Rethinking Depression The pathophysiology of depression is far from settled, but a closer look makes it clear that it is not a problem of low serotonin. The “chemical imbalance” theory was always an untested, ad-hoc hypothesis—more marketing than science—and is now largely abandoned. Serotonin depletion does not induce depressive symptoms in most healthy volunteers.[1] Depression is a multifactorial condition involving overlapping disturbances in neurobiology, metabolism, and stress-response systems. It is physiologically similar to anhedonia and overlaps heavily with anxiety, leaving little reason for a rigid distinction. The human brain accounts for just 2% of body weight yet consumes about 20% of total energy, underscoring its immense metabolic demand. In large part, depression is a problem of insufficient energy production, and in rat models, serotonin has been shown to decrease brain ATP.[2] Functionally, serotonin can act as a hormone of withdrawal,[3] and is often elevated in depressive phenotypes.[4] Unsurprisingly, adverse life circumstances explain depression more reliably than biological defects.[5] Qualifying criteria of Major Depressive Disorder (MDD): • Consistently feeling sad, empty, and hopeless • Markedly diminished interest in pleasurable activities • Significant weight loss or gain; increased or decreased appetite • Insomnia or hypersomnia • Fatigue or loss of energy • Feelings of worthlessness, or excessive/inappropriate guilt • Diminished ability to think or concentrate, or indecisiveness • Recurrent thoughts of death and suicidal ideation without a specific plan • Psychomotor agitation or retardation Per the DSM-5, at least five of nine of the listed symptoms (and at least one of the first two) must be present most of the day, nearly every day, during the same 2-week period to classify as having MDD. Symptoms must cause clinically significant distress or impairment and not be attributable to substances or another medical condition. Based on our (faulty) model, historically it was assumed you had low serotonin if you qualified for MDD. This is never tested, and if it were, it would be measured in the blood—which is a problem, because blood serotonin does not reliably reflect brain serotonin. Depression involves: • Oxidative stress[6] • Low brain ATP[7][8] • Low thyroid hormone activity[9][10][11][12] • Low sex hormone activity[13] • Increased inflammatory cytokines[14] • Increased stress hormones (HPA axis over-activity)[15] • Decreased dopamine activity[16][17] • Decreased allopregnanolone[18] • GABA/glutamate imbalance[19] • Dysbiosis[20] • Environmental factors[21][22] Not a Chemical Imbalance “In truth, the ‘chemical imbalance’ notion was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists.”[23] —Dr. Ronald Pies, Editor-in-Chief Emeritus, Psychiatric Times “There isn’t an iota of direct evidence that chemical imbalances are at the root of anyone’s mental disorder.”[24] —Dr. Steven Hyman, Former Director, U.S. National Institute of Mental Health (NIMH) “The serotonin theory is as close as any theory in the history of science to having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future.”[25] —Dr. Irving Kirsch, Associate Director, Program in Placebo Studies, Harvard Medical School What the Studies Show • The “chemical imbalance” theory is a controversial hypothesis that has yet to be proven[26] • A 2022 meta-analysis found no correlation between low serotonin and depression[27] • A significant portion of SSRI benefits are, on average, attributable to the placebo effect[28][29] • Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction,[30] while peripherally-acting serotonin promotes energy absorption and storage[31] • Exercise is effective and comparable to antidepressants for non-severe depression[32] • When Eli Lilly first tried to get Prozac approved in Germany, their own studies showed people taking Prozac committed suicide at a 3x higher rate than placebo, leading the German health authorities to reject it as "totally unsuitable for treating depression"[33] • 30% of babies whose mothers take SSRIs experience neonatal abstinence syndrome (NAS), which can cause jitteriness, irritability, and difficulty breathing, among other symptoms[34] • A 2015 study analyzing 856,000 SSRI users in Sweden found significant association between SSRIs and violent crime convictions for males and females aged 15-24[35] • There is substantial scientific evidence that depression is often a low dopamine state:[36] Wellbutrin (bupropion), an NDRI (Norepinephrine-Dopamine Reuptake Inhibitor), has demonstrated comparable efficacy to other antidepressants in treating depression[37] • Thyroid supplementation has been shown to be effective in treatment-resistant depression,[38] in one study cohort, 93.3% of moderate-severe grade depressives demonstrated low T3 (active thyroid hormone) levels[39] • A 1997 study found that six months after discontinuation, 81% of participants showed no improvement in symptoms of Post-SSRI Sexual Dysfunction (PSSD)[40] FAQs Q: If SSRIs are so bad, why do they work for some people? A: SSRIs don't just increase serotonin. 