Caffeine Tolerance: Anti-Aging, Anti-Diabetic and Anti-Obesity … Cognitive and Exercise Performance… Liver Info Including Taurine

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Many use coffee (or caffeine) to improve symptoms of mild hypothyroidism, but tolerance for caffeine seems to have a biphasic effect across individuals.

Severely hypothyroid experience caffeine-induced anxiety due to poor glycogen (sugar) storage and “the pathology of estrogen dominance,” where estrogen impairs the liver’s detoxification pathways and leads to greater accumulated estrogen. Estrogen interferes with normal thyroid function, primarily the production and retention of CO2, which itself tends to slow the breathing rate, and where its absence promotes hyperventilation and in extreme cases, panic attacks.

This supports the idea of a “sedative” increasing coffee tolerance: for example antihistamines (which oppose estrogen’s effects, and where histamine itself promotes glycogen depletion), aspirin (which directly improves liver glycogen storage), benzodiazepine and similar drugs (including niacinamide) and other B-vitamins like thiamine, all of which lead to greater CO2 retention, which itself stimulates thyroid activity and improves glycogen storage. Thyroid has a similar effect, as evident by its promotion of relaxation, as with the physical relaxation of the Achilles’ tendon, but also as an analogous mental relaxation experienced by many who first take T3; it also of course directly increases the activity of glycogen synthase (and increases glycogen storage.)

Euthyroid people find they drink less coffee and may become overheated or stimulated by the caffeine, but they won’t experience its anxiogenic effects.

Breathlessness can be a sign of low CO2 production and retention. The combination of benzodiazepine drugs (gabergic drugs) and caffeine (a dopaminergic drug) can cause euphoria. Many benzodiazepines have dopaminergic properties as well, such as alprazolam (Xanax) and the drug phenibut.

“Stress-related behaviors are accompanied by modification of a large number of neurotransmitters in the brain. Moreover, the binding to GABA(A) receptors does not account for all the effects of benzodiazepines. In this study we investigated the effect of repeated restraint stress and alprazolam treatment (1 mg/day os) on dopamine receptors (Bmax and Kd) in the striatum of adult rats by means of quantitative receptor autoradiography. After chronic restraint stress dopamine D1 receptors (Bmax value) decreased in the accumbens nucleus, whereas dopamine D2 receptors were not modified in any investigated area. After alprazolam treatment, a considerable increase in both dopamine D1 and D2 receptors in the striatum was observed. Chronic immobilization stress together with alprazolam treatment re-established dopamine D1 receptor density to control values in the accumbens nucleus and olfactory tubercle, whereas it resulted in an increase in dopamine D2 receptors comparable to that elicited by alprazolam treatment alone.”

Reference: https://www.ncbi.nlm.nih.gov/pubmed/9600648

Phenibut (beta-phenyl-gamma-aminobutyric acid HCl) is a neuropsychotropic drug that was discovered and introduced into clinical practice in Russia in the 1960s. It has anxiolytic and nootropic (cognition enhancing) effectsIt acts as a GABA-mimetic, primarily at GABA(B) and, to some extent, at GABA(A) receptors. It also stimulates dopamine receptors and antagonizes beta-phenethylamine (PEA), a putative endogenous anxiogenic. The psychopharmacological activity of phenibut is similar to that of baclofen, a p-Cl-derivative of phenibut. This article reviews the structure-activity relationship of phenibut and its derivatives. Emphasis is placed on the importance of the position of the phenyl ring, the role of the carboxyl group, and the activity of optical isomers. Comparison of phenibut with piracetam and diazepam reveals similarities and differences in their pharmacological and clinical effects. Phenibut is widely used in Russia to relieve tension, anxiety, and fear, to improve sleep in psychosomatic or neurotic patients; as well as a pre- or post-operative medication. It is also used in the therapy of disorders characterized by asthenia and depression, as well as in post-traumatic stress, stuttering and vestibular disorders.

Reference: https://www.ncbi.nlm.nih.gov/pubmed/11830761

“Raising CO2 levels by means of therapeutic capnometry has proven beneficial effects in both disorders [both panic disorder and asthma], and the reversing of hyperventilation has emerged as a potent mediator for reductions in panic symptom severity and treatment success.”

Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937087/

“…the histamine-induced glycogen breakdown in astrocytes may involve increases in cAMP formation and in intracellular Ca2+ levels…”

Reference: https://www.ncbi.nlm.nih.gov/pubmed/2163018

“Histamine mimics estrogen’s effects on the uterus, and antihistamines block estrogen’s effects (Szego, 1965, Szego and Davis, 1967). Estrogen mimics the shock reaction. Stress, exercise, and toxins cause a rapid increase in estrogen. Males often have as much estrogen as females, especially when they are tired or sick. Estrogen increases the brain’s susceptibility to epileptic seizures, and recent research shows that it (and cortisol) promote the effects of the “excitotoxins,” which are increasingly implicated in degenerative brain diseases.

Reference: http://raypeat.com/articles/hormones/h1.shtml

“The principal pathophysiologic effect of toxic doses of salicylates are characterized by (1) stimulation of the respiratory center of the brain, leading to hyperpnea and respiratory alkalosis; (2) uncoupling of oxidative phosphorylation, leading to increased oxygen utilization and glucose demand, increased oxygen utilization and glucose demand, increased glyconeogenesis [formation of glycogen], and increased heat production”

Reference: https://www.ncbi.nlm.nih.gov/pubmed/364398

“Thyroid and carbon dioxide are very inter-related. Carbon dioxide increases thyroid activity, and I imagine thyroid activity may increase carbon dioxide as well – swinging in both directions.” – Raymond Peat, PhD

Reference: http://180degreehealth.com/asthma-adrenaline-and-carbon-dioxide/

“The features of the stress metabolism include increases of stress hormones, lactate, ammonia, free fatty acids, and fat synthesis, and a decrease in carbon dioxide. Factors that lower the stress hormones, increase carbon dioxide, and help to lower the circulating free fatty acids, lactate, and ammonia, include vitamin B1 (to increase CO2 and reduce lactate), niacinamide (to reduce free fatty acids), sugar (to reduce cortisol, adrenaline, and free fatty acids), salt (to lower adrenaline), thyroid hormone (to increase CO2). Vitamins D, K, B6 and biotin are also closely involved with carbon dioxide metabolism. Biotin deficiency can cause aerobic glycolysis with increased fat synthesis (Marshall, et al., 1976).”

Reference: http://raypeat.com/articles/articles/lactate.shtml

Plasma epinephrine and norepinephrine levels were measured at rest and at 8 minutes, 11 minutes and maximal exercise…alprazolam reduces the plasma catecholamine response to exercise stress…”

Reference: https://www.ncbi.nlm.nih.gov/pubmed/4014019

“Isolated hepatocytes from hyperthyroid and euthyroid rats showed the same rate and extent of activation of glycogen synthase after addition of glucose (10 mM or 60 mM). In liver cells from hypothyroid rats this activation occurred at a 7-fold lower rate. However, complete activation of glycogen synthase occurred eventually in broken-cell preparations from either source during incubation in vitro. Glycogen synthase phosphatase was then quantitatively assayed in liver homogenates with exogenous synthase b as substrate. These assays revealed an increased synthase phosphatase activity (approximately 160%) in the hyperthyroid liver and a decreased activity (to approximately 60%) in the livers from hypothyroid rats.”

Reference: https://www.ncbi.nlm.nih.gov/pubmed/3131128

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Coffee (or caffeine) increases the basal metabolic rate (BMI).  Acute ingestion of 4 mg/kg (240 mg for a 60 kg person) caffeine via coffee, equivalent to three or four standard cups of coffee, raises plasma free fatty acids (FFA) in only non-obese subjects.[1] Obese individuals exhibit chronically elevated plasma free fatty acid (FFA) levels due to greater adipose tissue mass, which constantly releases free fatty acids (FFA), and impaired free fatty acid (FFA) clearance, which worsens with greater free fatty acid (FFA) concentrations in a destructive positive feedback loop.[2]

