More pieces to the puzzle about getti... - Parkinson's Movement

Parkinson's Movement
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More pieces to the puzzle about getting a more stable supply of levodopa to the brain

Here is my latest article about how the CYP3A4 enzyme metabolises levodopa and controls its bio-availability and haf-life. It is based on a 50-day cycle (n=1) during which CYP3A4 was alternatively non-inhibited and inhibited. The results confirm that CYP3A4 powerfully inhibits levodopa and may be more important in its action than DDC, the enzyme that is inhibited by Carbidopa. An important point concerns the processes and relative speeds of inhibition and regeneration of CYP3A4 which automatically lead to severe fluctuations in enzyme activity when inhibition is stopped or used casually. Daily controlled inhibition of CYP3A4 using grapefruit juice in this trial produced considerable attenuation of Parkinson's disease symptoms without off periods and improved quality of life, probably due to a more regular supply of levodopa to the brain. During CYP3A4 inhibition, levodopa can remain active for 6-8 hours. Inhibition stops or casual consumption of grapefruit juice however lead to worsening of the symptoms, which may be why some people have reported that grapefruit juice does not work for them. Daily, controlled inhibition gave excellent results. CYP3A4 inhibition by polyphenols in healthy and unhealthy diets is also briefly discussed in the light of good dietary practice and trying to relate on and off days to diet history.

This paper contains a great deal of information and ideas for anyone who is taking levodopa in any form. The information in the abstract is very limited compared to the body of the article, so if you are interested, download the whole paper.

By joining up the dots concerning inhibition and regeneration of CYP3A4, I now believe that the action of this enzyme is of major importance for PwP and is the principal cause of the on/off times of PD. Understanding the kinetics of these two processes is critical to learning about how it affects levodopa availability and degradation and how it affects your symptoms.

The information gained here provides a basis for questions that I could not have framed 6 months ago. We don't yet have the answers, but we have more pieces of the puzzle than we had 6 months ago.

AS usual, I won't be answering questions about specific drugs that could be dangerous if used with grapefruit juice. Please ask your doctor about that. The answer to those questions is also in the references at the end of this paper.

Albert

researchgate.net/publicatio...

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Albert,

You've put a ton of effort into this. Thank you.

Surely, I misunderstand something.

Lowering the dose of levodopa we put in our mouth only to increase the amount in our blood and therefore our brain is not really lowering the dose.

Marc

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I think there may be a crossed wire. What matters is how much we put in our brain. How much we put in our brain equals how much we put in our mouth, less how much gets converted into something else before it gets to our brain. Not only is that less wasteful (more bang per buck) but the "wasted" levadopa being converted to something else is not good. It is usually metabolised into dopamine - which cannot cross the blood brain barrier, and outside the brain contributes to nausea.

There is also your situation where levadopa doesnt work - because it is being used up in the body before it gets to the brain. So if we can stop it being wasted before it gets to the brain, the amounts you have been putting in your mouth might get you an effect.

Maybe you should volunteer to be n=2!

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I think we're saying the same thing. I'm saying that drinking grapefruit juice allows us to get more into our brain from putting less than her mouth.

It sounds like this has value if you're paying for your levodopa by cash and you want to stretch out your supply, otherwise what am I missing?

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This is not about cost.

It's about trying to smooth out the fluctuations in levodopa, due to short half life. I can't measure the half life, only how long between pills. And its long. I can go down to 1 pill per day with no problem. Although phase 4 of the test indicates there's a strong effect in the gut, the extra time between pills means there's also inhibition in the liver. What I was really trying to get across is that CYP3A4 is the problem.

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Again, I do not doubt that it works and I do not doubt that 3A4 is the problem. What I'm asking is, if we are getting more in the brain from less than the mouth, is it appropriate to say we have reduced the dose?

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I'm sure we agree really. The EFFECTIVE dose may have increased. The ingested dose has decreased. If the ingested dose decreases you save some cash - but also you have less levadopa wasted. The stuff that wasn't getting to the brain before, but now is, was being converted into dopamine OUTSIDE the brain, and making you vomit and other stuff. Most of the side effects of levadopa will be reduced by reducing the ingested dose relative to the same or increased effective dose

Does that work?

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That's part of it, absolutely no nausea, but thats not the point, levodopa stays longer in the blood because its not getting destroyed, the blood gats a stable supply and you feel better for longer. Here it's 17h45, I took my last pill at 08h00 this morning and I'm fine.

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Understood. Then, we have the issue of an unknowable dose in the brain. Same as Mucuna -- works better, but the dose is unknowable. And lastly, the other concern would be the effect on all other food and supplements of diminishing 3 A4.

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Marc, even without inhibiting CYP3A4, the dose in the brain is not known, It goes from 0 before dose, to " too high "and then falls back to 0 .

