline expectations predicting wellbeing gains in the prospective81-completer observational cohort. The exposure and expectancy were not randomized. The result informs competing models but neither proves exclusive placebo causation nor identifies an independent drug effect. Original PMID33479342.

Consensus correctly reports a controlled psilocybin microdose symptom null and second-block blind breaking. The original duration is three weeks and drug differs fromLSD; this is an observed companion boundary, not a complete direct4–12weekLSD-MDD refutation. Baseline decreases in one block do not become between-arm efficacy. Original PMID34915762.

Consensus emphasizes many microdosing nulls but its source coverage does not exhaust the selected2026 originals. The original pooled171-person truffle creativity report finds a restricted originality-quality positive surviving dose-guess adjustment. It is retained alongside effectively blinded cognitive/emotional null41110634; creativity is not sustained depression treatment and likely shared trials restrict independence. Original PMID41187880.

The original ADHD trial adds clinically diagnosed six-week controlled evidence beyond the provider’s main healthy/MDD narrative. Actual Methods specify20micrograms base, on-site dosing and guesses; Results show no primary clinical superiority, with21/22active and16/24placebo guessing active after the last dose. Its secondary cognition report42322409 shares allocation. This marks an ADHD boundary without being relabeled anMDD result. Original PMID40105807.

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. Original PMID36322843.

Consensus was used to identify literature and cross-check specific claims about design, endpoints, scope and research gaps. Those aspects were checked against original primary abstracts/status records and selected original Methods/Results passages. Consensus output was not treated as original full text. Provider search omissions are not evidence that a study does not exist. Source access and examination receipts are retained. Scite use or monthly unavailability is recorded per case; provider citation counts do not change causal grades.

Research timeline and gaps: Psychedelic Microdosing and Mental Health

Selected publication milestones, not an exhaustive history or discovery priority claim.

2018 — Intermittent rodent psilocin/ketamine anxiety-proxy study gives modest possible anxiogenic boundary rather than clinicalLSD evidence. Original PMID29537989.

2018 — Open-label microdose-event creativity tasks supply early quantitative exploratory support without placebo isolation. Original PMID30357434.

2019 — Controlled low-dose LSD alters interval timing without robust subjective effects; acute pharmacology becomes experimentally testable. Original PMID30478716.

2019 — Healthy acute dose-response study shows measurable subjective action while most cognition and mood outcomes remain unchanged. Original PMID31331617.

2019 — Six-week naturalistic tracking reports symptom declines and mainly dose-day changes, motivating controlled repeat-dose studies. Original PMID30726251.

2020 — Microdosing demographic/diagnosis survey identifies self-selection and concurrent-drug differences. Original PMID32108529.

2021 — Verified base-dose pharmacokinetics show5microgram subjective-null versus10/20microgram perception, defining a dose-dependent boundary. Original PMID32975835.

2021 — Citizen self-blinding separates randomized capsule exposure from guessed allocation and reports no accumulated between-group benefit. Original PMID33648632.

2021 — Prospective baseline expectations predict later wellbeing improvement, strengthening a competing explanation. Original PMID33479342.

2021 — Acute plasmaBDNF positive is reported; it remains a peripheral biomarker rather than validated treatment mediation. Original PMID33860175.

2022 — Repeated controlled10/20base-equivalent LSD produces subjective effects but no residual mood or cognitive advantage. Original PMID35106880.

2022 — Preregistered psilocybin microdose crossover is symptom-null with later blind breaking. Original PMID34915762.

2022 — Psilocybin mushroom microdose subjective recognition andEEG effects coexist with wellbeing/cognition nulls. Original PMID35918311.

2022 — Full-doseCOMP360TRDprimaryweek-three positive has dose and sustained-response limits distinct from microdosing. Original PMID36322843.

2023 — Six-week home LSD trial separates transient dose-day mood elevation from no persistent pre/post change. Original PMID36997080.

2024 — Restricted high-BDI acute low-dose crossover positive raises a symptomatic-population question without testing sustained treatment. Original PMID38042914.

2024 — Same home-trial wearable sleep analysis identifies a delayed measurable effect rather than clinical symptom efficacy. Original PMID38622150.

2025 — Two-center six-week ADHD clinical primary fails despite drug perception and measured allocation guesses. Original PMID40105807.

2025 — Same home-trial PK analysis finds no peripheralBDNF alteration, limiting uniform plasticity-marker claims. Original PMID40251818.