Coffee (or caffeine) increases the metabolic rate and cellular consumption of glucose, which lowers blood sugar and triggers the release of adrenocorticotropin (ACTH), and cortisol,[3] where high concentrations elevate serum corticotropin-releasing hormone (CRF).[4] Identical metabolic adaptations to lowered blood sugar appear after prolonged exercise.[5] Acute caffeine consumption reduces insulin sensitivity by antagonization of adenosine A1 and A2B receptors, which decreases expression of glucose transporter type 4 (GLUT-4),[6] raises free fatty acids (FFA),[7]  [8]  and raises blood pressure[9] due to elevated catecholamines, which includes stress hormones such as adrenaline and norepinephrine (the brain’s adrenaline.[10] Chronic caffeine intake decreases sympathetic nervous system activity including the release of stress hormones, increases insulin sensitivity, and lowers blood pressure.[11]

Caffeine aids in weight loss as a thermogenic.[12]  Acute caffeine decreases insulin sensitivity and decreases GLUT-4 expression,[13] while chronic intake has the ability to decrease visceral and total fat and increased expression of glucose transporter type 4 (GLUT-4), which reverses insulin resistance as a result of aging.[14] Caffeine ingested with sugar (glucose) before a two-hour exercise session increases exogenous carbohydrate (CHO) oxidation by a significant 26% compared to glucose alone.[15] Caffeine lowers blood glucose levels during a 40 minute, low-intensity exercise session.[16]  Cola, or sucrose (table sugar) with caffeine potentiates insulin growth factor 1 (IGF-1) and increases insulin sensitivity due to the caffeine, which can reverse pre-diabetes.[17]

Rats instinctively consume more of a sweetened caffeine solution on low-fat and sweetened high-fat diets; in the caffeine solution, replacement of glucose with the artificial sweetener saccharin resulted in greater weight gain.[18]  The rats consumed less calories and lost more weight with the calorically-dense glucose-caffeine solution versus the calorie-free saccharin-caffeine solution.[19]  Caffeine functioned as an appetite stimulant for sugar and caused the rats to consume significantly more sweet calories.[20]  By the end of the experiment, glucose-caffeine and saccarhin-caffeine rats had lower body fat percentages than their non-caffeinated counterparts, and glucose-caffeinated rats had the lowest body fat percentages of all.[21] The experiment demonstrates innate animal intelligence with the rats scaled self-administration of caffeine in the presence of more sugar, as well as the superiority of carbohydrate (specifically glucose) for weight loss compared with artificial sweeteners

Chronic caffeine consumption tends to suppress appetite if consumed directly before a meal:

“The literature review indicated that coffee administered 3-4.5 h before a meal had minimal influence on food and macronutrient intake, while caffeine ingested 0.5-4 h before a meal may suppress acute energy intake. Evidence regarding the influence of caffeine and coffee on gastric emptying, appetite hormones, and appetite perceptions was equivocal. The influence of covariates such as genetics of caffeine metabolism and bitter taste phenotype remain unknown; longer controlled studies are needed.”

Bodybuilders use the infamous drug, DNP to induce rapid weight loss; caffeine has similar effects:

“Treatment with caffeine and DNP also significantly increased oxidative metabolism and total metabolic rate compared with control.  Caffeine similarly increased metabolism and mitochondrial content compared with DNP.”

Caffeine and DNP both increase the activity of a protein called peroxisome proliferator-activated receptor coactivator 1 alpha:

“…both caffeine and DNP significantly induce PGC-1α, and increase both metabolism and mitochondrial content in skeletal muscle.”

Caffeine increases the potency of other herbal weight loss compounds:

We have found natural products exhibiting lipolysis-promoting activity in subcutaneous adipocytes, which are less sensitive to hormones than visceral adipocytes. The activities and a action mechanisms of a novel plant extract of Cirsium oligophyllum (CE) were investigated in isolated adipocytes from rat subcutaneous fat, and its fat-reducing effects by peroral administration and topical application were evaluated in vivo. CE-induced lipolysis was synergistically enhanced by caffeine, a phosphodiesterase inhibitor, and was reduced by propranolol, a β adrenergic antagonist. The peroral administration of 10% CE solution to Wistar rats for 32 days reduced body weight gain, subcutaneous, and visceral fat weights by 6.6, 26.2, and 3.0%, respectively, as compared to the control group. By the topical application of 2% of this extract to rats for 7 days, weight of subcutaneous fat in the treated skin was reduced by 23.2%. This fat mass reduction was accompanied by the up-regulation of uncoupling protein 1 (UCP), a principal thermogenic mitochondrial molecule related to energy dissipating, in subcutaneous fat and UCP3 in skin except for the fat layer. These results indicate that CE promotes lipolysis via a mechanism involving the β adrenergic receptor, and affects the body fat mass. This fat reduction may be partially due to UCP up-regulation in the skin including subcutaneous fat. This is the first report showing that repeated lipolysis promotion through CE administration may be beneficial for the systematic suppression of body fat accumulation or the control of fat distribution in obesity.

