# HSEF v5.3 review: Dual-Phase Psilocybin Therapy Hypothesis

> Sources: 60 primary reports; claims: 65; verified: 65; unverified: 0. Verification is bounded attribution. Access: 4 partial-body and 56 complete abstract/status examinations. Cutoff: 2026-10-04. No complete-paper audit or blinded calibration claimed.
>
> **Adversarial review:** Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-06. 0 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: **Approved as revised.**

## AT A GLANCE

**Psilocybin changes experimental synapses and can improve clinical treatment-package outcomes. Required formal integration and required subjective experience remain mechanistically plausible but unisolated (Γ).**

| Level | Confidence | Causal role | Momentum | Stability | Divergence |
|---|---|---|---|---|---|
| Γ — Mechanistically plausible, partial system support | Moderate | epiphenomenon | Mechanistic only | Stable | Contested |

**Deciding experiment:** Randomize baseline-defined depressed/anxious participants receiving the same psilocybin dose and preparation to formal postacute integration versus equal-contact supportive follow-up, with balanced allegiance, explicit protocol/fidelity, participant/rater allocation guesses and masked central assessments at six and twelve months. Add a prespecified early-versus-delayed integration contrast and a separately controlled drug-intact experience-removal study to distinguish timing, therapy and subjective mechanisms.

**Belief versus evidence:** The registered weakest-link conjunction returns Γ. All four therapeutic/mechanism clauses remain Γ under rubric 07, though cell/rodent plasticity and some clinical package effects are empirically positive. Primary-SC2 and scope-matched sensitivities also return Γ. The unresolved content is required formal consolidation, not whether the drug ever changes synapses or symptoms.

**Best-supported rival:** Generic plasticity plus environment. With identical drug and supportive safety contact, randomize structured integration versus equal-contact nonintegrative follow-up, balancing allegiance and expectancy; separately manipulate subjective experience while preserving drug exposure and measure durable remission.

## COMPETING MECHANISTIC MODELS

**Rank 1: Generic plasticity plus environment (Γ).** Drug-induced neural susceptibility interacts with activity and environment. Activity silencing, social-learning/metaplasticity and structural studies support defined rodent routes [18,20,24,30,36,52]. No human formal integration necessity or cortical scheduling window is isolated.

**Rank 2: Dose/receptor occupancy (Γ).** Dose and receptor exposure explain pharmacodynamic changes and some package response. Randomized dose response and human occupancy/acute antagonist data anchor pharmacology [1,40,55]. Dose changes experience/expectancy too; receptor engagement is not sufficient proof of lasting therapeutic mediation.

**Rank 3: Autonomous pharmacological reset (Γ).** A pharmacological change can persist without a required conscious or formal consolidation process. Persistent mouse synapses and nonhallucinogenic-like congeners provide plausibility [20,23,28,31,51,52,54]. Human treatment retains support/integration; no isolated autonomous durable-remission experiment.

**Rank 4: Expectancy/functional unblinding (Β).** Expectancy, contact and allocation inference contribute to symptoms. Placebo improvements, fixed-order ambiguity and unassessed blinding reveal uncontrolled competing influences [17,59]. These limitations do not establish expectancy as the sole cause; positive drug dose and rodent perturbation findings remain.

**Rank 5: Required psychotherapeutic consolidation (Γ).** Formal integration is necessary to convert drug-induced plasticity into lasting remission. Clinical packages and the rodent critical-period theory provide compatible observations [3,4,6,11,30,46,47]. No human component-removal or mediation-necessity result identifies this distinguishing requirement.

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

Psilocybin works best as psilocybin-assisted psychotherapy: the drug rapidly opens a neurodevelopmental-like window of synaptic plasticity, and formal post-acute psychotherapeutic integration is causally required to consolidate that state into lasting clinical remission.

The index explicitly prescribes weakest-link; SC2 is distinguishing content. Rubric 07 supersedes the index historical rubric-mismatch note.

Selection: public-interest rank 5 from the editorial ranking compiled 2026-09-23; categorical prior verdicts were visible. Private fresh review; earlier documents are preserved.

### Evidence and causal interpretation

The hypothesis is more specific than clinical efficacy. It requires drug-triggered plasticity, a human-relevant time window, formal postacute psychotherapeutic consolidation, and a necessary subjective experience. A treatment bundle can improve symptoms without identifying any one required component. The registered weakest-link rule therefore evaluates those clauses separately. The psychiatry rubric requires a credible human mediator or scaffold contrast before the clinical mechanism crosses Δ.

Clinical benefit is supported in several settings. The large COMP360 dose trial found a week-three symptom advantage at 25 mg versus 1 mg, while its sustained twelve-week response measure was not generally supportive [1]. The escitalopram comparison missed its primary between-group QIDS endpoint, though multiple secondary outcomes favored psilocybin [2]. Delayed-treatment and cancer-distress trials report substantial improvements within supportive treatment [3,4,6,11]. These are empirical observations, not demonstrations of formal integration necessity.

The 2023 multisite MDD trial improved depression and disability, with remote central raters. Its primary Methods explicitly include four hours of postdose integration in both arms, and its limitations say allocation-blinding success was not assessed [17]. Calling that trial psilocybin without integration would be factually incorrect. Niacin provides a flushing comparator but not a matched psychedelic experience. The positive outcome survives as a package result while its distinguishing component remains unidentified.

Recent evidence is not uniformly positive. The 2026 EPISODE active-placebo trial missed its prespecified primary response comparison; secondary symptom changes were exploratory [14]. A new CBT pilot combined two doses with twelve therapy sessions and retained gains, but had no randomized therapy counterfactual [46]. The mindfulness trial compared MBSR alone with MBSR plus group PAP and favored the larger package initially, with waning benefit by six months [50]. It tests adding drug and PAP, not removing formal integration while retaining the drug.

Long follow-up supplies durability observations but fewer independent trials than the publication count suggests. The twelve-month Hopkins analysis follows the original MDD cohort and found that meaning/mystical ratings predicted well-being, not depression improvement [9]. The six-month escitalopram follow-up is descriptive, has missing data and possible additional interventions, and does not significantly separate depression scores [53]. The earlier expanded TRD analyses share participants and open-label exposure [5,7,35,41]. Durability and mechanism identification remain different questions.

Preclinical plasticity is more directly perturbed. The 2021 mouse imaging study found rapid spine growth persisting for a month [20]. With ketanserin, head twitch disappeared while spine width and formation remained detectable; density significance was no longer present. The body acknowledges incomplete receptor blockade. This is a useful dissociation, not proof that 5HT2A is irrelevant or that a conscious human experience has been removed.

The 2025 targeted-deletion study narrows the receptor question in adult mouse cortex [24]. Local 5HT2A deletion removed structural responses and specified stress-assay effects while head twitch remained, emphasizing that pharmacodynamic behavior and local plasticity need not be identical. The primary body also notes that the learned-helplessness control response did not reach significance, limiting that specific contrast. Genetic targeting improves specificity, while strain/control and rodent outcome limitations remain.

Other mechanistic work identifies intracellular receptor localization, TrkB/BDNF signaling and broad receptor pharmacology [19,21,22,42]. Direct TrkB-binding dependence and apparent 5HT2A independence in one paradigm contrast with receptor-dependent results elsewhere. The assays, regions and interventions differ. They should not be flattened into either one universally established receptor chain or a declaration that every reported plasticity mechanism is false.

The critical-period study is particularly relevant to the dual-phase theory [30]. Its actual body shows psilocybin-treated mice learned social reward at two weeks but not three, and describes oxytocin-related metaplasticity rather than general baseline hyperplasticity. Ketanserin blocked the psilocybin learning result in that experiment but not every other drug's effect. A nucleus-accumbens social-learning window is distinct from persistent cortical spines and from human depression remission. Those distinctions prevent deriving a clinical integration schedule from one mouse timescale.

Activity silencing in the newer cortical-network study changes psilocybin-induced rewiring [18], and fear-extinction training accompanies benefits in another mouse model [36]. These results support learning/environment interaction in bounded systems. Nonhallucinogenic-like compounds and antagonists retain some plasticity and behavior effects [23,28,31,51,52,54]. They constrain a universal claim that hallucinogenic-like behavior is indispensable, but rodents do not report conscious experience and congeners are different exposures.