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While the dose in the brain is not precisely knowable from taking Sinemet, there is some data on what it is, but more important is that the dose would be consistent, whereas with grapefruit juice, as the amount of 3A4 keeps changing/diminishing, the availability is inconsistent and/or is slightly increasing.

We know that any amount of levodopa can induce dyskinesia in some people at any time frame, so if you inadvertently increase the amount of levodopa in a person who might be one of those persons who gets it in a few weeks (or a few months if you've Ben drinking grapefruit juice for months,) as has been reported on this forum, their discontinuing levodopa might not and probably would not stop the dyskinesia for several days.

Each successive day that you ingest grapefruit juice your reducing the 3 A4 from a reduced amount. 50% of 50% of 50% eventually gets to be a pretty small amount.

And still, there is the other issue of the impact on all other food and supplements of having a greatly reduced quantity of 3 A4 I imagine might easily cause deficiencies of other nutrients and vitamins - which is my primary concern.

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I don't think the CYP3A4 keeps on declining like radioactive decay. Its an equilibrium reaction. There's a steady state between inhibition and renewal.

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Hi marc,

All I can say Marc, is that it works. The symptoms are very much attenuated. It takes a week to settle down and then it's a smooth ride. I gradually reduced the dose I take, half a pill lasts 8 hours. Tremor is practically gone.

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Albert,

I have no doubt, at all, that it works. What I'm saying only is that with grapefruit juice you are getting more into the brain from less in the mouth. Isn't that true?

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I've tried it for two months, using it and suspending it twice, I report the same experience of Albert with good results. I take it in the evening 100ml and it prolongs the effect of the evening dose of ldopa and removes a small peak dose dystonia that I had before using it and during the day I am much more agile with a smaller dose of ldopa. IMO B1 and levodopa plus GJ are a spectacle. Some side effects to check out. Of course, always ask your doctor and pharmacist before using it.

The problem of ldopa is described here:

nature.com/articles/466S6a

IMO I suppose that the discovery of the Nobel prize winner Arvid Carlsson would have had even more difficult life today, but this is known history that the impulse of survival of man is always a fight between the security of the status quo against the change necessary to the evolution towards new existential states brought by research and discovery. Who will win? . . Whatever the answer, I only ask to all not to shoot the researcher would be a good step forward compared to past history.

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Thanks Gio, I don't know what the conversion would be between Med Diet and GJ, but I'm now totally converted to Med Diet My philosophy was to try and find a résolution to the half life pb, and then try to add in meds to help the neurons. Reduce inflammation, reduce free radicals etc, GJ + Med Diet does both. Add in B1 and life is good again. And seems to be getting better each day.

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Gio,

I am not shooting the messenger. If Albert is to put forth research, he understands it will be scrutinized like all other research. As to your 1st point, I've been clear that I believe it does what he and you say it does.

How do you feel about my last point, i.e., greatly reduced amount of 3A4 has to impact absorption and availability of many other nutrients?

I just think (if you're going to tamper with 3 A4) there are other issues you might want to consider.

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I beg your pardon Marc, it was not referred to your thought that it is rightful, I should have expressed myself better. I only said this in view of how they were treated researchers in history, ie very badly, just because they were against the pre-constituted interests.

Some minor undesirable effects could occur, I am verifying that they are due to the GJ, as soon as I determine it I will write it down. clearly it is my practical experience and nothing more.

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Something I've learned from this enzyme research is that they are only produced in quantity to combat their favourite enemy. That's why PXR is there scanning the environment.

As an example ,: If you don't eat toxins your CYP3A4 level will be very low. When you take levodopa, PXR spots it and sends the message to produce CYP3A4. 24 hours later there's lots of CYP3A4 to take out the next dose. If you stop taking levodopa or other toxins then CYP3A4 will decline back to low levels. It's not there in quantity all the time, just like antibodies for measles. It's made on demand via PXR.

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Very nice Albert, cellular Life acts with intelligence... who would have thought...:-)

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I hope you trust that I am very happy for you and for Albert and anybody else who has found something that smooths out the "off" periods and provides relief.

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Marc,I've never had any doubts about your great sensitivity and intelligence that makes you one of the main opinion leaders of this forum.

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Thank you.

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IMO The body cleans itself continuously, when arbitrarily introducing substances such as dopa which should be produced intelligently by the body in the necessary quantity, other arbitrary cascades should be added such as carbidopa, and so on until they become very complicated. Arbitrary pulls arbitrary. That's it, I can't do anything about it, the only thing is to be as simple as you can. Too many medicines interact each other. This is also the limit of modern medicine: in the end the treatments will hurt more than do good. End of the game.

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Spoken like a true philosopher.

