Sorry! We Meant To Say Lower Serotonin.

TheDopamines The simplistic idea that mood disorders like depression or anxiety result from insufficient serotonin in the brain, has never been properly demonstrated, and contradicts basic physiology.

Regardless, extremely profitable drugs – like SSRI’s (Selective Serotonin Reuptake Inhibitors) and other ‘anti-depressants’ – are generally prescribed with the intention of increasing levels of serotonin, and are still a first line of defense for many doctors and psychiatrists.

“Our…claim…is that the direct pharmacological effects of SSRIs are not responsible for symptom reduction…SSRIs cause…a worsening of symptoms…symptom reduction is due to…the brain’s homeostatic mechanisms that attempt to restore energy homeostasis…which explains why symptoms fail to alleviate for several weeks after the initiation of SSRI treatment…”

“The time differential between the onset of 5HT [serotonin] reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression.”

There is, however, a large body of scientifically demonstrated biological evidence, which points to the conclusion that rising serotonin is a central factor involved in the processes promoting learned helplessness-like symptoms, such as anxiety and depression.

When you see that depression is one of the possible side-effects of excessive stress, and if you examine the many situations where biological stress causes an increase in serotonin (as well as other related defensive stress substance), the upside down nature of the ‘official’ view of serotonin starts to become more obvious.

“While the literature on depressed patients is necessarily limited due to the methodological difficulties measuring serotonin…in the human brain, the most pertinent studies support the high serotonin hypothesis…that serotonin transmission is elevated in…depression.”

“We demonstrate invariably increased serotonin synthesis and transporter availability in patients with SAD [social anxiety disorder] relative to healthy controls, which supports an overactive presynaptic serotonin system.”

Anxiety and depression often go hand in hand, and evidence suggests that lowering serotonin (in the body and brain) promotes improvements in biological function, increasing protection against many inflammatory degenerative issues. Understanding how this works can lead to more effective treatment of mood disorders in general.

“Individuals with social phobia make too much serotonin. The more serotonin they produce, the more anxious they are in social situations…patients with social phobia produced too much serotonin in a part of the brain’s fear centre, the amygdala.”

It is important to know that most serotonin found in the body is produced in the intestines. A sub-optimal digestive system (from stress or metabolic suppression) often results in an overproduction of bacteria – and exposure to toxic byproducts like endotoxin – shown to be connected to rising serotonin, and other inflammatory substances (including estrogen, nitric oxide and histamine).

“More than 90% of the body’s 5-HT is synthesized in the gut…gut microbiota plays a key role in promoting levels of colon and blood 5-HT…Interestingly, the indigenous microbiota also modulates hippocampal levels of 5-HT……revealing a role for the microbiota in regulating the brain serotonergic system.”

These stress related substances which increase alongside serotonin – and can be promoted by excess bacteria – play an important role in the promotion of systemic inflammatory issues. This helps to explain the link between digestive distress and mood dysregulation.

Stress often has an immediately noticeable effect upon intestinal function, and when this is ongoing it leads to significant changes in overall biological performance. The more you understand how it works, the more logical it is.

“Regarding depression-related onset of diseases of the digestive system…experimental and clinical studies have demonstrated that acute and chronic stress have impacts on the gastrointestinal system, being permissive in the development of gut diseases.”

When stress goes up – and when the provision and availability of sugar is interfered with – cortisol and adrenalin rise, and greater amounts of free fatty acids are released out of storage for fuel. When fat entering circulation is polyunsaturated, it can result in chronic interference with energy metabolism and thyroid function.

The inflammatory breakdown products of the polyunsaturated fats (PUFAs) have been directly associated with depression, and it is no coincidence that serotonin and the byproducts of PUFA breakdown, have a powerful synergistic relationship.

“The highest rise was observed in linoleic acid, which is known to be a potent liberator of platelet serotonin in vitro and is the only precursor of all prostaglandins in the body.”

“…we assessed the effect of 4-hydroxy-2-nonenal (HNE), a component of oxidatively modified lipids…and its interaction with serotonin (5-hydroxytryptamine, 5-HT)…Our results suggest that HNE acts synergistically with 5-HT…”

PUFA interferes with steroid hormone production in general, promoting the substances which often rise during extended periods of stress (including estrogen), and which in and of themselves have been shown to be involved in the progression of depression and other mood issues. Serotonin is one of these stress substances, however the substances of stress in general fuel each other.

