I have often recommended Piracetam for cognitive issues. I have personally observed dramatic improvement within minutes in others, and observed it with myself. Unfortunately in the US it is not directly available because of FDA rulings (the same situation as for Mutaflor — E.Coli Nissle 1917 probiotic). Mutaflor is well documented (citations) with over 240 studies, and safely used in Europe for over a century — and works far better than any probiotic approved by the FDA.
Today, when I mentioned it, a facebook user wrote “Piracetam seems to come with warnings:” and linked to a JAMA article from 2019.
Our findings demonstrate that even after the FDA rejected an application to market piracetam as a new supplement ingredient,3 the drug was nevertheless introduced into the marketplace. Despite FDA warning letters,6 the products remain on the market. Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses.
This was not a warning of the dangers of this substance — but a warning of the sale of a substancedirect to retail as a supplement ignoring FDA rulings in some products (which seems like a very American attitude 🙂 )
Originally marketed by UCB Pharma in 1971, piracetam was the first nootropic drug to modulate cognitive function without causing sedation or stimulation 1. It is not approved for any medical or dietary use by the FDA. In the UK, piracetam is prescribed mainly for myoclonus, but is used off-label for other conditions such as learning difficulties in children, memory loss or other cognitive defects in the elderly, and sickle-cell vaso-occlusive crises 4. Evidence to support its use for many conditions is unclear.
“Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. …. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. ” 
The JAMA was concerned about supratherapeutic doses, i.e. above 1500 mg. Going over to DrugBank Pharmacology resource we read
The cases of overdose with piracetam is rare. The highest reported overdose with piracetam was oral intake of 75g which was associated with diarrhea and abdominal pain; the signs were most likely related to the extreme high dose of sorbitol contained in the used formulation
I suspect that the FDA ruling for piracetam is similar to that for Mutaflor. The decision was influenced by established american industries with a vested interest in selling their existing (ineffective often) products.
This week’s New Scientist is focused on it. Unlike medical professionals which are renowned for telling dying patients “You will be alright”, science journal writers tend to call spades — tools to bury the dead.
“Long covid: We have ignored post-viral syndromes for too long”
But it isn’t surprising. Post-viral syndromes, which often involve extreme, lasting fatigue and other symptoms, are common after many infections. About 1 in 10 people infected with SARS-CoV-2 seem to get lasting symptoms, a similar proportion to those infected with Epstein-Barr virus, one of the most common human viruses. The SARS virus, another coronavirus, left as many as 30 per cent of survivorsmeeting diagnostic criteria for chronic fatigue syndrome, also known as CFS/ME, four years later.
“There are no treatments, in part due to a lack of investment in research into chronic fatigue”
Sadly, governments and health systems have taken too long to pay attention. England now has 83 long covid clinics, which are indispensable for some patients, but there is a notable absence in the rest of the UK (see “Inside the UK’s first long covid clinic: ‘It was life-changing”). Clinics are unable to cope with the number of cases and waiting lists run long. This is especially problematic because early action – such as resting rather than taking on too much physical activity – could expedite recovery. Also notable is the absence of public health campaigns on long covid, to reach those who don’t know what is wrong with them or what to do about it.
For now, there are no treatments, in part because we are decades behind where we could be due to a lack of interest and investment in researching post-viral syndromes and CFS/ME.
This must change, and we now need a similar effort for treatments of long covid and other post-viral syndromes that we have seen in the race for a vaccine. In the meantime, people with long covid symptoms must be taken seriously, and given the financial and social support they need to allow them to get better.
My own model is that post-viral syndrome are supported by a stable microbiome dysfunction. Whatever the mechanism is, it needs the altered metabolites mixture from this dysfunction to maintain the syndrome. Correct the microbiome and the severity of the syndrome will decrease, frequently disappear entirely.
