Initial dose of Thiamine

Anyone prepared to speculate about why symptoms can temporarily worsen on the initial high dose of Thiamine then improve after the dose is lowered?

Theories welcomed

[Greenday]

Good question! Thiamine exerts cholinergic and Glutamatergic activity and able to increases the levels of acetylcholine, glutamate and GABA in the brain omicsonline.org/open-access... . Acetylcholine & Glutamate are excitatory neurotransmitters; high levels of acetylcholine and glutamate may cause side effects, such as agitations and increased tremors, as reported by some patients. High levels of Glutamate have a toxic effect in the brain ncbi.nlm.nih.gov/pmc/articl....

Therefore the side effects reported on high dosages of Thiamine may be attributed to the increased activity of acetylcholine and Glutamate.

However, the right dose of thiamine may normalize the reduced activity of certain enzymes specifically:

a) The α-ketoglutarate dehydrogenase (αKGDH), a key regulatory diphosphate-dependent enzyme, known for its role in the citric acid cycle, which is involved in brain glucose metabolism. The enzyme αKGDH plays a role in maintaining optimal levels of the neurotransmitters glutamate, and GABA pdfs.semanticscholar.org/d1...

b) The enzyme Acetyl CoA which an important component in the synthesis of the neurotransmitter acetylcholine. sciencedirect.com/science/a...

[Hidden]

Yes and Thiamine is a cofactor but not in itself an agonists or antagonist. My betting is on acetylcholine being enabled by the increased level of Thiamine. Then there’s GABA, which is too low in PD and don’t forget our friend Dopamine

[Greenday in reply to Hidden]

The increase in Acetylcholine as a result of excess thiamine intake may contribute to the manifestation of certain side effects, such as agitation, as reported by some patients, but less likely to cause the severe side effects such as the worsening of PD symptoms and increased dyskinesia. Glutamate, however, is likely to cause such adverse reactions. L-glutamate (L-glu) is the major excitatory neurotransmitter in the brain and is functionally involved in virtually all activities of the nervous system ncbi.nlm.nih.gov/pmc/articl... .

Glutamate is a potential neurotoxin. It is, likely that synergistic interactions between mitochondrial defects, oxidative stress, and glutamatergic stimulation take place at the SNc level. These interactions may create the conditions for the development of the nigrostriatal damage that characterizes PD ncbi.nlm.nih.gov/pubmed/209... & ncbi.nlm.nih.gov/pubmed/243... .

According to some studies, Thiamin deficiency results in the decreased synthesis of glutamate and GABA concomitantly pdfs.semanticscholar.org/d1...

The results from CSF levels of neurotransmitters Glutamate/Glutamine are equivocal in PD patients. Most human studies showed that CSF levels were normal, other studies show as decreased or even high in Parkinson’s patients, especially in patients with levodopa-induced dyskinesia ncbi.nlm.nih.gov/pmc/articl.... GABA is usually decreased, but can be normal or slightly decreased in levodopa-treated patients ncbi.nlm.nih.gov/pmc/articl... . The activity of the enzyme Acetyl-COA, which facilitates the synthesis of Acetylcholine, could be reduced ncbi.nlm.nih.gov/pmc/articl... .

Therefore Glutamate is more likely to cause the severe side effects, such as those reported by patients on excess doses of thiamine. Any increase in glutamate beyond normal levels may accelerate the progression of the disease and exacerbate the disease symptoms. omicsonline.org/open-access...

The increase of Glutamate shows that there may be a fine line between neuroprotection and excitoxicity on high doses of thiamine.

There is also an analogy with Citicoline (CDP-Choline), a natural neuroprotective and neurorepair compound ncbi.nlm.nih.gov/pmc/articl... and exogenous precursor of acetylcholine. Citicoline presents cholinergic activity lpi.oregonstate.edu/mic/oth... (Thiamine as well). Citicoline is able to stimulate Acetylcholine, norepinephrine and Dopamine ncbi.nlm.nih.gov/pubmed/171... , but unlike thiamine, Citicoline does not increase already normal levels of glutamate. Citicoline, mainly acts as a modulator of Glutamate. Citicoline is able to decrease excess levels of glutamate in certain conditions and therefore able to reduce the excitotoxic effect of glutamate ncbi.nlm.nih.gov/pubmed/156... .