2025 — Positive-controlled chronic mouse cardiac study finds no observedLSD remodeling, with human rare/longterm risk unresolved. Original PMID41789300.

2026 — Direct eight-week open-label MDD improvement is published, furnishing exploratory clinical support requiring causal isolation. Original PMID41202873.

2026 — Same depressed-mood crossover reward analysis relates neural changes to48hour symptoms without mediator manipulation. Original PMID41529826.

2026 — Later effectively blinded psilocybin longitudinal trials report no corrected emotional/cognitive benefit. Original PMID41110634.

2026 — Pooled original truffle creativity trials retain a restricted guess-adjusted originality positive. Original PMID41187880.

2026 — Full-doseEPISODEprimaryresponse null preserves endpoint hierarchy despite favorable exploratory scales and safety signals. Original PMID41848690.

Research gaps

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.

Dose/base-tartrate normalization and individual perceptibility measured before declaring a regimen subperceptual.

Independent expectancy manipulation and safe interpretation of postdose allocation-guess adjustment.

Clinical relevance of reward/connectivity/EEG/BDNF signals rather than assumed plasticity-mediated therapy.

Longerterm, uncommon and cardiovascular harms; small trial echo/mouse nulls do not quantify rarehuman risk.

Regimen-specific comparative efficacy, support intensity and function without transferring full-dose/ketamine positives ornulls.

Boundary experiment

Registered symptomatic-MDD trial of titrated 5–20 microgram base-equivalent LSD twice weekly for 8 weeks versus credible sensory-matched active comparator, with equal contact/co-care and an expectancy-factor manipulation or prespecified sensitivity analyses; follow through withdrawal and relapse.

ADVERSARIAL REVIEW AND APPROVAL

Authoring model: Sol 6.1. Adversarial reviewer: Claude Opus 5.5 (Anthropic). Date: 2026-10-14.

Scope of checks. REFERENCE PMIDs verified against PubMed metadata: 64/64 resolve to the stated title, first author, journal and year; no retraction, retraction-of-publication or expression-of-concern flag on any of the 64. DOIs cross-checked against PubMed for all 64 references (all match). Load-bearing claims spot-checked against PubMed abstracts or the locally stored original passages: 16 (LSDDEP1 open-label MDD result; the 80-participant home LSD trial; the two-centre ADHD trial; the self-blinding citizen study; the repeated 13/26 microgram dose-response study; the depressed-mood crossover; the pooled truffle creativity mega-analysis; the psilocybin microdose crossover; the two longitudinal truffle trials; the psilocybin-mushroom study; COMP360; EPISODE; psilocybin-versus- escitalopram; the esketamine randomized-withdrawal trial; the naltrexone-ketamine crossover; the microdose PK study). Scoring logic re-derived against references/hsef-framework.md and rubric 07-psychiatry-neuromodulation: ladder letter and canonical descriptor, hard-cap precedence, the pre-registered aggregation rule and its two reported alternatives, the causal-role derivation, and the momentum artifact requirement.

Findings.

Eleven distinct corrections (17 occurrences) were applied, all in the reader-facing AT A GLANCE and COMPETING MECHANISTIC MODELS blocks and the repeated decisive-experiment string. Residual defect of the same class: the builder's lost-space defect recurs throughout the technical body (approximately 130 further sites where a word abuts a numeral, e.g. "Original35106880 equates13/26micrograms"). These are a rendering fault in the reference/number interpolation step, not an attribution or scoring error; they are recorded here for an upstream builder fix rather than hand-patched in prose, so that the correction is applied once at the generator.

No level, confidence, role, momentum, stability or divergence value was changed. Final score remains Γ — Mechanistically plausible, partial system support; confidence Moderate; role epiphenomenon.

Rejected findings (checked, no change).

