Editing Proleariat Protocol - added text after copying the original. To be edited before translation.

== The Pile of Pills ==

<ol>
<li> Dextromethorphan (DM). http://en.wikipedia.org/wiki/Dextromethorphan http://www.als.net/forum/yaf_postst50482_Cough-Syrup-Restores-Speech-in-PALS-Overnight.aspx Over-the-counter cough suppressant, usually in the form of cough syrup. There are several kinds. Read the label carefully (get the pharmacist to help you if necessary). Get something that has only DM as the active ingredient, no antihistamines or decongestants or expectorants. Then take the stuff at twice the label recommended dosage for two days. There's a good chance it will help with bulbar and/or upper motor neuron symptoms. (You know what those are, right? If not, you need to revisit ALS 101.) Probably won't help with lower motor neuron symptoms. ...If you see improvements in symptoms, keep it up, but cut dosing back to the label recommendation. If at any time you notice mental side effects, reduce dosage or stop entirely. .....Long term use of DM probably reduces the rate of disease progression when combined with other cocktail ingredients: the mere fact of being a Ca++ channel inhibitor suggests this, see also http://www.als.net/forum/yaf_postst52536_SigR1.aspx . WARNING: if you are taking any prescription antidepressants, before taking DM you need to read up on Serotonin Syndrome inasmuch as combining DM with prescription antidepressants can lead to that syndrome: other potentially problematic substances include diphenhydramine (Benadryl) and grapefruit juice. http://en.wikipedia.org/wiki/Serotonin_syndrome If you experience any symptoms of serotonin syndrome, stop the DM and tell your medical doctor what happened. If the DM seemed to help with ALS symptoms, you might want to tinker with dosing or switching to a different antidepressant. Also, some of the other things you'll likely be taking (for example vitamin D, 5-HTP, and magnesium) have antidepressant action and may allow reduction in dosage of the prescription antidepressant. </li>
<li> Zinc 50 mg/day as chelate(for example picolinate). Do NOT supplement with copper. There is a lot of information in this forum about zinc. You probably won't feel any immediate effects, just do it on faith. Available almost anywhere that nutritional supplements are sold. UPDATE 23 Feb 2013: gluconate is the form preferred in treating Wilson's disease, and there's a pharmaceutical grade nutritional supplement form available that's designed for and marketed to Wilson's patients. http://www.wilsonsdisease.org/wilson-disease/wilsondisease-treatment.php http://www.wilsonsdisease.org/wilson-disease/wilsondisease-zinc.php http://www.wilsonsdisease.org/pdfs/extreme_V_Zinc_Digest_Wilsonsletter_5-26-2009.pdf http://www.extremev.com/zinc50mg.html http://www.extremev.com/zinc2.html {{Quotation|Kevin (and everyone else who DID NOT participate in the trial for that matter),<br /><br />You take your total serum copper level and then subtract your total serum ceruploplasmin level times three from it to get your total free copper level. It should be in the 5-15 range. Anything over and you have too much free copper running around in your body (most likely accumulating in your brain and spinal cord). Interestingly enough, our controls did not (for the most part) have elevated levels seen in every PALS in our trial.<br /><br />As a side note (if your doctor refuses to do the tests or you would prefer to get results quicker), you can purchase both tests at LEF (Life Extension foundation) for under $100 I believe around. Click Here For COPPER Blood Test Click Here For CERUPLOPLASMIN Blood Test<br /><br />You simply take the orders which you actually print off from what they send via email to you (or they may mail the orders to you also) and you simply take them to Labcorp for the blood draw. Results are emailed to you. Simple as that again if your doctor won't agree to do it or you want the results quicker.<br /><br />Also, here's the medical grade zinc we recommend to use (used in Wilson's patients too); Medical Grade Zinc Gluconate (the only one recommended from our trial results) ,<br /><br />Note - If you are within the 5-15 free copper range, then simply take 50mg. If you are above that, I recommend 100mg (like the majority of our trial patients took) as too much free copper is within your body if above 15 (especially if it is way above that number of 15). |jchexpress}}</li>
<li> Magnolia extract, for bulbar and UMN symptoms. In Chinese traditional medicine (and in my personal experience and that of others), especially effective in treating problems related to swallowing. Magnolia is rather new to ALS but it's gotten good reviews. The best dosage seems to be about 100 mg of the standardized concentrate, but that disappeared from the market late 2013 and now it's either 30 mg or 200 mg. I regard 200 mg as too high a dosage, and I expect that problems with that dosage unit will drive it out of the market. My source for 30 mg is www.roex.com. .......Give Magnolia extract a 2-day test drive. If no improvement in symptoms, stop. If improvement, continue, but be aware that there are theoretical reasons be concerned that tolerance may develop. My personal opinion is that this concern is unfounded but this is new territory and the verdict isn't in yet. ......Honokiol is a PPAR agonist, suggesting it may be of value to treat neurodegenerative processes, not just symptoms. http://www.als.net/forum/yaf_postsm371719_Magnolia-officinalis.aspx#371719</li>
</ol>

4. 5-HTP (anecdotal report of benefit, information scattered, use search tool)
http://www.webmd.com/vitamins-supplements/ingredientmono-794-5-HTP.aspx?activeIngredientId=794&activeIngredientName=5-HTP
5-HTP may help with lower motor neuron symptoms such as cramps and muscle spasms. It may also help slow down neurodegeneration. Before taking 5-HTP, read and understand the precautions. 5-HTP raises serotonin levels (that's its purpose) but so do many other drugs (esp. many prescription antidepressants). Too much serotonin leads to serotonin syndrome. If you are at risk for serotonin syndrome, learn the symptoms in detail and watch out for them. 

5. Vitamin D3. Most PALS are shut-ins and without exposure to sunlight, they're deficient in this very important anti-inflammatory and calcium regulator. 5,000 IU/day. Best to also take Vitamin K2, which is a co-factor with D3. 

6. Magnesium taurate. Glutamate antagonist and GABA agonist. Magnesium deficiency is widespread in the modern diet. Only manufacturer of mag taurate I know of is Cardiovascular Research Ltd., but it's widely available. If you can't get it, then do magnesium citrate or orotate(NOT oxide)and taurine separately, those are even more widely available. .......Magnesium is a traditional remedy for muscle cramps. ......At magnesium dosages above about 200 mg per day, you may experience noticeable improvement in some ALS symptoms. Also be aware of the potential for "intestinal relaxation": with magnesium "more" isn't always "better". Most people can tolerate up to about 400 mg/day of magnesium without any difficulty. .......Since many people are magnesium-deficient anyhow, and since magnesium has so many health benefits, taking magnesium supplements makes good sense. ...... http://george-eby-research.com/html/magnesium-treatment-resistant-depression.pdf The foregoing is an excellent review of magnesium. The authors express concern that that taurate may be too tightly bound to magnesium to release either: however if the stuff isn't being pissed out as magnesium taurate, then the body is breaking it down into its components. So far no data if it's being pissed out as magnesium taurate. If you're concerned about it, you can always do magnesium citrate and then the taurine separately. However, there is some evidence that supplementing with several grams a day of taurine will cause the body to downregulate the taurine transporter molecule, defeating the purpose; and, that the said downregulation kicks in above some threshold (i.e. it's not linear with dosage). Therefore is it probably not a good idea to supplement with more than about 2 grams of taurine a day. UPDATE: at some point in the future I intend to break up magnesium and taurine into separate categories.

