Researchers Discover Why L-Dopa Stops Working

Ever wonder why your L-Dopa meds eventually become ineffective at controlling the progression of symptoms? Recent research may shed some light and offer solutions (eventually...).

"In a discovery that might turn out to be a game changer in Parkinson’s research, University of Alabama at Birmingham researchers discovered that DNA methylation causes L-DOPA to stop being effective after a few years, instead giving rise to dyskinesia — involuntary jerky movements making life even harder for patients."

parkinsonsnewstoday.com/201...

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  • It is good to see general PD researchers starting to understand the properties of synthetic L-dopa/sinemet. From the article:

    "The team also treated animals with a compound called RG-108, or with methionine supplementation, and saw that they could change the dyskinetic behavior of the animals."

    In an internet posting entitled, 'What Doctors Don't Tell You: PARKINSON'S DISEASE'

    "The most impressive research on non orthodox treatment of Parkinson's concerns the use of L-methionine. WDDTY panel list Melvyn Werbach knows of several studies showing that L-methionine is as effective as L-Dopa after three weeks in people with previously untreated Parkinson's disease (Rev Neurol [Paris],1982; 138 (4): 297-303). It also brought about further improvement in Parkinsonian patients who'd reached a plateau in their orthodox treatment (South Med J, 1984; 77: 1577)."

    healthy.net/scr/article.asp...

    "It also brought about further improvement in Parkinsonian patients who'd reached a plateau in their orthodox treatment (South Med J, 1984; 77: 1577)."

    "It" meaning methionine, has already been used in conjunction with sinemet as reported 32 years ago. I am glad to see the researchers of this article are catching up with past research.

    [L-Methionine treatment of Parkinson's disease: preliminary results]. (1982)

    "Eleven patients with previously untreated Parkinson's disease were treated with L-Methionine for periods from 2 weeks to 6 months. The treatment was well supported and good improvement in clinical signs, particularly akinesia and rigidity, appeared within approximately three weeks, the effect on tremor being less marked. Therapeutic effects were similar to those observed with L-dopa treatment. Correlation of clinical effects with a marked increase in the number of 3H-Spiroperidol binding sites (Bmax) to lymphocytes was noted. This therapeutic effect suggests the role played by modifications of membrane fluidity on dopaminergic receptors, both lymphocytic and striatal, in the etiology of Parkinson's disease, and opens up new therapeutic possibilities in this disease."

    ncbi.nlm.nih.gov/pubmed/713...

    More about methionine:

    Methionine: Be sure to get enough folate , vitamin B 6 , and vitamin B 12 . 7

    Levodopa : Methionine might interfere with its action.

    therapy.epnet.com/nat/GetCo...

    _______________________________________________________________________________

    To summarize: researchers in 2016 have figured out why L-dopa causes dyskinesia in PWP and it involves the methylation process. Both a drug or methionine "could change the dyskinetic behavior of the animals."

    Yes methionine interferes with levodopa absorption, like any other amino acid, and perhaps it has to be taken with sinemet to prevent dyskinesia. What is needed is an experiment that balances the dose of sinemet and methionine, to find an optimum, efficient dose.

  • silvestrov,

    The parkinsonsnewstoday article says:

    "The team also treated animals with a compound called RG-108, or with methionine supplementation, and saw that they could change the dyskinetic behavior of the animals. While these treatments are not suitable for humans..."

    This seems to be saying that methionine supplementation is not a suitable treatment for humans. Do you know why they say this?

    Jeff

  • I think I've figured it out.

    In a similar article at ScienceDaily it says:

    "Modulating global DNA methylation -- either by injecting methionine to increase methylation or applying RG-108, an inhibitor of methylation, to the striatum -- modified the dyskinetic behavior of LID, down or up, respectively."

    EDIT: The following sentence has been reworded to improve clarity.

    So when they say "these treatments are not suitable for humans", what I think they are saying is that, as a therapy, injecting methionine into the brains of PWPs is not practical.

    sciencedaily.com/releases/2...

    Sorry for the distraction. Thanks for all the information, and the links.

    Jeff

  • The research scientists injected methionine (and the other drug) into lab animals but the research scientists from the 1984 methionine/PD study, of this I am certain, did not inject methionine into 'lab' humans and the supplemental methionine then 'brought about further improvement in Parkinsonian patients who'd reached a plateau in their orthodox treatment (South Med J, 1984; 77: 1577).'

    In the early 1980's a bunch of junkies in California used fentenyl (synthetic heroin) to get high not knowing the drug was synthesized with too much heat and was laced with the by product MPTP. MPTP, now a standard model for PD testing, caused destruction of the substantia nigra and thus parkinsonism. L-dopa relieved their symptoms and the usual L-dopa complications occurred. More information here:

    arstechnica.com/science/201...

