Caffeine And Progression Of Parkinson Disease: A Deleterious Interaction With Creatine

[Zpol]

Just as in the unanimous mechanism for lipofuscin formation, catalytic metals (Fe²⁺, Fe³⁺, Al³⁺) and unsaturated fatty acids are found in both Lewy bodies and neurofibrillary tangles. I think these are formative, and not a 'consequence of prions, βMAA, or genetics.' This would make the same risk factors for all three inclusion bodies: iron, unsaturated fatty acids, homocysteine, and aluminum perhaps being the four most significant.

@Travis thank you so much for explaining this in detail. Your reply has shifted my perspective back to the basics. The squalamine and alpha-synuclein got me off track a bit. I could see my hopefulness for this promising new therapy with squalamine was affecting my judgement but I did't know where else to direct my research. The factors of iron, unsaturated fatty acids, homocysteine, and aluminum are ones I am knowledgeable about and unfortunately I have the blood plasma lab work to verify I have elevated amounts of all except for unsaturated fatty acids (because I wasn't tested for that). These are the things I need to focus on for prevention of neuro-degeneration. I was knowledgable, but certainly didn't know about all the details that you have pointed out, so much appreciated!

'Incubation of purified recombinant human tau protein with aluminum salts at concentrations ≥100 μM induces aggregation of tau that prevents its entry into SDS-polyacrylamide gels and filtration through nylon membranes. This effect is noncovalent and can be reversed by addition of EDTA. However, when incubated along with ATP, GTP, or CTP, aluminum catalyzes a covalent linkage that results in incorporation of the α- and γ-phosphates into the tau protein (phospho-incorporation).' —Abdel-Ghany⁽²⁾

I have read about EDTA chelation in relation to mercury specifically, but not for iron and aluminum. On that note, I've read from member natedawgg (not sure if he's still a member) who has claimed success with cilantro, for iron chelation at least. For me, the aluminum is the especially disturbing one since I have blood plasma lab work indicating it is elevated. My natropath is confident I can reduce this by not consuming anything from a can and not using cookware, body products, etc. that contain aluminum... we shall see.

For the record (and for anyone else who might refer to this thread), I'm using creatine to reduce homocysteine (and continuing with my 2 cups of coffee per day), and Mitolipin to reduce/reverse the damage done by lipid peroxidation. Obviously not eating any overt PUFA in my diet as well. I've been eating relatively low fat in general but perhaps some more fully saturated fats would be helpful.

Besides squalamine, I think the similar pregnenolone could be useful. Coating the microtubule‐associated proteins with fully saturated lipids could stop lipid peroxidation chain reactions, and perhaps even protect phosphates from Al³⁺‐aggregation.

I've tried pregnenalone (topically) and didn't notice any benefits so I quit taking it. I need to get my guts working, fix the migratory motor complex, that's the next major thing. I think if I add in some chelation therapy plus the squalamine, maybe I'll be covered.

 

[Mossy]

I think the best anyone could do is to avoid iron and aluminum while letting the brain detoxify naturally, all the while taking either epicatechin gallate pills (perhaps from Amazon, perhaps from somewhere else) or drinking green tea with boron (to counteract the natural fluoride ions) to prevent the otherwise unavoidable O‐methyldopamine formed through high‐dose levodopa supplementation.

Great info--thanks.

For the boron, are you thinking by supplementing or could raisins be used?

 

[papaya]

Well, green tea should prevent O‐methyldopa from building‐up. This may sound like woo but it's not: the ability of epicatechin gallate to inhibit the enzyme COMT is uncanny—if you look at the enzyme kinetic data (IC₅₀=.07·μM)—and it even works better than the drugs synthetic chemists had designed specifically for that purpose . . . and it's safer: the most popular pharmaceutical COMT inhibitors damage the liver (Entacapone; Tolcapone).

Daniel Perl was the world's leading expert in alumimum in the 1980s, and has either authored or co‐authored hundreds of articles on this dangerous ion (Al³⁺). He makes a good case that Alzheimer's and Parkinson's are essentially the same thing. Both Alzheimer's (neurofibrillary tangle) and Parkinson's (Lewy body) are uniquely characterized by their respective inclusion bodies. They are resistant to proteolysis. Experimentally‐induced Parkinson's—using the drug MPTP to reduce dopamine—is actually reversible within weeks; it takes a more resistant particle to cause a longer problem. Mercury can increase free radicals, oxidation, lipid peroxiation, and inclusion bodies (lipid peroxidation products crosslink proteins). The brain regenerates just like any body part, but breaking down Lewy bodies and neurofibrillary tangles represents a challenge. I think the best approach could be preventing their formation by avoiding iron and aluminum while eating fruit for the citrate content (known to chelate both aluminum and iron). You might think that perhaps eventually some phagocyte—such as a killer T cell—would engulf these particles and break them down. It's been shown that immune cells can cross the blood–brain barrier.