7. Curcumin (turmeric extract)-- an anti-inflammatory that crosses the BBB and which is also a heat shock protein inducer. Don't expect immediate noticeable effects. However among old-timers who are doing cocktail therapies, curcumin is almost always on their list. ....Curcumin is variously marketed as "turmeric", "turmeric extract", "curcumin", and "curcuminoids". Bioavailability is poor, which has led to the development of formulas which supposedly enhance absorption. LEF Super Bio-Curcumin is an example of such a product which is widely available. http://en.wikipedia.org/wiki/Curcumin NOTE: if you're concerned about the piperine in Super Bio-Curcumin, they've recently taken that out and replaced it with tumerones. And there's the phospholipid complex formulation Meriva: http://www.swansonvitamins.com/swanson-ultra-turmeric-phytosome-meriva-500-mg-60-caps

8. Glutathione support: NAC, selenium chelate, and milk thistle extract. N-acetyl-cysteine, 1.2 grams per day. Selenium, 100 micrograms/day (see post on page 3 of this thread for discussion). Milk thistle extract: commercial product is typically standardized to about 80% silymarin, 500 to 800 milligrams per day of extract is about right on dosage. http://en.wikipedia.org/wiki/Glutathione http://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/ 

9. Mitochondrial support: acetyl-L-carnitine (800 to 1200 mg/day) plus alpha lipoic acid (500 to 1,000 mg/day). http://www.ncbi.nlm.nih.gov/pubmed/23421600 http://en.wikipedia.org/wiki/Acetylcarnitine http://en.wikipedia.org/wiki/Lipoic_acid
NOTE: recently R-lipoic acid has become commercial available, with appropriate dosing about 1/3 to 1/2 of the regular (racemic) alpha lipoic acid. 

10. Water-pack sardines, several ounces a day. Yep, them little fishies. They're high in CoQ-10 (an important antioxidant), Omega-3's (anti-inflammatories), purines (raise uric acid levels), protein, and minerals. Darn near a miracle health food-- IF you don't have gout. ......If you have gout, you already know to avoid sardines, you can get CoQ10 and Omega-3's in pill form almost anywhere that nutritional supplements are sold. Omega-3's are also widely available as hemp, flax, and fish oil. If you don't know if you have the metabolic disorder called "gout", before you start loading up on sardines, get your uric acid levels checked and then discuss the results with your doctor. 

10A. Suppose you can't do the sardines? In my opinion, when it comes to CoQ10, 100 mg/day of an advanced form (for example ubiquinol in oil) is probably enough, I haven't seen evidence that piling it on is better. My preferred brands are Dr. Mercola Ubiquinol 100 mg, and LEF Super Ubiquinol CoQ10 100 mg. When it comes to the Omega-3's, there are many ways to do that, from canned salmon (which is not high in purines like sardines are) to fish oil pills to flax oil to hemp oil and others. My personal preference is cold-pressed organic hemp oil inasmuch as it has a pleasant taste that goes well with almost anything. Hempseed is good stuff too, doesn't have that paint taste that flax has. Chia is another alternative, but tends to become a gooey mess. 

11. Citicoline (also called CDP choline), 400 to 1,000 mg/day. Try it for a couple days to see if you get a noticeable improvement in energy and reduction in "brain fog". Unclear if it has any effect on disease progression. http://en.wikipedia.org/wiki/Citicoline

12. Vitamin E complex (natural mixed tocopherols and tocotrienols). These can be purchased separately, but my personal preference is "TOCO-SORB", Jarrow #112026, which has everything in one softgel that's small enough to actually swallow. LEF has recently introduced Gamma E Tocopherol/Tocotreinols #00559 which as far as I can tell is the same thing. 

13. B-complex. Most so-called "B-50" formulations (for one a day dosing) seem fairly good, but read the label details before buying. B6 (pyridoxine) is important, but don't supplement more than 50 mg/day: http://www.als.net/forum/yaf_postst53654_Vitamin-B6.aspx Be warned also that quite a few nutritional supplements you wouldn't expect B-6 in contain B-6: read the fine print on the label. ...There's a whole slew of B-vitamins with different possible impacts on ALS, and it's going to take years to figure out what sort of combination is optimum. Some people are really big on B-12: if you're going to bother, go all the way to 5 mg/day methylcobalamin separately from your B-complex. ....12 April 2014 I started a new thread on B-vitamins: http://www.als.net/forum/yaf_postsm384696_B-vitamin-supplementation-in-ALS.aspx#384696

B-1 (Thiamine) deserves special attention (see http://www.als.net/forum/yaf_postst44708_Foot-drop-and-thiamine.aspx ). Here's a summary I posted about page 5 in that thread: 

Most of the posting relating to thiamine is over my head, but I do skim through it anyhow hoping to absorb some information by osmosis. The encouraging PubMed is tempered by an anecdotal report of benfotiamine toxicity.

Here's my tentative summary of what I think I've seen so far.

1. Thiamine deficiency is very common in ALS, probably because of genetic abnormalities and/or disease processes rather than inadequate dietary intake with food. 

2. Therefore supplementation is advisable at a level many times the RDA (1.6 mg). So-called "B-50" formulations usually contain 50 milligrams, or nearly 35 times the RDA.

3. Because benfotiamine is lipophilic (and perhaps for other reasons also), it has pharmacological actions of types believed to be beneficial in ALS, which go beyond what you get from regular thiamine. Therefore benfotiamine is the preferred form of thiamine supplementation. 

4. Ordinary B-complex vitamin "pills" always include thiamine but to my knowledge never include benfotiamine. Therefore benfotiamime supplementation has to be done separately. 



14. Trimethylglycine (TMG, Betaine). The addition of TMG to the list emphasizes lower motor neurons: see Persevering's "Fasciculations" thread for more details. http://en.wikipedia.org/wiki/Trimethylglycine TMG is also a methyl donor which (like methylcobalamin B-12 and methylfolate helps to suppress the inflammatory factor homocysteine. 

