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High Dose Methylcobalamin Appears to Slow ALS Progression in Early-stage Disease
Experts Cite Study Limitations

Article In Brief

A short randomized clinical trial of ultrahigh dose methylcobalamin found it slowed functional decline in people with early-stage amyotrophic lateral sclerosis (ALS). One ALS expert said she would consider offering it as a treatment option, with caveats, about its limitations. But other neuromuscular specialists said they were not confident that the results merited offering the drug.

High doses of methylcobalamin, the active form of vitamin B12, may help slow functional decline in patients with early-stage amyotrophic lateral sclerosis (ALS), according to a randomized clinical trial published online first in JAMA Neurology on May 9.

The phase 3 trial, which was conducted in Japan, lasted only 16 weeks, but in that time participants who received twice weekly injections of methylcobalamin experienced less decline as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) compared with a group of ALS patients given a placebo.

“This trial demonstrated ultrahigh-dose methylcobalamin resulted in a 43 percent reduction in clinical deterioration as evaluated with the ALSFRS-R total score throughout the 16-week treatment period in the patients with early-stage ALS,” said study coauthor Yuishin Izumi, MD, PhD, professor and chair of neurology at the Tokushima University Graduate School of Biomedical Sciences.

Dr. Izumi said in an email interview that the 43 percent reduction measured by the rating scale was enough to result in a “large clinical impact.” The ultrahigh dose of methylcobalamin also appeared to be safe.

The Japanese study grew out of a previous phase 2/3 clinical trial sponsored by Eisai Co., Ltd, which found that while “ultrahigh-dose methylcobalamin (25 mg or 50 mg) was safe and tolerable, it did not show significant efficacy in the overall cohort,” according to background information in the new study. However, a post-hoc analysis found that the treatment might be beneficial for ALS patients with early-stge disease.

The new paper noted that finding additional therapies for ALS is critical given that the only US Food and Drug Administration-approved treatments, riluzole and edaravone, have limited effectiveness.

The validation study, funded by the Japan Agency for Medical Research and Development, was conducted at 25 neurology centers in Japan from October 17, 2017, to September 30, 2019. It consisted of three stages: an observation period of 12 weeks, a treatment period of 16 weeks; and an open-label extension period scheduled to last until until March 2024.

The study initially enrolled 203 ambulatory patients 20 years of age or older who were diagnosed with sporadic or familial-ALS with definite, probable, or probable laboratory confirmation and within one year of symptom onset. Patients who remained ambulatory and presented with a 1- or 2-point decrease in the ALSFRS-R total score during the observation period were enrolled in the treatment phase.

A total of 130 patients (74 men, 56 women) were randomly assigned to receive twice weekly intramuscular injections of 50 mg of methylcobalamin or placebo. Most participants were already taking riluzole and could remain on it.

The main outcome measure was change in the ALSFRS-R score, which rates patients in 10 categories such as walking, breathing, swallowing, and dressing and hygiene on a scale of 0 to 4, for a total possible score of 0 (worst) to 40 (best). A total of 126 patients completed the double-blind stage of the trial.

The analysis found that the average change in the ALSFRS-R score for the treatment group was -2.66 compared with-4.63 for those on placebo, a difference of 1.97, which was statistically significant.

Dr. Izumi said that in addition to the overall difference of 43 percent in measure of function, “in the ALSFRS-R sub-scores, decreases in the fine-motor, gross-motor, and total limb (the sum of both) functions were significantly smaller with methylcobalamin.”

“Because the ability of limb function is critical to activities of daily living, the effect of methylcobalamin is likely meaningful for patients,” he said.

The beneficial effect of the vitamin therapy appeared even slightly greater if patients were also taking riluzole, which implies that the combination of riluzole and methylcobalamin has a greater therapeutic effect than riluzole alone,” the study authors wrote.

From a research perspective, Dr. Izumi said that it was noteworthy that the results of the post-hoc analysis of the previous trial data “were almost perfectly reproduced in this trial.”

“Methylcobalamin is a highly tolerable and safe drug, as indicated by the extremely low dropout rate of 3 percent and the incidence of side effects of 8 percent over the treatment period,” Dr. Izumi said. About 30 ALS patients continue to get methylcobalamin under the open-label phase of the trial. He said methylcobalamin for ALS is not used in Japan outside of the clinical trial setting, or the open-label study.