'Paradoxically, despite the presence of abundant activated microglia inthe brain of AD patients,these cells fail to mount a phagocytic response to Aβ deposits but can efficiently phagocytose Aβ fibrils and plaques in vitro.' ―Koenigsknecht​

So I think even in the worst case scenario (crosslinked protein–lipid–aluminum inclusion bodies) the body has a method for dealing with it (phagocytosis). If it can happen in vitro, it should happen in vivo (how could it not?). Iron (Fe²⁺, Fe³⁺) an aluminum (Al³⁺) are the ions which
appear to be the primary cause of Parkinson's and Alzheimer's (Alzheimer's proper, and not just hyperhomocysteinemia given a different name).

Melatonin has been shown to chelate metals, and increases at night when the the interstices relax and cerebospinal fluid perfuses the brain (this co‐incides with the lowered serotonin as the raphe nucleus begins firing at a slower rate; it starts again moments before waking). But melatonin works peripherally, like serotonin, so taking capsules delivers the highest amounts to an organ most sensitive to it (probably second or third most—arteries and the intestines do have serotonin and melatonin receptors). Folate is necessary for creating the methyl group eventually transferred to N‐acetyl‐serotonin (creating melatonin), and low‐light conditions increase the melatonin synthesis rate (light appears to actively suppress this). There can be found sporadic data that fluoride inhibits melatonin synthesis (in rats), the best evidence being a doctoral dissertation from The University of Florida.

I think the best anyone could do is to avoid iron and aluminum while letting the brain detoxify naturally, all the while taking either epicatechin gallate pills (perhaps from Amazon, perhaps from somewhere else) or drinking green tea with boron (to counteract the natural fluoride ions) to prevent the otherwise unavoidable O‐methyldopamine formed through high‐dose levodopa supplementation.

I just had an idea: Perhaps inclusion bodies are in flux; perhaps they are phagocytosed, only to release the metals to start the process all over again. There is simply no way to tell how long they exist for, and the ones viewed on microscope slides represent only one moment in time. If they can be broken down eventually in vitro, then you'd almost have to assume they also would be in vivo. Older people rarely change their dietary habits, and if
it was reversible nobody would really know. Some people are perpetually exposed to high‐aluminum water (introduced as a flocculant in city water supplies), frozen pizza (Al³⁺ both in dough (baking powder), and cheese (Na⁺[Al₃(PO₄)₈]), and iron from the multivitamin they assume is healthy.

Xie, Lulu. "Sleep drives metabolite clearance from the adult brain." science (2013)
Fournier, Isabelle. "Folate deficiency alters melatonin secretion in rats." The Journal of nutrition (2002)
Koenigsknecht, Jessica. "Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism." Journal of Neuroscience (2004)
Perl, Daniel P. "Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?." Annals of neurology (1998).
Chen, Dapeng. "Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure–activity relationship and molecular-modeling studies." Biochemical pharmacology (2005)​

what dose of egcg should i give my mother & how many times a day & should she take them at the same time or seperate from when she takes levodopa? also, how long should she wait to take her levodopa meds after she drinks her morning coffee, or is that only an issue if creatine is involved? thank you so much for your help!!! btw, i read something over thanksgiving that green tea extracts cause liver damage, so that's kinda interesting.

 

[Travis]

what dose of egcg should i give my mother & how many times a day & should she take them at the same time or seperate from when she takes levodopa? also, how long should she wait to take her levodopa meds after she drinks her morning coffee, or is that only an issue if creatine is involved? thank you so much for your help!!! btw, i read something over thanksgiving that green tea extracts cause liver damage, so that's kinda interesting.

Well, I think some Asians drink green tea multiple times per day so it doesn't appear to be that bad. If the green tea was extracted with alcohol or a nonpolar solvent, there would be molecules in there that wouldn't be in brewed tea (all water‐soluble molecules).

Shixian, Q. "Green tea extract thermogenesis-induced weight loss by epigallocatechin gallate inhibition of catechol-O-methyltransferase." Journal of medicinal food (2006)​

Inhibiting COMT also spares adrenaline, since this—along with dopamine—is O‐methylated:

'That catechin-polyphenols are known to be capable of inhibiting catechol-O-methyltransferase (the enzyme that degrades norepinephrine) is a possible explanation for why the green tea extract is effective in stimulating thermogenesis by epigallocatechin gallate to augment and prolong sympathetic stimulation of thermogenesis. Knowledge about thermogenesis-induced weight loss produced by green tea’s epigallocatechin gallate and its ability to inhibit catechol-O-methyltransferase is important for health benefits and for prolonging the action of norepinephrine in the synaptic cleft.' ―Shixian​

Somewhat troubling is that he starts out the article with an short apocryphal paragraph detailing the discovery of tea:

'ACCORDING TO THE CHINESE LEGEND, 4,000 years ago tea was discovered accidentally by the Emperor Shen Nung, as one day he was boiling water when a gust of wind blew leaves in from a tea tree. He was very pleased with the aroma and taste, and shortly after tea was invented.' ―Shixian​

It's always the Emperor who gets credit for everything—and everything.

