11 replies to this topic

[Phreak]

Hmmm, so I've read about all the nasty - and likely - side effects of L-DOPA (Levodopa), and have found that it is almost 100% to do with the fact that the L-DOPA is metabolised before it reaches the brain or CNS, and so excess dopamine is left floating around in your peripherals, causing things like nausea, confusion, dyskinesia etc... ie. pretty bad stuff.

This is why Sinemet (the prescription medicine for those with Parkinson's Disease) contains a mixture of Levodopa and Carbidopa. The Carbidopa is a DOPA-Decarboxylase and cannot cross the blood brain barrier, so it inhibits only peripheral enzymes that metabolize the primary drug (Levodopa), thus preventing the conversion of L-DOPA to dopamine peripherally. This reduces the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and dopamine in the brain.

On the bottle of L-DOPA 250mg that I have it highly recommends that I take it with Green Tea. It just so happens that I have a bottle of 90 x Green Tea Extract (500mg) caps that pretty much remain unused as I have no real need for them. However, I would really like to know if the green tea acts in a similar way to a decarboxylase, or has some sort of antioxidant properties which will minimize the risks associated with L-DOPA...?

Ah, I just read this:

The traditional way to do this [take a dopamine precursor] is to administer the L-dopa along with a peripheral DDC (dopamine decarboxylase) inhibitor such as carbidopa as well as with a COMT (Catechol-O-methyl transferase) inhibitor. I have read that green tea extract can act as a natural COMT inhibitor...

So that is quite interesting; I'll definitely be taking Green Tea along with my L-DOPA (that is, if I ever do decide to try it).
Does anyone have any articles which back up the fact that standardized green tea extract can act as a COMT, and at what dose?

Also, more interestingly, does anyone know of any naturally occurring (or synthetic but still "available") DDC's? If so, then surely this would greatly minimize the negative adverse effects with taking L-DOPA supplements making it much safer to take for it's positive ones....

Any research anyone finds I'll be most interested in

[Phreak]

No one? Surely some people on these boards take L-DOPA supplements and I know most people here do their research thoroughly beforehand... (they wouldn't be here if they didn't!)

[dopamine]

Hmmm, so I've read about all the nasty - and likely - side effects of L-DOPA (Levodopa), and have found that it is almost 100% to do with the fact that the L-DOPA is metabolised before it reaches the brain or CNS, and so excess dopamine is left floating around in your peripherals, causing things like nausea, confusion, dyskinesia etc... ie. pretty bad stuff.

This is why Sinemet (the prescription medicine for those with Parkinson's Disease) contains a mixture of Levodopa and Carbidopa. The Carbidopa is a DOPA-Decarboxylase and cannot cross the blood brain barrier, so it inhibits only peripheral enzymes that metabolize the primary drug (Levodopa), thus preventing the conversion of L-DOPA to dopamine peripherally. This reduces the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and dopamine in the brain.

On the bottle of L-DOPA 250mg that I have it highly recommends that I take it with Green Tea. It just so happens that I have a bottle of 90 x Green Tea Extract (500mg) caps that pretty much remain unused as I have no real need for them. However, I would really like to know if the green tea acts in a similar way to a decarboxylase, or has some sort of antioxidant properties which will minimize the risks associated with L-DOPA...?

So that is quite interesting; I'll definitely be taking Green Tea along with my L-DOPA (that is, if I ever do decide to try it).
Does anyone have any articles which back up the fact that standardized green tea extract can act as a COMT, and at what dose?

Also, more interestingly, does anyone know of any naturally occurring (or synthetic but still "available") DDC's? If so, then surely this would greatly minimize the negative adverse effects with taking L-DOPA supplements making it much safer to take for it's positive ones....

Any research anyone finds I'll be most interested in smile.gif

I'll field this question if you like, though I may sound a bit repetitive from the last L-Dopa thread. Green Tea catechins have shown some inhibitory activity for COMT in human liver tissue, though there are currently only about 4 studies confirming this observation. The dose used in the studies is measured in microM concentration rather than a mg/kg ratio, so extrapolating an actual dose to reproduce the specific effect may prove difficult.