1. In the short term, serotonin can “help” in a rough spot—it’s a stress-coping hormone—but dulling emotional responses to tolerate a bad life is hardly ideal. 2. SSRIs can indirectly raise dopamine and key neurosteroids: fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) increase allopregnanolone, a progesterone metabolite and major positive allosteric GABA_A receptor modulator.[41] 3. Many SSRIs—including fluoxetine, sertraline, and fluvoxamine—are functional inhibitors of acid sphingomyelinase (FIASMAs), potentially reducing neuroinflammation independent of serotonin. 4. With repeated use, plasma serotonin often decreases in responders[42]—consistent with compensatory feedback—though plasma may not reflect brain serotonin activity. 5. Serotonin can trigger bowel movements, and constipation is significantly associated with major depression.[43] 6. Serotonin has direct anti-fungal activity.[44] Q: Some of those things sound good—are SSRIs worth taking if they can confer those benefits? A: You don’t know if you will end up with PSSD until it happens. You don’t know if SSRIs will increase your aggression until it happens. You don’t know if you have a rare genetic condition or metabolic idiosyncrasy that will react poorly to an SSRI until it happens. Zoloft is 45x more likely to induce an otherwise rare genetic disorder called adult-onset multiple acyl-CoA dehydrogenase deficiency (MADD). Symptoms of MADD include: • Fat accumulation in skeletal muscle • Exercise intolerance • Muscle pain or weakness • Episodic vomiting • Fatigue • Rapid or difficult breathing • Seizures • Hypoglycemia • Prostate inflammation • Sensory neuropathy • Damage to the liver, heart, and skeletal muscle These are not gambles worth taking when there are so many safer alternatives for treating depression. For more on this, see SSRIs Can Cause Severe Mitochondrial Dysfunction by Chris Masterjohn, PhD. Q: How could the experts get this so wrong? A: The pharmaceutical industry has a history of major errors (e.g., Vioxx, thalidomide, the opioid crisis). When billions are built on a flawed premise, reversing course is nearly impossible. As Upton Sinclair said: “It is difficult to get a man to understand something when his salary depends on his not understanding it.” SSRIs have been linked to high-profile violent incidents, including school shootings. While causality isn’t proven, population data suggest higher aggression or violence risk in some young users, and SSRIs carry a black box warning for increased suicide risk in adolescents and young adults. Fully investigating serious side effects—and reexamining serotonin’s “happy hormone” reputation—would be costly and could destabilize the entire industry, leaving little financial incentive to do so. The bottom line is that there are many better options for alleviating depression—ones that don’t carry the risk of PSSD, suicidal ideation, or rare but catastrophic behavioral side effects. Disclaimer: I am not a medical professional, and nothing in this article should be considered medical advice. If you are considering tapering off of SSRIs, consult your primary care physician and do so gradually. Alternatives As we covered in the beginning, depression involves: inflammation, low brain energy, hypothyroidism, low sex hormone activity, stress, low dopamine, dysbiosis, environmental factors, and more. Logically, it follows that addressing these points is a priority. While individual physiology and circumstances will influence which of these deserve more attention, there are many safer, broad-spectrum approaches worth trying. The following recommendations are presented in order of safety and general likelihood of benefit. Lifestyle • Early morning sun exposure • Engagement in hobbies • Walking (5–10k steps) • Regular exercise • Nutrient-dense, digestible diet • Micronutrient tracking (Cronometer) • Adequate dietary carbohydrate intake • Adequate dietary calcium, choline, tyrosine, and gelatin • Coffee consumption (daily) • Carrot salad or white button mushrooms (daily) • Sauna use • Red light therapy • Lymphatic drainage Nutritional • Creatine[45][46][47] • Benfotiamine (B1) • TTFD (B1) • Niacinamide (B3) • Pyridoxal-5’-Phosphate (B6) • Inositol (B8) • Methylfolate (B9) • SAMe • Magnesium Glycinate[48] • Magnesium Chloride[48] • Magnesium Bicarbonate[48] • Magnesium N-Acetyl Taurinate[48] • Magnesium Oxide[48][49] • Calcium Pyruvate • Vitamin A • Vitamin D3[50] • Vitamin