'Green tea has been widely consumed in China and Japan for many centuries, and hence is regarded as safe. [...] The active constituents are polyphenols, contributing to approximately 30% of green tea [epicatechin (EC), EC gallate (ECG), epigallocatechin (EGC), and EGC gallate (EGCG)]. Although tea leaves contain more.' ―Shixian​

Here it is: Table 2: The effect of catecholamines in humans in response to green tea:

​

It is sparing norepinephrine; but more importantly, it is sparing dopamine. Since epicatechin gallate is a known, selective, and powerful COMT inhibitor you are almost forced to assume this would be accompanied by a concomitant change in O‐methyldopamine of equal and opposite magnitude. For these reasons, COMT inhibitors are sometimes used in Parkinson's treatment—even by conventional medical practitioners: Catechol-O-methyl transferase (COMT) Inhibitors | Parkinson's Disease Clinic and Research Center

But epicatechin gallate is just as powerful, if not more, in in vitro enzyme inhibition studies. It also has a track record of safety in Asia. I think any hesitance in using epicatechin gallate is mostly psychological, or the idea that 'synthetic is more effective.' Pharmacologists often see no fundamental difference between synthetic and natural compounds, and perhaps rightly so, and criticize those who do as falling for the 'naturalistic fallacy;' it is true that all‐natural molecules can be far more dangerous than some novel synthetic ones. However, wouldn't then the idea that 'synthetic is always better' represent a double standard? I think so; all‐natural drugs like aspirin and digitoxin are very effective and there is no fundamental reason to assume that all natural molecules would be less effective. If enough research goes into developing a drug which is less effective than an extant one, it is often marketed regardless.

The idea that 'synthetic is always better' creeps into the psyche from watching television, whose pharmaceutical advertisements and product placements give this impression—perhaps similar to the idea that 'expensive is always better.' These memes just help justify consumerism and the occupations of synthetic chemists.

If I were to inhibit the COMT enzyme, I would take epicatechin gallate pills. It is certainly cheaper, and appears both safer and more effective than they synthetic ones promoted by pharmacists. I think the dosing would depend on the individual, as the increase in norepinephrine would be apparent (allowing one to know when they'd had enough.) Epicatechin gallate is thought to increase metabolism by increasing both norepinephine and dopamine, and would be expected to mitigate Parkinson dyskinesia through the concomitant reduction of their O‐methylated analogues (i.e. the infamous 3‐methoxytyramine a.k.a . O‐methydopamine).

 

[LeeLemonoil]

Caffeine & Creatine - Synergists, not Antagonists!? RCT: "Caffeine Potentiates Effects of Creatine" on Torque (+68%) - SuppVersity: Nutrition and Exercise Science for Everyone

 

[papaya]

Well, I think some Asians drink green tea multiple times per day so it doesn't appear to be that bad. If the green tea was extracted with alcohol or a nonpolar solvent, there would be molecules in there that wouldn't be in brewed tea (all water‐soluble molecules).

Shixian, Q. "Green tea extract thermogenesis-induced weight loss by epigallocatechin gallate inhibition of catechol-O-methyltransferase." Journal of medicinal food (2006)​

Inhibiting COMT also spares adrenaline, since this—along with dopamine—is O‐methylated:

'That catechin-polyphenols are known to be capable of inhibiting catechol-O-methyltransferase (the enzyme that degrades norepinephrine) is a possible explanation for why the green tea extract is effective in stimulating thermogenesis by epigallocatechin gallate to augment and prolong sympathetic stimulation of thermogenesis. Knowledge about thermogenesis-induced weight loss produced by green tea’s epigallocatechin gallate and its ability to inhibit catechol-O-methyltransferase is important for health benefits and for prolonging the action of norepinephrine in the synaptic cleft.' ―Shixian​

Somewhat troubling is that he starts out the article with an short apocryphal paragraph detailing the discovery of tea:

'ACCORDING TO THE CHINESE LEGEND, 4,000 years ago tea was discovered accidentally by the Emperor Shen Nung, as one day he was boiling water when a gust of wind blew leaves in from a tea tree. He was very pleased with the aroma and taste, and shortly after tea was invented.' ―Shixian​

It's always the Emperor who gets credit for everything—and everything.

