Autoimmune Diseases: Histamines, Glutamate and Sleep Problems

My model is that the majority of auto-immune diseases is caused by gut dysfunction – aka. Microbiome has stabilized in an unhealthy state. I have seen personally and have had reported to me, that sets of symptoms disappears or are reduced by a single probiotic. Not all symptoms cured – no magic yogurt – just one set of them. A  dysfunction consists of many evil strains cross-supporting each other, each strain produces their own symptoms (and more than one strain may be responsible for a symptom). While this model does an awesome job of explaining the very wide variety of symptoms between patients for illnesses such as Chronic Fatigue Syndrome- CFS – [each patient has their own unique set of strains!], and appears to be well supported by PudMed articles and studies on the microbiome, it has more complexity for treatment than modern medical skills and knowledge has acquired – both main stream and alternative medicine.

The use of antibiotics have worked for some CFS patients but fails with others. For Crohn’s Disease, the use of the most commonly prescribed antibiotics have actually worsen the microbiome dysfunction (i.e. greater shifts away from healthy base lines after use than existed before — although symptoms can improve). Appropriate probiotics seem to be the “do least harm” if appropriate research is done first. Saying “Probiotics can reduce allergy problem” is an over-generalization that can do more harm — some probiotics can increase allergy issue. “Specific probiotics can reduce allergy problems, and others can make it worst — yogurt may not be your friend in Allergy Season!” is a better statement.

Sleep Issues

A reader contacted me because of increasing sleep issues — it seemed to have gotten worst since starting Yakult (the last item changed always get the blame!) although Yakult seem to have improved other symptoms significantly. Fortunately, there was a reliable record of supplements taken and not taken taken by a third party.  They had, too typically, stopped taking a set of supplements two weeks before starting Yalkult. Detail record keeping can be priceless!.

One cause of sleep issues

This reader has histamine issues, for example any citric fruit will trigger a severe histamine release, so I thought that I would look down that path as it seems the most probable mechanism is histamine related. The problem was that while exhausted, tired, with a calm mind — they were unable to get to sleep for hours and hours. Often getting only 2-3 hours of poor quality sleep a day. This is not good because the immune system generally “kick ass” against infections when a person is sleeping.

The medical Literature

The following is some samples of what I found – a bit of medical geek speak –

  • “The prominent role of histamine as a wake-promoting substance has drawn interest to treat sleep-wake disorders, especially narcolepsy, via modulation of H3 receptor function.” [2010]
  • “The histaminergic system modulates different processes including wakefulness, feeding, and learning and memory consolidation. Histamine receptors (H1R, H2R, H3R, and H4R) belong to the rhodopsin-like family of G protein-coupled receptors, present constitutive activity, and are subjected to inverse agonist action. ” [2014]
  • There were many recent (2013,2014) pub med articles saying there is no known prescription drug that impacts the H3 in the desired path — so, Plan B is required.
Going to Wikipedia on H3, I read
  • “whether H3 receptor ligands could be useful in modulating wakefulness (because of effects on noradrenaline, glutamate and histamine).
And then followed the glutamate lead on to this
  • “High levels of the neurotransmitter glutamate may be to blame for the insomnia associated with restless leg syndrome (RLS), a small study suggests.” [Gupta Guide]

Treatment Hypothesis

 The root cause of the sleep issue is the level of glutamate in the brain. Effective treatment may be to reduce those levels – but how??? The location of excessive glutamate is in the brain — this adds a challenge to treatment because of the Blood-Brain Barrier. Many supplements and herbs may be effective in lowering it in the body, but have no impact on the brain.


For a good description on the history and issues of the Blood Brain Barrier see this article[2005]. The article identifies that a compound should havemolecular weight below 450 in order to cross the barrier. Some examples for antibiotics are:

  • Minocycline: 457
  • Doxycycline: 444
  • Cefoperazone: 645
  • Sparfloxacin: 392

This aspects is often missed by treating physicians resulting in useless antibiotics and drugs being tried that cannot make it into the brain. 😦

Search Results

A logical starting point was to look at glutamate and each of the supplements that were stopped. This produced some interesting results:

  •  Piracetam caused a decrease in mouse brain glutamate content and glutamate/GABA rate.[1991]
    • According to the supplement records, the person had been taking 1000 mg of Piracetam daily but this was stopped two weeks before starting Yakult. A smoking gun? While Piracetam was being taken for other reasons, a side effect may have been the lowering of glutamate levels which slowly creep up after it was stopped being taken resulting is sleep problems as it increased.
  • Alpha Lipoic Acid (ALA) “observed a significant increase in glutamate content (37%) and a decrease in taurine level (18%) in rat hippocampus,” [2011]
    • Ah, this one should not be re-introduced, alternatives should be found for why it was being used.
  • Ashwaganda(Withania somnifera) ” pre-treatment inhibited glutamate-induced cell death and was able to revert glutamate-induced changes in HSP70 to a large extent.”[2012] “protected the glial and neuronal cells from oxidative as well as glutamate insult”[2015]
    • Tentatively  reads like it should be used.
  • Cinnamon: “attenuating the reduction in glutamate uptake”[2012]
    • A little fuzzy if good or bad
  • Turmeric (Curcumin): “curcumin-mediated inhibition of glutamate release involves modulating downstream events”[2012] “curcumin inhibited the release of glutamate”[2011]
    • Definite good. No release, no high levels

Bottom line appears to be that the glutamate levels likely increased significantly, once the above supplements were stopped. Not immediately next day, but slow rising and resulting in increasing difficulty with sleep due to high glutamate levels in the brain. None of the above was being taken explicitly for controlling glutamate levels, but for other reasons — it just happened that they impacted glutamate levels very positively.

With a working hypothesis appearing to be validated, now it is time to see if this patient will return these supplements and then see if sleep quality improves as a result. Recommendations to discuss with health professional:

  • Piracetam: 1000 – 6000 mg/day
  • Turmeric (kitchen spice): 1000 – 6000 mg/day