15. 3nB (celery seed extract) anti-inflammatory, gliosis inhibitor
http://www.als.net/forum/yaf_postst49608_dl3nbutylphthalide-Another-Drug-With-Exciting-Preclinical-Result.aspx#353299

16. ibuprofen anti-inflammatory, anti-gliosis, disinhibits neuron repair. http://www.als.net/forum/yaf_postst53530_pain-med-suggestions.aspx
http://www.ncbi.nlm.nih.gov/pubmed/17428993
http://www.nsaids-list.com/2012/07/25/ibuprofen-may-help-prevent-parkinsons-disease/
http://www.sciencedirect.com/science/article/pii/S0304394004013722 see also apigenin.
http://www.als.net/forum/yaf_postst53590_Ibuprofen.aspx

17. Peony root http://www.als.net/forum/yaf_postst48193_Peony-root-and-paeoniflorin-long-essay.aspx http://www.als.net/forum/yaf_postst53592_Licorice.aspx
Peony is usually taken with non-DG licorice, which enhances its effects. Two anecdotal reports here of benefit, good underlying science. Usually thought of in terms of HSP up-regulation, peony is also a sodium channel inhibitor, which makes it a promising therapeutic for lower motor neuron disease particularly: see Persevering's "Fasciculations" thread. 

18. Resveratrol + nicotinamide NOTE: nicotinamide = niacinamide. http://en.wikipedia.org/wiki/Nicotinamide http://en.wikipedia.org/wiki/Resveratrol
Check your B-complex vitamin for its niacinamide content (if any). For more detailed discussion regarding this combo, see the paragraph below on "Nicotinamide riboside + resveratrol". WARNING: if you're taking riluzole, be aware that resveratrol and several other natural substances may increase the toxicity of riluzole. I'd argue that if you're doing things that make sense, you shouldn't be taking riluzole anyhow. ......See also the thread http://www.als.net/forum/yaf_postsm384855_Resveratrol-delays-Wallerian-degeneration-in-a-NAD-and-DBC1-dependent-manner.aspx wherein we discuss ideal dosing of resveratrol and come to a tentative conclusion that the customary high dosages found in most supplements nowadays are inappropriate, and that dosage should probably not exceed more than several tens of milligrams. Another link supporting the assertion that high doses are a bad idea: http://www.resveratrolnews.com/how-modern-medicine-obfuscates-resveratrol-science/833/ 


CANDIDATES FOR ADDITION TO THE LIST 
The following are under consideration for addition to the list. Of course nobody needs my permission to go ahead and decide on their own to take them! ....The ones I regard as most promising (based on what I think I know at the moment) are at the top of the list, less promising stuff on the bottom. 

Gastrodin
http://www.als.net/forum/yaf_postst53416_Gastrodin.aspx

Ethyl alcohol (the beverage kind) 
http://www.als.net/forum/yaf_postst52660_ethyl-alcohol-booze.aspx
http://www.news-medical.net/news/20120813/ALS-risk-markedly-lower-among-alcohol-consumers.aspx Glutamate antagonist, GABA agonist, synergistic with glycine. "Candy is dandy but liquor is quicker", you'll know real soon if it provides symptomatic relief for you, plus it's cheap and needs no Rx. Epidemiological study showed drinkers are only half as likely to develop ALS as non-drinkers: the benefit would presumably extend to reduced rate of progression among those who get ALS anyhow. ......WARNING: Too much booze can be bad for you, I hope everyone knows that. Plus, some people readily become addicted to the stuff, which probably results from upregulation of NMDA receptors which would be a bad thing in ALS. So-- I'm not recommending getting smashed every day; and, if you have a family history of alcohol addiction, alcohol may be bad medicine for you. As I sometimes say, "Some people should drink, and some people shouldn't." It's up to you to figure out which category you're in. .......If you drink on a daily basis, it's a good idea to quit cold turkey for a week every now and then. Some people will experience withdrawal symptoms and others won't. If you experience withdrawal symptoms, probably the best thing to do is to taper off the drinking over a period of several weeks in order to detox without landing in the hospital, and thereafter don't touch the stuff. (Yep, I know this is contrary to AA dogma.)........ Going on a ketogenic diet? Sorry, the liver metabolizes alcohol into glucose, that's gonna work against you. .......If you drink, quaff a few pints (not all at once!) to support ALS research, no I'm not kidding: http://www.alesforals.com/ Since this is all about the hops, some pretty good IPA's are likely to come out of that project.

Nicotinamide riboside plus resveratrol 
http://www.als.net/forum/yaf_postst53368_Nicotinamide-riboside-NR.aspx 
http://www.als.net/forum/yaf_postst53465_What39s-the-take-on-NADH.aspx 
http://www.als.net/forum/yaf_postst53532_NAD-nicotinamide-adenine-dinucleotide-available-to-reserve-now-by-Biotivia.aspx
see also http://www.als.net/forum/yaf_postsm384855_Resveratrol-delays-Wallerian-degeneration-in-a-NAD-and-DBC1-dependent-manner.aspx#384855
Looks fairly promising, see especially the -NR thread. The related Nicotinamide is also worth investigation. The related NADH is so far looking like something we do not want to take. Although resveratrol seems to be the most popular candidate as a co-factor for NR, other molecules such as fisetin and even telmisartan have been proposed. NOTE: both theory and anecdotal reports indicate that NR should not be taken without a suitable co-factor. 

Baicalin (Baical Skullcap extract) Complex interactions (apparently mostly favorable) in molecular pathways involved in ALS. http://www.als.net/forum/yaf_postst52727_Baicalin.aspx http://examine.com/supplements/Scutellaria+baicalensis/

Idebenone Synthetic analogue of CoQ10 said to be much improved over the natural stuff. It'd be on "the list" except that its commercial availability has diminished probably due to harassment by the FDA. 

Creatine (long history of use in ALS, probably slightly beneficial, but several grams a day are needed)

Forskolin (cAMP agonist, information scattered, use search tool to search cAMP as well as forskolin) http://en.wikipedia.org/wiki/Forskolin UPDATE: there's now a forskolin thread here: http://www.als.net/forum/yaf_postst53906_forskolin-and-cAMP.aspx

Methylcobalamin B12 (methylating agent etc., info scattered, use search tool)

Vinpocetine There was a flurry of interest in it here a year or two ago. Usually thought of as a nootropic, but its sodium channel modulation properties make it of special interest as a prospective LMN therapeutic. Also inhibits degradation of cAMP, a good synergist for use with forskolin and/or methylxanthines if you're shooting the cAMP angle. http://en.wikipedia.org/wiki/Vinpocetine

Magnesium L-threonate
http://www.lef.org/magazine/mag2012/feb2012_Novel-Magnesium-Compound-Reverses-Neurodegeneration_01.htm Supposedly gets magnesium past the BBB better than other mag supplements. 

