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 . ” (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 . 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 .” …”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. 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.  Chronic intake of excessive dietary vitamin A may increase risk of osteoporosis and hip fractures. 
- Headache, nausea, and vomiting may occur and pseudotumor cerebri syndrome infrequently has been seen. 
- Hypothyroidism occurred with bexarotene treatment, reversible with cessation of the treatment.  Renal dysfunction with etretinate occurred, also reversible with cessation of treatment. 
- Hypertriglyceridemia and other blood lipid changes have been seen with retinoid treatments: bexarotene, isotretinoin, etretinate, and acitretin, , 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. 
- No causal association has been found between the retinoid treatment isotretinoin and depression, psychosis, or suicide attempts, but a link has been suggested. 
- 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.
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.
- 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
- 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  includes the suggestion that an abnormality in the interplay between retinoic acid and sex hormones may cause ASD ,” As noted in our review on GWI , 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
- 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/
- 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/
- 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
- 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/
- 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
- 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/
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- 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
- Vitamin A, Linus Pauling Institute, lpi.oregonstate.edu, https://lpi.oregonstate.edu/mic/vitamins/vitamin-A
- 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/
- 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
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