Human imaging confirms acute and persisting functional changes, not direct cortical synapse formation. Precision fMRI maps desynchronization and weeks-long hippocampal-DMN changes [34]. Depression network modularity, flexibility and emotional-response studies provide correlations and dissociations [8,35,37,49]. The cerebral-flow study also finds a vascular effect relevant to interpreting functional signals [56]. None randomizes learning during an independently measured human synaptic window to test durable remission.

Experience correlations are similarly bounded. Dose, receptor occupancy, acute intensity and later response can share pharmacokinetics, expectancy and baseline susceptibility [40,44,57]. Acute human antagonism blocks perceptual effects [55] but does not measure subsequent depression remission with drug exposure intact. The fixed-order trial found improvement after placebo and psilocybin without significant separation and no mystical-outcome correlation [59]. These results challenge simple mediation accounts without proving subjective experience never matters.

The most informative missing study is a component trial, not another successful bundled treatment. Equal drug exposure and safety contact, formal integration removal, fidelity, allocation guesses and masked durable outcomes would test necessity. An early/delayed contrast could test a validated human timing window. The anesthesia paper returned by SciSpace and Consensus is only a proposal and is excluded from the primary count. The full conjunction remains Γ with moderate confidence, alongside real experimental plasticity and clinical package findings.

## HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

<!-- consensus-consistency-2026-10-09 -->
### Consensus provenance reconciliation — 9 October 2026

Case-specific Consensus discovery records were located and linked to this final edition. This supplements the review's provenance; it leaves the original assessed claim, grades and source counts intact. Provider summaries and full-text badges do not establish examination of original primary passages by this reviewer. Source access and incorporation retain the limits stated in the original methods and any dated research update.

Recorded evidence artifacts:

- `deliverables/hsef_v53_popularity_batch_2026-10-04/psilocybin-dual-phase/consensus-initial-raw.json`
- `deliverables/hsef_v53_popularity_batch_2026-10-04/psilocybin-dual-phase/consensus-targeted-raw.json`
- `deliverables/hsef_v53_popularity_batch_2026-10-04/psilocybin-dual-phase/consensus/evidence-cards.json`
- `deliverables/hsef_v53_popularity_batch_2026-10-04/psilocybin-dual-phase/consensus/evidence-cards.md`
- `deliverables/hsef_v53_popularity_batch_2026-10-04/psilocybin-dual-phase/consensus/rejections.json`

The located artifacts do not state a reliable source-comparison count. No count is inferred.

A dated adversarial approval record exists for the separately identified psilocybin-dual-phase.review.md (2026-10-06; see edition-approval-audit.json). Its scope is that recorded edition. This supplement has no separate approval and no coverage is inferred from topic identity. No score or confidence change is made by this reconciliation.
<!-- end-consensus-consistency -->


### Subclaim matrix and aggregation

| Subclaim | Scope | Level | Decision |
|---|---|---|---|
| SC1 Psilocybin induces a transient 5-HT2A- and TrkB/BDNF-dependent window of heightened synaptic plasticity. | predefined cellular and rodent experimental settings; human inference separate | Γ | SC1 has directly perturbed cellular/rodent plasticity, including adult targeted receptor deletion and activity manipulation [18–24,30,52]. Exact universal 5HT2A/TrkB dependence differs by paradigm [20,22,24,54]. Rubric 07's preclinical/rodent cap and missing clinical trajectory mediator keep the therapeutic-window interpretation at Γ. |
| SC2 Formal post-acute psychotherapeutic integration is causally required for lasting remission. | human depressive and anxiety disorders studied clinically | Γ | SC2 remains Γ: positive treatment packages contain support/integration, but no admitted study randomizes removal of formal postacute integration with intact drug exposure, equal contact and masked durable outcomes [1–7,11,14,16,17,43,46,47,50,59,60]. The 2026 CBT pilot is single-arm; MBSR comparison adds PAP to training, not removes integration from psilocybin. |
| SC3 The rodent plasticity window generalizes to human cortex at a duration relevant to integration scheduling. | humans receiving defined clinical doses | Γ | SC3 remains Γ. Human fMRI and cognitive changes are measured, but do not directly establish a cortical synaptic learning-window duration or its required integration schedule [8,34,35,37,38,49,56–58]. Mouse two-week social learning and month-persistent spines are different phenomena [20,30]. |
| SC4 The subjective psychedelic experience is causally required for neuroplastic consolidation. | human clinical treatment | Γ | SC4 remains Γ: experience-outcome correlations and healthy-human blockade provide plausibility, not a drug-intact human mediator manipulation with durable remission [4,9–12,15,40,44,55,59]. Rodent/congener dissociations constrain universal necessity but cannot establish human dispensability [20,22–24,28,31,51,52,54]. |

Preregistered aggregation: weakest-link. The registered weakest-link conjunction returns Γ. All four therapeutic/mechanism clauses remain Γ under rubric 07, though cell/rodent plasticity and some clinical package effects are empirically positive. Primary-SC2 and scope-matched sensitivities also return Γ. The unresolved content is required formal consolidation, not whether the drug ever changes synapses or symptoms. Sensitivities: weakest-link Γ; primary-subclaim Γ; scope-matched Γ.

### Decisive-perturbation inventory and causal tally

[1] 25-mg psilocybin with psychological support improved the week-3 primary depression score versus 1 mg; sustained week-12 response was not supportive. Dose changes drug exposure and experience together; support was not removed and experience was not selectively manipulated.

[2] Psilocybin versus escitalopram with matched support did not differ significantly on the week-6 primary QIDS outcome; several unadjusted secondary outcomes favored psilocybin. Neither equivalence nor integration necessity follows; drug, experience and daily-treatment schedules differ.

[10] Psilocybin versus methylphenidate induced marked acute experiences and later meaning/attitude changes in healthy volunteers. Healthy spiritual outcomes do not establish depression remission or the necessity of subjective experience.

[14] The 2026 EPISODE trial missed its primary week-6 response comparison; secondary symptom changes were exploratory. Adjunct psychotherapy was present; a null package endpoint does not selectively falsify integration necessity.

[15] Escitalopram pretreatment reduced negative acute effects without changing psilocin exposure or positive mood; circulating BDNF was unchanged. Healthy acute pharmacodynamics do not measure lasting remission or cortical plasticity.

[18] Psilocybin rewired mouse cortical inputs, and silencing presynaptic activity disrupted the pattern. Activity-dependent mouse rewiring does not identify a human integration window or formal therapy necessity.

[19] Psychedelics increased neurites/spines and synaptic function with TrkB, mTOR and 5HT2A pathway support. Drug-class and culture/model plasticity is not a clinical mediator or a universal psilocybin receptor sequence.

[20] Psilocybin increased mouse frontal spines persistently; ketanserin abolished head twitch but retained spine-width/formation effects while density significance was lost. The antagonist was incompletely receptor-blocking; head twitch is not direct consciousness, and month-long spines do not define a month-long learning window.

[21] Molecular/genetic experiments identified intracellular 5HT2A involvement in psychedelic-induced cortical growth. Cellular receptor-location inference does not identify human therapeutic consolidation.

[22] TrkB-binding contrasts linked psychedelic plasticity/behavior to BDNF signaling independent of 5HT2A in the tested paradigms. Contrasts with receptor-necessity studies require model/assay separation; no demonstrated human experience blockade with remission outcomes.

[23] Tabernanthalog promoted rodent neural plasticity and changed drug-seeking and behavioral assays without hallucinogenic-like effects. A different compound and absent rodent head twitch do not establish subjective-experience dispensability in human psilocybin treatment.

[24] Adult local 5HT2A deletion removed specified psilocybin plasticity and stress effects while local deletion left head twitch intact; learned-helplessness control response had a floor-limit caveat. Cell-type specificity and genotype controls bound inference; rodent stress tests are not human remission and linked correction detail is unexamined.

[26] Antagonist contrasts changed microglial TNF and BDNF responses to psilocybin/psilocin. Inflammation/growth markers in LPS cultures are not cortical synapses or clinical antidepressant mediation.

[28] Structure-guided 5HT2A analogues showed antidepressant-like mouse activity with attenuated hallucinogenic-like responses. Biased compounds and behavioral proxies do not settle human experiential necessity.

[29] DOI and lisuride produced distinct downstream 5HT2A signaling in engineered cells and neurons. Signaling efficacy differences do not measure human subjective experience or lasting therapy.

