Coffee Cheer

coffeefeels Many ‘antidepressant’ drugs on the market today, are prescribed with the intention of increasing levels of active serotonin – the so called ‘happiness hormone’ – circulating in the brain. Unfortunately (and not for biologically inexplicable reasons) they have been associated with increased suicide rates among users. Coffee is protective.

“The FDA admitted in 2007 that SSRIs [selective serotonin reuptake inhibitors] can cause madness at all ages and that the drugs are very dangerous…All patients being treated with antidepressants…should be…observed closely for clinical worsening, suicidality, and unusual changes in behavior…The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported…”

Coffee seems to act in what could reasonably be described as the opposite direction – improving metabolic function and lowering exposure to serotonin – hence it is probably not a coincidence that regular coffee drinkers are known to have a low incidence of suicide.

“…suicide risk…decreased in a dose-dependent manner with increasing consumption of coffee. As compared with non-coffee drinkers…suicide was 45% lower among individuals who consumed 2–3 cups of coffee per day, and 53% lower among individual consuming ≥4 cups of coffee per day.”

“We conducted a 10-year follow-up study (1980 to 1990) in an ongoing cohort of 86 626 US female registered nurses aged 34 to 59 years…A strong inverse relationship was similarly found for caffeine intake from all sources and risk of suicide…The data suggest a strong inverse association between coffee intake and risk of suicide…”

“…repeated caffeine administration producing adaptive changes in the serotonergic neurons to decrease the conversion of tryptophan to 5-HT…”

“Restraint stress…caused a marked increase in dopamine and serotonin (5-HT) levels in the hippocampus…Pretreatment with 33 mg/kg coffee or 1.7 mg/kg caffeine reduced…restraint-induced increase in the neurotransmitters, especially 5-HT…”

Serotonin is closely tied to the regulation of emotion, and excess serotonin has been demonstrated to interfere with thyroid function, reducing metabolic rate, impeding brain function, thereby potentially promoting symptoms of anxiety and depression, including learned helplessness and despair.

Much like the physiological state of hibernation – which occurs in the presence of rising levels of serotonin (as well as suppressed body temperature and brain function) – many of the features of depression go hand in hand with an under performing thyroid energy metabolism.

“Patients affected by subclinical hypothyroidism had a prevalence of depressive symptoms of 63.4%…This study underlines a strong association between subclinical hypothyroidism and depressive symptoms, which could have some important diagnostic and therapeutic implications in the clinical practice.”

In both of these stressful scenarios (i.e. hibernation and depression) there is a shift towards the use of fat as fuel for the cells (away from the metabolism of glucose), similar in many ways to the physiological conditions which lead to blood sugar dysregulation, insulin resistance and diabetes.

In fact, plenty of good evidence exists which shows a relationship between emotional stress, anxiety and diabetes, and there is no shortage of biologically rational explanations for why this makes sense.

“Chronically high anxious arousal and inflammation increase one’s risk of developing type 2 diabetes…Individuals with low inhibition were more likely to have diabetes than those with high inhibition due to the serial pathway from high anxious arousal to IL-6…”

One good rationale is that stress and low blood sugar interfere with thyroid function and energy metabolism, promoting the release of many inflammatory stress substances (such as cortisol, serotonin, nitric oxide and estrogen) implicated in the progression of degenerative conditions including depression and diabetes.

This kind of metabolically suppressed state is more likely to become a persistent or chronic issue, as fat stores become increasingly polyunsaturated. This is due in large part to the many inflammatory, immunosuppressive and thyroid interfering features of the polyunsaturated fats (PUFAs), which are released as free fatty acids into the bloodstream, in larger amounts under conditions of stress.

As well as having powerful anti-thyroid and inflammatory effects, the breakdown products of the PUFAs can increase the harm potential of cortisol, serotonin, nitric oxide and estrogen, encouraging greater interference with metabolic energy production, worsening issues related to proper blood sugar regulation.

Depression and anxiety have been shown to be the result of a hypometabolic state, exacerbated by oxidative stress (resulting from the breakdown products of PUFAs), and directly associated with symptoms of blood sugar dysregulation and diabetes.

Inflammation has been shown to be a factor involved in the progression of mood dysregulation and suicidal thinking and behavior, and caffeine protects against inflammation and oxidative stress.

“…there is a growing body of evidence that inflammation, as manifested by increased levels of pro‐inflammatory cytokines and inflammatory metabolites, is present in patients with suicidal behaviour and ideation…”

“Caffeine provided an anti-fibrogenic, anti-inflammatory, and antioxidant effect that was associated with the recovery of hepatic histological and functional alterations…”

“…we have demonstrated that 7-day administration of pure caffeine induces unequivocally beneficial changes in a number of oxidative-stress biochemical indices…”

Stress and the breakdown of PUFAs increases exposure to bacterial endotoxin, and endotoxin (LPS) directly causes inflammation and interferes with oxidative energy production. Endotoxin is well known to be involved in the progression of metabolic disease, and has been studied in relation to depression and anxiety. Caffeine protects against the inflammatory stress promoting effects of endotoxin.