1. Citation year #30 (PMID 33591231). Review prints 2022; PubMed's publication-date field gives 2020 (ahead-of-print). The print issue is J Psychopharmacol 2022;36(1), so the printed year is correct. Rejected per the print-versus-e-pub convention.
2. Aggregation rule. Pre-registered rule is primary-subclaim with SC2 named as primary; the headline equals SC2 (Γ). Reported alternatives are correct: weakest-link returns Α (SC4), and scope-matched also returns Γ because SC2 is the only subclaim whose scope matches the central claim's scope (SC1/SC3 are narrower, SC4 is a different-regimen generalization). No change.
3. Momentum. "Mechanistic only" carries the required artifact (ANZCTR ACTRN12624000128594 recruitment status plus the September 2026 IJNP conference outcome abstract). The decisive trial is completed, not underway, so "Decisive work underway" would be wrong. No change.
4. Dose-unit conversions. "13/26 micrograms tartrate = 10/20 micrograms base" and "29 micrograms tartrate = 20 micrograms base" were both checked against the stored original Methods text of PMID 35106880 and PMID 40105807 and are stated correctly, including the apparently inconsistent tartrate:base ratio, which is what the two papers report.
5. Collective-author defect. No reference in this review has a dropped collective first author or a stray leading comma; the known builder bug does not fire here.
6. Framework validator version. The validator bundled with this package (v2.3) returns PASS on 30 checks. The newer v2.4 copy at the framework root adds a v5.lay_summary check that is mandatory only from v5.4; this review is v5.3 and the failure is a validator-version artifact, not a defect in the review. No lay summary was added.

Residual limitations. Verification remains bounded attribution: 61 of the 64 reports were checked at abstract/status depth and three at partial-body depth, so a claim that depends on an unexamined Methods detail cannot be certified here. The decisive LSDDEP2 outcome evidence is still a conference abstract; if the full report diverges from it, SC2's rationale will need revisiting.

Approval: Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-14.

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31. 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. PMID 40051483. DOI: 10.1089/psymed.2024.0005. Access: abstract_metadata. Study: PMID40051483.

32. 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. PMID 35106880. DOI: 10.1111/adb.13143. Access: full_text_partial. Study: PMID35106880.

33. 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. PMID 29537989. DOI: 10.1097/FBP.0000000000000394. Access: abstract_metadata. Study: PMID29537989.

34. 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. PMID 40251818. DOI: 10.1177/02698811251330747. Access: abstract_metadata. Study: ACTRN12621000436875.

35. Zarankin M, Pellegrini MS, Zenteno F. [Psilocybin fungi microdose treatment in major depressive disorder: a case report]. Vertex (Buenos Aires, Argentina). 2024. PMID 39024488. DOI: 10.53680/vertex.v35i164.544. Access: abstract_metadata. Study: PMID39024488.

36. Prochazkova L, Lippelt DP, Colzato LS et al. Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting. Psychopharmacology. 2018. PMID 30357434. DOI: 10.1007/s00213-018-5049-7. Access: abstract_metadata. Study: PMID30357434.

37. Ryan RS, Copello A, Fox AP. Experiences of microdosing psychedelics in an attempt to support wellbeing and mental health. BMC psychiatry. 2023. PMID 36918852. DOI: 10.1186/s12888-023-04628-9. Access: abstract_metadata. Study: PMID36918852.

38. Hutten NRPW, Quaedflieg CWEM, Mason NL et al. Inter-individual variability in neural response to low doses of LSD. Translational psychiatry. 2024. PMID 39009578. DOI: 10.1038/s41398-024-03013-8. Access: abstract_metadata. Study: PMID39009578.

39. 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. PMID 41789300. DOI: 10.1021/acsptsci.5c00202. Access: abstract_metadata. Study: PMID41789300.

40. Kaertner LS, Steinborn MB, Kettner H et al. Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing. Scientific reports. 2021. PMID 33479342. DOI: 10.1038/s41598-021-81446-7. Access: abstract_metadata. Study: PMID33479342.

41. Raison CL, Sanacora G, Woolley J et al. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023. PMID 37651119. DOI: 10.1001/jama.2023.14530. Access: abstract_metadata. Study: PMID37651119.

42. 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. PMID 41848690. DOI: 10.1001/jamapsychiatry.2026.0132. Access: abstract_metadata. Study: PMID41848690.

43. 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. PMID 36740140. DOI: 10.1016/j.jad.2023.01.108. Access: abstract_metadata. Study: NCT03775200.

44. 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. PMID 40858059. DOI: 10.1016/j.genhosppsych.2025.08.001. Access: abstract_metadata. Study: PMID40858059.

45. Carhart-Harris R, Giribaldi B, Watts R et al. Trial of Psilocybin versus Escitalopram for Depression. The New England journal of medicine. 2021. PMID 33852780. DOI: 10.1056/NEJMoa2032994. Access: abstract_metadata. Study: PMID33852780.

46. Davis AK, Barrett FS, May DG et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA psychiatry. 2021. PMID 33146667. DOI: 10.1001/jamapsychiatry.2020.3285. Access: abstract_metadata. Study: NCT03181529.

47. 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. PMID 38359838. DOI: 10.1016/j.medj.2024.01.005. Access: abstract_metadata. Study: PMID38359838.

