JETALS Trial (2022/2024) — Ultra-High-Dose Methylcobalamin for ALS
Methylcobalamin — the biologically active methylated form of vitamin B12 — has been used for decades in Japan and elsewhere as a nutritional supplement and as a treatment for peripheral neuropathy. At ultra-high doses delivered by intramuscular injection, it is something categorically different: a disease-modifying intervention that slows ALS progression, earned a regulatory approval in Japan under the brand name Rozebalamin, and holds a clinically meaningful position in the motor neuron disease treatment landscape because it is neuroprotective, mechanistically general, and practically accessible in a way that more targeted therapies are not. The JETALS trial is the pivotal evidence that established this.
What they did
The Trial Design
The JETALS trial — Japanese Early-Stage Trial of high-dose methylcobalamin for ALS — enrolled patients with ALS at a relatively early and defined stage: symptomatic disease with a moderate but not rapid rate of functional progression. This staging criterion was deliberate. Earlier work in the Eisai Phase 2/3 programme (the E0302 study) had suggested in post hoc analysis that survival benefit was concentrated in patients who began treatment within one year of symptom onset. JETALS was designed to test this window of opportunity prospectively by enriching the trial population for early-stage patients.
Participants were randomized to receive either methylcobalamin 50 mg by intramuscular injection twice weekly, or matched placebo injections on the same schedule. The 50 mg intramuscular dose is approximately 20,000 times the ordinary daily dietary requirement for vitamin B12 (roughly 2.4 micrograms per day for a healthy adult). This is not a nutritional dose. At 50 mg IM twice weekly, methylcobalamin is functioning as a pharmacological agent, not as a nutritional supplement. The distinction matters because it is the source of a common misunderstanding: ordinary B12 supplements, whether dietary or at typical oral supplementation doses, do not replicate the effects shown in this trial.
The trial ran for a 16-week double-blind period. The primary endpoint was the change in total ALSFRS-R score from baseline to week 16. The ALSFRS-R (ALS Functional Rating Scale — Revised) is a 48-point questionnaire covering 12 functional domains from speech and swallowing through limb function to respiratory status. It is the standard outcome measure for ALS clinical trials and the one most directly comparable across studies.
What they found
Primary Outcome: ALSFRS-R Decline
Methylcobalamin produced a statistically significant reduction in the rate of ALSFRS-R decline compared with placebo. At week 16, the least-squares mean difference between groups was 1.97 ALSFRS-R points: the placebo group declined by an average of 4.63 points, while the methylcobalamin group declined by 2.66 points. The confidence interval and p-value were statistically significant.
To give this number context: the PLS natural history benchmark from Gordon 2006 is 1.6 ALSFRS-R points of decline per year in PLS. ALS declines much faster — typically 4–6 points per year, depending on disease stage and subtype. A 1.97-point preservation over 16 weeks in ALS translates to approximately a 43% reduction in the rate of decline during that period in the treated group. This is clinically meaningful for a disease with no other neuroprotective intervention of comparable magnitude for the general ALS population.
Secondary Outcomes and Safety
Methylcobalamin produced a marked reduction in serum homocysteine levels. Homocysteine is an amino acid that accumulates when the methylation cycle is underactive — specifically when B12-dependent methionine synthase has insufficient substrate. At ultra-high methylcobalamin doses, the methionine synthase reaction is driven efficiently, reducing homocysteine to normal or subnormal levels. This homocysteine lowering is the candidate mechanism for the observed neuroprotection, discussed below.
Safety was comparable between groups over the 16-week treatment period. Methylcobalamin at these doses was well tolerated. No unexpected adverse events were attributed to the drug. The injection site reactions typical of intramuscular injections occurred, but were manageable and did not cause excess discontinuation in the treated group. This safety profile is consistent with decades of high-dose B12 clinical use in Japan, where injectable methylcobalamin has long been available for neurological indications.
The Regulatory Milestone
On the basis of the JETALS data and the supporting evidence from the Eisai Phase 2/3 programme, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) approved methylcobalamin under the brand name Rozebalamin in 2024 for the treatment of ALS. This is the first regulatory approval of methylcobalamin for ALS anywhere in the world, and the first new ALS drug approval in Japan since edaravone received its approval in 2015.
Regulatory approval in Japan does not automatically create access elsewhere. As of 2026, Rozebalamin was not approved by the FDA or EMA. However, the approval validates the evidence base — a regulatory agency reviewed the totality of the data and judged it sufficient for approval — and creates a clear reference point for prescribers in other countries who wish to use methylcobalamin off-label with a characterised dosing protocol.
Why it matters
The Mechanism: Homocysteine and Motor Neuron Vulnerability
Methylcobalamin is the coenzyme form of vitamin B12 that activates methionine synthase, the enzyme that converts homocysteine to methionine. At ultra-high doses, this reaction is driven far to completion, producing a dramatic reduction in circulating homocysteine. Homocysteine at elevated concentrations is neurotoxic through several mechanisms: it activates NMDA receptors (excitotoxicity), generates reactive oxygen species, impairs DNA repair, and disrupts mitochondrial membrane potential. Motor neurons, which are metabolically active, post-mitotic, and unable to regenerate, are particularly vulnerable to these stressors.
Homocysteine elevation is seen in motor neuron disease broadly — not just in ALS, and not through a disease-specific mechanism, but as a consequence of the metabolic stress of progressive neurodegeneration and the systemic changes that accompany it. This broad association is part of what makes homocysteine lowering a plausible neuroprotective target across motor neuron disease phenotypes, not just in ALS.
