The site of this post has disappeared (https://www.syndromea.org/2019/07/23/could-fisetin-be-a-new-treatment-for-me-cfs-autism/ ) and a reader asked me to repost it’s content from a saved copy. I have done an earlier post Fisetin – an off the radar flavonoid. At the bottom I am adding some additional notes.

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.

Comment by Jeff A

Additional Notes

• Fisetin inhibits IL-31 production in stimulated human mast cells: Possibilities of fisetin being exploited to treat histamine-independent pruritus [2018]
• Anti-inflammatory activity of fisetin in human mast cells (HMC-1) [2006]
• Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells [2008]
  ” Fisetin, kaempferol, myricetin, quercetin, and rutin inhibited IgE or phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-mediated histamine release in RBL-2H3 cells. These five flavonoids also inhibited elevation of intracellular calcium”
• Flavonoid inhibition of human basophil histamine release stimulated by various agents [1984]
  “The flavonols, quercetin and fisetin, and the flavone, apigenin, exhibited a predilection to inhibit histamine release stimulated by IgE-dependent ligands (antigen, anti-IgE, and con A)”
• Fisetin and Its Role in Chronic Diseases [2016]
• New Perspectives for Fisetin [2019]
  “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”