48. 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. PMID 27909165. DOI: 10.1177/0269881116675513. Access: abstract_metadata. Study: PMID27909165.

49. 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. PMID 35166158. DOI: 10.1177/02698811211073759. Access: abstract_metadata. Study: NCT03181529.

50. Ross S, Bossis A, Guss J et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of psychopharmacology (Oxford, England). 2016. PMID 27909164. DOI: 10.1177/0269881116675512. Access: abstract_metadata. Study: PMID27909164.

51. Murrough JW, Iosifescu DV, Chang LC et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. The American journal of psychiatry. 2013. PMID 23982301. DOI: 10.1176/appi.ajp.2013.13030392. Access: abstract_metadata. Study: PMID23982301.

52. Jelen LA, Lythgoe DJ, Stone JM et al. Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study. Nature medicine. 2025. PMID 40707608. DOI: 10.1038/s41591-025-03800-w. Access: abstract_metadata. Study: PMID40707608.

53. Reif A, Bitter I, Buyze J et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. The New England journal of medicine. 2023. PMID 37792613. DOI: 10.1056/NEJMoa2304145. Access: abstract_metadata. Study: PMID37792613.

54. Anand A, Mathew SJ, Sanacora G et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. The New England journal of medicine. 2023. PMID 37224232. DOI: 10.1056/NEJMoa2302399. Access: abstract_metadata. Study: PMID37224232.

55. 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. PMID 31166571. DOI: 10.1001/jamapsychiatry.2019.1189. Access: abstract_metadata. Study: PMID31166571.

56. Glue P, Neehoff S, Beaglehole B et al. Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study. Journal of psychopharmacology (Oxford, England). 2024. PMID 38293803. DOI: 10.1177/02698811241227026. Access: abstract_metadata. Study: PMID38293803.

57. Grunebaum MF, Galfalvy HC, Choo TH et al. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. The American journal of psychiatry. 2018. PMID 29202655. DOI: 10.1176/appi.ajp.2017.17060647. Access: abstract_metadata. Study: PMID29202655.

58. Goodwin GM, Aaronson ST, Alvarez O et al. The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression. Journal of affective disorders. 2025. PMID 39706482. DOI: 10.1016/j.jad.2024.12.061. Access: abstract_metadata. Study: NCT03775200.

59. 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. PMID 39427449. DOI: 10.1016/j.jpsychires.2024.10.009. Access: abstract_metadata. Study: NCT03775200.

60. 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. PMID 34743319. DOI: 10.1002/cpt.2487. Access: abstract_metadata. Study: PMID34743319.

61. 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. PMID 36322843. DOI: 10.1056/NEJMoa2206443. Access: abstract_metadata. Study: NCT03775200.

62. Holze F, Liechti ME, Hutten NRPW et al. Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants. Clinical pharmacology and therapeutics. 2021. PMID 32975835. DOI: 10.1002/cpt.2057. Access: abstract_metadata. Study: PMID32975835.

63. 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. PMID 33860175. DOI: 10.1021/acsptsci.0c00099. Access: abstract_metadata. Study: PMID33860175.

64. 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. PMID 41073618. DOI: 10.1007/s00213-025-06913-9. Access: abstract_metadata. Study: PMID41073618.

Source-specific evidence cards

[1] Self-blinding citizen science to explore psychedelic microdosing.

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.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[2] A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[3] Low doses of LSD reduce broadband oscillatory power and modulate event-related potentials in healthy adults.

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.

Does not show: Acute biomarkers and tartrate/base formulation requiring explicit equivalence; no persistent clinical symptom endpoint or mediator manipulation.

Access/status: 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. none_found. Subclaims: SC1.

[4] Greater subjective effects of a low dose of LSD in participants with depressed mood.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3.

[5] Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers.

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.

Does not show: Single-dose healthy population; no sustained symptomatic cohort endpoint and perceptibility varies by dose.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[6] Effects of repeated low-dose LSD on neuropsychological functioning in adults with ADHD: a randomized placebo-controlled study.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[7] Preliminary Report on the Effects of a Low Dose of LSD on Resting-State Amygdala Functional Connectivity.

Shows: Twenty healthy participants showed amygdala connectivity changes after 13 micrograms; positive mood correlated with connectivity amid weak variable mood effects.

Does not show: Single-dose imaging and observational mediator correlation cannot establish sustained therapy or that connectivity is required for benefit.

Access/status: 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. none_found. Subclaims: SC1.