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I work in a very rich country, full of old people and doctors. What I can see that there are several people who take 8 to 15 different pills a day mainly for cardiovascular diseases. Try to imagine stacking and reading all the package inserts for these medicines and understanding their interactions. No one will ever do it. 50% of these drugs probably consume CYP3A4 enzymes ... but there are also many people over eighty in very good health who take nothing... 😊

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They must have been the lovers.

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So, you're down to 1 1/2 pills from 4? 150mg down from 400?

How long have you been at this dose (or at least a greatly reduced daily dose)?

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I started reducing the dose 3 weeks ago. Now stable at 2 x 75. 8 am and 3 pm.

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Nice! Do you feel any differences during those amazingly-long stretches that would indicate over-medication or under-medication?

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How much GJ do you take with your half C/L?

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Really interesting concept. Obvious reservations about n=1 and no placebo control (difficult with grapefruit juice!). Always nice to get a bit of positive reinforcement for my Mediterranean diet choice. If / when I start levadopa supplementation I will bear this in mind (providing I am not on statins by then)

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Back to the point at hand.

Let's uses round, fictitious numbers to illustrate.

If normally we take a 3, 25/100 and 30 mg reaches our brain. Grapefruit juice allows us to reduce the amount we put in our mouth, so we go from 3 pills to one pill, i.e., 100 mg of levodopa in the mouth equals 10 mg in the brain. The grapefruit juice increases the viability, for sake of argument say, by 3 times or 30 mg.

How has that reduced the amount of levodopa we've taken?

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It hasn't, it has simply ironed out the peaks and the troughs. Peaks are bad, dyskinesia, troughs are bad, off times. If you can reduce the steep slope of the decline, you can start with less in the mouth and it lasts all day.

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I understand and I agree that the point you just made is an important one and is the purpose of taking the 2 together. Might a greatly diminished quantity of 3 A4 cause deficiencies in nutrients from food?

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My aim is not a greatly reduced quantity of CYP3A4, just enough to get a longer half-life for levodopa. The right dose of both have to be found. With a pill lasting 12 hours, that may be too much GJ, But you can't get the answers fast. Each attempt to reduce the GJ takes about 7 days, otherwise your not in a stable regime. Without PD and drugs for other conditions GJ every day does you no harm. My golf partner has been doing that for 40 years.

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This is a long thread!

Just to clarify, how much grapefruit juice do you have and what time of day? Do you take it with your l dopa?

Thanjs

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I think I've answered this elsewhere, for the trial it's stated 250 ml, 30 mins before first meds, never with levodopa. I've now cut down to 200 ml.

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Thanks

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What is DDI

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Drug Drug interactions

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Thank you

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So does this mean I can take grapefruit juice to reduce my 5 pills of Sinemet 100/25 mg to perhaps only two a day? With fewer side effects?

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That's what I did Not only fewer side effects, feeling tons better.

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I love grapefruit juice and was disappointed when the pharmacists told me I couldn’t drink it with my medication Sinemet,so your post makes me happy! How much grapefruit juice and how often? And how many pills are you taking now as compared to before?

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Hi Ocean, I suggest you read the article in full and the other artcle I wrote on the Metabolism of levodopa. All the info is there.

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Clearly I missed something! I’ll have another try.😊

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In conclusion, I like having my 3 A4 cursing around through my body in the amounts nature intended.

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Hi Marc,

Well, nature intended the amount of CYP3A4 in you to be normally zero. Nature then responded to the presence of levodopa by upping the CYP3A4 to get rid of the levodopa. What nature really intended was that no levodopa should be running round in your blood. But then nature hadnt intended that we get PD so hadnt worked that out fully

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Thank you for that. I would guess, though, that since many of us have stuff in our stomach much of the time, we also have 3 A4 much of the time. I mean, it's not a light switch that gets turned on-and-off. No?

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Hi Marc,

Yep, but probably not enough to knock out levodopa unless your on statins par ex. Its the levodopa that drives up CYP3A4. Negative feedback loop

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Albert,

Help me understand one more thing. If I remember correctly, you felt the grapefruit juice extended you're on time from approximately 2 hours to approximately 6 1/2 hours. Does that mean for your "on" duration to be 3 times as long is because your brain has roughly 3 times as much dopamine? And, would the same thing be accomplished if you took 2 more Sinemet 2 hours apart?

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Marc,

Avoiding taking large and frequent doses of synthetic C/L is what we want. This way, side effects of C/L are minimized. Wouldn't you rather take 2 tablets a day vs 6? As our Vanderbilt young MDS said "Less (meds) is more."

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Of course taking as little as possible is the goal, which is my mantra and that was the point in my concern, i.e., I thought people might think that reducing the dose in their mouth was reducing the dose, while it might be that they were actually increasing the dose in their brain.

While Albert's explanation that it extends the decline sounds reasonable, I'm not yet convinced that for the same reasoning (that it extends the decline,) the dose isn't increased -- at least somewhat.