Biochem Pharmacol. 2005 May 15;69(10):1523-31.

Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies.

Chen D, Wang CY, Lambert JD, Ai N, Welsh WJ, Yang CS.

Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.

(-)-Epigallocatechin-3-gallate (EGCG) is the major polyphenol present in green tea. We previously demonstrated that EGCG was both a substrate and potent inhibitor of human liver cytosolic catechol-O-methyltransferease (COMT). We now report the structure-activity relationship for the inhibition of COMT-catalyzed O-methylation of catecholestrogens in human liver cytosol by tea catechins and some of their metabolites. The most potent inhibitors were catechins with a galloyl-type D-ring, including EGCG (IC(50)=0.07 microM), 4''-O-methyl-EGCG (IC(50)=0.10 microM), 4',4''-di-O-methyl-EGCG (4',4''-DiMeEGCG) (IC(50)=0.15 microM), and (-)-epicatechin-3-gallate (ECG) (IC(50)=0.20 microM). Catechins without the D-ring showed two to three orders of magnitude less inhibitory potency. Enzyme kinetic analyses revealed that EGCG behaved as a mixed inhibitor, whereas 4',4''-di-O-methyl-EGCG exhibited competitive kinetics for the S-adenosylmethionine (SAM), and noncompetitive kinetics for the catechol binding site. These compounds may represent a new type of COMT inhibitor. In silico molecular-modeling studies using a homology model of human COMT were conducted to aid in the understanding the catalytic and inhibitory mechanisms. Either D-ring or B-ring of EGCG could be accommodated to the substrate binding pocket of human COMT. However, the close proximity (2.6A) of 4''-OH to the critical residue Lys144, the higher acidity of the hydroxyl groups of the D-ring, and the hydrophobic interactions between the D-ring and residues in the binding pocket greatly facilitated the interaction of the D-ring with the enzyme, and resulted in increased inhibitory potency. These results provide mechanistic insight into the inhibition of COMT by commonly consumed tea catechins.

PMID: 15857617.

COMT is, however, a relatively minor metabolizing enzyme for L-Dopa as opposed to aromatic acid decarboxylase (AADC). A two-pronged pharmaceutical approach has been developed in which entacapone (a COMT inhibitor) and carbidopa are combined with L-Dopa to increase brain L-Dopa levels in Parkinson's Disease patients. Only inhibiting COMT, however, will likely have minimal effects on L-Dopa metabolism. Toxicity is associated with 0-100% bioavailabilility, and the extent of absorption into the brain dose not foreclose the well-documented negative effects both in the brain and extraneuronal cell lines. In other words, increasing absorption will not necessarily decrease toxicity, but will rather transition those effects to other areas of the body (including the brain).

[PiMZ]

this appears to be a relevant study:

Green tea polyphenols: novel irreversible inhibitors of dopa decarboxylase.

Bertoldi M, Gonsalvi M, Voltattorni CB. Dipartimento di Scienze Neurologiche e della Visione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Verona, Strada Le Grazie, 8, Verona, 37134, Italy.

The green tea gallocatechins, (-)-epigallocatechin-3-O-gallate (EGCG), and (-)-epigallocatechin (EGC) were found to be inhibitors of Dopa decarboxylase (DDC). EGCG and EGC inactivate the enzyme in both a time- and concentration-dependent manner and exhibit saturation of the rate of inactivation at high concentrations, with efficiency of inactivation values (k(inact)/K(i)) of 868 and 1511 M(-1) min(-1), respectively. In contrast, gallic acid behaves as a weak inhibitor of DDC. Protection against inactivation by EGCG and EGC was observed in the presence of the active site-directed inhibitor D-Dopa. Either EGCG or EGC induce changes in the absorbance and CD bands of the visible spectrum of enzyme-bound PLP. Taken together, these findings indicate the active site nature of the interaction of DDC with both polyphenols. On the basis of the properties of the EGCG-inactivated enzyme, it can be suggested that inactivation could be ascribed to a covalent modification of not yet identified residue(s) of the active site of DDC. Copyright 2001 Academic Press.