[8] 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.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC4.

[9] Cognitive and subjective effects of psilocybin microdosing: Results from two double-blind placebo-controlled longitudinal trials.

Shows: Two longitudinal placebo-controlled psilocybin-truffle trials found no corrected cognitive or emotional benefit, while participants reportedly remained effectively blinded.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3, SC4.

[10] LSD increases sleep duration the night after microdosing.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[11] Psilocybin microdosing does not affect emotion-related symptoms and processing: A preregistered field and lab-based study.

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.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3, SC4.

[12] Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3.

[13] Reward-related neural activity after low doses of LSD in participants with depressed mood.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[14] The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial.

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.

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.

Access/status: 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. ErratumIn: PMID33089876. Subclaims: SC1.

[15] Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3, SC4.

[16] Microdosing psilocybin and its effect on creativity: Lessons learned from three double-blind placebo controlled longitudinal trials.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC3, SC4.

[17] Microdosing psychedelics: Motivations, subjective effects and harm reduction.

Shows: International 525 current-microdoser survey reports mental-health motivations, perceived mood/anxiety benefits, stronger-than-expected effects and anxiety adverse experiences.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[18] Psychedelic Microdosing: Prevalence and Subjective Effects.

Shows: Anonymous 2347-person survey included 383 microdosing respondents attributing improved mood/anxiety and cognition to the practice.

Does not show: Self-selected attribution and varying denominator; no verified dose, comparator or symptom trajectory. Report count is not evidence of pharmacologic causality.

Access/status: 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. none_found. Subclaims: SC2.

[19] Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities.

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.

Does not show: Cross-sectional diagnosis histories, self-selection and concurrent drug differences; temporal direction and causal reduction unestablished. Mainly young male/White sample limits generalization.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[20] A systematic study of microdosing psychedelics.

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.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[21] Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults: A Randomized Clinical Trial.

Shows: 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.

Does not show: 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.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3.

[22] Natural language signatures of psilocybin microdosing.

Shows: Thirty-four psilocybin participants showed speech-feature changes and cross-validated condition discrimination after 0.5 g mushrooms.

Does not show: Shares 35918311 sample/design; acoustic/semantic condition recognition is pharmacodynamic and may facilitate unblinding, not persistent therapy or externally validated predictor.

Access/status: 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. none_found. Subclaims: SC1, SC3, SC4.

[23] Psychedelic Microdosing, Mindfulness, and Anxiety: A Cross-Sectional Mediation Study.

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.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[24] Psychedelic microdosing benefits and challenges: an empirical codebook.

Shows: Qualitative 278 microdoser codebook reports improved mood 26.6%, discomfort 18% and anxiety 6.7%, identifying plausible outcomes and harms.

Does not show: Self-attributed experiences and coded-report proportions are not treatment response or incidence estimates; no blinded comparator and mixed drugs.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[25] LSD microdosing in major depressive disorder: results from an open-label trial.

Shows: 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.

Does not show: 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.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3.

[26] Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity.

Shows: Eighteen healthy adults showed enhanced reward ERP components after 13/26 micrograms versus placebo, mostly not correlated with subjective effects.

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.

Access/status: 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. none_found. Subclaims: SC1.

[27] Motives and Side-Effects of Microdosing With Psychedelics Among Users.

Shows: 1116 current/former microdosers reported performance motives, acute psychological negatives and ineffectiveness as the main stop reason;many did not know dose.

Does not show: Self-selected online sample, no verified compounds and retrospective benefit/AE attribution; neither universal safety nor treatment efficacy established.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[28] Might Microdosing Psychedelics Be Safe and Beneficial? An Initial Exploration.

Shows: Descriptive international daily PANAS reports from more than 1000 people suggested mood/work/health improvement with repeated microdosing.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[29] Microdosing psychedelics: personality, mental health, and creativity differences in microdosers.

Shows: Preregistered online observational comparison reports lower negative emotionality and greater openness/wisdom/creativity among current/former microdosers.

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.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[30] Microdosing psychedelics: Subjective benefits and challenges, substance testing behavior, and the relevance of intention.

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.

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.

Access/status: 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. ErratumIn: PMID37226829. Subclaims: SC2, SC3.

[31] Low-Dose LSD Alters Early and Late Event-Related Potentials to Emotional Faces.

Shows: Thirty-nine healthy adults in 26 microgram crossover showed selective neutral/happy-face ERP attenuation.

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.

Access/status: 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. none_found. Subclaims: SC1.