Sex hormone boosters and modulators DHEA, Tribulus, chrysin, natural estrogen and progesterone creams, Pueraria. Note: there is evidence that beta sitosterols (present in saw palmetto, nettle root, and pygeum) displace cholesterol in the formation of nervous tissue and may thus contribute to neurodegeneration. 

Green tea extract (popular anti-aging agent, specificity for ALS unclear)

Pomegranite extract (popular anti-aging agent, specificity for ALS unclear)

Fisetin (new but popular anti-aging agent, specificity for ALS unclear)

Lecithin 
http://en.wikipedia.org/wiki/Lecithin
http://en.wikipedia.org/wiki/Phosphatidylcholine
http://en.wikipedia.org/wiki/Phosphatidyl_serine
"Brain food", I'd rather get mine by eating eggs than popping pills. Mackerel and herring are high in PS (and also in purines if that matters to you for better or for worse). Soy-derived PS lacks the effectiveness of animal source PS; for this reason I don't think much of soy lecithin as a supplement. 

Lion's Mane Mushroom http://www.als.net/forum/yaf_postst53310_Neuroregenerative-potential-of-lion39s-mane-mushroom.aspx

Berberine http://en.wikipedia.org/wiki/Berberine
http://www.als.net/forum/yaf_postst48627_Berberine.aspx 
http://en.wikipedia.org/wiki/Goldenseal (most common herbal source of berberine)
http://examine.com/supplements/Berberine/
Note: There's lots of herbal supplements out there containing small amounts of berberine, but I haven't yet found one that contains berberine at meaningful dosage levels.

Butyrates HDAC inhibitors http://en.wikipedia.org/wiki/Butyric_acid
http://en.wikipedia.org/wiki/Sodium_butyrate
http://www.livestrong.com/article/557578-benefits-of-sodium-butyrate/
http://www.als.net/ALS-Research/SodiumPhenylbutyrate/ALS-Topics/
http://www.als.net/forum/yaf_postst53961_Sodium-butyrate.aspx
NOTE: although butyrate could theoretically be offered as a nutritional supplement, to my knowledge it's available only as Rx medications. 

Gardenia extract mitochondrial UCP2 agonist
http://www.als.net/forum/yaf_postst52984_Gardenia-jasmoides-extract.aspx#370971
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699730/

Apigenin anti-inflammatory, anti-gliosis. See also ibuprofen. 
http://www.sciencedirect.com/science/article/pii/S0304394004013722
http://en.wikipedia.org/wiki/Apigenin
http://www.swansonvitamins.com/swanson-ultra-apigenin-50-mg-90-caps

Luteolin closely related to apigenin and more widely available as a supplement.

Vitamin B-1 thiamine, benfotiamine If this makes it into the Prole Prote Toplist, it'll probably be as benfotiamine. 
http://www.als.net/forum/yaf_postst44708_Foot-drop-and-thiamine.aspx
Note: anecdotal report of benfotiamine toxicity, second post in the following thread:
http://www.als.net/forum/yaf_postst49223_Melanin-and-Vitiligo.aspx#334751 This was at high dosage, same patient chose to continue benfotiamine at a more moderate dosage. 

Nutritional supplements, herbs, and OTC's rejected for Proletariat Protocol: 
NOTE: This category does not mean the item is "bad", it only means that it seemed worthy of consideration, I did consider it, and regarded it as unsuited for the Proletariat Protocol. 

inosine raises uric acid levels,disinhibits neuron repair esp. of axons. Probably worthwhile under careful medical supervision, but the risk of gouty arthritis and/or kidneystones mean it's not for newbies. http://en.wikipedia.org/wiki/Inosine Inosine has been discussed quite a bit here on the forum.

Cannabis and CBD For most patients, cost, quality of the product, and legal obtainability are problems. If the goddamn government would treat it like tobacco or alcohol, it'd be legal, affordable, and you could know what you were buying. US government has patented the use of cannabidiol to treat neurodegenerative diseases (which however wouldn't stop individuals), see http://www.als.net/forum/yaf_postst53669_Patent-6630507.aspx The inventors seem to think that dosing on the order of half a gram a day would be appropriate, but this seems to be extrapolation from in vitro research and so may be highly inaccurate. In the absence of clinical data, actual anecdotal reports would have more relevancy. 

Ginseng http://en.wikipedia.org/wiki/Ginseng Although popular, the evidence in its favor is decidedly mixed, and unwanted side effects are common. 
http://www.als.net/forum/yaf_postst53520_GINSENG-.aspx 

Ginkgo biloba Like aspirin, the stuff turns many people into "bleeders". (Like me for instance, this isn't just hypothetical.) Ginkgo might have value for someone who pays close attention to its anti-coagulation properties and makes sure they don't get into trouble with the stuff. 

Methylene Blue TDP-43 aggregation inhibitor and other interesting actions. Not sold as a nutritional supplement, but available without Rx as a dye used in biological research. Failed in both SOD-1 and TDP-43 fALS mouse models, but that doesn't end interest in the stuff. http://www.als.net/forum/yaf_postst49812_Methylene-Blue.aspx http://www.als.net/forum/yaf_postst52580_Methylene-blue-Salubrinal-Guanabenz-and-Phenazine-were-each-tested.aspx 


* * * * PRESCRIPTION DRUGS THAT MIGHT BE WORTH TAKING * * * * *

Research carefully both here and on the Internet, any Rx drug before taking it. The Proletariat Protocol is based on the assumption of no Rx drugs (since doctors usually won't cooperate). However, realistically speaking, most patients who are on a do-it-yourself protocol such as the Prole Prote will also taking one or more Rx drugs either with the cooperation of their medical doctor, or without it. The following list is not intended to be a comprehensive list of interesting Rx drugs, but may serve as a place to begin investigation. Those drugs which in my opinion show the most promise I have shown in boldface. BOILERPLATE: I am not endorsing anything on this list. The only drug on this list that I take specifically for ALS is Deprenyl (Jumex), but that doesn't mean anyone else should. I also take Telmisartan for hypertension and occasionally inhaled beta agonists and steroids for COPD.

Riluzole (I'll catch hell for even mentioning that stuff!)

