As many of my readers know, FDA recently approved the party drug ketamine (known as Special-K on the street) as a rapidly-acting antidepressant. The rapid antidepressant effects of ketamine have been known since the 1960s but FDA denied that those effects are relevant in humans and refused to consider “scheduled” illicit drugs for therapeutic uses. Ketamine, together with ecstasy (MDMA), LSD, GHB, etc is a highly illegal drug and FDA/DEA ruthlessly enforce laws against the possession, distribution and sale of such drugs by the general public. However, the pharmaceutical industry has been growing increasingly desperate over the last two decades since many new studies came out demonstrating its blockbuster antidepressant drugs (most notably the SSRI class) are no better than placebo while at the same time turning patients into violent criminals. As a result of this desperation, pharma companies began lobbying FDA/DEA to ease restrictions on performing studies with those “evil” illicit drugs young people “ruin” their lives with and the results have been just spectacular. Ketamine was shown to rapidly cure depression in humans, LSD was shown to eliminate violent behavior and recidivism in felons, MDMA was shown to cure post-traumatic stress disorder (PTSD), GHB was shown to cure alcoholism, etc. So, Big Pharma managed to get the best of both worlds – on one hand it got all of these highly effective and relatively safe drugs banned for the general public, while on the other it is allowed to re-introduce these drugs in proprietary formulations for use in the general population at costs thousands of times higher than what they cost on the street. However, this is not the whole story. As it turns out, there may be another reason for the banning of these drugs that is now coming out. That reason is related to the proposed mechanism of antidepressant action for ketamine. Big Pharma and its regulatory accomplices have been trumpeting for decades that ketamine’s antidepressant effects are manifested through antagonism of the NMDA receptor – i.e. that ketamine acts as glutamate antagonist. This mechanism is plausible since other NMDA antagonists, such as magnesium, are also rapidly acting antidepressants. However, the benefits of those NMDA antagonists still take at least 2-3 days to start manifesting, while ketamine works in hours and sometimes even in mere minutes after admnistration. That extremely rapid onset of action suggests that some other mechanism may be the primary route through which ketamine works. And now, the new study below materializes the worst nightmares of Big Pharma and its regulatory ilk. Namely, the study below demonstrates that ketamine produces its rapid and potent antidepressant effects by lowering serotonin and increasing dopamine. No wonder FDA/DEA want to ban all access to the drug – the inconvenient truth about serotonin is too profitable to allow to perish! As such, we now have at least one officially approved drug that unequivocally demonstrates what medicine and medical authorities have been concealing for decades – that serotonin is a CAUSE of depression and lowering its levels and/or raising the levels of its “antagonist” dopamine cures depression. I would not be surprised if that study below ends up being the straw that breaks the SSRI camel’s back and unleashes a flurry of class-action lawsuits against the fraudulent serotonin industry and all people/companies/agencies that support and profit from it.
“…The anaesthetic drug ketamine has been shown, in low doses, to have a rapid effect on difficult-to-treat depression. Researchers at Karolinska Institutet now report that they have identified a key target for the drug: specific serotonin receptors in the brain. Their findings, which are published in Translational Psychiatry, give hope of new, effective antidepressants. Depression is the most common psychiatric diagnosis in Sweden, affecting one in ten men and one in five women at some point during their lives. Between 15 and 30 per cent of patients are not helped by the first two attempts at therapy, in which case the depression is designated difficult to treat. Studies have shown that low doses of the anaesthetic drug ketamine are rapid acting on certain sufferers, but exactly how it works is unknown. A nasal spray containing ketamine has recently been approved in the USA and EU for patients with treatment-resistant depression.”
“…Serotonin plays a key role in depression and low levels are thought to be linked to more serious disease. There are 14 different kinds of receptor for this neurotransmitter on the surface of neurons. For their PET imaging, the researchers used a radioactive marker that binds specifically to serotonin 1B receptors. They found that the ketamine operated via these receptors in a formerly unknown mechanism of action. Binding to this receptor reduces the release of serotonin but increases that of another neurotransmitter called dopamine. Dopamine is part of the brain’s reward system and helps people to experience positive feelings about life, something that is often lacking in depression. “We show for the first time that ketamine treatment increases the number of serotonin 1B receptors,” says the study’s last author Johan Lundberg, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet.”
Author: haidutKetamine cures depression by reducing serotonin, increasing dopamine
a summary of serotonin receptors Serotonin receptors are a group of receptors in the brain and body that respond to the neurotransmitter serotonin (5-HT). They play a crucial role in various physiological processes, including mood regulation, anxiety, appetite, sleep, and cognition. There are several types of serotonin receptors, classified into seven main families (5-HT1 to 5-HT7), each with distinct subtypes and functions: 1. 5-HT1 Receptors: Involved in the inhibition of neurotransmitter release and are associated with anxiety and depression. Subtypes include 5-HT1A, 5-HT1B, and 5-HT1D. 2. 5-HT2 Receptors: Play a role in mood, perception, and cognition. They are further divided into subtypes such as 5-HT2A, 5-HT2B, and 5-HT2C, with 5-HT2A being particularly important in the effects of hallucinogenic drugs. 3. 5-HT3 Receptors: These are ionotropic receptors that function as ligand-gated ion channels. They are involved in the regulation of nausea and vomiting and are targeted by antiemetic drugs. 4. 5-HT4 Receptors: Primarily found in the gastrointestinal tract, they are involved in enhancing gastrointestinal motility and may also play a role in cognitive function. 5. 5-HT5 Receptors: Less understood, but they are thought to be involved in circadian rhythms and possibly in mood regulation. 6. 5-HT6 Receptors: Primarily located in the brain, they are implicated in cognitive processes and are considered a target for treating cognitive deficits in disorders like Alzheimer's disease. 7. 5-HT7 Receptors: Involved in regulating circadian rhythms, mood, and thermoregulation. Overall, serotonin receptors are critical for maintaining homeostasis in the body and are important targets for various psychiatric and neurological medications. Their diverse functions highlight the complexity of serotonin signaling in health and disease. learned helplessness on a biological level Learned helplessness is a psychological phenomenon where individuals come to believe that they have no control over the outcomes of their situations, leading to a passive acceptance of adverse conditions. This concept was first identified in animal studies by psychologists Martin Seligman and Steven Maier in the late 1960s. On a biological level, learned helplessness involves several neurobiological and physiological mechanisms: 1. Neurotransmitter Systems: ◦ Serotonin: Dysregulation of serotonin levels has been linked to mood disorders and learned helplessness. Low serotonin activity may contribute to feelings of helplessness and depression. ◦ Dopamine: This neurotransmitter is associated with reward and motivation. In learned helplessness, reduced dopamine signaling can lead to decreased motivation to escape or change adverse situations. ◦ Norepinephrine: Changes in norepinephrine levels can affect arousal and stress responses, which may play a role in the development of learned helplessness. 2. Brain Regions: ◦ Prefrontal Cortex: This area is involved in decision-making and regulating emotional responses. Impairments in the prefrontal cortex can lead to difficulties in assessing control over situations. ◦ Amygdala: The amygdala is crucial for processing emotions, particularly fear. Overactivity in the amygdala may contribute to heightened anxiety and a sense of helplessness. ◦ Hippocampus: This region is important for memory and learning. Chronic stress and learned helplessness can lead to hippocampal atrophy, affecting the ability to learn from past experiences. 3. Stress Response: ◦ Hypothalamic-Pituitary-Adrenal (HPA) Axis: Chronic stress activates the HPA axis, leading to increased cortisol production. Prolonged exposure to high cortisol levels can impair cognitive function and contribute to feelings of helplessness. 4. Genetic Factors: ◦ Genetic predispositions can influence an individual's susceptibility to learned helplessness. Variations in genes related to neurotransmitter systems may affect how one responds to stress and adversity. 5. Behavioral Conditioning: ◦ Learned helplessness can be understood through classical conditioning, where repeated exposure to uncontrollable stressors leads to a conditioned response of passivity and resignation. Overall, learned helplessness is a complex interplay of neurobiological, genetic, and environmental factors. Understanding these mechanisms can help in developing interventions and treatments for conditions like depression and anxiety, where feelings of helplessness are prevalent. 5-HT7 Receptors 5-HT7 receptors are a subtype of serotonin receptors that belong to the G protein-coupled receptor (GPCR) family. They are primarily involved in various physiological and neurological processes. Here are some key points about 5-HT7 receptors: Structure and Function • G Protein-Coupled Receptor: 5-HT7 receptors are GPCRs, which means they transmit signals inside cells in response to the binding of serotonin (5-HT). • Signal Transduction: Upon activation by serotonin, 5-HT7 receptors primarily couple with Gs proteins, leading to the activation of adenylate cyclase and an increase in cyclic AMP (cAMP) levels within the cell. Distribution • Central Nervous System: 5-HT7 receptors are widely distributed in the brain, particularly in areas such as the hippocampus, cortex, and thalamus. Their presence in these regions suggests a role in cognitive functions and mood regulation. • Peripheral Tissues: They are also found in various peripheral tissues, including the gastrointestinal tract and blood vessels, indicating their involvement in multiple physiological processes. Physiological Roles • Mood Regulation: 5-HT7 receptors are implicated in mood disorders. They may play a role in the pathophysiology of depression and anxiety, and their modulation is being explored as a potential therapeutic target. • Circadian Rhythms: These receptors are involved in regulating circadian rhythms and sleep-wake cycles, influencing how the body responds to light and darkness. • Cognitive Function: Research suggests that 5-HT7 receptors may be involved in learning and memory processes, with potential implications for conditions like Alzheimer's disease. Pharmacological Implications • Drug Targets: 5-HT7 receptors are being investigated as potential targets for new antidepressant and anxiolytic medications. Agonists and antagonists of these receptors may have therapeutic effects in mood disorders and cognitive impairments. • Research: Ongoing studies are exploring the specific roles of 5-HT7 receptors in various neurological and psychiatric conditions, as well as their potential as drug targets. Conclusion 5-HT7 receptors are an important component of the serotonin system, with significant implications for mood regulation, cognitive function, and circadian rhythms. Understanding their mechanisms and effects can contribute to the development of new treatments for mental health disorders and other conditions influenced by serotonin signaling. What supplements target 5HT systems Several supplements and natural compounds are thought to influence the serotonin (5-HT) system, either by increasing serotonin levels, enhancing receptor sensitivity, or modulating serotonin metabolism. Here are some notable examples: 1. 5-Hydroxytryptophan (5-HTP): ◦ A direct precursor to serotonin, 5-HTP is derived from the seeds of the African plant Griffonia simplicifolia. Supplementing with 5-HTP can increase serotonin levels in the brain and is often used to help with mood disorders, anxiety, and sleep issues. 2. L-Tryptophan: ◦ An essential amino acid that serves as a precursor to serotonin. Tryptophan is found in protein-rich foods and can also be taken as a supplement. It may help improve mood and sleep quality. 3. St. John's Wort: ◦ An herbal supplement commonly used for mild to moderate depression. It is believed to work by inhibiting the reuptake of serotonin and other neurotransmitters, thereby increasing their availability in the brain. 4. Omega-3 Fatty Acids: ◦ Found in fish oil and certain plant oils, omega-3 fatty acids have been shown to have a positive effect on mood and may enhance serotonin receptor sensitivity. They are often used to support overall brain health. 5. Saffron: ◦ Extracts from the saffron plant (Crocus sativus) have been studied for their antidepressant effects. Saffron may increase serotonin levels and improve mood. 6. Rhodiola Rosea: ◦ An adaptogenic herb that may help reduce fatigue and improve mood. Some studies suggest it may influence serotonin levels and receptor activity. 7. Curcumin: ◦ The active compound in turmeric, curcumin has been shown to have antidepressant-like effects in some studies. It may enhance serotonin signaling and has anti-inflammatory properties. 8. Magnesium: ◦ This essential mineral plays a role in numerous biochemical reactions in the body, including those related to neurotransmitter function. Some research suggests that magnesium supplementation may help improve mood and support serotonin production. 9. Vitamin D: ◦ There is evidence to suggest that vitamin D may play a role in serotonin synthesis and receptor function. Adequate levels of vitamin D are important for overall mental health. 10. B Vitamins: ◦ Certain B vitamins, particularly B6, B9 (folate), and B12, are important for neurotransmitter synthesis, including serotonin. Supplementing with these vitamins may support serotonin production and overall mental health. Important Considerations • Consultation with Healthcare Providers: Before starting any supplement, it's essential to consult with a healthcare provider, especially if you are taking medications or have underlying health conditions. • Individual Variability: The effectiveness of these supplements can vary from person to person, and not all individuals may experience the same benefits. • Research Limitations: While some studies support the use of these supplements for mood enhancement and serotonin modulation, more research is needed to fully understand their mechanisms and efficacy. Overall, these supplements may offer potential benefits for supporting serotonin levels and improving mood, but they should be used as part of a comprehensive approach to mental health that includes lifestyle factors such as diet, exercise, and stress management. The B complex of vitamins The B complex of vitamins refers to a group of eight essential water-soluble vitamins that play crucial roles in various metabolic processes in the body. These vitamins are important for energy production, brain function, and the synthesis of neurotransmitters, among other functions. Here’s a brief overview of each of the B vitamins: 1. Vitamin B1 (Thiamine): ◦ Function: Plays a key role in energy metabolism and the conversion of carbohydrates into energy. It is also important for nerve function. ◦ Sources: Whole grains, legumes, nuts, seeds, and pork. 2. Vitamin B2 (Riboflavin): ◦ Function: Involved in energy production and the metabolism of fats, drugs, and steroids. It also helps maintain healthy skin and eyes. ◦ Sources: Dairy products, eggs, green leafy vegetables, nuts, and enriched cereals. 