COMT is, however, a relatively minor metabolizing enzyme for L-Dopa as opposed to aromatic acid decarboxylase (AADC). A two-pronged pharmaceutical approach has been developed in which entacapone (a COMT inhibitor) and carbidopa are combined with L-Dopa to increase brain L-Dopa levels in Parkinson's Disease patients. Only inhibiting COMT, however, will likely have minimal effects on L-Dopa metabolism. Toxicity is associated with 0-100% bioavailabilility, and the extent of absorption into the brain dose not foreclose the well-documented negative effects both in the brain and extraneuronal cell lines. In other words, increasing absorption will not necessarily decrease toxicity, but will rather transition those effects to other areas of the body (including the brain).

[yowza]

There's some good info. at wikipedia that lists some of the compounds that are commonly taken with L-dopa along with a good diagram of synthisis pathways. This isn't a scientific source but is good for some basic info. http://en.wikipedia.org/wiki/L-dopa


Anyway, I'm kind of wondering what's traded off at the expense of using a DDC vs. COMT vs. MAOB inhibitor?

This could help in terms of whether any of these routes is safe to go with.

Edited by yowza, 26 April 2009 - 07:06 AM.

[yowza]

I'll try and answer the COMT part to the best of my ability (even though the DDC enzyme seems to inhibit dopamine to a greater extent than the COMT, I've read about the COMT before so I'll give it a try):

The COMT enzyme's role in the liver is to transfer a methyl group (supplied from methyl donors) to a catecholamine (dopamine, norepinephirine, or epinephirine), which methylates the catacholamine thus inactivating it.

Methylation=rate at which various enzymes, (in this case COMT) transfers a methyl group to something (for COMT this would be catecholamines) to deactivate it as explained above

The COMT enzyme (controlled by the COMT gene) is what's said to control the rate at which our body methylates. This is what's said to control the high vs. low methylation (which I'm sure many of you have seen in other threads).

Slow COMT:
If your COMT gene is slowed down either due to a genetic polymorphism or a COMT inhibitor, then you could possibly have below normal levels of methylation (due to the COMT gene only partially inactivating the catecholamines at a below normal rate).

From a genetic standpoint (if you have a polymorphism in the COMT that slows down the rate at which it works), for lowered levels of methylation, you might not need to take as much dopamine (since the COMT enzyme isn't breaking it down too fast) but would need to limit the amount of methyl donors (methyl B12, SAMe, or any other supplement that contains a methyl group in it). This is to prevent a buildup of unused methyl groups backed up behind the slow moving COMT enzyme cause if too many methyl groups are taken, this would only further exacerbate the already high catecholamine levels (however, this of course is a generalised assumption and sometimes things simply can't go according to plan; for more information on this I'd google to find out supplements that can be used to support "high methylation vs. low methylation").

However, if the COMT enzyme is purposefully slowed down (using an inhibitor to treat something like PArkinsons), then you'd probably want to ignore the common sense advice above since your dopamine levels are low even when the COMT enzyme isn't working that fast.

Therefore, low amounts of the COMT enzyme (from an inhibitor) would result in higher amounts of catecholamines since they're not being methylated (to be deactivated) and possibly (maybe not always) correlate to lower than methylation/high histamine (histadelia).

High COMT Activity:
This is getting away from the topic (of COMT inhibition) so I'll make this short just to compare with what's said above (for lower COMT activity).
This is associated with higher a higher rate of methylation (only a problem if above normal levels), lower catacholamine levels (due to the COMT enzyme methylating these at a greater rate); if methylation (the transfer of methyl groups) is abnormally high histapenia (high histamine) is common

Conclusion:
All in all, I'm not sure if slowing down the COMT enzyme using an inhibitor would be a very great idea since methylation is tied to so many key biochemical processes (just search "methylation" and look under images and you'll see what I mean) that it just doesn't seem smart to purposefully downshift the COMT gene since this is a key mediator behind methylation. If methylation is slowed down this can cause all sorts of issues that would require a couple more long ass posts!