Secondly, when we tinker with the primary metabolizing enzyme, we can be sure there are other consequences beyond its effect with levodopa. I'm hoping Albert will respond to my other concern that diminishing 3 A4 might impair nutrient absorption.

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One other consideration was Albert's description of the consequences of discontinuing were pretty gruesome, "...intolerable...," even traumatic. The probability is that a lot of people will develop another condition that requires another pharmaceutical which would require the cessation of grapefruit juice.

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This is true Marc, but for most meds that are over-sensitive to CYP3A4 inhibition (these are inherently bad meds), there are alternatives that aren't, See ref. Bailey et al.

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Marc,

My image of the problem is the following. I imagine there is a range of dopamine concentrations that we can push into the brain using levodopa. Lets say this range is from 0 to 10 and the good range is from 4 to 6. In a healthy brain the neurons can deliver up to 8, but adjust to keep in the good range. In a PD brain, the neurons only provide 2. At 2 we are in a bad off state. With standard levodopa the pill provides 9 at the peak. Its too much, you get dyskinesia even tho the neurons deliver zero and can take up some excess to store it. Very quickly it drops to 7, still too much. Then to 5 , ok, then to 3. This is still ok since the neurons provide enough to stay in range. Then to 2, which with 2 from neurons is lower limit.all this rakes 3 hours

Now, with GJ, you can start with a lower dose if you can slow the decline. Ideally, the ½ pill with GJ provides 6, but the decline is slow, as CYP3A4 is not eating it up. Thee hours later the pill provides 4, and neurons add enough to keep things good. Three hours later the pill still provides 2½ and the neurons 2 making 4½, still in range.

The total delivered to the brain is about the same, but over 6 hours rather than 3, and in range most of the time.

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I understand now. Thanks.

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MBAnderson asked: "would the same thing be accomplished if you took 2 more Sinemet 2 hours apart?"

Wriga, you didn't answer this question directly, but from what you did say, I think it's clear that the answer is "no".

Would it be correct to say that if instead you took 4 more half Sinemets 1 hour apart, then that would be getting reasonably close?

And that using a Duodopa Pump would pretty much accomplish the same thing as GJ?

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Everytime you take a new dose of levodopa, you're going to get a new peak of dopamine. You want to avoid that as far as possible. Peaks and troughs are periods of stress and suffering for the synapses. Having to adapt to too much and too little dopamine many times per day can damage them. So adding more pills is not the answer. Also, adding more levodopa, by any means (including CR or a pump), will increase CYP3A4 induction via PXR signalling, to get rid of it faster. It's a vicious circle. The virtuous circle is to reduce levodopa intake and stop its destruction by CYP3A4.

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This graph might help in this discussion: healthunlocked.com/parkinso...

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Hello Albert! I was looking forward to your newest research results. I know it works for my husband. My question is: He takes MP + Carbidopa (2 MP 15% (L-dopa,100mg) X 2 day. At night he takes 1/2 tablet of Sinemet + 1 MP (50mg L-dopa). This specific protocol works great. He takes his morning vitamins, after breakfast, with a cup of GJ. Do you think he would have to drop carbidopa(25mg) since he drinks GJ daily?

I will read your research paper a little later in the day. . .too many responsibilities right now and need plenty of time to read it, analyze/digest it!

Dr. Mischley's hair test results indicated that he LUCKS STOMACH ACID! That means his body can't break down/absorb vitamins and minerals. She recommended liquid forms of foods or at least soft. "Essential and other Elements" are all the way to the left of this paper with test results. She is going to forward the right vitamins/supplements to ameliorate the problem.

Fortunately NO TOXIC METALS found, thank God!

We still haven't heard anything from the cardiologist about his R Carotid Artery Stenosis MRA test results which he had on June 19. Too many fires simultaneously to put out. :(

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Hi Despe, how is Ray doing after his eye problem ? With GJ, I don't think he would need as much Carbidopa Carbidopa especially as he's on the 25/100 version. My philosophy is to take the smallest dose of drugs as possible that works. If you find that he's doing very well, you might want to consider reducing the MP and check if he stays good. My experience is that you need less after 2 or 3 months I have the impression that the brain needs less because the flow to the brain is more stable. No proof of that tho' . Just a feeling

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Hi Albert. He is only on a 1/2 tablet Sinemet which he takes it at night with one capsule MP. The rest of the day he takes MP WITH carbidopa. I was thinking about dropping carbidopa as GJ is such a good inhibitor and take MP only.

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Hi Despe, Carbidopa inhibits a different enzyme, DDC, I dont think GJ inhibits DDC, so you shouldn't stop all Carbidopa, keep at least 5mg per day. The two pathways are differen6

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Thank you! He might take the mid-day MP without carbidopa, as he takes it in the morning with his MP. At night he has more carbidopa with his 1/2 tablet of Sinemet. Trial and error the name of the game.