Various human studies provide evidence that Citicoline is a safe and effective when administered to PD patients. For example, in one study Citicoline 20 patients received 500-1000mg Intramuscular Injections (IM). Results revealed that symptomatology was improved in 15 of the 20 patients. No side effects were reported even on 2000 IV. ncbi.nlm.nih.gov/m/pubmed/1... . In a double-blind crossover study conducted on 28 Parkinsonian patients comparing 600 mg/d IV citicoline to a placebo showed that citicoline is an effective treatment for these patients by achieving improvements in assessments of bradykinesia, rigidity, and tremor researchgate.net/publicatio... . Another human study with 85 patients on 1,200mg oral Citicoline and half the usual dose of levodopa, concluded that citicoline has levodopa saving effects and could be used to decrease the incidence of side effects and retard the loss of efficacy of levodopa in long-term treatment. researchgate.net/publicatio... . Studies on Citicoline show that no serious side effects have occurred in any series of patients treated with citicoline, which attests to the safety of treatment with citicoline researchgate.net/publicatio....

Citicoline is a choline donor for the synthesis of acetylcholine. The above studies show that acetylcholine may not be the main cause of exacerbated PD symptoms in patients who are on excess thiamine dose, but the excess levels of glutamate could be. ncbi.nlm.nih.gov/pmc/articl... .

Excess levels of thiamine may cause the excitatory glutamate NMDA receptors to become hyperactive and mediate cell death, but these same receptors are critical for neurogenesis and neuronal plasticity. Therefore the aim is to normalize the excess or deficient levels of glutamate in the brain. Dopamine itself may compensate for the increased activity of Glutamate, but is not as effective in patients who don't respond well in levodopa treatment nature.com/articles/cddis20...

Some studies suggest that the benefits of thiamin administration in neurodegenerative diseases may be due to both the coenzyme and non-coenzyme roles of thiamin omicsonline.org/open-access... . L Bettendorff, a pioneer researcher on thiamine studies, suggests a coenzyme-independent effect of thiamine on neurotransmitter release, affecting at least three different neurotransmitters (acetylcholine, dopamine, and noradrenaline) oapublishinglondon.com/arti...

Bottom line, in the whole literature no study exists which establishes the safety profile and efficacy on long-term treatment with oral thiamine administration in Parkinson's patients. Human studies on thiamine in PD were mainly observational and any benefits were reported with IM administration, which is not affected by absorption issues. Any recommendations on oral thiamine use are currently based on anecdotal reports.

[Hidden in reply to Greenday]

I am impressed by your diligent research. It leads to many questions.

The only consolation is that oral thiamine excess is quickly dealt with -hours not weeks as pharmaceuticals tend to be!

[Hidden]

And the cerebellum has a role. Mainly on the motor front

link.springer.com/article/1... check out some of the references as well! Some weird stuff here!

[LAJ12345]

When you say symptoms worsen does this include anxiety? My husband started on 1g per day to start with and got more and more anxious each day until on day 11 he was suicidal! Not sure if it was the B1 or something else. We are almost at the shortest day here in New Zealand so could be low light as we have had bad weather. I don't think anything else has changed.

[Hidden in reply to LAJ12345]

Quite the contrary. The very noticeable effect for me is a sustained calmness. I can deal with frustration and queuing again on 2 to 3 grams per day

[ConnieD in reply to Hidden]

What are the negative effects of too much thiamine? Do people experience only agitation or also additional Parkinson’s symptoms such as increase in rigidity or worse tremor? Important for people to be on the Look out for. Thanks for any info

[Hidden in reply to ConnieD]

Dr . Costantini , generally says that a worsening of existing symptoms is an indication that the dose is too much or has become too much. Look at question and answer number 11 and 18 on the thiamine FAQ page here:

healthunlocked.com/parkinso...

Art

[ConnieD in reply to Hidden]

Thank you Art!!