Dihydroquercetin (sold as Taxifolin) was suggested in a comment on Fisetin and praised that it worked better for the reader than other items, etc. A friend tried it, as to date, noticed a distinct improvement after just a few days — especially in not having histamine issues after a meal. It’s time to review and summarize what is known about it.
Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in onion, milk thistle, French maritime pine bark and Douglas fir bark. It is also used in various commercial preparations like Legalon™, Pycnogenol®, and Venoruton®…. Modulated NF-κB activation Suppressed the NF-κB activation, protein kinase activation by C-Fos and mitogen, and reduced the expression of osteoclast-specific genes, including Trap, Cathepsin K, Mmp-9, Nfatc1, C-Fos and Rank Inhibited the osteoclast differentiation induced by RANKL Suppressed the NF-κB signaling pathway and inhibited the osteoclastogenesis
Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin) is a flavonoid commonly found in onion, milk thistle, French maritime pine bark and Douglas fir bark. It is also used in various commercial preparations like Legalon™, Pycnogenol®, and Venoruton®….
Now, for histamines we find “low concentrations of H2O2[Hydrogen Peroxide] appeared to augment … histamine release induced by anti-IgE…. Since taxifolin inhibited Hydrogen Peroxide generation but had little inhibitory effect on histamine release indicates that H202 generation is not a prerequisite for anti-lgE-induced histamine release….By contrast, taxifolin caused a large inhibition of H202 formation but had a much smaller effect on histamine release. ” .
Reading thru several studies [most from the 1980’s], we find that it was inactive against some forms of histamine release. I suspect that it dropped off the radar of people suffering with mast cell and histamine issues because of these studies (using older methodologies)
“There was a remarkable correspondence of inhibitory activity for each of these flavonoids against TF’A-, teleocidin-and aplysiatoxin-induced histamine release. Taxifolin was essentially inactive against each tumor promoter,” 
However we also read “Dihydroquercetin in the capacity of antioxidant may be compared or exceeds many synthetic and natural antioxidants and, in particular, known bioflavonoids (quercetin) ”
The status changed in a more recent study specific to mast cells and not generic histamine.
Taxifolin inhibited degranulation, generation of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) through blocking intracellular Ca2+ mobilization, phosphorylation of phospholipase Cγ (PLCγ) and mitogen-activated protein kinases (MAPKs), translocation of cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO), and Akt/IKK/NF-κB pathway, in BMMC cells.
An earlier study also point to too narrow a focus with these “no effect” studies
” Dihydroquercetin (taxifolin), previously considered as inactive, showed an interesting cromoglycate-like behaviour. ”
What is this behavior??
“Cromoglicic acid — also referred to as cromolyn, cromoglycate, or cromoglicate — is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium. This drug prevents the release of inflammatory chemicals such as histamine from mast cells….The underlying mechanism of action is not fully understood; ” Wikipedia
This compound seems to act in a different way than antihistamines. It does not require a prescription. In some ways it acts like cromolyn (which some people take for other conditions “in Crohn’s disease … 60% improved clinically” ). IMHO, it is likely worth trying one bottle of it. A related suggestion is to take Catelase to reduce hydrogen peroxide (and thus lower histamine release).
I recently got this email (with samples uploaded to Microbiome Prescription). I am going to compare these samples to see if I can gain any insight.
Just this morning received the new Thryve results. ***** was in really bad shape when this sample was taken – full crash. For reference he would have been a “5” for the first sample and a “1” or “2” for this one.
The top one was for “5” and bottom for “1”. There was an apparent drop in ‘rare’ bacteria. With “5”, we have 16.3% in the top 16% (i.e. expected) and with “1” we are down to just 5%. This implies some bacteria have become intolerant or bias against others. In the video below, I am going to walk thru my explorations (i.e. playing hide and seek with the cause). The fact that these two samples were taken close to each other means discovery is a lot easier because microbiome drift is greatly reduced.
Do we have genocide happening?