Georgi Dinkhov supplied the study for DNP; Georgi has a webstore at http://www.idealabsdc.com where he sells supplements and other merchandise that improve metabolism.

 

References

Schubert, M. M., Irwin, C., Seay, R. F., Clarke, H. E., Allegro, D., & Desbrow, B. (2017). Caffeine, coffee, and appetite control: a review. International Journal of Food Sciences and Nutrition, 1–12. https://doi.org/10.1080/09637486.2017.1320537

Coffee and caffeine consumption has global popularity. However, evidence for the potential of these dietary constituents to influence energy intake, gut physiology, and appetite perceptions remains unclear. The purpose of this review was to examine the evidence regarding coffee and caffeine’s influence on energy intake and appetite control. The literature was examined for studies that assessed the effects of caffeine and coffee on energy intake, gastric emptying, appetite-related hormones, and perceptual measures of appetite. The literature review indicated that coffee administered 3-4.5 h before a meal had minimal influence on food and macronutrient intake, while caffeine ingested 0.5-4 h before a meal may suppress acute energy intake. Evidence regarding the influence of caffeine and coffee on gastric emptying, appetite hormones, and appetite perceptions was equivocal. The influence of covariates such as genetics of caffeine metabolism and bitter taste phenotype remain unknown; longer controlled studies are needed. 

Effects of Caffeine on Metabolism and Mitochondria Biogenesis in Rhabdomyosarcoma Cells Compared with 2,4-Dinitrophenol. (n.d.). Retrieved July 12, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698477/

Purpose:  This work investigated if treatment with caffeine or 2,4-dinitrophenol (DNP) induce expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) and increase both mitochondrial biosynthesis and metabolism in skeletal muscle.  Methods:  Human rhabdomyosarcoma cells were treated with either ethanol control (0.1% final concentration) caffeine, or DNP at 250 or 500 μM for 16 or 24 hours. PGC-1α RNA levels were determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). PGC-1α protein and mitochondrial content was determined using flow cytometry and immunohistochemistry. Metabolism was determined by quantification of extracellular acidification rate and oxygen consumption rate.  Results:  Treatment with either caffeine or DNP induced PGC-1α RNA and protein as well as mitochondrial content compared with control. Treatment with caffeine and DNP also significantly increased oxidative metabolism and total metabolic rate compared with control. Caffeine similarly increased metabolism and mitochondrial content compared with DNP.  Conclusion:  This work identified that both caffeine and DNP significantly induce PGC-1α, and increase both metabolism and mitochondrial content in skeletal muscle.  “We have found natural products exhibiting lipolysis-promoting activity in subcutaneous adipocytes, which are less sensitive to hormones than visceral adipocytes. The activities and a action mechanisms of a novel plant extract of Cirsium oligophyllum (CE) were investigated in isolated adipocytes from rat subcutaneous fat, and its fat-reducing effects by peroral administration and topical application were evaluated in vivo. CE-induced lipolysis was synergistically enhanced by caffeine, a phosphodiesterase inhibitor, and was reduced by propranolol, a β adrenergic antagonist. The peroral administration of 10% CE solution to Wistar rats for 32 days reduced body weight gain, subcutaneous, and visceral fat weights by 6.6, 26.2, and 3.0%, respectively, as compared to the control group. By the topical application of 2% of this extract to rats for 7 days, weight of subcutaneous fat in the treated skin was reduced by 23.2%. This fat mass reduction was accompanied by the up-regulation of uncoupling protein 1 (UCP), a principal thermogenic mitochondrial molecule related to energy dissipating, in subcutaneous fat and UCP3 in skin except for the fat layer. These results indicate that CE promotes lipolysis via a mechanism involving the β adrenergic receptor, and affects the body fat mass. This fat reduction may be partially due to UCP up-regulation in the skin including subcutaneous fat. This is the first report showing that repeated lipolysis promotion through CE administration may be beneficial for the systematic suppression of body fat accumulation or the control of fat distribution in obesity. Mori, S., Satou, M., Kanazawa, S., Yoshizuka, N., Hase, T., Tokimitsu, I., … Yada, T. (2009). Body fat mass reduction and up-regulation of uncoupling protein by novel lipolysis-promoting plant extract. International Journal of Biological Sciences5(4), 311–318.” 

