I'm psyched that we now have identified 3 supplements that can potentially prevent or even break up alpha-synuclein clumping.
1. Vitamin B12
2. Carnosine (although potentially it is better to take the precursor, beta alanine) [Edit to add this IMPORTANT NOTE: I personally stopped taking carnosine supplements because I became aware of the possibility of hydrazine contamination. Hydrazine is a toxic chemical that has been used in the synthesis of carnosine.]
I think it's important to note that the B12 research I cited is "in vitro", and not "in vivo". In other words, it was done in test tubes, and not in live animals or humans. To be fair, in some of the tests, they were testing different treatments on a line of cultured nerve cells. They found that vitamin B12 reduced the toxicity of alpha-synuclein.
I wonder if vitamin B12 reduces alpha-synuclein protein clumping and toxicity in animal and human brains?
A fourth potential treatment is gamma waves sound and flashing light. (40 Hz). There was an article in Nature a year or two ago where beta-amyloid plaque was reduced in mice that were exposed to sound and light at this frequency. The hypothesis was that it entrained to the brain to fire at that frequency, thereby triggering a mode which induces cell repair and reduces inflammation.
I am going by a comment made by Jandeb yesterday on another carnosine thread.
Jandeb said,
"The challenge is that [carnosine] is quite expensive and gets metabolized by the enzyme carnosinase in the gut. The solution to that is to feed beta alanine. Numerous human studies show beta alanine ingestion will increase carnosine. beta alanine is cheap and available. The down side of taking high levels is that it can cause a temporary hot tingling sensation."
I did look at one article which said that beta alanine is the rate limiting component of carnosine synthesis.
Carnosine is synthesized abundantly in the muscle tissue but it is not clear that any of that carnosine makes it into the bloodstream. Therefore alanine supplementation may not be sufficient to receive the Parkinson's benefit as set forth in the carnosine study.
Carnosine costs about $30 /month. Expensive as supplements go but not so much as compared to prescription medications. Worth it to me personally if it helps.
Reading that article, it looks like the hydrolysis of carnosine (by carnosinase) in the blood plasma is a much bigger issue than Jandeb's contention that it gets metabolized by the same enzyme in the gut.
The article says there is a "remarkably short half-life of carnosine in plasma".
"This suggests that enzymic activity in plasma hydrolyses the added carnosine with a half-life of the order of 1 min."
How much is getting to the brain? It seems like the carnosine doesn't just all disappear immediately, because fair amount (up to 14% of what was ingested) makes it out into the urine. The authors of the study hypothesize some kind of "compartment" where carnosine is quickly gathered and held, such as perhaps the liver. It sounds to me like we are a bit unclear as to what is happening.
Relevant questions: What is your daily dose of carnosine at $30/month? How does that compare to the amounts that people were taking in the Russian trial (where "carnosine was prescribed in a daily dose of 1.5 g")?
[I hope I don't sound cheeky or confrontational, because I absolutely don't mean to. I'm should I'm sure you'll appreciate that I'm just trying to dig into this. I want us all to have the best chance to find something that works.]
"Serum carnosinase activity was assayed in five groups of patients with neurological disorders. Enzyme activities in patients with idiopathic epilepsy (mean ± S.E.M., 148 ± 11 nmol/ml per min) and motor neurone disease (155 ± 15 nmol/ml per min) were similar to the control group (161 ± 7 nmol/ml per min). Reduced serum carnosinase activity was observed in patients with Parkinson's disease (109 ± 11 nmol/ml per min, P < 0.005), multiple sclerosis (82.5 ± 10.0 nmol/ml per min, P < 0.005) and patients following a cerebrovascular accident (74.6 ± 5.4 nmol/ml per min, P < 0.001) compared with the control group. Carnosinase activity, 5–10% of that found in serum, was detected in CSF samples. "
So if carnosinase is already reduced in PWP we should already have more carnosine. Perhaps a feedback loop is involved and carnosinase levels are lowered by the body when more carnosine is needed.
I'm glad I read this again, because the first time I read it, I thought it said that PWP were found to have lower levels of CARNOSINE. I didn't realize it was lower levels of CARNOSINASE. Recalibrating my understanding. Now I wonder whether carnosinase higher or lower with people with PD. Anyone have a clue?