The above leads us to look at natural antibiotics, we see some very dramatic shifts – especially in bacteriocins (a protein produced by bacteria of one strain and active against other strains). As we saw above, the natural “push and shove” between bacteria has been suppressed with lots of bacteria dropping off the radar.
Hydrogen peroxide is another known bacteria killer, it too had a similar increase of amount
By clicking on the numbers, we can see the bacteria responsible — for example, Hydrogen Peroxide, we see that it’s main producer is Lactobacillus where we went from double the upper normal range to triple the upper normal range .
We can do this for the others (see video for a walk thru). The biggest impact at a genus, was Blautia (from 64%ile to 93%ile)
We see that Lactobacillus is sitting at the 90th %ile with “1” and was at the 86%ile with the “5”. Almost all of the Lactobacillus is Lactobacillus rogosae. Here was have a catch — it is not a lactic acid producer but one of the greatest hydrogen peroxide (H2O2) producer!it was also high in “5” but much less.
Keeping Focus on the recent change and not the long term condition
There was some shifts that were surprising — for example KEGG computed supplements decreased with the “1” sample. Probiotic suggestions were similarly reduced with less weight.
Using the Krona Charts, we see the overall shift well. First the “5” sample
Then the “1” sample, notice that the green area took a major decrease.
With the Krona Charts, we can drill down by just double clicking. Below are the drill downs on Clostridia , again “5” first and then “1”. Drilling down allows us to see how the composition of a group changed.
The main item was an increase of Blautia, especially Blautia wexlerae (91%ile to 98%ile) and Blautia faecis (63%ile to 92%ile). Most of the Blautia species increased — resulting in a lot of bacteriocins being produced.
Because Blautia and Lactobacillus appears to be a major players, we hand picked for them:
The suggestions were no lactobacillus probiotics (obvious)
I am not too happy with these, because of the dominant item, Lactobacillus rogosae , having no known modifiers, so the items are generic lactobacillus modifiers — which may or may not apply. I went back and just picked the high blautia.
It is reduced by Methicillin-resistant Staphylococcus aureus 
“The species most frequently related to vaginal health were Lactobacillus jensenii and Lactobacillus rogosae.”  This actually hints at why other bacteria appeared to be suppressed — it is a strong hydrogen peroxide producer.
Some interesting nodes:
“. The hydrogen peroxide-producing colonic bacteria have been also suggested as causative agents of IBD in young adults (107).” and “hydrogen peroxide … are dangerous to mucosal cells, easily penetrating through membranes and causing, depending on their concentration, their apoptosis and necrosis[death]”
“Resistance to hydrogen peroxide is proportional to pyruvate oxidase expression.”  This is Enzyme 126.96.36.199 in KEGG – which we can look up! The count increase from 12%ile in “5” to 29%ile in “1” indicating an increase of bacteria that tolerates hydrogen peroxide. The following appear in the new sample that have this enzyme: Weissella ceti, Aerococcus urinae and a doubling of Staphylococcus haemolyticus.
Unfortunately, KEGG data applies only to those that are fully sequenced, so data is incomplete and often is only for one strain of a species.
We can see the probable cause, increase of L.Rogosae which may have saturated the gut with hydrogen peroxide killing off or reducing many other bacteria. Hydrogen Peroxide tolerant bacteria grew. I was unable to find any explicit information on B. Wexlerae being hydrogen peroxide tolerant. However we do find B. Wexlerae, and Blautia in general are “catalase-negative, indole-negative and produced acetate and succinate as end products of metabolism” . Since catalase breaks down hydrogen peroxide — it implies that they may be tolerant (at least not consuming).
The logical way would be to reduce or eliminate L.Rogosae — but we have no information on what effects it which is acceptable (or affordable!). Contrary to general opinion, Hydrogen Peroxide: the body’s best defence system, too much is not desired.