[30] Psilocybin reopened mouse social reward learning for two weeks but not three; oxytocin metaplasticity and ketanserin contrasts mapped the circuit. A nucleus-accumbens mouse learning assay is not human cortical synaptogenesis, depression remission or randomized integration scheduling.

[31] 2-bromo-LSD promoted culture plasticity and changed chronic-stress behavior without head twitch; a receptor antagonist blocked active coping. Different compound and rodent behaviors constrain transfer to human psilocybin experience.

[32] New Ariadne pharmacological profiling and mouse motor rescue mapped a lower-efficacy 5HT2A agonist. Only the new empirical component is counted; historical clinical anecdotes and PD rescue do not establish psilocybin antidepressant mediation.

[33] Cortical receptor-expression and signaling contrasts differentiated hallucinogenic from nonhallucinogenic ligands. Construct/signaling sufficiency is not endogenous human therapeutic necessity.

[34] Precision imaging found acute desynchronization, task modulation and persistent hippocampal-DMN connectivity changes after psilocybin. Functional connectivity is not directly measured synaptic growth or a tested integration-timing mediator; participants were healthy.

[36] Psilocybin plus extinction training improved mouse fear retrieval/renewal and coincided with hippocampal plasticity measures. No selective mediation or human integration-necessity test; extinction is not formal postacute psychotherapy.

[39] Psilocybin plus manualized psychotherapy reduced heavy drinking versus diphenhydramine plus the same psychotherapy. AUD is outside the registered depressive/anxiety scope; no psychotherapy removal, and linked erratum detail remains unexamined.

[42] New profiling of 41 psychedelics across 318 GPCRs identified broad receptor actions and multiple 5HT2A transducers. Polypharmacology constrains unique-target accounts but is not proof of an alternative clinical mediator.

[45] Psilocybin/local psilocin improved allodynia and mood-like behaviors in mouse pain models with prefrontal circuit/receptor contrasts. Partial receptor replication and pain-model behavior are not human depression remission or formal therapy necessity.

[50] MBSR plus group PAP outperformed MBSR alone on short-term depressive symptoms; the effect waned by six months. Tests addition of drug plus PAP, not integration removal from drug; contact intensity differed and corrected secondary outcomes were null.

[51] An engineered biosensor identified a nonhallucinogenic-like analogue with lasting rodent behavioral activity. New compound discovery is not proof that human psilocybin works without experience or integration.

[52] TBG required cortical spinogenesis for sustained rodent behavioral effects without the immediate gene/glutamate burst of psychedelics. Different compound/model; no general human clinical experiential necessity conclusion.

[54] Ketanserin preserved psilocybin's mouse antianhedonic and hippocampal synaptic effects despite blocking its behavioral pharmacodynamic response. Antagonist/region and rodent proxy limits prevent proof of absence of human consciousness or therapeutic experience necessity.

[55] Human ketanserin/risperidone pretreatment blocked acute psychotomimetic effects while haloperidol increased them. No durable depression outcome; acute blockade is not a therapeutic-mediator necessity experiment.

[56] Acute psilocybin versus ketanserin altered cerebral blood flow and internal-carotid diameter in healthy volunteers. Direct drug comparison is not antagonist coadministration with intact psilocybin; vascular effects complicate functional imaging interpretation.

[59] A fixed-order placebo then psilocybin therapy study improved both conditions without significant difference; mystical ratings did not predict antidepressant change. Fixed order, carryover, unequal completion and expectancy limit the negative contrast; metadata RCT label does not override actual design.

Tally: 31 discriminating contrasts. Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines. No listed discriminator is a completed human integration-removal necessity experiment. Drug dose, receptor blockade and congeners are not interchangeable with selective experiential manipulation. Primary reports can share clinical cohorts; neither follow-up nor a preprint version adds independent replication.

### Cap audit, precedence and Β/Γ/Δ boundary

Rodent knockout, activity suppression and drug-congener contrasts identify real experimental biology. Rubric 07 requires controlled human mediator/scaffold or credible subjective-effect-matched contrasts for the clinical mechanism. A preclinical success is not silently renamed human integration necessity. Positive package efficacy is retained; no blanket claim that all support is inert is made. Niacin is a side-effect comparator, not an inert placebo, but does not solve subjective matching or component identification.

Gamma hard-rule audit: Functional-unblinding: low-dose or niacin controls do not automatically match intense subjective effects; Raison explicitly did not assess allocation-blinding success. Mediation-by-correlation: mystical/emotional/imaging predictors were not selectively manipulated to test durable human necessity. Open-label/waitlist/fixed-order designs leave expectancy, contact, regression and order confounded. Acute pharmacodynamics and rodent proxies cannot alone cross the clinical mechanism boundary. Adult genetic receptor deletion narrows mouse biology without identifying human integration.

SC1 cap: “Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.” SC1 has directly perturbed cellular/rodent plasticity, including adult targeted receptor deletion and activity manipulation [18–24,30,52]. Exact universal 5HT2A/TrkB dependence differs by paradigm [20,22,24,54]. Rubric 07's preclinical/rodent cap and missing clinical trajectory mediator keep the therapeutic-window interpretation at Γ.

SC2 cap: “Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.” SC2 remains Γ: positive treatment packages contain support/integration, but no admitted study randomizes removal of formal postacute integration with intact drug exposure, equal contact and masked durable outcomes [1–7,11,14,16,17,43,46,47,50,59,60]. The 2026 CBT pilot is single-arm; MBSR comparison adds PAP to training, not removes integration from psilocybin.

SC3 cap: “Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.” SC3 remains Γ. Human fMRI and cognitive changes are measured, but do not directly establish a cortical synaptic learning-window duration or its required integration schedule [8,34,35,37,38,49,56–58]. Mouse two-week social learning and month-persistent spines are different phenomena [20,30].

SC4 cap: “Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.” SC4 remains Γ: experience-outcome correlations and healthy-human blockade provide plausibility, not a drug-intact human mediator manipulation with durable remission [4,9–12,15,40,44,55,59]. Rodent/congener dissociations constrain universal necessity but cannot establish human dispensability [20,22–24,28,31,51,52,54].

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. SC1 has directly perturbed cellular/rodent plasticity, including adult targeted receptor deletion and activity manipulation [18–24,30,52]. Exact universal 5HT2A/TrkB dependence differs by paradigm [20,22,24,54]. Rubric 07's preclinical/rodent cap and missing clinical trajectory mediator keep the therapeutic-window interpretation at Γ.

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. SC2 remains Γ: positive treatment packages contain support/integration, but no admitted study randomizes removal of formal postacute integration with intact drug exposure, equal contact and masked durable outcomes [1–7,11,14,16,17,43,46,47,50,59,60]. The 2026 CBT pilot is single-arm; MBSR comparison adds PAP to training, not removes integration from psilocybin.

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. SC3 remains Γ. Human fMRI and cognitive changes are measured, but do not directly establish a cortical synaptic learning-window duration or its required integration schedule [8,34,35,37,38,49,56–58]. Mouse two-week social learning and month-persistent spines are different phenomena [20,30].

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. SC4 remains Γ: experience-outcome correlations and healthy-human blockade provide plausibility, not a drug-intact human mediator manipulation with durable remission [4,9–12,15,40,44,55,59]. Rodent/congener dissociations constrain universal necessity but cannot establish human dispensability [20,22–24,28,31,51,52,54].

### 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 Δ in therapeutic-window interpretation, a human mediator perturbation must link plasticity change to a preregistered clinical trajectory with credible exposure/comparator controls.

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. Randomize scaffold removal or integration components with intact psilocybin, equal safety/contact, masked raters, fidelity and durable remission; demonstrate loss and rescue of the alleged required component.

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. Directly validate human plasticity duration and randomize experience/learning timing to establish outcome-relevant consolidation; network imaging alone is insufficient.

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. Keep drug exposure intact while blocking experience or dosing under anesthesia with matched anesthesia/support controls, and measure preregistered durable symptoms/remission rather than acute biomarkers.

Upper ladder: Blinding-integrity-reported subjective-effect comparators, drug-intact mediator manipulation, discontinuation/rechallenge, component dismantling and a plausible exposure genetic instrument are eligible equivalents. None of the admitted results identifies formal integration necessity or its human synaptic timing. Sponsor/site multiplicity and shared-cohort analyses do not supply independent failure-mode exclusion for the full mechanism.

