Serotonin Excess, Not Dopamine Deficiency, May Be The Cause Of Parkinson

Discussion in 'Scientific Studies' started by haidut, Jul 16, 2019.

  1. haidut

    haidut Member

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    One of the most paradigm-challenging studies I have seen this year and, unsurprisingly, mainstream media is pulling all sorts of tricks to avoid naming the culprit directly. Even the press release and the study abstract are worded in a convoluted way, talking about a "serotonin dysfunction" instead of what the results of the study demonstrated - serotonin excess. The findings of the study are simple. Loss and/or decreased functionality of the SERT protein precedes full-blown Parkinson disease by more than a decade and is likely a direct cause of it. SERT is the protein that de-activates serotonin and it depends on adequate sodium levels for its function. The SERT protein is the primary target of the SSRI drugs as they inhibit its function and as such promote the effects of serotonin. This decrease in SERT and consequent increase in serotonin not only precede actual PD symptom development but can also be used to measure its progression. The changes in the dopamine system and the dopamine deficiency now seem to be a very late-stage phenomenon, which may not even be causally related to the signs/symptoms. As such, serotonin antagonists like cyproheptadine or TPH inhibitors may be the actual viable treatment for PD before it even manifests in most people.

    Serotonin transporter - Wikipedia

    "...The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene.[5] SERT is a type of monoamine transporter protein that transports serotonin from the synaptic cleft back to the presynaptic neuron.[6] This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is the target of many antidepressant medications of the SSRI and tricyclic antidepressant classes.[7]"

    So, the study below found that a state of serotonin excess similar to the one caused by SSRI drugs may be the direct cause of Parkinson disease (PD) and can be used to diagnose the disease decades before it manifests in tremors, gait abnormalities, etc. This makes perfect sense since tremors are known clinically to be caused by serotonin excess and are one of the definining signs/symptoms of serotonin syndrome.
    https://raypeatforum.com/community/threads/tremor-in-parkinson-disease-pd-is-due-to-high-serotonin.22427/
    Conversely, anti-serotonin drugs are known to stop tremors and twitching. Considering the inverse relationship between serotonin and dopamine it also makes perfect sense that an excess of serotonin results in a deficiency of dopamine. The findings of the study below may also explain why dopamine agonist drugs seem to be better at treating PD than standard therapy such as L-DOPA. The dopamine agonists are known to inhibit the enzyme tryptophan hydroxylase (TPH), which is the rate limiting step for synthesis of serotonin, and as such lead to lower systemic serotonin load. On the other hand, L-DOPA is not known to have such effects, so the serotonin excess continues while L-DOPA-only treatment.

    Two major takeaways from this study. First and foremost, academic institutions (no matter how prestigious) cannot be trusted to say the truth. The fact that neither the study abstract, not the the press release directly expose serotonin excess as the possible cause of PD cannot be explained away as a simple error. Too many convoluted words and evasion when the findings of the study are so simple and direct. As a confirmation that this is not a simple error, another study with the same findings but in relation to dementia pulled the same trick.
    Higher Serotonin Availability May Be The Cause Of Cognitive Impairment / Dementia

    Second, PD joins the long list of conditions directly stemming from an energetic dysfunction mediated in this case by serotonin and likely driven by stress or, even more likely, iatrogenic factors like SSRI drugs.

    https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(19)30140-1/fulltext

    "...Our findings provide novel insights into the premotor pathology and evolution of Parkinson’s disease, suggesting that serotonergic dysfunction, which can be detected by use of in-vivo molecular imaging in patients at risk of Parkinson’s disease, precedes the development of motor symptoms and visualisation of dopaminergic pathology. Moreover, we found that the presence of serotonergic pathology in the brainstem is associated with the overall burden of Parkinson’s disease."

