Author: Jenny

Health is wealth and we tend to learn that only after running low on our health. Self care is the daily habits of good food, exercise, rest and de-stressing fun activities that help us relax and rev up for another day of work and play. I am a Registered Dietitian with a low health budget due to autoimmune disease but I have found daily choices can help me stay in remission. Food and sleep, and purposeful activity mixed with exercise and relaxation all help keep me in a healthier and happier body and mind. Self care doesn't mean spa day at an expensive resort so much as just spending a few minutes each morning washing, dressing, and showing up in a relaxed state of mind - lovely images or art objects or just a pretty rock or wildflower in a glass jar can also help. Nature may have a little extra soothing ability whether we see an image or make the time to visit a park. Even taking time to smell the roses in a mental trip to your imagination might help you relax and breath a little more deeply. Extra oxygen can help stress because it is used up and we tend to hold our breaths. So take time to pause and breath and sometimes enjoy the flowers in a park or just in your memory's imagination. Thanks for visiting.
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Mast cell activity & Hyperexcitable mood

I told you that long story to tell you another – hyperexcitability may be a symptom of mast cell over activity – and by hyperexcitability I mean VERY hyper-excitable. Actin filaments may be involved. They are important within the synapses between nerve axons of one brain or body nerve cell and the dendritic connections of the next brain or body nerve cell.

Picture toll gates on a super highway system throughout the body. Very long nerve projections can exist between nerve cells in the brain, spine, and the arms and legs. Just a handful of nerves may exist in the signal pathway that senses that you just stepped on Lego or rock with your barefoot and your spine to say reflexively lift your foot before stepping down all the way, and your brain to say, #%$&@! Between each of this handful of nerve cells is a synapse which needs a certain amount of chemical messengers and energy to activate the next cell. If only a small amount of signal is present, maybe from only one incoming nerve cell then the next in line won’t be activated. If a large load of signal is released by the incoming nerve cell, or if several incoming nerve cells are all sending signals then then the next one in line is more likely to be activated and keep the message rolling down the super highway of axon projections.

Actin filaments are in the tips of growing axons and may help guide it in the direction it is supposed to grow. Regrowth of a cut nerve is more likely to occur in body parts than within the brain. New connections are more likely to occur between a different pair of cells may be more likely to grow in a case of brain trauma. How do we grow these connections? Practice – the long work of physical rehabilitation after a stroke or major wound may mean having to spend long hours relearning how to walk or do other seemingly simple tasks that you had known how to do all your life. We can also unlearn how to do a nerve pathway, but that is a little different strategy.

To unlearn a nerve super highway, we need to literally stop using that pathway, stop thinking those thoughts, or doing those actions – which is as easy as saying don’t think of white elephants – uh oh, now you’re thinking about a herd of white elephants aren’t you? The easiest way to unthink thoughts or not do long term habits is to substitute new thoughts and new habits and keep practicing those until the nerve super highways are set in place – and in the process of doing all that thinking, practicing, and building new pathways, the old unused pathways will be unbuilt, retracted by the body and the parts, the chemicals, may be used to rebuild elsewhere, maybe the new pathways.

The benefits of meditation for stress reduction is measurable but takes time, just doing it – thinking about nothing in particular for several minutes or more every day. See: Peace may take practice, for some tips from Jon Kabat-Zinn about mindfulness – meditation can be simply going for a walk or doing dishes with a peaceful relaxed mindset. Our bodies are made to move and be active, for some people sitting meditation may not be the easiest way to start practicing a meditative mindset.

So while we weren’t thinking about hyperexcitability due to mast cell over activation, some of those hyperexcitable pathways may have been left unstimulated and may have been taken up for reuse elsewhere – bonus.

An aside on my writing style and target readers – I am a public health educator and worked with busy parents of young children – keep it short, keep it simple was key. Even the ones with more interest in complex topics may not have had the time or energy for the complexity while corralling young children with too little sleep. Translational medicine is the study and practice of translating medical research for use in patient care. (Post/translational medicine)

My writing style is built from practicing writing for my public health readers, I wrote handouts and lesson plans that were supposed to be at the 6th grade reading level, 8th grade was more what I achieved. The complexity of neuroscience is more post graduate college however, so my writing also has some ground breaking at levels that may interest science and medical professionals – the reference lists are for you and any non-science readers who are interested in more information.

My impression is that my writing style is appreciated by some readers, while also annoying scientists as being too brief or summary style and being too complex for non-scientists – try to please everyone and you may only please English as a second language folks. Scientists – remember you are also writing for English as a second language scientists, and ultimately the goal of science is to help the majority (I hope) not just collect a growing number of journal articles. Solutions for simple everyday habits that help health is the goal of my approach to translational health writing – what may be helping health, what may not be helping in my daily life? or my reader’s daily life? Simple solutions that aren’t expensive is also better for a more sustainable lifestyle in the present and for the future.

Hyperexcitable and mast cells – for me symptoms became frightening, a whirl of worries and negative social messaging that led to repetitive speech at times instead of just whirling thoughts in my brain. Calming, just letting it gradually slow to a stop was necessary, people trying to intervene with soothing statements with an expectation that I could, or would, just stop tended to lead to trouble, because the outpouring verbal statements weren’t normal conversation or anger, more like an old-fashioned record stuck in a groove that kept skipping to the same line of the music. I found substituting less negative words could help at least tone down the negativity of what I was repeating -> “Calm, serene, rational” – my mantra – it is good to have goals, even if incapable of achieving them in the moment.

Histamine has modulating effects in the brain and normal levels help with balance, just the right amount of stimulus, toning down, or amping up as needed to keep an even midpoint. Hyperexcitable may be a lack of modulating brain chemicals, there are many involved including endogenous cannabinoids, glycine, magnesium, and GABA. Due to genetic differences I may tend to be low in all of those calming chemicals.

I take supplemental powder of the amino acid glycine and topical Epsom salts seems to be essential for me to have enough magnesium, even though I eat many magnesium rich foods. Genetic differences are possible in the ion channels needed to absorb magnesium within the intestines, (3), or increased levels of the hormone version of vitamin D can signal for more calcium absorption instead of magnesium. Either way, it seems that I get more moody, and more muscle cramps, if I am unable to have my Epsom salt soaks once or twice per week.

Avoiding the histamine foods has helped a lot in not having the hyperexcitable, can’t stop repeating negative worries, episodes. It is not the same as a mood or anything I’ve experienced in my life until more recent years, so it may not just be histamine problems alone, or the problem got more severe than my previous seasonal allergy suffering. Changes in F-actin within the brain may affect brain excitability but the exact mechanism is unknown – from a book chapter about chemically induced seizures and epilepsy. (1)

The extreme verbal episodes and whirling anxiety started after I was put on a high dose of a psychiatric medication. I was only on it for a couple months but it was very difficult to withdraw from due to difficult to control and frightening suicidal thoughts, self harm urges that occurred in addition to the odd repetitive speech and agitated motions. Akathisia is considered a restless motion symptom associated with drug side effects, however among patient forums it is clear that suicidal urges and thoughts can also be a big part of the symptom and sadly leads to many deaths. Maybe the chemical use causes changes in the actin between synapses that leads to hyperexcitable, agitation of thoughts and motions.

Cannabinoid receptors in the prefrontal cortex have been found to be associated with suicidal thoughts in patients with anorexia or severe alcoholism. The drug I was put on, olanzapine, acts to inhibit break down of cannabinoids, which would lead to more overactivity of cannabinoid receptors, which then might cause a sudden drop in activity when the drug was stopped.