Memantine NMDA receptor antagonist (Ca++ channel blocker), also 
exhibits activity at several other receptors of neurological interest.
Clinical trial failed (of course) since it was not cocktailed.
http://en.wikipedia.org/wiki/Memantine

Prozac and other SSRI's (risky if used with other serotonin enhancers)

Tricyclics (risky if used with other serotonin enhancers) 

Prednisone and other corticosteroids

Dilantin (phenytoin) sodium channel inhibitor, long history of use
as an anti-epileptic drug. http://en.wikipedia.org/wiki/Dilantin

Deprenyl (selegiline)and related drugs MAO-B inhibitor; may also 
inhibit apoptosis in neurons. Widely used to treat Parkinson's.
http://en.wikipedia.org/wiki/Selegiline 
http://en.wikipedia.org/wiki/Rasagiline probably superior to selegiline 
http://www.als.net/ALS-Research/197/ClinicalTrials/ (rasagiline) 
http://www.als.net/forum/yaf_postst45697_selegiline-Deprenyl-vs-ciclosporin.aspx

Losartan and related drugs

Albuterol and other selective beta agonists

Theophylline and theobromine http://en.wikipedia.org/wiki/Theophylline
Theophylline used to be an OTC bronchodilator but was reclassified as an
Rx drug with the popularization of the safer inhaled beta agonist drugs.
Theophylline raises cAMP, inhibits TNF-alpha, is an adenosine receptor
antagonist, and histone deacetylase agonist. ......The closely related
theobromine and caffeine have somewhat similar drug actions but with 
different profiles. http://en.wikipedia.org/wiki/Theobromine
http://en.wikipedia.org/wiki/Caffeine

Valproic acid and valproates Sodium channel blocker, 
HDAC1 inhibitor, possible neuron apoptosis inhibitor. 
http://en.wikipedia.org/wiki/Valproic_acid 
http://en.wikipedia.org/wiki/Sodium_valproate
http://www.als.net/ALS-Research/SodiumValproate/ALS-Topics/

Ramelteon ("sleeping pill", melatonin agonist)
http://www.als.net/forum/yaf_postst53582_Rozerem-ramelteon.aspx

Copper chelating agents

Benzodiazepides

Brintellix (Vortioxetine) new antidepressant different from the oldies, acts on a number of different types of serotonin receptors, Jason (jchexpress) reports definite improvement in motor neuron symptoms. http://en.wikipedia.org/wiki/Vortioxetine

Quinidine (often used in conjunction with dextromethorphan)

B12 injection

Acamprosate NMDAr antagonist, GABA agonist, used to suppress alcohol withdrawal.
http://en.wikipedia.org/wiki/Acamprosate

Gabapentin (Neurontin) GABA agonist, although its pharmacology
is poorly understood. http://en.wikipedia.org/wiki/Gabapentin
WARNING: http://www.wellnessresources.com/main/printable/neurontin_and_lyrica_are_a_death_sentence_for_new_brain_synapses/#ref1 

Pregabalin (Lyrica) GABA agonist closely related to gabapentin, 
Schedule V drug in the USA. http://en.wikipedia.org/wiki/Pregabalin 
WARNING: http://www.wellnessresources.com/main/printable/neurontin_and_lyrica_are_a_death_sentence_for_new_brain_synapses/#ref1

Baclofen GABA-B agonist often used to control cramps and spasms, but 
once you're on it, stopping is difficult due to withdrawal syndrome.
http://en.wikipedia.org/wiki/Kemstro (that link looks wrong but works)

Naltrexone (low dose protocol) 

Edaravone (MCI-186) powerful nervous system antioxidant
http://en.wikipedia.org/wiki/Edaravone

Mexiletine (sodium channel inhibitor)
http://en.wikipedia.org/wiki/Mexiletine
http://blogs.als.net/post/Mexiletine-channeling-ALS.aspx
http://blogs.als.net/post/2013/03/14/Taming-the-Charley-Horse.aspx

Ivermectin (AMPA antagonist?) 
http://en.wikipedia.org/wiki/Ivermectin
http://www.als.net/forum/yaf_postst50414_Ivermectin.aspx

Retigabine and Flupirtine (Potassium channel openers)
http://en.wikipedia.org/wiki/Flupirtine
http://www.als.net/forum/yaf_postsm384498_Retigabine--potassium-channels.aspx#384498

Dichloroacetic acid (DCA) This stuff's a chemical, not an approved drug or natural supplement. Looks easy to obtain on the gray market. A lot of excitement over its purported anti-cancer benefits, including in neuroblastomas. 
http://thedcasite.com/
http://en.wikipedia.org/wiki/Dichloroacetic_acid

Prescription drugs and related OTC's etc. to avoid in ALS

Statins (unless supplementing generously with CoQ10) This includes Red Yeast Rice, a natural source of lovastatin. 

Anticholinergic antihistamines (including non-Rx OTC's)

Retinoids (related to vitamin A) 

Drugs or supplements containing copper

Drugs or supplements intended for supplementing iron, unless for the purpose of correcting a diagnosed iron deficiency

Arguably the GABA agonists Neurontin and Lyrica: http://www.wellnessresources.com/main/printable/neurontin_and_lyrica_are_a_death_sentence_for_new_brain_synapses/#ref1




* * * * * OTHER PROTOCOLS WORTHY OF MENTION HERE * * * * * * *

Dr. Kathy Graham's commentary and critique of the Prole Prote: 
http://drkathygraham.com/2014/03/19/als-treatments-part-4/#more-1645
She's a physician naturopath in BC Canada who lost her mother to ALS a few years back, hence her interest in ALS. Some of her critique is a little off-base, in part because she was working with an early version of the Prole Prote, and because I'm not sure she fully understood what it is and what it isn't. However, some of it is definitely worth some investigation, for example her low opinion of curcumin and her high opinion of boswellia and berberine. Kinda sounds like she wants to be done with ALS now, but I sure wish we could get her posting here!

2004 LEF "Yellow Book" ALS Protocol This publication revolutionized DIY ALS therapeutics a decade ago. I regard the new 2014 "Blue Book" revision as inferior because of its emphasis on the drug pipeline rather than on DIY now.

Chelation Protocols The emphasis used to be on lead and/or mercury, but the attention has recently shifted to copper. I have a low opinion of protocols based on amalgam dental work: supplementing with selenium helps to protect against mercury toxicity. 

Ketogenic diet In my opinion, it's valuable for athlete patients, and for non-athlete patients who are losing a lot of muscle mass. Lots of discussion here on the ALSTDI forum. I don't do it myself and haven't researched it well enough to integrate it into the Proletariat Protocol. 