[32] Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC3.

[33] Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats.

Shows: Forty male rats intermittently dosed with low psilocin/ketamine had modest/borderline elevated-plus-maze effects tending mildly anxiogenic 48 hours later.

Does not show: Different compounds and rodent anxiety proxy;multiple pairwise testing and small groups. Does not establish human LSD harm or clinical inefficacy.

Access/status: 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. none_found. Subclaims: SC1, SC2, SC4.

[34] Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[35] [Psilocybin fungi microdose treatment in major depressive disorder: a case report].

Shows: Single 19-year-old MDD case reports remission during seven-month psilocybin microdosing accompaniment and conventional-drug withdrawal.

Does not show: One uncontrolled case, different compound and concomitant advice;cannot establish dose-specific therapy, safe medication discontinuation or general response.

Access/status: 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. none_found. Subclaims: SC2, SC4.

[36] Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting.

Shows: Nonblinded truffle microdose event shows before/after convergent/divergent task improvement with fluid intelligence unchanged;alkaloids subsequently quantified.

Does not show: No placebo, practice/expectancy effects or clinical symptoms;creativity mechanism speculation does not establish therapeutic efficacy.

Access/status: 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. none_found. Subclaims: SC1, SC3, SC4.

[37] Experiences of microdosing psychedelics in an attempt to support wellbeing and mental health.

Shows: Thirteen anonymous qualitative interviews describe purposeful microdosing and perceived mental-health/cognitive/social benefits.

Does not show: Experiential meaning informs hypotheses but lacks comparator/exposure verification;interpretative themes are not causal evidence or response prevalence.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[38] Inter-individual variability in neural response to low doses of LSD.

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.

Does not show: Neural adaptation and exploratory moderation are not clinical 4–12 week symptom benefit;subgroup selection must precede outcome, and not all markers improve.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[39] Assessing the Potential Cardiovascular Risk of Microdosing the Psychedelic LSD in Mice.

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.

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.

Access/status: 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. none_found. Subclaims: SC1, SC2.

[40] Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing.

Shows: Prospective naturalistic four-week study 81 endpoint completers reports symptom/wellbeing improvement and baseline positive expectancy predicting wellbeing gains.

Does not show: No randomized expectancy or treatment;association supports competing explanation but does not prove every pharmacologic effect is placebo. Attrition and mixed exposure constrain interpretation.

Access/status: 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. none_found. Subclaims: SC2, SC3.

[41] Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.

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.

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.

Access/status: 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. ErratumIn: PMID38277159. Subclaims: SC4.

[42] Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.

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.

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.

Access/status: 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. none_found. Subclaims: SC4.

[43] Single-dose psilocybin for a treatment-resistant episode of major depression: Impact on patient-reported depression severity, anxiety, function, and quality of life.

Shows: COMP360233 TRDparticipants 25/10/1 mg with support showed week 3 patient-reported symptom/function improvements strongest 25 mg.

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.

Access/status: 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. none_found. Subclaims: SC4.

[44] Psilocybin-assisted psychotherapy for depression and anxiety associated with life threatening illness: A phase 2b randomized controlled trial.

Shows: Thirty-five life-threatening-illness patients 25 mg psilocybin versusniacin with psychotherapy had 6–7 week depression/anxiety advantages and 26 week persistence.

Does not show: Smallsingle-site and lateropenlabel/allactive extension lose randomizedlongtermcontrast;niacin mismatch andoneanxietywithdrawal. Distinct disease/support scope, not LSDmicrodose efficacy.

Access/status: 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. none_found. Subclaims: SC4.

[45] Trial of Psilocybin versus Escitalopram for Depression.

Shows: Fifty-nine MDDpatients two 25 mg psilocybin versusescitalopram with 1 mg sessions/support had nonsignificant primary QIDSdifference P.17, while uncorrectedsecondary outcomes favoredpsilocybin.

Does not show: Head-to-head not placebo;smallimpreciseprimaryresult neither establishes equivalence norpsilocybin superiority. Functionalunblinding/supportdrugpackages notisolated.

Access/status: 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. none_found. Subclaims: SC4.

[46] Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.

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.

Does not show: Waitlist doesn’tmatchcontact/expectancy, outcomeawareintervention andevaluablepopulation;full-dose package distinct. Correction 33566065 attachedmetadataonly.

Access/status: 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. ErratumIn: PMID33566065. Subclaims: SC4.

[47] Psilocybin-assisted psychotherapy for treatment resistant depression: A randomized clinical trial evaluating repeated doses of psilocybin.

