"So it doesn’t look like there is a strong association between low thiamine levels and PD."
"The (Costantini) researchers proposed that “the motor and non-motor symptoms of PD could derive from a chronic thiamine deficiency” in specific regions of the brain. And by increasing in thiamine levels in these regions of the brain (via high dose treatment) may help to improve the motor performance. This is an intriguing idea, but the blood thiamine levels were normal and the investigators provided no evidence to support this speculation (the levels of thiamine in the brain/cerebrospinal fluid were not examined)."
"... thiamine (and its derivatives) cannot cross the blood-brain barrier by simple diffusion ... "
... raising levels of thiamine in the blood does not lead to an increase in thiamine transportation across the blood-brain barrier or to a corresponding increase in brain levels.
"The first trial of high dose thiamine (3 grams per day) in Alzheimer’s was a 12-month, double-blind, parallel-group study, which reported “No significant differences were found between the placebo and thiamine groups at any point during the study..."
"In this study, the researchers tested benfotiamine treatment in an Alzheimer’s mouse model. These mice produce very high levels of the human TAU gene carrying the P301S genetic mutation. The investigators found that benfotiamine-treated P301S mice lived significantly longer than P301S mice fed with a control diet (An average of 390 vs 322 days, or a 21% increase in longevity)"
"Benfotiamine treatment also reduce behavioral issues in these mice, and decreased neurodegeneration. It also reduced advanced glycation end (AGE) products (Click here to read a previous SoPD post about AGE and RAGE inhibition)."
"The researchers also found that benfotiamine treatment reduced inflammation and oxidative stress, via activation of the NRF2 pathway (Click here to read a previous SoPD post on the NRF2 pathway)."
"In this study, the investigators recruited 70 people with mild cognitive impairment or mild dementia due to Alzheimer’s, and they randomly assigned them to daily treatment with benfotiamine (N=34) or placebo (N=36) for 12 months. The treatment involved one 300 mg capsule of benfotiamine in the morning and another one in the evening everyday."
"More importantly, the progression in cognitive issues was 43% slower in the benfotiamine group than in the placebo group...This result suggested that there was less cognitive decline in the benfotiamine-treated group. And this effect was also seen in the clinical dementia rating (CDR) score which found that the benfotiamine-treated group was 77% better off compared to the placebo group (curiously, this effect was stronger in the APOE ε4 non-carriers..."
"And remember that this study was randomized, placebo-controlled, double-blinded trial of benfotiamine..."
"I think the take home message from the SoPD point of view is that there simply isn’t enough research on thiamine (high-dose or otherwise) in the context of Parkinson’s to make any kind of statement. I have tried to be fair in this post, but most of the preclinical work was conducted last century. And while Dr Costantini and his colleagues have provided stimulating pilot data, more carefully controlled studies are required. The gold standard is a randomised, double-blind, placebo-controlled clinical trial, and that is what is missing from this story."
And until that is conducted, we here at the SoPD will politely defer from making any judgements or statements on thiamine.
The benfotiamine study disproves all of the claims that ‘if it’s not hugely profitable no one will fund a study.’ Which has actually been disproven many times with all of the natural products that have been studied, e.g. vitamin C.
I had a better response to Allithiamine than I did to thiamine Hcl, both IM injections and oral. But that was only for the first month I took it. My feeling from what I read here is that more people have tried it with no response than have had success with it but the non-responders tend to keep it to themselves. I believe that people are convinced it makes a difference therefore it does.
If it’s not hugely profitable a study may or may not get funded depending upon the attitudes of the investigators, whereas if a drug candidate is patentable it will almost certainly get funded if it shows any sign of efficacy.
I haven't responded to B1. I took injections (subcutaneous) 6 months and nada. I continue taking a gram to 1 & 1/2 g/day and have recently switched to sublingual. When I use up my current supply, I will try benfotiamine.
If B1 doesn't cross BBB, what is the mechanism of action?
Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex
If B1 doesn't cross BBB, what is the mechanism of action? ".
Good question Marc.
In a world that is increasingly complicated and not surprisingly made more chaotic to hide our misdeeds, sometimes man lacks the ability to “ observe the obvious”.
I know, life is hard, it is not always easy to make the right decisions and often our point of view is altered by personal experience, but your question brings us back exactly where we should be to observe the obvious: “If B1 doesn ' t cross BBB, what is the mechanism of action? ".
Simon explains it thus: ”TPP is the active form of thiamine and it is involved in many important biological functions. Chief among these is energy metabolism, cell viability, and proper neuronal functioning. Crucially, TPP is a cofactor in the production of adenosine triphosphate (ATP) - this is the fuel that cells run on (Click here to read a previous SoPD post discussing ATP). "
IMO This is what thiamine does and it does it directly ie it enters the blood and goes to the brain through the BBB and exits through the kidneys, very quickly. So you won't find much thiamine for a long time in the blood. (and there are several studies on this).
Is it little? I don't know, but it's easy to imagine the cascading effects and limitations of thiamine on the body. It will certainly help the cells that survived Parkinson's disease, but here we have introduced another obvious thing:
the extent of the lesion or stage of the disease modifies the response to drugs, to levodopa, and I suppose also thiamine.
Doctor C knew these things well as he postulated in his interview on YT (in Italian unfortunately) but here's a part:
"… From here we started, when we treated the fatigue of a genetic disease that is transmitted in a dominant way, that is, from father to son in 50 percent of the cases, we saw that in addition to fatigue improved neurological symptoms; so we thought that fatigue and neurological symptoms were the same thing ... right? and allowed the improvement of a minor symptom and of the most important neurological symptoms; the results were evident, it is called an ex adiuvantibus evaluation, ie the treatment was effective. Since for this disease they have found the first positive results, they have genetic links with parkinsonism, in the sense that there are patients, families that have the genetic alteration of spinocerebellar ataxia type 2, that is, they should have the result for the affected gene, for the chromosome affected an non coordination, a damage of the cerebellum, instead the symptoms are those of parkinson's disease, so it is enough that the genetic alteration instead of being prevalent in a functional system prevailing in another there from another disease. ... ".