[1] Acheson KJ, Zahorska-Markiewicz B, Pittet P, Anantharaman K, Jéquier E. Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals. Am J Clin Nutr. 1980 May;33(5):989–97.

[2] Boden G. Obesity and Free Fatty Acids (FFA). Endocrinol Metab Clin North Am. 2008 Sep;37(3):635–ix.

[3] Dallman MF, Akana SF, Jacobson L, Levin N, Cascio CS, Shinsako J. Characterization of corticosterone feedback regulation of ACTH secretion. Ann N Y Acad Sci. 1987;512:402–14.

[4] Nicholson SA. Stimulatory effect of caffeine on the hypothalamo-pituitary-adrenocortical axis in the rat. J Endocrinol. 1989 Aug;122(2):535–43.

[5] Tabata I, Ogita F, Miyachi M, Shibayama H. Effect of low blood glucose on plasma CRF, ACTH, and cortisol during prolonged physical exercise. J Appl Physiol. 1991 Nov;71(5):1807–12.

[6] Sacramento JF, Ribeiro MJ, Yubero S, Melo BF, Obeso A, Guarino MP, et al. Disclosing caffeine action on insulin sensitivity: effects on rat skeletal muscle. Eur J Pharm Sci. 2015 Apr 5;70:107–16.

[7] van Dam RM, Pasman WJ, Verhoef P. Effects of Coffee Consumption on Fasting Blood Glucose and Insulin Concentrations. Diabetes Care. 2004 Nov 23;27(12):2990.

[8] Lee S, Hudson R, Kilpatrick K, Graham TE, Ross R. Caffeine Ingestion Is Associated With Reductions in Glucose Uptake Independent of Obesity and Type 2 Diabetes Before and After Exercise Training. Diabetes Care. 2005 Mar 1;28(3):566–72.

[9] Mesas AE, Leon-Muñoz LM, Rodriguez-Artalejo F, Lopez-Garcia E. The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis. Am J Clin Nutr. 2011 Oct;94(4):1113–26.

[10] van Dam RM, Pasman WJ, Verhoef P. Effects of Coffee Consumption on Fasting Blood Glucose and Insulin Concentrations. Diabetes Care. 2004 Nov 23;27(12):2990.

[11] Conde SV, Nunes da Silva T, Gonzalez C, Mota Carmo M, Monteiro EC, Guarino MP. Chronic caffeine intake decreases circulating catecholamines and prevents diet-induced insulin resistance and hypertension in rats. Br J Nutr. 2012 Jan;107(1):86–95.

[12] Yoshida T, Sakane N, Umekawa T, Kondo M. Relationship between basal metabolic rate, thermogenic response to caffeine, and body weight loss following combined low calorie and exercise treatment in obese women. Int J Obes Relat Metab Disord. 1994 May;18(5):345–50.

[13] Sacramento JF, Ribeiro MJ, Yubero S, Melo BF, Obeso A, Guarino MP, et al. Disclosing caffeine action on insulin sensitivity: effects on rat skeletal muscle. Eur J Pharm Sci. 2015 Apr 5;70:107–16.

[14] Guarino MP, Ribeiro MJ, Sacramento JF, Conde SV. Chronic caffeine intake reverses age-induced insulin resistance in the rat: effect on skeletal muscle Glut4 transporters and AMPK activity. Age (Dordr). 2013 Oct;35(5):1755–65.

[15] Yeo SE, Jentjens RLPG, Wallis GA, Jeukendrup AE. Caffeine increases exogenous carbohydrate oxidation during exercise. J Appl Physiol. 2005 Sep;99(3):844–50.

[17] da Silva LA, de Freitas L, Medeiros TE, Osiecki R, Garcia Michel R, Snak AL, et al. Caffeine modifies blood glucose availability during prolonged low-intensity exercise in individuals with type-2 diabetes. Colomb Med. 2014 Jun;45(2):72–6.