Shows: Thirtycomplex TRD/MDD/bipolar IIpatients randomizedimmediate versuswaitlist 25 mgwithpsychotherapy showedweek 2 MADRSbenefit;additionaldoses associatedwithfurtherdecline.

Does not show: Unmatchedwaitlist andeventualactive dosing don’tisolatepharmacologyorcausalrepeat-doseincrement;safety/scopeunderpowered. Not LSDmicrodosegeneralization.

Access/status: 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. none_found. Subclaims: SC4.

[48] Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.

Shows: Fifty-onecancer-distresspatients high 22/30 mg versus 1/3 mg-per 70 kg crossover psilocybin showedpersistentclinician/self/community-ratedmoodbenefits andexperience-outcomemediation.

Does not show: Lowdosecomparator maynotmatchacuteexperience;statisticalmysticalmediationnotmanipulation ornecessity. Crossover/alltreatedfollowup andcancerscaffold limittransfer.

Access/status: 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. none_found. Subclaims: SC3, SC4.

[49] Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up.

Shows: Same 33146667 parent 24 completers showedlarge 12 monthdepressionscaledecline,response 75%/remission 58%;mysticalmeaning predictedwellbeingbutnotdepression improvement.

Does not show: Longtermalltreatedobservations have nocontemporaneousrandomizedcontrol;notnewindependenttrial orproofmysticalexperiencecausestherapy. No serious AEsinsmallsampleisnotuniversalsafety.

Access/status: 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. none_found. Subclaims: SC3, SC4.

[50] Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.

Shows: Twenty-ninecancer-distresspatients 0.3 mg/kg psilocybin versusniacinwithpsychotherapy hadpre-crossover 7 weeksymptompositivesandsustainedalltreatedfollowup.

Does not show: Experience-matching/blindingintegrity notconfirmedfromabstract;statisticalmediationnotnecessarycausalexperience. Distinctfull-doseoncologycontextcannotvalidate LSDmicrodose.

Access/status: 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. none_found. Subclaims: SC3, SC4.

[51] Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.

Shows: Two-site 73 TRDpatients ketamine versusmidazolam produced 24 hour MADRSdifference 7.95 points and 64%versus 28%response.

Does not show: Active psychoactive comparator important but integrity/sensorymatch notverifiedfromabstract;single-day effectnot 4–12 week LSDtherapy andketamine mechanism notsame serotonergicmicrodose.

Access/status: 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. none_found. Subclaims: SC4.

[52] Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study.

Shows: Twenty-six MDD crossover participants receivingnaltrexone beforeketamine hadattenuatedglutamate/glutamine response andday 1 MADRSreduction versusplacebopretreatment.

Does not show: Actualmediator perturbation narrower opioid-dependency evidence,notexperience-removal orproofonlyopioidmechanism;acuteoutcomeandpotentialnaltrexonedirecteffects requirecontrols. Differentdrugcannotqualify LSDclinicalclaim.

Access/status: 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. none_found. Subclaims: SC3, SC4.

[53] Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression.

Shows: 676 TRDpatients randomizedesketamine versusquetiapine augmentation withblindraters hadweek 8 remission 27.1%versus 17.6% andmaintainednonrelapse advantage.

Does not show: Openlabelparticipants,ongoing SSRI/SNRI anddifferingdrugpackages;notcleanexpectancy separation ormicrodosegeneralization. Sponsor-linkedtrialnotindependent mechanisticclass.

Access/status: 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. none_found. Subclaims: SC4.

[54] Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

Shows: Five-site 403 randomizednonpsychotic TRDpatients ketamine versus ECT metprespecifiednoninferiority for 3 weekself-ratedresponse;memorydeclinegreater ECT.

Does not show: Openlabel with 38 predosingwithdrawals anddifferenttreateddenominators;noninferiority doesn'tproveuniversal superiority/equivalence orseparatepackageexpectancy. Not LSDregimen efficacy.

Access/status: 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. none_found. Subclaims: SC4.

[55] Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Shows: 297 stableesketamineresponders/remitters randomizedcontinuation versuswithdrawal whileoralantidepressantcontinued showedlowerrelapse;remitters 26.7%versus 45.3%.

Does not show: Field-validwithdrawal withinprespecifiedmaintenancescope,notallnewpatients;dissociationimbalance threatensblind andwithdrawaleffects needconsideration. Responder-definedtrialeligibility isdeclaredprospectively,notposthocscopeforscoring LSD.