Okay, as for carnosinase, there are two kinds: one in the tissue, one in blood serum. People who are totally lacking in Serum carnosinase (usually for genetic reasons) can have a lot of problems, including mental impairment, in addition to the indicative signs of carnosine in the blood and urine.
I never cease to be amazed at how in spite of all the reading and research that is collectively done on this forum, a supplement appears that has significant potential. How many other supplements are out there that we've never heard of?
By the way, thanks for the tip on celery seed extract. Another 1 out of the blue.
It can be hard to tell sometimes if something is working. Another bit of evidence that the celery seed extract is working is I just had to reduce my dose of levodopa because I was becoming overmedicated.
Update: celery seed extract caused me dystonia and I no longer recommend it.
Thanks. Interesting. Add it to the ever increasing list😊
Interesting it flushes out the system. I wonder if that is what mannitol does too as hubby has restarted on it and his need to pee has increased again so definitely the mannitol effect.
Do you know if despe had success with her brand? I can get that from vitacost in my bulk orders of other things. Postage is so expensive to NZ for Amazon etc to be able to buy one offs so I try to get them all from one place and vitacost postage is cheaper.
Well, I've just ordered 180 capsules of 500 mg of carnosine. From Germany. Should get here by the end of the week.
We do a lot of work collectively, but there is so much research out there. Simon from SoPD says that there are over 700 scientific articles tagged "Parkinson's" on pub med every month. Something like 8500 per year. Then consider all of the relevant articles that aren't tagged Parkinson's, but may still be important. Then consider the backlog of science going back to 1950 or so. Then consider the fact that sometimes you have to look rather closely to be able to find and evaluate important information. All told, the relevant literature is about as large as the Himalayas! I'm happy that we are doing as well as we are!
The Russian team was really "burying the lede" in both of the articles I've looked at. In the one about carnosine, they show an extraordinary positive impact on the functionality of people with Parkinson's (UPDRS scores), just by taking carnosine for a month. But they didn't hyped that, and they didn't even make that the title! The title of that article was just indicating that carnosine "increases the efficiency of DOPA therapy". What the hell?
In their article on oxidative stress, they found two measures of greater oxidative impact on people who had been treated with anti-Parkinson's medication, compared to unmedicated people. In my mind, that's really big news, because it goes against the conventional wisdom that levodopa and other Parkinson's medications don't cause any harm. But again, they reported things, but didn't raise any flags to highlight these findings.
Anyway, I'm glad that other people are now typing carnosine a little bit, so that it has come to our attention and we may try it out.
What are the next things on the list? What are the next supplements to try?
Maybe you want to consider adding Agmatine to your stack, along with Carnosine?
Autism actually is a very difficult, truly taxing condition. Now we have the prospect of its successful treatment with a couple of supplements. That's marvelous ! Thank you.
"Dr. Michael Chez of the Autism and Epilepsy Services Center reports that he has now put about 1,000 autistic children on L-carnosine with about a 90% success rate. Sometimes the results are dramatic, but since most autistic children receive multiple medications, multiple therapies, and multiple nutritional supplements, it is hard to tell how well any individual child will do after starting L-carnosine. The complete recommendation of the Autism and Epilepsy Services Center (for children) is:
400 mg of L-carnosine, twice a day,
50 IU of vitamin E (as alpha-tocopherol, although mixed tocopherols and tocotrienols would also be acceptable) twice a day, and
5 mg of zinc twice a day. Any form of zinc is acceptable.
EDIT: Chez also did a double-blind study which found carnosine helped autistic kids:
Just be aware that melatonin can cause a gassy diarrhea. This is especially pernicious because typically people do not realize that the melatonin is the cause. I only found out that such was my problem by accidentally encountering a comment on the internet.
Melatonin also apparently can exacerbate the muscle weakening side effects of zopiclone, sleeping medication. I thought my parkinsons was getting much worse, but it may have been this.
But I haven't been having diarrhea, thank God. Thanks for the heads up. I only took zopiclone for a few days. Melatonin on its own seems to be helping me sleep pretty good.