I suppose someone could look up "low methylation" support and get on a nutritional program while intentionally downregulating their COMT but this sounds kind of dumb unless the person is older and has a chronic condition like Parkinsons. For Attentional/motivational issues, there may be better routes depending on how bad it is.

Other Options?:
Now all that's needed is for someone to report on DDC inhibition...

1) If this has too much crap associated with it as well then either low levels of L-dopa alone (to avoid potential issues) or possibly with a light+natural COMT/DDC inhibitor (like Green Tea or EGCG) may not cause extreme problems...

2) The other option seems to be to forego the above stuff all together and simply go with an MAOB like Deprenyl too. This is a totally different route and gets away from the topic heading but I'm kind of wondering how this route compares in terms of safety/efficacy?

Edited by yowza, 26 April 2009 - 07:33 AM.

[Phreak]

*** lots of very interesting and helpful information but would clutter the page if I were to quote the entire thing... ***

Other Options?:
Now all that's needed is for someone to report on DDC inhibition...

1) If this has too much crap associated with it as well then either low levels of L-dopa alone (to avoid potential issues) or possibly with a light+natural COMT/DDC inhibitor (like Green Tea or EGCG) may not cause extreme problems...

2) The other option seems to be to forego the above stuff all together and simply go with an MAOB like Deprenyl too. This is a totally different route and gets away from the topic heading but I'm kind of wondering how this route compares in terms of safety/efficacy?

I will let you know today
I used to take L-DOPA + Green Tea Extract along with my Nootropic stack. I stopped both about 2 weeks ago and today I am going to substitute that combo with a simple 2.5mg of Selegiline HCl (Deprenyl).

[noorderheks]

I will let you know today
I used to take L-DOPA + Green Tea Extract along with my Nootropic
stack. I stopped both about 2 weeks ago and today I am going to
substitute that combo with a simple 2.5mg of Selegiline HCl (Deprenyl).

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[russianBEAR]

Wait, let me get this straight, you're thinkin about taking supplements with LEVODOPA!??!?!?!?!?!

Now I don't know if you're prescribed this for Parkinson's but if you're not (even if you are), you might want to drop that idea immediately.

Are you kidding me? This stuff has ridiculous side effects (your urine turning red is just a minor annoyance compared to the big hitters, like messing up all kinds of blood levels of everything) and is meant to be taken by senior citizens to prevent "dopamine deterioration" when they're near the end of their life cycle.

No way should anyone else take this extremely strong pharamaceutical.



Or are you guys talking about something else, because that just seems soooooo outlandish to me.

[jasonshadow]

Wait, let me get this straight, you're thinkin about taking supplements with LEVODOPA!??!?!?!?!?!

Now I don't know if you're prescribed this for Parkinson's but if you're not (even if you are), you might want to drop that idea immediately.

Are you kidding me? This stuff has ridiculous side effects (your urine turning red is just a minor annoyance compared to the big hitters, like messing up all kinds of blood levels of everything) and is meant to be taken by senior citizens to prevent "dopamine deterioration" when they're near the end of their life cycle.

No way should anyone else take this extremely strong pharamaceutical.


Or are you guys talking about something else, because that just seems soooooo outlandish to me.

What about Mucuna Pruriens?

[russianBEAR]

What about Mucuna Pruriens?

Not really very familiar with the velvet bean, but from what I know cocoa leaves look like a good analogy. Some cocoa leaf tea? Pretty good, even better than green tea some say. Cocaine made out of these leaves ? Pretty bad  


I couldn't be bothered translating the instruction manual to Levodopa but here's a list of side effects from wikipedia (it doesn't seem to mention all the very hardcore side effects though)

Possible adverse drug reactions include:
Hypotension, especially if the dosage is too high
Arrhythmias, although these are uncommon
Nausea, which is often reduced by taking the drug with food, although protein interferes with drug absorption
Gastrointestinal bleeding
Disturbed respiration, which is not always harmful, and can actually benefit patients with upper airway obstruction
Hair loss
Confusion
Extreme emotional states, particularly anxiety, but also excessive libido
Vivid dreams and/or fragmented sleep
Visual and possibly auditory hallucinations
Effects on learning; there is some evidence that it improves working memory, while impairing other complex functions
Sleepiness and sleep attacks
A condition similar to amphetamine psychosis.