“The potency of the unsaturated fatty acids paralleled to some degree the number of cis double bonds and carbon…The arachidonate inhibition was dose-dependent in the tissue steroid hormone receptors, except for dose-dependent potentiation of the brain cortical estrogen receptors.”

“When patients with depression were compared with healthy controls, depression was associated with higher oxidative stress MDA levels [malondialdehyde – resulting from lipid peroxidation of polyunsaturated fats]…suggest[ing] that oxidative stress plays a role in depression and that antidepressant activity may be mediated via improving oxidative stress/antioxidant function.”

“…we evaluated the association between…a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older adults…A growing body of small clinical studies reported an association between oxidative damage markers and depression…Our study adds to this growing literature by showing evidence for this association in a large sample of older persons from the general population.”

The substances of stress in general promote mood dysregulation, and high cortisol (which is linked to high serotonin) is central to a number of mood disorders, in a likely causative manner.

Nature didn’t create a system that works in ways that make perfect sense across the board – protecting against harm and promoting improved results – in order for things to work in a completely paradoxical manner in a couple of circumstances for the sake of some external agenda.

High serotonin isn’t going to be harmful in every biological circumstance, except for depression. That’s just science-fiction. Low serotonin can’t be a sign of health everywhere, except the brain. That’s just really bad science-fiction.

“…depression has been associated with disturbances in the hypothalamic–pituitary–adrenal axis (HPA) in humans…depressed patients have enhanced levels of adrenal hormones and corticotropin-releasing factor (CRF) in the blood…it is clear that serotonin and adrenal hormones may contribute to the symptoms of depression.”

“There is now a growing consensus that serotonin acts at multiple sites to contribute to stress-induced HPA axis activation…Depression has long been linked to dysregulated HPA axis function, and depressed men exhibit higher levels of salivary cortisol across the day compared to healthy men…”

Although it is still a commonplace argument that SSRI’s – and other ‘serotonin increasing antidepressants’ – improve mood regulation by boosting serotonin levels in the brain, there is rising evidence showing that the positive effects which do sometimes coincide with their use, do not occur as a result of high serotonin.

“…we propose that the brain is attempting to restore energy homeostasis rather than serotonin homeostasis…the upward trajectory in serotonin during initial ADM [antidepressant medication] treatment is often associated with a worsening of symptoms…the downward trajectory…with symptom reduction.”

“…the effects of…inactivation of the 5-HTT [serotonin transporter or SERT] on anxiety-like behavior in mice are robust and provide an independent line of evidence supporting a link between the low-expressing 5-HTT…with anxiety in humans.”

When stress is high and resources are limited, one way of understanding the role of serotonin (in relation to depression) would be to see it as part of an attempt by the body to survive on less, shutting down whatever it can get away with. Although from an evolutionary perspective this can be helpful, there are potentially serious metabolic consequences if this continues for too long.

Many people now understand depression to be one of the results of a hypo-metabolic state, and the relationship between serotonin, the polyunsaturated fats and animal hibernation (in many ways similar to human depression) is not random.

Sub-optimal body temperature is a symptom of a hypo-metabolic state, and the factors which interfere with thyroid and energy metabolism – including rising levels of endotoxin, serotonin, nitric oxide, cortisol and estrogen – can all suppress thyroid function, and have all been implicated in the pathophysiology of mood dysregulation.

“T3 deficiency is responsible for the clinical and biochemical manifestations of hypothyroidism…The decrease in energy metabolism and heat production is reflected in the low basal metabolic rate, decreased appetite, cold intolerance, and slightly low basal body temperature.”

Just raising body temperature can alone be enough to treat depression. Many of the things which help to lower the substances of stress and improve indicators of proper thyroid metabolism (pulse and temperature changes are a good measure) – like sufficient intake of sugar and animal protein – can be used to improve symptoms of anxiety and depression.

“Participants…received heating…until their core body temperature reached 38.5°C…the current study found that WBH [whole-body hyperthermia] was associated with a substantial reduction in depressive symptoms…WBH holds promise as a safe, rapid-acting, antidepressant modality with a prolonged therapeutic benefit.”

Serotonin exposure has been shown to go up as a result of a hypometabolic, hypothyroid stress state. A suppressed metabolism promotes the release of polyunsaturated free fatty acids. Because PUFAs are known to suppress digestion and interfere with liver function, they have the effect of further encouraging bacterial overgrowth, increasing exposure to the damaging effects of endotoxin and serotonin. All of these factors then promote the circulation through the system of serotonin and estrogen, dramatically increasing levels of stress and the potential to suffer from mood dysregulation.