Independence: No subclaim or model assigned Ζ. Receptor genetic deletion, drug antagonists, synapse imaging and learning assays address different mouse errors but do not independently establish the human formal-consolidation dependency. COMP360 reports [1,13,44], Imperial TRD [5,7,35,41], Imperial escitalopram [2,12,49,53] and Hopkins MDD [3,9,37] share programmes/participants; Daws [8] combines two of those existing cohorts.

### Falsification and pitfalls

Blocking the acute experience, or dosing under anaesthesia, leaves the effect intact. Mouse head-twitch-blocking antagonist contrasts preserve some structural/synaptic/behavioral effects [20,54]. This is a rodent proxy, not a completed human experience-removal result. Additional downgrade: False.

A non-subjective congener reproduces the therapeutic effect. Nonhallucinogenic-like compounds reproduce specified rodent plasticity and behavioral effects [23,28,31,51,52]. Clinical human subjective status and remission transfer are not established. Additional downgrade: False.

Multi-site replication with blinded central raters fails to reproduce a single-site effect. EPISODE's primary null challenges uniform package efficacy [14], but does not selectively remove integration and cannot falsify its necessity by itself. Additional downgrade: False.

13. Therapeutic effect misread as mechanistic proof. Successful drug-plus-support is not integration necessity.

16. Untested generalization confused with mapped boundaries. Mouse social-learning metaplasticity, persistent spines and human cortical duration are separate outcomes.

22. Scope fitted to the result. Post-treatment mystical responders cannot supply predeclared integration requirement.

21. A universal cap re-applied to a convergent evidence set. Model dissociations are retained as a set; no independent full-scope human necessity chain is present to re-cap.

### Adversarial steelman: above, then below

The strongest Δ case combines randomized drug-package benefit, long follow-up, experience associations and directly manipulated mouse plasticity. The missing identifying experiment is human component dismantling or drug-intact mediator removal with durable outcomes. The package can work while the claimed required consolidation mechanism remains untested.

The strongest Β case stresses that formal integration itself is merely co-delivered and its human causal benefit not isolated. It understates experimentally causal model plasticity, environment/activity dependence and pharmacological human acute perturbations supporting a mechanistically plausible bridge. Γ retains that support without treating it as clinical necessity.

Reject Δ because no scope-matched human integration/experience mediator-removal result identifies the dependency. Reject Β for the conjunction because mechanistic support extends beyond association; avoid scoring the easier acute clause as the whole hypothesis.

### Final score, causal direction and M/S/D

The registered weakest-link conjunction returns Γ. All four therapeutic/mechanism clauses remain Γ under rubric 07, though cell/rodent plasticity and some clinical package effects are empirically positive. Primary-SC2 and scope-matched sensitivities also return Γ. The unresolved content is required formal consolidation, not whether the drug ever changes synapses or symptoms.

For the nominal human formal-integration-to-remission dependency: acute dosing/support precedes remission, so a purely outcome-produced label is not established (step 1). No examined result demonstrates an isolated causal dependency of remission on formal postacute integration, or the reverse; its co-delivery with successful drug packages matches step 2 at this identification level. This provisional evidence-role label does not demonstrate integration is useless and does not deny causal mouse plasticity. Because the procedure stops at step 2, a proven necessary permissive-factor role is not inferred from the theory.

Momentum: Mechanistic only. Completed activity-dependent network rewiring [18], adult cell-type receptor deletion [24], nonhallucinogenic spinogenesis [52] and CBT feasibility [46] programmes are concrete artifacts. The anesthesia paper discovered by SciSpace/Consensus is a proposal, not a verified running trial or completed result.

Stability: Stable. No specifically verified pending integration-dismantling or drug-intact human experience-removal trial result identified in this bounded search. Proposals and completed efficacy trials are not pending triggers.

Divergence: Contested; no single implied-level arithmetic. These dimensions do not change level or confidence.

## PROPOSED DECISIVE EXPERIMENTS

Randomize baseline-defined depressed/anxious participants receiving the same psilocybin dose and preparation to formal postacute integration versus equal-contact supportive follow-up, with balanced allegiance, explicit protocol/fidelity, participant/rater allocation guesses and masked central assessments at six and twelve months. Add a prespecified early-versus-delayed integration contrast and a separately controlled drug-intact experience-removal study to distinguish timing, therapy and subjective mechanisms.

Readout: Durable remission/relapse and independently assessed function, with validated plasticity measures as distinct mechanistic endpoints. Controls: Equal drug exposure, safety support and contact; measured expectancy/alliance and masking integrity; fidelity; co-interventions and multiplicity. Supporting: Selective loss of durable remission when formal integration is removed or outside the validated window, with benefit restored by component rescue. Falsifying: Preserved durable remission under credible scaffold removal, with a prespecified adequately powered equivalence/noninferiority boundary.

## KNOWLEDGE GAPS

Is formal integration beneficial, necessary, or one of several sufficient learning environments?

Does a mouse social-learning critical period have a comparable human cortical clinical window?

Which receptor/TrkB effects generalize across region, dose and assay?

Does subjective experience independently mediate benefit when exposure and support are held intact?

What net durable functional benefit survives expectancy, co-intervention and masking assessment?

## REVIEWER NOTES

Sixty primary reports examined at complete abstract/status level; four selected primary-body examinations include Raison Methods/limitations via the public PMC web page, mouse antagonist dissociation, adult receptor deletion and critical-period/metaplasticity. XML access failed for Raison, but primary web body was directly examined and recorded. Ariadne is admitted only for its new empirical pharmacology/mouse work, not historical clinical claims. No hypothetical anesthesia proposal, review, correction notice or duplicate preprint pads the count. Linked unexamined corrections limit fine quantitative interpretation. No blinded calibration or controlled estimate of search-quality improvement.

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.

## ADVERSARIAL REVIEW AND APPROVAL

**Authoring model:** Sol 6.1. **Adversarial reviewer:** Claude Opus 5.5 (Anthropic). **Date:** 2026-10-06.

**Scope of checks:** All 60 reference PMIDs re-fetched with the PubMed MCP tool get_article_metadata and cross-checked against NCBI E-utilities (title, first author, journal, year, DOI): 60/60 correct; no retraction or expression of concern; 9 linked errata, all disclosed on the cards. 16 load-bearing claims spot-checked against PubMed abstracts: refs 1, 2, 3, 9, 14, 17, 20, 24, 30, 34, 46, 50, 53, 55, 59, 60. Scoring logic checked: index-prescribed weakest-link with four Γ subclaims, reported alternatives, rubric 07 routing, and the conjunctive-claim rule in SKILL.md Step 1.

**Findings and corrections**

| ID | Severity | Location | Original → corrected | Evidence |
|---|---|---|---|---|
| — | — | — | No correction required | — |

**Rejected findings (checked, no change)**

- Headline Γ: all four subclaims are Γ, so weakest-link, primary-subclaim and scope-matched all return Γ. The sensitivities are reported correctly.
- Causal role 'epiphenomenon': this is assigned to the registered formal-integration-to-remission dependency, not to psilocybin's clinical effect, and the scorecard derivation states so. It is a defensible judgement call under the role procedure, so no change.
- SC1 Γ despite adult cell-type-specific 5-HT2A knockout evidence: the subclaim is scored as a therapeutic-window claim under rubric 07, and the rodent plasticity result does not establish the human window. Defensible.
- Trial descriptions checked against abstracts: the 25 mg versus 1 mg week-3 result with non-supportive sustained 12-week response; the escitalopram trial's null primary QIDS comparison with uncorrected secondaries; the 2026 active-placebo trial's missed primary and exploratory secondaries; the 2023 multisite trial's psychological support in both arms; the mindfulness trial's 2-week advantage waning at 6 months with secondaries not surviving correction; and the fixed-order trial's absent mystical-outcome correlation. All accurate.
- Year differences for refs 7, 15, 18 (print vs e-pub, one year apart): acceptable under convention. PubMed dropping an italicised receptor subscript in ref 32's title is a rendering artifact.

**Residual limitations**

- Verification was mostly at abstract depth; the 4 receipted partial-body passages were not re-read here, including the statements attributed to trial Methods and Limitations sections.
- Scorecard provenance_header.generated_by reads 'Codex; HSEF v5.3' and was not altered.