EGCG, an active component of green and other teas such as white tea, looks like it may be useful through multiple pathways and in a different type of manner :
"Green tea extract and concentrated infusions of green tea have been implicated in many cases of clinically apparent acute liver injury, including instances of acute liver failure and death."
Note: Do check out that link. The author said they still took green tea extracts. They recommended things you can take to protect the liver.
EDIT: There's a broken link in the three-year-old post. Here's an archived link to two cases where people had liver injury (which they recovered from) after taking "Herbalife" type supplements which contained more than 1 g of green tea extract per day, plus other junk.
"Preclinical and human data implicate the catechin component of green tea as the culprit of hepatotoxicity. Approximately 10% of the green tea extract is composed of catechins; of these, epigallocatechin-3-gallate (EGCG) is present in highest concentration. There is great variability in the concentration of green tea extract, EGCG and other components among marketed products, which may explain while some products have been implicated in hepatotoxicity. Exposure of rat hepatocytes to EGCG has been shown to induce mitochondrial toxicity and generation of reactive oxygen species. The association of liver injury with higher doses of green tea (as in extracts) suggests a component of direct hepatotoxicity, perhaps in the context of some degree of host susceptibility exacerbated by environmental features such as obesity, fasting or glutathionine depletion."
I found this study. I have not read the paper, but only the abstract. Lower concentrations of EGCG seemed to be okay, higher concentrations were problematic. Lower concentrations reduced reactive oxidative species (ROS), whereas higher concentrations increased ROS formation.
There may be some effect on mitochondria at lower levels, I can't tell without reading more of the paper.
Kucera, Otto, et al. "In vitro toxicity of epigallocatechin gallate in rat liver mitochondria and hepatocytes." Oxidative medicine and cellular longevity 2015 (2015).
Epigallocatechin-3-gallate (EGCG) is the main compound of green tea with well-described antioxidant, anti-inflammatory, and tumor-suppressing properties. However, EGCG at high doses was reported to cause liver injury. In this study, we evaluated the effect of EGCG on primary culture of rat hepatocytes and on rat liver mitochondria in permeabilized hepatocytes. The 24-hour incubation with EGCG in concentrations of 10 μmol/L and higher led to signs of cellular injury and to a decrease in hepatocyte functions. The effect of EGCG on the formation of reactive oxygen species (ROS) was biphasic. While low doses of EGCG decreased ROS production, the highest tested dose induced a significant increase in ROS formation. Furthermore, we observed a decline in mitochondrial membrane potential in cells exposed to EGCG when compared to control cells. In permeabilized hepatocytes, EGCG caused damage of the outer mitochondrial membrane and an uncoupling of oxidative phosphorylation. EGCG in concentrations lower than 10 μmol/L was recognized as safe for hepatocytes in vitro.
I imagine if alpha synuclein is like other protein they’renot that soluble in anything that is good in the brain! You can dissolve protein in strong acids but that won’t help in the brain.
This article talks about using yeasts to dissolve amyloid fibres:
Maybe there is a bacteria or virus or yeast that can dismantle it. Otherwise anything that can stop it forming is useful. Do your 3 things dissolve it or stop it forming?
I'd have to review them to be sure, but this is what I remember:
1) vitamin B12: I think the study said that it prevented clumping and helped break it down some. But note, this was done "in vitro", meaning in test tubes.
2) Carnosine: I don't rightly remember now. But maybe both? I need to check. It does other good stuff too.
3) Mannitol: the Israeli study reported that it prevented clumping, but didn't break down existing clumps. But my memory is that their study wasn't really set up to see whether it broke down existing clumps (?). Anecdotally, several people I have encountered have said that mannitol improved their sense of smell. This suggests to me that perhaps it DOES dissolve alpha-synuclein clumps. It is likely that alpha-synuclein clumps deposit in the olfactory lobe before they deposit in the striatum nigra. People are getting their sense of smell back, it stands to reason that these are dissolving???
Anyway, that's what I got for you. It's a bit hand wavy.
Interesting. It’s hard to see how a chemical alone can dissolve a protein without some kind of biological agent helping out. But if b12 does in vitro it must I guess. A suppose it might have a chemical reaction which makes it into a soluble compound, or one that opens out the folds to make it a long chain so it can’t clump?
