ISR over-activation may play an important role in ALS pathogenesis, as supported by data from pre-clinical models and PALS. Several different ISR inhibitors have been tried in ALS models or inPALS with mixed results; but given the differents pecific actions of these, it is not possible to generalize across the whole class. ISRIB can attenuate parts of the ISR and has shown benefits in cell models of familial ALS. A group of PALS in Spain who are taking ISRIB report subjective improvements in some ALS-related symptoms, but objective evidence is lacking. Reported side effects are minimal, but no published trials of ISRIB exist,leaving questions about safety and tolerability unanswered. In addition, concerns remain about its solubility and human bioavailability. Currently,there is not enough information to support the regular use of ISRIB for treating ALS. Furthers tudies are required to evaluate its pharmacokinetics, safety, and efficacy in PALS.
Patient trials
Alpha Lipoic Acid
ALA has several plausible mechanisms for slowing ALS progression, including enhancing energy production, reducing oxidative stress as a potent antioxidant and anti inflammation. Preclinical studies demonstrated better motor function and improved survival. One open label study suggested improved QOL and fatigue when administered as a palladium lipoic acid complex, but motor function was not assessed. Several PALS in the ALS online community reported improved muscle strength when taking ALA as part of extensive supplement regimens, but most did not. Therefore, it is unclear whether the reported improvement was directly related to ALA. Although one clinical trial was completed in PALS, the result has not been published. ALA was safe and well-tolerated based on self report from PALS and in clinical trials for other disease conditions at 600 mg daily. Given the above, we cannot endorse ALA as an effective therapy for PALS. We support more research on the efficacy of ALA in slowing ALS progression.
Psilocybin
Psilocybin may be able to influence ALS relevant mechanisms including neuroinflammation and brain glutamate levels, but this ability has not yet been demonstrated in ALS models or in PALS.There have been no studies of psilocybin in ALS relevant preclinical models, and no case reports documenting the effects of psilocybin on ALS progression. Given the potential for serious side effects, we do not currently support the use of psilocybin to slow ALS progression.
WAHLS Protocol
Because components of the Wahls diet may affect inflammation, oxidative stress and mitochondrial dysfunction, it has plausible mechanisms for slow-ing ALS. Although a cross sectional study suggests the intake of certain macro and micronutrients enriched in the Wahls diet was associated with better baseline motor function and lower risk for getting ALS, no case reports or clinical trials are showing the Wahls diet affects disease progression or survival in PALS. On the contrary, the clinical trial in MS patients showing significant weight loss and essential vitamin and mineral deficiencies raises serious concerns; two thirds of PALS already experience weight loss at the time of diagnosis, and weight loss is a strong predictive factor for fast disease progression and shorter survival. Therefore, we cannot endorse the Wahls protocol for slowing ALS progression.
PoNS Device
Considering the fact that electrical stimulation was first used as a medical treatment more than 100 years ago (30), and first used as an ALS treatment 30 years ago (31), it is disappointing that we have yet to find a clear way to use this to help PALS. PoNS™ is a newer version of this. There is a vague theoretical mechanism (neuromodulation) by which PoNS™ could potentially modulate neuroplasticity in the brainstem and cortex, but whether it provides any beneficial or deleterious effects on ALS progression is currently unknown. While there are early, promising data showing that the PoNS™ device improving gait in patients with multiple sclerosis, this may not translate to PALS. There are no pre clinical data or clinical trials of PoNS™ therapy in PALS to determine efficacy. The PoNS™ device appears to be relatively safe but its substantial cost and prescription only status will limit accessibility for PALS. Given the current lack of ALS relevant data, we cannot currently support the use of PoNS™ therapy to slow, stop, or reverse ALS progression. We hope that this review of PoNS™ and the broader topic of neurostimulation spurs future research toward helping PALS.
Ashwagandha
WS appears reasonably safe, has plausible mechanisms by which it might slow ALS progression, and has promising data obtained in multiple different clinical models of ALS. While there are also some interesting self reports from PALS and one verified ALS reversal on a compound containing WS, these must be interpreted with caution because of the variable natural history of ALS progression. We conclude that WS is a reasonable compound for ALS trials, and we look forward to the results of the one trial that is underway.
Lions Mane
While Lion’s Mane may have neuroprotective, neurotrophic, antioxidant, and anti inflammatory properties that could, at least in theory, potentially help ALS, there are still no studies in ALS relevant cell or animal models, nor in humans with ALS. Therefore, we do not have enough information to support the current use of Lion’s Mane for treating ALS. We hope to see the validation of its neuroprotective and anti inflammatory benefits in ALS disease models, which may ultimately lead to clinical trials in PALS.
Insulin
Insulin treatment for ALS is an intriguing area for future research. However, the risks of insulin administration are significant and potentially lethal. Currently, there is no clinical evidence to support its use in PALS. Therefore, we cannot endorse insulin as a way to slow, stop, or reverse ALS progression at this time.