Another obvious thing that is often objected is that there is a lack of double-blind research that determines the effectiveness or otherwise of thiamine but it should also be noted that even today the exact cause of PD is not known, and only a few researches go in this direction.
How is it possible that millions of dollars are spent in trials to find a medicine that treats PD without knowing the causes or even having an objective examination, such as a biomarker of the disease, which accurately determines the progression?
In my opinion, if the cause of PD were known, this discussion would be superfluous and therefore I wonder, but I would also ask Simon and the whole scientific world: why is the cause of Parkinson's disease still unknown today?
"How is it possible that millions of dollars are spent in trials to find a medicine that treats PD without knowing the causes or even having an objective examination, such as a biomarker of the disease, which accurately determines the progression?"
Hikoi Your problem is that you believe too much in pharmaceutical propaganda or you are part of it, I sincerely hope you never have to deal with cancer in any way.
Odd you should know what motivates me when you don't know me. I'm just glad I didn't get caught up in previous miracles - Fast walking or Coconut oil. They haven't delivered. ... yet.
"Strange that you should know what motivates me when you don't know me."
It's true and I apologize.
I understand that it is not nice to be told "your problem is ..." from another.
Yet you do it often and I quote: JP you don't have PD, You are under medicated, Your improvement is just a placebo.
These are all indications that you give to unknown people!
Now on this side of the planet we have the golden rule: "Don't do to others what you don't want them to do to you."
We also have the positive version that which is "Do to others what you would like them to do to you".
I know you are someone you want to help and you know the subject well, so you have my respect.
The placebo effect is taken very seriously by Pharma in trials, they are terrified of it. They still have not understood it and still do not understand the fact that the belief and a high expectation of being cured by a treatment, gives equal or superior results, UNDER THE SAME CONDITIONS, of the medicine itself.
They are terrified of this. LoL. Witchcraft sometimes works better than modern medicine and they still don't know why. Extra LoL.
Your video is beautiful, it describes well what has happened lately in mondial healthcare
PS: In your link on placebo I find contradictory that they explain the placebo effect as due to the brain emitting more levodopa, but they don't give a similar explanation for the nocebo effect, If the placebo effect causes the brain to produce more dopamine and other things, the nocebo effect should do the reverse ... but we're sure it does, umh .. No. Wrong theory.
How is it possible that millions of dollars are spent in trials to find a medicine that treats PD without knowing the causes …..In my opinion, if the cause of PD were known, this discussion would be superfluous and therefore I wonder, but I would also ask Simon and the whole scientific world: why is the cause of Parkinson's disease still unknown today?
I reply
what is the cause of cancer? Or more specifically breast cancer or if you prefer leukemia? We treat both but I doubt the cause is certain.
Gio replies with
Implications that I am in some way connected to drug companies, or at least believe their propaganda and hopes I don't get cancer.
Later he says that I tell people “you are under medicated” “your improvements are just placebo”. I would like to see the evidence of this. I am usually careful to frame statements as my opinion not as unequivocal fact. He quotes a Bible verse and then gives some opinions as facts.
Sorry WTP but if we only communicate with those who think exactly like us what exchange of ideas do we have? No one. It's true that if we're too different it's the same thing: no exchange. But here as different as we all have the same problem as the disease and there is no cure. So let's be similar, inviting not to communicate doesn't seem like a good idea to me. Unless you do not accept the chance to make mistakes and think you are always right.Not me.
Bah ! Do everything yourself, first you call me then you are a victim if I answer and you agree with WTP in ignoring me, but if you don't want to communicate with me don't call me and stay in your "Parallel Universe", Whatever it is!
“Very very interesting, it would seem that the effects and reactions of allithiamine TTFD are comparable to the effects of intramuscular injections of thiamine HCL.
This is very relevant because it could open the door to the full benefits of vitamin b1 for everyone.
This is the first time I have heard this from a thiamine, (vitamine b1) in pills.
I ordered it but temporally out stock on Iherb here in Italy.”
Copy and paste Of my response recently given to @Gcf51.
Hello Gio, Do you think some people don’t respond to thiamine because they may be low in biotin? I found in a research paper this: SLC19a3, a thiamine transporter regulated by biotin. Perhaps the people who don’t respond are lacking co-factors that are needed. Just a thought, I have no expertise.
In my experience with thiamine I know that if you add a normal dose of b complex and minerals such as magnesium and calcium lots of fresh vegetables and plenty of Vitamin, B1 works better than before for an obvious reason which is that the enzymatic processes in which the thiamina are numerous, but I don't think that's the point of non-responders. If you are drunk and they take you to an emergency room they give you an intravenous injection of thiamine and after a quarter of an hour you are completely sober, whether you are unresponsive or not. So for what thiamine does there are no non-responders, but 1) there are different stages of PD where the lesion is less extensive and 2) these nasty thiamine hcl pills that don't work well for everyone. (Maybe for the reasons you mention). Thiamine hcl pill last too little time in the body, maybe a couple of hours. I tried the pills of b1 hcl but there is no comparison with the intramuscular injections .I know, I have seen it on me very often.I can tell you that in the last week I switched to benfothiamine 250mg 2 X day with results comparable to the injections of b1 hcl (being a veteran in b1 I know it works when I arrive in the evening less tired, without sleepness and with a strong desire for sweets or carbohydrates ie overdose of b1 = it works) 😁😁😁. I am waiting for the TTDF or allithiamine to try it.
