2026 — Metformin clinical-trial landscape in neurological disorders

One-paragraph summary

Systematic clinical-trial-landscape analysis of metformin repurposing in central-nervous-system disorders. Searching ClinicalTrials.gov (excluding type-2-diabetes and cancer indications), 23 metformin trials in CNS conditions are identified, with MS the largest indication (5 trials), followed by schizophrenia/psychosis (4) and fragile X syndrome (4). Over two-thirds of trials are completed (n=7) or actively recruiting (n=9). The mechanistic rationale: metformin activates the AMPK pathway, supporting neuroprotection and promoting remyelination. Trial outcomes use both functional measures (Timed 25-Foot Walk Test, MATRICS Consensus Cognitive Battery) and advanced biomarkers (diffusion tensor imaging for white matter integrity; NfL and GFAP molecular markers). The review is descriptive — no efficacy claims yet because the trials are mostly ongoing or recently completed. For the project, metformin enters the cure-path program through the EBV → MS connection (Bjornevik 2022): if EBV-driven plasma-cell reprogramming operates similarly in MS and FM-autoimmune subset, and metformin's MS efficacy reflects AMPK-mediated remyelination + neuroprotection, then metformin becomes a candidate adjunct for HERV+ / EBV+ FM. Drug-repurposing tier — established safety profile, generic, no IND required for off-label investigational use. The review's NfL biomarker emphasis aligns directly with the post-COVID-FM differentiator dimension already in the project's biomarker-mapping cohort design (white paper §10.2).

Claims as triples

• metformin — bridges → multiple_sclerosis [evidence: 5 active MS trials per ClinicalTrials.gov landscape; confidence: established (clinical-stage)]
• metformin — bridges → fm_autoimmune [evidence: extrapolation via EBV→MS→FM-autoimmune chain; confidence: bridging]
• metformin — modulates → neuroinflammation_glial [evidence: AMPK pathway activation, remyelination promotion, neuroprotection in CNS disorders; confidence: bridging]
• NfL — predicts → multiple_sclerosis [evidence: NfL used as molecular biomarker across MS metformin trials; confidence: established (reinforces existing edge)]

Methods note

Systematic clinical-trial-landscape review. Data source: ClinicalTrials.gov only. Inclusion: neurological, neurodegenerative, and neurodevelopmental conditions. Exclusion: trials primarily targeting type 2 diabetes or cancer. After screening, 23 studies retained. Extraction emphasized disease types, therapeutic goals, and measurable neurobiological / functional outcomes. No efficacy claims because most trials are not yet reported.

Limitations

• Single-source ClinicalTrials.gov landscape. Does not include international registries (EudraCT, JAPIC, ChiCTR), so the global metformin-in-CNS landscape is partially captured.
• No efficacy data. The review documents what's being trialed, not what works. Translation to FM cure-path planning requires waiting for trial readouts (most expected 2026-2028).
• No FM trials. Metformin in FM specifically is not yet on ClinicalTrials.gov in the reviewed set.
• Bridging-tier confidence appropriate. The MS → FM extrapolation rests on the project's EBV-driven-plasma-cell-reprogramming working hypothesis, which itself is bridging-tier (Bjornevik 2022 establishes EBV → MS necessity, but the FM-specific application is by analogy).

Open questions raised

• Do completed metformin MS trials (n=7) report NfL or remyelination signal? Trial readouts should be tracked quarterly; project should add metformin-MS-trials to the watch-list alongside STING inhibitors and temelimab.
• Does metformin reduce plasma cell-free mtDNA or ISG signature in MS or FM patients? AMPK activation has documented mitochondrial-quality-control effects; could intersect with the HERV-mito-loop's mitochondrial-damage step.
• If a metformin MS trial reports positive efficacy, what's the right design for an investigator-initiated stratified pilot in HERV+ / EBV+ FM? 6-month exploratory design with NfL primary endpoint is plausible.

Triangulation notes

• Connects via Bjornevik 2022 (EBV → MS) to the project's H1 chain. If EBV-driven plasma-cell reprogramming is a candidate upstream cause of FM-autoimmune subset (B11 bridge), and metformin shows MS efficacy via AMPK-mediated remyelination, the MS-FM mechanistic overlap creates a candidate metformin application for FM.
• Adds a 7th cure-path arm to the white paper §10 program. Drug-repurposing tier with established safety; AMPK-pathway-targeted; intersects with mitochondrial-quality-control and possibly the HERV-mito-loop's mitochondrial-damage step.
• Compatible with idebenone / MitoQ / elamipretide. Both metformin and the mitochondrial-protective agents target mitochondrial homeostasis but via different mechanisms (AMPK activation vs. ETC support / cardiolipin stabilization). Combination-therapy designs become plausible.
• Aligns with the biomarker-mapping cohort's NfL dimension. Metformin trials' NfL biomarker emphasis reinforces the value of including NfL in the 13-dimensional cohort design.

Bridges

• New candidate B17 — metformin / AMPK-activator class ↔ FM via MS / EBV / mitochondrial-quality-control connection. Drug-class bridge bridging the project's HERV-mito-loop framework with MS clinical-development literature.
• Reinforces B11 (MS↔FM via shared EBV-driven plasma-cell reprogramming, introduced 2026-05-09) by adding a candidate shared therapy class.