**Approval:** Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-06.

## REFERENCES

1. 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](https://pubmed.ncbi.nlm.nih.gov/36322843/). DOI: 10.1056/NEJMoa2206443. Access: abstract_metadata. Study: NCT03775200.

2. 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](https://pubmed.ncbi.nlm.nih.gov/33852780/). DOI: 10.1056/NEJMoa2032994. Access: abstract_metadata. Study: NCT03429075.

3. 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](https://pubmed.ncbi.nlm.nih.gov/33146667/). DOI: 10.1001/jamapsychiatry.2020.3285. Access: abstract_metadata. Study: NCT03181529.

4. 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](https://pubmed.ncbi.nlm.nih.gov/27909165/). DOI: 10.1177/0269881116675513. Access: abstract_metadata. Study: NCT00465595.

5. Carhart-Harris RL, Bolstridge M, Rucker J et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The lancet. Psychiatry. 2016. [PMID 27210031](https://pubmed.ncbi.nlm.nih.gov/27210031/). DOI: 10.1016/S2215-0366(16)30065-7. Access: abstract_metadata. Study: ISRCTN14426797.

6. 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](https://pubmed.ncbi.nlm.nih.gov/38359838/). DOI: 10.1016/j.medj.2024.01.005. Access: abstract_metadata. Study: NCT05029466.

7. Carhart-Harris RL, Bolstridge M, Day CMJ et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 2018. [PMID 29119217](https://pubmed.ncbi.nlm.nih.gov/29119217/). DOI: 10.1007/s00213-017-4771-x. Access: abstract_metadata. Study: ISRCTN14426797-expanded.

8. Daws RE, Timmermann C, Giribaldi B et al. Increased global integration in the brain after psilocybin therapy for depression. Nature medicine. 2022. [PMID 35411074](https://pubmed.ncbi.nlm.nih.gov/35411074/). DOI: 10.1038/s41591-022-01744-z. Access: abstract_metadata. Study: Imperial-TRD+NCT03429075.

9. 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](https://pubmed.ncbi.nlm.nih.gov/35166158/). DOI: 10.1177/02698811211073759. Access: abstract_metadata. Study: NCT03181529.

10. Griffiths RR, Richards WA, McCann U et al. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006. [PMID 16826400](https://pubmed.ncbi.nlm.nih.gov/16826400/). DOI: 10.1007/s00213-006-0457-5. Access: abstract_metadata. Study: PMID16826400.

11. 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](https://pubmed.ncbi.nlm.nih.gov/27909164/). DOI: 10.1177/0269881116675512. Access: abstract_metadata. Study: NCT00957359.

12. Erritzoe D, Barba T, Spriggs MJ et al. Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression. Journal of psychopharmacology (Oxford, England). 2024. [PMID 38520045](https://pubmed.ncbi.nlm.nih.gov/38520045/). DOI: 10.1177/02698811241237870. Access: abstract_metadata. Study: NCT03429075.

13. 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](https://pubmed.ncbi.nlm.nih.gov/36740140/). DOI: 10.1016/j.jad.2023.01.108. Access: abstract_metadata. Study: NCT03775200.

14. 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](https://pubmed.ncbi.nlm.nih.gov/41848690/). DOI: 10.1001/jamapsychiatry.2026.0132. Access: abstract_metadata. Study: NCT04670081.

15. 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](https://pubmed.ncbi.nlm.nih.gov/34743319/). DOI: 10.1002/cpt.2487. Access: abstract_metadata. Study: PMID34743319.

16. Back AL, Freeman-Young TK, Morgan L et al. Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial. JAMA network open. 2024. [PMID 39636638](https://pubmed.ncbi.nlm.nih.gov/39636638/). DOI: 10.1001/jamanetworkopen.2024.49026. Access: abstract_metadata. Study: NCT05163496.

17. Raison CL, Sanacora G, Woolley J et al. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023. [PMID 37651119](https://pubmed.ncbi.nlm.nih.gov/37651119/). DOI: 10.1001/jama.2023.14530. Access: full_text_partial. Study: NCT03866174.

18. Jiang Q, Shao LX, Yao S et al. Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks. Cell. 2026. [PMID 41352354](https://pubmed.ncbi.nlm.nih.gov/41352354/). DOI: 10.1016/j.cell.2025.11.009. Access: abstract_metadata. Study: PMID41352354.

19. Ly C, Greb AC, Cameron LP et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell reports. 2018. [PMID 29898390](https://pubmed.ncbi.nlm.nih.gov/29898390/). DOI: 10.1016/j.celrep.2018.05.022. Access: abstract_metadata. Study: PMID29898390.

20. Shao LX, Liao C, Gregg I et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron. 2021. [PMID 34228959](https://pubmed.ncbi.nlm.nih.gov/34228959/). DOI: 10.1016/j.neuron.2021.06.008. Access: full_text_partial. Study: PMID34228959.

21. Vargas MV, Dunlap LE, Dong C et al. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science (New York, N.Y.). 2023. [PMID 36795823](https://pubmed.ncbi.nlm.nih.gov/36795823/). DOI: 10.1126/science.adf0435. Access: abstract_metadata. Study: PMID36795823.

22. Moliner R, Girych M, Brunello CA et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature neuroscience. 2023. [PMID 37280397](https://pubmed.ncbi.nlm.nih.gov/37280397/). DOI: 10.1038/s41593-023-01316-5. Access: abstract_metadata. Study: PMID37280397.

23. Cameron LP, Tombari RJ, Lu J et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021. [PMID 33299186](https://pubmed.ncbi.nlm.nih.gov/33299186/). DOI: 10.1038/s41586-020-3008-z. Access: abstract_metadata. Study: PMID33299186.

24. Shao LX, Liao C, Davoudian PA et al. Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors. Nature. 2025. [PMID 40175553](https://pubmed.ncbi.nlm.nih.gov/40175553/). DOI: 10.1038/s41586-025-08813-6. Access: full_text_partial. Study: PMID40175553.

25. Zhao X, Du Y, Yao Y et al. Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice. Journal of psychopharmacology (Oxford, England). 2024. [PMID 38680011](https://pubmed.ncbi.nlm.nih.gov/38680011/). DOI: 10.1177/02698811241249436. Access: abstract_metadata. Study: PMID38680011.

26. Laabi S, LeMmon C, Vogel C et al. Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling. International immunopharmacology. 2025. [PMID 40424654](https://pubmed.ncbi.nlm.nih.gov/40424654/). DOI: 10.1016/j.intimp.2025.114940. Access: abstract_metadata. Study: PMID40424654.

27. Davoudian PA, Shao LX, Kwan AC et al. Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin. ACS chemical neuroscience. 2023. [PMID 36630309](https://pubmed.ncbi.nlm.nih.gov/36630309/). DOI: 10.1021/acschemneuro.2c00637. Access: abstract_metadata. Study: PMID36630309.

28. Cao D, Yu J, Wang H et al. Structure-based discovery of nonhallucinogenic psychedelic analogs. Science (New York, N.Y.). 2022. [PMID 35084960](https://pubmed.ncbi.nlm.nih.gov/35084960/). DOI: 10.1126/science.abl8615. Access: abstract_metadata. Study: PMID35084960.

29. Banerjee AA, Vaidya VA et al. Differential signaling signatures evoked by DOI versus lisuride stimulation of the 5-HT2A receptor. Biochemical and biophysical research communications. 2020. [PMID 32814630](https://pubmed.ncbi.nlm.nih.gov/32814630/). DOI: 10.1016/j.bbrc.2020.08.022. Access: abstract_metadata. Study: PMID32814630.

30. Nardou R, Sawyer E, Song YJ et al. Psychedelics reopen the social reward learning critical period. Nature. 2023. [PMID 37316665](https://pubmed.ncbi.nlm.nih.gov/37316665/). DOI: 10.1038/s41586-023-06204-3. Access: full_text_partial. Study: PMID37316665.

31. Lewis V, Bonniwell EM, Lanham JK et al. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell reports. 2023. [PMID 36884348](https://pubmed.ncbi.nlm.nih.gov/36884348/). DOI: 10.1016/j.celrep.2023.112203. Access: abstract_metadata. Study: PMID36884348.