Greetings from Italy, the sun on HU never sets.Gio
Yes I’ve been taking benfotiamine too, it seems to help my swallowing more than thiamine hcl does. You make such lovely replies I can see and feel the Italian sunshine ☀️ you are warm and kind to everyone 🌟
'Switched toBenfothiamine 250mg 2 X day with results comparable to the injections of b1 hcl... '
This I find interesting as Benfothiamine is my preferred B1 supplement. The choice is academic - best for diabetic or prediabetic conditions. I give my spouse (PwP) 300mg once a day.
Cannot claim that I have observed an effect, but I will double it, based on your observations.
In my case it restored normal G.I. peristalsis which of course does not require crossing the BBB. I also believe I received some neurological improvement but that was less dramatic.
I think that is why you have to take such a strong amount of it. If it gets past a certain concentration in the blood it kind of forces itself across the bbb? Maybe non responders haven’t tried high enough doses.And maybe it works better on certain people eg ones eating a very high carb pasta diet who might be critically short of it like the sailers. Or people that are pre diabetes.
It is still undecided, i.e., controversial. I will read the other threads linked here, but in the meantime, Simon Stott will have the final word - for me. He says, essentially, there is no evidence (of B1 efficacy.) (He links to studies showing benfotiamine does cross BBB.)
"Comparative autoradiographic investigations on the tissue distribution of benfotiamine versus thiamine in mice"
And I guess there is a chance the Thiamine does not need to reach the brain, if you think PD is fed by the gut. Here is a video from Elliot Overton:
In the presentation, I explain why vitamin B1 (thiamine) is absolutely essential for a healthy gut. This deficiency often gets overlooked, and it is likely a LOT more common than many believe.
Thiamine is necessary for the health of the autonomic nervous system, which is responsible for:
1. Gut motility
2. Stomach acid, bile, and digestive enzyme secretion
3. Preventing/modulating gut permeability
A deficiency in this key nutrient can lead to all of the symptoms associated with individual gut-related disorder including IBS and SIBO.
Aside from the fact that high dose B1 helps to significantly reduce the inflammatory IL-17, which is significantly elevated in PwP compared to healthy controls who are usually reflecting very low to undetectable IL-17 levels, little discussion is given to the effect of B1 in the gut microbiome and how that might affect the gut/brain axis. Considering that multiple B vitamins including thiamine are produced in the healthy gut microbiome, but likely not so much in the perturbed gut microbiome of PwP, thiamine is much more important than generally realized. Keeping in mind that a healthy gut microbiome contains bacteria to produce multiple B vitamins, with thiamine being one, clearly the body has definite uses for thiamine with all organisms requiring it , but if production dwindles due to dysbiosis, that has to be harmful to the the gut and any parts of the body not receiving their thiamine needs.
>>> ' Thiamine is required by all organisms due to its role in essential metabolic pathways, including glycolysis and the tricarboxylic acid (TCA) cycle [3]. Among gut microbes, approximately half encode the enzymes for de novo thiamine synthesis [3]. This synthesis includes production of the precursors thiazole and hydroxymethyl pyrimidine followed by the combination of these precursors into thiamine [4]. ' <<<
I think the sentence in bold print is worth highlighting and very significant as it gives a clue as to the importance of thiamine in the body.
I think in time as more studies elucidate the activities and effects of thiamine in the gut microbiome, the reasons why it has shown benefit in many PwP will become clearer. I am just doubtful that that will happen in my lifetime, but for those who don't mind waiting, no problem.
Thanks Art. So, from this you feel Simon got it wrong? He complains about getting a flood of emails about B1, which is what motivated this latest blog, nevertheless I am tempted to send him your explanation.
We don't know yet because studies have not yet revealed the needed information about all that thiamine is doing in the body that could relate to PD in one way or another and more specifically in the brain. I definitely feel that the available science can not confirm that thiamine benefit in PD is a placebo effect, but at the same time it can not confirm that it isn't. The way it took so many users of thiamine to find their most effective dose does not seem like a placebo effect either, though it possibly could be.
When I read that sentence from the link I referenced,
>>> 'Among gut microbes, approximately half encode the enzymes for de novo thiamine synthesis [3]. '<<<
it gives the impression that the human body has evolved to have significant use for thiamine and can generate it in the gut microbiome in significant amounts. The dysbiosis seen in PwP seems like it would certainly alter this natural production of thiamine in the gut, but again, to what extent is not known yet. FMT initial attempts to return the gut biome of PwPs to homeostasis and the limited FMT data for PD, shows significantly positive motor and non motor symptom improvement. Is this at least partly due to increased gut microbiome production of thiamine and the bacteria that produce it?
Another consideration is that there was another researcher here in the US who was testing even higher doses of B1 in his PD patients and getting very similar results to what Dr. Costantini was reporting at approximately the same time as Dr. C, but he died and when he died, his research ended. He was clearly opposed to the idea that thiamine is a placebo effect in PD and he goes on to layout the details of how thiamine is likely to have positive effects in PD. As far as I can tell, his case reports have been removed from PubMed, but I remember reading them at the same time as Dr. C's reports and his results were the same, but I remember he reported using higher dosing in his patients than Dr. C was reporting . In this link below, he details all of the reason's why he thinks B1 would be useful in PD. I actually tried to contact him first before I contacted Dr. C and that is how I found he had died and that nobody was going to continue his research.
I think that part of the problem is that currently there are no practical ways to test thiamine levels in the brain, and whole blood measures of thiamine do not accurately depict thiamine levels in all areas of the body and the brain in particular. It is already established that thiamine deficiency in the brain causes neuroinflammation and neuroinflammation is a main component in PD.
