The NP001 formulation of sodium chlorite acts through a plausible mechanism and preliminary data suggest that it is safe and may slow ALS progression in some PALS. The WF10 formulation of SC appears to act through this same mechanism. Although WF10 is available for off-label use, it is very expensive, may have more side-effects than NP001, and at this time has only scant anecdotal evidence for efficacy in PALS. ALSUntangled supports further carefully monitored studies of NP001 and WF10 in PALS. In contrast, oral sodium chlorite has potentially dangerous and toxic side-effects may hasten disease progression, and is not clearly absorbed from the gut. We do not recommend further use of oral sodium chlorite unless it can at least be shown to be safe and to act on mechanisms in humans that are relevant to ALS.
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’.
Acetyl-L-Carnitine
There are good theoretical mechanisms for carnitines, some pre-clinical evidence for LC and ALCAR, and a single clinical trial that suggested ALCAR could slow disease progression in PALS. All three carnitines appear to be well-tolerated, generally safe, and inexpensive. We believe that there is a need for future clinical trials of carnitines in PALS to further elucidate their efficacy. Until there is further data, we cannot endorse any of these supplements as a definite way to slow ALS progression; however, oral ALCAR at 1000mg three times daily (3000 mg total daily dose) appears to be a theoretically promising supplement available for PALS whom would like to self-experiment.
Basis
Basis has mechanisms of action that could theoretically be useful in treating ALS. It appeared reasonably safe in a small, short duration study of healthy volunteers and it is fairly inexpensive. However, we found no data in preclinical ALS models, no case reports, and no trials in PALS. Based on this lack of data, ALSUntangled cannot currently recommend use of Basis to slow, stop, or reverse the progression of ALS.
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L-Serine
L-serine is a reasonably inexpensive, widely available nutritional supplement that has a plausible mech-anism by which it could help a subset of patients who might have ALS from BMAA-toxicity. A small Phase I trial showed that L-serine up to 15 g twice daily is relatively well tolerated. A larger follow up trial is planned and will shed further light on its safety and utility as an ALS therapeutic. Unfortunately, since it is challenging to reliably measure BMAA in PALS, it will be difficult to identify the subset most likely to respond. Until a reliable assay for measuring BMAA exposure in living people arises, or a follow up trial confirms safety and demonstrates benefit independent of this, we cannot recommend L-serine as a treatment for ALS.
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Endotherapia
Endotherapia has a proposed mechanism that hinges on the ability of an isolated laboratory’s immunoblots to identify the cause and specific pathways that are driving ALS progression. In our opinion this ability has never been convincingly demonstrated. While there is a flawed animal study supporting the utility of Endotherapia in rats, such studies rarely translate into useful human treatments (29). The data on Endotherapia in PALS have so many problems that we believe they are uninterpretable. ALSUntangled does not recommend the use of Endotherapia for ALS at this time. A reasonable next step would be a study to validate the utility of the above-described immunoblots, ideally by a group without a potential conflict of interest.
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Methylcobalamin
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).
Acupuncture
Acupuncture is reasonably safe, and has potential mechanisms of action, pre-clinical studies and case reports suggesting that it could be a useful treatment for ALS. However, before it can be endorsed even as a candidate for a phase II trial, the studies described above need to be independently replicated using more clearly verified diagnoses and more rigorous designs, including appropriate controls and validated ALS outcome measures.
Vitamin D
At this time, there is evidence that PALS, like those with other chronic illnesses, are at increased risk for vitamin D deficiency. It is, therefore, reasonable to screen PALS for this. If vitamin D deficiency is found, it seems reasonable to supplement vitamin D according to established guidelines (31) in order to avoid medical complications of vitamin D deficiency. It is not yet clear, however, that vitamin D supplementation can slow disease progression, improve muscle strength, or reduce falls in PALS. We support further studies to answer these questions.