“There is no greater unmet need than therapy for patients with ALS. Even so, the limitations of the trial of methylcobalamin need to be spelled out before one jumps on the bandwagon and says, ‘This is an incredible treatment for ALS.’”—DR. STANLEY H. APPEL

The researchers said it is not clear why ultrahigh-dose methylcobalamin may provide a benefit in ALS, though in vivo human and in vitro research suggests multiple mechanisms may be involved.

“Methylcobalamin may exert its efficacy through complex mechanisms of action: for instance, neuroprotective effects against homocysteine-induced or glutamate neurotoxicity, antioxidant or anti-inflammatory effects, modulation of the gut microbiome, upregulation of gene transcription and protein synthesis, and promotion of nerve regeneration,” Dr. Izumi said.

The researchers noted their study had limitations, including the fact that the randomized phase lasted 16 weeks instead of the usual 24 weeks for most clinical trials. Because the trial only enrolled patients with early-stage ALS without rapid progression, it is impossible to say whether ALS patients with other profiles would be helped by methylcobalamin.

Expert Commentary

Raymond Roos, MD, FAAN the Robert E. Straus Professor in Neurologic Science at University of Chicago, said the study does not convince him that methylcobalamin has a place in ALS care.

“We don't really have a drug as effective as we should have, but I'm not sure that ultrahigh-dose methylcobalamin will fill that role,” Dr. Roos said

Dr. Roos said that although the study was well organized and well conducted, he had several concerns about its design, including its short duration and the possibility that there could have been some unblinding because the active vitamin treatment might cause reddening of the urine. He said he would have liked to know more about the possible effect of methylcobalamin on respiratory function, which may have not been possible since the trial included only patients in early-stage disease.

Dr. Roos said it would be useful for researchers to understand the mechanism by which high doses of vitamin B12 might affect the processes involved in ALS because “knowing why drugs work is valuable to assess its effect on the disease.”

Lauren Elman, MD, director of the Penn Comprehensive ALS Center at the University of Pennsylvania, said that she would consider recommending methylcobalamin to ALS patients based on the new findings.

“For patients who meet the criteria it would be a reasonable and safe thing to do,” she said. “I am not saying this should be standard of care, but I am saying this is worth discussing.”


“For patients who meet the criteria it would be a reasonable and safe thing to do. I am not saying this should be standard of care, but I am saying this is worth discussing.”—DR. LAUREN ELMAN

Dr. Elman said patient-doctor conversations need to include information on the limitations of the study and the reported benefits—for example, saying this is something that looks helpful, but it will not save your life—and the financial aspects of taking the therapy, which would not be covered by insurance. She said she did some preliminary checking and found that a monthly injectable supply from a local compounding pharmacy would be at least $200. “I will be at the ready to prescribe this for those who are interested,” noting the paucity of highly effective traditional drugs for ALS.

Stanley H. Appel, MD, FAAN, an ALS researcher and director of the Ann Kimball & John W. Johnson Center for Cellular Therapeutics at Houston Methodist Hospital, said he is confident based on the reported results for methylcobalamin that the vitamin therapy is safe for ALS patients. But he said the limitations of the study, laid out by the researchers themselves in their published paper, raise important questions about the therapy's worth in everyday clinical practice

“There is no greater unmet need than therapy for patients with ALS,” he said. “Even so, the limitations of the trial of methylcobalamin need to be spelled out before one jumps on the bandwagon and says, ‘This is an incredible treatment for ALS.’”

He said that the overwhelming majority of ALS patients would not meet the definition of early-stage disease and a small number of people can get an inaccurate diagnosis early on. He also noted that a small subset of ALS patients has limited progression of disease in the early months, so the slower decline for patients on methylcobalamin outlined in the study may reflect the natural course of disease.

Dr. Appel said he did not think the data and tables as presented in the journal report were detailed enough to allow clinicians to come to conclusions about the merits of methylcobalamin.

“Patients come in using all sorts of supplements and many argue the main consideration is ‘above all do no harm,” he said. But he said that there are considerations beyond safety, including potential financial and emotional harms, including the possibility of raising unrealistic patient expectations.


Drs. Izumi, Roos, and Appel had no disclosures. Dr. Elman reported a one-time fee for providing a lecture for NeuroPace.

Link Up for More Information

• Oki R, Izumi Y, Fujita K, et al. Efficacy and safety of ultrahigh-dose methylcobalamin in early-stage amyotrophic lateral sclerosis: A randomized clinical trial JAMA Neurol 2022; Epub 2022 May 9.