Access/status: 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. none_found. Subclaims: SC4.

[56] Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study.

Shows: Twenty-five TRD crossoverpatients ketamine 0.5/1 mg/kg versusfentanyl hadgreater 24 hourdepression/anxietyresponses withsome 7 daypersistence.

Does not show: Activecontrolbutsmall,carryoverandexperiencematching unresolvedfromabstract;similarantidepressanteffectacrossdoses despitegradedsideeffects. Differentdrug short horizon not LSDmicrodose.

Access/status: 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. none_found. Subclaims: SC4.

[57] Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial.

Shows: Eighty MDDpatients ketamine versusmidazolam showed 24 hoursuicidalideationdifference 4.96 points and 55%versus 30%response.

Does not show: Suicidalideationscaleisnotattempt/death prevention;6 weekpersistencefolloweduncontrolledoptimizedpharmacotherapy. Statisticaldepressionmediationnotnecessity anddifferentdrug/scope.

Access/status: 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. none_found. Subclaims: SC4.

[58] The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression.

Shows: COMP360233 trialsecondaryanalysis reportsdose-relatedexperiencesandspecificweek 3 MADRSexperiencecorrelations withoverlapacrossdoses.

Does not show: Experienceobservednotrandomizedmediator;overlapdoesn'tmeasureallocationguessintegrity orprovecausation. Same 36740140/39427449 allocation;correction 41075579 metadataonly.

Access/status: 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. ErratumIn: PMID41075579. Subclaims: SC3, SC4.

[59] The impact of antidepressant discontinuation prior to treatment with psilocybin for treatment-resistant depression.

Shows: Posthoc COMP360233 analysis foundantidepressantdiscontinuationnotassociatedwithworseningscreeningsymptomsorcompromisedpsilocybineffects.

Does not show: Discontinuationgroupnotrandomized;cannotgeneralizeallwithdrawalregimensorconcomitantdrugs. Sameparentallocation,notnewreplication orvalidatation LSDwithongoingantidepressants.

Access/status: 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. none_found. Subclaims: SC3, SC4.

[60] Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.

Shows: Healthy-subjectescitaloprampretreatment crossoverretainedpositive 25 mgpsilocybinmoodwhileattenuatinganxiety/negativecardiovascularresponses;PKunchangedandperipheral BDNFnull.

Does not show: Two-week SSRIpretreatment andacutehealthyfull-doseoutcomenot MDDtreatmentorlongtermmedicationcombination. Experience-qualitymanipulationdoesnotprovenecessityorabsenceofneuroplasticity.

Access/status: 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. none_found. Subclaims: SC1, SC3, SC4.

[61] Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

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.

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.

Access/status: 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. none_found. Subclaims: SC4.

[62] Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants.

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.

Does not show: Acute healthy crossover not persistent therapy;definesdose-dependent perception rather than universal subperceptual threshold. PK/subjectivitynot independently demonstrated clinical mechanism.

Access/status: 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. none_found. Subclaims: SC1, SC3.

[63] Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers.

Shows: Placebo-controlled within-subject 5/10/20 microgram LSD study found selected plasma BDNF rises at 4/6 hours.

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.

Access/status: 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. none_found. Subclaims: SC1.

[64] Daily self-assessment within a regimen of microdosing indicates enhanced psychological functioning on microdosing days relative to non-microdosing days.

Shows: Prospective 1435-adult naturalistic survey found higher self-rated wellbeing/productivity/connectedness/focus on microdosing days versus nondosingdays;previousmacrodoses modifiedcreativity.

Does not show: Within-person unblinded dose scheduling doesnotrandomizeexposure/expectancy;daychanges are not persistent 4–12 weekdepression therapy anddifferent denominators reflectmissingdomainresponses.

Access/status: 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. none_found. Subclaims: SC2, SC3.

Documentary record

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• ADVERSARIAL_REVIEW.md
• CONSENSUS_CROSSCHECK.html
• CONSENSUS_CROSSCHECK.md
• RESEARCH_TIMELINE.html
• RESEARCH_TIMELINE.md
• SHA256.txt
• adversarial-findings.json
• codex-correction-provenance.json
• consensus-validation.json
• edition-approval-audit.json
• psychedelic-microdosing-symptoms.review.md
• psychedelic-microdosing-symptoms.scorecard.json
• reader-summary.json
• research-timeline.json
• validation-report.json
• validation-round2-2026-10-14.json
• validation.txt
• video-insert.md
• web-page.md

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