This is my second paper on the subject of Cytochrome P450 enzymes in Parkinson's disease and represents a significant update on the first draft, following considerable research on recent published data and a refinement of the arguments and conclusions. It lays out where we are on the understanding of the metabolism of L-Dopa, the areas that need clarification and the problems related to the development of synthetic CYP 450 inhibitors due to the risk of serious drug-drug interactions. A controversial solution may lie in the use of a the very effective, natural CYP 450 inhibitors in grapefruit juice.
It is a long and detailed paper on a complex and, as you will find out, a controversial subject. I have tried to make it as understandable as possible, so please try to read it right through to the end. Print it out to be able to read it several times if necessary.
If you have questions, please ask me and I'll try to explain what you don't understand.
You can distribute this to anyone you wish. even your neuro if he/she is open to discussion. I am looking for critical comments from anyone who knows the field.
Thank you for this. Indeed, we under estimate the risks herbal supplements pose. I read S. Waminolruk, too (which, itself, is also an important read) hoping for long list supplements, but he/she only addressed Echinacea, Ginkgo biloba, garlic, St. John's wort, goldenseal, and milk thistle. As you know, many of us take a dozen or more of herbal supplements and concoctions such as apple cider vinegar. After reading these 2 pieces and looking at the list supplements I take, I feel like it's hopeless for me to ever sort out possible DDI's. And, as you know, because of our age, many of us also take a number of pharmaceuticals. I, for one, take a chemo drug (nilotinib) extensively metabolized by 3A4. I hope I don't kill myself -- which I am surprised, sometimes, I have not already done.
Yep, DDIs are a big unkown for most people, but I take the view that big pharma $$$ are to blame for pushing bad drugs that are too sensitive to CYPs. There are alternatives. The best ref for this is Bailey. It's quite strange that the two papers by Wanwimolruk dont mention Grapefruit. There are several chapters just on GJ in the Book on Enzyme Inhibition edited by Lu & Li. It's a black hole for pharma. They're scared stiff of CYP3A4.
For those not in the know (which included me until a minute ago), here are Wanwimolruk's two articles on "Cytochrome P450 enzyme mediated herbal drug interactions". They are from 2014.
When I first came across the Book by Lu and Li, I was întrigued by the title . Enzyme Inhibition : the good and the bad. It was the bad that I wanted to know about. It's a real goldmine. Got it second hand for $60.
So, I do have one question now (and perhaps more as I re-read your paper) which I referenced last time you posted and that is there is no way for us to know or figure out if we are a poor, moderate, or rapid metabolizer, is there? What is involved in our being screened? Expensive? Complex?
Great information, just skimmed through it and will read in detail later. I have 1 homozygous and 1 heterozygous variant of CYP3A4 (out of 10 on my report) and 1 homozygous CYP1A2 (out of 5 on the report). Just wonder if this puts me into "Poor Metabolizers, Intermediate Metabolizers, or Ultra Rapid Metabolizers"?
Thanks Albert, very illuminating and useful. I've been looking for this since I started using ldopa. When the information is aligned so well as you did a lot of facts are explained a lot of confusion goes away from the mind. A good researcher knows how to evaluate information by relating it to the purposes of life. In this case improve PD medications. To do this need a lot of intention, attention and a lot of intuition: you have these qualities. People like you make a difference and I'm happy to find you, but also many others here on HU. I'm not exaggerating. ok? Now all that remains is to put hard testing on this data as I am already doing. A question: taking ldopa and CJ at the same time can further increase its bio availability, because it would seem so?
This paper is the result of hundreds of hours of research and head scratching. Although there are still areas that need to be clarified, I'm personally convinced that Grapefruit protects L-Dopa from metabolism be CYP3A4, initially in the gut and with continued use in the liver. This is not yet proven, so I don't confirm it in the paper, but the indirect evidence is appealing. The latter, inhibition in the liver, if correct, will significantly increase the half-life and therefore the ON periods. There will be no rush by pharma companies to confirm this as it will cost them $$$. They might try to dissuade PWP and Med professionnels by pointing out the dangers of drug- drug interactions (DDIs) but that would point the finger at bad drugs. My feeling is that they will ignore it. I'm pleased that some forumers here have picked up on DDIs, as it is important, but bear in mind that that's not the fault of GJ, which is a drug protector. If you're taking a bad drug, change it. There are alternatives. See reference : Bailey listed above thanks to ElliotGreen.