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Despe - what form of Carbidopa does he take with the MP? Thanks- John G

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Carbidopa, the synthetic part of C/L (Sinemet). Carbidopa is the enzyme inhibitor and allows MP to reach the brain. IOW, Levodopa in its natural form (MP) and synthetic Carbidopa (the inhibitor).

Actually, our MDS prescribed Lodosyn, brand name Carbidopa, but it is extremely expensive, and I have been fighting with our insurance to get the brand name.

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"Tropicana, pamplemousse rose. . ."

Is it regular (yellow) GJ or pink GJ? One of THE patients/subscribers on NeuroTalk asked if the kind of GJ (yellow, pink) makes any difference. We drink pink GJ organic, cold pressed with pulp, vegan.

I sure enjoyed reading your research paper, and I really, really appreciate the long hours you spent on it. Very educational, but especially HELPFUL, for us who are not scientists. :)

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Hi Despe,

I used that brand of GJ in the trIal because it's good quality and has a good taste. It's also easily available here. It's the pink variety. BUT, it absolutely doesn't matter. The cheapest non-branded stuff works just as well.

I take this opportunity to repeat what I mentioned earlier.

Some people are concerned that inhibiting CYP3A4 may be in someways harmful. In answer to this we have to consider what has caused it to be present in quantity in the first place. And the answer to that may surprise some. If CYP3A4 is active against levodopa, it is because levodopa binds to PXR which then instucts the CYP genes to synthsise CYP3A4. In the absence of levodopa or anther toxic drug that are now collectively called xenobiotics, CYP3A4 is practically absent. CYP3A4 is generated ( induced) by the action of levodopa on PXR in order to get rid of levodopa, which it does remarkably well. It's a feedback process. GJ simply opposes the outcome of this process. The reason why people in good health, not on drugs can drink Grapefruit everyday without adverse effects is that they don't have any CYP3A4 to inhibit. To become a good drug, levodopa should be prescribeď jointly with a CYP3A4 inhibitor, just as it is prescribed with a DDC inhibitor which is Carbidopa. PXR and the mechanism for inducing CYP3A4 was discovered only recently, long after levodopa was put on the market. When I've received all your comments, I will update the file to make this clearer.

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Again, THANK YOU! My husband is doing great, tremors although they were never constant and intense have almost diminished. :) His frequent urination is almost eliminated as well as his nycturia. He slept until 09:10 this morning! He will continue his consumption of GJ which he was taking before his diagnosis, although at that time he was on BP meds and Synthroid.

Unfortunately, he will have an operation for his R Carotid Artery Stenosis (>70% :( ). We will see the surgeon on 2 July. Our European cardiologist indicated that stenosis could have caused PD, or stenosis was caused by PD. Interesting. . .

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Albert, husband likes to have green tea in the morning with his MP and 1 tsp of mannitol dissolved in it. He tried GJ first think in the morning on an empty stomach but caused him discomfort. He has started drinking GJ later in the morning after breakfast. Still works just great. I am mentioning it because you have indicated that in your trial you didn't add another inhibitor which tea is. Your insight?

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Despe

Not adding another inhibitor is an example of how scientists like to keep things simple. Dont leave any possibility to have more than one way of explaining the results. Human biology is already very complicated .

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I hear you.

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Can you put in a easy quick step guide, also if you start grapefruit juice, when do yo start reducing cardopa/levadopa, and you have to use juice everyday or can you skip days, and if you stop juice you'll get bad symptoms ? Also if wanting to try adding macuna the juice would help with that instead of cardopa/levadopa. Also can you use a natural MOA -B inhibitor with the juice. Thank you, Maria

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Maria, I don't want to get into the business of setting up a protocol for changing your drug use that might or might not work for you or others. I try to inform you of what I've discovered. It's then up to you to read the article and the references and make up your own mind. The answers to your questions are all in the article. I get stats on how many people read the article. Only abiut 40% of you actually download the file. You can only understand what's going on if you read it all ... and probably many times.

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I noticed parsnips and celery have furanocoumarins also although slightly different. Do these have any effect?

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Difficult to know that LAJ, It all depends on the quantities of the furanocoumarins, but I have recently become a regular celery eater.

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Interesting furanocoumarins are classed as toxic and increase in strength the longer celery is stored, and is found less in organic celery!

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Hi Wriga,

Thank you for making the result of your research available to help those of us on Levodopa medication. If it works for other PwPs the way it has worked for you without serious long-term side effects, your discovery would be nothing short of a revolutionary contribution to the use of Ldopa for Parkinson’s symptom control. I know from my own experience that the ‘OFF’ periods are the worst disrupters of my everyday life as they are so unpredictable and can be brought on by many different factors such as food, physical exertion, stress, etc.