    Here is the original PBS documentary, Case of the Frozen Addicts:

    openvault.wgbh.org/catalog/...

    When the researchers injected MPTP into rats it did nothing. Later they found out that it did not cross the rat's blood brain barrier and thus had to inject it directly into their brains. So scientists often inject drugs, etc, into rodents to be certain it reaches the desired brain area.

    Methionine does cross the human blood brain barrier and is easily purchasable:

    amazon.com/NOW-Foods-L-Meth...

    The question is, what is the desired proportion (amounts in mg) between methionine and levodopa to ensure the effectiveness of the latter without sacrificing its efficacy in treating PD and decreasing dyskinesia. I think the L-dopa dose will have to be increased to take into account the competition of a fellow amino acid in passing the blood brain barrier. The same is true when taking tyrosine and levodopa, more levodopa is required to have the same effect because of amino acid competitiveness at the BBB.

    Here is a followup documentary produced by the BBC entitled 'Awakening the Frozen Addicts' which contains much of the prior PBS documentary and updates the condition of the affected drug users.

    Rich

  • Rich, thanks for sharing this. I read the Case of the Frozen Addicts when I was first diagnosed. Fascinating but scary to read. As you mention, the positive in this sad story is that now scientists / researchers had a tool (MPTP) that they could inflict on animals, create an instant PD state, and then test possible cures on those animals. While methionine can easily pass the blood brain barrier I wonder why it shouldn't be acceptable for trials on humans. So I wonder why do they state "The treatments we have used here, methionine supplementation or RG-108, are not practical for human use; but they point to the opportunity to develop methylation-based epigenetic therapeutics in Parkinson's disease."

    I ran across this to share on epigenetic therapeutics as the new thing for trials in cancer, "There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade. "

    It seems to me that there are a lot of potential avenues to explore in the treatment of PD and while L-dopa was a tremendous break through it seems like in the past 40 years (and it's been around longer than that) we might have come up with something more viable than Ldopa given the significant downside of dyskinesia (!!!!!). So all this brings me to how to get money / funding for more research. Has there been much brainstorming on this across the group?

  • Thanks for the information about epigenetic regulation. I am rather old fashioned (in at least a few situations) and prefer a simple solution to problems (and 'epigenetic regulation' sounds neither simple nor cheap).

    This morning, by chance, I was investigating Wilson's disease, yes I have strange hobbies and as an artist I have quit studying art decades ago, and as a consequence I found a methylation agent that may be good for dyskinesia: Betaine hcl.

    ______________________________________________________

    First Wilson's disease (an atypical, genetic form of PD which is characterized by early onset and is caused by toxic accumulation of copper):

    Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease.

    "betaine treatment increased S-adenosylmethionine and up-regulated Dnmt3b levels, and both treatments restored global DNA methylation levels."

    ncbi.nlm.nih.gov/pubmed/229...

    __________________________________________________

    Betaine acts as an antioxidant and methyl donor agent versus levodopa-induced oxidative stress and hyperhomocysteinemia in the rat kidney

    "In contrast, betaine acts as a promising antioxidant and methyl donor agent versus LD-induced complications."

    congress.tbzmed.ac.ir/TILC/...

    Other betaine/PD studies:

    Betaine protects cerebellum from oxidative stress following levodopa and benserazide administration in rats.

    ncbi.nlm.nih.gov/pubmed/267...

    And,

    Recognition of Betaine as an Inhibitor of Lipopolysaccharide-Induced Nitric Oxide Production in Activated Microglial Cells

    ncbi.nlm.nih.gov/pmc/articl...

    ________________________________________________________

    Betaine hcl is not an amino acid, like methionine, so it will not 'compete' with levodopa in passing the blood brain barrier. After looking at the label on a commercially available brand of betaine hcl, it says to take it at the beginning of a meal and to not take it on an empty stomach.

    swansonvitamins.com/now-foo...

    Then again,

    AjiPure L-Methionine, Pharmaceutical Grade

    is cheap and it too is recommended to be taken on with water and meals:

    swansonvitamins.com/swanson...

    Considering protein can minimize the effects of amino acids, Betaine hcl may be the first choice (over methionine) PWP should eat protein-free morning and lunch time meals because protein interferes with the absorption of levodopa and protein should be consumed at dinner. So methionine will be adequately absorbed in 2 of 3 meals whilst betaine will be absorbed at all 3 meals.

    I hope this helps and have a great weekend.