It seems that finding a practical way of measuring thiamine levels in the Substantia Nigra pars compacta and other areas of the brain would be quite revealing about thiamine and PD. This may be the simplest approach to determine how thiamine might be affecting PD.
Wernicke's Encephalopathy is another case where thiamine deficiency results in neuroinflammation.
The way they treat Wernicke's Encephalopathy is via three 500 mg injections of thiamine per day for two or three days and then a reduced dose after that. Is it such a stretch to think that thiamine deficiency in the Substantia Nigra pars compacta might also have devastating effects?
My final thoughts are that it may be beneficial to determine the relevance of B1 in the bigger picture of PD before spending a ton of time and resources on determining how or if it really works when those resources may be better spent elsewhere. Nobody is claiming that B1 is curing PD. The claims are that B1 is improving quality of life for the majority of people who test it. Similar claims are made for quite a few supplements such as cinnamon, sulforaphane, melatonin, mucuna, citicoline, FMT, etc. To me, I would rather see those resources allocated to FMT because imo it appears that FMT may offer the greatest improvement in quality of life when compared to the other supplements suggested as useful. Next in line would be citicoline or sulforaphane followed possibly by melatonin at very high dose. The lower dose studies have already proven melatonin beneficial and safe for PD.
Given the very good safety profile of thiamine, I think it is more appropriate to just test it to see if it offers you any benefit, rather than wait for studies which may never come. If it helps you through placebo effect or actual healthful changes to your system, great! If it doesn't, then move on to the next item showing benefit through studies if you are actively trying to improve your quality of life. I do not see a cure on the horizon, so it is mainly about improving your quality of life to the greatest extent possible through available means.
FMT = Fecal Microbiota Transplantation. I wrote a little about it regarding only two small preliminary studies that have been done so far, but there have been no further studies to confirm these first two studies. Here is a link to what I wrote about FMT :
The results were very good and both studies are very small, but the results are positive in the same way that other non PD/FMT studies have been. Unfortunately, I have not seen similar FMT/PD studies originating from the US. Now that would be a study that many PwP would like to see MJFF fund!
Thank you Art. I jumped the gun. Across the living was my wife who knew what it stood for. She said at the nursing home where she works a few have had the procedure for Cdiff. with success.
Yes, C-diff is the standard use for FMT in the US. There are actually quite a few repeat studies to support its effectiveness for C-diff, but where are the US studies for other uses such as PD and AD?
To be clear, nothing works for everybody except perhaps air, water and food. The gold standard treatment does not work for every PwP.
Regarding Benfotiamine, if the standard for selection of supplements is to have studies which clearly indicate efficacy for a specific disease, in this case PD, then the following should be relevant, in searching PubMed for studies relevant to Benfotiamine (Ben) and PD, this is what turns up :
To me this says that you are going to use Ben for PD based on studies not actually about PD and Ben, but rather studies about other health issues where Ben may have shown a benefit that would also be considered useful for PD such as being anti inflammatory and or neuroprotective in dementia or AD. There is nothing wrong with doing that, but should you really throw shade on thiamine for having insufficient studies to support its use in PD while suggesting Ben would be a better supplement to choose based on zero PD and Ben studies?
You can do the same for thiamine and I have done as much in a post I wrote about how thiamine appears to be a potent IL-17 inhibitor at high dose in a study that had nothing to do with PD and I went on to say that this is very important in PD because IL-17 is at elevated levels in PD whereas healthy controls have IL-17 levels that range from low to undetectable. IL-17 is higher in the inflammatory cascade than say IL-6 or TNF-alpha, so this is important also. Here is a link to that :
If you scroll through the replies section of that post, you will see that there are reason's why B1 may be beneficial in PD based on non PD studies and B1 to good effect.
Here is a study which explains exactly how bad a player IL-17 is in neurodegenerative diseases :
' Recently, several studies have suggested a pivotal role for the interleukin-17A (IL-17A) cytokine family in human inflammatory or autoimmune diseases and neurodegenerative diseases, including psoriasis, rheumatoid arthritis (RA), Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and glaucoma. Studies in recent years have shown that the mechanism of action of IL-17A is more subtle than simply causing inflammation. Although the specific mechanism of IL-17A in neurodegenerative diseases is still controversial, it is generally accepted now that IL-17A causes diseases by activating glial cells. '
So if you want to use Ben for PD based on non PD/ Ben studies, I don't see an issue with that as long as you are keeping the dose in a known safe range. I don't think it would be well advised to be looking at gram size dosing and higher with Ben longer term.
As far as using Ben and B1 simultaneously, I have no clue. The studies I see for Ben are usually related to AD and diabetes and or diabetic neuropathy. I'm sure it has many other uses, but that is what I have noticed.
Btw, Melatonin, with 4 actual PwP studies beats both Ben and B1 in terms of actual PwP/Melatonin studies that all show to be beneficial for PD, but they get little if any mention.
Lastly, Marc, I am in agreement with what Simon wrote in his article. Basically, there is insufficient evidence to make a claim one way or the other. I also still think that one of the reasons that Dr. C chose thiamine HCI is because he knew it would likely be one of the most widely available forms of thiamine available around the world.
Different subject; I’m formerly CCRaspberry. I had no desire to change my name but I’ve had some perplexing online issues and am seeking anonymity so I think a user name that doesn’t include my nickname is best. IRL people don’t know I have PD and I hope to keep it that way.
In the same line of thinking, observation of cell-free mitochondria.
I actually think that these little things could be very helpful to us but mitochondria transfer is not yet studied in PD as far as I know.
But what if all stem cells transplantation is doing is transfer healthy mitochondria? I am pushing too far, but I think that in light of what we know, it certainly seems to be a significant phenomenon.