Mannitol is pretty inert so could that react? Or maybe it grows bacteria that chomp on the protein too?
I wonder where the byproducts go once broken up? Into the gymphatic system and out the nose and down the throat? Maybe runny nose is a good thing washing out rubbish!
EDIT: oh! I see that it is suggested in one of the scientific articles as a way to get around the enzyme that breaks down carnosine in the blood serum.
The third scientific article you referenced there looks huge.
Hipkiss, Alan R. "Glycotoxins: Dietary and Metabolic Origins; Possible Amelioration of Neurotoxicity by Carnosine, with Special Reference to Parkinson’s Disease." Neurotoxicity research 34.1 (2018): 164-172.
Wow, it brings so much together. We have hyperglycemia leading to glycated alpha-synuclein, which could be spread to the brain in erythrocytes (red blood cells), which accumulates and triggers microglia to get all aggressive in the brain. We also have elevated carnosine in the red blood cells (that's the container, that's where it was hiding). And carnosine may be our special friend! And we may want to snort it. But according to the Russian study, may be 1.5 g a day orally might be okay, too.
I read it in the article right there. Hipkiss 2018. You just need to know the lingo. The word "erythrocyte" just means red blood cell.
In the body of the text, they say, "A recent study has detected carnosine within erythrocytes at a level about tenfold greater than in plasma (Chaleckis et al. 2016)."
The cited reference is this, and the article is free:
Chaleckis R, Murakami I, Takada J, Kondoh H, Yanagida M (2016)
Individual variability in human blood metabolites identifies age related differences. Proc Natl Acad Sci U S A 113(16):4252–4259.
Which is better? Acetyl l carnosine or carnosine? The acetyl is a lot dearer. Is there added benefit? All I can see is it gets coverted to carnosine so I’m wondering what the advantages are.
There is L-carnosine and acetyl L-carnosine. I ordered the L -carnosine.
In a chemical reaction 2 isomers (forms of the same molecule, mirror images) will be formed but nature usually only makes the one as it is an enzyme processing it . Eg In this case the L form. In the same way nature can only use one precursor so if you take a chemically made mixture half of it can’t be used by the enzyme. With sugars you will need the D form.
Oh yes, but interesting mannitol is the “inert” bulking agent! I wonder how many times it is the bulking agent that is active and not the active ingredient. Or at least adding a synergistic effect. Funny.
Nice find. It is starting to look like a lot of things can keep alpha-synuclein from clumping.
I'm a little dubious of this one in practice, because
1) It is a common allergen.
2) As with the Vitamin B12 study, this one for the fish protein was done in test tubes, which is an environment that is substantially different from that inside the body.
3) Most importantly, it forms clumps. The fish protein itself forms amyloid plaques.
That’s because your brain is a workaholic, always chugging along overtime, relaying messages from neuron to neuron. Those messages are whirling around you brain right now as you read this article.
And to keep those messages moving requires a prodigious amount of cellular energy. The brain makes up about two percent of your body’s weight, but consumes around 20% of your energy.
If things get sloppy, the production and consumption of energy throws off a flood of waste products – free radicals – that can tear cell membranes apart. Cellular energy production releases pollution end-products just like a fossil-fuel-burning power plant.
That’s why your brain cells need a shield against free radicals.1 Otherwise your memory would be as full of holes as Swiss cheese – the oxidative damage caused by uncontrolled free radicals in the brain.
We’ve sounded the warning about this before, and now recent research from Australia and Slovakia confirms it. The new findings are eye-openers. . .
A nutrient called carnosine helps rein in the oxidative mess. Carnosine is a potent antioxidant that combines two amino acids. Along with fighting oxidation, it also keeps other harmful chemicals from interfering with your neurons, and it performs a similar function in muscle tissue.
Although your body can make its own carnosine, studies show your muscles, brain and other parts of the body can get a healthy advantage from carnosine supplements and foods – primarily meats – rich in this natural substance.
Ancient Chinese had a Hunch
While carnosine as a natural chemical was first identified in 1900 by a Russian scientist, the ancient Chinese indirectly knew about it a thousand years ago. That’s when they discovered that the meat of a bird called the black bone silky fowl was useful as a health tonic. The bird -- covered with white plumage that sits over black skin, black meat and even black bones -- is a rich source of carnosine.