E • Vitamin K2 (MK4) • Zinc[51] • CoQ10 • CDP-Choline/Alpha-GPC • Theanine • Tyrosine • Glycine • Taurine Herbal, Probiotic, Bioactive • Agmatine Sulfate • Saffron[52] • Apigenin • Naringenin • Pau D’Arco • Cascara Sagrada • Oregano Oil • Activated Charcoal • Colostrum • Kefir • B. subtilis • S. boulardii • L. reuteri Hormonal • Progesterone (low, non-suppressive doses in men) • Pregnenolone (high-purity) • DHEA (≤5 mg per dose, max 15 mg/day) • Testosterone (males) • DHT (males) • Thyroid hormone (T3 or T3:T4 combination) Pharmaceutical • Aspirin • Penicillin VK (low dose, short duration) • Tetracyclines, e.g., minocycline or doxycycline (low dose, short duration) • Cyproheptadine • Metergoline • Memantine • Selegiline[53] • Ketamine[54][55] • Lithium Thank you (give these accounts a follow) @PSSDNetwork @PrometheanAngel @ChrisMasterjohn @dannyroddy @haidut

High dose thiamine therapy changed my life. I have recommended this versatile B vitamin to many people for many different reasons. Throughout my own experience with it, I have learned a lot and received a lot of questions, so I have taken the time to organize all the answers here. Disclaimer: I am not a doctor and this is not medical advice. Thiamine Therapy FAQs 1. What is thiamine? Thiamine, or vitamin B1, is a water-soluble vitamin and, as the "1" implies, the first water-soluble vitamin ever discovered. It was found in 1910 by Japanese agricultural chemist Umetaro Suzuki but it wasn't until 1934 that its structure was determined by Robert Runnels Williams. It was named by the Williams team as a portmanteau of "thio" (sulfur-containing) and "vitamin". Modern spellings of thiamine often omit the "e" since it is not an amine as was previously thought, but still the spelling with the "e" remains the most common. Thiamine is necessary for: • Energy metabolism • Nervous system function • Cardiovascular health • Cellular function • Digestive health • Muscle function • Immune function • Hormone health • Detoxification Conditions improved with thiamine supplementation include: • Beriberi • Wernicke-Korsakoff syndrome • Depression • Shingles • Cataracts • IBS • IBD • POTS • CFS • MS • MCAS • Sleep apnea • Parkinson's • Alzheimer's • Autism • Fibromyalgia • Diabetes • Dysautonomia • Cancer These are all metabolic illnesses, or illnesses which have a major metabolic component, and thiamine is crucial for metabolism. 2. What is the difference between the different forms? The active form of thiamine is thiamine pyrophosphate (TPP), and it is this form that makes its way into the cell. The most common forms of supplemental thiamine are thiamine hydrochloride (B1 HCl) and thiamine mononitrate (TMN)—these are low-bioavailability salt forms. More potent forms of thiamine were developed in Japan in the '50s, and these consist of TTFD, benfotiamine, sulbutiamine, allithiamine, and prosultiamine, among others. Some of these are naturally occurring (allithiamine), while others are synthetic (TTFD, benfotiamine, sulbutiamine, and prosultiamine). These potent forms are often considered "fat-soluble", although this classification is not entirely accurate. Technically, these forms are still water-soluble, but their chemical structure allows for greatly increased permeability through the cell membrane as if they were fat-soluble. What makes these "fat-soluble" forms so unique is their ability to bypass the need for transporter proteins (ThTR1, ThTR2), making them effective in people who have thiamine transport issues. 3. What can cause a thiamine deficiency? • Refined carbohydrate intake* • High intake of coffee, teas, and raw fish** • Alcoholism • Kidney disease • Diabetes • Diarrhea • Metformin • Antibiotics (Flagyl) • Diuretics • Metabolic disease • Digestive issues • Surgery • Stress *This does not make carbohydrates inherently bad, it is simply a metabolic reality that carbohydrate metabolism needs thiamine. **These contain thiaminases, or enzymes that break down thiamine. This does not make coffee, tea, or raw fish inherently bad, but it is something to keep in mind if one is consuming these regularly. 4. Why such a high dose? Because of the generality of potential symptoms, thiamine deficiency is greatly underdiagnosed. Thiamine deficiency can be brought on by a "functional deficiency", where oxidative stress and inflammation block enzymes that use thiamine or destroy the molecule entirely. There are also regional deficiencies that are localized to just the brain, the heart, or the digestive system. In some people, transport proteins can be deficient or defective. In such a circumstance, either larger doses or more potent forms are necessary. Part of the high-dose therapy is the aspect of total saturation—using the vitamin in supraphysiological doses, making it drug-like, and helping the body to "remember" how to use this crucial nutrient. Unlike pharmaceuticals, however, this "drug-like" use of thiamine is much safer than patented drugs. 