Cannabinoids in balance can stop mast cell activity and tended to help me a lot to just not have the whirling thoughts – while I had plenty of the cannabinoids, but as soon as I was getting due for more the withdrawal extreme would start again – solution, lots of external cannabinoids all day and the middle of the night too sometimes – that gets excessive too. Be glad to not have genetic differences in your ability to make cannabinoids – not having enough can lead to paralysis eventually, I hope to avoid that but dietary sources of cannabinoids doesn’t help all of my symptoms as much as having the lots of a concentrated source (medical marijuana of a balanced strain – too much THC is not good for brain or body health either, CBD is needed and THCV seems particularly helpful for my mood balance.)

Cannabinoids are also involved in the unlearning process of the brain pathways – called neuroplasticity – forget the old phone number, you don’t need to remember it any longer, and learn the new phone number. (Learn more on neuroplasticity: an interview of Dr Huberman or TED talk by Lara Boyd.) Cannabinoids may help people with PTSD because they help with unlearning – forgetting the traumatic pathways. Meditation may help as well but for me without an concentrated source of cannabinoids, meditation wouldn’t prevent the whirling thought/speech episodes, avoiding the histamine foods also seems essential. (See previous post.)

What kind of changes could a medication that I took for two months seven years ago have done that left me more susceptible to overactive mast cell and histamine problems? Could F-actin be involved? Could retinoic acid be involved? People with multiple vaccines are more prone to vaccine injury and excess release of retinoic acid by the liver may be involved according to a theory presented in a recent publication. (2) Retinoic acid is an active form of vitamin A which can cause toxicity and birth defects when present in excess due to diet or skin care products or medications. (6) Retinoic acid also activates mast cells, so it could be adding to the hyperexcitable histamine excess.

Retinoic acid is a bitter tasting chemical – are bitter taste receptors in the brain involved?

“Correspondingly, it has been demonstrated that GPCRs (the group of bitter taste receptors- G protein-coupled receptors (GPCRs) ) are involved in neurotransmitter function and in the regulation of neuronal and hormone signaling. Furthermore, impairment of this signaling by these TAS2Rs potentially contributes to CNS-related disorders, including Alzheimer’s disease, schizophrenia, and Parkinson’s [38, 39]. In rats, taste-transducing molecules are predominantly located in neurons, and TAS2R expression has been detected in multiple regions of the rat brains, including the brain stem, cerebellum, cortex, and nucleus accumbens [9, 40]. To date, natural ligands for TAS2Rs in the brain have not been reported, although bitter tasting di- and tri-peptides from food have been shown to access the brain via a peptide transporter [41]. ” (4)

The bitter tasting chemical/phytonutrient, chloroquine and quinine, help reduce allergic asthma symptoms when given as an inhalant in an animal study. (5) Bitter tasting citrus flavonoids have also been studied for asthma treatment, see post/bitter taste receptors. Might bitter tasting molecules also help reduce allergic/inflammation symptoms within the brain? Might an excess or retinoic acid be overstimulating activity in the brain and causing hyperexcitability? (1, 2) Excess retinoic acid can have negative effects in the brain, particularly the hippocampus, (6), the area damaged initially in Alzheimer’s dementia, and may cause cell death. (7)

“The three active forms of vitamin A in the body are retinol, retinal, and retinoic acid.” … “Retinol and retinyl esters are often referred to as preformed vitamin A. Retinol can be converted by the body to retinal, which can be in turn be oxidized to retinoic acid, the form of vitamin A known to regulate gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. β-Carotene and other food carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids (see the article on Carotenoids). ” (11)

Malfunction of CYP enzymes could increase the risk of excess retinoic acid as they are required to break down the active forms of vitamin A. (12)

The source of active retinoic acid within the body is primarily activity by T and B immune cells which is promoted by dendritic cells which present antigens to immune cells: “Tolerogenic CD103+ [dendritic cells] DCs, which are located mainly in the lamina propria of the small intestine and gut-associated lymphoid tissue (GALT), such as PPs and mLNs [39, 40], are responsible for the maintenance of homeostasis. … The migration of T and B cells is mediated by CD103+ DCs due to their ability to synthesize RA [10, 41] as these cells have a high expression of the RALDH1 and RALDH2 enzymes, which are responsible for the conversion of retinal to RA; thus, these cells are the main synthesizers of RA [42]. Other RALDH+ DC populations that also produce RA are mainly located at mucosal interfaces, such as the skin, the lungs, and the corresponding draining lymph nodes [43, 44]. ” (12) Got it? Press on anyway.

“Mice with a vitamin A-deficient diet (VAD) exhibit reduced expression and activity of the RALDH enzyme in intestinal DCs, which is essential for the regulation of immune and inflammatory responses [51].” …”There are other sources of RA, such as lamina propria stromal cells, intestinal epithelial cells, and macrophages. Intestinal macrophages express RALDH1 and RALDH2, but that expression is dependent on external stimuli, such as cytokines and TLR ligands, whereas in CD103+ DCs, the expression of these enzymes appears to be related to dietary vitamin A [51, 58].” (12)

Beta-carotene, is an inactive form of vitamin A that is generally considered non-toxic, it provides the orange color of carrots, and since it is a fat soluble nutrient it can collect within our skin if eaten in excess and cause an orange color to the skin. (8, 13) It is unlikely to eat enough of the nutrient to cause the skin color change unless regularly drinking juice made with carrots, or kale or other fruits and vegetables that are very rich in beta- carotene. It is unlikely to cause any health problems other than to appear orange for a while (stop drinking so much carrot juice to make it fade). Infants and toddlers who are fed limited numbers of foods but daily may also develop the problem if carrots and sweet potatoes are given consistently instead of including more variety.

Beta-carotene may be broken down to the active retinal form in the intestinal lining or in the liver. (13)

Sources of Pre-formed vitamin A and Provitamin A – beta-carotene and other carotenoids.

“…vitamin A toxicity can occur from either topical or oral use. Oral vitamin A delivery comes in two forms: provitamin A (a prodrug that is metabolized to vitamin A) and preformed vitamin A. Pre-formed vitamin A is obtained from animal food sources, including dairy products and liver, and in most supplements. A list of other foods containing Vitamin A includes milk, cheese, margarine, butter, eggs, chicken, chicken liver, beef, beef liver, processed meats, pizza, fish, and cold breakfast cereals[1]. Provitamin A (beta-carotene and other carotenoids), found in plants such as green leafy vegetables, sweet potatoes, and carrots, must be metabolized to vitamin A. As a result, it is less likely to cause toxicity.” (9)

Symptoms of Retinoid Toxicity

“Acute retinoid toxicity has resulted in mucocutaneous and laboratory abnormalities. Mucocutaneous effects include dry lips, cheilitis, and dry oral, ophthalmic, and nasal mucosa. The putative mechanism is decreased sebum production, reduced epidermal thickness, and altered barrier function. Other cutaneous effects seen include overall skin dryness and pruritus, peeling of palms and soles, and fingertip fissuring. Telogen effluvium may be seen with higher doses.” (9) Telogen effluvium is a hair loss and thinning without scarring, the problem may be acute or chronic. (10)