    Rich

  • silvestrov said:

    "The question is, what is the desired proportion (amounts in mg) between methionine and levodopa to ensure the effectiveness of the latter without sacrificing its efficacy in treating PD and decreasing dyskinesia."

    It seems to me that if the question was as simple as that, they would have found the answer decades ago.

    I think the question is how to restore, to the appropriate DNA nucleotides, the methyl groups that levodopa has (effectively) removed. Just giving methionine tablets doesn't seem to do it.

  • The use of methionine my be a moot point because I discovered a promising adjuvant treatment for PD which just happens to be a methyl donor, betaine hcl.

    Here is the first study about DNA methylation in Wilson's disease:

    Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease.

    " betaine treatment increased S-adenosylmethionine and up-regulated Dnmt3b levels, and both treatments restored global DNA methylation levels."

    ncbi.nlm.nih.gov/pubmed/229...

    Betaine protects cerebellum from oxidative stress following levodopa and benserazide administration in rats.

    ncbi.nlm.nih.gov/pubmed/267...

    Betaine acts as an antioxidant and methyl donor agent versus levodopa-induced oxidative stress and hyperhomocysteinemia in the rat kidney

    "In contrast, betaine acts as a promising antioxidant and methyl donor agent versus LD-induced complications.Therefore, this research highlights the therapeutic antioxidant and methyldonor effects of betaine in line with our previous reports in cerebellum,testis, ovary, liver, and brain of rats."

    congress.tbzmed.ac.ir/TILC/...

    Also:

    Recognition of Betaine as an Inhibitor of Lipopolysaccharide-Induced Nitric Oxide Production in Activated Microglial Cells

    ncbi.nlm.nih.gov/pmc/articl...

    _________________________________________________

    Yes, I asked a simple question and the answer may already exist in the prior, 1984, study which combined methionine and standard L-dopa therapy. But there is no money to be made from this solution and no drug company is going to test it because of the lack of economic prospects.

    Regardless of the use of methionine, betaine looks promising but what drug company (again) is going to test a supplement that is cheap and readily available:

    google.com/webhp?sourceid=c...

    Methionine is dirt cheap also:

    swansonvitamins.com/swanson...

    ______________________________________________________

    I am not on sinemet/madopar and do not have dyskinesia and have posted this info for the benefit of others here. I hope that either betaine or methionine supplementation spurs experimentation and helps PWP with dyskinesia.

  • If I understand you correctly, you are hoping that research will be conducted on finding a dosage of betaine and/or methionine (or some other supplement) which can prevent levodopa from (effectively) removing methyl groups from certain DNA nucleotides.

    Well, I won't disagree with that.

  • The betaine research is happening in Iran and it will be interesting to see where this research goes. If it proves to be successful in relieving dyskinesia I wonder if we will see it in the states because our drug approval process is expensive and lengthy. If it works it will probably be used else where, say Europe, Asia, but not in the states.

  • Jeffreyn, I agree that it would not seem as simple as that but sometimes I feel that the answer to some of this could be right in front of us.

    Therefore, I am in favor of leaving no stone unturned in the pursuit of a cure for PD - exploring all avenues. I have no medical training and am in a learning stage. Your post is greatly appreciated and is generating good thinking.

  • Rich, it sounds like you are self managing much of your medication, perhaps brilliantly and through much intensive study, vs traditional therapies such as Ldopa. It strikes me similarly that I am hesitant to engage in traditional L-dopa therapy and that being as knowledgeable as possible is a responsibility that falls to us in managing our own health. This board helps us share info and adds an element of personal history and real life examples that research can't match - even by big pharma.

    You probably have shared this info many times, but I am curious when you were dxd with PD and how you are doing today. In other words, how well are you managing PD with your approach?

    I know you mentioned you got great benefit immediately from COQ10 and also NAC, and as we discussed, I am very interested in NAC and looking into a clinical trial, and it seems you are effectively managing an assortment of other supplements. It would be interesting to get a better understanding of how you are managing PD with this approach vs a more traditional method - comparing the outcomes. Also, do you see traditional movement disorder neurologists? If so, maybe you could make a recommendation.

  • I will answer your questions later or perhaps tomorrow (it takes a long response). Right now I noticed I was a bone head in not reading the final paragraph in the Wilson's disease study - I was in a hurry to fix my car (on my day off):

    Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease.

    ".. S-adenosylhomocysteine (SAH).."

    "We propose that increased SAH levels and inflammation affect widespread epigenetic regulation of gene expression in WD."

    ncbi.nlm.nih.gov/pubmed/229...

    Doh!

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