32. Cunningham MJ, Bock HA, Serrano IC et al. Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs. ACS chemical neuroscience. 2023. [PMID 36521179](https://pubmed.ncbi.nlm.nih.gov/36521179/). DOI: 10.1021/acschemneuro.2c00597. Access: abstract_metadata. Study: PMID36521179.

33. González-Maeso J, Weisstaub NV, Zhou M et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007. [PMID 17270739](https://pubmed.ncbi.nlm.nih.gov/17270739/). DOI: 10.1016/j.neuron.2007.01.008. Access: abstract_metadata. Study: PMID17270739.

34. Siegel JS, Subramanian S, Perry D et al. Psilocybin desynchronizes the human brain. Nature. 2024. [PMID 39020167](https://pubmed.ncbi.nlm.nih.gov/39020167/). DOI: 10.1038/s41586-024-07624-5. Access: abstract_metadata. Study: PMID39020167.

35. Carhart-Harris RL, Roseman L, Bolstridge M et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific reports. 2017. [PMID 29030624](https://pubmed.ncbi.nlm.nih.gov/29030624/). DOI: 10.1038/s41598-017-13282-7. Access: abstract_metadata. Study: ISRCTN14426797-expanded.

36. Du Y, Li Y, Zhao X et al. Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity. Chinese medical journal. 2023. [PMID 37000971](https://pubmed.ncbi.nlm.nih.gov/37000971/). DOI: 10.1097/CM9.0000000000002647. Access: abstract_metadata. Study: PMID37000971.

37. Doss MK, Považan M, Rosenberg MD et al. Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Translational psychiatry. 2021. [PMID 34750350](https://pubmed.ncbi.nlm.nih.gov/34750350/). DOI: 10.1038/s41398-021-01706-y. Access: abstract_metadata. Study: NCT03181529.

38. Carhart-Harris RL, Erritzoe D, Williams T et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences of the United States of America. 2012. [PMID 22308440](https://pubmed.ncbi.nlm.nih.gov/22308440/). DOI: 10.1073/pnas.1119598109. Access: abstract_metadata. Study: PMID22308440.

39. Bogenschutz MP, Ross S, Bhatt S et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA psychiatry. 2022. [PMID 36001306](https://pubmed.ncbi.nlm.nih.gov/36001306/). DOI: 10.1001/jamapsychiatry.2022.2096. Access: abstract_metadata. Study: NCT02061293.

40. Madsen MK, Fisher PM, Burmester D et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2019. [PMID 30685771](https://pubmed.ncbi.nlm.nih.gov/30685771/). DOI: 10.1038/s41386-019-0324-9. Access: abstract_metadata. Study: PMID30685771.

41. Erritzoe D, Roseman L, Nour MM et al. Effects of psilocybin therapy on personality structure. Acta psychiatrica Scandinavica. 2018. [PMID 29923178](https://pubmed.ncbi.nlm.nih.gov/29923178/). DOI: 10.1111/acps.12904. Access: abstract_metadata. Study: ISRCTN14426797-expanded.

42. Jain MK, Gumpper RH, Slocum ST et al. The polypharmacology of psychedelics reveals multiple targets for potential therapeutics. Neuron. 2025. [PMID 40683247](https://pubmed.ncbi.nlm.nih.gov/40683247/). DOI: 10.1016/j.neuron.2025.06.012. Access: abstract_metadata. Study: PMID40683247.

43. Aaronson ST, van der Vaart A, Miller T et al. Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial. The American journal of psychiatry. 2025. [PMID 39741440](https://pubmed.ncbi.nlm.nih.gov/39741440/). DOI: 10.1176/appi.ajp.20231063. Access: abstract_metadata. Study: PMID39741440.

44. 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](https://pubmed.ncbi.nlm.nih.gov/39706482/). DOI: 10.1016/j.jad.2024.12.061. Access: abstract_metadata. Study: NCT03775200.

45. Hammo A, Wisser S, Cichon J et al. Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain. Nature neuroscience. 2025. [PMID 41039182](https://pubmed.ncbi.nlm.nih.gov/41039182/). DOI: 10.1038/s41593-025-02068-0. Access: abstract_metadata. Study: PMID41039182.

46. Weintraub MJ, Jeffrey JK, Ichinose MC et al. Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trial. Journal of affective disorders. 2026. [PMID 41707717](https://pubmed.ncbi.nlm.nih.gov/41707717/). DOI: 10.1016/j.jad.2026.121423. Access: abstract_metadata. Study: PMID41707717.

47. 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](https://pubmed.ncbi.nlm.nih.gov/40858059/). DOI: 10.1016/j.genhosppsych.2025.08.001. Access: abstract_metadata. Study: PMID40858059.

48. Aboharb F, Davoudian PA, Shao LX et al. Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression. Nature communications. 2025. [PMID 39939591](https://pubmed.ncbi.nlm.nih.gov/39939591/). DOI: 10.1038/s41467-025-56850-6. Access: abstract_metadata. Study: PMID39939591.

49. Wall MB, Demetriou L, Giribaldi B et al. Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression. The American journal of psychiatry. 2025. [PMID 40329640](https://pubmed.ncbi.nlm.nih.gov/40329640/). DOI: 10.1176/appi.ajp.20230751. Access: abstract_metadata. Study: NCT03429075.

50. Lewis BR, Hendrick J, Byrne K et al. Psilocybin-assisted group psychotherapy and mindfulness-based stress reduction for frontline healthcare provider COVID-19-related depression and burnout: A randomized controlled trial. PLoS medicine. 2025. [PMID 40972137](https://pubmed.ncbi.nlm.nih.gov/40972137/). DOI: 10.1371/journal.pmed.1004519. Access: abstract_metadata. Study: NCT05557643.

51. Dong C, Ly C, Dunlap LE et al. Psychedelic-inspired drug discovery using an engineered biosensor. Cell. 2021. [PMID 33915107](https://pubmed.ncbi.nlm.nih.gov/33915107/). DOI: 10.1016/j.cell.2021.03.043. Access: abstract_metadata. Study: PMID33915107.

52. Aarrestad IK, Cameron LP, Fenton EM et al. The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nature neuroscience. 2025. [PMID 40760185](https://pubmed.ncbi.nlm.nih.gov/40760185/). DOI: 10.1038/s41593-025-02021-1. Access: abstract_metadata. Study: PMID40760185.

53. Erritzoe D, Barba T, Greenway KT et al. Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial. EClinicalMedicine. 2024. [PMID 39764567](https://pubmed.ncbi.nlm.nih.gov/39764567/). DOI: 10.1016/j.eclinm.2024.102799. Access: abstract_metadata. Study: NCT03429075.

54. Hesselgrave N, Troppoli TA, Wulff AB et al. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences of the United States of America. 2021. [PMID 33850049](https://pubmed.ncbi.nlm.nih.gov/33850049/). DOI: 10.1073/pnas.2022489118. Access: abstract_metadata. Study: PMID33850049.

55. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998. [PMID 9875725](https://pubmed.ncbi.nlm.nih.gov/9875725/). DOI: 10.1097/00001756-199812010-00024. Access: abstract_metadata. Study: PMID9875725.

56. Larsen K, Lindberg U, Ozenne B et al. Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2025. [PMID 40007438](https://pubmed.ncbi.nlm.nih.gov/40007438/). DOI: 10.1177/0271678X251323364. Access: abstract_metadata. Study: PMID40007438.

57. Madsen MK, Stenbæk DS, Arvidsson A et al. Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2021. [PMID 34246868](https://pubmed.ncbi.nlm.nih.gov/34246868/). DOI: 10.1016/j.euroneuro.2021.06.001. Access: abstract_metadata. Study: PMID34246868.

58. Smigielski L, Scheidegger M, Kometer M et al. Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage. 2019. [PMID 30965131](https://pubmed.ncbi.nlm.nih.gov/30965131/). DOI: 10.1016/j.neuroimage.2019.04.009. Access: abstract_metadata. Study: PMID30965131.

59. Sloshower J, Skosnik PD, Safi-Aghdam H et al. Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. Journal of psychopharmacology (Oxford, England). 2023. [PMID 36938991](https://pubmed.ncbi.nlm.nih.gov/36938991/). DOI: 10.1177/02698811231154852. Access: abstract_metadata. Study: PMID36938991.