  • Chronic retinoid toxicity can increase risk of bone spurs, calcinosis, and hypercalcemia. [6] Chronic intake of excessive dietary vitamin A may increase risk of osteoporosis and hip fractures. [7]
  • Headache, nausea, and vomiting may occur and pseudotumor cerebri syndrome infrequently has been seen. [8]
  • Hypothyroidism occurred with bexarotene treatment, reversible with cessation of the treatment. [9] Renal dysfunction with etretinate occurred, also reversible with cessation of treatment. [10]
  • Hypertriglyceridemia and other blood lipid changes have been seen with retinoid treatments: bexarotene, isotretinoin, etretinate, and acitretin, [11][12], and occasionally was accompanied by acute hemorrhagic pancreatitis and eruptive xanthomas.
  • Elevated serum transaminases may occur with retinoid treatments, and liver damage leading to fibrosis and hepatic stellate cell activation have both been seen in patients with hypervitaminosis A. [13]
  • No causal association has been found between the retinoid treatment isotretinoin and depression, psychosis, or suicide attempts, but a link has been suggested. [14]
  • Summarized from (9) – see the paper for more details and [ref] list.
  • “Disturbances related to nervous functions also appear on the list of side effects resulting from excessive vitamin A intake, as for instance confusion, irritability, anxiety, depression, and suicide ideation (Snodgrass 1992).” Effects on neuronal function may include: “impaired bioenergetic parameters related to mitochondrial function, oxidative and nitrosative stress, alterations of dopamine signaling, and behavioral disturbances.” Cell death may also occur as a result to excess Vitamin A. “Increased β-amyloid1-40 peptide [also found in Alheimer’s dementia] and tumor necrosis factor-alpha (TNF-α) contents in substantia nigra and striatum” areas of the brain was found in an animal study. Increased “Mn-SOD and monoamine oxidase (MAO) enzyme activities may lead to increased hydrogen peroxide (H2O2) production, which may diffuse from mitochondria to other organelles.” (7)
  • “Vitamin A content in the liver of adult humans is about 100 µg/g (Furr et al. 1989). It was suggested that a concentration of vitamin A of roughly 300 µg/g in the liver reveals intoxication (Olson 1993). ” (7)

This is really complicated – gist may be that chemical or antigen excess may affect liver enzymes that metabolize active vitamin A. If excessive active retinoic acid collects it may then over activate mast cells and other tissues of the body and lead to a variety of negative health and mental illness symptoms or conditions. The solution may be to reduce vitamin A foods but more study is needed, and I need to do more reading to see if there is more available on the topic.

The symptom list is a story of my last few uncomfortable years, or decade and I did cut out animal products in order to heal what may have been a calcinosis type skin symptom that can also be associated with hyperparathyroidism. (14) Current medical diagnosis tends to wait until problems are severe. I have been getting bone spurs on my feet and a doctor dismissed it as not a problem yet – maybe not a problem that surgery would be considered for. I would rather stop the condition from worsening personally – they do hurt when I walk. Mental health symptoms, liver or kidney injury are also problems I would rather skip or prevent.

This is still a work in progress, or a series in progress.

12/21/2020 – a step in the progress – a Symptom Questionnaire to gather survey responses from many people in hope of seeing if there is a pattern between symptoms of retinoid toxicity and vaccine injury or medication injury (akathisia):

https://www.surveymonkey.com/r/T3H2Q8Z

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Frederic Dorandeu, Guilhem Calas, Gregory Dal Bo, Raafat Fares, Chapter 36 – Models of Chemically-Induced Acute Seizures and Epilepsy: Toxic Compounds and Drugs of Addiction, Editor(s): Asla Pitkänen, Paul S. Buckmaster, Aristea S. Galanopoulou, Solomon L. Moshé, Models of Seizures and Epilepsy (Second Edition),Academic Press, 2017, Pages 529-551, ISBN 9780128040669, https://doi.org/10.1016/B978-0-12-804066-9.00037-7. https://www.sciencedirect.com/science/article/pii/B9780128040669000377 “Alterations of the neuronal cytoskeleton, and more precisely disruption of actin dynamics, seem then to contribute to changes in brain excitability, but the mechanisms leading to these changes remain still unresolved (Spence and Soderling, 2015).” Excerpt viewable in F-actin, ScienceDirect, https://www.sciencedirect.com/topics/neuroscience/f-actin
  2. Mawson AR, Croft AM, Multiple Vaccinations and the Enigma of Vaccine Injury. Vaccines, 2020, 8, 676; doi:10.3390/vaccines8040676, published online Nov 12, 2020 “Neurodevelopmental disorders—A review of the role of retinoids in NDDs [58] includes the suggestion that an abnormality in the interplay between retinoic acid and sex hormones may cause ASD [59],”  As noted in our review on GWI [41], mast cells are increased in patients with atopic dermatitis and express high levels of retinoic acid receptor-alpha. Retinoic acid (RA) also interferes with the proliferation of skin mast cells and promotes their degranulation, supporting the concept that RA has a pro-allergic and pro-inflammatory-maintaining function in skin mast cells. The retinoid toxicity hypothesis of vaccine injury is depicted in the figure below” pdf https://t.co/sinJK6UTSc?amp=1
  3. Song Y, Hsu YH, Niu T, Manson JE, Buring JE, Liu S. Common genetic variants of the ion channel transient receptor potential membrane melastatin 6 and 7 (TRPM6 and TRPM7), magnesium intake, and risk of type 2 diabetes in women. BMC Med Genet. 2009;10:4. Published 2009 Jan 17. doi:10.1186/1471-2350-10-4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637850/
  4. Seo Y, Kim YS, Lee KE, Park TH, Kim Y. Anti-cancer stemness and anti-invasive activity of bitter taste receptors, TAS2R8 and TAS2R10, in human neuroblastoma cells. PLoS One. 2017;12(5):e0176851. Published 2017 May 3. doi:10.1371/journal.pone.0176851 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414998/
  5. Sharma, P., Yi, R., Nayak, A. et al. Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice. Sci Rep7, 46166 (2017). https://doi.org/10.1038/srep46166 https://www.nature.com/articles/srep46166
  6. McCaffery PJ, Adams J, Maden M, Rosa-Molinar E. Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen. Eur J Neurosci. 2003 Aug;18(3):457-72. doi: 10.1046/j.1460-9568.2003.02765.x. PMID: 12911743. https://pubmed.ncbi.nlm.nih.gov/12911743/
  7. OLIVEIRA, MARCOS ROBERTO DE. (2015). The neurotoxic effects of vitamin A and retinoids. Anais da Academia Brasileira de Ciências, 87(2, Suppl. ), 1361-1373. Epub August 04, 2015.https://doi.org/10.1590/0001-3765201520140677 https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0001-37652015000301361
  8. Smile S. Case 2: Persistent skin discolouration in a child with autism spectrum disorder. Paediatr Child Health. 2016;21(2):67-68. doi:10.1093/pch/21.2.67a https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807796/
  9. Olson JM, Ameer MA, Goyal A. Vitamin A Toxicity. [Updated 2020 Oct 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532916/
  10. Elizabeth CW Hughes, MD; Chief Editor: Dirk M Elston, MD, et al., Telogen Effluvium. Sept. 17, 2020, emedicine.medscape.com https://emedicine.medscape.com/article/1071566-overview
  11. Vitamin A, Linus Pauling Institute, lpi.oregonstate.edu, https://lpi.oregonstate.edu/mic/vitamins/vitamin-A
  12. Oliveira LM, Teixeira FME, Sato MN. Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases. Mediators Inflamm. 2018;2018:3067126. Published 2018 Aug 9. doi:10.1155/2018/3067126 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109577/
  13. Charles Ophardt, Vitamin A: β-Carotene. Virtual ChemBook, Last updated Aug 10, 2020 https://chem.libretexts.org/Bookshelves/Biological_Chemistry/Supplemental_Modules_(Biological_Chemistry)/Vitamins_Cofactors_and_Coenzymes/Vitamin_A
  14. Le C, Bedocs PM. Calcinosis Cutis. [Updated 2020 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448127/ https://www.ncbi.nlm.nih.gov/books/NBK448127/
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Epigenetic changes may also be involved in Covid19 or LongCovid

Epigenetic changes may be involved in Covid19 and LongCovid, which might be able to be changed back with the addition of plenty of methyl donor vitamins. People with methylation genetic alleles would be more at risk for epigenetic changes to DNA or actin protein filaments. Actin are semi flexible proteins in a double helix shape which support the fluid and organelles inside of cells and around cells and organs of our bodies. Actin also is involved in guiding the work of DNA replication and growth and development of cells or infants.