Strategy to reduce the Hydrogen Peroxide
The basic concept is that the environment and other bacteria are symbiotic (a mutually beneficial relationship). If you alter the environment, then the bacteria will change. We want to shift it away from high Hydrogen Peroxide levels and consuming bacteria. We do not know how to alters those identified — but we do know how to break down the Hydrogen Peroxide.
Catelase [Wikipedia] breaks down hydrogen peroxide (H2O2) and is available as a supplement. It appears to be the simplest path forward.
There have been NO STUDIES of this supplement with ME/CFS. It is a novel approach.
As a side note: high hydrogen peroxide (H2O2) is associated with loss of hair color. It was during a ME/CFS relapse that I lost most of my color (older brother and both parents retained their hair colors until they were decades older).
NOTE: Suggested dosage: for 110lb person – 1000mg/day (see Comments)
In my very first post on this site, I reported that I have a remarkable response to high dose biotin. It reduces my ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) symptoms like severe fatigue and the mental confusion that people with ME/CFS call brain fog. It also reduces my autistic symptoms, relieving anxiety and irritability while improving my ability to read people.
A natural substance called fisetin gives me similar but better results and fisetin’s effects can last for days and possibly weeks for me. On high dose biotin, I relapse badly if I miss a twice daily dose. I have switched from biotin to fisetin because fisetin seems to improve the function of my brain and body for longer periods of time.Fisetin is found in many fruits in vegetables, but is found in the highest quantities in strawberries.
Fisetin helps pull me out of post-exertional malaise. As a mild ME/CFS patient, I could historically expect to get a few days to a couple of weeks of postexertional malaise after mild exercise like moderate digging in my garden. With fisetin, I am able to dig significantly more without a problem and recover more quickly when I overdo it. Things like going on a bike ride around the block will trigger about 2 days of PEM instead of 5 or 7. Not a panacea, but an improvement.Day to day, in the absence of attempting to exercise, I am so much clearer and sharper mentally. My memory and focus is so much better and I feel less physically weak and forgetful.
Like a lot of autistic people and like many people with my connective tissue disorder, Ehlers-Danlos syndrome, I deal with a lot of anxiety. Three capsules of fisetin reduces my anxiety greatly within 24 hours. It’s like meditation in bottle. Fisetin also helps a great deal with the constant low level depression that I have had most of my life, that many people with autism have.A bottle of fisetin will generally tell you to take 1 capsule. I have never had results with less than three capsules and have taken 5 capsules twice daily with good effects. Fisetin has exceptionally low toxicity. Existing fisetin research might shed light on why it works for me.
Fisetin Inhibits Mast Cell Activation
Like many people with ME/CFS, Ehlers-Danlos Syndrome and autism, I also have mast cell activation syndrome (MCAS), an inflammatory disorder of a certain type of immune cell called a mast cell. MCAS caused the bouts of flushing and I hives I got when I first became ill with ME/CFS.
This 2007 article found that fisetin downregulated mast cell activation in part by suppressing one of the major inflammatory molecules in the body: NF-kappaB. NF-kappaB
NF-KappaB is considered the master regulator of the inflammatory response in the body. Indeed, fisetin has other effects in the body related to suppression of NF-KappaB activation. In animal study published last year, fisetin inhibited airway inflammation and hyperresponsiveness in an animal model of asthma by interfering with NF-KappaB. In another study, fisetin reduced signs of disease in an experimental animal model of inflammatory bowel disease. In a chronic inflammatory disorder such as ME/CFS, it might make sense to try something that broadly downregulates the inflammatory response. Ischemia-Reperfusion InjuryI actually chose fisetin to try specifically because it seems to protect the body and brain against the effects of a type of damage called ischemia-reperfusion (I/R) injury. I/R injury occurs when cells are temporarily deprived of blood and then blood is re-introduced. Cells don’t do well being deprived of oxygen, but serious damage also occurs when the oxygen supply is re-established.