“In LPS-exposed rats IL-1β and CD68 cell counts both increased at p8 compared to NS controls. These increases in proinflammatory markers were no longer present in caffeinetreated LPS-exposed pups…suggesting a protective effect of caffeine on respiratory function via an anti-inflammatory mechanism.”

It has been demonstrated that the stress hormone cortisol, more commonly promotes depression in men, with estrogen being a stronger driver of depression in women. Experimental evidence continues to show that depression and anxiety is actually a high serotonin state, and caffeine has been shown to reduce serotonin levels, including brain serotonin.

“Corticosteroids may play an important role in the relationship between stress, mood changes and perhaps suicidal behavior by interacting with 5-HT1A receptors. Abnormalities in the HPA axis in response to increased levels of stress are found to be associated with a dysregulation in the serotonergic system, both in subjects with mood disorders and those who engage in suicidal behavior.”

Serotonin promotes cortisol and estrogen, and estrogen induces nitric oxide production. Nitric oxide has been demonstrated to be involved in the progression of anxiety and depression, and is also associated with suicide. Caffeine and some other things found in coffee can lower nitric oxide.

“A significant percentage fall in mean eNO from baseline was seen 1 hour after either caffeinated coffee or a caffeine capsule when compared with placebo…”

“In recent studies, it has been shown that kahweol, coffee-specific diterpene, exhibit chemoprotective effects…The nitrite production induced by LPS was markedly reduced in a dose-dependent manner…kahweol suppressed the expression of iNOS protein and iNOS mRNA.”

Coffee is known to stimulate thyroid function as well as having been shown to suppress estrogen and cortisol levels, and so it can be seen to be helping with depression and related mood issues on a variety of metabolic fronts.

“Coffee extract blocked 11beta-HSD1-dependent cortisol formation…We suggest that at least part of the anti-diabetic effects of coffee consumption is due to inhibition of 11beta-HSD1-dependent glucocorticoid reactivation.”

“…caffeine mimicked the actions of the antiestrogen fulvestrant, which inhibits ER-dependent functions and decreases ER expression, resulting in suppression of tumor cell growth…”

An increase in dopamine relative to serotonin is another factor which it has been suggested has antidepressant significance, and there is evidence that caffeine (whilst lowering serotonin) also increases dopamine.

Caffeine assists with the production of the protective hormones pregnenolone and progesterone, and both these substances are protective against depression and anxiety, as well as other mood disorders such as bipolar and schizophrenia. Low pregnenolone production is associated with suicide.

“Caffeine…increased the plasma concentrations of pregnenolone and progesterone with a dose-response relation similar to that observed in the brain…”

“The study showed that pregnenolone was significantly decreased in the parietal cortex in the combined group of patients with schizophrenia or bipolar disorder who died by suicide compared with patients with these disorders who died of other causes.”

Caffeine is a non-selective adenosine antagonist, increases cAMP by inhibition of PDE-4, promotes GABA and glutathione, and inhibits parathyroid hormone, and these are also factors involved in protection against mood dysregulation and other metabolic inflammatory conditions.

Coffee and caffeine (much like improved thyroid function) increase body temperature, and whole body hyperthermia has been used successfully to treat depression.

“The thermic effect of the meal was significantly greater after coffee than after decaffeinated coffee… caffeine/coffee stimulates the metabolic rate in both control and obese individuals…”

“The internal temperature started to increase after both treatments, but became slightly different 2 h after caffeine consumption. Mean skin temperature after caffeine consumption increased, and became significantly different compared to the control treatment after 90 min…”

“WBH [whole body hyperthermia] was associated with a substantial reduction in depressive symptoms that was apparent within 1 week of treatment.”

Caffeine increases metabolic rate and promotes the production of mitochondria, and it is not by coincidence that mitochondrial dysfunction is involved in the progression of mood dysregulation. As with any substance that stimulates metabolism however, caffeine increases the amount of glucose which is able to be used by the cells.

“From our data we gather that caffeine stimulates metabolism and favorable mitochondrial production…Our findings support the advertised metabolic benefits of caffeine, making it a potential contributor in humanity’s struggle against obesity.”

When sufficient sugar is not consumed with coffee (especially if glycogen stores are low as a result of stress) this can result in an increase in the release of adrenalin and cortisol (as a means to sourcing out an alternative fuel supply), turning what is able to be a mood stabilizing (as well as enhancing) disease protective food, into something potentially stress increasing and anxiety promoting.

