Serotonin syndrome is described as a drug-related condition and is commonly believed to be rare. Serotonin is a neurotransmitter, but its actions make it sound like a hormone. It is made in the central nervous system and the gastrointestinal nerve complex. The symptoms of serotonin syndrome arise as a result of an over-abundance of its release from the nervous system into the blood and can be mild to severe, depending on the amount of serotonin in circulation. For normal function, serotonin is stored in a tiny cavity at the end of a nerve, known as a synaptosome and is released by passing through the membrane that surrounds the synaptosome, into the brain. The syndrome is caused by medications, either alone or in combination that increase serotonin levels, e.g. antidepressants, migraine medications, opioid pain medications, or illegal drugs. It is treated by the withdrawal of the causative drugs. There are multiple symptoms arising from an excess of serotonin in the brain and there are also symptoms arising from a deficiency. It is perhaps the prime example of the importance of moderation in everything.
Too Much or Too Little Serotonin
Just as excess serotonin is linked with a variety of symptoms, including: shivering, diarrhea, irritability and/or restlessness, confusion, increased heart rate, high blood pressure, dilated pupils, twitching muscles, muscle rigidity, excessive sweating, headache, tremors, goose bumps, hallucinations, and in more severe cases, unresponsiveness, high fever, seizures, irregular heartbeat, unconsciousness or coma, too little serotonin may be linked to mood disturbances. Deficiency is associated with several psychological symptoms, such as anxiety, depressed mood, aggression, irritability, low energy and low self-esteem. It can cause carbohydrate craving, weight gain, fatigue and nausea, but also, digestive or gastrointestinal motility problems such as irritable bowel syndrome and constipation. It is also a key neurotransmitter in the sleep cycle and is an essential brain chemical.
Thiamine Deficiency and Serotonin
Since many of the posts on this website discuss the problem of symptoms that are frequently associated with deficiency of vitamin B1 (thiamine), I turned to the literature to see if there was any connection between this deficiency and the role of serotonin. I found two important studies that demonstrate the critical role of this vitamin and its association with serotonin. In the first study, researchers explored the role of thiamine deficiency in synaptic transmission, the high affinity uptake and release systems for neurotransmitters using synaptosomal preparations isolated from different parts of the brain in thiamine deficient rats. There was significant decrease in the uptake of serotonin by the synaptosomal preparations of the cerebellum. The administration of the vitamin in vivo resulted in a significant reversibility of the inhibition of serotonin uptake, coinciding with dramatic clinical improvement. The study supports the possibility of an important innervation of the cerebellum by serotonin and suggests a selective involvement of this system in the pathogenesis of some of the neurologic manifestations of thiamine deficiency.
The negative societal impacts associated with the increasing prevalence of violence and aggression needs to be understood. In the second study, researchers investigated the role thiamine using a mouse model of aggression. Ultrasound aggression in mice was induced and the molecular and cellular changes were studied. They found that the ultrasound-induced effects were ameliorated by treatment with thiamine and benfotiamine, both of which were able to reverse the ultrasound-induced molecular changes.
The clinical effects of both deficiency and excess of serotonin are all well described online. The deficiency symptoms described are exactly those associated with beriberi, the vitamin B1 deficiency disease. Serotonin cannot cross the blood brain barrier. Therefore, it must be produced separately in the brain and the gastrointestinal system. Its association with thiamine in the bowel amply reinforces the mystery of gastrointestinal beriberi.
The many posts on thiamine deficiency in Hormones Matter suggests that a mild deficiency of thiamine is responsible for the large number of the polysymptomatic illnesses reported. High calorie malnutrition is a common cause by its increase in the calorie/thiamine ratio. The relationship with drugs is another matter. Although the mechanism of an excess of circulating serotonin is described as the drug-related cause of this syndrome, I could not help but notice that I have seen some of these symptoms corrected by the use of megadose thiamine. For example, excessive sweating, dilated pupils, increased heart rate and “goose bumps” are all caused by increased activity in the sympathetic branch of the autonomic nervous system. Thiamine deficiency is a prime cause of imbalance in this system. Certain therapeutic drugs used in medical practice may trigger mitochondrial toxicity leading to a wide range of clinical symptoms and even a compromise of the patient’s life. Contemplating this made me wonder whether the vitamin might have an important bearing on maintaining serotonin in its median state of concentration, because of its vital role in energy metabolism.
Serotonin and COVID-19
Since it has been claimed that Americans consume a high calorie diet, it is important to stress the imbalance which is commonly high in carbohydrate and fat. Serotonin is synthesized from tryptophan, an amino acid that is found in first-class protein and is an essential component of the human diet. It plays a part in many metabolic functions including the synthesis of serotonin and melatonin. Supplementation of this amino acid is considered in the treatment of depression and sleep disorders. It is also used in helping to resolve cognitive disorders, anxiety, or even neurodegenerative diseases. Reduced secretion of serotonin is associated with autism spectrum disorder, obesity, anorexia and bulimia nervosa, as well as other diseases presenting with a variety of symptoms.