    "...Premotor A53T SNCA carriers had normal striatal dopamine transporter scans, but loss of serotonin transporters was noted in raphe nuclei, brainstem, striatum, thalamus, hypothalamus, and amygdala. A53T SNCA carriers with Parkinson’s disease had loss of striatal dopamine transporters and loss of serotonin transporters extended to additional subcortical and cortical regions (eg, cingulate and insula), which were not seen in premotor A53T SNCA carriers. Our findings indicate that premotor A53T SNCA carriers with normal visualisation of dopamine transporters show an average of 34% loss of serotonin transporters in raphe nuclei and 22% loss in the striatum compared with healthy controls. In A53T SNCA carriers with Parkinson’s disease, the loss of serotonin transporters is extended to 48% in raphe nuclei and 57% in striatum, whereas the loss of striatal dopamine transporters in this group is 71%. In line with previous studies,18,19,24 A53T SNCA carriers with Parkinson’s disease showed increased loss of dopamine transporters in the caudate and no differences in the putamen compared with patients with idiopathic Parkinson’s disease. Furthermore, the severity of loss of serotonin transporter in premotor A53T SNCA carriers was in line with decreases observed in patients with idiopathic Parkinson’s disease, whereas A53T SNCA carriers with Parkinson’s disease showed greater losses of serotonin transporters than did idiopathic patients."

    Study reveals roots of Parkinson's in the brain

    "...The new study, funded by the Lily Safra Foundation, provides the first evidence of a central role for the brain chemical serotonin in the very earliest stages of Parkinson's. The results suggest changes to the serotonin system could act as a key early warning signal for the disease. Chief investigator Professor Marios Politis, Lily Safra Professor of Neurology & Neuroimaging at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), says: 'Parkinson's disease has traditionally been thought of as occurring due to damage in the dopamine system, but we show that changes to the serotonin system come first, occurring many years before patients begin to show symptoms. Our results suggest that early detection of changes in the serotonin system could open doors to the development of new therapies to slow, and ultimately prevent, progression of Parkinson's disease.'

    "...Data from the 14 people with SNCA gene mutations were compared with 65 patients with non-genetic Parkinson's disease and 25 healthy volunteers. The researchers found that the serotonin system starts to malfunction in people with Parkinson's well before symptoms affecting movement occur, and before the first changes in the dopamine system. First author Heather Wilson, from the IoPPN, says: 'We found that serotonin function was an excellent marker for how advanced Parkinson's disease has become. Crucially, we found detectable changes to the serotonin system among patients who were not yet diagnosed. Therefore, brain imaging of the serotonin system could become a valuable tool to detect individuals at risk for Parkinson's disease, monitor their progression and help with the development of new treatments.'
     
  2. Goobz

    Goobz Member

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    Thanks for this, very interesting.

    Only glanced at this as its late where I am, but this would seem to make sense to me.

    REM sleep disorder - where people act out their dreams violently - is considered a sign of the prodromal period of a Parkinsonian illness developing. The only other known cause for this set of symptoms is that the person is taking certain antidepressants which act on the serotonin system.
     
  3. OP
    haidut

    haidut Member

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    Yep, and the tremor so commonly seen in PD is well-known to NOT be connected to low dopamine. In animal research, tremor and twitching are known to be reliably induced by serotonin excess. Too bad the story we always here is "just because it happens in all these animal species does not mean it happens in humans too". True, but since it happens in so many different animal models it would be more plausible to assume it DOES also happen in humans rather than wait for direct proof. Such impossibly high standards of evidence are usually only demanded when convenient to Big Pharma.
    https://raypeatforum.com/community/threads/tremor-in-parkinson-disease-pd-is-due-to-high-serotonin.22427/
     
  4. ecstatichamster

    ecstatichamster Member

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    Would cyproheptadine be helpful?
     
  5. tankasnowgod

    tankasnowgod Member

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    This study helps to explain a study I happened upon recently. On another thread, I saw it mentioned that cortisol can eliminate skin pigmentation, and wondered if cortisol was elevated in vitilago. I did a quick search, and found this study that measured many hormones in subjects with Active and Stable Vitilago-

    Neural and Endocrinal Pathobiochemistry of Vitiligo: Comparative Study for a Hypothesized Mechanism

    The stress hormones, like cortisol, prolactin, estrogen, TSH and serotonin were elevated in both vitilago groups, higher in the active group, while more beneficial hormones like T4, T3, and testosterone were lower in both vitilago groups. However, surprising to me, Dopamine was also elevated in the vitilago groups. But if a main cause of this (and other) diseases is an excess of serotonin and/or other stress hormones, it might make sense that Dopamine might also be elevated in an attempt to antagonize at least some of the effects of the serotonin excess.
     