A couple of questions:

Do you take your GJ on empty stomach in the mornings? No issues with acidity?

When there is a more stable supply of Ldopa in the blood throughout the day, would it allow us to eat more protein without suffering the effect of not having enough Ldopa reach the brain?

Thanks again!

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Hi Skydome.

I take GJ first thing in the morning on an empty stomach, along with my B1. Then levodopa, now ½ pill only always away from food. If I take levodopa with food it does not work so well

I can't answer your question about protein.

If your off periods are linked to diet affecting CYP3A4, then think of it this way

A good day may mean you ate stuff that inhibited CYP3A4 (fruit, salads veggies, nuts) the day before .

A bad day may mean that you ate stuff that inhibited CYP3A4 three days before, but then ate unhealthy food for the last 2 days.

Check it out and let me know if it makes sense.

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....And it suffered the repercussion of the increased production of CYP3A4 made by the body in the next two days.

Very wise Albert. I like this study.

It is not easy to fully understand, but I really like it.

Thank you

:-)

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You're a wise man Gio, you take in the info and you check to see if it makes sense to you. If it doesn't you question it. That's how we make progress .

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Thank you, Wriga! So far my off periods have mainly been happening at Ldopa end-of-dose times. I’m generally following what you described as the Mediterranean diet and being careful with my protein intake as it does reduce the effect of my Ldopa. I look forward to starting trying the GJ regime alongside the Mediterranean diet, and I hope to report back with good results in due course.

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Thank you for advancing this research/conversation. I downloaded your previous research paper and found it quite interesting. At the time, I went out to get some grapefruit juice. Imagine my surprise when I could hardly find a bottle and then it was a bit pricey. Husband did try for a week (how long the bottle lasted) and didn't seem to have any response, so he quit. Obviously he needs to trial this a bit longer if i can find a reliable source of GJ.

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MBAnderson asked: "How has that reduced the amount of levodopa we've taken?"

wriga answered: "It hasn't, it has simply ironed out the peaks and the troughs."

I think this is a key benefit.

It also highlights a weakness of examples using "round, fictitious numbers". Let's use a real example.

I get good control of my tremor with 600mg levodopa per day. But taking whole 25/100s at a time causes dystonic dyskinesia on and off throughout the day. So instead of taking the 600mg as 6 doses of 100mg, I'm currently taking the 600mg as 7 doses (100mg,75mg, 75mg, 75mg, 75mg, 100mg, 100mg).

The new dosage is working fine (i.e. good tremor control and no dyskinesia). However, I realise that dyskinesia and/or tremor will one day be again a problem, and at 7 doses per day I'm already at the practical limit. The neuro has already given me a script for amantadine, which he says might help with dyskinesia.

I'm now considering experimenting with GJ to see if that will enable me to just take half a 25/100 several times per day.

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Hello Wriga!

Thank you so much for all the tedious work you have accomplished in producing this CYP3A4 study. I feel you will be helping many more people than you think! I was diagnosed 3 years ago and currently taking Sinemet 25/250 four times a day and Requip 2mg ER once a day. About 6 months ago I started getting what my neurologist said were Dyskinesia symptoms, mainly during sleep, involuntary limb movement, jaw clamping shut resulting in biting my tongue or cheek and during the day I experience uneasy, fidgety and uncomfortable feelings when trying to just sit still or when driving or on the PC. I understand your position about instructing anyone medically but just want your opinion on the following.

At my current dose of Sinemet 25/250, four times a day (Some nights another 1 or 2 100mg tabs for severe foot cramps during sleep) would you say that reducing this dosage before starting GJ testing would be wise, since the dose is a lot higher than most taking this drug?, my point being if Gj allows substantially more Levodopa to enter the brain at my current dose amount (1000-1200mg per day) should there be a concern that too much Levodopa could end up being utilized by the brain causing adverse effects?

Thank you! God Speed!

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That's a difficult one. Taking a high dose of levodopa probably means that your CYP3A4 levels are high. If you've followed the replies today, you will understand that more levodopa creates the signal to make more CYP3A4 via PXR. The high dose does not mean that the 1000 mg gets very far, but it does mean that the decline after the dose in the blood will be very steep. In reality, the term half-life for levodopa is incorrect. It supposes that the decomposition reaction is first order, but in this case it's clearly second order. It depends on the concentration of both levodopa and CYP3A4 which are both changing fast. Knocking out CYP3A4 could then have a big effect on levodopa dose on target since there will be lots of levodopa in your gut. You are asking the right questions, but I don't have the answer. If GJ helps you to get the levodopa dose down, it's win win since the CYP3A4 induction will also fall and the persistence of levodopa will increase..