Anti-catabolic therapy Note how much this has in common with ketogenic protocols. 
Possibly a better approach than what we presently think of as ketogenic protocols? http://www.lef.org/protocols/health_concerns/catabolic_wasting_01.htm
http://en.wikipedia.org/wiki/Glutamine

Deanna Protocol This is a general purpose throw-everything-at-it protocol which began as a personal protocol so complex that it was almost impossible for mere mortals to replicate. DP fans are trying hard to simplify the thing to make it easier for mere mortals to do. Philosophically it's traceable to the 2004 LEF "Yellow Book". I predict that as both the Deanna and Proletariat protocols evolve, there will be some tendency toward convergence. There's already quite a bit of overlap.

Mitochondrial Disease Protocol "Mitochondrial Diseases" can be loosely described as diseases caused by defects in mitochondria. Defective mitochondria play a key role in ALS, although defective mitochondria are not usually believed to be the root cause of the disease. However since ALS is many diseases, it's entirely possible that some ALS is a type of mitochondrial disease. The United Mitochondrial Disease Foundation obviously thinks so: http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=8032195 A number of therapeutics have been developed for treatment of mitochondrial disease, the United Mitochondrial Disease Foundation's list of which I've named "the Mitochondrial Disease Protocol" although it is actually a shopping list and not specific protocol as such. http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=7934635 Notice how much similarity there is between that "protocol" and what we bandy about in relation to motor neuron disease! Also notice that the UMDF has actually published such a list: where are the much larger ALS organizations doing the same? In ALS, it's patients and freelance medical doctors who are working on protocols. 

The Ultimate Ducktail Back in Nov 2010, I proposed this therapeutic cocktail based on a fairly short list of carefully targeted "pills". I don't know if anyone ever used it as the basis of their own personal cocktail. If you have access to prescription drugs it's still worth a look. http://www.als.net/forum/yaf_postsm327843_The-Ultimate-Ducktail.aspx#327843

The Olly ADAR2 Protocol http://www.als.net/forum/yaf_postst53503p4_Gene-therapy-of-Tokyo-University-for-Sporadic-ALS-additional-information.aspx See page 4, post 3 Feb 2014. A work in progress, here's a glimpse: .....Olly wrote: Correcting declining ADAR2 seems to be the better of several other approaches so I'll start there. First a list of possible therapeutic substances followed by a very simple explanation of why they may work. In no particular order: IP6 - Inositol Hexakisphosphate - a cheap ready available supplement. 5-HTP - a cheap ready available supplement but can be dangerous if mixed with certain drugs causing serotonin overdosing. You may want to take B6 -daily amount only - as 5-HTP requires B6 to function. Thiamine (Vitamin B1) High fat diet Selective Anti-depressant/s 

Anti-copper protocol This is a project led by fellow forum denizens jchexpress and inventor2, based on the theory that in many ALS patients, a key component of the disease process is misregulation of copper resulting in copper toxicity, having some similarity to Wilson's Disease. Stay tuned to their posts here, this could be a biggie. 

Jock Science I love hiking in the desert mountains, and researched the DIY sports medicine literature for ways to temporarily extend my physical abilities and to recover quickly after serious hikes. My ability to go hiking seems to be gone now, but for several years the effectiveness of "jock science" made a huge difference in my life. ...To my knowledge, I'm the only PALS doing "jock science", probably because most PALS have progressed to a point where there's not much left to apply "jock science" to. It's also another pile of stuff that you have to do your own research and get it figured out for yourself. 

Cannabis Otherwise known as "marijuana". Many ALS patients, including people who never thought they'd smoke weed, engage in cannabis therapy because it works for themin the area of symptom relief, both upper and lower motor neuron symptoms. It probably slows disease progression as well. Cannabis is arguably the single most useful therapeutic available for ALS, but it's mostly illegal. ....... Cannabis is actually two different pharmaceuticals, THC and its relatives (psychoactive) and CBD (not psychoactive). Both are valuable drugs but their pharmacology is different, and how they impact neurological symptoms and disease processes is only beginning to be unraveled. .......Since CBD is not psychoactive, the legalities surrounding it are less complicated. Dixie Botanicals (located in Colorado) has decided that CBD isn't even a controlled substance and has begun marketing it nationwide. I'd have put it on the Proletariat Protocol list except that the stuff costs several hundred bucks a month, that's not proletariat pricing. I suppose that in another couple years the price will come 'way down. NOTE: Echinacea also contains (non-psychoactive) cannibinoids and might have therapeutic value in ALS: however there seems to be very little research on this. 

Anaesthetics Propofol is reported to have helped several ALS patients, but it has to be administered by an anaesthesiologist in a clinical setting. Just about the only way to DIY is to decide that you need a routine colonoscopy and hope you can get the anaesthesiologist to follow your instructions. 

Chlorite therapy This is a do-it-yourself project. To do it, it helps if you know a thing or two about chemistry. Several patients have reported benefit. It's not clear how the stuff actually works. 

So-called "Stem Cell" therapies These have been going on for decades for many diseases, and have produced virtually nothing. In ALS, there are a few isolated poorly documented reports of some benefit in bulbar and upper motor neuron disease, but even those (if real) are almost certainly a temporary result of the procedure itself and not of new neurons replacing dead ones. And forget LMN's, that'll never happen. .....There is some genuine stem cell research going on, but the field is rife with incompetency and outright fraud because there's so much popular press hype aimed at gullibillies, creating flocks ready to be fleeced. ......If you are being tempted by a stem cell clinic, first vet it here in this forum and on ALSUntangled. 

Therapeutic regime targeted to lower motor neuron disease 
http://www.als.net/forum/yaf_postst49311_Are-Fasciculations-Good-or-Bad.aspx
For most ALS patients, it looks like loss of the neuromuscular junction is the major driver of physical disability and of maintaining the neurodegenerative cascade. Unfortunately most of what we think we know about treating neurodegenerative disease is borrowed from biggies like stroke and Alzheimer's which don't involve lower motor neurons. We need a therapeutic regime targeted to the lower motor neurons, and the Fasciculations thread seems to contain enough information to at least get us pointed in the right direction: see also Aketri's "ALS theories summary" thread. ...We're making some progress on identifying promising LMN therapeutics and eventually an LMN protocol will probably be integrated into the Proletariat Protocol. 

Therapeutic regimes targeted to specific types of ALS There is scattered here and in other places, information on the biological differences between the different types of ALS, which implies specifically targeted therapeutics are needed. It is my goal to be able to flesh out the Proletariat Protocol with those kinds of targeted therapeutics, but that's probably going to take at least several months, possibly years inasmuch as the data we have to work with is so little, so fragmented, and in many cases contradictory. ....We do however have the beginnings of such an approach with DM already on the list being targeted particularly to bulbar symptoms, and the ongoing work on LMN targeted therapeutics which is beginning to be pulled into the Proletariat Protocol.