Although there are many adverse effects associated with levodopa, particularly psychiatric ones, it has fewer than other anti-Parkinson's drugs, including anticholinergics, amantadine, and dopamine agonists.

More serious are the effects of chronic levodopa administration, which include:
End-of-dose deterioration of function
On/off oscillations
Freezing during movement
Dose failure (drug resistance)
Dyskinesia at peak dose.
Recent studies have demonstrated that use of L-dopa without simultaneously giving proper levels of serotonin percursors depletes serotonin.
The long term use of L-Dopa in Parkinson's disease has been linked to the so called dopamine dysregulation syndrome.[2]

Clinicians will try to avoid these by limiting levodopa dosages as far as possible until absolutely necessary.



Look at that last line. That right there tells me everything I need to know about me not touching this hopefully ever



EDIT: here's some more


 Though the drug is generally safe in humans, some researchers have reported an increase in cytotoxicity markers in rat pheochromocytoma PC12 cell lines treated with levodopa.[4] Other authors have attributed the observed toxic effects of levodopa in neural dopamine cell lines to enhanced formation of quinones through increased auto-oxidation and subsequent cell death in mesencephalic cell cultures.[5][6] Though levodopa is generally considered safe, some controversy surrounds use of the drug in Parkinson's Disease given some data indicating a deleterious effect on intracellular and neuronal tissue involved in the pathogenesis of the disease.[7]

Edited by russianBEAR, 11 July 2009 - 09:18 AM.

[madanthony]

Hmmm, so I've read about all the nasty - and likely - side effects of L-DOPA (Levodopa), and have found that it is almost 100% to do with the fact that the L-DOPA is metabolised before it reaches the brain or CNS, and so excess dopamine is left floating around in your peripherals, causing things like nausea, confusion, dyskinesia etc... ie. pretty bad stuff.

This is why Sinemet (the prescription medicine for those with Parkinson's Disease) contains a mixture of Levodopa and Carbidopa. The Carbidopa is a DOPA-Decarboxylase and cannot cross the blood brain barrier, so it inhibits only peripheral enzymes that metabolize the primary drug (Levodopa), thus preventing the conversion of L-DOPA to dopamine peripherally. This reduces the side effects caused by dopamine on the periphery, as well as increasing the concentration of L-DOPA and dopamine in the brain.

On the bottle of L-DOPA 250mg that I have it highly recommends that I take it with Green Tea. It just so happens that I have a bottle of 90 x Green Tea Extract (500mg) caps that pretty much remain unused as I have no real need for them. However, I would really like to know if the green tea acts in a similar way to a decarboxylase, or has some sort of antioxidant properties which will minimize the risks associated with L-DOPA...?

Ah, I just read this:

The traditional way to do this [take a dopamine precursor] is to administer the L-dopa along with a peripheral DDC (dopamine decarboxylase) inhibitor such as carbidopa as well as with a COMT (Catechol-O-methyl transferase) inhibitor. I have read that green tea extract can act as a natural COMT inhibitor...

So that is quite interesting; I'll definitely be taking Green Tea along with my L-DOPA (that is, if I ever do decide to try it).
Does anyone have any articles which back up the fact that standardized green tea extract can act as a COMT, and at what dose?

Also, more interestingly, does anyone know of any naturally occurring (or synthetic but still "available") DDC's? If so, then surely this would greatly minimize the negative adverse effects with taking L-DOPA supplements making it much safer to take for it's positive ones....

Any research anyone finds I'll be most interested in

Hi, I'm sorry I didn't catch what a DDC is, but if you are asking for a naturally occurring COMT inhibitor, I just ran across one. It is rhodiola rosea. Check this link:
www.salugen.com/assets/documents/COMT Med Hyp Publication.pdf

I think you can find out more by searching for Synaptamine, which uses it for curbing cravings, or by searching for COMT genotype (for instance the COMT +/+ genotype Val158Met is a natural COMT inhibitor). Um, you want a COMT INHIBITOR to increase dopamine.