60. Aaronson ST, van der Vaart A, Miller T et al. Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial. JAMA psychiatry. 2024. [PMID 38055270](https://pubmed.ncbi.nlm.nih.gov/38055270/). DOI: 10.1001/jamapsychiatry.2023.4685. Access: abstract_metadata. Study: PMID38055270.

## Source-specific evidence cards

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

**Shows:** 25-mg psilocybin with psychological support improved the week-3 primary depression score versus 1 mg; sustained week-12 response was not supportive.

**Does not show:** Dose changes drug exposure and experience together; support was not removed and experience was not selectively manipulated.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [2] Trial of Psilocybin versus Escitalopram for Depression.

**Shows:** Psilocybin versus escitalopram with matched support did not differ significantly on the week-6 primary QIDS outcome; several unadjusted secondary outcomes favored psilocybin.

**Does not show:** Neither equivalence nor integration necessity follows; drug, experience and daily-treatment schedules differ.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

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

**Shows:** Immediate psilocybin plus supportive therapy improved MDD symptoms versus delayed treatment.

**Does not show:** Waitlist does not control expectancy/contact or remove integration; a linked erratum remains attached.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID33566065. Subclaims: SC2.

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

**Shows:** High versus low dose with support improved cancer-related distress; experience statistically mediated outcomes.

**Does not show:** Statistical mediation and crossover follow-up do not isolate experiential or psychotherapy necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [5] Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study.

**Shows:** Open-label psilocybin with support showed rapid symptom reduction in TRD.

**Does not show:** No control group; support preceded, accompanied and followed dosing.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

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

**Shows:** Immediate PAP improved symptoms versus waitlist in complex TRD; flexible repeats were associated with further improvement.

**Does not show:** Each dose included preparation and integration; repeat dosing was not randomized independently.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [7] Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.

**Shows:** The expanded open-label TRD cohort retained symptom improvement through six months; acute experience predicted early response.

**Does not show:** Shares the feasibility programme and lacks controlled long-term or manipulated-experience inference.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [8] Increased global integration in the brain after psilocybin therapy for depression.

**Shows:** Imaging across two clinical cohorts linked lower network modularity to symptom response.

**Does not show:** Brain network integration is not psychotherapy integration or directly measured synaptogenesis; cohorts overlap prior trials.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

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

**Shows:** The MDD cohort retained symptom reductions at 12 months; meaning/mystical ratings predicted well-being but not depression improvement.

**Does not show:** Follow-up lacks an untreated long-term counterfactual and shares the original delayed-treatment cohort.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [10] Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance.

**Shows:** Psilocybin versus methylphenidate induced marked acute experiences and later meaning/attitude changes in healthy volunteers.

**Does not show:** Healthy spiritual outcomes do not establish depression remission or the necessity of subjective experience.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

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

**Shows:** Psilocybin versus niacin within psychotherapy improved cancer-related symptoms before crossover, with later persistence.

**Does not show:** Both arms had psychotherapy; observed mystical mediation is not a mediator manipulation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [12] Effects of discontinuation of serotonergic antidepressants prior to psilocybin therapy versus escitalopram for major depression.

**Shows:** Post hoc antidepressant discontinuation status predicted smaller clinical response without corresponding experience differences.

**Does not show:** Discontinuation was not randomized and continuation was not tested; exploratory association only.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

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

**Shows:** The COMP360 trial follow-up reports favorable exploratory patient-rated function and symptoms at week three.

**Does not show:** Same dose trial, not independent replication; functional unblinding and no scaffold removal.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

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

**Shows:** The 2026 EPISODE trial missed its primary week-6 response comparison; secondary symptom changes were exploratory.

**Does not show:** Adjunct psychotherapy was present; a null package endpoint does not selectively falsify integration necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

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

**Shows:** Escitalopram pretreatment reduced negative acute effects without changing psilocin exposure or positive mood; circulating BDNF was unchanged.

**Does not show:** Healthy acute pharmacodynamics do not measure lasting remission or cortical plasticity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [16] Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial.

**Shows:** Psilocybin versus niacin with preparation and three integration visits improved clinician-rated depressive symptoms in frontline clinicians.

**Does not show:** Both arms had integration; secondary burnout was not significant, and linked correction details are incompletely examined.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID39804652; ErratumIn: PMID40638123. Subclaims: SC2.

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

**Shows:** The MDD trial improved depression and disability with psilocybin versus niacin within identical support.

**Does not show:** Methods include four hours of postdose integration; allocation-blinding success was not assessed. It cannot show benefit without integration.

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: Web-Study-Procedures-L469-471, Web-Efficacy-Assessments-L473-477, Web-Limitations-L695-705. No complete-paper or supplement audit claimed. ErratumIn: PMID38277159. Subclaims: SC2.

### [18] Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks.

**Shows:** Psilocybin rewired mouse cortical inputs, and silencing presynaptic activity disrupted the pattern.

**Does not show:** Activity-dependent mouse rewiring does not identify a human integration window or formal therapy necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [19] Psychedelics Promote Structural and Functional Neural Plasticity.

**Shows:** Psychedelics increased neurites/spines and synaptic function with TrkB, mTOR and 5HT2A pathway support.

**Does not show:** Drug-class and culture/model plasticity is not a clinical mediator or a universal psilocybin receptor sequence.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [20] Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo.

**Shows:** Psilocybin increased mouse frontal spines persistently; ketanserin abolished head twitch but retained spine-width/formation effects while density significance was lost.

**Does not show:** The antagonist was incompletely receptor-blocking; head twitch is not direct consciousness, and month-long spines do not define a month-long learning window.

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: S6. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

### [21] Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.

**Shows:** Molecular/genetic experiments identified intracellular 5HT2A involvement in psychedelic-induced cortical growth.

**Does not show:** Cellular receptor-location inference does not identify human therapeutic consolidation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [22] Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.

**Shows:** TrkB-binding contrasts linked psychedelic plasticity/behavior to BDNF signaling independent of 5HT2A in the tested paradigms.

**Does not show:** Contrasts with receptor-necessity studies require model/assay separation; no demonstrated human experience blockade with remission outcomes.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [23] A non-hallucinogenic psychedelic analogue with therapeutic potential.

**Shows:** Tabernanthalog promoted rodent neural plasticity and changed drug-seeking and behavioral assays without hallucinogenic-like effects.

**Does not show:** A different compound and absent rodent head twitch do not establish subjective-experience dispensability in human psilocybin treatment.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [24] Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors.

**Shows:** Adult local 5HT2A deletion removed specified psilocybin plasticity and stress effects while local deletion left head twitch intact; learned-helplessness control response had a floor-limit caveat.

**Does not show:** Cell-type specificity and genotype controls bound inference; rodent stress tests are not human remission and linked correction detail is unexamined.

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: S6, S7. No complete-paper or supplement audit claimed. UpdateOf: PMID39554087; ErratumIn: PMID41023408. Subclaims: SC1, SC4.

### [25] Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice.

**Shows:** Psilocybin improved chronic-corticosterone mouse behavioral proxies alongside plasticity/BDNF-mTOR measures.

**Does not show:** Co-occurring molecular changes were not selectively shown necessary for the behavioral effect.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [26] Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling.

**Shows:** Antagonist contrasts changed microglial TNF and BDNF responses to psilocybin/psilocin.

**Does not show:** Inflammation/growth markers in LPS cultures are not cortical synapses or clinical antidepressant mediation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [27] Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin.

**Shows:** Whole-brain cFos mapping identified shared and distinct acute psilocybin/ketamine activation regions.

**Does not show:** Immediate early gene activation is not itself structural plasticity, remission or a necessary mediator.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [28] Structure-based discovery of nonhallucinogenic psychedelic analogs.

**Shows:** Structure-guided 5HT2A analogues showed antidepressant-like mouse activity with attenuated hallucinogenic-like responses.

**Does not show:** Biased compounds and behavioral proxies do not settle human experiential necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [29] Differential signaling signatures evoked by DOI versus lisuride stimulation of the 5-HT2A receptor.

**Shows:** DOI and lisuride produced distinct downstream 5HT2A signaling in engineered cells and neurons.

**Does not show:** Signaling efficacy differences do not measure human subjective experience or lasting therapy.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [30] Psychedelics reopen the social reward learning critical period.

**Shows:** Psilocybin reopened mouse social reward learning for two weeks but not three; oxytocin metaplasticity and ketanserin contrasts mapped the circuit.