'Green tea has been widely consumed in China and Japan for many centuries, and hence is regarded as safe. [...] The active constituents are polyphenols, contributing to approximately 30% of green tea [epicatechin (EC), EC gallate (ECG), epigallocatechin (EGC), and EGC gallate (EGCG)]. Although tea leaves contain more.' ―Shixian​

Here it is: Table 2: The effect of catecholamines in humans in response to green tea:

View attachment 7761 ​

It is sparing norepinephrine; but more importantly, it is sparing dopamine. Since epicatechin gallate is a known, selective, and powerful COMT inhibitor you are almost forced to assume this would be accompanied by a concomitant change in O‐methyldopamine of equal and opposite magnitude. For these reasons, COMT inhibitors are sometimes used in Parkinson's treatment—even by conventional medical practitioners: Catechol-O-methyl transferase (COMT) Inhibitors | Parkinson's Disease Clinic and Research Center

But epicatechin gallate is just as powerful, if not more, in in vitro enzyme inhibition studies. It also has a track record of safety in Asia. I think any hesitance in using epicatechin gallate is mostly psychological, or the idea that 'synthetic is more effective.' Pharmacologists often see no fundamental difference between synthetic and natural compounds, and perhaps rightly so, and criticize those who do as falling for the 'naturalistic fallacy;' it is true that all‐natural molecules can be far more dangerous than some novel synthetic ones. However, wouldn't then the idea that 'synthetic is always better' represent a double standard? I think so; all‐natural drugs like aspirin and digitoxin are very effective and there is no fundamental reason to assume that all natural molecules would be less effective. If enough research goes into developing a drug which is less effective than an extant one, it is often marketed regardless.

The idea that 'synthetic is always better' creeps into the psyche from watching television, whose pharmaceutical advertisements and product placements give this impression—perhaps similar to the idea that 'expensive is always better.' These memes just help justify consumerism and the occupations of synthetic chemists.

If I were to inhibit the COMT enzyme, I would take epicatechin gallate pills. It is certainly cheaper, and appears both safer and more effective than they synthetic ones promoted by pharmacists. I think the dosing would depend on the individual, as the increase in norepinephrine would be apparent (allowing one to know when they'd had enough.) Epicatechin gallate is thought to increase metabolism by increasing both norepinephine and dopamine, and would be expected to mitigate Parkinson dyskinesia through the concomitant reduction of their O‐methylated analogues (i.e. the infamous 3‐methoxytyramine a.k.a . O‐methydopamine).

i always prefer natural over synthetic. i only mentioned it because i thought it was interesting that i recently read that green tea extracts also caused liver damage. i didn't look into it further but remembered it because i sometimes take theanine. what would you give your mother as a starting dose/how many times a day? i literally have no clue where to start. can she take it at the same time as depo? can she drink coffee with depo or should that be seperate?

 

[Zpol]

Caffeine & Creatine - Synergists, not Antagonists!? RCT: "Caffeine Potentiates Effects of Creatine" on Torque (+68%) - SuppVersity: Nutrition and Exercise Science for Everyone

Interesting article. One thing to note, is that the creatine supplementation amount was 3 grams across the board which is a moderate dose and definitely not an overdose. The caffeine dose was dependent on the participant's weight and in the caffeine+creatine group it was 6 mg/kg so for an average weight person, lets say a 130lb person, that amounts to about 350mg. 6 mg/kg of caffeine is a moderate amount for most people, that's about 3 cups of coffee for the 130lb person.
I'd say this info fits in well with my theory that the problem comes in when a person starts overdosing, which many people do thinking that 'if something is good, more is better.' Also, my theory that the participants in the OP's study were body builder types who take harmful supplement stacks or people drinking multiple energy drinks per day.

I'm curious about the work fatigue mentioned briefly at the end.

"What did not differ (significantly) between groups was the work fatigue, but a slight reduction in work fatigue was detected for the creatine + caffeine group."​

I guess it was too slight to go into detail, but made me curious.

 

[jb116]

Interesting article. One thing to note, is that the creatine supplementation amount was 3 grams across the board which is a moderate dose and definitely not an overdose. The caffeine dose was dependent on the participant's weight and in the caffeine+creatine group it was 6 mg/kg so for an average weight person, lets say a 130lb person, that amounts to about 350mg. 6 mg/kg of caffeine is a moderate amount for most people, that's about 3 cups of coffee for the 130lb person.
I'd say this info fits in well with my theory that the problem comes in when a person starts overdosing, which many people do thinking that 'if something is good, more is better.' Also, my theory that the participants in the OP's study were body builder types who take harmful supplement stacks or people drinking multiple energy drinks per day.

I'm curious about the work fatigue mentioned briefly at the end.

"What did not differ (significantly) between groups was the work fatigue, but a slight reduction in work fatigue was detected for the creatine + caffeine group."​

I guess it was too slight to go into detail, but made me curious.

I tend to agree with your conclusion as well. If ya think about it, people have issues with large doses of creatine by itself.