[Gioc in reply to ConnieD]

Sometimes it seems that the headlights of cars in the evening are blinding me, on the days when I do the injection of b1,

[ConnieD in reply to Gioc]

Thanks Gio good to know! 🌷

[Gioc in reply to ConnieD]

hi Connied

what a pleasure to hear from you. Greetings from Italy for you. Gio

[ConnieD in reply to Gioc]

Thanks Gio ! Always happy to hear from you too!! Hope you are doing well!😊🌷

[Gioc in reply to ConnieD]

The life for us PwPs is always hard you know, but let's try to make it go well with a bit of b1 + ldopa and a lot of solidarity help and understanding from the friends of HU like you and everyone else,

[ConnieD in reply to Gioc]

Well said my friend!🌷😊

[Hidden in reply to ConnieD]

Everyone is different, in my case it was a worsening of bradykinesia and slurred speech but it improved on lower dose

[ConnieD in reply to Hidden]

Thanks retry, I also felt a worsening of bradykinesia during my off periods. So lowered the dose, do you think it’s important to take an entire week off before restarting Lower dose? Also dumb question but the pull test would be during your “on” time right? I’d have different results during off time. Thank you anyone for info!

[Hidden in reply to ConnieD]

Email Dr C with your concerns. I think the pull test should be worst case but if in doubt send him both on and off . How much levodopa are you on?

[andrehypnotic]

I personally would stop the B1 for a few days,and restart on a lower dose 500mg daily for 7 days and then increase the dosage to 1000mg again,

[Gioc]

In my experience with 100mg intramuscular injections twice a week, there has never been a problem of initial dosage, nor problems of overdosing, nor of side effects, only a couple of times a little excitement that ceases practically immediately suspending for once or twice. I understand this variability in response with the pills, but with the injections it is much less present, at least in my case. I am well aware that these injections require a prescription, but not in all countries such as Germany.

Gio

[Despe in reply to Gioc]

Ciao Gio (Hi, right? :))

My US family doctor prescribed B1 injections. Took the prescription to the pharmacist, they didn't have it on stock, so he ordered it from their distribution center. A week later, the pharmacist STILL has not received them. I then asked my alternative doctor to administer it to my husband (the PwPD), said "I don't have it on stock, have to order it." He hasn't received the B1 vials yet either!!! I am not sure if they will ever get them. . .cheap meds don't sell. . .

Since I ran out of US sources, I ordered them on line from a company in Germany. Actually, someone in the forum had the link on one of her comments (thank you whoever you are for providing that link). The funny thing is postage was more expensive than the vials. I bet I will receive these I ordered on line a lot faster than the ones my pharmacist or alt doctor ordered.

[Gioc in reply to Despe]

Ciao Despe

Each country is in its own way, however, if you have a doctor who makes you the recipe keep it tight and keep the recipe, I also had problems at the beginning to find it and there will always be, but with the recipe is easier to find them. The deadline is very long, 1 or 2 years.Gio

[Despe]

Thanks, Gio!

Sono greco e mi diverto a leggere i tuoi commenti!

[Gioc in reply to Despe]

Hi Despe,Thank you.

Ah well we are cousins!

Gio

[Don_oregon_duck]

I am one who found my upper limit of Thiamine. Soon I will be posting my experience and what Dr. Constantini recommended for me. For this thread today, I will tell you that I started off taking 4 g/day of Thiamine, and got my boost of energy about 7 days later. The energy boost was fantastic and lasted until around the 72 nd day. The energy started falling off and my PD symptoms started coming back,

That is what happens when you fill up the capacity your system can use.

I will post more details of my experience under the long thiamine thread. It may be a week from now before I can get it done. I am working on a chart to help explain my experience. Check the follow box on this reply and you will be notified when I post it.

[Hidden in reply to Don_oregon_duck]

How is the chart coming along? I think/hope that you maybe on to something . I am also bouncing around my personal limit of Thiamine and have some theories forming!

[Don_oregon_duck in reply to Hidden]

Retry,

The charts are taking longer than I thought. I believe I have them figured out and hope to post this weekend.

[Annieartist in reply to Don_oregon_duck]

Interested to know about chart when ready

[KERRINGTON in reply to Don_oregon_duck]

Hi, were you able to figure out your best thiamine dose ?

[Don_oregon_duck in reply to KERRINGTON]

Yes, Kerrington I did. It is 21/2 grams. What I can tell you after one year, the B-1 gave me so much more energy add loss of use of much of muscle my severely deformed back took over my life. The added pain used up my energy reserves so much that my Parkinson's symptoms are steady increasing. I will not stop taking B-1. It has made such a positive difference.

[KERRINGTON]

Wow, that is incredible, and very encouraging. It doesn't seem to give me energy, but it helps with my balance, and rigidity issues. How many years have you had PD ? I'm going on 13 ish.