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ALSUntangled™ reviews alternative and off label treatments (AOTs), with the goal of helping people with ALS make more informed decisions about them.

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Methylcobalamin

Updated Review
Published: May 16, 2022
Since our review, the 373 patient trial we described seeing at a meeting has been published (J Neurol Neurosurg Psychiatry 2019;90:451-457). Again, this did not show an overall benefit for patients with ALS. In a subgroup of patients in the first 12 months of their symptoms, MeCbl was associated with slower ALSFRS-R progression and longer survival. A very recently published follow up study focused only on patients in the first 12 months of their ALS symptoms with an ALSFRS-R progression rate of 1-2 points over a 12-week lead in (JAMA Neurol 2022;May 9:epub). Again, this was randomized, double-blind and placebo controlled. This study showed that patients on 50-mg IM twice weekly had significantly slower ALSFRS-R progression over 12 weeks than those on placebo. This study was well designed. We change our Trials grade to A, but caution that both trials only show benefit from treatment in patients who are in the first year of their ALS symptoms. We see no evidence that MeCbl helps patients who have had symptoms for longer than 1 year.

Key Information

Click on any letter grade below for more info:
Mechanism Grade: A
Preclinical Trials Grade: C
Cases Grade: D
Trials Grade: A
Risks Grade: B
Published: Jul 2015
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MeCbl has promising mechanisms and positive preclinical data from two different ALS models. Unfortunately, the anecdotal data we found did not identify any clear specific benefit, and the best of three clinical trials was unable to show an overall difference in ALSFRS-R progression or survival between PALS treated with MeCbl and those treated with placebo (26). A sub-group of patients with very specific pretreatment progression rates of 1–3 ALSFRS-R points over 12 weeks, and very early disease (less than 12 months from symptom onset) may have had benefit (26). This finding needs to be replicated, especially since an earlier study suggested patients with longer disease duration were more likely to benefit (20). We would like to see a full traditional sub-group analysis (28) carried out on the data from the third trial (26). This sub-group analysis could then be used to design inclusion criteria for a new phase III trial comparing MeCbl 50 mg twice a week IM to placebo. The new trial could measure serum B12 and homocysteine, and have pre-planned sub-group analyses that are both logical and practical. While we wait for this, PALS who wish to try MeCbl are reminded that the above studies used very high, injected doses, which appear to be available only by prescription. Lower over-the-counter doses administered orally have not been studied. It is well established that over-the-counter oral supplements may be of poor and inconsistent quality (32). Some over-the-counter oral vitamin B supplements contain not only B12 but also B6, which in large quantities can be harmful to the nervous system (33).

Mechanistic plausibility

Grade A: Shown in a peer-reviewed publication to act on a relevant mechanism in humans

Mechanistic plausibility

Grade B: Shown in a peer-reviewed publication to act on a relevant mechanism in pre-clinical model(s)

Mechanistic plausibility - C

Grade C: Theoretically and plausibly acts on an ALS-relevant mechanism in humans

Mechanistic plausibility

Grade D: Acts on a biological mechanism but it is not clear that this mechanism is relevant in ALS

Mechanistic plausibility

Grade F: Implausible; would violate known principles or laws of biology

Mechanistic plausibility

Grade U: No useful information was found for this category

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade A: Two or more peer-reviewed publications reporting benefits in well-designed studies.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade B: One peer-reviewed publication reporting benefits in a well-designed study.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade C: One or more peer-reviewed publication(s) reporting benefits in flawed studies.

Animal studies are assumed to be ‘well designed’ when they follow published guidelines. When they deviate from these they are considered ‘flawed’.

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade D: One or more non-peer reviewed studies reporting benefits (published on a website or in an abstract)

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade F: The only studies available show no benefit

Pre-clinical models (animal or cell models recognized by ALSUntangled reviewers to be relevant to ALS)

Grade U: No useful information was found for this category

Patient case reports

Grade A: One or more peer-reviewed publications reporting benefits with validated diagnosis and benefits

Patient case reports

Grade B: More than one unpublished report of benefit with validated diagnosis and benefits

Patient case reports

Grade C: One unpublished report of benefit with validated diagnosis and benefits

Patient case reports

Grade D: Subjective report(s) of benefit without validated diagnoses and/or benefits

Patient case reports

Grade F: The only reports available show no benefit

Patient case reports

Grade U: No useful information was found for this category

Patient trials

Two or more peer-reviewed publications describing benefits in well-designed randomized, blinded placebo-controlled phase III trials

Patient trials

Grade C: One or more peer-reviewed publications reporting benefits in a well-designed randomized, blinded, placebo-controlled phase I or II trial

Patient trials

Grade D: One or more peer-reviewed publications reporting benefits in a flawed trial.

Flawed trials means those in which there are identifiable problems with patient selection, randomization, blinding, controls or follow-up. These have ‘high or unclear risk of bias’ according to published criteria. Well-designed trials are those that have ‘low risk of bias’.

Patient trials

Grade F: The only trials available show no benefit

Patient trials

Grade U: No useful information was found for this category

Risks (harms that occurred on this treatment)

Grade A: No exposed patients appear to have experienced harms

Risks (harms that occurred on this treatment)

Grade B: More than 0% but less than 10% of exposed patients experienced harms (no hospitalizations or deaths)

Risks (harms that occurred on this treatment)

Grade B (oral): More than 0% but less than10% of exposed patients experienced harms (no hospitalizations or deaths)

Grade D (intravenous): More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Risks (harms that occurred on this treatment)

Grade C: At least 10% of exposed patients experienced harms (no hospitalizations or deaths)

Risks (harms that occurred on this treatment)

Grade D: More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Risks (harms that occurred on this treatment)

Grade D: More than 0% but less than 5% of exposed patients experienced death or hospitalizations

Grade F: At least 5% of exposed patients experienced death or hospitalization

Risks (harms that occurred on this treatment)

Grade F: At least 5% of exposed patients experienced death or hospitalization

Risks (harms that occurred on this treatment)

Grade U: No useful information was found for this category

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