Methylation is the addition of a methyl group – one carbon atom and three hydrogen atoms, to genes, or actin filaments. A methylated gene is not active for encoding proteins while a demethylated gene is available to be transcribed into a messenger mRNA to be made into a matching protein. Actin filaments are a double helix shape like DNA but do other functions throughout our body. Some have methyl groups also that seem to be essential for proper function of the actin protein whether in muscle contraction or in guiding chemicals within cells to make DNA or do other work. Actin filaments add structure to the jelly like fluid around and in cells and may tether chemicals in place for chemical reactions or guide cellular organization during growth and development.

Actin may be involved with energy fields of our body along with microtubules also, but that is not discussed in greater detail in this post (more information about quantum energy fields and actin is included in Cracking Nature’s Code (2019) (1), and in several posts on another site of mine first in the series, 2nd, 3rd, 4th).

Viral infection and epigenetic changes with a focus on Postural Orthostatic Tachycardia Syndrome and possible dietary and lifestyle changes that may help reverse epigenetic changes is the focus of this post – which got long. It is also available as a section of this document that includes the series on Mast Cells and Histamine. Current standard of treatment for patients with POTS symptoms may leave them unwell for years – a few get better more rapidly. I got better on my own within a few months – twice. More about possible strategies for improvement of epigenetic changes will be included later in the post. More about the epigenetics involved in POTS is included in the Genetics/Epigenetics chapter of my book draft which is available on a platform where you can get an e-copy early (minimum price Free, Leanpub/Tipping The Clock Toward Health) and then be informed of updates with an email subscription.

Viral infection can cause Epigenetic changes.

“Bacterial (Pacis et al., 2015, 2) and viral infection (Lichinchi et al., 2016, 3) directly impact methylation patterns, most likely orchestrated by actin since it is universally hi-jacked in viral infectivity (Cudmore et al. 1997, 4; Ohkawa and Volkman, 1999, 5; Lu et al., 2004, 6; Marek et al., 2011, 7).”

page 34, JB Head, PhD, Cracking Nature’s Code (2019) (1)

I found I have methylation gene alleles in a genetic screening (post: Methylation Cycle Defects – in me – genetic screening “for research purposes only”). Since finding out I stopped taking standard supplements of B12 and folic acid because they are not methylated, not bioactive. I take methyl B12 & methyl folate supplements now. Postural Orthostatic Tachycardia Syndrome (POTS) (9) has been a problem for me in past years a couple times and I got better. Symptoms include a rapid heart rate, tachycardia, and feeling faint or blacking out, especially when getting up quickly from a seated or laying down position to standing. (9) I have heard anecdotal reports of it being a symptom for some LongCovid survivors who had never had the problem before.

To slow the rapid heart rate during an episode I found it helpful to stop and sit or lay down with my feet above my heart if possible and just wait a couple minutes for the rapid heart rate to slow again. Continuing to exercise would make the rapid heart rate worse. Preventing the faintness upon rapidly getting up required trying to remember to slow down and have a support ready to hold if I felt wobbly. I did faint once, odd to find yourself on the floor unexpectedly.

POTS has been found to potentially involve a genetic difference in the norepinephrine transporter gene (SLC6A2) sequence and it can also be an epigenetic problem with links to excess formaldehyde. (9) Formaldehyde can donate methyl groups to DNA that normally would be unmethylated – active. (10) Methylation of DNA is a little like a on/off switch for genes, or the cap on bottle – add the methyl groups and the DNA gene is inactive.

“Formaldehyde as a methyl donor for the methylation of DNA, RNA, and histone acts as an epigenetic factor participating in the reversible and dynamic methylation. DNA demethylation elicits formaldehyde generation in the dividing cells and post-mitotic neurons.” (10) Memory formation involves methylation of DNA and cognitive impairment in older adults is associated with increased internal formaldehyde levels (self-made) and demethylation of DNA. Use of nutrients to remove formaldehyde helped improve memory in an animal based study. (10)

Formaldehyde can be prevalent in secondhand or thirdhand smoke in enclosed rooms, or smog, or we make our own during normal metabolism, and physical or emotional stress conditions may cause an increase, as well as the level potentially increasing in older adults. (11) Elevated levels of formaldehyde within cells causes more breakdown of sugar for energy and increased removal of an antioxidant out of the brain cells, which may increase risk for cognitive damage. “As excess formaldehyde accelerates glycolysis and glutathione export in neural cells, formaldehyde‐induced alterations in brain metabolism and oxidative stress may contribute to the pathological progression of neurodegenerative disorders.” (11)

Formaldehyde is very reactive and can use the methyl group to form links between protein groups or parts that wouldn’t normally be linked – like bungee cords holding parts together in places that would be separate in normal function. (11) Formaldehyde is used with tissue samples to preserve material for viewing under a microscope. Studies of the effect of formaldehyde on the actin protein of live cells that were low on blood sugar found that modifications to the protein did occur – the authors suggest any prior research on the actin protein in formaldehyde treated samples may be inaccurate. (12) Take home point – formaldehyde is not good for our brain cells and may effect the protein of our brain cytoskeleton structure. (12) Protein tangles in brain cells are associated with dementia and autism.

What is a cytoskeleton? We are mostly water, so how do we walk around? With a balance in tension between string like ligaments and muscles and rod like bones of our skeleton. Within the cellular environment, inside and outside the cell membrane – the tent wall, there are rod like microtubules and string like actin protein that is more flexible, it can change shape but isn’t stretchy as much as structurally able to modify in shape. Actin is a double helix, two spirals like DNA except without the ladder like steps joining the two lengths of protein. When force is applied the double helix can get a little longer or shorter as the coils compress or lengthen slightly – tensile strength – and the protein gets stiffer from a side to side direction – torsion – and is less flexible along the length, less able to bend sideways. (13)

The actin protein may act as torsion sensors – is the environment changing in pressure around that section of the protein length – from increased fluid or gas? How full is the balloon like membrane? (14) Channels in a membrane will open and start to leak rather than letting the membrane burst like an overfull balloon. This may seem like a silly discussion – however it is your brain and organs – leaking is better than bursting. Leaking membranes will release fluid and some types of chemicals while a bursting open, as when viral replication is complete and the virus exit a cell, the membrane bursts and all the remaining chemicals in the cell flood into the surrounding cytoskeleton and can cause inflammatory damage to surrounding cells.

These flexible yet firm cytoskeleton actin filaments also may act like guidelines for directing traffic or tethering organelles in place for activity such as replication of DNA during cell division (one cell doubles its DNA and then divides into two cells). Too much of the proteins within a cell nucleus will prevent DNA replication rather than guiding it. (15) Actin is also involved in muscle fiber motion. The double helix structure can also be methylated with methyl groups doing an unknown but critical function. Loss of methylation of actin in one location is associated with cancer and autism spectrum disorders, (16), loss of it in another location along the protein chain is associated with muscle changes that cause female animals to have delivery problems and fewer babies. (17, 18)

So actin is important stringy protein that effects muscle power, cell division, and the brain – and formaldehyde can cause demethylation of DNA, likely it can cause demethylation of actin also which may lead to autism spectrum disorders, cancer, and muscle problems that can affect a healthy delivery of infants (in an animal study). The visual – we want our jelly like insides to have a strong yet flexible tent membrane, tent poles (microtubules), and tie downs (actin) – without having so many tie downs it starts looking like a haunted house full of cobwebs. The amyloid beta protein associated with Alzheimer’s dementia and autism may be protective against a low level infection (post: Magnesium might help protect against beta amyloid placques) but also may increase changes in actin stress fibers (24) and an excess seems to add to chronic inflammatory damage over time.

How do we achieve this? Healthy actin?

