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).
Patient case reports
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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Ursodiol has interesting mechanisms of action, appears reasonably safe and well-tolerated, has anecdotal reports of benefit in 6/21 of patients who report taking it, and a form of it (Yoo’s solution) was associated with slightly slower ALS progression in one out of three outcome measures within a poorly designed study that did not account for large numbers of drop-outs. However, analyses of ursodiol data from the well-conducted randomized, double-blind ceftriaxone trial show that ursodiol 300 mg twice a day is no better than placebo at prolonging survival or slowing ALS progression. Based upon this review, ALSUntangled does not recommend off-label use of ursodiol as a treatment for ALS, at least at doses of 300 mg twice a day. Determining whether higher doses or different formulations are effective will require further well-designed studies.
It is possible, although currently unsettled, that ALS in some individuals may be due to a retrovirus. Even if true, however, Rife’s microscope technology, his identification of specific frequencies for pathogens, and the ability of Rife radio frequency machines to kill pathogens, are all unproven and highly implausible. We have identified no verified cases of ALS improving on any objective outcome measure with the Rife Machine. At this time ALSUntangled does not support the use of the Rife Machine for ALS.
Propofol has mechanisms of action that may be relevant in treating ALS, although the short action of the drug makes it unlikely that a single infusion could influence ALS pathophysiology in a meaningful way. On ALS.net, six patients with ALS reported wide-ranging subjective benefits coincident with propofol use. Unfortunately, none of these benefits has been verified on validated ALS outcome measures. Only one of 235 patients with confirmed ALS who received propofol for PEG at an ALS center, or in the PRO-ACT database, or in a stem cell trial, improved objectively. The improvements in this patient were much slower to begin, and longer in duration, compared to those reported by the cohort on ALS.net, suggesting that they were more likely due to other longer-acting medications the patient received (such as immunosuppression), the stem cell treatment, or an unusual reversible form of ALS (27–30). While we cannot conclusively rule out a very brief benefit from propofol in rare patients with ALS, the risks and costs involved do not appear to justify its use. We strongly discourage the off label use of propofol in ALS patients at this time. Patients with ALS who are going to have propofol on label for a procedure or surgery may wish to have their ALS neurologist measure an ALSFRS-R and FVC before and in the first few days after propofol exposure and to send these results to ALSUntangled for a possible follow-up review.
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.
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.
There is a rationale by which the calcium binding protein apoaequorin could work to slow ALS progression. Unfortunately, at this time there is insufficient information available to determine whether it does. The one small case series referred to above utilized a cocktail of therapies and is further weakened by the loss of its standardized outcome measurements. Information from the manufacturer suggests that apoaequorin is reasonably safe and well tolerated but there is no independent, systematic confirmation of this; two PatientsLikeMe members reported serious adverse events while taking it and it is fairly expensive.
At this time ALSUntangled does not recommend that patients with ALS take apoaequorin. Reasonable next steps would include a controlled study of apoaequorin in an ALS animal model and/or a small series of well-characterized patients with ALS using validated outcome measures and including serum and CSF pharmacokinetics.