  6. ecstatichamster

    ecstatichamster Member

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  7. OP
    haidut

    haidut Member

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  8. OP
    haidut

    haidut Member

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    Dopamine does rise initially as an attempt to offset serotonin but response wanes with age or continued stress similar to how in young people high cortisol elevates DHEA as well but in older/sicker people elevated cortisol ends up suppressing DHEA and gonadal androgens.
     
  9. ecstatichamster

    ecstatichamster Member

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  10. Soren

    Soren Member

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    Great Post haidut!

    What dose is needed of cyproheptadine or Metergoline to effectively lower serotonin for someone suffering from PD?

    I'm assuming it would have to be either a high dose or would require long term usage to be effective as someone with PD is likely to have a much higher level of serotonin than is typical for most.

    Does anyone know of a study with serotonin antagonists for treatment of PD, if not a human study maybe an animal one where human equivalent dose can be determined?
     
  11. Mito

    Mito Member

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    Why don’t long term SSRI users develop PD?
     
  12. Goobz

    Goobz Member

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    Well if this study shows that the serotonergic system is involved in PD, and it’s dysregulation produces some of the symptoms. However that doesn’t mean that it’s the only or even the primary cause.

    In my opinion both the serotonin and dopamine changes likely occur downstream from whatever the main cause of PD is - toxins, infections, hypoxia, nutritional deficiencies, severe chronic emotional stress, have all been implicated.

    And at least for the case of Alzheimer’s disease, the old tricyclic antidepressants have indeed been shown to contribute to that disease. I wouldn’t be surprised to see the same of PD.
     
  13. Goobz

    Goobz Member

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    SSRIs are a different story İ guess.

    I know that mouse models of PD and a few PD patients have found St Johns Wort to be helpful, which I thought would raise serotonin like an SSRI but maybe functions differently.
     
  14. Mito

    Mito Member

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    The OP says that disfunction of SERT (serotenergic system) comes many years before the degeneration of the dopamine system. This implies it’s a probably a primary cause.
     
  15. OP
    haidut

    haidut Member

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  16. OP
    haidut

    haidut Member

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    I think any dose would help. Serotonin antagonist probably won't lower serotonin while in use, they just block its effects. Cyproheptadine has been used clinically to control individual cases of severe PD, and the dosage used was 16mg-32mg daily. But for prevention or controlling lighter cases probably even 2mg daily would suffice if used on a regular basis. Aspirin is also a great tool for PD.
     
  17. Goobz

    Goobz Member

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    Well no, it doesn’t really. Many events take place early on in a disease process which have nothing to do with causation.

    We have to be careful not to read our own ideas into scientific results - this is the opposite of a good skeptical scientific approach, which works on the null hypothesis.

    Ie the study starts with the assumption there is no relationship between serotonin and PD (null hypothesis) and tries to disprove it. Which the study does. Hence proving there is a relationship between serotonin and PD. But, importantly, it says nothing of causation.

    It’s very easy at this point as a reader to insert our own ideas about causation, and then use the study as “proof” to back them up since they “fit” our theory.

    For example - my question would be, what causes the serotonin system in PD to go haywire? My suspicion would be something to do with kynurenine / tryptophan / NAD+ pathway being dysregulated due to infections, toxins, injury etc, and the serotonin changes are merely downstream of that. If this is the case, then changing ones serotonin without fixing this situation may not do much to help.

    It’s also important to mention PD probably has many many causes, which converge on these pathways. “Parkinsonism” is different from full blown Parkinson’s disease, which itself is still called “idiopathic Parkinsons”
     
  18. OP
    haidut

    haidut Member

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    You are right, so far it is just a correlation. But there is another thread that I posted before and it lists other studies too. At some point, all that correlation starts to look more and more like a cause.
    https://raypeatforum.com/community/threads/tremor-in-parkinson-disease-pd-is-due-to-high-serotonin.22427/

    And if that is not enough, here is another study that does find a causal link and reverses some of the PD pathology (dyskinesia) by blocking the excessive serotonergic transmission with 5-HT1A agonist, which induces inhibitory effects on serotonergic activity through negative feedback.
    Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. - PubMed - NCBI
    "...In addition, excess serotonin release can act directly on the dopamine terminals to induce an activityindependent, amphetamine-like release of dopamine, probably via reversal of the dopamine transporter (21–23), and may further enhance the dysregulation of dopamine release, worsening GIDs. The attenuation of GIDs that we observed is thus readily explained by the ability of 5-HT1A agonists to dampen serotonergic neurotransmission by activation of the inhibitory autoreceptors."