It may help promote appropriate methylation of DNA and actin to have adequate antioxidants and methyl donor nutrients in our diet, to reduce oxidative stress chemicals and provide adequate methylation to DNA and actin. Avoiding excessive physical and emotional stress may also be an important strategy, so we aren’t embalming ourselves with self produced formaldehyde (the mummy in the haunted house being our own brain).

We also want to avoid formaldehyde in our environment, which would include improving air quality, especially during sleep hours when our body is focused on detoxification of the brain. Parkinson’s Disease is another chronic condition that may involve epigenetic changes and reducing formaldehyde exposure may be protective. More information is in this post with a link to a longer post about formaldehyde sources: The Cholinergic System

Increasing methyl donor vitamin rich foods and/or supplements should focus on the methylated form if unsure whether there is a genetic allele problem causing lack of methylation.

“Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline.” … “Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders.” … “Hypomethylation has a wide spectrum of effects that include genetic, epigenetic, and metabolic alterations.” (8)

Gastrointestinal problems have been found to be common among patients with Postural Orthostatic Tachycardia Syndrome (POTS) with malfunction or slowing, dysmotility, of the smooth muscle lining of the intestinal tract. “Case study 1: A 20-year-old woman presented to clinic for further evaluation of a several year history of fullness and epigastric discomfort associated with eating and irregular bowel habits. Her weight was stable. She also described frequent migraine headaches, episodic palpitations and lightheadedness with progressively increasing episodes of syncope. A systems review was notable for profound fatigue, dry eyes and mouth and intermittent flushing and pruritus.” (19) The patient’s symptoms include many in common with Mast Cell Activation Syndrome, however testing for mast cell activation was normal. Patients whose symptoms followed a viral infection tend to get better more often than patients with a family history of POTS. (19)  

“A number of chronic conditions are frequently seen in patients with POTS and contribute to symptom burden and reduced quality of life. Common comorbidities include chronic fatigue syndrome, fibromyalgia, interstitial cystitis, and migraine headaches. Other unique conditions that seem to occur with increased frequency in POTS are autoimmunity, the hypermobile form of Ehlers-Danlos syndrome (HM-EDS), and mast cell activation disorder (MCAD).” (19)  

“Unlike mastocytosis, idiopathic mast cell activation [MCAD] occurs in the absence of mast cell proliferation and with episodic accumulation of mast cell mediators in the plasma or urine, usually present when symptomatic. Patients with MCAD typically present with episodic “attacks” of flushing, urticaria and pruritus accompanied by lightheadedness, dizziness, dyspnea, nausea, headache, diarrhea, and/or syncope; symptoms representative of the hyperadrenergic type of POTS with biochemical evidence of MCAD (20).” (19)

The patient in case study 2 had ongoing nausea, vomiting, abdominal pain, and weight loss continuing for years following a viral infection. She was found to have deficiency in iron, zinc, and vitamin B12 and gastroparesis (slow or little intestinal muscle action). Intravenous iron and B12 were provided and an oral zinc supplement. Nutrient levels improved however the GI symptoms and weight loss continued and the patient was given tube feedings which improved weight, however some intolerance to the tube feedings continued and abdominal pain persisted. (19)  

If demethylation of actin protein in the muscle tissue of the intestinal wall was a problem for the patient in case study 2, then it may have been a factor in the gastroparesis. Genetic screening for methylation defects is not mentioned. Supplements of B12 are often an unmethylated form, cyanocobalamin, and which include cyanide. (21) In a study of 12 patients by Huang et al, (22): “Disturbances in GI motility were found to involve not only the stomach, but also multiple segments of the gut spanning the esophagus to the anus.” (19) The commonly used treatments for GI symptoms associated with POTS (see Table 5) do not include nutrients and do include proton pump inhibitors, (19),  a medication that takes the place of magnesium as a calcium channel blocker, and which may lead to worse magnesium deficiency for some people, a genetic difference may be involved. See post: Original Prilosec Warning, edited.

Small intestinal bacterial overgrowth (SIBO) may occur along with GI problems and lead to fat and carbohydrate digestion and absorption problems and bloating from excessive bacterial growth. Changes in diet due to the discomfort are common in patients with POTS and these more severe GI symptoms and which may lead to deficiencies in fat soluble vitamins A, D, E and K. Megaloblastic anemia may result from deficiencies in iron, folate and vitamin B12. (19) Sulfate deficiency may be an underlying factor (23) and providing Epsom salt soaks of the lower legs and feet, or in a bath one to two times a week might help by providing a topically absorbed form of magnesium and sulfate. See post: To have optimal Magnesium needs Protein and Phospholipids too.

