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Chronic Fatigue Syndrome (ME/CFS) May Be Caused By Increased Serotonin Sensitivity

Discussion in 'Scientific Studies' started by haidut, Dec 18, 2017.

  1. haidut

    haidut Member

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    Despite the denials of mainstream medicine that CFS exists as an organic disorder, many studies have been done on the etiology of the fatigue and how it often follows an acute illness, usually of "viral" origin. Due to the fact that the role of serotonin in inducing fatigue is well-known everywhere except in clinical practice, many of those studies have examined the changed in the serotonergic system but the results were inconsistent. No major changes were found in brain tryptophan, serotonin or 5-HIAA levels in CFS patients. This new study below discovered that while systemic levels of serotonin and its precursors/metabolites do not change, the expression of the 5-HT2A receptor is increased, which results in dramatic increase in serotonergic signalling in the cells that express that receptor. Apparently, it has been known since the 1980s that the same receptor is increased in suicidal people, which would mean that drugs that agonize 5-HT2A are expected to increase risk of suicide. Well, most SSRI drugs are actually 5-HT2A agonists. Thus, despite that fact that some of them are antagonists at 5-HT2C (Prozac) their overall effect would be expected to be pro-suicidal, which has been confirmed by vritually all trials and has resulted in blackbox warnings by the FDA.
    The good news is that the study suggests that something as simple as cyproheptadine or another non-selective serotonin antagonist may be a viable treatment for both CFS and suicidal ideation.

    A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice. - PubMed - NCBI
    "...It is well documented that serotonin (5-HT) plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS), which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5 mg/kg i.p.), at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS."

    "...Perhaps the most commanding results here are the changes we have observed in the 5-HT system. In this study, treatment with LPS caused a significant increase in 5-HT2A receptor expression in a number of discrete brain regions. We have also demonstrated that this results in a functional outcome, i.e. there is a significant alteration in 5-HT2A-mediated behaviours. This is in accord with our previous studies on acute sickness, where increases in 5-HT2A receptor expression were also associated with functional changes [24]. Our data also indicate that these changes are receptor specific, rather than a general change in 5-HT receptor expressing cells, as we do not see similar changes in other 5-HT receptors, such as 5-HT1A (S5 Fig). The involvement of the 5-HT2A receptor in mood is currently controversial. Studies from the late 80s indicate that receptor expression increases in patients with suicidal depression [4749], with further data suggesting that this increase may be non-neuronal [50]. In terms of inflammation, and as a consequence sickness behaviour, increases in 5-HT2A receptor expression have been seen in models of inflammatory pain [51], as well as in other studies using LPS [5] indicating that systemic inflammation is capable of regulating this response in vivo. The mechanisms by which changes in receptor expression occur were beyond the scope of this study; however, hypotheses can be generated based on existing research. Studies linking the 5-HT2A receptor with inflammation have suggested that its activation may result in the down-regulation of inflammatory cytokines [52], specifically TNF expression [53]. Furthermore, studies in cultured glioma cells have demonstrated an inhibition of inducible nitric oxide synthase (iNOS) by 5-HT2Aagonists [54]. Work by Zhang and colleagues [51] demonstrated that the up-regulation of 5-HT2A after inflammation was not co-localized with 5-HT, indicating that it was not in serotonergic neurons. Furthermore, 5-HT2A receptors have been shown to be present on astrocytes and microglia [55]. Therefore, increased 5-HT2A receptor expression after a peripheral inflammatory stimulus could potentially occur in non-neuronal cells for the purposes of potentiating an anti-inflammatory response in the CNS."

    "...Overall, this study has explored the association between late phase LPS-induced depression-like behaviour and the expression of 5-HT related genes. The data presented here demonstrate that inflammation does not appear to regulate CNS tryptophan levels, but rather may mediate depression-like behaviours by altering the expression and function of CNS 5-HT receptors. This could significantly affect the direction of future research into inflammation associated fatigue and mood disorders, and argues for the use of selective 5-HT receptor agonists and antagonists in their treatment."
     
  2. tomisonbottom

    tomisonbottom Member

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    Do you know anyone who's treated their CFS with a serotonin antagonist successfully?
     
  3. dilantinoid

    dilantinoid Member

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  4. Rad

    Rad Member

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    Not successfully. Barely managed 4 days on ritanserin before I had to give up. Felt really bad.

    Maybe something else would be worth a try. I took some screws out of a laptop today and the mental fatigue was immense. Novel actions are the hardest. If I do something regularly it gets easier. Listening to people talk for more than a minute is crushing.

    Ritanserin - Serotonin Antagonist For R&D Use Only
     
  5. OP
    haidut

    haidut Member

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    I know of 4 that were not able to do much except lie in bed all day (not even watch TV). All of those people are now employed and have active social lives. Two of them (one female and one male) started families (not with each other).
     
  6. tomisonbottom

    tomisonbottom Member

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    Wow, that's so awesome! Do you know if they changed their diet too?