“Ovarian hormones have also been shown to affect numerous factors regulating serotonin synthesis and serotonin levels…ovarian hormones promote…tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin, and reduce serotonin reuptake transporter…expression…numerous serotonergic receptor subtypes are reportedly regulated by ovarian steroids, as well as implicated in depression…”

“…estrogen may increase the capacity for serotonin synthesis…and…contribute to distinct components of anxiety behavior.”

Stress and thyroid suppression causes cortisol to go up. As cortisol levels continue to rise, more muscle tissue is broken down causing an increase in the release of the inflammatory amino acids, in particular tryptophan. Tryptophan is the precursor to serotonin.

Rising levels of stress and the associated interaction between greater amounts of tryptophan and PUFA throughout the system, can set in motion a self-fueling inflammatory hypo-metabolic stress state, encouraging increasingly harmful levels of serotonin in the body and the brain. Preventing stress induced muscle tissue breakdown can significantly decrease tryptophan levels, limiting serotonin production.

“The rate of serotonin synthesis was reduced by ATD [acute tryptophan depletion] by a factor of about 9.5 in males and of about 40 in females.”

“The administration of amino acid…mixtures that are selectively deficient…in tryptophan…can decrease serotonin…synthesis…Neuroimaging, cerebrospinal fluid, microdialysis and postmortem tissue punch studies indicate that this magnitude of decline decreases brain 5-HT”

Estrogen, serotonin and endotoxin (as well as other inflammatory substances released in the body under stress), interact powerfully with the polyunsaturated fats, suppressing thyroid energy metabolism and worsening many of the symptoms of depression and anxiety.

Bacterial overgrowth and suppression of metabolic function promote nitric oxide (NO) which further interferes with energy metabolism and has been closely associated with mood issues. Reducing bacterial issues reduces exposure to NO and promotes thyroid function, protecting against anxiety and depression. Serotonin can cause NO to increase and vice versa.

“…during stress exposure, pharmacological inhibition of nitric oxide production displays reduction in indicators of anxiety- and depressive-like behavior in animal models.”

“…studies have also noted that glutamate and nitric oxide (NO) play a causal role in anxiety-related behaviors….nitrergic pathways may have an important role in stress-related hippocampal degenerative pathology and cognitive deficits seen in patients with PTSD.”

Rising levels of estrogen, serotonin and nitric oxide have also been shown to be important factors in the progression of many kinds of degeneration and disease, including cancer. This makes sense, and this is all just as relevant to any discussion with regards to the impact of ongoing exposure to a hypometabolic/hypothyroid state of stress.

“…this report makes…a parallel between induced tumorigenicity by expression of the 5-HT2B receptor in nontransformed fibroblasts and its expression by spontaneous tumors…”

“…hypothyroidism increases cadiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties…Up-regulation of cadiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism…”

The high stress inflammatory condition – where thyroid is under active and tryptophan and cortisol are rising – encourages an increase in serotonin throughout the body and in the brain. Based on this alone, it would be illogical to suggest that mood dysregulation could be the result of some kind of serotonin lack. It is far more logical to conclude that the mainstream understanding of serotonin is not accurate.

A diet removing the polyunsaturated fats and limiting intake of difficult to digest starches and fibers, whilst providing sufficient protein from milk, cheese and gelatin, and plenty of sugar from sweet ripe juicy fruits, fruit juice, honey and white sugar, is one way to help limit serotonin and protect against depression and anxiety.

Maintaining blood sugar stability can help by reducing stress and limiting the release of polyunsaturated free fatty acids into the blood. This protects against interference with energy metabolism, and can go a long way towards improving mood stability.

Regular snacks throughout the day – made up of a combination of the above sources of protein and carbohydrate in varying ratios depending on individual metabolic needs – can help to achieve this.

Although the relationship between mood and serotonin is not black and white, protection from the disorders of the mind can, at least to some extent, come from improvements in the functioning of overall thyroid systems and metabolism as well as an increase in the provision of energy, enhanced by – and resulting in – a lowering of serotonin.

Some things which can help to lower serotonin or nitric oxide, and generally lower stress and improve overall metabolic performance (and which have been successful in the treatment of mood related issues) include cyproheptadine, methylene blue, thyroid hormone, pregnenolone, progesterone, aspirin, glycine, theanine, caffeine and coffee, salt and sugar, niacinamide and others.

What do most doctors understand about the biological role of serotonin in relation to depression, and how would a change in perspective influence the treatment approaches recommended by them?