Secondary proposed mechanisms include support of methylation reactions in neurons (proper gene expression, neurotransmitter synthesis, myelin maintenance), and direct neurotrophic effects — methylcobalamin has been shown in cell culture and animal studies to support motor neuron survival independent of homocysteine lowering, though the relative contribution of these pathways in vivo is not fully established.
Implications for PLS
The honest statement first: no trial of methylcobalamin in PLS exists. JETALS was conducted in ALS patients. The evidence base for methylcobalamin in PLS is entirely extrapolated from ALS trial data, and a neurologist considering this intervention for a PLS patient would be making an extrapolation that no published trial has yet validated directly.
With that caveat clearly stated, the extrapolation from ALS to PLS is more mechanistically supported than many off-label extrapolations in neurology. The proposed mechanism — homocysteine-mediated motor neuron oxidative damage — is not ALS-specific. It does not depend on TDP-43 aggregation, SOD1 mutation, C9orf72 repeat expansion, or any of the disease mechanisms specific to ALS subtypes. It is a general neuroprotective mechanism relevant to any condition in which motor neurons are under metabolic stress. PLS motor neurons — whether the upper motor neuron cell bodies in the primary motor cortex or the axons traversing the corticospinal tract — are under ongoing metabolic stress as the disease progresses.
For a PLS patient whose neurologist is considering neuroprotective options, methylcobalamin has the strongest evidence base of any general neuroprotective intervention currently available outside of disease-specific approaches like tofersen (which requires an SOD1 mutation that PLS patients do not have). The regulatory approval in Japan, the characterised 50 mg IM twice weekly dosing protocol, and the decades of Japanese clinical experience with high-dose injectable B12 all provide a framework that prescribers can reference.
The early-stage timing constraint is worth noting. JETALS enriched for early-stage ALS patients, and the Eisai Phase 2/3 post hoc analysis suggested that the survival benefit was concentrated in patients treated within one year of symptom onset. If this timing effect is real and reflects a window during which the drug can slow the initial phase of motor neuron loss more than the later phase, then it implies that methylcobalamin should be started as early as possible in the disease course — not reserved for advanced disease. For PLS patients, where the disease trajectory is slower and the early stages are less clinically dramatic than in ALS, this timing consideration has direct relevance to when to begin the conversation about neuroprotective options.
Practical Access
In France, methylcobalamin 50 mg IM is not a standard hospital formulary item — Rozebalamin is only approved in Japan. However, pharmaceutical-grade methylcobalamin at high doses is available through compounding pharmacies (pharmacies préparatrices) with a prescription, and injectable methylcobalamin at lower doses (500 micrograms to 1 mg) is widely available as a branded neurological preparation. A neurologist who has reviewed the JETALS protocol and decided to recommend this off-label can work with a compounding pharmacy to obtain the 50 mg IM formulation. This pathway requires more effort than a standard prescription, but it is not unreachable.
Limitations
The 16-week trial duration is the central limitation for PLS. Sixteen weeks is a reasonable period for demonstrating an effect on ALS ALSFRS-R decline, where the rate of change is high enough that a treatment difference is detectable in that timeframe. In PLS, where the baseline decline rate is approximately 1.6 ALSFRS-R points per year rather than 4–6, a 16-week observation window would detect only 0.6 ALSFRS-R points of expected decline — well below the detectable threshold for most trials. This means that even if methylcobalamin has a proportional neuroprotective effect in PLS comparable to what JETALS showed in ALS, a direct PLS replication of JETALS would need to be substantially longer and larger to demonstrate it.
The early-stage enrollment criterion also raises a question for PLS. Many PLS patients are not diagnosed until several years after symptom onset, because the diagnostic criteria require a period of symptom duration (four years under the 2020 consensus criteria) before PLS can be confidently distinguished from ALS. A drug that may need to be started early to achieve maximum benefit is harder to access in PLS than in ALS, where earlier diagnosis is more reliably available.
The Japanese regulatory approval does not create availability in France, the United Kingdom, or the United States. This is a real practical barrier. Compounding pharmacy access is available in principle but not standardised, and the quality assurance for compounded injectables requires verification on a case-by-case basis.
How this connects
Methylcobalamin sits within the broader framework of neuroprotection in motor neuron disease discussed across the Drug Trials Hub. Unlike the cerebellar and basal ganglia compensation approaches covered on the Targeting Compensatory Circuits page — which aim to rescue compensatory walking circuits while they are still functional — methylcobalamin is attempting to slow the underlying neurodegenerative process that makes compensation necessary in the first place. The two approaches are not competing; a patient could reasonably pursue both.
For the most targeted neuroprotective approach currently in use for ALS — limited to patients with SOD1 mutations — see the Tofersen VALOR trial. For another neuroprotective ALS approach based on immune modulation, see the MIROCALS IL-2 trial. The Drug Trials Hub provides orientation across all these approaches and their applicability to PLS.
Citation
Oki R, Izumi Y, Fujita K, Ogata K, Tanaka H, Shimatani Y, Nakao S, Kawaguchi T, Morita M, Kuzuhara S, Takahashi R, Shimizu T, Sobue G, Kimura F, Arisato T, Maruyama H, Abe K; JETALS Study Group. Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurology. 2022;79(6):575–583. doi:10.1001/jamaneurol.2022.0901. PMID: 35532908.