As well as stimulating cortisol and adrenalin, the consumption of too much coffee relative to energy availability, can lead to a rise in other stress substances like serotonin, nitric oxide and estrogen, and can also promote the release of the polyunsaturated free fatty acids, worsening stress and inflammation.

In this sense, consuming lots of coffee without the accompaniment of plenty of fuel, can create the impression that coffee per se is harmful and responsible for a worsening of metabolic issues.

Many of the experiments showing negative aspects of coffee or caffeine have been designed without taking these factors into consideration, and often use unnaturally high doses, leading to results which are highly misleading and unhelpful.

Regular consumption of coffee combined with a sufficient intake of sugar is known to protect against many inflammatory conditions including liver disease, diabetes, MS, Parkinson’s, cardiovascular disease and cancer.

“High versus low coffee consumption was associated with a lower risk of prostate cancer, endometrial cancer, melanoma, oral cancer, leukaemia, non-melanoma skin cancer, and liver cancer. For prostate, endometrial, melanoma, and liver cancer there were also significant linear dose-response relations indicating benefit.”

The ability of coffee or caffeine to protect against depression and suicide, is most likely also directly connected to the liver protective (and healing) impact of regular coffee consumption, as a well functioning liver is important for proper thyroid function and for protection against systemic exposure to the inflammatory stress substances, including estrogen and endotoxin. Sufficient intake of sugar and protein are fundamental to good liver function.

A diet removing PUFA and limiting intake of difficult to digest grains, seeds, nuts, beans and lots of under cooked vegetable matter, with sufficient protein from milk, cheese and gelatin, and plenty of sugar from sweet fruits, fruit juice, white sugar and honey, is one good way to improve liver function, lower inflammation, and help to get the benefits from regular coffee (and other caffeinated drink) consumption.

Some other things that can help improve metabolism, liver function and mood issues include aspirin, niacinamide, glycine, K2, methylene blue, thiamine, vitamin E, taurine, activated charcoal and cyproheptadine.

Ironically, sensitivity to coffee has been shown to be an effective measure of liver damage.

Are you consuming enough sugar with your coffee?

For those who are super sensitive to the effects of coffee, one thing that has been known to work, is to start by introducing it gradually, consuming small amounts combined with milk and sugar or with meals.

See More Here

The Link between Thyroid Function and Depression

Depressive symptoms and major depressive disorder in patients affected by subclinical hypothyroidism: a cross-sectional study.

Does coffee consumption protect against thyroid disease?

Executive functioning and diabetes: The role of anxious arousal and inflammation

Nitric Oxide and Major Depressive Disorder: Pathophysiology and Treatment Implications.

Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function.

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

The impact of caffeine on mood, cognitive function, performance and hydration: a review of benefits and risks

Serotonin directly stimulates cortisol secretion from the interrenals in goldfish.

Coffee inhibits the reactivation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1: a glucocorticoid connection in the anti-diabetic action of coffee?

Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes

Effects of coffee consumption against the development of liver dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.

Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.

SSRIs double the risk of suicide and violence in healthy adults

The role of inflammation in suicidal behaviour

Coffee, caffeine, and risk of completed suicide: results from three prospective cohorts of American adults.

Antidepressants increase the risk of suicide, violence and homicide at all ages

Methylxanthines cause a decrease of prolactin plasma levels in healthy non‐pregnant women

The effects of caffeine and aspirin on mood and performance.

Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation.

Modulation of the stress response by coffee: an in vivo microdialysis study of hippocampal serotonin and dopamine levels in rat.

Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer

The hypothalamic-pituitary-adrenal axis and serotonin abnormalities: a selective overview for the implications of suicide prevention.

A prospective study of coffee drinking and suicide in women.

Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women.

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

Coffee and Liver Disease

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

Estrogen induces nitric oxide production via nitric oxide synthase activation in endothelial cells.

Estrogen-mediated effects on depression and memory formation in females.

Elevated Brain Serotonin Turnover in Patients With Depression

The brain 5-HT1A receptor gene expression in hibernation

Caffeine attenuates lipopolysaccharide-induced neuroinflammation

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

The coffee diterpene kahweol suppress the inducible nitric oxide synthase expression in macrophages.

Serotonin Synthesis and Reuptake in Social Anxiety Disorder

Relationship between parathyroid hormone and depression in heart failure.

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

Coffee Consumption, Newly Diagnosed Diabetes, and Other Alterations in Glucose Homeostasis: A Cross-Sectional Analysis of the Longitudinal Study of Adult Health (ELSA-Brasil)

Caffeine downregulates inflammatory pathways involved in autoimmunity

Anti-Inflammatory Effect of Caffeine is Associated with Improved Lung Function after LPS-induced Amnionitis

Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies.