The meat of this bird – which the Chinese have long consumed to fight aging, boost immunity and improve endurance – contains twice the carnosine of anything you’ll find in the poultry sold at the supermarket or fast food joints like KFC.2
How does carnosine protect us? Each of your cells has its own tiny organs called organelles. Recently, some of the modern research into carnosine has focused on how this nutrient protects a certain type of organelle -- mitochondria – found in neurons, muscle tissue and other cells. Mitochondria both produce energy and release the free radicals that are the byproducts of energy production.
Now a study in Asia shows that after a stroke, carnosine can help defend the mitochondria in neurons from destruction. It limits autophagy – “self-eating” -- a process that would otherwise allow mitochondria to be broken apart and eliminated.3
Supports Immune Function, Too
And carnosine does more than clean up the mitochondrial waste products. Research in Israel demonstrates it can also keep microglia – immune cells that roam the brain – from adding to destructive oxidative stress and inflammation.4
Studies now show that microglia are complicated immune cells. While they usually protect brain cells and keep them functional, they can also be harmful when they are switched into inflammation mode.
But according to a study that involved researchers from Italy and the University of Kansas, carnosine can play a central part in keeping microglia on their best behavior – defending brain cells from harm rather than ramping up inflammatory processes that can kill them.5
The end result of carnosine’s protection: better brain function. A test at the University of South Florida indicates that taking carnosine along with vitamin D3, blueberry extract, green tea and other nutrients may help boost memory as we get older.
The study, performed on people without obvious memory problems, found that two months of the supplements improves folks’ ability to process new information fast. The Florida researchers also report that the supplements improve the health of neurons in aging brains.6
Other carnosine benefits include:
•Reducing the health risk of air pollution – Tests at the University of Louisville find that while air pollution can interfere with the stem cells in bone marrow and impair heart function, carnosine may prevent these types of harm.7
•Improving the movement issues linked to Parkinson’s disease – A study at the University of Cincinnati indicates that taking carnosine intranasally (through your nose) may slow down the deterioration of muscle control that takes place during Parkinson’s.8
•Preventing and treating diabetic retinopathy – A study in China demonstrates that carnosine stops destruction in the eye caused by diabetes. Left unchecked, retinopathy can destroy vision.9
I’ve written about carnosine before, but in preparing this article I’m still surprised by all of this nutrient’s crucial functions in the brain and body. Why doesn’t it get more attention from the press? Beats me.
But consider this – there are some researchers in England who think carnosine might also be developed into a supplement or treatment that could battle the flu!10 If the research works out, it’s a benefit that could prove to be a lifesaver for many people.
Going well. I've been taking it now for 3 weeks I guess.
I wish I had done some kind of test to establish a baseline. I can't say whether I've noticed a difference regarding akinesia or other symptoms. I am sleeping much better now, but I mainly attribute that to a combination of melatonin and cannabis at night.
I started the melatonin earlier and have been raising the dosage to my current levels. I started cannibis later than the carnosine. Sleep benefits coincide with those and not the carnosine.
Thanks. Do you take the carnosine with food or empty stomach? I’m finding lots of things require empty stomach and getting enough time slots in the day is a challenge! It would be handy to know what things can be mixed without reacting together.
I see two sellers of carnosine saying it is best on an empty stomach, but the russian article doesn't say that that was a part of their protocol. They divided their doses to "3 times daily". I think there may not be research on carnosine absorption. We may be getting the default recommendation.
"Researchers tested 48 different plant compounds able to cross the blood-brain barrier to see if any were able to stop alpha synuclien proteins from clumping together. To their surprise, not only did a variety of flavonoids inhibit these proteins from accumulating but they could also break up existing deposits.(114)"
p. 236 of How Not To Die, by Michael Greger.
Citation 114:
Meng X, et al. 2010. Effects of various flavonoids on the alpha-synuclein fibrillation process. Parkinson's Disease. 2010: 650794.
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Which supplements?? Your top 5
Day 17 of taking TTDF:
Great Video on Berberine