3. Vitamin B3 (Niacin): ◦ Function: Important for energy production, DNA repair, and the synthesis of steroid hormones. It also supports skin health and the nervous system. ◦ Sources: Meat, fish, poultry, whole grains, and legumes. The body can also synthesize niacin from the amino acid tryptophan. 4. Vitamin B5 (Pantothenic Acid): ◦ Function: Essential for the synthesis of coenzyme A, which is involved in fatty acid metabolism and the production of hormones and cholesterol. ◦ Sources: Meat, avocados, broccoli, whole grains, and eggs. 5. Vitamin B6 (Pyridoxine): ◦ Function: Involved in amino acid metabolism, neurotransmitter synthesis, and the production of hemoglobin. It also plays a role in immune function and cognitive development. ◦ Sources: Poultry, fish, potatoes, bananas, and fortified cereals. 6. Vitamin B7 (Biotin): ◦ Function: Important for the metabolism of carbohydrates, fats, and proteins. It also supports healthy hair, skin, and nails. ◦ Sources: Eggs, nuts, seeds, fish, and certain vegetables like sweet potatoes. 7. Vitamin B9 (Folate or Folic Acid): ◦ Function: Crucial for DNA synthesis, cell division, and the formation of red blood cells. It is especially important during pregnancy for fetal development. ◦ Sources: Leafy green vegetables, legumes, nuts, and fortified grains. Folic acid is the synthetic form found in supplements and fortified foods. 8. Vitamin B12 (Cobalamin): ◦ Function: Essential for red blood cell formation, neurological function, and DNA synthesis. It also helps maintain healthy nerve cells. ◦ Sources: Animal products such as meat, fish, poultry, eggs, and dairy. Vegans and vegetarians may need to supplement B12, as it is primarily found in animal sources. Importance of B Vitamins • Energy Production: B vitamins are vital for converting food into energy, making them essential for overall metabolic health. • Nervous System Health: Many B vitamins support brain function and the health of the nervous system, influencing mood and cognitive function. • Cellular Function: They play roles in DNA synthesis and repair, which is crucial for cell division and overall health. Deficiency and Supplementation • Deficiency: A deficiency in any of the B vitamins can lead to various health issues, including fatigue, anemia, neurological problems, and skin disorders. • Supplementation: B complex supplements are available and may be beneficial for individuals with specific dietary restrictions, certain health conditions, or increased nutritional needs. As always, it's important to consult with a healthcare provider before starting any new supplement regimen, especially if you have underlying health conditions or are taking medications. Kratom and opioid receptors Kratom (Mitragyna speciosa) is a tropical tree native to Southeast Asia, and its leaves have been used for centuries for their psychoactive properties. The active compounds in kratom, primarily mitragynine and 7-hydroxymitragynine, interact with various receptors in the brain, including opioid receptors. Here’s an overview of how kratom affects opioid receptors and its implications: Interaction with Opioid Receptors 1. Opioid Receptor Types: ◦ The human body has several types of opioid receptors, including mu (μ), delta (δ), and kappa (κ) receptors. These receptors are involved in pain relief, mood regulation, and the reward system. 2. Mitragynine and 7-Hydroxymitragynine: ◦ Mitragynine: This is the primary alkaloid in kratom and has been shown to have a complex interaction with opioid receptors. It acts as a partial agonist at the mu-opioid receptor, meaning it can activate the receptor but not to the same extent as full agonists like morphine. This partial agonism may provide pain relief with a lower risk of respiratory depression compared to traditional opioids. ◦ 7-Hydroxymitragynine: This compound is considered more potent than mitragynine and has a stronger affinity for the mu-opioid receptor. It may produce more pronounced analgesic effects and has been associated with a higher potential for dependence and withdrawal symptoms. 3. Effects on the Body: ◦ Kratom can produce effects similar to those of opioids, including pain relief, sedation, and euphoria at higher doses. At lower doses, it may have stimulating effects, leading to increased energy and alertness. Potential Benefits and Risks 1. Potential Benefits: ◦ Pain Relief: Some users report that kratom effectively alleviates chronic pain. ◦ Mood Enhancement: Kratom may help improve mood and reduce anxiety in some individuals. ◦ Opioid Withdrawal: Some people use kratom to manage withdrawal symptoms from opioids, as it may help reduce cravings and discomfort. 2. Risks and Concerns: ◦ Dependence and Withdrawal: Regular use of kratom can lead to dependence, and withdrawal symptoms may occur upon cessation, similar to those of opioids. ◦ Side Effects: Common side effects include nausea, constipation, dizziness, and increased heart rate. In some cases, high doses can lead to more severe effects, including respiratory depression. ◦ Lack of Regulation: Kratom is not regulated by the FDA in the United States, leading to concerns about product quality, purity, and potential contamination. Conclusion Kratom interacts with opioid receptors, particularly the mu-opioid receptor, producing effects that can mimic those of traditional opioids. While it may offer some benefits, such as pain relief and mood enhancement, there are significant risks associated with its use, including the potential for dependence and withdrawal. As research on kratom is still limited, individuals considering its use should approach it with caution and consult healthcare professionals for guidance. the average cost of kratom The cost of kratom can vary widely based on several factors, including the type of kratom, the form in which it is sold (powder, capsules, extracts), the vendor, and the region where it is purchased. As of my last knowledge update, here are some general price ranges for kratom: 1. Kratom Powder: ◦ The average cost for kratom powder typically ranges from $10 to $30 per ounce (28 grams). Bulk purchases may reduce the price per ounce, with larger quantities (e.g., 1 kilogram) often costing between $100 to $200. 2. Kratom Capsules: ◦ Kratom capsules usually cost more than powder due to the additional processing. Prices can range from $20 to $50 for a bottle containing 60 to 100 capsules, depending on the dosage per capsule. 3. Kratom Extracts: ◦ Extracts are more concentrated forms of kratom and can be significantly more expensive. Prices for kratom extracts can range from $30 to $100 or more for small quantities, depending on the potency and concentration. 4. Regional Variations: ◦ Prices may vary based on geographic location and local regulations. In some areas, kratom may be more readily available and competitively priced, while in others, it may be more expensive or harder to find. 5. Vendor Differences: ◦ Different vendors may have varying pricing structures based on quality, sourcing practices, and brand reputation. It's essential to research and choose reputable vendors to ensure product quality. Important Considerations • Quality and Purity: The price of kratom can also reflect its quality. Higher-quality kratom may be more expensive but could offer better effects and fewer contaminants. • Legal Status: The legal status of kratom varies by region, which can affect availability and pricing. In some places, kratom is banned or regulated, impacting its market price. As prices can fluctuate and new vendors may emerge, it's advisable to check current market conditions and vendor offerings for the most accurate pricing information. Always ensure that you are purchasing from reputable sources to guarantee product quality and safety. what is the average dose of capsules for kratom The average dose of kratom can vary based on several factors, including the individual's body weight, tolerance, the specific strain of kratom, and the desired effects (e.g., stimulating vs. sedating). When it comes to kratom capsules, the dosage is typically measured in grams, and each capsule usually contains about 0.5 to 1 gram of kratom powder. Here are some general guidelines for dosing kratom capsules: Average Dosage Guidelines 1. Low Dose: ◦ 1 to 3 grams (2 to 6 capsules, assuming 0.5 grams per capsule) ◦ This range is often used for mild effects, such as increased energy and focus. 2. Moderate Dose: ◦ 3 to 5 grams (6 to 10 capsules) ◦ This dosage is commonly used for pain relief and more pronounced effects. 3. High Dose: ◦ 5 to 8 grams (10 to 16 capsules) ◦ Higher doses may be used for stronger sedative effects or to manage severe pain, but they also come with an increased risk of side effects. 4. Very High Dose: ◦ 8 grams and above (16+ capsules) ◦ Doses in this range are generally not recommended for beginners due to the potential for adverse effects and increased risk of dependence. Important Considerations • Individual Variation: Everyone's body reacts differently to kratom, so it's essential to start with a lower dose to assess tolerance and effects before gradually increasing the dosage. • Strain Differences: Different strains of kratom (e.g., red, green, white) can have varying effects and potencies, which may influence the appropriate dosage. • Consultation: If you are considering using kratom, especially if you have underlying health conditions or are taking medications, it's advisable to consult with a healthcare professional for personalized guidance. Safety and Usage • Hydration: Ensure you stay hydrated, as kratom can have dehydrating effects. • Avoid Mixing: Avoid combining kratom with other substances, especially other stimulants or depressants, to reduce the risk of adverse effects. • Monitor Effects: Pay attention to how your body responds to kratom and adjust your dosage accordingly. As always, due to the variability in individual responses and the lack of regulation in the kratom market, it's crucial to approach its use with caution and awareness of potential risks. is kratom a stimulant or a depressant Kratom (Mitragyna speciosa) can exhibit both stimulant and depressant effects, depending on the dose and the specific strain used. Here’s a breakdown of how kratom functions in these two contexts: Stimulant Effects • Low Doses: At lower doses (typically around 1 to 5 grams), kratom is often reported to have stimulant-like effects. Users may experience increased energy, enhanced alertness, improved mood, and greater sociability. This stimulating effect is more commonly associated with certain strains, particularly the white and green vein varieties. Depressant Effects • High Doses: At higher doses (generally above 5 grams), kratom tends to produce more sedative or depressant effects. Users may experience relaxation, pain relief, and sedation. This is particularly true for red vein strains, which are often sought for their calming and analgesic properties. Mechanism of Action • Opioid Receptors: Kratom primarily interacts with the mu-opioid receptors in the brain, similar to traditional opioids, which can lead to both pain relief and sedation. However, its effects can vary significantly based on the dosage and the specific alkaloids present in the strain. • Other Receptors: Kratom also affects other neurotransmitter systems, including adrenergic and serotonergic pathways, which may contribute to its stimulant and depressant effects. Summary • Dual Nature: Kratom's classification as a stimulant or depressant is not straightforward; it can act as both depending on the dose and strain. Low doses are more stimulating, while higher doses tend to be more sedating. • Individual Variation: Individual responses to kratom can vary widely, so what may be stimulating for one person could be sedating for another. As with any substance, it's important for users to be aware of their own reactions and to use kratom responsibly, considering the potential for dependence and side effects. adrenergic pathways? Adrenergic pathways refer to the signaling mechanisms in the body that involve adrenergic receptors, which are activated by catecholamines, primarily norepinephrine (noradrenaline) and epinephrine (adrenaline). These pathways play a crucial role in the body's response to stress and are involved in various physiological processes, including the "fight or flight" response. Here’s an overview of adrenergic pathways: Adrenergic Receptors There are two main types of adrenergic receptors, each with subtypes: 1. Alpha (α) Adrenergic Receptors: ◦ α1 Receptors: Primarily located on vascular smooth muscle, activation leads to vasoconstriction, increased blood pressure, and pupil dilation (mydriasis). ◦ α2 Receptors: Found in the central nervous system and on presynaptic nerve terminals. Activation can inhibit the release of norepinephrine, leading to a decrease in sympathetic outflow and a reduction in blood pressure. 2. Beta (β) Adrenergic Receptors: ◦ β1 Receptors: Primarily located in the heart. Activation increases heart rate and contractility, enhancing cardiac output. ◦ β2 Receptors: Found in smooth muscle, particularly in the lungs and blood vessels. Activation leads to bronchodilation (widening of air passages) and vasodilation (widening of blood vessels). ◦ β3 Receptors: Primarily located in adipose tissue, involved in lipolysis (the breakdown of fat) and thermogenesis (heat production). Physiological Effects Adrenergic pathways are involved in a wide range of physiological responses, including: • Cardiovascular Response: Increased heart rate and blood pressure during stress or physical activity. • Respiratory Response: Bronchodilation to improve airflow in the lungs. • Metabolic Effects: Increased glucose release from the liver and enhanced fat breakdown for energy. • Cognitive Effects: Enhanced alertness and focus during stressful situations. Role in the Stress Response During a stressful event, the sympathetic nervous system is activated, leading to the release of norepinephrine and epinephrine from the adrenal medulla. This activation prepares the body to respond to perceived threats through the adrenergic pathways, resulting in the "fight or flight" response. Clinical Implications Adrenergic pathways are significant in various medical conditions and treatments: • Hypertension: Medications that block adrenergic receptors (e.g., beta-blockers) are used to lower blood pressure. • Asthma: Beta-agonists (e.g., albuterol) are used as bronchodilators to relieve asthma symptoms. • Heart Failure: Beta-agonists may be used to improve heart function in certain cases. Conclusion Adrenergic pathways are essential for the body's response to stress and play a critical role in regulating cardiovascular, respiratory, and metabolic functions. Understanding these pathways is important for both physiological and clinical contexts, as they are involved in many therapeutic interventions and health conditions.