I think you should go slowly on this. If you start GJ, then start at a very low dose, say 50 ml per day for a week and adjust up each week if all goes well. Even if you dont feel any positive effect, you can be sure that GJ is slowly knocking out CYP3A4 . Keep the dose constant, no days off. You will at some stage have to reduce levodopa . Let the how you feel be your guide. Good luck

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Hello Wriga, thank you so much for the reply, and your time, I will report back to the forums periodically as I get the Gj testing underway and will also heed your advice...

Blessings...God Speed!

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Albert, is this saying the same thing you are saying?

ascpt.onlinelibrary.wiley.c...

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1953, it's exactly that, except that big Pharma refuses to acknowle that levodopa is metabolised by CYP3A4.

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Thanks! I thought it was aging the same thing, and it’s from 2005!

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Saying not aging

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One more question Albert, do you think it makes any difference when you take the GJ?

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Since the main aim is to inhibit CYP3A4 before the day's meds, I prefer to take Grapefruit first thing in the morning, 30 mins before meds. Others have reported good results when taking GJ at other times. Since CYP3A4 is knocked out for 24-48 hours, it shouldn't make much difference. Prefer morning over evening since vit C may interfere with sleeping.

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JAS9 has spotted a typo on page 3.

For 3 x 300 mg, read 3 x 100 mg.

I'll edit this out later.

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From what I’m reading CBD oil does the same. I need to visit with my dr because one of my meds has a drug interaction with CBD. Great! Maybe why my anxiety has been so bad lately

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Was looking into purchasing some CBD myself, any suggestions on brands?, so many to choose from especially on Amazon, thx in advance!

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Check your meds with the article by Bailey

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Mornin Wriga

Could you post a link to this Bailey article..thx you Sir.....

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It's reference No 7 at the end of the article. To make them easy to access, all the references have active links.

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This is a great post, thanks for all your work. My question is, can someone take a low dose GJ, 50ml for example and this will provide provide some benefit? Or even a low dose every second day? is the amount of this enzyme produced dependant on the amount or frequency of GJ?

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I haven't studied the long term effets of low dose GJ. My feeling is that it could be helpful, but only if taken EVERY DAY. The amount of enzyme produced should be a function of both levodopa and GJ, but daily GJ then destroys that induced on previous days. Gj should be taken only once per day, since that means minimum induction and is effective in inhibiting CYP3A4 for 24h or more

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Thanks tons for the post, wriga.

I'm struggling to get my head around how I can apply this information to Rytary. Rytary is time-release C-L, so it would behave differently. Rytary can be somewhat simulated by taking multiple instant doses, each separated by an hour or so, like this:

neurotalk.org/parkinson-s-d...

So, if the L-dopa isn't diminished between these releases, it will build up higher and higher. I have thought of switching to Sinemet to avoid this, but switching between Rytary and Sinemet isn't simple. Any other ideas or is Sinemet in my future?

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That's a useful graph from John Turner, With Rytary, I have mixed feelings about Rytary. Slow release of levodopa in the gut means that PXR is likely to be permanently stimulated to generate more CYP3A4 to get rid of it. If so, the GJ effect could be even stronger than with Sinemet. You would then have to cut the dose down a lot. Now you begin to understand why big Pharma might find this annoying.

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Albert I agree, but IMO with the extended release madopar I had some problems because I didn't have a linear response that with the addition of GJ made things even more complicated and the body went little crazy. Since I took it off and I only use madopar normal dispersible capsules and GJ is much better. More simple I do, more I feel safe.

Now by reading your work, I can see why. Thank you

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I was wondering about Grapefruit juice if on Rytary also. Husband on lowest does of Rytary but feels is a bit under medicated but hates to up dose unless has to so thought maybe 50 ml a day would help????

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Just curious if anyone else is considering doing this? I'm seriously thinking about starting small and slowly adjusting GJ up while adjusting my meds down. I might start this week.

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I plan to start today, as follows...

I will drink a full glass of GJ every day (from the start) while reducing my C/L dosage by roughly 50% (from the start)... And then tweak the C/L dosage from there...

If this experiment is a success, and I find a new "effective reduced C/L dosage", I may then try another experiment where I endeavor to determine the minimum GJ dosage to maintain this "effective reduced C/L dosage"...

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Hi pdinva,

Just to be cautious, why not start at ½ glass , 100ml, for a few days before reducing your meds, then do as you have said. Remember, if you interrupt the GJ, you will not get a good result.

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I agree... I have now reduced to 100 ml of GJ a day and it is much better, as I am not trying to reduce ldopa but to give it a more linear performance without a period of off nor annoying dose peaks. I'm still on trial, very promising.

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Hi wriga, I really want to prevent getting over medicated, and I thought the best (most cautious) way to do this was to reduce the C/L dose from the start... This approach sets a ceiling on the maximum level of medication...

Note, when I am under medicated I have slowness and tremors... which is not terrible... OTOH, I have passed out in the past, from being over medicated...