Science or art?I’m not going to attempt to add anything to the scientific discussion about B1. I just want to point out that finding success with the B1 protocol is an art. Knowing whether to increase, or take a break and reduce your dose, takes thought, experience and sensitivity. This and this alone is the key to finding success with B1.
The answer to your question Marc, is fairly obviously "Yes". The benefits of B1 could be placebo effect. I would go one further. The benefits are probably placebo effect.
Clearly there is (currently) no valid scientific explanation for any B1 benefit.
Equally, there has not been a valid (double blind placebo controlled) clinical trial to demonstrate a benefit regardless of a scientific explanation
Simon's article also confirmed that the lack of a clinical trial is neither related to a big Pharma conspiracy nor due to the lack of profit potential. To quote Juliegrace below "The benfotiamine study disproves all of the claims that ‘if it’s not hugely profitable no one will fund a study.’". There have been valid clinical trials of exercise and other non-patentable therapies
Moreover, the core original claim for B1, that it stopped progression, has been thoroughly debunked by the likes of JimCaster, and of course Royprop - who by his own assessment in the form of UPDRS scores, deteriorated 20 points in 2 years having been on a "full" B1 regimin for many years.
For those who get a benefit - keep taking it. Most of us, yourself included Marc, don't get a benefit. And that's probably because its a placebo effect
Arts explanation, like all art's explanations is long. That anything, including B1, could act on the gut which in turn influences the brain is mainstream WTP. But its speculative and if you asked Simon, I don't think it is going to change anything. Why not ask Simon? He invited comments and questions
It needs a double blind placebo trial to demonstrate it works. It doesn't need speculative THEORIES as to Mechanism of operation when the balance of probability is that actually it doesn't work. It didn't work for you, or me, or Jimcaster. Really, it didn't work for Royprop who in his last year here was clearly struggling and changing c/L B1 and everything else without success. It doesn't work for Despe's infamous hubby although she loudly proclaims it does. But I've lost count of the posts where she's trying a different dose or asking for dose advice because it's not working
Which brings us to Daphne. Whilst in the case of Despe's husband the fault lies in his poor attitude, for the rest of us the problem is we're not doing it right. It's not a treatment that works with a regular dose. There is a black art to success (although a few folk get lucky first dibs. Roy used to tell me that you use the "pull test" to determine the right dose. But at the time I had a pull test like a rugby prop forward, so the optimum dose was nothing
It's this black art tuning process which shouts "placebo" and is what makes it so hard to devise a clinical trial.
That said I could devise an inexpensive trial if you could find me a hundred volunteers from existing users who currently think their dose is stable and won't change for a year. Even 50 would be interesting
Trouble is I don't think you would find 5 prepared to risk being switched to a placebo for a year
So not getting a viable trial has nothing to do with blocking by big pharma and is due to lack of support by B1 advocates
There's nothing wrong with a good placebo effect. 30 years ago after 23 years of suffering from psoriasis I started drinking Aloe Vera gel daily. It took a couple of years to clear up and I haven't had psoriasis since. I still take the gel daily. Nobody has claimed it will work. There are no double blind placebo trials to support it. But I'm buggered if I'm going to stop taking it
So if B1 works for you, keep taking it and be happy. Stop angsting for acceptance and validation from science. Enjoy the result whatever its due to
I take both. Which is not to say it’s not a bad idea. (I regret I’m now stuck with the name NeuroReasearcher. I was just brainstorming a new name and was just curious if it was taken and now I can’t switch it. 😞. I tried novice newbie researcher but it was too long. ). Anyways, it might be a bad idea but I have yet to encounter evidence of it being bad so I take both.
Here is a recent study on thiamine precursors with a focus on benphotiamine conducted by Laboratory of Neurophysiology, GIGA-Neurosciences University of Liègi Conducted by the most authoritative people on thiamine and its derivatives such as L. Bettendorff.
Title
“Neuroprotective Effects of Thiamine and Precursors with Higher Bioavailability: Focus on Benfotiamine and Dibenzoylthiamine”.
2.4.1. Effects on Glucose Metabolism and Mitochondrial Function
The mechanism underlying the cytoprotective effects of BFT was first investigated in diabetic pathologies. High glucose concentrations are believed to cause superoxide overproduction by the mitochondrial electron transport chain as well as inactivation of glyceraldehyde phosphate dehydrogenase, resulting in accumulation of glyceraldehyde 3-phosphate and increased production of methylglyoxal and AGEs (Figure 1) [54]. In cultured endothelial cells, BFT could block three major pathways of hyperglycemic damage [24]: the hexosamine pathway, the AGE formation pathway and the diacylglycerol-protein kinase C pathway. To explain those effects, the authors proposed that BFT administration causes a removal of glyceraldehyde 3-phosphate and fructose 6-phosphate through activation of TKT, a ThDP-dependent enzyme that catalyzes a rate-limiting step in the non-oxidative part of the pentose phosphate pathway (Figure 1). BFT was thus supposed to act by increasing intracellular ThDP levels. Likewise, several investigators considered that BFT might have beneficial effects in neurodegenerative diseases as it could increase brain ThDP levels, stimulating ThDP-dependent enzymes and boosting energy metabolism [55]. It is indeed well known that disturbances in glucose metabolism are associated with the pathogenesis of AD. This disease has even been considered as an “insulin-resistant brain state” [56]. On the other hand, there are several common mechanisms associated with the neurological symptoms observed in TD and AD, notably memory loss [14]. It has been known for a long time that disturbances in ThDP-dependent steps in glucose metabolism are associated with AD [57]. For instance, there is a significant decrease in OGDHC activity [58] and ThDP content [59] in post mortem brains of AD patients. More recently, it was shown that TD increases β-amyloid accumulation in the brains of AD mouse models [60].