Mitochondrial Dysfunction in Depression

Increased plasma nitric oxide level associated with suicide attempt in depressive patients.

An oxidized metabolite of linoleic acid stimulates corticosterone production by rat adrenal cells.

Caffeine inhibits STAT1 signaling and downregulates inflammatory pathways involved in autoimmunity.

Caffeine promotes wakefulness via dopamine signaling in Drosophila

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression.

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

A critical review of human endotoxin administration as an experimental paradigm of depression

Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study

Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals.

The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: A review

Effects of caffeine on anterior pituitary and thyroid function in the rat.

Neuroactive steroid levels in patients with generalized anxiety disorder.

Lipopolysaccharide induced anxiety- and depressive-like behaviour in mice are prevented by chronic pre-treatment of esculetin.

Caffeine-induced increases in the brain and plasma concentrations of neuroactive steroids in the rat.

Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression

Association of Coffee Consumption With Total and Cause-Specific Mortality in 3 Large Prospective Cohorts.

Effects of Caffeine on Metabolism and Mitochondria Biogenesis in Rhabdomyosarcoma Cells Compared with 2,4-Dinitrophenol

Exploratory investigation of biomarker candidates for suicide in schizophrenia and bipolar disorder.

Caffeine decreases exhaled nitric oxide

A prospective study of coffee drinking and suicide in women.

Progesterone reduces depression-like behavior in a murine model of Alzheimer’s Disease

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

Caffeine links dopamine and serotonin release during passive heat loading

Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states

Lipid peroxidation at various estradiol concentrations in human circulation during ovarian stimulation with exogenous gonadotropins.

Tolerance to the humoral and hemodynamic effects of caffeine in man.

Coffee and caffeine consumption and depression: A meta-analysis of observational studies.

Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea.

Beneficial effects of oral pure caffeine on oxidative stress

Chronic caffeine treatment enhances the resilience to social defeat stress in mice.

Caffeine inhibits exercise-induced increase in tryptophan hydroxylase expression in dorsal and median raphe of Sprague-Dawley rats.

The role of ventral striatal cAMP signaling in stress-induced behaviors

Caffeine intake decreases oxidative stress and inflammatory biomarkers in experimental liver diseases induced by thioacetamide: Biochemical and histological study

Caffeine potentiates the release of GABA mediated by NMDA receptor activation: Involvement of A1 adenosine receptors.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Modulatory effects of caffeine on oxidative stress and anxiety-like behavior in ovariectomized rats.

Chronic caffeine intake decreases circulating catecholamines and prevents diet-induced insulin resistance and hypertension in rats.

Hippocampal GABA enables inhibitory control over unwanted thoughts

Inhibition of Parathyroid Hormone Secretion by Caffeine in Human Parathyroid Cells

Estrogen-mediated effects on depression and memory formation in females

Coffee Consumption and Oxidative Stress: A Review of Human Intervention Studies.

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

Relationship Between Caffeine Intake and Plasma Sex Hormone Concentrations in Premenopausal and Postmenopausal Women

Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species.

Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states

Effects of the consumption of caffeinated and decaffeinated instant coffee beverages on oxidative stress induced by strenuous exercise in rats.

Evidence for anxiolytic effects of acute caffeine on anxiety-related behavior in male and female rats tested with and without bright light.

A pilot study of cortical glutathione in youth with depression.

Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA (“Ecstasy”) and MDA (“Love”).

24h withdrawal following repeated administration of caffeine attenuates brain serotonin but not tryptophan in rat brain: implications for caffeine-induced depression.

Phosphodiesterase inhibitors

Effect of long-term caffeine administration on depressive-like behavior in rats exposed to chronic unpredictable stress.

Moderate coffee consumption increases plasma glutathione but not homocysteine in healthy subjects.

Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder

Severity of anxiety- but not depression- is associated with oxidative stress in Major Depressive Disorder.

Caffeine and uric acid mediate glutathione synthesis for neuroprotection.

Effects of coffee consumption on oxidative susceptibility of low-density lipoproteins and serum lipid levels in humans.

Comparison of changes in energy expenditure and body temperatures after caffeine consumption.

Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson’s disease.

Coffee, Caffeine, and Risk of Depression Among Women

Coffee Intake Is Associated with a Lower Liver Stiffness in Patients with Non-Alcoholic Fatty Liver Disease, Hepatitis C, and Hepatitis B

Coffee polyphenols protect human plasma from postprandial carbonyl modifications.

Psychiatric aspects of phosphodiesterases: An overview

Glutathione as a cerebral substrate in depressive behavior.

Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress


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