Protocols targeting sex hormone levels Scattered through the forum is a lot of information relating to the possible influence of sex hormones on motor neuron disease, but it's never been collected all into one place for a good overview. There was a good thread recently on progesterone. 

Over the years, on this information, I've performed using the grey matter meat-technology CPU, a decimate-integrate-and-dump operation. What comes out of that particular information processing pipeline is this: 

1. Reduced hormone levels increase risk of developing ALS, and this is one reason why age and sex are such important ALS demographics. 

2. It's not just one hormone, it's all of 'em-- testosterone, estrogens, and progesterone. 

3. Probably the easiest way to raise hormone levels in a relatively balanced way, is to supplement with DHEA. 

4. There's a lot of angles to consider: hormones in OTC-supplement form, Rx hormones, tribulus, puereria, epimedium, anti-aromatase, finasteride, minoxidil, vitex, beta sitosterols, etc. 

5. But not to make it sound too dangerous or complicated, this is ALS we're dealing with, not acne! Doing nothing has a solid track record of poor outcomes, whereas we're not all dying like flies from overdoses of nutritional supplements. Therefore in my opinion (nonprofessional, your mileage may differ, etc.) if you're into serious ALS therapeutics and over 50 years of age, supplementing with 100 mg a day of DHEA is a good place to begin targeting hormone levels. Preferably getting hormone levels tested occasionally, and preferably staying current on the subject and changing your approach if warranted based on new or additional information. 

Guys, pay attention to possible BPH. The traditional supplement fix for that is beta sitosterol plant extracts, which however may possibly represent a long-term risk of neurotoxicity (information on that is rather sparse, sorry!). There's other stuff like chrysin and pollen extract and boswellia which however don't have as solid a track record in treating BPH as beta sitosterol does.

The OFF-LABEL PROTOCOL http://www.als.net/forum/yaf_postst53854_The-OFFLABEL-PROTOCOL.aspx This thread is intended to develop a protocol based on a mix of Rx drugs prescribed off-label, and herbal and nutritional supplements. So far (17 May 2014) unfortunately not much has happened in that thread. 

* * * * * *

REFERENCES AND RESOURCES


The background of this project is found in the following thread: http://www.als.net/forum/yaf_postst53404_The-price-tag-of-hope.aspx

Aketri's "ALS Theories Summary" thread: http://www.als.net/forum/yaf_postst48203_ALS-theories-summary.aspx A long and difficult read, but arguably the best thread on ALS anywhere on the entire planet. Anyone who is putting together their own DIY formula needs to plow through this thread.

http://www.lef.org/protocols/neurological/als_01.htm Best short introduction to the subject, greatly revised from the contents of the 2003 edition of the Big Yellow Book which still afford good reading. You probably know Life Extension Foundation, but if you don't, becoming a member is worth it. Wide range of leading-edge herbs & supplements, every late spring they have a sale on medical testing, and they are affiliated with a USA mail order pharmacy which is good at saving you money if you have appreciable prescription drug expenses. Of those who have reported doing things that helped them with their ALS, many have said that LEF played a key role in their education and in supplying good nutritional supplement products. I'm one of those people. 

http://violentmetaphors.com/2013/08/25/how-to-read-and-understand-a-scientific-paper-2/
Scientific papers are hard to read and make sense out of, especially if you're not familiar with the subject matter. This web essay explains how to get started, and the emphasis is on medical science. Its biggest weakness is that it begins with the assumption that you have access to the whole paper, whereas the reality is that most of the time we only have access to the abstracts.

http://www.als.net/forum/yaf_postsm387608_New-website-to-comparefilter-ALS-therapeutics-and-protocols.aspx#387608 "TuKa's List". A resource for comparing various ALS therapeutic protocols and their ingredients.

http://www.vitaminshoppe.com/store/en/vitamins_minerals/index.jsp My primary source for herbal and nutritional supplements. Used to buy online until they built a bricks & mortar store in El Paso, so now I shop in person. They carry many LEF products.

http://www.antiaging-systems.com/ My primary source for supplements and a few Rx items that have to be obtained internationally. I used to be able to go down the street and across the "river" to get some stuff in Mexico, but in 2009 the drug wars got too nasty and I haven't been back. At last report (Jan 2014) they're taking Visa and bank drafts, but not any other credit cards or bitcoin. 

http://www.nutritionexpress.com/ Used to be my primary mail-order source for "jock science stuff". However nowadays I can get most of that at the VitaminShoppe locally.

http://www.patientslikeme.com/als/community Good tools for keeping track of your "disease progression" and comparing it to that of others, and "social networking" with other ALS patients and their caregivers. I recommend staying out of the forums, they're a reminder that half the population has an IQ below 100 and they also get ALS. (Nearly all ALS forums are dominated by bozos, ALSTDI's forums being an exception.) Once upon a time I was a member of PLM but they kicked me out and erased my profile. I believe my posts are still in the forum archives.

http://www.dixiebotanicals.com Located in Colorado, source of mail-order CBD. To my knowledge they're presently (Jan 2014) the only online source shipping nationwide, but I expect it won't be long until they have competition.

http://www.swansonvitamins.com/ Major online retailer of nutritional supplements, etc. Swanson was around a long time before there was an Internet. I haven't used them much, but have been happy with them as a supplier. They're a favorite supplier of some PALS, and have a far broader range of stuff nowadays than they used to. Nowadays they often have stuff that's almost impossible to find elsewhere. 

http://www.iherb.com Another popular online supplier of nutritional supplements. Don't recall having used them myself.

http://www.roex.com/ Relatively new company, seems to have been put together from the pieces of a couple other suppliers that went belly up. It's where I get magnolia extract. 

http://www.lef.org/Vitamins-Supplements/Blood-Tests/Blood-Tests.htm Wide selection of medical tests (primarily bloodwork)available mail-order, the blood will be drawn at a local medical lab under contract. The product offering includes ceruloplasmin and copper, two tests that all ALS patients should probably get but medical doctors don't know that. Every late spring they have sale with huge discounts. 

http://alsuntangled.com/ Unique resource based on a social networking model, their primary mission is to research and to publish reviews on various proposed ALS therapeutics. Some would say they tend to err too much on the side of caution, but they're far less biased than the well known "Quackwatch" which is prone to label anything that didn't come from Big Pharma as quackery. I just now checked out Untangled's report on Prevagen: it looked fairly well done and it convinced me that Prevagen probably doesn't belong in anyone's Pile of Pills (although someone else's informed opinion may differ).

http://www.als.net/forum/yaf_postst48193_Peony-root-and-paeoniflorin-long-essay.aspx People sometimes ask me what my protocol is or has been. There are in the Peony thread several links to snapshots of my protocols as they have evolved over time. This thread is also the basic resource here on peony if you happen to be interested. 