[18] Swithers SE, Martin AA, Clark KM, Laboy AF, Davidson TL. Body weight gain in rats consuming sweetened liquids. Effects of caffeine and diet composition. Appetite. 2010 Dec;55(3):528–33.

[19] Swithers SE, Martin AA, Clark KM, Laboy AF, Davidson TL. Body weight gain in rats consuming sweetened liquids. Effects of caffeine and diet composition. Appetite. 2010 Dec;55(3):528–33.

[20] Swithers SE, Martin AA, Clark KM, Laboy AF, Davidson TL. Body weight gain in rats consuming sweetened liquids. Effects of caffeine and diet composition. Appetite. 2010 Dec;55(3):528–33.

[21] Swithers SE, Martin AA, Clark KM, Laboy AF, Davidson TL. Body weight gain in rats consuming sweetened liquids. Effects of caffeine and diet composition. Appetite. 2010 Dec;55(3):528–33.

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[23] Kendig EL, Schneider SN, Clegg DJ, Genter MB, Shertzer HG. Over-the-counter analgesics normalize blood glucose and body composition in mice fed a high fat diet. Biochem Pharmacol. 2008 Jul 15;76(2):216–24.

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[25] Lanas A, Scheiman J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment. Curr Med Res Opin. 2007 Jan;23(1):163–73.

 

Many face an initial stress response from coffee, flee from it, and lose its numerous health benefits. Coffee’s side effects subside in within two weeks of continuous consumption, and even moderate consumption has health benefits.
Complete tolerance to caffeine’s effects on the central nervous system develops after 18 days of chronic consumption:

“Subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days…after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group.  This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.”

Caffeine continues to raise blood pressure even after tolerance develops:
“BP responses to caffeine above those found on placebo-placebo (P-P) week were found for both tolerance groups when caffeine was consumed after a week of receiving a placebo.”
Even low doses (<75 mg) of caffeine improve exercise performance, but tolerance develops to this effect, so athletes should consume more:
“…performance benefit was no longer apparent after 4 weeks of caffeine supplementation, but was retained in the placebo group…chronic ingestion of a low dose of caffeine develops tolerance in low-caffeine consumers…individuals with low-habitual intakes should refrain from chronic caffeine supplementation to maximize performance benefits from acute caffeine ingestion.”
In rats, after about 2 weeks, the anxiogenic effects of caffeine diminishes completely as tolerance develops:  

“Adenosine receptors to fully upregulate to caffeine’s antagonism. It seems that a gradual increase in caffeine dosage, and maybe co-administration with a benzodiazepine during the 14-day period will completely eliminate any side effects from caffeine.”

Tolerance to caffeine develops after 14 to 21 days of chronic consumption:

“Subchronic administration of caffeine for 21 days, in different groups of animals, induced a significant degree of tolerance…statistically significant after 14 and 21 days.”

Caffeine anxiety appears around 48 hours after the last time of consumption:

“When caffeine was withdrawn after 21 days administration, to a separate group of rats, significant withdrawal anxiety was observed 48 h later as noted in the elevated plus-maze test. The investigations support clinical evidence of caffeine-induced anxiety, tolerance to anxiety on continued use, and withdrawal anxiety in chronic caffeine-containing beverage users.”

Caffeine shows promising effects in Parkinson’s disease at around the 3-week mark:

“Patients with PD with daytime somnolence were given caffeine 100 mg twice daily ×3 weeks, then 200 mg twice daily ×3 weeks, or matching placebo.  Caffeine reduced the total Unified Parkinson’s Disease Rating Scale score (−4.69 points; −7.7, −1.6) and the objective motor component (−3.15 points; −5.50, −0.83).”

“In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions.  With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.”

Signs of caffeine withdrawal include headache, fatigue, anxiety, cognitive impairment, nausea, vomiting, and caffeine craving:

“…headache and fatigue are the most frequent withdrawal symptoms, with a wide variety of other signs and symptoms occurring at lower frequency (e.g. anxiety, impaired psychomotor performance, nausea/vomiting and craving).”

Caffeine withdrawals begins the same day of cessation, worsens the following day, and lasts for about a week:

“The withdrawal syndrome has an onset at 12-24 h, peak at 20-48 h, and duration of about 1 week.”