See More Here

Serotonin Synthesis and Reuptake in Social Anxiety Disorder

Individuals with social phobia have too much serotonin – not too little

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala

Hypothyroidism – new aspects of an old disease

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

Cyproheptadine for prevention of neuropsychiatric adverse effects of efavirenz: a randomized clinical trial.

Lipid Peroxidation and Depressed Mood in Community-Dwelling Older Men and Women

Effects of the 5HT antagonist cyproheptadine on neuropsychological function in chronic schizophrenia.

Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis

Synthesis of serotonin in traumatized rat brain.

Differences between males and females in rates of serotonin synthesis in human brain

Lipid peroxidation product 4-hydroxy-2-nonenal acts synergistically with serotonin in inducing vascular smooth muscle cell proliferation.

Aspirin inhibits Chlamydia pneumoniae-induced NF-kappa B activation, cyclo-oxygenase-2 expression and prostaglandin E2 synthesis and attenuates chlamydial growth.

Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain

Glutamate, GABA, glycine and taurine modulate serotonin synthesis and release in rostral and caudal rhombencephalic raphe cells in primary cultures.

Brain hypometabolism of glucose in anorexia nervosa: A PET scan study

A new method for rapidly and simultaneously decreasing serotonin and catecholamine synthesis in humans

miR-1202: A Primate Specific and Brain Enriched miRNA Involved in Major Depression and Antidepressant Treatment

Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

Estrogen-mediated effects on depression and memory formation in females

Cortisol responses to emotional stress in men: Association with a functional polymorphism in the 5HTR2C Gene

Oxidative Stress and Antioxidant Parameters in Patients With Major Depressive Disorder Compared to Healthy Controls Before and After Antidepressant Treatment: Results From a Meta-Analysis

Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms

Role of individual free fatty acids in migraine.

[Effects of theanine on monoamine neurotransmitters and related genes in cerebral ischemia-reperfusion injury rats].

Chronic Caffeine Alters the Density of Adenosine, Adrenergic, Cholinergic, GABA, and Serotonin Receptors and Calcium Channels in Mouse Brain

Social Behavioral Deficits Coincide with the Onset of Seizure Susceptibility in Mice Lacking Serotonin Receptor 2c

Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety.

An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents

Hyperthermia for Major Depressive Disorder?

Thyroid hormone control of serotonin in developing rat brain.

Ras Involvement in Signal Transduction by the Serotonin 5-HT2B Receptor

Chronology of Onset of Mental Disorders and Physical Diseases in Mental-Physical Comorbidity – A National Representative Survey of Adolescents

Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder

Genetics of emotional regulation: the role of the serotonin transporter in neural function.

Nitric oxide as inflammatory mediator in post-traumatic stress disorder (PTSD): evidence from an animal model

Treatment of Depression With Cyproheptadine

The role of dopamine in methylene blue-mediated inhibition of estradiol benzoate-induced anterior pituitary hyperplasia in rats.

Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism.

Role of Nitric Oxide in Stress-Induced Anxiety: From Pathophysiology to Therapeutic Target.

Reducing peripheral serotonin turns up the heat in brown fat

Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field.

Aspirin attenuates pulmonary arterial hypertension in rats by reducing plasma 5-hydroxytryptamine levels.

A controlled trial of methylene blue in severe depressive illness.

Effects of neurosteroids on the human corticotropin-releasing hormone gene.

Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects.

Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study.

5-Hydroxytryptamine is biotransformed by CYP2C9, 2C19 and 2B6 to hydroxylamine, which is converted into nitric oxide

Peripheral Serotonin: a New Player in Systemic Energy Homeostasis

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

The nitric oxide hypothesis of aging.

Low cholesterol is associated with depression among US household population.

Inhibition of iNOS induces antidepressant-like effects in mice: pharmacological and genetic evidence.

Caffeine prevents LPS-induced inflammatory responses in RAW264.7 cells and zebrafish.

Nitric oxide increases dopamine and serotonin release in the medial preoptic area.

Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

Inhibition of iNOS alleviates cognitive deficits and depression in diabetic mice through downregulating the NO/sGC/cGMP/PKG signal pathway.

Arachidonic acid as a possible modulator of estrogen, progestin, androgen, and glucocorticoid receptors in the central and peripheral tissues.

Beneficial effect of aspirin against interferon-α-2b-induced depressive behavior in Sprague Dawley rats.

Serotonin in peripheral blood reflects oxidative stress and plays a crucial role in atherosclerosis: Novel insights toward holistic anti-atherothrombotic strategy.

Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists.


Artist: walmazan: “Serotonin & the Dopamines”

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