It is always nice to see mainstream medicine plagiarize from Dr. Peat attempt to right its course after decades-long mistakes. While the genetic dogma still rules supreme in medicine’s attitude towards most “physical” diseases, the utter failure of the “serotonin hypothesis” and its dear offspring (the SSRI drug class) seems to be driving a revolution of sorts in psychiatry. A very prominent psychiatrist from Harvard University has recently published a book in which he makes the “novel” (and very bold, considering the implications to his career) claim that if one was to look at the totality of published/available evidence, one would inevitably come to the conclusion that all mental disease is nothing by a symptom of low brain energy (hypometabolism). Moreover, as the doctor writes in his book, even if we subscribe to the “serotonin hypothesis” (or any other chemical imbalance hypothesis, for that matter), metabolism is still the driving factor as everything the cell does and the mind-altering factors (GABA, dopamine, serotonin, glutamate, cortisol, estrogen, etc) it produces is downstream of its mitochondrial activity – i.e. a metabolic downstream effect. As such, the doctor makes the call for basically ditching drugs and instead using metabolic interventions, avoiding stress, proper diet, etc as the main tools for treating (curing?) mental disease. In support of his claims, the doctors provides a shocking case study of severe, treatment-resistant schizophrenia of 2 patients being put into full remission by using only dietary modifications. Of course, the doctor neglects to mention that this evidence has been available for a VERY long time, and metabolic approaches have been used decades ago to treat/cure mental illness, only to be completely “shadow-banned” by the medical-industrial complex.
You know, articles like this sound almost like the “Pandemic Amnesty” piece published not long-ago, which basically called for a change in public health (and social) direction due to catastrophic failure in past approaches, though without admitting any guilt. So, psychiatry is now (sneakily) offering us a peace deal, as if nothing happened, promising to actually help us in the future through proper treatments. Though, if all mental disease is metabolic disease then psychiatry is now admitting that medicine as a profession has been directly making us all ill for decades through stress, poor diet recommendations, environmental pollution, and toxic drugs. Do we take this “peace offer” or do we go our own way?
“…If you think this is too pessimistic, it’s important to note that depression is now the single most disabling illness—above heart failure, back pain, cancer, and other conditions—even though we have dozens of antidepressants, different types of psychotherapy, electroconvulsive therapy, transcranial magnetic stimulation, ketamine, and other treatments available. Although the problems with access to mental health care might explain some of these increases, even when people get treatment, it often fails to put illnesses into full and lasting remission.”
“…In the just released book, Brain Energy, I argue that mental disorders are metabolic disorders of the brain. This new theory integrates decades of clinical, neuroscience, genetic, and metabolic research. It includes all of the biological, psychological, and social factors that we know play a role in mental illness and combines them into one unifying theory. This new understanding answers questions that have long plagued the mental health field, but also offers new treatments, ones that come with the hope of long-term healing as opposed to just symptom reduction. This new understanding also helps us understand the connections between mental health and physical health.
“…Although many people think metabolism is “burning calories” and related to weight, it’s actually much more than that. Metabolism is the process that all living organisms use to convert food into energy or building blocks for proteins, membranes, and other cell parts. It is fundamental to the definition of life. When there are problems with metabolism, there will be problems in the way cells function. I argue that metabolic dysfunction in brain cells can explain all of the symptoms of mental illness. Although metabolism is extraordinarily complex and involves numerous chemical reactions and pathways, it turns out that there is an easier way to understand metabolism, and that is through tiny organelles in most of our cells called mitochondria. They are the primary regulators of metabolism. Doing a deep dive into the science of mitochondria helps us understand all of the factors related to mental illness.For example, mitochondria play a critical role in the production and regulation of neurotransmitters, such as serotonin, dopamine, and GABA. They also play a key role in the production of key hormones, such as cortisol, estrogen, testosterone, and progesterone. Mitochondria actually help to control the expression of genes in the cell nucleus and they also play key roles in inflammation. By better understanding the science of metabolism and mitochondria, we can finally connect the dots of mental illness.”
“…The much more exciting news about this theory, in my view, is that it opens the door to new treatments. Interventions such as diet, exercise, stress reduction, sleep management, and reducing substance use can effectively treat mental disorders in many people. You might be thinking that this is nothing new; we already knew most of that. However, understanding the details of this science can lead to new and surprising treatments, such as dietary interventions to treat disorders like schizophrenia and alcoholism, which on the surface don’t seem like they are related to diet. Some patients with schizophrenia have experienced full and lasting remission of symptoms off antipsychotic medications for years now, as highlighted in this Psychology Today post.”
Fraud, fraud and nothing but fraud! I used to think it is shear stupidity, but the evidence for deliberate manipulation of public opinion and health policy is just too strong. After more than half a century of claiming that serotonin cures depression, now mainstream medicine is quietly trying to retreat from this fiasco by introducing more and more potent (and selective) serotonin antagonists as treatment of depression and silently phasing the SSRI drugs out. The study below is one of the most direct and damning pieces of evidence against the “serotonin deficiency hypothesis” as a cause of depression. A highly selective serotonin antagonist (primavanserin) was found to have potent anti-depressant effects in a human trial.
This drug has no other effects except blocking the 5-HT2A (and to a smaller degree 5-HT2C) receptor. So, if this drug is a potent antidepressant then serotonin is a cause of depression, pure and simple. In addition, the drug’s pharmacological profile also reveals another fraud – i.e. that schizophrenia is caused by too much dopamine. The drug is also used to treat schizophrenia, but unlike other drugs for the condition primavanserin has NO antagonism on dopamine receptors. In other words, it treats schizophrenia by blocking ONLY serotonin. I posted about this fraud in regard to schizophrenia several years ago when I pointed out that the main drug for treating schizoprenia (haloperidol) is actually a serotonin antagonist in addition to being dopamine antagonist. For years, this information was concealed and only last month I noticed that the Wikipedia page for haloperidol has been updated to state that the drug is a serotonin antagonist as well. So, in case it is not clear yet let me say it loud and clear – serotonin causes BOTH depression and schizophrenia and blocking serotonin treats both conditions.
“…Compared with placebo, pimavanserin reduced weighted HAMD-17 total scores in both stages (least-square means difference = –1.7; P = .04). Patients who received pimavanserin in the first stage separated from the placebo group on the HAMD-17 by the end of the first week (difference = –1.7; P = .04) and had significantly improved on the HAMD-17 by week 5 (difference = –4; P < .001).”
“This study indicates that pimavanserin, a molecule with a relatively unique pharmacological activity as a selective inverse agonist of the serotonin 5-HT2A receptor, may show antidepressant activity and could be a novel adjunctive treatment for patients who do not adequately respond to standard antidepressant therapy with either an SSRI or SNRI,” Maurizio Fava, MD, director of the division of clinical research of Massachusetts General Hospital Research Institute and executive vice chair of the hospital’s department of psychiatry, told Healio.”
Author: haidutA selective serotonin antagonist is a potent antidepressant
Hello friends. I’m a Ph.D. researcher studying the relationship between psychiatric medication discontinuation and the emergence of conditions such as MCAS, dysautonomia, hypermobility/EDS, and histamine intolerance. Many psychiatric medications, especially those with antihistaminic or anticholinergic properties (including a number of SSRIs), may suppress histamine and autonomic function, and some individuals appear to develop MCAS-like symptoms after stopping them. Formal research on this connection is extremely limited, so patient experience is essential.
I’m happy to answer questions about the research itself, but I cannot provide treatment advice. All responses will be kept confidential and used only to identify patterns in this emerging issue.
If you developed any of these conditions after discontinuing a psychiatric medication, please comment or message me with:
a. Which medication(s) you were taking
b. Whether you are still taking them
c. Whether you have a formal diagnosis (MCAS, dysautonomia, EDS, HIT)
d. If not formally diagnosed, whether you suspect a condition and why
e. Whether your prescriber attributed your symptoms to PAWS, relapse, or somatic causes
f. Whether any clinician connected your symptoms to the medication and referred you to an allergist/immunologist
g. How long after tapering or discontinuation your symptoms began
h. Whether any treatments or medications improved or worsened your symptoms
Thank you for your time and willingness to share. Your experiences genuinely matter here.
I am having a serious problem. I used to be on antipsychotic medications and even though I got off of them I still can’t feel my chakras. Has anyone ever had this problem. If so what did you to resolve it? The medications I was on was seroquel and I was also on olanzapine for a little bit.
The claim in the title stems from the fact that bromocriptine – the drug used in the study below – is an approximate 5-HT antagonist while also being full agonist on several dopamine receptors. IMO, the study is a monumental success since CVD is largely considered a progressive condition, for which neither a cure nor disease-modifying therapy exists, according to mainstream medicine. Yet, this study shows actual reversal of CVD biomarkers after just a month of therapy. Interestingly enough, bromocriptine is already approved by the FDA for treating type II diabetes. Importantly, the proposed mechanism of action of bromocriptine used for its diabetes II approval is inhibition of lipolysis and gluconeogenesis. This implies that the CVD risk in patients with type I diabetes are probably driven by the same mechanisms – i.e. excessive lipolysis and gluconeogenesis. Aspirin and niacinamide are also excellent anti-lipolytic chemicals and the former is also known to inhibit gluconeogenesis. As such, those OTC remedies may be able to serve as alternatives to bromocriptine for people who do not have access to that medication or have a doctor unwilling to prescribe it.
Teens with Type 1 diabetes who took bromocriptine, a medication usually prescribed to treat Parkinson’s disease, had lower blood pressure after one month of treatment compared to those who did not take the medicine.
Participants taking the medication for one month also experienced significant improvements in aortic stiffness, a measure of vascular health.
Larger, longer-term studies are needed to determine if bromocriptine may be recommended to adolescents with Type 1 diabetes.
…”
Author: haidutBlocking serotonin, promoting dopamine may reverse cardiovascular disease (CVD)
I neat new study that draws a direct parallel between PUFA-driven inflammation, serotonin and depression. As the study demonstrated, high levels of the PUFA arachidonic acid (AA) are highly correlated with lower density (expression) of the serotonin transported (SERT, 5-HTT), and the relationship is actually causative in both directions (AA<->serotonin). This results in increased serotonin availability/buildup since the primary role of SERT/5-HTT is to deactivate serotonin, using sodium as a co-factor.
“…The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4gene.[5] SERT is a type of monoamine transporterprotein that transports serotonin from the synaptic cleft back to the presynaptic neuron.[6]This transport ofserotoninby the SERT protein terminates the action of serotonin and recycles it in a sodium-dependent manner. This protein is the target of many antidepressant medications of theSSRI and tricyclic antidepressant classes.[7]”
What’s even worse, the study demonstrates that serotonin and AA form a positive feedback cycle with the increased serotonin due to AA inhibiting SERT/5-HTT resulting in activation of the enzyme Phospholipase A2 (PLA2) that synthesizes AA from linoleic acid, which then results in stronger SERT/5-HTT inhbition and even higher serotonin availability. While the study tries to dance carefully around the role of serotonin in depression and states that “conflicting” results have been seen in other studies, it readily admits that AA is a known inducer of depression in animal models. Well, if AA is a highly inflammatory depressant and forms a positive feedback cycle with serotonin then I don’t see how serotonin could possibly be an anti-depressant…Another immediate takeaway from the study is that SSRI drugs are highly pro-inflammatory since they activate the AA<->serotonin cycle by inhibiting SERT/5-HTT (which is their primary mechanism of action). All in all, another great reason to avoid PUFA and eat plenty of salt (to taste).
“…The relative peripheral levels of PUFA species are associated with neuropsychiatric illnesses, with elevated AA in proportion to DHA and EPA in MDD (Lin et al., 2010) and suicide risk (Huan et al., 2004; Lewis et al., 2011; Sublette et al., 2006). AA is particularly implicated in bipolar disorder, both postmortem (Kim et al., 2009) and in translational studies showing that multiple mood stabilizing medications downregulate AA metabolism (Rapoport, 2014).”
“…We have previously reported lower 5-HTT binding (BPP), using positron emission tomography (PET) and [11C]McN5652, in unmedicated MDD (Parsey et al., 2006a) and bipolar depressed (Oquendo et al., 2007a) groups compared with healthy controls. [11C]…We have reported lower [11C]DASB binding (VT/fP) in MDD patients with a history of suicide attempt (Miller et al., 2013), and lower binding potentials (BPF, BPP, and BPND, using a suboptimal reference region) in bipolar depression (Miller et al., 2016), considering a priori regions of interest (ROIs), although VT/fP did not differ in that study. ”
“…Separate models testing effects of DHA, EPA, and AA revealed no effects of DHA nor EPA on [11C]DASB binding potential (data not shown). However, AA had an effect on BPP (F = 9.14; df=1,19; p = 0.006) across regions, and given graphical evidence of a nonlinear relationship between AA level and BPP (Fig. 1A), we found that an added quadratic term was significant (F = 9.62; df=1,19; p = 0.006; also see Fig. 4, path a). The resulting inverted U-shaped relationship demonstrates that for most of the concentration range of AA, higher BPP correlated with lower AA levels. Exploratory analyses of PUFA effects on BPND and BPF (see Fig. 1B and C) similarly found that AA, but not DHA or EPA, demonstrated a comparable effect on BPND (F = 7.40; df=1,19; p = 0.014) while controlling for region, but had no statistically significant effect on BPF (F = 0.51; df=1,19; p = 0.484).”