It has been hypothesized that aging occurs because of failure of the pineal gland to produce melatonin from serotonin. Evidence has been presented for a role of melatonin and serotonin in controlling the neuroendocrine and immune networks inhibiting the development of ischemic heart and Alzheimer’s disease, tumor formation and other degenerative processes associated with aging. However, a more modern concept for aging is that the production of intracellular reactive oxygen species is a major determinant of lifespan.
One important feature of Covid 19 pathophysiology is the activation of immune cells, with consequent massive production and release of inflammatory mediators that may cause impairment of several organ functions including the brain. In addition to its classical role as a neurotransmitter, serotonin has immunomodulatory properties, down regulating the inflammatory response by central and peripheral mechanisms. Although the interferon system is the first line of defense against viral infection in mammals, almost all viruses have evolved mechanisms to evade the interferon system by partially blocking their synthesis or action.
The Case for Thiamine Supplementation in COVID 19
Thiamine is an essential cofactor for four enzymes involved in the production of energy (ATP) and the synthesis of essential cellular molecules. The total body stores of the vitamin are relatively small and its deficiency can develop in patients secondary to inadequate nutrition, alcohol use disorders, increased urinary excretion and acute metabolic stress. Patients with sepsis are frequently thiamine deficient and patients undergoing surgical procedures can develop the deficiency. It can lead to congestive heart failure, peripheral neuropathy, Wernicke disease and gastrointestinal beriberi. It can result in the development of intensive care unit complications such as heart failure, delirium, critical care neuropathy, gastrointestinal dysfunction and unexplained lactic acidosis. Consequently clinicians need to consider thiamine deficiency in patients admitted to intensive care units and the development of this deficiency during the management of critically ill patients. Intravenous thiamine can correct lactic acidosis, improve cardiac function and treat delirium, without there being any possibility of toxicity. The many symptoms developed in Covid 19 patients are interpreted as a direct effect of the virus, whereas the evidence written in this post strongly suggests that deficiency or excess of serotonin are responsible and that intravenous thiamine could be given with impunity in the emergency room. The persistence of thiamine deficiency following the cessation of the acute phase of the disease would explain the long term symptoms that have been described, following what is generally accepted as recovery.
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Dr . Lonsdale,
I am hoping you can help. I was given a vaccine on Jan 19 and on 22nd started having shortness of breath. The next week I was waking gasping during the night and in the 2 months since am practically couch bound with Pots like symptoms and major sleep issues and anxiety. Labs revealed I was actually high on folic acid. I have been diagnosed with post covid pots but after reading many of your articles im thinking maybe it was the vaccine since the timeline seems to fit better. I am having terrible nights with nightmares along with so many of the thiamine deficiency symptoms. During all this dysautonomia they have found low dao levels( possibly bc I’m on several antihistamines) which is making me more sensitive to foods. Would you recommend a trial of thiamine and, if so, does the type matter? I also read to take magnesium with it but I’m not sure which one. Thank you so much fir any help you can provide. My husband is US active duty but we are in a foreign country with few medical options.
Here is my reasoning. Any physical or mental action requires energy. But also, when we are stressed by any outside influence, even a vaccine, it invokes a reaction as a response and that also requires energy. Several years ago I was emailed by a mother who had a daughter that had received a vaccine that had crippled her for four years. She did her own research and found that her daughter was suffering from vitamin B1 deficiency. The condition that was affecting the daughter was POTS and I think that that is what is affecting you. I believe that supplemental thiamine and magnesium would restore your energy (and avoid sugar and alcohol). Thiamine should start with a relatively low dose like 10 or 20 mg and then increased gradually when the paradoxical symptoms have abated. In order to understand this I suggest that you read some of the posts on Hormones Matter.
Hi Dr. Lonsdale,
I noticed some Twitter posts suggesting the use of Fluvoxamine, an SSRI (Selective Serotonin Reuptake Inhibitor), for treatment of Covid symptoms. Here are some links:
I immediately thought of your article. From which, it seems increasing serotonin in the brain is what’s needed. On the other hand from Angela Stanton’s article “Silent Death – Serotonin Syndrome” on Hormones Matter it seems like the use of SSRI’s is fraught with danger. I am wondering what you think of this as a proposed treatment. Is it likely to be the ultimate answer for Covid long-haulers, or, given the connection you draw between serotonin and thiamine, do you perhaps see it as evidence that high dose thiamine is what is needed to rectify the serotonin deficiency?
I believe that it is megadose thiamine that is needed.