Neuroprotective effects of BFT were tested for the first time in 2010 showing powerful beneficial effects in a mouse model of AD [25], but this occurred without any concomitant increase in brain ThDP content. Thus, the therapeutic actions of BFT do not appear to be linked to a stimulation of glucose oxidative metabolism in this model. These findings point to a specific pharmacological effect of BFT (more probably its metabolite S-BT) or a presently unsuspected thiamine derivative.
In another investigation on the neuroprotective effects of BFT in a mouse model of tauopathy, brain ThDP levels were also unchanged [26]. However, there was a significant improvement of mitochondrial function, increasing respiratory complex I immunoreactivity and superoxide dismutase activity. Interestingly, there was a marked upregulation of PGC-1α mRNA levels, suggesting that BFT treatment stimulates mitochondrial biogenesis.
Mitochondrial dysfunction is involved in the onset and progression of neurodegenerative diseases [61,62,63,64]. It is therefore likely that the beneficial effects of BFT administration on mitochondrial function is not restricted to the activation of the ThDP-dependent enzyme complexes PDHC and OGDHC. The mechanism of action of BFT metabolites on mitochondrial biogenesis and function remains largely unknown and deserves further investigation.”.
This is just out of respect for the HUCP community who deserves all possible information from the correct source.
You ask whether the benefits B1 produces are caused by a placebo effect but that doesn’t explain the ups and downs. You start on a dose full of hope and anticipation. Nothing happens.
You try different doses. Eventually you see improvements.
After a bit of time, you start to feel worse. You take a break and restart at a lower dose. You feel better again. Etc etc
I’ve been doing this for five years. I just feel placebo doesn’t work like that. With placebo, you believe something is going to make you better and it does. If it was just placebo it would be a lot easier to manage and get right!!
They were. But disturbingly it worked for everyone. When I was first diagnosed I took Perlmutters book to my Dad (who also had PD) to share new possible treatments with him. He had worked in Pharmaceuticals. "But everything he tries succeeds" was his objection. It doesn't work like that in practice.
And of course, as this forum bears out, it has not been replicated like that on this forum. Why did anyone Dr C treated respond well? Did they all respond as well as the video samples chosen ? (the implication was "Yes")
I think you have tried B1, and not had Dr C's patients responses. I don't question his integrity - just his methodology (I think Simon rather questions his theoretical scientific approach too). His patients were all on other (conventional) medication. And like any other trial for PD - would have been potential placebo responders. Take a look at a few trials to see how well the placebo group often do. Within that will be some who hardly improve or don't improve at all. And a fair handful who do really well on placebo. If you cherry pick your success from the best...
One of the big problems with "alt therapies" generally on this forum is the reporting of individual responses by individuals taking multiple supplements and/or medicines. If I buy an orange ice lolly today and get worse tremor than yesterday, do I conclude it was the lolly, the natural fluctuation of my disease, the lolly in conjunction with my aloe vera?
I appreciate part of the reason Dr C's patients might do better than the hoi poloi having a go on a forum, was his personal supervision and ability to tailor the therapy. But that response to attention - that close interaction and involvement with a physician, is a great way to get a placebo effect, which is why there are so many on clinical trials
And placebo effects are not imagining a benefit or wishful thinking. They are real physical responses - but not related to the molecule being tested.
edit : you're own survey results confirmed that whilst B1 was popular it was far from a universal panacea. Most including it on their list of "helps" didn't rank it first. How does that make sense in the context of the improvements in the videos on Dr C's site?
I have been injecting thiamine Hcl twice a week for 7 years and every time I take a break the non-motor symptoms worsen over 15 days and then improve again when I resume the injections. It's a little hard for me to think it's a placebo effect after all this time.
Some of the forum members believe strictly in pharmaceuticals! That is great, but why should they try to convince many of this forum's members that supplements don't work, PLACEBO OR NOT? Exchange experiences is great, but arguing about methods to achieve a goal that everyone here strives to achieve--QOL-- IS UNACCEPTABLE. WTP made some sarcastic remarks about my husband. He is provocative and he's got a sharp mouth for a PD patient.
I have no qualms about gender. The name seemed feminine so I assumed WTP was a she. There are no threads attached to my comment and dont need any now as well
I dont see people trying to convince people, that supplements dont work. just honest responses about their experience which happens to upset some people . Its like there is only one right way to think and questioning is unacceptable.
? What does that mean?
what race, gender, ethnicity, origin, culture, political leanings or religion someone on HU is is irrelevant.
“He might be a Trans” is that transgender? Irrelevant. We all need support. This is about Parkinson’s.
Not just poor taste. Worse. You are better than such a joke. It is beneath you. WTP is a name caller and sarcastic who thinks he is insulting others when he labels them or defines them. He and others who do this fail to realize they are saying much more about themselves than their target.
I guess this is one of the longest discussions we’ve had. Nevertheless I need to add a few points (I hope I’m not repeating):Simon doesn’t say that thiamine doesn’t cross the BBB, he says it doesn’t do it by diffusion. And although I didn’t check today, a few weeks ago I reviewed thiamine physiology in humans and I remember there were transporters all over the place, so I think he is right stating that.
But frankly, I don’t care. First of all, nutritional deficiency in thiamin causes syndromes whose origins are in the brain. And these brain syndromes are treated for decades by administration of thiamin. So assuming it doesn’t get the brain is not how thiamin is used in neurology.
Furthermore, thiamin is not less than a vitamin critical for energy production. And guess what, the brain, is the organ that requires most energy to function, and dopaminergic neutrons do in particular. So I’d feel personally it makes sense for me to support my beloved dopaminergic neutrons with thiamin supplements, devoted of known toxicity.
Second, Cure Parkinson’s Trust has funded research for molecules that just had pre-clinical data. In my books, human data, from patients, has more value than animal data, including in observational studies (the type of studies done by Pr Costatini & team). I take the opportunity to say I am very, profoundly grateful to them for the work they’ve done for their patients, because not many did actually help us, am I right or not?