5. Which enzymes need thiamine? • Pyruvate dehydrogenase, a rate-limiting step in glucose oxidation and the "key" for entry into the Krebs cycle from glycolysis (a crucial step in breaking down carbs) • α-Ketoglutarate dehydrogenase, another rate-limiting step, this time in the Krebs cycle, which involves the metabolism of the 3 main fuel substrates (carbs, fats, and proteins) • Branched-chain ketoacid dehydrogenase, needed to process branched-chain amino acids from protein • Transketolase, the enzyme which connects the pentose phosphate pathway to glycolysis, crucial for antioxidant defenses and damage repair 6. How bioavailable are the different forms? • Thiamine hydrochloride (B1 HCl), 3-10%* • Thiamine mononitrate (TMN), 3-10%* • TTFD (thiamine tetrahydrofurfuryl disulfide, also known as fursultiamine), 50-90% • Sulbutiamine, 50-90% • Benfotiamine, 50-90% *Due to passive diffusion, doses above 500 mg will increase the bioavailability, however, opting for B1 HCl over TMN due to the latter's nitrate content would be preferable. 7. Which forms cross the blood-brain barrier? • B1 HCl*, limited entry • TMN*, limited entry • TPP**, limited entry • TTFD, crosses BBB • Sulbutiamine, crosses BBB • Benfotiamine, crosses BBB *While B1 HCl and TMN cannot cross the BBB, bolus doses can increase bioavailability due to passive diffusion. People with serious neurological issues like Parkinson's have been shown to get relief from 2 - 4 grams of B1 HCl, so it should not be written off for being "low bioavailability". **TPP is the active form of thiamine but when supplemented orally, it reaches the intestine and is converted back into normal thiamine. However, phosphorylated forms of thiamine such as TMP and TDP can cross the BBB. 8. What is the best form? There is no best form of thiamine; it is entirely dependent on a person’s individual needs. A good form to start with is B1 HCl: it’s cheap, least likely to provoke a "paradoxical reaction", and can accustom one to thiamine so that one feels more ready to try potent forms. 9. What is the best dose? This is another impossible question to answer. Not only regarding thiamine, but with most any supplement that is correcting a metabolic problem. The amount of thiamine needed to fix metabolic problems is so widely variable that it would be useless to know how much helped someone else. However, there are effective dose ranges: • B1 HCl, 500 mg - 4,000 mg • TTFD, 100 mg - 800 mg • Benfotiamine, 300 mg - 1,000 mg Use common sense: start low and titrate up slowly. Never take more than one new supplement at a time to keep track of what is doing what. Additionally, the upper ranges listed for TTFD and benfotiamine will rarely need to be reached. 10. When is the best time to take thiamine? At least 30 minutes after the first meal of the day with plain or sparkling mineral water. If taking a second dose, 30 minutes after lunch. Some find that thiamine helps with sleep, but taking it at night is less common due to it being mentally stimulating. 11. Is there a dosage-equivalence between different forms? There is not enough available data to answer this question. Based on bioavailability estimates, one can assume benfotiamine and TTFD are similar, but these are not equivalent in their action. Elliot Overton has observed lower doses of TTFD achieving similar effects to higher doses of benfotiamine. Although this is anecdotal, it is worth keeping in mind. 12. How long to take thiamine for? Yet again, it is entirely dependent on the person’s unique physiology and circumstances! Some take a high dose for 3 - 6 months and find that they can taper down to nothing; others use thiamine on an as-needed basis for mentally or physically demanding tasks; and still others need to take it for life, as in the case of serious neurological illnesses like Parkinson's. Still, taking a relatively inexpensive and widely available B vitamin is preferable to relying on a patented pharmaceutical with a concerning list of side effects. 13. Does high-dose thiamine therapy increase the need for other nutrients? Yes. HDT therapy may increase the need for: • B2 • B3 • B5* • B6 • B7* • B9 • B12* • Salt • Magnesium* • Potassium • Copper • Selenium • Molybdenum* • CoQ10* • Glutathione* *These tend to be the nutrients put under the most pressure by thiamine. Is the solution to panic and start taking all of these supplementally? Definitely not. Eat a balanced diet, start with a B complex, add in magnesium, and go from there. Additional troubleshooting may or may not be required down the line. Thiamine HCl is the easiest to titrate up and typically involves the least troubleshooting. Disulfide derivatives (TTFD, allithiamine, sulbutiamine, and prosultiamine) may put pressure on sulfur metabolism which may be remediated with CoQ10 and/or molybdenum. 