Clinical trials support symptom effects in selected settings, and mouse experiments establish specific receptor/cell dependencies. These findings do not yet show that a temporary rise in human structural plasticity mediates lasting antidepressant benefit; recent null and context-dependent results are central to that distinction.
This dated addendum adds selected evidence and tests that could resolve the remaining questions. It does not regrade the archived review.
Each question identifies a limit in the checked evidence. A missing search result alone does not establish a gap in the entire field.
Competing explanation: Functional adaptation or support-related learning may matter without increased synaptic density.
Discriminating test: Randomized clinical studies with time-ordered orthogonal plasticity measures, functional readouts and symptoms; complement with selective mediator perturbation in models.
Competing explanation: Acute subjective effects can reveal allocation and modify learning or clinician interactions.
Discriminating test: Prespecified masking assessment, credible comparators and standardized support; where feasible compare support components while retaining treatment fidelity.
Competing explanation: A mouse cell-type dependency may reflect acute excitability rather than the proposed human repair mechanism.
Discriminating test: Independent model replication with acute versus delayed interventions and human target-engagement measures; separate receptor necessity from mediator necessity.
Competing explanation: Selected samples, retreatment, added care or dropout can shape follow-up effects.
Discriminating test: Longer blinded follow-up with predefined relapse, retreatment, co-interventions and adverse-event ascertainment; prespecified subgroup interactions.
Electronic publication dates are used where recorded, with issue years shown separately. This is a selected chronology, not a claim of scientific priority or independent replication for every entry.
Symptoms improved after psilocybin with psychological support.
What it cannot establish: Small uncontrolled study cannot separate drug, expectancy, support and natural course.
The primary depression outcome did not show a significant between-treatment difference.
What it cannot establish: Secondary outcomes favoured psilocybin but lacked multiplicity correction; support accompanied treatment.
A single dose increased frontal dendritic-spine measures for weeks.
What it cannot establish: Mouse structural change does not establish mediation of human depression relief.
The higher dose improved the short-term primary outcome over low dose.
What it cannot establish: Durability and adverse-event findings bound benefit; low-dose control does not guarantee successful blinding.
Depressive symptoms and disability improved through the measured follow-up.
What it cannot establish: Acute experiential differences and psychological support complicate causal component separation.
PT-cell activity and targeted 5-HT2A receptors were required for selected lasting effects.
What it cannot establish: Blocking a receptor/cell affects multiple processes; it does not isolate structural plasticity as the mediator.
Enduring behaviour and functional plasticity occurred without detected structural-density changes.
What it cannot establish: Species, sampling and measurement sensitivity limit how broadly this structural null applies.
Rapid symptom benefit was reported; some late effects were secondary outcomes and anxiety required care in some participants.
What it cannot establish: Endpoint hierarchy and follow-up attrition must remain visible in durability claims.
The report found no significant overall synaptic-density increase; setting-related differences were observed.
What it cannot establish: Small context-dependent before/after study is not a randomized mediator test or universal absence of plasticity.
Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected.
Main P12 and statistical Methods P62: cell-type-specific chemogenetic silencing with control virus/ligand timing, and receptor-knockout structural comparisons. This does not isolate structural plasticity as the human mediator.
This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.
Selected full-text checks: 1; abstract checks: 8; metadata-only anchors: 0. Complete-paper examinations credited in this update: 0.
New enrichment: HSEF v5.3 causal distinctions. Archived scorecard schema: 5.4; retained as recorded.
Primary source 37 reports a nonsignificant overall SV2A result. Positive setting-related comparisons must not replace that overall finding. The 2025 mouse study carries a correction notice.
PMID 27210031 · DOI 10.1016/S2215-0366(16)30065-7
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 33852780 · DOI 10.1056/NEJMoa2032994
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 34228959 · DOI 10.1016/j.neuron.2021.06.008
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 36322843 · DOI 10.1056/NEJMoa2206443
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 37651119 · DOI 10.1001/jama.2023.14530
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
Linked notices: Correction 38277159
Linked notice presence was checked in the primary record; its scientific impact was not verified in this update.
PMID 40175553 · DOI 10.1038/s41586-025-08813-6
Selected full-text passages checked. Main P12 and statistical Methods P62: cell-type-specific chemogenetic silencing with control virus/ligand timing, and receptor-knockout structural comparisons. This does not isolate structural plasticity as the human mediator.
Linked notices: Correction 41023408
Linked notice presence was checked in the primary record; its scientific impact was not verified in this update.
PMID 41224969 · DOI 10.1038/s41386-025-02272-3
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 42457666 · DOI 10.1038/s41398-026-04285-y
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 42138922 · DOI 10.1001/jamanetworkopen.2026.12589
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
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