ALS Untangled®

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

Mechanistic plausibility

L-Serine

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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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Hyperbaric Oxygen

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Although there are plausible mechanisms by which HBOT could work in ALS and a flawed pre-clinical study showing benefit in a mouse model, the best available human trial of HBOT showed no benefit. Given this negative human trial and the fact that HBOT has potentially serious complications, we do not recommend HBOT for patients with ALS at this time.

Kim Cherry’s ALS reversal, which occurred on HBOT and several other alternative treatments, appears very interesting. We do not think this is due to HBOT alone. There are other rare examples of ALS reversals on different (or sometimes no) treatments (28). Other explanations for these reversals include undetected ALS mimics syndromes or endogenous mechanisms that confer resistance to the disease (28). We look forward to further study of cases like this (29).‌‌

Declaration of interest: ALSUntangled is sponsored by the ALS Association and the Motor Neurone Disease Association.‌

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Precision Stem Cell

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At ALSUntangled our goal is to provide guidance on the mechanism, pre-clinical data, anecdotal evidence, trials and risks of various alternative treatment options. Our goal is not to challenge the rights of PALS to pursue these options. Along these lines, MSC transplants in general have a promising mechanism, good pre-clinical data in ALS models and appear reasonably safe when performed with approved standardized protocols, proper oversight, and monitoring. However, the specific protocols used at PSC for PALS are poorly detailed, appear variable in terms of the sources of MSCs being used, the ways these are being modified and the places where these are being inserted, have no provision for confirming the material being inserted, and have only subjective and usually brief improvements associated with them. ALSUntangled strongly supports further study of MSC in PALS, but only with transparent, reproducible protocols that include confirmation of transplanted material and objective outcome measures. At this time, it does not appear to us that PSC is meeting these criteria.

Protandim

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Protandim appears reasonably safe and inexpensive, has a promising mechanism by which it could help ALS, and there is a patient with a validated ALS diagnosis whose ALSFRS-R score improved on it. There are significant problems with the data described, including small study sample sizes, failure to demonstrate that Protandim increases Nrf2 in humans, failure to establish an optimal dose, and potential conflicts of interest among several of the key individuals involved. Nonetheless, in our opinion, further study of Protandim in ALS appears warranted.

Declaration of interest: ALSUntangled is sponsored by the ALS Association and the Motor Neurone Disease Association.‌

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Mito Q

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MitoQ has a promising mechanism, positive preclinical data from two different ALS models, and appears reasonably safe and inexpensive, especially at doses of 10 mg daily. Available anecdotal data are insufficient to determine how helpful this might be in PALS. A small open-label pilot trial with validated ALS diagnoses and outcomes appears warranted.

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Acupuncture

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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.

Fecal Transplants

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There is rapidly expanding evidence implicating alterations in the fecal microbiome in wide-ranging human diseases, including potential contributions via a gut-brain signaling axis in neurodegenerative and neuroimmunologic disorders. Proposed mechanisms such as immune modulation and the production of neurotoxins by clostridia or other microbiota could bypass an intact blood-brain barrier. To date, there are no data directly implicating the fecal microbiome in ALS, nor published case reports of FMT being tried in PALS. Data in other neurodegenerative and neuroimmunologic disorders are largely circumstantial, comprising a handful of published case reports. Therefore, ALSUntangled does not recommend FMT as a treatment for ALS at this time. However, it is plausible that the fecal microbiome plays a role in some neurologic disorders, including ALS. Given the lack of effective therapies and the relatively low cost and low risk of FMT – if performed by experienced clinical centers we support further investigations in this developing field. A reasonable next step would be a detailed molecular analysis of gut bacteria in ALS patients; certainly, these are the types of studies being advocated by the NIH Human Microbiome Project. If alterations are detected in the gut microbiome of ALS patients, a following step would be properly controlled studies in animal models, such as ALS mice. These studies could employ the same germ-free, and/or probiotic treatment regimens published in mouse models of EAE, Alzheimer’s disease, and obesity.

Deanna Protocol

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Mitochondrial dysfunction, glutamate excitotoxicity, and oxidative stress have all been implicated in ALS pathogenesis, and targeting these mechanisms individually or by a cocktail such as the Deanna Protocol could play a role in future ALS therapies. However, many of the preclinical and animal studies related to these pathways have not translated into successful treatments in patients with ALS. While there are anecdotal reports of improvements in patients with ALS on the Deanna Protocol, there is no convincing objective evidence of benefit yet. Thus, at this time, ALSUntangled does not recommend the Deanna Protocol to patients with ALS.

Before it can be recommended, a reproducible version of the Deanna Protocol should be shown to influence plausible physiologic mechanisms such as central nervous system ketone bodies, as well as clinically meaningful outcome measures such as ALSFRS-R and FVC in patients with ALS.