Hi Dr Lonsdale love your work it may have changed my life. What do you think about the sublingual form of Thiamine Pyrophosphate as an alternative to TTFD?. Also I had a question thats been playing on my mind I have mild autism and I’ve noticed when I take any form of B12 I get short of breath and show signs of thiamine deficnecy do you think this is relevant or not? Is the B12 lowering my Thiamine or inhibiting usage. Regards Tom
Well, as I see it, we have to produce energy and thiamine is an important part of the “engine”. But we have to consume that energy so we have the equivalent of a “transmission”. Folate and B 12 are part of it. It has been found that an elevated blood folate and B12 in a pregnant woman forecasts autism in the as yet unborn child. A patient of mine whose medical problem came from thiamine deficiency, had raised blood folate and B 12 that became normal when he was treated with thiamine. When thiamine was stopped, they both rose again and decreased when thiamine was restarted. That is why I treated autism with megadoses of thiamine
Wow! Thank you so much Dr. Lonsdale! This is very interesting! I am compound heterozygous for MTHFR, and as I am sure you are aware, many autistic folks have this history. I have a sis who most likely is slightly autistic although no formal diagnosis. Menopause threw everything out of whack for me. I must have seen 100 docs (many in ER for what I later learned were panic attacks, not heart attacks). I thought I was loosing my mind. Was extremely unstable/depressed but so determined to figure it out. Many docs offered and prescribed antidepressants (Paxil, valium) but I somehow knew that was not the answer (although my familial history is supposed bi-polar with Mom and brother both dead due primarily to drug/alcohol abuse, both script and non). Fast forward to Functional Med MD who found the genetic anomaly (not defect) and discovered Melatonin so high it was untestable/way out of range. Additionally both folate and b12 were considerably elevated without supplementation although not out of range but Nutreval said not getting inside the cell. She turned me around with a high quality multi with b-complex containing active Bs including a decent dose of Thiamin (25 mg), and a significant dose of Trimethylglycine each day. It was literally like Christmas…. My mind was finally quiet. Meanwhile I added whey protein as Nutreval revealed low on protein. I was always a healthy eater, low sugar no junk but this got me on my way. I still struggle physically to a certain degree but mentally I am good. Gut serotonin is still high but diversity is good to excellent with lots of butyrate. I am currently experimenting with dosage of Benfotiamine as recent Nutreval revealed somewhat elevated MMA, and sky high (out of range) b12! I have idiopathic neuropathy but it is not unbearable. B1 was still lowish and B2, 3 and 6 all were very low. Clearly there is a trafficing problem somewhere as this is with the supplementation. I am getting some relief I think with just 150mg Benfo. Definitely energy improved and sleeping better, but it does bother my stomach a tad. Lots of things do bother my stomach. Sad thing is that this may have been thiamin related all along, oof! Recent endoscopy found polyp in stomach/mild gastritis, and gastro doc wanted me to do acid blocker – ugh! My FM doc says “rediculous, you already have a polyp for goodness sakes!” Wanted me to add a B complex in afternoon but I have not found one yet that does not upset my stomach. I tried one with 100mg B1 but hydrochloride seems to be too much for the tummy at least for now. Using brewers yeast to get some extra B instead for now. It will be very interesting to see if the Benfo brings the b12 down into normal range. You will be the first to know if this works! You are a blessing for all you have learned and shared!
Kim C 🙂
I wonder if there is correlation to COVID19 outcome. It is now known (although not widely) that severe acute COVID is immune-mediated platelet hyperreactivity coupled with corresponding hyper-serotonin state. The platelets go crazy and clot and dump their serotonin contents. Many Long Haulers are benefiting from Thiamine and Niacin (Nicotonic Acid) supplementation. Possibly repleting NAD+ levels and Kynurenine Pathway homeostasis, allowing more Tryptophan to shuttle toward serotonin and melatonin. Seems like severe acute COVID may be serotonin overdose, and Long COVID is somehow a downstream serotonin depletion due to poor metabolic state.
Serotonin excess drives lymphopenia: https://www.sciencedirect.com/science/article/abs/pii/0008874984903071
Serotonin stimulates B cells, increases NK cell cytotoxicity, IFN-γ secretion, reduces macrophage antigen presentation, increases IL-1β, IL-6, IL-8: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517399/
Serotonin drives neutrophil infiltration: https://pubmed.ncbi.nlm.nih.gov/23243271/
Serotonin induced cerebral vascular injury & BBB breakdown: https://www.nejm.org/doi/full/10.1056/NEJMc2033369
Also curious whether these platelets are viral reservoirs to long-lived immune cells as they are for other viruses. Viral persistence in Long COVID: https://ashpublications.org/bloodadvances/article/4/18/4512/463771/Platelets-function-as-an-acute-viral-reservoir
I have suffered from Dysautonomia symptoms and fatigue for many years and upon reading your book and articles have come to the conclusion that I was thiamine deficient. My GP agreed to injecting me with 100 mg thiamine HCl into the muscle a couple of times a week and has done so for a couple of months. I am feeling a lot better with both the fatigue and dysautonomia symptoms improved. Now I want to switch to taking TTFD instead of the injections, because my GP reckons that the thiamine deficiency must by now be over.
I, however, am scared to relapse and would want to continue taking TTFD.
Would 200 mg of TTFD a day be enough, do you think? Or what would be a good dose?
As of recently I also take nicotinic acid a few hundred mg a day, as this seems to have helped quite a few Covid Long Haulers to get rid of some of their many symptoms and they are the same symptoms that I have suffered from for years. I hope there is nothing wrong with that and that it doesn’t affect the thiamine status/supplementation in a bad way.
Thank you very much for your book, your work and your advice!
You can titrate the dose to the symptom improvement
Will do, thank you, Dr. Lonsdale!