I’m not sure if anyone has seen this.... not Parkinson’s specific but very interesting that someone from the medical profession is finally speaking out.
To answer your question, I get the best results with a glass of GJ first thing in the morning to give it time to work. That's when I also take my Thiamine. I take L-Dopa ( mucuna) 30 mins later together with a Green tea extract pill. In the afternoon I take a smaller dose of mucuna with half a glass of GJ and in the evening just a small dose of mucuna. Always away from meals. I have had a big improvement especially with tremor over a period of 6 weeks.
Great stuff Albert! It certainly answers a lot of questions for me. Am I to understand you only take the green tea extract one time in the morning for the day? And your last dose of mucuna for the day do you use more grapefruit juice? Thanks! - Steven
I used to take up to 4 green teal extract capsules per day. The label says max 3. I now take one or 2 in the morning and drink real green tea in the day. I dont take grapefruit after 3pm. Too much vit C can be bad for sleeping.
This is a scientific papar on a controversial subject, so has to have sufficient scientific justification to prove various points which makes it long and complicated. Let me simplfy, which also means being less precise.
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- only a very small amount of L-Dopa gets into the blood.
- It is quickly degraded by several enzymes even when the two main known ones, DDC and COMT are blocked, so I strongly suspect that there is a third one that becomes dominant when the other two are blocked. We can forget MAOB and Tyrosinease at this stage.
- The most potent enzymes that degrade nearly all drugs are the Cytochrome P450 type, CYP3A4 is the most active in the gut (70%) and the liver (30%). % relates to % of total CYP enzymes in each place, but the liver has 100 times more CYP3A4 than the gut.
- There is no direct experimental proof that CYP3A4 degades L-Dopa, but plenty of indirect evidence (more than I cite in the paper).
- This lack of direct evidence means that this is just a hypothesis.
- Why has this not been examined ? It surely has by big pharma, but not published because it could lead to demands for CYP3A4 inhibitors.
- Big pharma will never propose CYP3A4 inhibitors since they would cause serious problems for patients using certain other drugs which means they would not be approved. There is a list of these CYP3A4- sensitive drugs in the reference by Bailey.
- One glass of Grapefruit juice is proven to totally inhibit CYP3A4 in the gut (this increases the quantity of a drug that gets into the blood).
- Drinking one glass every day lowers the amount of CYP3A4 in the liver (this slows the rate at which drugs are cleared from the blood).
- When CYP3A4 is inhibited (destroyed) it takes more than 24 hours (up to 3 days) to be renewed, so daily doses cause a cumulative effect in the liver.
- if you are taking C/L, the DDC enzyme is already inhibited. If you are taking Mucuna and not C/L, green tea is said to partially inhibit DDC but not so well as the C in C/L. Too much green tea can be toxic to the liver.
Mate, I seriously thank you. I do not understand 100% of what you are saying but the 80% that I do understand is so logical. I immediately charged uptown to buy grapefruit juice but in country Queensland nothing is assured and there wasn't any. (Sunday afternoon with a local grocery store open. Shall try the big ones tomorrow. Most places here close 1pm Saturday.) Thank you so much.
I make a tea in the morning with MP, Dandelion root, and green tea, and I usually have my thiamine etc with a glass of water. Am now going to take thiamine etc with grapefruit juice and half hour later have my M, green tea, and dandelion root. Breakfast smoothie half hour later. So excited with your post. Shall see how it goes in my body. Please accept a genuine thank you.
Please be sure to check that you are not taking other drugs that could seriously interact with Grapefruit. Look up the list in the ref by Bailey. These interactions could be dangerous. THIS IS IMPORTANT !
Thanks for your concern. I am not on any drugs but I take supplements like mushrooms for immune health, fish oil, ashwaganda and rhodiola. All natural products. Medical mob in country Queensland have no solution to Parkinson's so I'm not interested in their drugs.
Hi wriga. What dosage of MP do you recommend? I get it in powder form and put a rounded dessert spoon in my breakfast smoothie. I bought a couple of bottles of grapefruit juice this morning and at lunch I put a level dessert spoon of MP into the grapefruit juice and blended it with some frozen raspberries.
I don't recommend mixing MP with with Grapefruit juice. We want the active agents in GJ to inhibit CYP3A4 before L-Dopa reaches the gut. Thats why i suggest taking GJ half an hour before MP.