The vast majority of caffeine users experience caffeine withdrawal:

“The proportion of heavy caffeine users who will experience withdrawal symptoms has been estimated from experimental studies to range from 25% to 100%.”

Partial tolerance develops to caffeine’s effects of slowing reducing cerebral blood flow and mood, but it continues to raise blood pressure and improve cognitive performance:

“Twelve healthy volunteers were randomized using a double-blind, cross-over design to take either 200 mg caffeine or placebo twice daily for 1 week.  Following baseline measurements being made, the responses to 200 mg caffeine (blood-pressure, middle cerebral artery velocity, mood and cognitive performance) were examined over the subsequent 120 min.  Blood glucose was not allowed to fall. …middle cerebral artery blood velocity decreased in both conditions but was greater in the placebo group.  Systolic blood pressure rise was not significantly different.  Mood was adversely affected by regular caffeine consumption with tense aspect of mood significantly higher at baseline in the caffeine group.  Cognitive performance was not affected by previous caffeine exposure.  Tolerance is incomplete with respect to both peripheral or central effects of caffeine.”

Further evidence of the initiation of physical dependency points to a period of adenosine adaptation of one to two weeks:

“Withdrawal symptoms have been documented after relatively short-term exposure to high doses of caffeine (i.e. 6-15 days of greater than or equal to 600 mg/day).”