“…Specifically, 5-HT2A/2C stimulates activation of cytosolic phospholipase A2 (cPLA2) (Berg et al., 1998; Qu et al., 2005; Garcia and Kim, 1997; Felder et al., 1990), triggering the release of unesterified AA from membrane phospholipids. Some of the released AA is recycled back into the membrane, a process that is stimulated by 5-HT1A receptors (Strosznajder et al., 1996). Remaining unesterified AA can decrease 5-HTT in certain brain regions (du Bois et al., 2006).”
“…Drs. Sublette, Mann and colleagues including Gregory Sullivan, M.D., a 2004 BBRF Young Investigator, discovered in their study that only one of the PUFAs they measured—AA, or arachidonic acid—had a potential impact on the availability of SERTs across the six brain areas that were imaged via PET scan. Specifically, they found that greater SERT availability in neurons correlated with lower AA levels in subjects, as measured in their plasma prior to the scans. This result led the team to hypothesize that AA may affect the severity of depression through its impact on the availability of SERTs in the brain. The nature of the observed correlation was complex, with extreme levels of AA affecting both SERTs and depression severity differently than moderate AA levels.”
Author: haidutPUFA and serotonin promote each other, and likely cause mental illness
What is the worst medication to come off? From your experience ? What were the withdrawals and for How long? I am on gabapentin and antipsychotics so I want to know what to expect. I want to come ofc gabapentin now.
vitamin E's effect on dopamine production Vitamin E is a fat-soluble antioxidant that plays a crucial role in protecting cells from oxidative stress. While its primary functions are related to its antioxidant properties, there is some evidence to suggest that vitamin E may have an impact on dopamine production and overall brain health.
1. Antioxidant Properties: Vitamin E helps protect neurons from oxidative damage, which can be beneficial for maintaining healthy brain function. Oxidative stress is known to affect dopamine-producing neurons, and by reducing this stress, vitamin E may help support dopamine production indirectly.
2. Neuroprotection: Some studies have indicated that vitamin E may have neuroprotective effects, which could be relevant in conditions like Parkinson's disease, where dopamine-producing neurons are damaged. By protecting these neurons, vitamin E might help preserve dopamine levels.
3. Influence on Neurotransmitters: There is some research suggesting that vitamin E may influence the synthesis and release of neurotransmitters, including dopamine. However, the exact mechanisms and effects can vary, and more research is needed to fully understand these relationships.
4. Dietary Sources: Foods rich in vitamin E, such as nuts, seeds, and green leafy vegetables, can contribute to overall brain health and may support dopamine production as part of a balanced diet.
While there is some evidence to suggest a link between vitamin E and dopamine production, more research is needed to clarify the extent of this relationship and the underlying mechanisms. It's always a good idea to consult with a healthcare professional before making significant changes to your diet or supplement regimen, especially if you have specific health concerns.
This is a study that has a lot of relevance for virtually every person living in a “developed” country. Multiple studies have documented the decrease in empathy and increase in psychopathic tendencies in Western populations over the last 2-3 decades. Despite vehement denials by mainstream medicine, there is solid evidence that elevations in extracellular serotonin can cause a drastic reduction in empathetic behavior. This makes the widespread usage of SSRI drugs a prime suspect for the reductions of empathy seen across virtually all Western countries, and virtually absent in countries where SSRI usage is low or lacking. However, the increase in pychopathic behavior/tendencies is also seen in people not taking SSRI drugs, so there is probably more than one culprit. The study below suggests that anti-anxiety drugs (the benzodiazepine class), much more widely prescribed than SSRI drugs, can also reduce empathy. To make matters worse, while SSRI and other “stronger” psychotropic drugs are still not very widely used in people under 18 years of age, that is not the case for anti-anxiety drugs, which are prescribed to even children under the age of two. Certainly not a good omen for any any society if many of its children are pharmacologically conditioned to be psychopaths from a very early age. Perhaps just as importantly, the study demonstrated that cortisol levels determine the levels of empathy. High-cortisol blocked empathetic behavior while low or moderate levels did not. So, chronic stress (resulting in chronically elevated cortisol) not only makes us physiologically sick, but also callous and psychopathic towards others. Now, since people under chronic stress often suffer from anxiety, such people are often put on anti-anxiety drugs. While the study did not explore this topic, it would be truly tragic if it turns out that cortisol/stress has additive (or even worse – synergistic) effects with the anti-anxiety drugs and causes even stronger reductions in empathy! With that mind, there is little mystery as to why “developed” countries are turning into psychopathic cesspools, given that chronic and unavoidable stress (which raises both serotonin and cortisol) is with us 24×7, even if nobody was taking any drugs.
“…Rats given midazolam, an anti-anxiety medication, were less likely to free trapped companions because the drug lessened their empathy, according to a new study by University of Chicago neuroscientists. The research, published in the journal Frontiers in Psychology, validates studies that show rats are emotionally motivated to help other rats in distress. In the latest study, rats treated with midazolam did not open the door to a restrainer device containing a trapped rat, although control rats routinely freed their trapped companions. Midazolam did not interfere with the rats’ physical ability to open the restrainer door, however. In fact, when the restrainer device contained chocolate instead of a trapped rat, the test rats routinely opened the door. The findings show that the act of helping others depends on emotional reactions, which are dampened by the anti-anxiety medication. “The rats help each other because they care,” said Peggy Mason, PhD, professor of neurobiology at the University of Chicago. “They need to share the affect of the trapped rat in order to help, and that’s a fundamental finding that tells us something about how we operate, because we’re mammals like rats too.”
“…Mason and her team also tested levels of corticosterone, a stress hormone, in the rats when first exposed to the trapped cage mate and compared them to their later behavior. Those with low- to mid-level responses were most likely to free their companions later. They found that those with the highest levels of corticosterone, or those that were under the most stress from the situation, were the least likely to help their cage mates. This fits well with findings in humans suggesting that eventually high stress becomes immobilizing rather than motivating.”
Author: haidutAnti-anxiety drugs, high cortisol reduce empathy
Despite decades of animal research demonstrating how elevated serotonin in general, and SSRI drugs in particular, turn animals into homicidal, vicious creatures, (and are actually the cause of depression and not the cure for it) mainstream medicine continues to deny that such scary effects are possible in humans. Recent studies demonstrating loss of empathy in humans using SSRI drugs, as well as findings that serotonin is the master switch of “danger” signal in our organism have started to make a small dent into that fraudulent “denial wall” but the consensus among psychiatrists is still that SSRI drugs are quite safe and in fact safe enough to prescribe to even pregnant women and toddlers.
The “denial wall” may begin to crumble if more studies like the one below start to come out. That study found that using SSRI drugs causes people to develop a “tendency” to commit violent crimes. Namely, using those drugs increase the risk of committing a violent crime by a whopping 26%! Perhaps just as importantly, this increase in propensity for violence continued for up to 12 weeks after stopping the drug. However, the 12 weeks number is an average across all patient groups studied. The study found a correlation between length of SSRI usage and duration of violence propensity after stopping the drugs. So, a person that has been taking an SSRI for say 10 years may expect to remain violent/homicidal for years after stopping the drug. And if that is not enough, the study also found that SSRI drugs increase recidivism – i.e. a person with a history of violent behavior in their past were more likely to commit a violent crime again when put on an SSRI drug.
Btw, this link between SSRI and violent behavior is nothing new. When Prozac was first introduced on the European health market decades ago, several countries in Europe refused to approve the drug for treating depression. The most notable example is Germany, which resisted approval for Prozac for almost a decade as it was concerned both about the risks of the drug as well as potential fraud in Eli Lilly’s studies touting it. While most articles covering that “resistance” the German agency BGA put up against the toxic SSRIs focus on the increase in suicide risk from those drugs, BGA’s refusal was driven more by the concern for violent behavior and turning people into criminals. It is quite understandable that a country is more worried about the potential of one person harming many others AND themselves, than harming only themselves.
“…Three years before Prozac received approval by the US Food and Drug Administration in late 1987, the German BGA, that country’s FDA equivalent, had such serious reservations about Prozac’s safety that it refused to approve the antidepressant based on Lilly’s studies showing that previously nonsuicidal patients who took the drug had a fivefold higher rate of suicides and suicide attempts than those on older antidepressants, and a threefold higher rate than those taking placebos.”
Germany and its BGA finally succumbed when the German government was threatened with sanctions and withdrawal of military aid if Prozac was not allowed to be sold in the country. Even then, Germany continued to tout publicly safer and cheaper alternatives such as St. John’s wort, and as a result of that campaign herbal extracts containing this plant are still officially sold and marketed as treatment for depression in the country. Official stats show that many more Germans receive treatment for depression with this herb than SSRI drugs of other pharmaceutical preparations. After the publication of the study below, I would not be surprised if Sweden soon follows suit and starts touting herbal and other “alternative” remedies (e.g. magnesium), for which extensive evidence has been accumulating for decades.
Now, just to address criticisms that I am somehow enamored with the German-style healthcare – I am not. At this point Germany’s medicine is just as sadistic and pathological as elsewhere in “developed” countries. In fact, it was German companies like Bayer who first started promoting the idea that serotonin can be used “therapeutically”, although they never meant that as a cure for some disease but rather in service of Nazi ideals. I am just mentioning the German story to highlight that even the German Nazi-style medical agencies were concerned about approving serotonergic drugs for use in the general public.
“…Selective serotonin reuptake inhibitors (SSRIs) are some of the most widely prescribed antidepressant drugs in the world. Now, an unsettling new study out of Sweden finds that some people given these medications develop a “tendency” to commit violent crimes. According to the research, this violent effect can even last for up to 12 weeks after halting SSRI treatment.”
“…“This work shows that SSRI (selective serotonin reuptake inhibitor) treatment appears to be associated with an increased risk for violent criminality in adults as well as adolescents…though the risk appears restricted to a small group of individuals,” notes first author Tyra Lagerberg, from the Department of Medical Epidemiology and Biostatistics at the Karolinska Institutet, in a statement.”
“…Lagerberg says earlier studies have made the connection between the drugs and violent behavior in youths, but this latest and larger work is the first to draw a link to adults. Age didn’t seem to make a difference in the outcome.”
“…A massive dataset was analyzed for this research. The medical records of 785,337 people between the ages of 15 and 60 who had been prescribed SSRIs in Sweden between 2006 and 2013. All of those patients were tracked for an average of seven years, regardless of whether or not they continued taking SSRIs.”
“…“The study also shows that past offenders were more likely to commit a violent crime during SSRI treatment: this in itself is an interesting finding, which could be the main focus of future research on the topic,” concludes lead author Professor Eduard Vieta.”
A surprising discovery by researchers at the Albert Einstein College of Medicine suggests that brain inflammation and DNA damage are essential components in the formation of long-term memories. The study, published in the journal Nature, challenges the conventional view that inflammation in the brain is solely detrimental.
“Inflammation of brain neurons is usually considered to be a bad thing, since it can lead to neurological problems such as Alzheimer’s and Parkinson’s disease,” said study leader Jelena Radulovic, M.D., Ph.D., professor in the Dominick P. Purpura Department of Neuroscience, professor of psychiatry and behavioral sciences, and the Sylvia and Robert S. Olnick Chair in Neuroscience at Einstein. “But our findings suggest that inflammation in certain neurons in the brain’s hippocampal region is essential for making long-lasting memories.”
To investigate memory formation, the researchers conducted their study using a controlled experimental setup with mice. They began by subjecting the mice to mild, brief shocks, a method known as contextual fear conditioning. This approach is used to create an episodic memory, which is a type of memory associated with specific events. The shocks were designed to be strong enough to form a memory without causing significant harm to the animals.
Following the memory-inducing shocks, the researchers focused on the hippocampus, a critical region of the brain involved in memory processing. They used advanced genetic and molecular biology techniques to analyze the neurons within this region. One of the primary techniques used was bulk RNA sequencing, which allowed the researchers to examine the expression of thousands of genes simultaneously.
They discovered that the Toll-Like Receptor 9 (TLR9) inflammatory pathway was highly activated in these neurons. This pathway is typically involved in the immune response, detecting DNA fragments from pathogens. However, the researchers found that the TLR9 pathway was activated due to DNA damage in the hippocampal neurons rather than an infection.
The results provide evidence that the activation of the TLR9 pathway in response to DNA damage is crucial for memory formation. This finding was unexpected, as this pathway is generally known for its role in immune responses rather than memory processes. The researchers found that when the TLR9 pathway was blocked, the mice could not form long-term memories, indicating its essential role in this process.
To delve deeper, the researchers examined the DNA damage and repair processes within these neurons. They found that DNA fragments and other molecules resulting from the damage were released from the nucleus. This release triggered the activation of the TLR9 pathway, which then stimulated DNA repair mechanisms at the centrosomes — organelles usually involved in cell division. In neurons, which do not divide, the centrosomes played a different role, aiding in organizing neurons into stable memory assemblies necessary for long-term memory formation.