Hi Munchy. I buy my MP from Ayur Organics in Melbourne and it comes in powder form. I usually put about a rounded dessert spoon in my smoothie. Shall check with wriga for the correct amount.
I take 6 Solbia or Biovea Capsules per day, prefer Solbia, both dosed at 100mg L-Dopa, That's maybe lot compared to some C/L doses, since Carbidopa does a good job to inhibit the DDC enzyme. So far I'm not taking that, and green tea is less effective than Carbi. I had been up to 15 caps without much improvement and having nausea before grapefruit juice. No nausea with GJ.
Very interesting! Wondering if you always took your pills away from meals or if you just started doing so when you added the grapefruit juice?
I ask because I’ve noticed that taking my Sinemet near meals always seems to inhibit absorption and I end up having to take the next dose at 3 or 3 and a half hours instead of four.
wriga, would it be ok to take other pills with Gj and B1 on rising? Particularly L-theanine, vinpocetine,folic acid, lithium orotate, CoQ10 and fish oil, CDP. I'm just trying to combine your protocol with Dr Laurie Mischley.
I plan on taking MP with beetroot (oxygenation) 30 mins later then having a cup of green tea and dandelion tea.
Round an hour after the GJ my breakfast smoothie of blueberries, beetroot juice, grape juice, and eggs.
As I've said many times, don't take advice from people who aren't medical professionals and that includes me. I'm not a consultant so I'm not able to give an opinion on specific meds that you take. That would be irresponsible of me. It's up to you to do your own research AND to discuss it with your Dr and/or pharmacist. GJ can be very useful, but it can also be dangerous. Read the research I've done AND especially the references on drug interactions to understand the importance of the issue. If in doubt, don't mix !!! It's that simple.
As the most important of these paths are inhibited the relative power of the remaining ones increase. So, an inhibitor that initially seemed insignificant becomes an important target once the more powerful paths have been addressed.
See also Simon Stott's article on the role of the gut in the metabolism of levodopa.
It seems to me that the outcome that has the major therapeutic effect of inhibition is that it should increase the effective half life of levodopa. Thus, reducing the up and down nature of levodopa plasma levels.
You may wish to cross-post this discussion on Neurotalk/Parkinsons, where it is easier to follow a technical thread over years.
Thanks for that reference John. Kaakkola suggests that the short half life may be because the COMT inhibition is not effective enough, but I prefer the cascade theory where a low affinity enzyme becomes dominant when the higher affinity enzymes are inhibited. I'm already in contact with Simon. I'll send him this when I've received your comments.
Hi wriga. I must admit I got a bit lost on yr paper but I’m very interested in what you say. My husband has no improvement with leva dopa. He has the rigidity type and apparently it is common if you have no tremor to not get any help from leva dopa. So do you think that a glass of grapefruit juice might possibly help? Do you know if grapefruit interacts with azikect pls ?? Thanks so much for yr fascinating article.
Azilect (rasagiline) is metabolised by CYP 1A2, which is also inhibited by GJ, so with GJ more will get to the brain. However since rasagiline totally inhibits the MAO-B enzyme for up to 24 hrs, more wil not have much effect.
Your husband may be an ultra fast metaboliser (very active CYP3A4 ), in which case GJ could have a big effect on CYP3A4 and improve the effect of L-dopa if taken regularly.
Seeing as the azilect doesn’t make any difference to him anyway, is it worth do you think just stopping taking that but then drinking some grapefruit juice which might help with madopar working?
I would suggest just to start on 1 glass of Grapefruit juice in the morning. The effect of GJ will build up over time. I got a noticeable result after a couple of days, but the best results after 6 weeks. Keep all the other meds the same. Azilect will only work when more dopamine gets to the brain. It helps to conserve it so the GJ may help that too.
For green tea try two caps in the morning (2 x 250 mg), then 1 at lunch and 1 evening.
There are two different mechanisms. The Gj will help protect the levodopa in madopar from being degraded by CYP3A4. That should get more levodopa to the brain where it's converted to dopamine. Azilect will help to protect the dopamine from being degraded by MAO-B.
Does the green tea extract need to be decaffeinated to avoid liver damage? Also, will taking the green tea capsules spread out in the day like that work the same as taking green tea each time one is dosing mucuna? I guess I am wondering if taking green tea extract 3 times a day, will be effective for someone dosing levodopa 6 times a day. Thank you for all your work and any insight you have!!