But I guess the question is, which results in the greatest level of medication:

1/2 glass GJ + 100% C/L dose

or

1 glass GJ + 50% C/L dose

???

I presume the relationship between GJ and enzyme inhibition is not linear, and further, I take a wild guess that enzyme inhibition curve rises rather steeply when GJ is introduced...

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I too want to start this and am going to be careful about overmedication. But under-medication is no joke either, so I'm going even slower. I'm currently slightly under-medicated as I've reduced by about 15% over the past 4 weeks. I've started this morning by drinking 50 ml of GJ 30 minutes before my 1st normal dose of today. I see no improvements in PD symptoms yet. I'll do this every day for a week, and if I still have no improvement, I'll up the GJ to 100 ml but leave everything else the same.

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Hi pdinva,

The subject may be more complex than we think. This is my current understanding.

Levodopa induces CYP3A4 via the PXR receptor. The CYP3A4 induction is likely to be levodopa dose dependent, but also dependent on the frequency of the dose.

GJ probably also induces CYP3A4 via PXR. It may even be a more potent inducer than levodopa.

CYP3A4 knocks out levodopa.

Gj knocks out CYP3A4.

Then there's the kinetics.

Levodopa and Gj will induce CYP3A4 rapidly in the gut (24h) and more slowly in the liver (days).

Gj will knock out CYP3A4 rapidly in the gut (minutes) and more progressively in the liver (days and dose dependent).

That's why we can't guess what will happen short term, we don't know the relative strengths of the opposing forces. Lower or intermittent doses of GJ could favour induction. Higher regular doses of GJ will definitely favour inhibition.

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Hi wriga:

You wrote in your paper:

"Potent inhibitors such as the furanocoumarins in grapefruit juice, rapidly inactivate most or all of the existing CYP3A4 in the gut in one pass, and simultaneously activate the regeneration process at t = 0, via PXR, a process that requires 24-48 hours."

And you wrote here:

"Gj will knock out CYP3A4 rapidly in the gut (minutes) and more progressively in the liver (days and dose dependent)."

Regarding the gut aspect alone, is this "most or all" inactivation/knocking-out response independent of GJ dose? E.g., Will 50 ml of GJ inactivate most or all CYP3A4 in the same way that 200 ml would... Or is it actually dependent on GJ dose (as you suggest is the case for the liver)?

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Hi pdinva,

The evidence for this is scarce and indirect. There is surely a lower dose threshold below which it will become dose dependent. I don't know that threshold. 50 ml would be my first guess. 200 ml already gets past the gut and on to the liver.

There may also be non linear effects. At a low dose the induction of CYP3A4 by GJ could be more important than the inhibition effect. These are all unknowns. There is so much work to be done, but this is a no-go area for many labs.

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My husbands levodopa hasn't worked as it should. He's had its effect measured by "the watch" several times. He's now had the dose upped and a trial drug, Xadago,has been added. He is marginally better ,but I suspect it's not working as it should. Xadago works with the levodopa, so I guess, if the levodopa is not working, neither is the Xadago. AS FAR AS THE GRAPEFRUIT JUICE GOES, HOW MUCH AND HOW OFTEN? Any suggestions in that regard? Thank you for your efforts.

PS The drug that worked for my husband (like magic) was the Neupro patch, but, after several years, doesn't appear to be working at all.

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I'm not qualified to give a recommendation of dosage for personal cases. From my own experience and other peoples comments, the min useful dose is about 100ml, so to be cautious, why not start at this level. Effective results have been obtained with 200 ml per day. If you drink GJ casually, missing some days, you will get bad results.

Important, before starting, download and read fully, both of my most recent papers on this subject : "Metabolism of levodopa.." and "Daily inhibition of CYP3A4...... " as well as the paper by Bailey on Drug-Drug interactions....

Ref 7 in my latest paper.

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Thanks wriga. You're a Gem.

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Hi wriga, any thoughts if you take selegiline together with GJ..??

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Is not from concentrate grapefruit better than the from concentrate?products?

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I found this table of drugs that inhibit cyp3a4. One of them sertraline is an antidepressant my husband takes. Is this likely to be having the same effect as grapefruit?

ebmconsult.com/content/page...

Also this article says honey, and St. John’s wort induce the enzyme. I knew St. John’s wort was not allowed to be mixed with drugs but honey? How many people mix honey into their grapefruit or green tea? Would this offset their effectiveness?

onlinelibrary.wiley.com/doi...

This is also interesting. A table of different plant components that inhibit and induce cyp3a4. There are lots I recognise from various foods and herbs, and supplements. Do you know the relative strength and ability of these compared to grapefruit? It appears that everyday foods are pulling in both directions, especially brightly coloured fruits and Veges. Or is grapefruit strong enough that it overrides these?

hindawi.com/journals/omcl/2...

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