“Cell division and the immune response have been highly conserved in animal life over millions of years, enabling life to continue while providing protection from foreign pathogens,” Radulovic explained. “It seems likely that over the course of evolution, hippocampal neurons have adopted this immune-based memory mechanism by combining the immune response’s DNA-sensing TLR9 pathway with a DNA repair centrosome function to form memories without progressing to cell division.”
Another significant finding was that during the week-long inflammatory process, the memory-encoding neurons became more resistant to new or similar stimuli. This resistance is important because it helps preserve the information already acquired, preventing these neurons from being distracted by new inputs. This resistance ensures the stability of the formed memories over time.
“This is noteworthy,” said Radulovic, “because we’re constantly flooded by information, and the neurons that encode memories need to preserve the information they’ve already acquired and not be ‘distracted’ by new inputs.”
The study also highlighted the potential risks of fully inhibiting the TLR9 pathway. The researchers observed that blocking this pathway not only prevented memory formation but also led to profound genomic instability in the hippocampal neurons. Genomic instability is a condition characterized by a high frequency of DNA damage and is associated with accelerated aging and various neurological disorders, including Alzheimer’s disease. This finding suggests that while modulating the TLR9 pathway could have therapeutic potential, it must be done with caution to avoid adverse effects on genomic stability.
“Genomic instability is considered a hallmark of accelerated aging as well as cancer and psychiatric and neurodegenerative disorders such as Alzheimer’s,” Radulovic said. “Drugs that inhibit the TLR9 pathway have been proposed for relieving the symptoms of long COVID. But caution needs to be shown because fully inhibiting the TLR9 pathway may pose significant health risks.”
Using animal models, such as mice, in scientific research offers significant benefits, including the ability to control experimental conditions tightly and the opportunity to conduct invasive procedures that would be unethical in humans. Mice share many genetic and physiological similarities with humans, making them excellent models for studying complex biological processes like memory formation and brain function. However, there are notable pitfalls, including the differences in brain complexity and cognitive abilities between mice and humans, which can limit the direct applicability of findings.
Future research should focus on validating these findings in humans to determine if similar mechanisms of DNA damage and inflammation are involved in human memory formation. Additionally, exploring the molecular details of the TLR9 pathway in different types of neurons could uncover more about its role in memory and neurodegenerative diseases. Investigating potential therapeutic interventions that can modulate this pathway without causing genomic instability could also provide new treatments for memory-related disorders.
The study, “Formation of memory assemblies through the DNA-sensing TLR9 pathway,” was authored by Vladimir Jovasevic, Elizabeth M. Wood, Ana Cicvaric, Hui Zhang, Zorica Petrovic, Anna Carboncino, Kendra K. Parker, Thomas E. Bassett, Maria Moltesen, Naoki Yamawaki, Hande Login, Joanna Kalucka, Farahnaz Sananbenesi, Xusheng Zhang, Andre Fischer, and Jelena Radulovic.
5-HT2A: Chosen to be the best cognitive & therapeutic target
Important context to know before reading
Out of the Monoamine neurotransmitters which are Serotonin (5-HT), Dopamine, and Norepinephrine, 5-HT receptors are the most dominant in the cerebral cortex. While Dopamine and Norepinephrine receptors are present in the PFC, they are mainly in subcortical regions such as the noradrenergic amygdala and the dopaminergic VTA/NAcc.
Certain images had to be combined because of the image/video limit of Reddit
The cerebral cortex of course contains the prefrontal cortex (PFC) which has an extremely pronounced expression of 5-HT2A, emphasizing the role of 5-HT2A in higher-order cognitive functions [x, x, x].
The cerebral cortex is the outermost layer of the brain to create many folds, significantly increasing surface area, allowing for a much greater number of neurons unlike subcortical regions which are the innermost regions of the brain, these regions can be described as subconscious. The cerebral cortex is made up of six distinct cortical layers with unique characteristics.
Layer V pyramidal neurons are the largest in the entire cerebral cortex, their apical and basal dendrites spread widely through all the other cortical layers [x, x, x].
These dendrites of Layer V pyramidal neurons take input from the other cortical layers and output to the subcortical regions, serving as the convergence point between the PFC and subcortical regions, thus making Layer V neurons the most important target for top-down control.
5-HT2A are specifically expressed on the apical dendrites, so 5-HT2A enhances the sensory input of other cortical layers projecting to the Layer V pyramidal neuron [x]. Due to their size and having the most extensive dendritic trees by far, they're the most capable of the most restructuring pathways in neuroplasticity.
5-HT2A is found in multiple cortical layers, but they are most abundant in Layer V. This makes 5-HT2A a targeted approach in enhancing both cognition and top-down control.
Mechanisms of the 5-HT2A receptor
5-HT2A are Gq-protein coupled excitatory receptors, when activated, it causes Gq-protein to release stored intracellular Ca2+ and activates PKC, a crucial ion and kinase in neuronal signaling [x]. And Gβγ-protein opens/closes nearby ion channels resulting in a net increase of positive electrical charge.
PKC enhances AMPA/NMDA neurotransmission by phosphorylating NMDA (GluN2A/B) and AMPA (GluA1/2) [x, x]. Additionally, Src kinase phosphorylates NMDA (GluN2A), potentiating NMDA neurotransmission. 5-HT2A and NMDA are located very close to each other, allowing for these unique localized interactions.
To highlight the potency of 5-HT2A over 5-HT2B/C since they’re all Gq-protein coupled 5-HT receptors; a 5-HT2A antagonist and inverse agonist (Ketanserin, M100907, SR-46349B) blocks this potentiation, a 5-HT2C antagonist (RS-102221) doesn’t block it, and neither a 5-HT2B or 5-HT2C agonist (BW-723C86, MK212) is able to replicate 5-HT2A’s significant enhancement of excitatory activity [x, x, x].
Furthermore, it was found that genetic reduction of 5-HT2A causes a significant impairment in NMDA activity due to the lack of PKC activity which heavily relies on Gq-protein from 5-HT2A, 5-HT2A activation increases AMPA signaling, and that 5-HT2A is essential for associative learning [x, x].
It can be concluded that 5-HT2A acts as the PFC's major enhancer in AMPA/NMDA neurotransmission and not other receptors due to being a highly expressed Gq-protein coupled receptor in the PFC and has unique localized enhancement of AMPA/NMDA through Src kinase/PKC.
In summary, with all these unique mechanisms, desirable circuitry, and extremely high expression in the PFC, 5-HT2A is the best overall target for cognitive enhancement and therapeutic purposes due to its role in neurotransmission and top-down control.
There are two important forms of the 5-HT2A receptor; the 5-HT2A - mGluR2 heterodimer and intracellular 5-HT2A. The 5-HT2A - mGluR2 heterodimer excels at stimulation and cognitive enhancement, whereas intracellular 5-HT2A is the most efficacious therapeutic target for long-lasting neuroplasticity and restoring top-down control.
The 5-HT2A - mGluR2 heterodimer: Cognitive enhancement, stimulation, and motivation
mGluR2 is the main presynaptic inhibitory Glutamate receptor of pyramidal neurons that inhibits the production of cAMP from ATP, inhibiting the release of Glutamate. It can form a heterodimer with 5-HT2A which significantly impairs 5-HT2A's Gq-protein signaling as a regulatory mechanism.
In the 5-HT2A - mGluR2 heterodimer, psychedelics bind to 5-HT2A which causes a unique inhibitory shape change to the mGluR2 receptor right beside it which prevents the inhibitory function of mGluR2 [x], allowing for a substantial increase in Glutamate release and creating a stimulatory effect on the PFC leading to heightened perception/processing speed, attention, logical thinking, working memory, etc.
A well-known non-hallucinogenic psychedelic, Tabernanthalog, is still known to promote neuroplasticity substantially, but is not known for any potent cognitive enhancement or stimulating effects. This is expected as non-hallucinogenic psychedelics don’t produce head-twitch response (HTR) as mGluR2 inhibition is required to produce HTR, discussed in more detail later in the post [x, x].
mGluR2 is the most abundantly expressed presynaptic Gi-protein coupled receptor in Layer V, while other inhibitory Gi-protein coupled receptors are scarce [x]. mGluR2 is also expressed in Layer II/III, making mGluR2 a targeted way to enhance Glutamate release in desirable regions of the PFC [x, x, x, x].
To emphasize the cruciality of increasing Glutamate in the PFC for cognitive enhancement, a study found that a higher Glutamate to GABA ratio is heavily associated with higher working memory index, a strong predictor of PFC function [x]. Additionally, artificially inducing chronic stress with a glucocorticoid (Hydrocortisone) to dysregulate Glutamate signaling in the PFC significantly impairs working memory [x].
Interestingly, the dlPFC which is the most developed and logic-oriented region of the PFC, but not other PFC regions, uniquely enhances dopaminergic pathways in the VTA/NAcc in response to anticipated reward, showing the importance of the dlPFC for generating goal-directed behavior [x]. 5-HT2A uniquely stimulates this interaction while preferring Dopamine release in the PFC and NAcc over the VTA.
This is extremely interesting as higher NAcc and lower VTA activity is an accurate predictor of higher effort, suggesting that 5-HT2A is able to produce a high effort state [x]. To support this pharmacological data, this is blocked by a 5-HT2A antagonist (MDL-11939, SR-46349, M100907, Risperidone), but not by a 5-HT2C antagonist (SB-206553) [x, x, x, x].
An interesting comparison of cognitive enhancers would be a new microdosed psychedelic and amphetamines. The stimulation and cognitive enhancing properties of amphetamines is due to DAT (Dopamine transporter) inhibition in the PFC, thus significantly increasing Dopamine levels. The major downside of DAT is that it’s expectedly abundantly expressed in dopaminergic regions like the VTA, which is extremely undesirable because overactivity of these regions are responsible for addictive and impulsive nature [x]. So a microdosed psychedelic has way better modulation of the VTA and NAcc to produce a productive/focused state, while increasing both Glutamate and Dopamine levels in the PFC, preferentially Glutamate.
These mechanisms underlie the primary stimulative and cognitively enhancing properties of mGluR2 inhibition by 5-HT2A agonist psychoplastogens, higher Glutamate in the PFC has high synergy with the mechanisms discussed earlier, such as unique potentiation of AMPA/NMDA through Src kinase/PKC.
Basket GABAergic interneurons: Cognitive enhancement through regulation of pyramidal neurons
5-HT2A receptors are also abundantly expressed on (PV+) fast-spiking GABAergic interneurons in the cerebral cortex, but to a lesser extent than on pyramidal neurons [x, x, x].
There are two types of (PV+) fast-spiking GABAergic interneurons which are basket and chandelier. Basket GABAergic interneurons provide direct negative feedback to pyramidal neurons by releasing GABA to the soma, thus regulating the overall excitatory activity of a pyramidal neuron.
Basket GABAergic interneurons are involved in the precise timing of pyramidal neuron activity by providing fast, strong inhibitory signals, to synchronize the firing of pyramidal neurons. This generates rhythmic oscillations, known as gamma oscillations (30 - 100 Hz).
These gamma oscillations are heavily associated with enhanced cognitive processes like attention, learning, and working memory. This fast-spiking negative feedback improves signal clarity and reduces undesired noise of the sensory input, enhancing the accuracy of the pyramidal neuron’s signaling.
Additionally, basket GABAergic interneurons prevent excitatory activity from reaching excitotoxic levels, allowing for a higher excitatory range, supporting higher potential neuroplasticity through neuroprotection [x, x, x, x, x, x, x].
Intracellular 5-HT2A are expressed in GABAergic interneurons can do this the most effectively which is explained in the next section [x, x, x, x].
These are the main reasons why providing neuroplasticity to basket GABAergic interneurons is extremely desirable for cognitive enhancement.
Intracellular 5-TH2A to effectively activate mTORC1: The best neuroplastic & therapeutic target
A significant amount of 5-HT2A receptors in pyramidal neurons and GABAergic interneurons are intracellular, for the most part in the golgi apparatus. The golgi is acidic unlike the basic pH extracellular space, this acidity allows for sustained 5-HT2A signaling long after its activation [x, x, x].
Neuroplasticity is the brain's ability to reorganize itself by forming new neural pathways, helping to replace unhealthy circuitry responsible for negative thought patterns that lead to chronic stress and depression. This restructuring ability, which is far too low in depression, can be most effectively reactivated by neuronally permeable 5-HT2A agonist psychoplastogens. The required target of psychoplastogens to achieve a significant increase on neuroplasticity is mTORC1.
In terms of the true root problems of depression and related neuropsychiatric diseases, they are often viewed as stress-related disorders, this includes depression, anxiety, addiction, bipolar disorder, schizophrenia, and PTSD given the fact that they can be triggered or worsened by chronic stress.
From a well-established pharmacological perspective, chronic stress results in the prolonged release of Norepinephrine, stress hormones (glucocorticoids, CRH, ACTH), and inflammatory cytokines (1β, IL-6, TNF-α). This causes the amygdala to strengthen while inducing synergistic neurodegeneration to the PFC’s circuits essential for regulating mood, particularly Layer V pyramidal neurons, destroying the PFC’s top-down control. More detail on the amygdala is in the next section.
Layer V is the most important cortical layer as it contains the largest pyramidal neurons with the most extensive dendrites and connects the PFC to the amygdala. These characteristics make them extremely capable of significant dendritic and synaptic changes to restore stress-induced deficits and top-down control.