http://www.naturdoctor.com/Chapters/Research/ALS/ALS1.html Lengthy and well-researched 9-part essay on ALS and potential therapeutics. I disagree with the author on several points, esp. his recommendations to increase SOD1 and to supplement with copper, which at one time seemed to make sense, but nowadays are pretty much proven wrong. Despite a few glitches like that, overall it is an excellent essay and a heckuvalot easier to read than Aketri's ALS theories summary thread.

iStrong wrote:

Somewhat off topic but great information on this als online genetics database and this ALS gene website.
The genetics of ALS is in the very early stages of being unravelled. At this (Jan 2014) stage it's nearly useless to patients other than a few known familial cases. It's looking like in sporadic two main groups may emerge: TDP-43 and SOD-1, and that the corresponding targeted therapeutic approaches will be somewhat different. 

http://www.yorku.ca/hamadeh/CLINNUTRTABLES2009.pdf Emphasis on ALS from the perspective of antioxidant therapy. In vitro, in vivo, and human trials of various nutritional supplements, a summary of what's been done. 28 pages! 

http://examine.com/ This is a website which collects information on nutritional and herbal supplements and summarizes the information in convenient form. All kinds of stuff you never heard of. Excellent resource esp. for unusual stuff, but their perspective is often different from ours and that has to be considered when relying on their information. 

Questioner made a great find. Here's the thread http://www.als.net/forum/yaf_postst53895_Review-of-nutritional-supplements-for-ALS.aspx and here's what he found http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631353/ It's a review of the scientific basis of DIY cocktail therapies, the lead author of which was none other than Dr. Jeff Rosenfeld, Ron's hero neurologist. Recommendations don't get better than that! I'm hoping someone will copy the document into Aketri's ALS Theories Summary thread. 


http://www.als.net/docs/pdf/ips/Full_Experimental_Protocol.pdf
ALSTDI has embarked on a research project that integrates genome analysis with in- vitro "drug trials" on tissue samples. This is a revolutionary technology, we're very fortunate to have something like this going on with ALS. Most diseases that aren't in the top 10 get very little research. ........ It'd be easy to explain the expected long-term benefits from this research project, but unlike most research this one stands a chance of benefitting a few PALS while they're still alive. How? If you have a list of your genetic abnormalities, that provides clues to potential therapeutics that may already be available. An obvious example is that if you've got genetic abnormalities known to be associated with dysregulation of copper, you probably really oughta be taking zinc. 2014 was a landmark year, the year we began to develop therapeutic protocols targeted to different types of ALS. On this very forum. It looks like 2015 will also be a landmark year, the year in which genome sequencing finally becomes relevant to therapeutics. Thanks to ALSTDI. 

Short Essay: ALS Fads The field of ALS therapeutics goes through fad cycles. I'm constantly tweaking my therapeutic regime based on what people are posting about that sounds interesting at the time. .....What gets forum action doesn't necessarily have anything to do with the merit of the stuff in question. It can have to do with availability of information about the stuff, with availability of the stuff itself, or with reports from PALS of supposed benefit or lack of benefit. ....Several years ago, lithium was all the rage: that probably won't happen again with lithium. Nowadays, DM is at the top of my Proletariat Protocol list: it was clinically trialed 'way back when and the results were evidently bowdlerized, the whole time it was a well known NMDA receptor inhibitor, and here we are with the stuff in clinical trial again and more useful information coming from DIY'ers than out of the clinical trial. ........As an ALS patient researching potentially useful therapeutics, you've got a huge pile of possibilities to choose from and not much time to decide and act. I can't tell you to stick with the stuff that's proven, because the only protocol that meets the criterion of proof is the do-nothing protocol and I don't like what it proves. ..... So, I don't discourage newbies from trying stuff that may not have won any popularity contests here. What interests you might be something new (like Gastrodia)or something old that somehow failed to trigger excitement (ibuprofen?). If it looks affordable and safe and the evidence in its favor dials your number, have at it! Sure beats "placebo therapy"! 

WARNING ABOUT RILUZOLE
Olly wrote:



Neurodegener Dis. 2013 Dec 20. [Epub ahead of print]
The Neuroprotection Exerted by Memantine, Minocycline and Lithium, against Neurotoxicity of CSF from Patients with Amyotrophic Lateral Sclerosis, Is Antagonized by Riluzole.

Abstract
In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. 

We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. 

Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µM; this cell damage was similar to that elicited by 30 µM glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µM), minocycline (0.03-1 µM) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µM, riluzole antagonized the protection afforded by the 3 agents. 

These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. 

Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds. 

© 2013 S. Karger AG, Basel.

PMID: 24356417 [PubMed - as supplied by publisher]


Short essay: What does "neuroprotective" mean? The word is bandied about here as though it actually meant something important. Sure sounds important when the topic is ALS.

The list of substances described as "neuroprotective" in the PubMed Pile is almost limitless. Most commonly, a substance is described in this way for one of the following reasons: 

1. It inhibited damage or death to neurons in in vitro testing, when the neurons were exposed to some kind of agent known to cause damage to neurons. 

2. In an animal model of stroke or other localized experimentally induced ischemia, the substance reduced death and/or improved recovery. The underlying molecular biology is almost always either modulation of glutamate, or modulation of glutamate receptors. 

In the context of ALS therapeutics, this isn't very good news. 

In vitro research is useful for discovering molecular pathways. However the molecular biology of living animals is very complex, and what works in the test tube usually doesn't work in clinical trials (often doesn't even work in lab animals engineered for the purpose).

In my opinion, stroke and related experimental ischemias are nearly worthless as models of neurodegenerative processes.

Substances trialed on animal models of neurodegenerative disease, when successful in those models, almost never translate to provably useful therapeutics in humans with those purportedly same diseases because the disease in humans is so variable, unlike in the engineered animal strains which have variability bred out of them. 

When it comes to the underlying molecular biology of substances which get referred to as "neuroprotective", there are two big groups: antioxidants, and glutamate modulators (inclusive of GABA agonists etc.). Huge amounts of those kinds of stuffs have been thrown at ALS patients, with very little to show for it. 

This does not mean I regard such things as useless, only that in human ALS they're not much use all by themselves. I regard antioxidants and glutamate modulators as essential ingredients in any promising cocktail therapeutic regime. 

Also, keep in mind that antioxidants are not all the same and neither are glutamate modulators. These mechanisms of action include many actual molecular pathways, and the substances in question often have pharmacological activity beyond antioxidation or glutamate modulation. Therefore it's possible that something that's been labeled as an antioxidant or glutamate modulator (or words of generally similar meaning) could prove to be an extremely valuable therapeutic.