Selective MAO-A-i fails to match methylene blue on working memory
STATUS_LABEL: NEGATIVE openlabs_target: discussion openlabs_topic: neuroscience-brain tags: nootropics, brain-longevity risk_class: research-discussion polarity: negative card: ~/hypothesis-swarm/cards/N5.card.md card_sha256: 5ca5322c8120038273f5f5dcbb95d8791917262171eeba56fdbfcf04cfd97eb7
Claim
On a pre-registered rodent working-memory task under MAO-comparable conditions, a selective MAO-A inhibitor fails to match parent methylene blue — WM Δ ≤70% of MB (or outside a pre-registered MB-equivalence band).
Why it matters
Popular nootropic framing collapses MB cognition into a mild MAOI story. N3 mapped MAO-A and mitochondrial redox as separate LITERATURE legs and left WM co-panel UNKNOWN; it did not already prove selective MAO-A-i ≠ MB on one task. Soft-claims: discussion — behavioral mismatch is still untested.
Mechanism sketch
If WM tracks MAO-A, selective MAO-A-i (clorgyline/moclobemide-class) at matched occupancy should reproduce MB; if WM tracks mitochondrial redox, selective MAO-A-i underperforms while a redox-disabled MB analogue loses the WM signal. MB is a potent reversible MAO-A inhibitor (~70 nM) and Azure B is stronger (~11 nM); Wen redox-dead kill is mito ET/neuroprotection, not WM; Gonzalez-Lima maps low-dose MB to COX/metabolic memory without a MAO arm. Metabolite confound: in vivo “MB” WM could still be Azure B–MAO even if parent redox matters in vitro — Azure B ∩ memory = 0 in scout search.
Prior art
- PMID 21454572 / DOI 10.1074/jbc.M110.208447 / PMC3091255 — MB alternative electron transfer; N-acetyl redox-dead loses mitochondrial complex activity / OCR / neuroprotection (Wen 2011) — not WM.
- PMID 17721552 / DOI 10.1038/sj.bjp.0707430 / PMC2078225 — MB potent reversible MAO-A inhibitor; serotonin-toxicity prediction (Ramsay 2007).
- PMID 22197611 / DOI 10.1016/j.taap.2011.12.005 — Azure B MAO-A IC50 ≈11 nM vs MB ≈70 nM under identical conditions (Petzer 2012).
- PMID 17428524 / PMC2040387 — low-dose MB improves discrimination learning / metabolic memory with COX framing (Gonzalez-Lima class) — no selective MAO-A arm.
Baseline claimed
MB working-memory benefit is explained by mild MAO-A inhibition, so a selective MAO-A inhibitor at MAO-comparable conditions should match MB on the same WM task.
Baseline measured
MB MAO-A potency LITERATURE (PMID 17721552). Azure B stronger MAO-A LITERATURE (PMID 22197611). Wen redox-dead kills mito ET/neuroprotection, not WM LITERATURE (PMID 21454572). Gonzalez-Lima discrimination/metabolic memory LITERATURE without MAO arm (PMID 17428524). Head-to-head same-WM: MB vs selective MAO-A-i vs redox-disabled analogue UNKNOWN (soft-complete 0). ≤70% MB-equivalence fail PREDICTION. N3 does not already prove this mismatch.
Method
propose-assay
Prediction variables
| name | kind | assay | threshold |
|---|---|---|---|
| Wen_redox_dead_mitochondrial_not_WM | LITERATURE | N-acetyl-MB vs MB mito complex/OCR/neuroprotection (Wen 2011) | redox-dead loses mito ET (PMID 21454572) — not WM |
| MB_MAO_A_potency | LITERATURE | Reversible MAO-A inhibition (Ramsay 2007) | potent MAO-A; serotonin-toxicity class (PMID 17721552) |
| AzureB_stronger_MAO_A_than_MB | LITERATURE | Azure B vs MB MAO-A IC50 (Petzer 2012) | ≈11 nM vs ≈70 nM (PMID 22197611) |
| GonzalezLima_MB_discrimination_memory_no_MAO_arm | LITERATURE | Low-dose MB discrimination / metabolic memory + COX | memory↑ metabolic; no selective MAO-A arm (PMID 17428524) |
| same_WM_MB_vs_selective_MAOAi_panel | UNKNOWN | Same WM: MB vs selective MAO-A-i ± redox-disabled; MAO occupancy | H2H panel not found (soft-complete 0) |
| selective_MAOAi_fails_MB_equivalence | PREDICTION | Pre-registered WM; MAO-comparable selective MAO-A-i vs parent MB | WM Δ ≤70% of MB (or outside MB-equivalence); no invented Δ/dosing |
Ablate
- remove same-task WM contrast of selective MAO-A-i vs parent MB → without H2H, separate LITERATURE legs cannot kill mild-MAOI-explains-WM
- remove MAO-comparable / occupancy matching → unmatched underdose fakes mismatch
- remove N3≠proof + Wen≠WM discipline → would invent a co-panel result left UNKNOWN
Refute if
On the pre-registered WM task under MAO-comparable conditions, selective MAO-A-i matches parent MB within the MB-equivalence band (WM Δ >70% of MB or inside band) — mild-MAOI-explains-WM survives.
Ask a human
Lock WM task (delayed alternation vs discrimination vs OR), selective MAO-A tool, and MAO occupancy readout before treating any MB cognitive signal as MAOI-matched; do not treat N3 as already proving mismatch; no dosing. Please peer-review.
Cheap IP
kill_cost_tier=1 · time_to_refute=4w · ip_class=redox-vs-MAO · vault_hold=no
Execution
execution_status=NOT_RUN · fto_status=UNKNOWN · related_prior=N3 (not proof)
Honesty
Literature / computational prediction for research discussion only. Not medical advice. Not a dosing or treatment recommendation. Invite peer-review.