    And how many mg did they take, and for how long?
     
  7. OP
    haidut

    haidut Member

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    I think their diet changed but it was not conscious. When they had severe CFS they would eat little and mostly junk food. Now that they are active, they eat better food but I have not seen them consciously avoid PUFA like I do. They do avoid fried food as it makes them irritable.
     
  8. Rad

    Rad Member

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  9. Collden

    Collden Member

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    Doesn't coffee increase sensitivity to serotonin?
     
  10. LeeLemonoil

    LeeLemonoil Member

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    Any idea why Viruses or other Pathogens would profit evolutionarily if "they" imcrease the suicide receptor? Profiting from a fatigued host that has a Hard time taking Initiative to act against its Infection seems obvious though
     
  11. debored13

    debored13 Member

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    I've seen this study but find it less convincing than Naviaux's work. Naviaux did one of the biggest data gathering CFS studies and was focused on the role of purinergic signalling and metabolism
     
  12. debored13

    debored13 Member

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    don't get me wrong, I would be super excited if this cortene stuff helped, but if serotonin was the main cause of CFS I feel like we'd see more anecdotes of trazodone or cypro curing people. I have cfs and have tried anti-serotonergic drugs of many kind as well as pro-serotonergic and none of them helped
     
  13. OP
    haidut

    haidut Member

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    Most of the serotonergic drugs on the market (including cypro and trazodone) are also antihistamines and can make people feel tired. People who have tried more targeted anti-serotonin chemicals like TPH inhibitors or 5-HT3 antagonists like ondansetron have reported very good results. Dopaminergic drugs have been used in the past for CFS. The actoprotector drugs like bromantane, kemantane, bemitil, etc used for CFS in Eastern Europe are all dopaminergic and anti-serotonin.
    The Dopamine Imbalance Hypothesis of Fatigue in Multiple Sclerosis and Other Neurological Disorders
    "...Further, dopaminergic psychostimulant medication has been shown to alleviate fatigue in individuals with traumatic brain injury, chronic fatigue syndrome, and in cancer patients, also indicating that dopamine might play an important role in fatigue perception. This paper reviews the structural and functional neuroimaging evidence as well as pharmacological studies that suggest that dopamine plays a critical role in the phenomenon of fatigue. We conclude with how specific aspects of the dopamine imbalance hypothesis can be tested in future research."
     
  14. debored13

    debored13 Member

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    Interesting--I have had odansetron once or twice just for nausea since getting sick, but ginger has a similar compound. should try
     
  15. debored13

    debored13 Member

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  16. OP
    haidut

    haidut Member

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    Others did find benefit.
    Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. - PubMed - NCBI
    Treatment of chronic fatigue syndrome with 5-HT3 receptor antagonists--preliminary results. - PubMed - NCBI
    Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. - PubMed - NCBI


    I think a dopamine agonist or a non-selective serotonin antagonist would be better as they would address the entire serotonin receptor family. More recent studies are now looking at TPH inhibition or tryptophan/serotonin depletion in the brain to achieve the same effect. So, a combination of BCAA/tyrosine/phenylalanine as described in other threads may also help.
     
  17. debored13

    debored13 Member

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    I’ll read those studies. I do have a problem with lumping chronic fatigue syndrome in with fatigue based on other causes. I think it probably has a specific mechanism , like purinergic signalling
     
  18. OP
    haidut

    haidut Member

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    Ultimately, all fatigue has a single mechanism of manifesting itself. If it is mental/central fatigue, it has been conclusively linked to serotonin. If it is peripheral fatigue, it is usually lactic acid, which can also be caused by high serotonin and a few other things.
     
  19. debored13

    debored13 Member

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    That sounds oversimplified but I’ll admit I’m no expert. I’ve read quite a bit of the literature on chronic fatigue syndrome though, and by far the most compelling was naviauxs study on chronic fatigue syndrome using metabolomics. He talks about the cell danger response as something that has to do with purinergic signalling. It involves possibly every body system and makes sense as a unifying theory that links immune system response to metabolism. I saw your thread on that study so I know you're aware of it. I'm also aware that Ray disagrees with naviaux and thinks CFS is simpler--that it's simply hypothyroidism and/or reductive stress.

    Does the serotonin theory fit with the purinergic signalling theory? Imo naviaux's theory is very convincing, and he had decent results with his suramin trial in autistic children. Empirical evidence is always the best test of a theory, and I think that Naviaux's metabolomics study on CFS was convincing for that reason--for the sheer volume of information he was collecting.
    "Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism...

    Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer."
     
  20. debored13

    debored13 Member

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    Not many people have trialled anti-purinergics informally for cfs. emodin and sytrinol seem like the most safe so far, apparently to be at all safe, suramin has to be administered in a very controlled, slow infusion and blood levels monitored, so this isn't something your average cfs sufferer could just administer to themselves
     
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