Wriga, you are God's send! Glad you are helping PwP who are not helped by med doctors in this difficult path. My husband has been following your research and discovery on GJ. I believe it's working, but with your latest personal protocol I believe his ON time will be extended.
A couple of questions: 1) What brand/strength of MP are you taking? 2) can a big cup of green tea substitute the green tea extract capsules?
My husband doesn't take any drugs except for a compounded thyroid med twice a day. Would GJ be contraindicated? Thank you for a terrific job and bear with us who have not your scientific background.
I'm just sharing where my research takes me. It's important for me to share it because writing it down to make it clear to others shows up the strengths and weaknesses of the arguments. I hope that some of you will provide feedback so we can all know if and under what conditions it works. Bailey does not list thyroid drugs as being sensitive to GJ, but always check with what's on the label. Give me the names of the drug and I'll look it up. I suggest starting with a low dose of GJ, say half a glass/day for the first few days to avoid complications.
Thank you so much! Like I wrote his thyroid med is compounded by our pharmacists who don't carry synthetic meds only compound meds based on results of tests in cooperation with our FD. Bottle label: T4/T3 (non-porcine) 50MCG/7.5MCG. His free T3 was barely above normal and his Synthroid med didn't fix his low Free T3 although the doctor tried different strengths.
You are more than 200 to have downloaded and read this article. I hope you found it useful. Any feedback, positive or negative, would helpful to us all. Thanks.
There are several drugs that are inhibitors of CYP3A4, not by design, but in spite of trying to avoid this outcome, since this gives rise to the risk of drug-drug interactions. For this reason, the therapeutic use of such drugs is severely restricted.
First thank you for the all the time and research that you do and for sharing it with our community, its members like you that give us hope! I have read your paper and I am not too proud to admit I am not very scientific and don’t really understand all the enzyme references etc. Please tell me if the take away if you will is that by adding a 1/2 glass of gf juice with my dose of cd/ld it could very possibly extend the length of its duration? Also the caution is to be sure that the gf juice does not negatively interact with any other medications you may be taking? Would one need a 1/2 glass I would assume with each dose or does the gf juice have possibly a longer life than the cd/ld and remains in your system for the day. Is it possible that gf juice by extending the life of cd/ld it could potentially be helpful with dyskinesia by smoothing out the dosage? Thank you!! Connie
Don't be worried that you don't understand it all. 3 month's ago I had the same problem and I used to earn a living as a research chemist. It's complicated and the nomenclature does not help. I will rework the summary I did for Getz and repost it as a header, so that more people can understand. Your takeaway is nearly correct.
Start with half a glass first thing in the morning before taking any other meds so that it has time to work on the CYP Enzymes. Take L-Dopa half an hour later.
Dose : Half a glass for the first few days to avoid any eventuel side effects.
Then : One glass (250ml) for a few days.
After that you can add a half glass in the afternoon always half hour before L-Dopa. These doses work for me, but could be different for others, for some this may be too much (we don't all have the same CYP3A4 and the differences can be large). It takes several days/weeks get a stable good result. Be patient.
I have noticed that after the first few days, there seemed to be a noticeable relapse. The body may react to having its CYP3A4 knocked and respond by producing a greater quantity to compensate. This is why the dose should be increased slowly and then maintained stable to reach a balanced situation. If you know that you can't keep up the stable dose (travelling for ex.) it should also be decreased slowly over several days for the same reason. If you have been on GJ for some time and you stop suddenly, the enzyme will likely go into a phase of over-activity and knock out all your L-Dopa (and maybe other drugs as well).
I don't believe that the GJ has a long life in the system. Given its chemical structure, it will be rapidly taken out by other enzymes. It works because the CYP3A4 tries to degrade the GJ but loses the battle and both the GJ and the Enzyme are destroyed. The long lasting effect is due to the fact that the cells producing the CYP enzymes take a long time (up to 3 days) to regenerate the enzymes destroyed by the GJ.
If GJ does give the L-Dopa a longer life in the system and smooths the available supply of dopamine in the brain, it may help reduce dyskinesia by facilitating the life of the synapses, but lt's take one step at a time. If we can get feedback on whether it improves the C/L ON-times for you, that will be progress.
Thank you so much wriga for an excellent explanation and at a level that even I can understand! I will let you know if I achieve the same success. As you say one must be patient (something I’m working on!)😊
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What's in ER C/L vs. IR C/L?
Taurine powder? L-taurine pills? 
Should he increase C/L dosage?