I have been concerned that some version of mild I/R injury in the brain occurs in ME/CFS because we tend to have low blood pressure as well as syncope or light-headedness when standing.
Low blood pressure makes it hard to pump adequate blood to the brain all the time and syncope is a sign that the brain doesn’t have enough blood. A number of studies have found problems with blood flow to the brain in ME/CFS.I am also concerned that changes in the circulatory system in the body produce conditions of periodic blood impairment to cells. Research from the Open Medicine Foundation has found that red blood cells in ME/CFS fail to deform and flow smoothly through small blood vessels, a situation which would cause cells to be periodically denied oxygen. Fisetin has been found to prevent I/R injury in the heart as well as the brain and protect mitochondria from the damaging effects of I/R injury.Fisetin, Leaky Gut & Microglial Activation.
ME/CFS patient have show elevated antibodies to LPS, a component of bacteria that inhabit the gut. When this component ends up in the blood stream in larger than normal quantities, it can potentially trigger sepsis, an often deadly inflammatory response to bacterial infection.While the quantity of LPS in the blood of ME/CFS patients doesn’t reach that of sepsis patients, one of our researchers has suggested that ME/CFS is like a slow, chronic sepsis.
One part of the body that circulating LPS affects is the brain and many of the symptoms of ME/CFS seem to emanate from the brain, in particular flu-like malaise and brain fog. In animals, LPS exposure causes a depression-like response that may be related to the sensations of fatigue, depression and malaise that people feel when exposed experimentally to LPS. Brain inflammation in general causes feeling of fatigue, malaise, pain and depressed and anxious mood, regardless of the trigger. This response is related to the activation of immune cells in the brain called microglia.
Fisetin inhibits the microglial inflammatory response to LPS, and reduces the depression-like response to LPS.
Fisetin may be able to broadly suppress brain inflammation caused by microglial activation, even if the cause is something other than LPS exposure.
For more about the involvement of brain inflammation and microglial inflammation in ME/CFS, check out Jarred Younger’s work. He is making really interesting progress with imaging brain inflammation in ME/CFS.Children with autism have also been found to have an ongoing neuroinflammatory process involving microglial activation.Fisetin Affects Pathways Connected to AutismmTOR is a molecule frequently implicated in the pathogenesis of autism. It is involved in the development of the brain and the communication between brain cells. ( Taube added : see Dr Alex Vasquez on NAC inhibiting mTOR ) In animal models, cow’s milk allergic animals show autistic symptoms when exposed to cow’s milk and this effect appears to be caused by increased mTOR signaling in the brain. My food allergies trigger autistic symptoms in me.
Fisetin inhibits mTOR signaling in the brain.
Fisetin also inhibits a molecule implicated in autism called p38 MAPK. p38 MAPK triggers microglial inflammation as well as high serotonin levels, which are often seen in autism. Glutathione is one of the most important antioxidants in the body. Oxidative stress is high in autism and in ME/CFS while glutathione is low (here and here) in both conditions. Animal studies suggest that fisetin is able to increase glutathione levels in the presence of oxidative stress.
Fisetin also counteracted a neurotoxin called aluminum chloride. Fisetin blocked aluminum chloride’s effects on inflammation and oxidative stress and protected against the neurobehavioral deficits alumnum chloride can cause, in part by restoring glutathione levels.
Fisetin With Mast Cell Stabilizers When I started taking fisetin, I was already on a very helpful mast cell stabilization regimen that includes ketotifen and Benadryl. I don’t know exactly what difference fisetin would have made for me without additional mast cell stabilization, but added to a mast cell stabilization regimen, fisetin is sort of like a wonder treatment for me.
New Perspectives for Fisetin  “exhibits a specific biological activity of considerable interest as regards the protection of functional macromolecules against stress which results in the sustenance of normal cells cytoprotection. Moreover, it shows potential as an anti-inflammatory, chemopreventive, chemotherapeutic and recently also senotherapeutic[anti-aging] agent”