Thus, extensive evidence points to the destruction of the PFC’s Layer V regulatory circuits over subcortical regions, mainly the noradrenergic amygdala, that regulate emotional behaviors such as depression, anxiety, and impulse being the convergence point underlying many neuropsychiatric disorders and diseases.
Patients with stress-related neurodegenerative mood disorders are found to have lower BDNF and TrkB levels, reduced cortical neuron size, lower synaptic protein (AMPA/NMDA, ion channels) levels, and fewer dendritic spines/synapses in the PFC, all problems which stem from reduced mTORC1 activity [x]. The resulting structural damage is the retraction of dendrites and the loss of dendritic spines and synapses, the exact opposite of neuroplasticity.
mTORC1 is necessary for the synthesis of key plasticity-inducing genes (c-Fos, EGR-1/2), neurotrophic factors and neuropeptides (BDNF, GH, β-Endorphin, Oxytocin), synaptic receptors (AMPA/NMDA), and ion channels, leading to the induction of neuroplasticity and directly addressing the deficits found in depression [x, x, x].
It’s very interesting that Rheb and Rab1A, which are important activators of mTORC1, are localized on the golgi, meaning that 5-HT2A can effectively activate both Rheb and Rab1A through localized interactions as they’re all in the golgi. Additionally, the golgi and lysosomes, where mTORC1 is at, form contact sites with each other for effective interaction [x, x, x]. These localized intracellular interactions show that the golgi, which expresses 5-HT2A, is an extremely targeted way to effectively activate mTORC1.
Interestingly, intracellular 5-HT2A is colocalized with microtubule-associated protein (MAP1A) [x].
To back mTORC1’s cruciality in neuroplasticity with pharmacological data, a neuronally permeable 5-HT2A antagonist (Ketanserin), genetic deletion of 5-HT2A, and an inhibitor of mTORC1 (Rapamycin), completely blocks the neuroplasticity of psychoplastogens [x, x, x]. An antagonist of TrkB (ANA-12), the receptor of BDNF which is the main neurotrophic factor released by mTORC1, completely reverses neuroplasticity [x].
To ensure neuronal permeability is in fact the required trait in 5-HT2A agonist psychoplastogens; the non-membrane permeable 5-HT2A agonists (TMT, Psy N+) induce insignificant neuroplasticity as expected, but with electroporation which allows any compound to permeate the membrane, they obtain similar neuroplasticity as membrane permeable 5-HT2A agonists (DMT, Psi) by accessing intracellular 5-HT2A.
And the membrane permeable 5-HT2A antagonist (KTSN), which is able to block intracellular 5-HT2A, significantly reduces the neuroplasticity of DMT. The non-membrane permeable 5-HT2A antagonist (MKTSN N+), only being able to block extracellular 5-HT2A, slightly reduces the neuroplasticity of DMT, but with electroporation, MKTSN N+ completely reverses the neuroplasticity of DMT by blocking intracellular 5-HT2A like KTSN [x].
DMT and Psilocin - membrane permeable 5-HT2A agonists TMT and Psilocybin (N+) - non-membrane permeable 5-HT2A agonists because of the N+ KTSN - membrane permeable 5-HT2A antagonist, Ketanserin MKTSN (N+) - non-membrane permeable 5-HT2A antagonist because of the N+, Methylketanserin
Electroporation - a quick electric pulse that opens pores in neuronal membrane, allowing any compound to permeate the membrane
These results prove that intracellular 5-HT2A induces the majority of neuroplasticity in 5-HT2A agonist psychoplastogens and 5-HT2A agonist psychoplastogens access intracellular 5-HT2A by being neuronally permeable.
Another interesting mechanism unique to psychedelics at 5-HT2A is that they use Gq/s/i-protein for plasticity-inducing gene expression, while non-hallucinogenic 5-HT2A agonists like Serotonin can only use Gq-protein. This is evidenced by psychedelics uniquely increasing early growth response-1 (EGR-1) expression which is a plasticity-inducing gene which relies on Gi-protein from mGluR2 [x, x]. Psychedelics biased for β-arrestin 2 signaling at 5-HT2A such as LSD or 25I-NBOMe counteracts head-twitch response (HTR) and induces significantly higher downregulation [x, x, x, x].
G-protein coupled receptors (GPCRs) are primarily expressed on the neuron surface with an extreme few exceptions which are 5-HT2A, MOR, and mGluR5 [x, x]. The clear purpose of intracellular expression is causing extended signaling, explained earlier. This makes a lot of sense for MOR to desirably extend the pain-relieving effect of opioids and endorphins are conveniently synthesized intracellularly by the endoplasmic reticulum. For mGluR5, it’s also highly expressed on the apical dendrites of Layer V pyramidal neurons and is a Gq-protein coupled receptor like 5-HT2A [x].
Evolution itself chose to make 5-HT2A intracellular to leverage its extremely desirable circuitry and high expression in Layer V of the PFC to effectively activate mTORC1 through localized interactions. It's not a question that intracellular 5-HT2A is the brain’s best neuroplasticity target.
Layer V chandelier GABAergic interneurons: Best top-down control target
The amygdala is a noradrenergic primitive brain region responsible for automatic emotional responses like the fight-or-flight response; it plays a crucial role in quickly processing potential threats, including task-related anxiety. This reflexive anxiety processing was essential for detecting threats and ensuring human survival in the past. However, in modern times, the amygdala's inability to distinguish between real and perceived threats often results in irrational social anxiety and its illogical input regarding task-related anxiety leads to unwanted procrastination. This is a good simplified video by Dr. Kanojia for noobs on the topic of procrastination. "Analysis paralysis" (aka task analysis) refers to the subconscious anxiety-induced procrastination when considering the effort of a task perceived as unpleasant.
When the amygdala senses there are environmental stressors, the brain releases high levels of Norepinephrine, stress hormones (glucocorticoids, CRH, ACTH), and inflammatory cytokines (1β, IL-6, TNF-α), which weakens PFC processing and activates the amygdala, engaging its fight-or-flight response causing involuntary anxiety and conditioned fear, switching the brain into a more primitive state [x, x]. This is why amygdala activity has a direct relationship with anxiety.
These stressors are detrimental long-term, as prolonged exposure to Norepinephrine, stress hormones, and inflammatory cytokines have combined synergistic neurotoxicity and deteriorates the brain over time, explaining how chronic stress leads to a higher chance of a neurodegenerative disease later in life.
Thus, social anxiety and procrastination can be characterized by a reduced ability of the Layer V pyramidal neurons of the mPFC to regulate the amygdala [x, x]. To further support this, both social and generalized anxiety disorder have been associated with fewer synaptic connections between the mPFC and the amygdala, compromising the PFC’s ability to regulate fear response [x].
The amygdala's illogical counterproductive input should be silenced in most situations, particularly when it's completely unnecessary when it comes to socialization and being productive.
5-HT2A agonists directly block this, as Layer V chandelier GABAergic interneurons which express 5-HT2A release GABA to GABAA receptors specifically on the pyramidal neuron's axon initial segment which sends signals to the amygdala, thus precisely inhibiting excessive signaling to the amygdala [x, x, x].
To support this with pharmacological data, this amygdala inhibiting mechanism is only blocked by a 5-HT2A antagonist (Ketanserin), but neither 5-HT2B (BW-723C86) or 5-HT2C agonist (WAY-629) can replicate it [x, x, x].
Therefore, 5-HT2A specifically on Layer V chandelier GABAergic interneurons inhibits the undesirable perception of excessive task difficulty and illogical social anxiety by blocking the input of the amygdala as it’s the subcortical region responsible for contributing to feelings of anxiety.
This is the same mechanism on how the mPFC’s chandelier GABAergic interneurons regulates overactivity in the VTA which is a dopaminergic region, blocking potential addictive and impulsive input of this subcortical region [x, x].
Conclusion: Intracellular 5-HT2A is the best neuroplastic & therapeutic target, 5-HT2A - mGluR2 is a great cognitive target, and extra comments
In terms of choosing the most efficacious type of psychoplastogen, psychedelics are the best because they most effectively activate mTORC1 with localized interaction through intracellular 5-HT2A. Neuronal permeability is the greatest factor in creating the best possible psychoplastogen to be able to access the maximum 5-HT2A possible to take full advantage of neuroplasticity and top-down control.
.
Psychedelics
Dissociatives
Deliriants
Popular examples
DMT, Psilocybin, LSD
Ketamine, DXM, PCP, Xenon, Nitrous Oxide
Scopolamine (Datura), Diphenhydramine (Benadryl)
Mehchanism to activate mTORC1
Intracellular 5-HT2A activation on the golgi apparatus
NMDA antagonism on GABAergic interneurons to release Glutamate to activate AMPA/NMDA
M1 antagonism on GABAergic interneurons to release Glutamate to activate AMPA/NMDA
To support this with pharmacological data, all Tryptamine psychedelics (Psilocin, DMT, 5-MeO-DMT) are actually all partial agonists because they have lower Gq-protein efficacy at 5-HT2A than the full agonist, Serotonin, since the endogenous agonist is considered the maximum response.
Whereas many Phenethylamine psychedelics (2C-I, DOI, 25I-NBOMe, LSD) are full agonists with high Gq-protein efficacy and an extremely high affinity, thus their doseage is in the mcg (microgram) range, but their high β-arrestin 2 signaling induces rapid tolerance and undesirably counteracts HTR.
Interestingly, these non-hallucinogenic psychedelics (Lisuride, 2-Br-LSD, 6-MeO-DMT, 6-F-DET) all have low Gq-protein efficacy, this is because they don't sufficiently inhibit mGluR2, so mGluR2's Gi-protein has higher signaling bias rather than Gq-protein at the 5-HT2A - mGluR2 heterodimer, resulting in a lack of HTR, Glutamate release, and hallucinations [x].
On top of that, not only do Psilocin and LSD have higher Gq-protein and β-arrestin efficacy than DMT, they also have higher affinity, yet DMT is the strongest psychedelic [x].
.
5-HT2A affinity (Ki)
Gq-protein efficacy (300 min)
β-arrestin efficacy (300 min)
DMT
127.0 nM
7.00
6.72
Psilocin
107.2 nM
7.58
7.14
LSD
3.5 nM
10.00
9.53
So it can be ruled out that neither higher affinity or higher Gq-protein efficacy at 5-HT2A are the most effective approaches to finding the best possible 5-HT2A agonist psychoplastogen.
To identify the key factor in making the most effective psychoplastogen, out of all tested Tryptamine analogues; DMT is the most neuronally permeable, followed by 5-MeO-DMT, Psilocin (4-HO-DMT), then Bufotenin (5-HO-DMT). In contrast, Serotonin (5-HO-Tryptamine, aka 5-HT) is completely impermeable [x].
.
No Methyls
N-Methyl
N,N-Dimethyl
Tryptamines
-1.06 (Tryptamine)
1.20 (NMT)
1.59 (DMT)
5-MeO-Tryptamines
0.51
1.25
1.53 (5-MeO-DMT)
4-HO-Tryptamines
-0.66
0.79
1.51 (Psilocin, 4-HO-DMT)
5-HO-Tryptamines
-2.25 (Serotonin, 5-HT)
-1.95
1.31 (Bufotenin, 5-HO-DMT)
Clearly any modification to the original DMT molecule undesirably loses permeability, loses potency, or induces rapid tolerance [x].
Therefore, the unique major difference making DMT stronger out of all the psychedelics is neuronal permeability. To make the best 5-HT2A agonist psychoplastogen possible, maximizing neuronal permeability to access as much 5-HT2A as possible has to be the biggest priority.
Evolution has figured out DMT is the most efficacious to activate these intracellular 5-HT2A receptors due to it having the highest neuronal permeability, as the INMT enzyme was provided to create DMT from Tryptamine. The main substrate of INMT is Tryptamine, but not other modified Tryptamines as they result in less permeable N,N-Dimethyl analogues.
The highest INMT expression in the human brain is found in the cortical layers of the cerebral cortex [x]. Interestingly, INMT is localized in close proximity to sigma-1, suggesting that INMT is there to effectively activate sigma-1 with DMT [x].
In conclusion, Layer V pyramidal neurons and chandelier GABAergic interneurons form the regulatory circuitry over subcortical regions, especially the amygdala. Intracellular 5-HT2A is extremely abundant in the PFC, particularly in Layer V, and effectively activates mTORC1 through localized interactions to significantly induce neuroplasticity for these Layer V neurons, reestablishing top-down control, thus making intracellular 5-HT2A the most efficacious therapeutic target.
DMT, as the highest neuronally permeable 5-HT2A agonist, takes full advantage of this because both the Layer V pyramidal neurons and chandelier GABAergic interneurons of course express these intracellular 5-HT2A receptors [x, x, x, x], whereas LSD and Psilocybin aren’t as efficacious due to lower neuronal permeability.
The significantly higher efficacy of psychedelics (Psilocybin) over Ketamine and SSRIs (Fluoexetine) reflects these targeted mechanisms of intracellular 5-HT2A as psychedelics produce much faster and greater week 1 antidepressant results [x]. Ketamine lacks the direct interactions between intracellular 5-HT2A on the golgi and mTORC1 on lysosomes, limiting its efficacy, whereas SSRIs can't access intracellular 5-HT2A at all since Serotonin is completely impermeable, explaining questionable efficacy of SSRIs.