    Toxin-induced PD is well-known clinically from studying manganese toxicity. Given the sheer number of PD cases diagnosed every year and the very high correlation with age, argues against infection/toxin as a cause. Btw, those angles have been explored already decades ago. Many companies tried to link viruses to PD and so far have failed. The toxin angle has also been largely disproven through autopsies of people with PD.
    Endotoxin, however, is strongly implicated as just posted in another thread. Not sure if you would consider this toxin/infectious cause but it still manifests its effects on the brain mostly through serotonin/NO.
    https://raypeatforum.com/community/threads/new-study-parkinson-could-be-linked-to-intestinal-infections.29883/
     
  19. Goobz

    Goobz Member

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    Yep I agree it very much looks like a key player, and may well be a major cause. Its too early to say that though IMO, from what Ive read.

    However if its anything like Alzheimers, and it looks like it is, it probably has many different causes. Ithink certain individual infections and angles may have been explored, but since not every patient has every factor and cause, the studies seem inconclusive. Dale Bredesen has talked about this with Alzheimers disease and identified about 36 different causes. That disease has lots of evidence for an infective component. Multiple infections are found in AD brains, antibiotıcs seem to slow it, etc.

    "We are saying there is incontrovertible evidence that Alzheimer’s Disease has a dormant microbial component, and that this can be woken up by iron dysregulation. Removing this iron will slow down or prevent cognitive degeneration – we can’t keep ignoring all of the evidence"
    Researchers Identify Virus and Two Types of Bacteria as Major Causes of Alzheimer’s

    As for the good point you raise about the late onset, Ive read some researchers hypothesise that this is due to the infection being one that has a long incubation period,and most likely requires a level of immune deterioration that comes with age before becoming progressive.

    And yep I very much consider the endotoxin as part of the whole "infection" line of thinking. They mention it specifically in that above article.

    Its well known that syphillis causes a dementia, and it used to be one of the most common causes. Lyme and other stealth infections like chlamydia pneumoniae have been found in AD brains, and
    a) are very closely related to syphillis
    b) are involved in iron dysregulation
    c) produce endotoxin / LPS
    d) massively dysregulate the tryptophan / NAD+ / kynurenine pathway (the body attempts to control these intracellular infections by activating the kynuerine pathway and starving the cell of tryptophan). This also dysregulates serotonin of course.

    And the same is likely going to be true of PD in my opinion - it will have multiple causes.
    For example a brain infection of encephalitis is a well known cause of "Parkinsonism".
    A known toxin pathway is fungal toxins - the most common mycotoxin, Ochratoxin A, competitively inhibits phenylalanine. This leads to less dopamine and some symptoms that resemble Parkinsons, which can improve a lot with toxin binding treatment. There are cases of people being diagnosed with PD, being treated by a specialist mold doctor like Dr Shoemaker, and their symptoms being reversed.
    Phenylalanine, Tyrosine, L-Dopa, Dopamine and Parkinson's Disease

    Theres a similar theory for a different toxin dysrupting a different amino acid - toxins from cyanobacteria being taken up in the body as serine, causing AD, PD and ALS.
    Could This Radical New Approach to Alzheimer’s Lead to a Breakthrough?

    So in the face of all this, the "multifactorial" hypothesis is the one that seems the most likely to me. And hence why I made the point about being careful to not infer causation in studies which show correlations. And also why Id be skeptıcal of any theory that claims to be the one single cause of these diseases, at this point
     
  20. aguineapig

    aguineapig Member

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    "...The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene.[5]"

    Does "sodium dependent" relate in any way to/implicate sodium chloride/salt lowering serotonin?
     
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