Finally, I don’t know you, but I don’t have time to wait for properly designed R&D. Even successful, this would give us a treatment in 5 years from now in the best case. And I’m being generous. So far, PD is not COVID!
So proper R&D is for the next generation of patients . We need solutions now, yesterday.
It’s been since September I am taking thiamine, and not only my symptoms are better, but I need less L-dopa. And it’s not placebo effect. And although I have thoughts on the reason it requires mega-doses, treating patients doesn’t require to understand the treatment mechanism of action. The fact charities, investors and regulators like to understand how a treatment works is a way for them to manage their respective risks. And mostly, that’s how contemporary drug discovery works. But that’s not how things worked until very recently. Many drugs have been discovered by accident or used without really knowing anything on their mechanism of action except urban legends.
And finally again, I’d like to add that the work Art is doing for us is out of this world, and I have a profound gratitude for it, and respect. Saying it’s long shows lack of expertise as there is no such thing as a short quality scientific nor medical discussion, especially on the management of an as yet untreatable neuro degenerative disease.
So well said and I agree. It’s interesting that there is the expectation that the method of action of the therapy must be fully understood to be valid when the disease it is treating is largely unknown and misunderstood.
If you were familiar with my positions/comments, you would know that I am a staunch defender of taking supplements that do not have an evidenced based mechanism of action
Hahaha! So well spotted Watson! It's because it is about the money they invest. And that's fine. The limit is when there's evidence it works for patients. It's like with mannitol. With mannitol, there are a number of patients sharing it worked for them, and we also know what is the effective dose. That's much more than animal data. It is allowing to jump into a phase IIb clinical trial.
I agree with everything you said except, "Simon doesn’t say that thiamine doesn’t cross the BBB, he says it doesn’t do it by diffusion." "... raising levels of thiamine in the blood does not lead to an increase in thiamine transportation across the blood-brain barrier or to a corresponding increase in brain levels."
Perhaps it should be noted I posed it as a question and I am glad it generated such a robust discussion.
I appreciate every long, thorough reply. I learn from them.
One thing is that I am not going to switch away from taking B1, but instead will l ad benfotiamine and perhaps allithiamine.
Secondly, too often, I feel we read into other's comments intentions that are not there.
To me "raising levels of thiamine in the blood does not lead to an increase in thiamine transportation across the blood-brain barrier or to a corresponding increase in brain levels." is supposed to be a reinforcement of a mechanism different from diffusion. If I may advise, I would stop thiamine before you start another form. No need to take something that doesn't help. Maybe it doesn't help because you didn't get to a dose high enough. But that's fine to try something else.
And apologies if I was read intentions that were not there
All three of them, HCL, Benfo, and Allithiamine? Like you, I have thought about it many times. To me it's like Magnesium, there are different types, and you can find all of them in one capsule. Shouldn't B1 act the same?
Why allithiamina? if you think benfothiamine works because it is lipophilic, … It is not, at least according to this authoritative research that I have already posted above by L Bettendorf of the GIGA institute of Liège and I quote:
“2.2.Metabolism of BFT
BFT is a fairly stable polar compound that cannot diffuse through cell membranes as it is not lipophilic (in contrast to what is claimed in many articles). However, after oral administration, BFT can be rapidly dephosphorylated in the small intestine through the action of alkaline phosphatases (ectoenzymes) bound to brush-borders of epithelial cells (Figure 3) [30]. This yields S-benzoylthiamine (S-BT) which is the lipophilic metabolite of BFT that easily diffuses through cell membranes and crosses the epithelium to reach the blood stream. “
At this point there are conflicting data between Simon and Bettendorf which means that one of the two is wrong.
Either his father and/or him was/are MDs. He mocks everything that is not "medically approved." He'd better keep his mouth shut and think twice before he insults forum members. To be honest with you, I read "jealousy" all over his posts.
What about TTFD form of B1? It is used in Japan and has recently become more accessible here. I posted links about it today.
No. I want to but not sure how to best incorporate it. I need to read up more and would benefit from people wiser than myself researching it.❤️ Novice Newbie Neuro Researcher 😊
Another pointer is the enthusiastic response of those who know Dr C was right, although using the wrong sort of thiamine, and so are looking for another form to substitute for the one that worked so well it proved the theory
Since this thread is discussing picking up Benfotiamine(Ben) as a substitute or alongside thiamine, I think it is worth mentioning something mentioned in this new Ben/AD study which should matter to anyone considering taking Ben :
Here is an important and relevant quote from the study :
>>> ' On the other hand, we found that lysine levels decrease dramatically by more than 10-fold with the intake of BFT for a prolonged time, while in AD, it was found to increase in plasma levels (Table 1) [29,47]. It was also found that lysine level in serum increases with thiamine deficiency, which, in turn, increases stress-induced anxiety level [48]. ' <<<
Why is this important? Previously I did a self test where I used L Arginine in conjunction with N Acetyl Cysteine(NAC) for a specific purpose. While the combination worked quite well for the purpose I was testing it for, I ran into a problem where I started catching colds one after another 4 times in a row. I had never gotten two colds in a row in my life and knew something wasn't right. So I did some reading about Arginine because I knew NAC couldn't cause this issue.