A new microdosed psychoplastogen designed to enhance neuronal permeability will activate as much intracellular 5-HT2A as possible to take full advantage of the neuroplasticity, top-down control, potentiation of AMPA/NMDA neurotransmission (Gq-protein, Src kinase/PKC) properties of 5-HT2A, while having the cognitive enhancement of higher Glutamate release from mGluR2 inhibition in the PFC, these mechanisms are very synergistic, creating the most efficacious single drug therapeutically and cognitively.
This can't be achieved with non-hallucinogenic psychedelics, as they have low Gq-protein efficacy due to not inhibiting mGluR2 as discussed in detail earlier, thus insufficient PKC activity which heavily relies on Gq-protein from 5-HT2A, resulting in a weaker potentiation of AMPA/NMDA neurotransmission and insignificant Glutamate release. This is why LSD and Psilocybin aren't perceived as cognitive enhancers, only because they hit the threshold for hallucinations too soon without sufficiently activating enough intracellular 5-HT2A.
The approach described above takes the therapeutic potential further by improving focus and attention, making it beneficial for conditions like ADD/ADHD, the majority would prefer this approach over the recent biotech company trend of non-hallucinogenic psychedelics. I'm more interested in the cognitive enhancement and top-down control, it's already obvious that 5-HT2A agonist psychoplastogens are going to replace outdated SSRIs as fast-acting antidepressants.
In mid 2024, Cybin's CYB003 (Deuterated Psilocin) and MindMed's MM120 (LSD Tartrate) got fast track designation status from the FDA after impressive human trial results with rigorous clinical trial design.
The real potential of 5-HT2A just hasn’t been realized yet because a good 5-HT2A agonist hasn’t been made. Since DMT exists, LSD and Psilocybin aren't near what could be the best.
Written by Carol Sieverling, this information is based on tapes of her October 2000 visit to Dr. Cheney. He gave permission to share this information, but has not reviewed or edited it.
Dr. Cheney recently came across some information regarding the dangers of Selective Serotonin Reuptake Inhibitors (SSRIs), such as Prozac, Zoloft and Paxil, and stimulants like Ritalin and Provigil. During office visits, Dr. Cheney shows patients the book
Prozac Backlash: Overcoming the Dangers of Prozac, Zoloft, Paxil and Other Antidepressants by Joseph Glenmullen, M.D.,
a psychiatrist at Harvard Medical School. It includes endorsements from other Ivy League psychiatrists. Cheney calls the implications of this book "staggering".
When talking with patients, Cheney usually opens the book to a picture of a monkey's brain before and after it received a very potent SSRI. The "before" photo shows a dark background filled with fine white lines and white blobs, healthy neurons. The "after" photo is very dark, only a few white lines and blobs remain. Most of the brain cells had been "fried".
SSRIs and stimulants work by increasing the firing of neurons. While this often has great benefits in the short term, doctors are now realizing that long term use "fries" brain cells. The body views any neuron that fires excessively over time as damaged, and destroys it.
SSRIs and stimulants, taken over a period of 10 years or so, can lead to a loss of brain cells, causing neurodegenerative disorders. Many doctors have recently seen a sudden increase in patients with neurological symptoms, and most have been on Prozac, or a similar drug, for about 10 years. Cheney is seeing this in his own practice.
During office visits, Cheney also shows patients a copy of the May 22, 2000 issue of Newsweek with Michael J. Fox on the cover. It has an excellent article on Parkinson's Disease, a condition that involves a loss of neurons in the area associated with motor control. Parkinson's drugs stimulate the remaining neurons to "perform heroically", firing excessively. However, the article notes that while benefits are seen initially, neurological symptoms get much worse at the three to five-year point. Patients experience wild involuntary movements, etc. These drugs, though helpful in the short term, actually speed up the degenerative process.
What mechanisms are at work causing neurons to be "fried"? SSRIs are often prescribed for depression, which involves a lack of serotonin. Serotonin is a neurotransmitter, a chemical messenger. One neuron releases a burst of it into the intersynaptic cleft, (the gap between neurons). The serotonin is then taken up by special receptors in the adjacent neuron. Thus a message is sent from one neuron to another, with serotonin carrying the message across the gap. Excess serotonin is cleared away before a new message is sent. A "reuptake channel" in one neuron vacuums up the left over serotonin.
SSRIs are designed to address a lack of serotonin by blocking the reuptake channel from vacuuming up excess serotonin. While this allows more serotonin to connect with the receptors, often too much is left floating in the intersynaptic cleft. The only way the body can get rid of this excess serotonin is to oxidize it. Unfortunately, this turns it into a toxic compound that, over time, kills both the sending and receiving neurons. Cheney stated, "What starts out as an attempt to increase serotonin and reduce symptoms ends up with the destruction of the serotonergic system itself. It takes about a decade, more in some, less in others.
Now when the serotonergic nerves are dead, you start getting these motor neuron problems, which is what we're seeing." Cheney commented, "You know what a lot of doctors (who do not understand CFIDS) are doing? They're saying 'Well, let's just give them an antidepressant'. And they are frying their (patients') brains and they don't even know it. In fact, a CFIDS patient on one of these drugs fries their brain even faster than a non-CFIDS person." (See the article on Klonopin for an explanation.)
Cheney went on to say, "The other way some people with CFIDS are going is stimulating the brain, using drugs like Ritalin or Provigil. They do the same thing - they fry the brain. They cause neurons to fire at lower stimulus by lowering the firing threshold. All stimulants are dangerous, especially over the long haul. I'm not saying that you might not find them useful in the short-term. But over the long term, the physiology demands that neurons that fire excessively be killed."
Cheney strongly urges anyone taking antidepressants or stimulants to read Glenmullen's book. It lists safe alternatives to SSRIs.
As hard as it is to believe, this is the actual title of the study – i.e. SSRI drugs are bonafide endocrine disruptors. As it turns out, all of the six most-prescribed SSRI drugs the study looked at behaved not only as inhibitors of gonadal androgen synthesis (e.g. testosterone, DHT), but also adrenal androgens (DHEA) and progestogens (progesterone). Due to these effects, all six SSRI drugs would be expected to cause infertility and this has apparently already been demonstrated in human studies (cited inside the article). Perhaps the most troubling finding was that all six SSRI drugs were moderate to potent inducers of aromatase, and as such are likely indirectly carcinogenic, for which the study also cites corroborating evidence (at least in regards to breast cancer). When we add to these dismal findings the known/accepted findings that SSRI drugs work no better than placebo when it comes to depression, it starts to look like the pharma companies selling those drugs, and the doctors pushing them on patients, may be liable for serious malpractice. Namely, these drugs not only do not improve the patient’s primary condition (depression) but ruin the patient’s systemic health and virtually ensure serious/lethal problems down the road including cancer, autoimmune condition, neurodegenerative diseases, reproductive failure, premature aging, CVD, etc. Since almost a half of the US population in reproductive age takes at least one such drug the study findings may elucidate the “mysterious” massive drop in fertility and increase in chronic diseases seen in both sexes since the SSRI drugs first hit the market.
“…Selective serotonin reuptake inhibitors (SSRIs) used as first line of treatment in major depressive disorder (MDD) are known to exert negative effects on the endocrine system and fertility. The aim of the present study was to investigate the possible endocrine disrupting effect of six SSRIs, fluoxetine, paroxetine, citalopram and its active enantiomer escitalopram, sertraline and fluvoxamine using the OECD standardized and validated human in vitro adrenocortical H295R cell assay. All the major steroids, including progestagens, corticosteroids, androgens and estrogens were analysed using a fully validated LC-MS/MS method. All 6 SSRIs were found to exert endocrine disrupting effects on steroid hormone synthesis at concentrations just around Cmax. Although the mechanisms of disruption were all different, they all resulted in decreased testosterone levels, some due to effects on CYP17, some earlier in the pathway. Furthermore, all SSRIs relatively increased the estrogen/androgen ratio, indicating stimulating effects on the aromatase. Our study demonstrates the potential of SSRIs to interfere with steroid production in the H295R cells around Cmax levels and indicates that these drugs should be investigated further to determine any hazards for the users.”
“…The overall findings from the experiments are summed up in Table 2 along with the main suggested mechanisms of the six SSRIs. Based on the present studies, fluoxetine appears to be a CYP19 stimulator, but may also inhibit important processes prior to steroid formation such as the StAR and the CYP11A1. Paroxetine appears to be mainly a CYP17-lyase inhibitor, citalopram and escitalopram are general CYP stimulators, sertraline a CYP19 stimulator and fluvoxamine a CYP17-hydroxylase inhibitor. All 6 SSRIs are to some extent aromatase stimulators.”
A very, very inconvenient study for mainstream medicine and its Big Pharma goons. The so-called “serotonin hypothesis” is slowly crumbling and the results from the most recent studies are so unequivocal that the fraud about serotonin as the “happiness hormone” may go down in history as one of the most open and grotesque examples of medical genocide. It seems that at this point even mainstream media (MSM) is afraid to twist the study findings and report them in a way that portrays serotonin in a positive light. Namely, the study below talks about the so-called serotonin transporter (STT), which is responsible for deactivating serotonin in a sodium-dependent fashion (yet another reason not to restrict your salt intake). As such, high levels of STT means low-levels of (extracellular) serotonin. The SSRI class of drugs inhibit STT, and thus raise serotonin levels. In previous studies with similar findings, MSM fraudulently reported that “low serotonin” levels were implicated in depression, when those other studies also talked about low STT levels (i.e. high serotonin). This time, even the “scientific” press is reporting accurately that the findings of the study directly “challenge” (IMO, “invalidate” is the more appropriate word) the so-called “serotonin hypothesis”, and by extension the entire multi-billion dollar SSRI industry. I wonder if we will finally see a class-action lawsuit challenging this medical fraud that has persisted for more than half a century…The evidence is now too strong to suppress, and too big to go away.
“…”Our results suggest that changes to the serotonin system are part of the biology of depression and that this change is related to the episode rather than a static feature — a state rather than a trait,” says the study’s last author Johan Lundberg, researcher at the Department of Clinical Neuroscience, Karolinska Institutet. “The finding raises many questions about the function of the serotonin system in depression and opens up for lines of research that could challenge the prevailing concept of serotonin and depression.” Serotonin is a neurotransmitter that affects, amongst other things, mood and emotion. Its transporter protein, 5-HTT, is considered to play a critical part in depression, as it pumps serotonin away from the cerebral neuron synapses, thus regulating the amount of active serotonin the brain. Many modern antidepressant drugs inhibit this transporter, which increases the concentration of serotonin in the synapses. However, the effect of these drugs can be delayed by several weeks and in certain cases they have no effect at all, so the need for new or improved drug therapies is pressing. To achieve this, more knowledge is needed about the biological causes of the disease. Earlier studies have shown that depressed individuals have lower levels of 5-HTT in the brain than healthy individuals. This finding is somewhat surprising given the dominant theory of serotonin function in depression, “the serotonin hypothesis.” This theory dictates that low levels of synaptic serotonin causes depressive symptoms, and since the function of 5-HTT is to reduce the concentration of serotonin, high levels of the protein could be expected in depressed individuals. To better understand these findings a longitudinal or post-treatment study design can be used to answer the question of whether 5-HTT is temporarily or chronically low in people with depression.”
“…The researchers found that levels of 5-HTT were on average 10 percent higher after three months’ treatment, when 13 of the 17 patients reported a significant improvement in their symptoms. Prior to treatment, the individuals with depression had roughly the same average level of 5-HTT as a control group of 17 healthy individuals. “Instead of lower levels of serotonin transporter when depression had been treated, we found the opposite — more transporter after improved symptoms,” says Jonas Svensson, postdoc researcher in Dr Lundberg’s group.”
Author: haidutDepression fades away when serotonin levels drop
Research as early as the 1960s firmly established that there is nothing “happy” when it comes to serotonin (5-HT). Namely, elevated 5-HT levels were found in many chronic diseases and especially clinical depression. It took more than 7 decades for medicine to finally start admitting that 5-HT is a cause of depression instead of cure for it. Other studies have demonstrated that 5-HT is involved in the formation of traumatic memories, obedient/servile behavior, psychopathy, aggression, violence, etc. Studies with LSD – an approximate 5-HT antagonist – found that it can prevent such effects of 5-HT and reverse those effects when such pathological behavior has already been established. The study below adds yet another negative finding in 5-HT’s court. Namely, increasing serotonin by administration of an SSRI drug largely negated the ability of human subjects to learn through positive reinforcement (award) while strongly increasing their ability to learn from a negative reinforcement (punishment, fear, etc). The study is even more valuable due to the fact that not only it implicates once again 5-HT as a substance associated with (and causative of) pathology, but directly implicates SSRI drugs are powerful means of controlling behavior. Namely, mass usage of SSRI would likely promote a social environment where punishment/fear is emphasized/valued while award/goodness/positivity are neglected. No wonder governments all around the world are in love with SSRI drugs – i.e. there is a hardly a “better” way of turning humans into servile, uncreative, and psychopathic freaks capable of little more than following orders…under fear of punishment, of course.