**Does not show:** A nucleus-accumbens mouse learning assay is not human cortical synaptogenesis, depression remission or randomized integration scheduling.

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: Sec3, Sec4, Sec5. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [31] A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

**Shows:** 2-bromo-LSD promoted culture plasticity and changed chronic-stress behavior without head twitch; a receptor antagonist blocked active coping.

**Does not show:** Different compound and rodent behaviors constrain transfer to human psilocybin experience.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [32] Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs.

**Shows:** New Ariadne pharmacological profiling and mouse motor rescue mapped a lower-efficacy 5HT2A agonist.

**Does not show:** Only the new empirical component is counted; historical clinical anecdotes and PD rescue do not establish psilocybin antidepressant mediation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [33] Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.

**Shows:** Cortical receptor-expression and signaling contrasts differentiated hallucinogenic from nonhallucinogenic ligands.

**Does not show:** Construct/signaling sufficiency is not endogenous human therapeutic necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [34] Psilocybin desynchronizes the human brain.

**Shows:** Precision imaging found acute desynchronization, task modulation and persistent hippocampal-DMN connectivity changes after psilocybin.

**Does not show:** Functional connectivity is not directly measured synaptic growth or a tested integration-timing mediator; participants were healthy.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID37701731. Subclaims: SC3, SC4.

### [35] Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.

**Shows:** TRD imaging changes correlated with symptoms and predicted early response in an open-label cohort.

**Does not show:** Shared cohort and imaging association do not identify a structural plasticity or integration mediator.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [36] Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity.

**Shows:** Psilocybin plus extinction training improved mouse fear retrieval/renewal and coincided with hippocampal plasticity measures.

**Does not show:** No selective mediation or human integration-necessity test; extinction is not formal postacute psychotherapy.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

### [37] Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder.

**Shows:** Cognitive flexibility improved after treatment, but was not correlated with antidepressant change; larger neural flexibility shifts could predict less improvement.

**Does not show:** Shares MDD participants and does not directly measure cortical plasticity or its necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [38] Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin.

**Shows:** Acute human imaging mapped reduced hub activity/connectivity alongside psychedelic effects.

**Does not show:** Acute neurovascular/functional signals do not establish synaptogenesis or durable remission.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

### [39] Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial.

**Shows:** Psilocybin plus manualized psychotherapy reduced heavy drinking versus diphenhydramine plus the same psychotherapy.

**Does not show:** AUD is outside the registered depressive/anxiety scope; no psychotherapy removal, and linked erratum detail remains unexamined.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID36103174. Subclaims: SC2.

### [40] Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.

**Shows:** PET occupancy and plasma psilocin tracked subjective intensity in healthy adults.

**Does not show:** Occupancy-experience correlation does not show experience is necessary for lasting clinical benefit; correction detail not fully examined.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID30846853. Subclaims: SC4.

### [41] Effects of psilocybin therapy on personality structure.

**Shows:** Open-label TRD personality changes and acute insight were associated at follow-up.

**Does not show:** Shares the expanded TRD cohort; personality association is not remission mediation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [42] The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.

**Shows:** New profiling of 41 psychedelics across 318 GPCRs identified broad receptor actions and multiple 5HT2A transducers.

**Does not show:** Polypharmacology constrains unique-target accounts but is not proof of an alternative clinical mediator.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [43] Single-Dose Psilocybin for Depression With Severe Treatment Resistance: An Open-Label Trial.

**Shows:** A severe-TRD open-label pilot with three integration sessions reported sustained symptom change and exploratory experience correlations.

**Does not show:** No counterfactual or component randomization; PTSD subgroup is exploratory.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

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

**Shows:** COMP360 experience and emotional breakthrough correlated with week-3 response despite overlapping dose experience distributions.

**Does not show:** Same dose trial; correlation does not establish causation or measured blinding integrity; correction detail remains incompletely examined.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID41075579. Subclaims: SC4.

### [45] Single-dose psilocybin rapidly and sustainably relieves allodynia and anxiodepressive-like behaviors in mouse models of chronic pain.

**Shows:** Psilocybin/local psilocin improved allodynia and mood-like behaviors in mouse pain models with prefrontal circuit/receptor contrasts.

**Does not show:** Partial receptor replication and pain-model behavior are not human depression remission or formal therapy necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

### [46] Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: A pilot trial.

**Shows:** The 2026 single-arm CBT programme retained symptom/function gains through follow-up.

**Does not show:** All participants received twelve therapy sessions; no randomized CBT or integration counterfactual.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

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

**Shows:** The 2025 life-threatening-illness trial favored psilocybin over niacin on selected symptom outcomes within psychotherapy.

**Does not show:** Both arms had six integration sessions; open-label extension weakens isolated long-term inference.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [48] Classification of psychedelics and psychoactive drugs based on brain-wide imaging of cellular c-Fos expression.

**Shows:** Drug-specific cFos patterns classified psychoactive compounds above chance in mice.

**Does not show:** A successful drug classifier is not validated plasticity or clinical-mechanism stratification.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID38826215. Subclaims: SC1.

### [49] Reduced Brain Responsiveness to Emotional Stimuli With Escitalopram But Not Psilocybin Therapy for Depression.

**Shows:** Psilocybin and escitalopram differed in emotional BOLD responses with matched preparation/integration.

**Does not show:** Same comparative trial; no human structural plasticity or integration removal.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [50] Psilocybin-assisted group psychotherapy and mindfulness-based stress reduction for frontline healthcare provider COVID-19-related depression and burnout: A randomized controlled trial.

**Shows:** MBSR plus group PAP outperformed MBSR alone on short-term depressive symptoms; the effect waned by six months.

**Does not show:** Tests addition of drug plus PAP, not integration removal from drug; contact intensity differed and corrected secondary outcomes were null.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. UpdateOf: PMID39802794. Subclaims: SC2.

### [51] Psychedelic-inspired drug discovery using an engineered biosensor.

**Shows:** An engineered biosensor identified a nonhallucinogenic-like analogue with lasting rodent behavioral activity.

**Does not show:** New compound discovery is not proof that human psilocybin works without experience or integration.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [52] The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation.

**Shows:** TBG required cortical spinogenesis for sustained rodent behavioral effects without the immediate gene/glutamate burst of psychedelics.

**Does not show:** Different compound/model; no general human clinical experiential necessity conclusion.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [53] Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial.

**Shows:** The escitalopram comparison retained improvement in both arms at six months without significant depression-score separation; secondary function favored psilocybin.

**Does not show:** Descriptive follow-up, missingness and additional interventions limit durability attribution.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

### [54] Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice.

**Shows:** Ketanserin preserved psilocybin's mouse antianhedonic and hippocampal synaptic effects despite blocking its behavioral pharmacodynamic response.

**Does not show:** Antagonist/region and rodent proxy limits prevent proof of absence of human consciousness or therapeutic experience necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

### [55] Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.

**Shows:** Human ketanserin/risperidone pretreatment blocked acute psychotomimetic effects while haloperidol increased them.

**Does not show:** No durable depression outcome; acute blockade is not a therapeutic-mediator necessity experiment.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC4.

### [56] Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans.

**Shows:** Acute psilocybin versus ketanserin altered cerebral blood flow and internal-carotid diameter in healthy volunteers.

**Does not show:** Direct drug comparison is not antagonist coadministration with intact psilocybin; vascular effects complicate functional imaging interpretation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [57] Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience.

**Shows:** Plasma psilocin and subjective intensity tracked network integrity/segregation during healthy-subject imaging.

**Does not show:** Acute correlation does not define cortical learning-window duration or clinical mediation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

### [58] Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects.

**Shows:** Psilocybin during a mindfulness retreat changed DMN measures and later psychosocial ratings.

**Does not show:** Healthy retreat context, bundled training and observed predictors do not prove depressive integration necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [59] Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial.

**Shows:** A fixed-order placebo then psilocybin therapy study improved both conditions without significant difference; mystical ratings did not predict antidepressant change.

**Does not show:** Fixed order, carryover, unequal completion and expectancy limit the negative contrast; metadata RCT label does not override actual design.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

### [60] Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial.

**Shows:** An open-label bipolar-II depression trial with three integration sessions showed sustained symptoms/function improvement.

**Does not show:** No control or component manipulation; distinct diagnosis and linked erratum constrain generalization.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID38598187. Subclaims: SC2.