What I found is that Lysine and Arginine should be maintained at a certain ratio. If the Lysine/Arginine ratio get's too low, you can become more susceptible to some viral infections. In my case, I became susceptible to colds, but in others who might have herpes, it could result in increased herpes flare ups. I don't know what other viruses might be attracted to a lowered Lysine/Arginine ratio, but in this day and age of Covid-19, it certainly gives me pause to take something that has shown itself to lower lysine by 10 fold! To further accentuate that point, let's look at another recent study(July 2021) that shows that lysine can attenuate SARS CoV-2 infection in cell culture :
Here is the quote from the study highlighting this point :
>>> ' We showed that lysine and Lys-ester can attenuate SARS-CoV-2 infection in the cell culture system (Figure 2A). Consistent with a previous study, IAV replication was also inhibited by lysine (Figure 4) [20]. Lysine therapy has long been recommended against HSV infection because it can suppress viral replication and inhibit virus yield [23,26,27,28,38]. HSV growth in both cell and tissue cultures that were supplemented with arginine was suppressed upon the addition of lysine [22]. A trial conducted on subjects with recurrent HSV infection also proved the efficacy of lysine treatment against HSV when the lysine group reported less recurrence, shortened healing time, and milder symptoms during six months of taking L-lysine monohydrochloride tablets while avoiding arginine-rich foods. [27]. These are just a few of the studies proving the efficacy of lysine as a prophylactic agent for HSV infection. Considering the prophylactic effects of lysine, a recent observational study was conducted using lysine therapy as prophylaxis for SARS-CoV-2 infection.
Among 30 medical professionals with daily face-to-face exposure to COVID-19 patients, all remain negative of the virus after taking 2000 mg lysine daily with required dietary restrictions (no caffeine, marijuana and arginine-rich foods) for 3 months, as compared to an average of two employees being infected every month prior to the study and to a public health department with similar capacity as their control group [39]. Our study validates that lysine has protective effects against SARS-CoV-2 and IAV infection. Thus, lysine supplementation may be considered as prophylaxis and therapeutic tool against these viruses. ' <<<
So I am not saying you should or should not take Ben, but you should be aware of what the research shows about how it can very significantly lower your lysine levels unless you happen to have AD. This could have significant implications regarding increasing your chances to get certain viruses and I think that is a very important point to consider in order to make an informed decision.
Thank you, Art, for all that you do to help everyone on this forum.
And thank you for rising above and not responding to the ‘inferior sarcasm’ that was directed to you and others by a certain individual!
The following saying comes to mind and is quite relevant...’his sarcastic insinuations are too highly obnoxious to be mentally appreciated by your far superior intellect’.
So what are you saying? Because it won't work on mice it won't work on me! Suck it and see - if it works for you as it does for me jolly good luck. I am a convert and don't need to be told it doesn't work. It does - I sleep better, no more constipation, no trouble swallowing I can smile again and do not appear to be cognitively impaired. It is a great sadness to me that Dr. C had to go and die before his cloud funding page took off.
No where did I say it would not work on you. I published what Simon Stott said in his blog The Science of Parkinson's, but, since you bring up mice, it has been demonstrated thousands of times what does or doesn't work in mice has little relevancy to people.
I am glad it works well for you as it does for many others.
This is an old post but I’ve just come across it!!
A couple of points…
1. Is benfotiamine all they make out that it is?
Before you leap to benfotiamine, can I point to some research I have come across which suggests that benfotiamine might not be the best derivative choice.Dr Derrick Lonsdale, the thiamine expert, on his website ‘Hormones matter’ quotes research by Volvert et al (2008) “Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and different pharmacological profile than lipid-soluble thiamine disulphide derivatives”. I should say at this point that a version of thiamine needs to be lipid-soluble to pass through a cell without the help of a transporter. The conclusion of Volvert et al was “our results show that though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain”.
And then, from the website ‘science news’ comes the accusation that ‘benfotiamine is marketed heavily using a selection of unsubstantiated ‘not-quite-medical’ claims.
The researcher Dr Lucien Bettendorff, a researcher from the University of Liege in Belgium, says “We suspect that those companies selling benfotiamine have poisoned much of the recent literature in an attempt to bestow it with properties that it doesn’t have”. And “Benfotiamine is very often considered a ‘lipid soluble’ thiamine precursor from the disulphide derivative family though it is not either lipid-soluble nor a disulfide”.
2. Does it matter if the thiamine version you are using is lipid soluble or not?
Dr Lonsdale informs us that there is no difference between the thiamines from a biological activity standpoint. This suggests to me that they all have the capacity of producing symptom improvements when the right dosage is found. It’s just that some use a ‘transporter’ - a genetically determined protein’ to gain entry to cells.
3. If you do want to try a lipid-soluble thiamine derivative which doesn’t need a transporter, and passes straight into brain cells, then TTFD (tetrahydrofurfryl disulphide) is apparently the one. But beware, a little goes a very long way. And we have little research published or anecdotal yet on its effect on Parkinson’s or long term usage. We would, however, be grateful if you feel like trialing TTFD, but I’m not sure about benfotiamine.
Of course there is a third derivative available - allithiamine. Mind you that one makes your breath smell of garlic, caused because it uses a disulfide derivative found in garlic.
So your post was two months ago. I wonder if you tried any of the derivatives???
I was kind of hopeful. Hesitantly. I thought by taking magnesium and b complex with it, it would be able to cross the bb line? Whats just frustrating is we are tired of chasing rabbits. Repeating and beating the dead horse yet one more time. If there is a cure we would all know it. So let’s turn the page. Did I see you started to write a post stating your weary as well? Then deleted it? Either way we are all in the same boat, headed to the same place. Everyone with their own uniquely crafted oars. Some took years to create and some took one hour. All of us rowing in different directions gaining nothing but exhaustion. When will we see that the only thing in common is our oars are made of mesh? We need new eyes. A new goal a new prize and a new direction. Check out Imshakeydad’s blog. I will try and find the link
That would be a shame Marc. The post contains a lot of information and interesting discussions. Has there been any significant new insights in the past 2 years that would render this post worthless? So, I'm more curious about an update from you and other participants! 🙏
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