Zinc is also involved in DNA methylation and deficiency of the trace mineral can lead to epigenetic changes and gene transcription problems. Zinc is needed along with actin and other proteins to tell the cell nucleus and cell which genes to make into mRNA to be encoded into a protein. “Accumulating evidence has demonstrated that several key enzymes and zinc finger proteins with zinc atom(s) in the reactive center and binding site play important roles in DNA methylation and histone modifications. Therefore, zinc deficiency may disrupt the functions of these enzymes and proteins and result in epigenetic dysregulation. Furthermore, zinc deficiency may enhance inflammatory response and subsequently alter DNA methylation status of the genes involved in inflammation.” (20) Also see posts: Zinc – big news, CoV and other illness related, and Zinc, cancer, and bitter taste receptors.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. JB Head, PhD, Cracking Nature’s Code: The Potential Answer to Everything. (Balboa Press, Bloomington, IN, 2019) https://www.balboapress.com/en/bookstore/bookdetails/792280-cracking-natures-code
  2. Pacis A, Tailleux L, Morin AM, et al., Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res 2015. 25: 1801-1811 https://doi.org/10.1101/gr.192005.115 https://genome.cshlp.org/content/25/12/1801
  3. Lichinchi G, Zhao BS, Wu Y, et al. Dynamics of Human and Viral RNA Methylation during Zika Virus Infection. Cell Host Microbe. 2016;20(5):666-673. doi:10.1016/j.chom.2016.10.002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155635/
  4. Cudmore S, Reckmann I, Way M. (1997). Viral manipulations of the actin cytoskeleton. Trends in microbiology. 5. 142-8. 10.1016/S0966-842X(97)01011-1. https://www.researchgate.net/publication/14077627_Viral_manipulations_of_the_actin_cytoskeleton
  5. Ohkawa T, Volkman LE, Nuclear F-Actin Is Required for AcMNPV Nucleocapsid Morphogenesis, Virology, Vol 264, Issue 1, 1999, Pages 1-4, ISSN 0042-6822, https://doi.org/10.1006/viro.1999.0008. https://www.sciencedirect.com/science/article/pii/S0042682299900089
  6. Lu, S., Ge, G. & Qi, Y. Ha-VP39 binding to actin and the influence of F-actin on assembly of progeny virions. Arch Virol149, 2187–2198 (2004). https://doi.org/10.1007/s00705-004-0361-4 https://link.springer.com/article/10.1007/s00705-004-0361-4
  7. Marek M, Merten OW, Galibert L, Vlak JM, van Oers MM. Baculovirus VP80 protein and the F-actin cytoskeleton interact and connect the viral replication factory with the nuclear periphery. J Virol. 2011;85(11):5350-5362. doi:10.1128/JVI.00035-11 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094977/
  8. Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients. 2013;5(9):3481-3495. Published 2013 Sep 9. doi:10.3390/nu5093481 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798916/
  9. Richard Bayles, Harikrishnan KN, Elisabeth Lambert, et al., Epigenetic Modification of the Norepinephrine Transporter Gene in Postural Tachycardia Syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:1910–1916 https://doi.org/10.1161/ATVBAHA.111.244343 https://www.ahajournals.org/doi/full/10.1161/atvbaha.111.244343
  10. Su, Tao & He, Rong-Qiao. (2017). Formaldehyde Playing a Role in (De)methylation for Memory. 10.1007/978-94-024-1177-5_3. https://www.researchgate.net/publication/320523716_Formaldehyde_Playing_a_Role_in_Demethylation_for_Memory
  11. Ketki Tulpule Ralf Dringen, Formaldehyde in brain: an overlooked player in neurodegeneration?, J. Neurochem. (2013) 127, 7– 21 https://onlinelibrary.wiley.com/doi/10.1111/jnc.12356
  12. Vasicova P, Rinnerthaler M, Haskova D, et al. Formaldehyde fixation is detrimental to actin cables in glucose-depleted S. cerevisiae cells. Microb Cell. 2016;3(5):206-214. Published 2016 Apr 12. doi:10.15698/mic2016.05.499 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349148/
  13. Effect of tensile force on the mechanical behavior of actin filaments. J Biomechanics (2011), 44(9): 1776-1781, 2011-06-03 , https://repository.kulib.kyoto-u.ac.jp/dspace/handle/2433/152437 https://core.ac.uk/download/pdf/39280196.pdf
  14. Hayakawa K, Tatsumi H, Sokabe M. Actin filaments function as a tension sensor by tension-dependent binding of cofilin to the filament. J Cell Biol. 2011;195(5):721-727. doi:10.1083/jcb.201102039 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257564/
  15. Hu, X., Liu, Z.Z., Chen, X. et al. MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation. Nat Commun10, 1695 (2019). https://doi.org/10.1038/s41467-019-09636-6 https://www.nature.com/articles/s41467-019-09636-6
  16. Seervai RNH, Jangid RK, Karki M, et al., The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase. Science Advances, 02 OCT 2020 : EABB7854 SETD2 regulates actin dynamics and cell migration via methylation of actin at Lys68 in a cellular complex containing Huntingtin. https://advances.sciencemag.org/content/6/40/eabb7854? “Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration. Together, these data identify SETD2 as a previously unknown HTT effector regulating methylation and polymerization of actin filaments and provide new avenues for understanding how defects in SETD2 and HTT drive disease via aberrant cytoskeletal methylation.“… “Loss of SETD2 and the H3K36me3 chromatin mark is embryonic lethal in Drosophila (7) and mice (8), and SETD2 defects have been linked to several diseases, including cancer (9–11) and autism spectrum disorder (12–14).”
  17. Wilkinson, A.W., Diep, J., Dai, S. et al. SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature 565, 372–376 (2019). https://doi.org/10.1038/s41586-018-0821-8, https://www.nature.com/articles/s41586-018-0821-8 lack of the methylation at histidine 73 seems to interfere with muscles and causes the genetically different animals to have fewer babies due to maternal delivery problems. Graphic from the article shows a CH3 methyl group being added to an actin filament at Histidine 73: https://twitter.com/anandb4/status/1073255833813671937?s=20
  18. Kwiatkowski S, Seliga AK, Veiga-da-Cunha M, et al., SETD3 protein is the actin-specific histidine N-methyltransferase. bioRxiv 266882; doi: https://doi.org/10.1101/266882Now published in eLife doi: 10.7554/elife.37921 https://www.biorxiv.org/content/10.1101/266882v1?platform=hootsuite “Finally, Setd3-deficient HAP1 cells were devoid of methylated H73 in β-actin and exhibited phenotypic changes, including a decrease in F-actin content and an increased glycolytic activity. “
  19. DiBaise JK, Lunsford TN, Harris LA, Nutrition Issues in Gastroenterology, Series #187: The POTS (Postural Tachycardia Syndrome) Epidemic: Hydration and Nutrition Issues. June 2019, Practical Gastro, Vol XLIII, Issue 6 https://practicalgastro.com/2019/10/14/the-pots-postural-tachycardia-syndrome-epidemic-hydration-and-nutrition-issues/
  20. Gu H.F., Zhang X. (2017) Zinc Deficiency and Epigenetics. In: Preedy V., Patel V. (eds) Handbook of Famine, Starvation, and Nutrient Deprivation. Springer, Cham. https://doi.org/10.1007/978-3-319-40007-5_80-1 https://link.springer.com/referenceworkentry/10.1007%2F978-3-319-40007-5_80-1
  21. Dody Chiropractic, Why Do Vitamin B12 Supplements Contain Cyanide?, dodychiro.com,  https://www.dodychiro.com/why-do-vitamin-b12-supplements-contain-cyanide/
  22. Huang RJ, Chun CL, Friday K, et al. Manometric abnormalities in the postural orthostatic tachycardia syndrome: a case series. Dig Dis Sci 2013;58:3207-3211 https://pubmed.ncbi.nlm.nih.gov/24068608/
  23. Elliot Overton, Sulfate IV: Chronic SIBO/Gut Dysbiosis As A Protective Adaptation To Supply Sulfate. July 21, 2018, Eonutrition.co.uk, https://www.eonutrition.co.uk/post/sulfate-iv-chronic-sibo-gut-dysbiosis-as-a-protective-adaptation-to-supply-sulfate 
  24. Song C, Perides G, Wang D, Liu YF. beta-Amyloid peptide induces formation of actin stress fibers through p38 mitogen-activated protein kinase. J Neurochem. 2002 Nov;83(4):828-36. doi: 10.1046/j.1471-4159.2002.01182.x. PMID: 12421354. https://pubmed.ncbi.nlm.nih.gov/12421354/
  25. Frederic Dorandeu, Guilhem Calas, Gregory Dal Bo, Raafat Fares, Chapter 36 – Models of Chemically-Induced Acute Seizures and Epilepsy: Toxic Compounds and Drugs of Addiction, Editor(s): Asla Pitkänen, Paul S. Buckmaster, Aristea S. Galanopoulou, Solomon L. Moshé, Models of Seizures and Epilepsy (Second Edition),Academic Press, 2017, Pages 529-551, ISBN 9780128040669, https://doi.org/10.1016/B978-0-12-804066-9.00037-7. https://www.sciencedirect.com/science/article/pii/B9780128040669000377 “Alterations of the neuronal cytoskeleton, and more precisely disruption of actin dynamics, seem then to contribute to changes in brain excitability, but the mechanisms leading to these changes remain still unresolved (Spence and Soderling, 2015).” Excerpt viewable in F-actin, ScienceDirect, https://www.sciencedirect.com/topics/neuroscience/f-actin

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Long Covid survivors – may have antibodies against several coronavirus

Cross-immunity to several human coronaviruses has been found in survivors with “LongCovid”, symptoms lasting months after the initial infectious symptoms. (1)

Mast cells can be activated by viruses. (2) People suffering with over activity of mast cells tend to not have very many colds or flu symptoms, even though they may have many other symptoms associated with the excessive inflammation and elevated histamine levels. Polyphenolic flavonoids are known to reduce mast cell inflammation and some have antiviral benefits such as luteolin. (2) Suppressing a mast cell response while trying to actively fight a viral infection would be limiting the body’s natural defense against a virus.

“A recent report correlated coronaviruses infection with activation of mast cells and subsequent cytokine storms in the lungs. 7 Mast cells are known to be triggered by viruses. 8″ Inhibition of mast cell‐associated inflammation could be accomplished with natural molecules, especially the polyphenolic flavonoids. 23 The flavone luteolin (not lutein, which is a carotenoid) has been shown to have broad antiviral properties.24, 25, 26” (2)

In Long Covid there may be residual virus but it is possible, maybe probable, that there is simply an overactivation of the mast cell system continuing to react to any food or toxin or even stress. See previous post.

“Colds and flu often last longer for people with Mast Cell Activation Syndrome or Histamine Intolerance. This is because these viral infections can set off a cascade of mast cell reactions lasting weeks or a few months.” (6)

Mast cell activation may vary based on what each individual is more sensitive to, as well as including some more typical problem foods or chemicals that everyone with overactive mast cells might find problematic. Symptoms can include a broad range and include mental health and behavior changes so diagnostic approaches might miss an inflammatory as the cause. See previous post.

