Clemastin for Re-Myelinisation – maybe also for Amyotrophic Lateralsclerosis

A patient with amyotrophic lateral sclerosis (AMS) of Dr. Renate Thiele (Linz) consults us about TPS adjunctive therapy (according to the SOZO protocol developed by Petros Kattou).

She reports that the fasciculations have disappeared under clemastine. Her gait has improved overall (but she also undergoes neuromodulation with Dr. Thiele).

She tells of a severely impaired patient with multiple sclerosis who alleviated all her symptoms under clemastine. I will follow up on this and interview this patient to verify the veracity of this.

This literature search complements a research article I wrote a few months ago.

conducted due to feedback from the patient described above.

Remyelinisierung des Hirns bei Multipler Sklerose, QUERSCHNITT, traumatischer Hirnverletzung und ME/CFS bzw. Longcovid, möglich

Here is my PubMed-based research on clemastine in neurological diseases (MS and ALS):

PubMed: Clemastine in Multiple Sclerosis (MS)

• ReBUILD (Greene et al., 2017) – Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomized, controlled, double-blind, crossover trial
  – Clemastine fumarate (5.36 mg bid/day) reduced VEP P100 latency by approximately 1.7 ms per eye (95% CI 0.5–2.9; p=0.0048). Fatigue was the most common side effect; no serious AEs were observed.
  – Link: [PubMed entry with abstract & Trial Details] (PubMed)

• RESTORE (Hofetal., 2024) – Protocol of a current Phase II study (INO measurement)
  – Investigates clemastine fumarate (4 mg bid/day) over 6 months versus placebo for remyelination in MS with internuclear ophthalmoplegia. Target variables: Improvement of oculomotor parameters using infrared oculography.
  – Link: [PubMed entry: Trial protocol RESTORE] (PubMed)

PubMed: Clemastine in Amyotrophic Lateral Sclerosis (ALS)

• — No pure PubMed entries for ALS studies found. The data available to date come from animal or preclinical studies; there are no human clinical studies.

Further reviews / mechanistic work

• Yamazakietal., 2025 – The potential of repurposing clemastine to promote remyelination
  – Overview of clemastine’s effect on remyelination in white matter injury and MS.
  – Link: [Open‑Access PMC‑Review] (PMC)
• Jiangetal., 2023 – Mechanistic Review: Clemastine promotes remyelination via CHRM1 antagonism (M1 muscarinic receptor)
  – In animal models (e.g., EAE rats), a myelination-promoting effect is observed.
  – Link: [PMC review on mechanisms] (PMC)

Summary

• ReBUILD (Greenetal., Lancet2017): Clemastine shortens VEP latency in RRMS patients; Link: PubMed ReBUILD (PubMed)
• Kocotetal. (JClinInvest2025): Clemastine arm stopped in TRAP-MS study due to accelerated disability progression; Link: PubMed JClinInvest (PubMed)
• Kocotetal. (medRxiv2024): Preprint for the same study; Link: medRxiv (PMC)
• RESTORE (Hofetal., BMJ Open2024): Protocol Clemas-INO study; Link: PubMed RESTORE (PubMed)
• Yamazakietal. (FrontCellNeurosci2025): Review Clemastin‑Repurposing; Link: PMC Review (PMC)
• Jiangetal. (FrontMolNeurosci2023): Mechanisms via M1 antagonism; Link: PMC Review (PMC)

Researchgate Search

Researchgate has many entries that have not yet been published, so I conducted my own Researchgate study!

Clemastine – ResearchGate Evidence Overview (Focus on MS and ALS)

Short Conclusion

• Multiple Sclerosis (MS): There are clinical signals for remyelination with clemastine (especially shortening of VEP latency) in small Phase II studies and in optic neuropathy; clinically relevant improvements in disability have not yet been demonstrated. One arm in a progressive MS platform study was stopped early in 2024 due to a safety/progression signal. (ResearchGate)
• Amyotrophic lateral sclerosis (ALS): No human evidence. Preclinical clemastine showed neuroprotective and anti-inflammatory effects in SOD1-G93A mice. (ResearchGate)

Mechanism of action (conceptual)

• Antimuscarinic (M1 antagonism) on OPCs → promotion of oligodendrocyte differentiation and remyelination; additional microglial modulation. (ResearchGate)

Multiple Sclerosis – Researchgate Clemastine

Positive Signal Studies

• ReBUILD (Phase II, Crossover): Clemastine fumarate vs. placebo in RRMS with chronic stable optic neuropathy. Primary: Shortening of VEP P100 latency under therapy; Trend, but not significant in low-contrast letter acuity. Side effects: mainly fatigue. (Original dose: approximately 5.36 mg twice daily.) (ResearchGate)
• Acute optic neuritis (RCT): 90-day treatment resulted in more favorable VEP parameters and less RNFL/GCL loss vs. placebo. (ResearchGate)

Ongoing/Newer MS Approaches

• CCMR-Two (protocol, 2025): Metformin + Clemastine in RRMS with chronic optic neuropathy; endpoints include VEP latency over 24 weeks. (ResearchGate)

Negatives/Signals of Harm

• TRAP-MS (progressive MS, platform): Clemastin arm 2024 due to accelerated disability progression in 3/9 patients and unfavorable Premature progression of the disease. Evidence of metabolic syndrome and innate immune activation; exploratory CSF proteomics. (ResearchGate))

Overall MS Assessment

• Efficacy: Evidence for biomarker-assisted remyelination (VEP) available; clinical benefit (disability, function) not secured.
• Safety: Usually fatigue, anticholinergic effects; Possible risk signal in progressive MS (TRAP-MS). (ResearchGate)

Amyotrophic lateral sclerosis – Reserachgate / Clemastine

Preclinical Evidence

• SOD1-G93A mouse model: Neuroprotection, reduced microgliosis, anti-inflammatory gene programs, prolonged survival, and improved pathology in subparameters under clemastine. Mechanistically, microglial modulation, among others. No human studies identified. (

ResearchGate

)

Overall Assessment ALS

• Efficacy: currently preclinical; clinical data lacking. Translation remains unclear. (ResearchGate)

Further reviews and animal data

• Narrative/review-style studies on clemastine as a remyelinator and in other CNS indications; confirm OPC differentiation and remyelination rationale. (ResearchGate)
• Animal models beyond MS/ALS (cuprizone, SCI, hypoxic WM damage) show remyelination and cognitive/functional improvement. Clinical transferability remains open. (ResearchGate)
  

  Practical Clinical Assessment

  • MS (RRMS, chronic optic neuropathy): Clemastine can be considered off-label as a remyelination trial, primarily for VEP improvement; patient education regarding limited clinical benefit and fatigue is required. Progressive MS: Caution due to TRAP-MS signal. (ResearchGate)
  • ALS: Currently no recommendation outside of studies; Evidence only from animal models. (ResearchGate)

   

  Sources (ResearchGate)

  • ReBUILD study (Lancet article page on RG): Clemastine fumarate as a remyelinating therapy… (ResearchGate)
  • RCT optic neuritis: Randomized Control Trial of Evaluation of Clemastine Effects on VEP… (ResearchGate)
  • Protocol CCMR-Two (metformin + clemastine): (ResearchGate)
  • TRAP-MS Preprint page (clemastine arm stopped): (ResearchGate)
  • ALS Mouse Model: Clemastine Confers Neuroprotection… SOD1G93A (ResearchGate)
  • Reviews/Overviews (mechanism/remyelination): Insights on therapeutic potential of clemastine…; The potential of repurposing clemastine…; Cuprizone Model (ResearchGate)