14. What about brewer's yeast? Nutritional yeast? Nutritional yeast and brewer's yeast both contain phytoestrogens and can cause gut upset when used supplementally at the frequency needed for high dose thiamine therapy due to their probiotic content. It is possible to boil off the phytoestrogens and probiotics, but it would be more practical to use a quality B complex supplement. 15. Can thiamine deficiency be tested for? Currently, there are five methods to measure thiamine status, however, not all or accurate or practical: • Blood thiamine • Urinary thiamine excretion • Pyruvate and lactate • Whole blood high-performance liquid chromatography (HPLC) • Erythrocyte transketolase activity/thiamine pyrophosphate effect (ETKA/TPPE) Blood thiamine is the most common thiamine test and is useless because it only shows whether or not thiamine was ingested recently. The blood contains only 0.8% of total body free thiamine, making this test not at all reflective of tissue levels. Concentration of thiamine in the blood or plasma can be completely normal even in an advanced deficiency. It is likely a doctor's first choice if their patient tells them they are concerned about a thiamine deficiency, though. Urinary thiamine excretion is a similar story. Since thiamine is required for pyruvate metabolism, elevated pyruvate and lactate can be a sign of thiamine deficiency. HPLC is one of the newest methods of testing and it is used to measure thiamine, TPP, and its esters in the erythrocytes. HPLC is more accurate than blood or urine tests and more able to identify the early stages of a thiamine deficiency, however, it is costly and not easy to order. The most accurate thiamine test available to the general public, therefore, is the ETKA/TPPE: a pair of tests which assess thiamine usage and reflect stores at the tissue level. • First, baseline transketolase activity (TKA) is measured in international units per liter of blood per unit of time (normal ranges being between 42-86 mU/L/min). • Next, TKA is repeated after active thiamine (TPP) is added to the reaction medium. • If TKA increases, it is taken as proof that the enzyme was not saturated with its cofactor. • This is reported as the percentage increase over base activity and is known as the “thiamine pyrophosphate effect”, or TPPE (normal ranges being 0% - 18%). Derrick Lonsdale and Chandler Marrs have made some useful observations on ETKA/TPPE results: • Sometimes the TKA is low while the TPPE is normal and this would suggest abnormality in the TKA enzyme. • In most cases of thiamine deficiency, the TPPE is increased, sometimes remarkably so, while the TKA is in the normal range. • In a more severe deficiency state, the TKA is low, but in the normal range, and the TPPE is high. "Correlating the patient's symptoms with a fall in the TPPE and a rise in TKA (remaining within the normal range) is an excellent way of proving the clinical effect of thiamine supplementation," they conclude. While the ETKA/TPPE is the best test for thiamine deficiency, even this test is imperfect. With this in mind, it is best to try thiamine regardless because of how low risk it is. 16. How to tell if thiamine is working? Generally, whether thiamine is working or not is obvious. For many—especially when higher doses are reached—the difference is night and day. For others, they may have paradoxical reactions or need to dial in other nutrients which thiamine may put undue pressure on. If someone wanted to be sure thiamine was helping, buying an at-home lactate meter (such as the Nova Biomedical Lactate Plus Meter) to see whether thiamine raises or lowers lactate would be reasonable. 17. Which products to take? • B1 HCl - Pure Bulk, Dr. Clark Store • TTFD - Objective Nutrients ThiaMax* • Mixed - Objective Nutrients ThiaMega* • Benfotiamine - Bulk Supplements • B Complex - Objective Nutrients ThiActive methylated B complex, Premier Research Labs Complete B, -Pure Encapsulations B-Complex Plus, Dr. Clark Store Super B100 *If you feel you are ready to try the most potent forms of thiamine, use code "TAKETHIAMINE" for 10% off your order at Objective Nutrients. The only quality TTFD product without excipients on the market is ThiaMax, and I trust it enough to take daily. 18. Additional resources? • Dr. Antonio Costantini's YouTube channel • Elliot Overton's YouTube channel • Elliot Overton's protocols for addressing thiamine deficiency & the paradoxical reaction PDF • Hormones Matter blog • "Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition" by Derrick Lonsdale and Chandler Marrs • Chris Masterjohn's Energy Metabolism Masterclass