Luteolin is found in celery, thyme, green peppers, and chamomile tea. (3) Some with over activity of mast cells might do better with the celery and thyme. Green peppers may be a mast cell/histamine problem food (4) and chamomile tea is a flower which some people with seasonal allergies (mast cell activation) may react to. See reference G10.12, Nrf2 Promoting Foods, chamomile tea is discussed and may be beneficial for people who are not sensitized to its pollen.

The excess Interleukin-6 that is commonly seen in COVID-19 illness may lead to over active mast cells in people who did not have seasonal allergy or Mast Cell Activation Syndrome symptoms for most of their lives (it can be genetic based). “Constant IL-6 exposure can cause the body to form more reactive mast cells.” (5)

The terminology and diagnostic criteria for mast cell over activity is still new. Some problems may include stimulation of mast cells without complete degranulation – release of histamine and other cytokines (IL-6 is a cytokine – a cell signal chemical). The name ‘Mast Cell Mediator Disorders (MCMD)’ has been established for symptoms involving less severe mast cell activity than full degranulation. (7)

How mast cell activation relates to Long Covid survivors may also vary based on personal genetic and other unknown factors in their environment or body burden of toxins (yes, we tend to contain a large mixture of modern toxins and heavy metals, (8)). Histamine containing or promoting foods could be a factor that varies based on a person’s diet and food sensitivities, in addition to mast cell activity throughout the body. Diet information and links were included in the first post about histamine in this series.

Based on the information about MCAS and histamine foods, I have improved my own odd symptoms and it is a huge relief to have found a cause that can be controlled, with some difficulty, and which explains the odd behavior and mood extremes. Histamine is involved in a wide range of brain functions and is involved in balance, not too much or too little activity – homeostatic control. Anxiety or whirling thoughts that only escalate are frightening and calling it a psychiatric problem wouldn’t help a histamine problem get any better. (Histamine’s function was included in the previous post.)

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Rafael Osswald, @RafaelOsswald, Tweet about research findings regarding crossimmunity in LongCovid survivors, Nov. 16, 2020 https://twitter.com/RafaelOsswald/status/1328408081487835152?s=20
  2. Theoharides TC. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors. 2020;46(3):306-308. doi:10.1002/biof.1633 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267424/
  3. USDA/Agricultural Research Service. “Luteolin stars in study of healthful plant compounds.” ScienceDaily. ScienceDaily, 16 July 2010. https://www.sciencedaily.com/releases/2010/07/100708141622.htm
  4. Hidden in Plain Sight: Histamine Problems, westonaprice.org, https://www.westonaprice.org/health-topics/modern-diseases/hidden-in-plain-sight-histamine-problems/
  5. Mast cells: MCAS, genetics, and solutions, geneticlifehacks.com, https://www.geneticlifehacks.com/mast-cells/ https://www.geneticlifehacks.com/mast-cells/#Other_substances_that_activate_mast_cells
  6. Immune Supports and Supplements that May Reduce Risk of Cold or Flu in Mast Cell Activation Syndrome and Histamine Intolerance. mastcell360.com, https://mastcell360.com/immune-supports-and-supplements-that-may-reduce-risk-of-cold-or-flu-in-mast-cell-activation-syndrome-and-histamine-intolerance/
  7. Theoharides TC, Tsilioni I, Ren H. Recent advances in our understanding of mast cell activation – or should it be mast cell mediator disorders?. Expert Rev Clin Immunol. 2019;15(6):639-656. doi:10.1080/1744666X.2019.1596800 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003574/
  8. Gennings C, Ellis R, Ritter JK. Linking empirical estimates of body burden of environmental chemicals and wellness using NHANES data. Environ Int. 2012;39(1):56-65. doi:10.1016/j.envint.2011.09.002 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249606/
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Glyphosate increases histamine, both may be a factor in COVID19

Recent posts include a long one on glyphosate, biofuel, and liver disease and how it may be increasing inflammation in severe COVID19; and two other posts (a, b) are about how an immune allergy type reaction increases histamine and a variety of symptoms, and which may be a factor in LongCovid. Foods and the health of our intestinal microbiome, bacteria and other microbes, can also increase histamine directly or indirectly. Some foods contain histamine and others cause more histamine to be produced. Glyphosate residue may also cause an increase in histamine. (1)

Genetics may be a factor in who is more at risk for having excess histamine. There is an enzyme needed to break down the excess histamine from foods, within the intestinal tract, which some people may not be able to make. It can be purchased as a supplement and taken with meals. Other people may have overactive mast cells which are the type of immune cell that produces histamine throughout the body. (1 , 2)

If the mast cells are overactive, MCAS – Mast Cell Activation Syndrome, symptoms may be more severe than a seasonal allergy type of histamine reaction and may include: “rashes, hives, itching, flushing, fainting, headache, abdominal pain, nausea, vomiting, gastroesophageal reflux disease (GERD), fatigue, chronic pain, trouble breathing and many more.” (2) To complicate trying to figure out if this is a problem for oneself or a patient the overactivity of mast cells may also be associated with other complex conditions that have varied symptoms too, including: “allergies, autism, autoimmune disorders, cancer, diabetes, Ehler-Danlos syndrome, postural orthostatic tachycardia syndrome (POTS), fibromyalgia, Lyme disease, mastocytosis, migraines and obesity.” (2) Add the various symptoms together and a person might have a confusing mixture of “twenty to thirty symptoms” and feel “extremely ill.” (2)

Lab tests frequently are not helpful for many of the conditions or MCAS and it may also be unclear whether a person is having histamine symptoms because of intestinal digestion or microbiome problems or due to overactive mast cells throughout the body. Severity of symptoms may be worse if the problem is related to mast cell activation throughout the body. Treatment approach would also be different. Some people might be helped by use of the digestive histamine enzyme while others wouldn’t need it. Both types, digestive histamine excess and mast cell over activity, would be helped by decreasing histamine containing foods or ones that increase release of histamine from mast cells. Eliminating all histamine from the diet would be impractical if not impossible. Reducing the amount might make a significant difference though in reducing the negative symptoms. More details about identifying the type of problem with lab tests or other clinical indicators and an elimination diet description are available here: westonaprice.org. (2)

Glyphosate as a stimulator of histamine release (1) would create a different list of foods to avoid. See the previous post “a long one on glyphosate,” the list of tips are summarized at the top of the post, so the full length can be skipped if desired.

Over active mast cells may involve cannabinoid deficiency. Mast cells have both Cannabinoid Receptor Type 1 and Type 2 on the cell surface and when activated they cause an inhibition of the mast cell.

“Mast cells contain CB1 and CB2 receptors, which when activated inhibit mast cell release (R). Research shows that cannabinoids can suppress mast cell degranulation. … Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. ” (3, 4)

“We have previously shown that exposure of mast cells to cannabinoids that bind to both CB1 and CB2 cause a net suppression in the proinflammatory responses.” […] “At short time points, ligation of either CB1 or CB2 leads to a suppression of cAMP levels. However, over a longer exposure time course, the cAMP responses that follow ligation of the two receptors are diametrically opposed. These results allow us to draw two conclusions. First, the results imply that CB1 and CB2 receptors are not redundant when co-expressed in mast cells. Secondly, the results suggest that the two receptors couple to distinct signalling pathways that diverge downstream of the Gαi/o proteins to which they are both coupled.” (4) – that may suggest that a short time, small amount of THC & CBD may not help suppress the mast cells, by increasing cAMP sufficiently, a longer exposure, larger dose is needed – and that both the CB1 and CB2 receptor types need to be activated for the suppression of mast cell. CBD activates CB2 receptors and THC activates CB1 receptors.