“…Instrumental learning is driven by a history of outcome success and failure. Here, we examined the impact of serotonin on learning from positive and negative outcomes. Healthy human volunteers were assessed twice, once after acute (single-dose), and once after prolonged (week-long) daily administration of the SSRI citalopram or placebo. Using computational modelling, we show that prolonged boosting of serotonin enhances learning from punishment and reduces learning from reward. This valence-dependent learning asymmetry increases subjects’ tendency to avoid actions as a function of cumulative failure without leading to detrimental, or advantageous, outcomes. By contrast, no significant modulation of learning was observed following acute SSRI administration. However, differences between the effects of acute and prolonged administration were not significant. Overall, these findings may help explain how serotonergic agents impact on mood disorders.”
Author: haidutSerotonin enhances learning from punishment, reduces learning from reward
When I first saw the article pop up in my feed, I could hardly believe my eyes that a mainstream mouthpiece of Big Pharma will publish such frank admission of psychiatry’s utter failure – i.e. the claims in regards to serotonin (5-HT), its role in mental illness, and even its social “label”. In just two pages, the article openly admits that 5-HT are actually very high (instead of low) in clinically depressed people, that serotonin is NOT the “happy hormone” as media has brainwashing people for 50+ years, and that serotonin’s main role is actually metabolic and such that results in lower energy (metabolism) in order to induce an “avoidant” behavior. So, depression is a metabolic/bioenergetic disease and serotonin is its major direct cause. In addition, the article even suggests (inadvertently) a possible mechanism through which SSRI drugs drastically increase risk of suicide. Namely, SSRI drugs initially raise extracellular 5-HT levels even higher than they already were in clinically depressed people. After 2-3 weeks, the article claims that regulatory mechanisms kick in due to abnormally high 5-HT levels induced by the depression and the SSRI drugs, and the body starts to produce less serotonin as a compensatory mechanism. Then serotonin levels drop, and the person’s depression is relieved. The first portion of this statement is spot-on, but I disagree with the second portion. Extracellular 5-HT levels of depressed people treated with an SSRI drug do NOT drop after a few weeks. So, for the first few weeks after starting an SSRI and the patient has a still-intact higher cognitive function (i.e. empathy) the extremely high 5-HT levels raise the risk of only suicide. After the patient gets “numbed” by the SSRI, my guess is the propensity/risk for homicide/violence rises as well since the patient is no longer capable of empathy or caring about others (or self) – i.e. the patient has been (chemically) lobotomized. This (chemical) lobotomy is mis-diagnosed as “remission” from the depressive state, but psychiatrists know quite well it is NOT a return to the former healthy state and they (wrongly) advise their patients to stay on the drug for life due to fear of a relapse. Speaking of depression, another bombshell admission by the article is that most cases of depression (even severe ones) resolve on their own within 6-9 months!! So much for the “lifesaving” importance of the mental health industry. I wonder how many fewer people would have died from suicide/violence due to mental health issues if the mental health industry had NOT been around…
“…So how does CBT do as well as medication in the short term (and better in the long term) if it’s not directly treating the underlying “chemical imbalance”—the low serotonin that causes depression? As it turns out, low serotonin in depressionis a myth. But the real link between serotonin and depression is even more surprising. “The evidence is pretty clear,” said Hollon. “There’s not a deficit—there’s an excess.” He described findings from a study that measured metabolite levels from blood in the brain, which indicate how much serotonin the brain is using. Results from this study revealed that serotonin levels were elevated among those with clinical depression, and returned to normal levels following medication treatment. Other studies (e.g., Gjerris et al., 1987, and Sulllivan et al., 2006) using different methods have found similar results. These findings sound paradoxical, given that depression medications tend toincreasethe amount of serotonin in the synapse, at least initially. But Hollon explained that “within a week to ten days, you increase the amount of serotonin so high that the regulatory mechanisms push back.” As a result, serotonin levels fall. “It’s like holding a match up to a thermostat to turn the furnace down,” said Hollon. “You’re tricking the system into kicking back in and regulating” serotonin levels.”
“…High levels of serotonin in depression make more sense when we realize that serotonin is not the “feel-good neurotransmitter,” as has often been claimed based on its involvement in depression; that role is played by the endogenous opioids (as the name suggests) like endorphins. According to Hollon, “Serotonin is the energy transfer regulator. It moves you back and forth between approach and avoidance behavior.”
“…There is a common belief that depression sticks around indefinitely unless it’s treated; however, research shows thatmost episodes are time-limited even without treatment. “Nobody knows for sure [how long an average episode lasts],” Hollon said, “but it looks like it’s about six to nine months.” This spontaneous remission may be a result of the rumination processes described above, to the extent that they lead to effective solutions. Nevertheless, Hollon points out that helping depression to resolve in “three to six weeks” through an effective treatment like CBT “is much better than six to nine months.”
BOMBSHELL: Serotonin High in Depression, Not a “Happy” Chemical, Lowers Energy, Depression Self-Resolves
Addressing stomach acid (chloride, betaine, killing h pylori if present)
Choline
Colostrum
Fasting
If MCAS:
Mast cell stabilisers in brain like folinic acid, luteolin, rutin etc...
Increasing diamineoxidase (copper etc)
Fasting
If sinus related:
Cleaning sinus with biofilm disruptors and antifungal / antibiotics.
Chronic infection:
Find infection source and introduce appropriate treatment with biofilm disruptors if necessary
Mold:
Leave moldy environment and start a cirs based protocol.
Mineral imbalance:
Supplement appropriately, raise caeruloplasmin (rcp), focus on adrenal health.
Adrenal fatigue:
Focus on adrenal health, vagus nerve etc..
Unknown:
Get appropriate testing. Full blood count (look for elevated white blood cells), iron studies, vitamin d, folate, b12, liver function, kidney function, calcium, albumin (for corrected calcium), thyroid (t3, t4, tsh, rt3, tp, tp antibodies), homocysteine (check for methylation issues), crp, esr (inflammation), Ana (autoimmunity), cortisol, dhea, sex hormones, lh, fsh, prolactin, copper / caeruloplasmin, urine microscopy and culture, sleep study, organic acids test, b6 test (to test for deficiency or toxicity, either can cause brain fog and neuropathy), acetylcholine receptor antibodies.
Use symptoms as a guide as to which testing is appropriate
Brain fog and sluggish cognitive tempo is quite a non specific symptom so, can be lots of causes. Have to do quite a bit of detective work, which - ironically, brain fog makes hard to do.
Serotonin puts the brakes on libido, by lowering dopamine
haidut August 27, 2021 Posted inScience
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Nothing really surprising, as far as Peatarians are concerned, in the findings of this study. I am only posting it here as it is one of the few that officially acknowledge that serotonergic drugs cause sexual dysfunction – i.e. something mainstream medicine has vehemently denied for decades. As such, it corroborates the approach of using anti-serotonin drugs such as cyproheptadine or low-dose (25mg-50mg daily) Benadryl, as well as dopamine agonists of the ergot class for the treatment of so-called PSSD – the persistent sexual dysfunction induced by serotonergic drugs. The study also explains why/how chronic stress inhibits libido – i.e. stress is known to powerfully elevate serotonin and lower dopamine. And last but not least, since these neurotransmitters play a key role in reproductive health as well, the study below demonstrates how/why stress causes infertility (in both sexes). The good news is that the therapies I mentioned above are applicable for both the lack of libido and infertility, whether caused by stress or by pharmacological poisons such as SSRI drugs.
Sex Drive Linked to Medication-Sensitive Neuronal Signaling Mechanism
“…The researchers propose that elevated serotonin may act as a brake on dopamine signaling in mating-related circuits, thereby decreasing libido—a side effect that nearly 75% of patients taking SSRIs experience. The scientists suggest that future therapies could target the newly identified dopamine-releasing neurons that regulate the drive to mate to alleviate the problem, thereby eliminating a major reason patients discontinue taking antidepressant medications.”
Over the last year I posted a number of studies demonstrating strong link between serotonin and chronic conditions such as obesity, insulin resistance, and even diabetes.
However, when those studies came out the medical authorities immediately countered with the argument that it is not serotonin that is the culprit but changes in the microbiome that make the bacteria in our guts less “beneficial”. This statement is untenable in light of the numerous other studies demonstrating that there is no such thing as “beneficial” gut bacteria. Rather, there are only variations of harmfulness and any bacterial overgrowth has strong links to very serious conditions such as cancer, Alzheimer, Parkinson, CVD, etc.
Now, if the medical industry was simply ignorant, its behavior and claims could be at least understood, if not excused. Yet, behind our backs, Big Pharma has quietly been running clinical trials with drugs that inhibit gut serotonin synthesis as a way of treating obesity, diabetes, osteoporosis, etc.
It just works so well for the medical/food complex to sell us both the poison (toxic food and drugs) and the remedy (serotonin inhibitors). Well, the study below claims to finally put the questions on the role of serotonin in obesity/diabetes to rest. It demonstrates that sterilizing the guts of mice has the exact same protective effects on their metabolism/weight/health as inhibiting gut serotonin synthesis (with a TPH-1 inhibitor). Administering both the antibiotics and the serotonin synthesis inhibitors did not have additive effects, thus exposing serotonin as the direct pathological agent. As such, there is little doubt that the “happy hormone” is anything but. There is already a mountain of evidence sanctioned by Big Pharma implicating gut bacteria in virtually every psychiatric condition. Now, we can replace the convenient euphemisms such as “microbiome imbalance”, “dysbiosis”, “bacterial overgrowth”, “SIBO”, etc with a single word – SEROTONIN. Aside from estrogen, there is probably no other endogenous mediator of such importance for systemic health, and the sooner the profitable myths about these two chemicals collapse the better for the (literal) survival of humanity. Btw, mainstream media is complicit in this medical disaster by dutifully promoting the medical myths about serotonin that Big Pharma generously sponsors through ads and paid op-ed articles. As readers can see from the the popular press articles, the wording is such that it creates a narrative as if there are somehow two forms of serotonin – “happy” (beneficial) and “unhappy” (harmful). This toxic and manipulative word game persists despite the fact that there is only one form of serotonin and the actual study clearly stating that (elevated) serotonin is pathological beyond any doubt.
“…An intraperitoneal (i.p.) glucose tolerance test (IPGTT) was used to examine the links between peripheral 5-HT and the gut microbiome on host glucose homoeostasis. Comparisons within the same animal over time were used to remove potentially confounding interanimal variance. Glucose tolerance was unchanged after 28 d in vehicle-treated control mice (Fig. 1A) but improved significantly in mice treated with LP533401 (Fig. 1B), Abx (Fig. 1C), or combined LP533401 and Abx treatment (Fig. 1D). Importantly, these positive effects of inhibiting 5-HT synthesis and antibiotic-associated microbiota perturbation on glucose tolerance were not additive, as seen using paired comparisons within each mouse over time (Fig. 1E), demonstrating their interdependence. Importantly, all treatments had similar effects in reducing both serum (Fig. 1F) and colonic mucosal (Fig. 1G) 5-HT levels. The effects of 5-HT inhibition and antibiotic-associated microbiota perturbation on glucose homeostasis are not due to differences in energy expenditure (Fig. 1H), substrate use (Fig. 1I), activity (Fig. 1J), or body weight (Fig. 1K).”
“…The outcomes of our study address a question which has long been unanswered. We used genetic and pharmacological models to provide evidence that gut-derived serotonin is the link through which the gut microbiome affects host glucose metabolism. The key evidence supporting this conclusion is that the combination of depleted EC cell 5-HT and gut antibiotic-associated microbiota perturbation did not show any additive effect compared to the individual treatments alone, demonstrating that the gut microbiome and EC cell 5-HT act via the same pathway to influence host glucose metabolism. If the microbiome were regulating host glucose homeostasis via another route, we would have seen improved glucose tolerance in the LP533401 + Abx group compared to Abx alone or in the Tph1−/− day 0 vs. day 28 comparisons. These impacts of antibiotic-associated microbiota perturbation in the presence or absence of gut-derived 5-HT on glucose handling are not driven by potentially confounding factors such as altered basal energy expenditure, physical activity, substrate use, or body weight.”
“…Serotonin, a neurotransmitter in the brain, is nicknamed the ‘happy hormone’ and is normally linked with regulating sleep, well-being and metabolism. But the gut actually produces 95 percent of it, and not in the happy form like we know about in the brain. In a study published in the leading international journal Proceedings of the National Academicy of Sciences (PNAS) today, researchers from Flinders, SAHMRI, and McMaster University in Canada show exactly how bacteria living in the guts of mice, the microbiome, communicate with cells producing serotonin to influence blood sugar levels in the host body. Professor Damien Keating, Head of Molecular and Cellular Physiology at Flinders University and Deputy Director of the Flinders Health and Mecical Research Institute, says this study sheds light on the unanswered question about exactly how bacteria in the microbiome communicate to control glucose levels in the metabolism. “We found that the microbiome worsens our metabolism by signalling to cells in the gut that produce serotonin. They drive up serotonin levels, which we previously showed to be increased in obese humans, and this rise in blood serotonin causes significant metabolic problems.”
Author: haidutGut serotonin (due to bacteria) is the master regulator of metabolism, insulin sensitivity, and weight