“CBD alone without THC maybe ineffective at treating dysfunctional mast cells because THC has a strong binding affinity for both CB1 and CB2 receptors, cannabidiol (CBD) has no particular binding affinity. Instead, many of the therapeutic benefits of CBD are created through indirect actions.” (3)

Edibles or smoke? “However, when it comes to MCAS patients who are more severe, they tend to not tolerate ingesting the Medical Cannabis oil or edibles but may can inhale the actual Organic Medical Cannabis Flower and find great relief from MCAS symptoms.” (3)

More information about mast cells and what they do is included in Mast Cells: MCAS, genetics and solutions. geneticlifehacks.com (1) Viruses can activate mast cells, which then release histamine and other inflammatory cytokines and chemicals. The immune mast cells are also called granulocytes because when activated they release little packets, granules, full of the inflammatory chemicals. Flu virus has been found to activate mast cells and mast cell inhibitors helped reduce lung damage and mortality in severe cases of influenza. Too much inhibition during an active infection might not be helpful though, because the goal is to kill the virus infected cells or other pathogens that can activate mast cells. (1)

What does histamine do?

“Brain histamine promotes wakefulness and orchestrates disparate behaviors and homeostatic functions.” […] “Dysfunctions of the histaminergic system may also contribute to the pathogenesis of multiple sclerosis and its murine model of experimental autoimmune encephalomyelitis,” […] “Histamine neurons send broad projections within the CNS that are organized in functionally distinct circuits impinging on different brain regions.” (5)

Histamine promotes wakefulness, so an excess may lead to insomnia problems, and it affects a lot of varied behaviors and balance of functions throughout the body, disparate – a wide range of behaviors, which suggests why there can be such a wide range of symptoms, and homeostatic – balance of body functions – no longer as able to stay at an even center, too tired, or too excited, too cold or too flushed, numbness or pain – roughly. Too itchy too often.

“Histamine itch and non-histamine itch are mainly mediated by TrpV1 and TrpA1 respectively. In addition, Trp channels can be coupled to cytokine receptors, toll like receptors or may even be directly activated by pruritogens.” (6)

Inflammatory bowel disease (IBD) can involve overactive mast cells and excess histamine activating Trp channels in the intestines, (1), leading to sudden diarrhea and/or pain. “Pruritigens” refers to other chemicals that directly activate Trp channels such as horseradish or Latex that cause itching, (pruritus). Others may cause the bowel symptoms of IBD including cinnamaldehyde from cinnamon, capsaicin from hot pepper, curcumin in turmeric, and other chemicals in spices or herbs like ginger, cloves, and mint. Previous post 1, post 2/webpage G3.5-3.6.2, G5.

Yes, it is not easy to figure out what you can eat if you have Mast Cell Activation Syndrome, or to safely use as skin care products or medications as some of the ingredients might be Trp channel activators.

Medications that may help reduce mast cell activation in the condition of Irritable Bowel Syndrome, similar to Inflammatory bowel disease but less severe, include mast cell stabilizers and “a medication to reduce prostaglandin E2 synthesis (e.g. a COX2 inhibitor) stopped the hypersensitivity in the animal model of IBS. [ref]” (1) Pomegranate peel extract and other antioxidants may act in part through COX2 inhibition. (previous post) Prep tips for pomegranate & the peel: G13.

Mast cell activation may also be involved in autoimmune diseases including Multiple sclerosis, Type 1 Diabetes, and Rheumatoid arthritis. (1) The excessive release of cytokines and inflammatory chemicals can lead to cell damage in surrounding tissue. Mast cells tend to be located within specific tissue areas of the body or along epithelial layers (skin and membrane linings of blood vessels or other tissue), rather than be free moving like some other types of immune white blood cells. (1) Some people may have overactivity in some areas of the body rather than throughout the entire body.

Regarding COVID19 illness, the cytokine interleukin 6 (IL-6) tends to be present in excess, (8), and it is a mast cell activator. (1) Vitamin C can help inhibit IL-6. (7)

Psychological stress causes mast cells to release their histamine and other chemicals – uh oh, time to think serenely about that. (1)

Tips to worry less – can you do anything about them? If no, try to let them go. Writing worries on notes and putting them in a worry jar is one idea – you did something about it. You can look through your worries later. If yes, plan your time – 1. write down your goals, long term – 5-10 years, mid length, this year, and short term, this day/week/month, and 2. make an action plan, what steps to take today, write a list. 3. Do your plan, cross off your list items. It can feel more organized and good to check off your short term goals, and more peaceful to have a plan. (9)

Regarding the complexity of Mast Cell Activation Syndrome, or histamine from food – writing down your symptoms and daily food, beverages, and other lifestyle issues that standout from your routine can help to start seeing a pattern of which foods or habits might be adding to the problem. Elimination diets are quiet simple to start and need to be followed for a couple weeks to get the body cleared out of the potential problem foods and hopefully start feeling better, whether itchy, headaches, fatigue, brain-fog, or pain, numbness, or other symptoms. Then add only one thing back and see if symptoms return. Symptoms may be fairly immediate, or the next day or two so gradual reintroduction will be easiest to track whether it seems to cause symptoms.

Lab tests and other help and medication may be nice too, if available, but an elimination diet can be done fairly easily and safely. Stick to a variety of foods from the different food groups and read bottles on any supplements or medications to check for ingredients that might also be trigger substances ‘starch’ is usually wheat or corn based unless specifically labeled like tapioca or arrowroot starch. Other post (a) includes links with a food diary and information about elimination diets for histamine issues. Not all people have exactly the same sensitivities and there can be an additive effect, many problem foods on the same day as stress – may become a flare up. Some of the lists vary and some are more restricted than others, but most have similarities in the worst risk foods. Starting with eliminating some of those and seeing if you start feeling better can also be a way to work towards learning what are problem foods for you personally.

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

  1. Mast cells: MCAS, genetics, and solutions, geneticlifehacks.com, https://www.geneticlifehacks.com/mast-cells/
  2. Hidden in Plain Sight: Histamine Problems, westonaprice.org, https://www.westonaprice.org/health-topics/modern-diseases/hidden-in-plain-sight-histamine-problems/
  3. Www.TickedOffMastCell.Org, Medical Cannabis: Mast Cell Activation Syndrome, 10/24/2019, ibcnj.com https://ibcnj.com/medical-cannabis-mast-cell-activation-syndrome/
  4. Small-Howard AL, Shimoda LMN, Adra CN and Turner H, Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells. Biochem. J. (2005) 388, 465–473 https://anandaenterprises.com.au/wp-content/uploads/2019/12/Anti-inflammatory-Potential-of-CB1-mediated-CAMP-Elevation-in-Mast-Cells.pdf.pdf
  5. Passani MB, Panula P, Lin JS. Histamine in the brain. Front Syst Neurosci. 2014;8:64. Published 2014 Apr 28. doi:10.3389/fnsys.2014.00064 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009418/
  6. Sun S, Dong X. Trp channels and itch. Semin Immunopathol. 2016;38(3):293-307. doi:10.1007/s00281-015-0530-4 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798920/
  7. Härtel C, Puzik A, Göpel W, Temming P, Bucsky P, Schultz C: Immunomodulatory Effect of Vitamin C on Intracytoplasmic Cytokine Production in Neonatal Cord Blood Cells. Neonatology 2007;91:54-60. doi: 10.1159/000096972 https://www.karger.com/Article/Abstract/96972#
  8. Grifoni E, Valoriani A, Cei F, et al. Interleukin-6 as prognosticator in patients with COVID-19. J Infect. 2020;81(3):452-482. doi:10.1016/j.jinf.2020.06.008 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278637/
  9. Gerry McCann, How to Manage Your Time Worry Less and Discover more Happiness, youtube.com, https://youtu.be/RgBb4xNrM-s