Substances that lower cortisol can help caffeine adaptation and include adequate carbohydrate as sugar, aspirin, niacinamide, pregnenolone, progesterone, l-theanine, taurine, glycine and anti-serotonin drugs that also lower adrenaline including cyproheptadine and mirtazapine.
References
Evans, S. M., & Griffiths, R. R. (1992). Caffeine tolerance and choice in humans. Psychopharmacology, 108(1–2), 51–59.
Thirty-two healthy subjects with histories of moderate caffeine consumption abstained from dietary caffeine throughout the study. Subjects were stratified into two groups based on several factors including caffeine preference, which was assessed using a caffeine versus placebo choice procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days, and thereafter were exposed again to a caffeine versus placebo choice procedure. The study documented tolerance development to the subjective effects of caffeine: after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group. The study also provided indirect evidence for tolerance development: during chronic dosing, the chronic caffeine and placebo groups did not differ meaningfully on ratings of mood and subjective effect. When subjects were categorized into caffeine choosers or nonchoosers, caffeine choosers tended to report positive subjective effects of caffeine and negative subjective effects of placebo. Nonchoosers, in contrast, tended to report negative subjective effects of caffeine. Chronic caffeine did not alter the reinforcing effects of caffeine as assessed by caffeine versus placebo choice, possibly because the relatively short duration of caffeine abstinence in the placebo condition was not sufficient to result in maximal withdrawal effects after termination of the relatively high caffeine dose. This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.
Ammon, H. P. (1991). Biochemical mechanism of caffeine tolerance. Archiv Der Pharmazie, 324(5), 261–267.
Most of the biological actions of caffeine are possibly mediated through its antagonistic effects to adenosine. Adenosine activates an inhibitory GTP-binding protein (Gi). One of the physiological actions of Gi is the inhibition of cAMP formation. Caffeine overcomes this action thus leading to elevation of cAMP. Firing of neurons and the release of neurotransmitters is also inhibited by adenosine. Caffeine overcomes this effect, thus producing increased CNS-activity. During long term administration of caffeine many functions of the organism develop tolerance including cardiovascular and central nervous systems. Present evidence suggests that caffeine tolerance following continuous severe coffee ingestion is the response of the body against caffeine through the upregulation of adenosine receptors.
Farag, N. H., Vincent, A. S., Sung, B. H., Whitsett, T. L., Wilson, M. F., & Lovallo, W. R. (2005). Caffeine Tolerance is Incomplete: Persistent Blood Pressure Responses in the Ambulatory Setting. American Journal of Hypertension, 18(5 Pt 1), 714–719. https://doi.org/10.1016/j.amjhyper.2005.03.738
Background Caffeine in dietary doses is a well-established pressor agent. Tolerance to this pressor effect occurs in only about half of regular consumers in acute laboratory tests. The clinical significance of this incomplete tolerance depends on whether the pressor effect is maintained throughout the day with repeated intake. Therefore, we examined the ability of a standard dose of caffeine (250 mg × 3) to maintain a blood pressure (BP) elevation during 18 hours of ambulatory BP monitoring (ABPM) after 5 days of regular daily intake of varying background doses.  Methods Eighty-five men and women completed a four-week double blind, crossover trial. During each week, subjects consumed capsules totaling 0, 300, or 600 mg/day of caffeine in 3 divided doses. On day 6, they consumed capsules with either 0 or 250 mg at 9:00 am and 1:00 pm, in the laboratory, and again at 6:00 pm during ABPM. Tolerance was defined as a reduction in the diastolic BP response to two challenge doses given in the lab in response to increasing daily intake. Data were analyzed using multivariate repeated measures analysis of variance.  Results BP responses to caffeine above those found on placebo-placebo (P-P) week were found for both tolerance groups when caffeine was consumed after a week of receiving a placebo. However, only the low tolerance group showed increases, above those found on P-P week, after 300 mg/day in systolic/diastolic BP during the waking hours (mean ± standard error of the mean = 2.8 ± 1.1, P = .01/2.2 ± 0.9, P = .02) and in systolic BP during sleep (2.3 ± 1, P = .03).  Conclusions Persistent elevations in BP occurring on a daily basis in some habitual caffeine consumers may hold clinical significance.
Beaumont, R., Cordery, P., Funnell, M., Mears, S., James, L., & Watson, P. (2017). Chronic ingestion of a low dose of caffeine induces tolerance to the performance benefits of caffeine. Journal of Sports Sciences, 35(19), 1920–1927. https://doi.org/10.1080/02640414.2016.1241421
This study examined effects of 4 weeks of caffeine supplementation on endurance performance. Eighteen low-habitual caffeine consumers (<75 mg · day(-1)) were randomly assigned to ingest caffeine (1.5-3.0 mg · kg(-1)day(-1); titrated) or placebo for 28 days. Groups were matched for age, body mass, V̇O2peak and Wmax (P > 0.05). Before supplementation, all participants completed one V̇O2peak test, one practice trial and 2 experimental trials (acute 3 mg · kg(-1) caffeine [precaf] and placebo [testpla]). During the supplementation period a second V̇O2peak test was completed on day 21 before a final, acute 3 mg · kg(-1) caffeine trial (postcaf) on day 29. Trials consisted of 60 min cycle exercise at 60% V̇O2peak followed by a 30 min performance task. All participants produced more external work during the precaf trial than testpla, with increases in the caffeine (383.3 ± 75 kJ vs. 344.9 ± 80.3 kJ; Cohen’s d effect size [ES] = 0.49; P = 0.001) and placebo (354.5 ± 55.2 kJ vs. 333.1 ± 56.4 kJ; ES = 0.38; P = 0.004) supplementation group, respectively. This performance benefit was no longer apparent after 4 weeks of caffeine supplementation (precaf: 383.3 ± 75.0 kJ vs. postcaf: 358.0 ± 89.8 kJ; ES = 0.31; P = 0.025), but was retained in the placebo group (precaf: 354.5 ± 55.2 kJ vs. postcaf: 351.8 ± 49.4 kJ; ES = 0.05; P > 0.05). Circulating caffeine, hormonal concentrations and substrate oxidation did not differ between groups (all P > 0.05). Chronic ingestion of a low dose of caffeine develops tolerance in low-caffeine consumers. Therefore, individuals with low-habitual intakes should refrain from chronic caffeine supplementation to maximise performance benefits from acute caffeine ingestion.
Bhattacharya, S. K., Satyan, K. S., & Chakrabarti, A. (1997). Anxiogenic action of caffeine: an experimental study in rats. Journal of Psychopharmacology (Oxford, England), 11(3), 219–224. https://doi.org/10.1177/026988119701100304
The anxiogenic action of caffeine (10, 25 and 50 mg/kg, i.p.) was investigated in rats and compared with that of yohimbine (2 mg/kg, i.p.). The experimental methods used were the open-field, elevated plus-maze, social interaction and novelty-suppressed feeding latency tests. Caffeine produced a dose-related profile of behavioural changes, which were qualitatively similar to those induced by yohimbine and which indicate an anxiogenic activity in rodents. Thus, both the drugs reduced ambulation and rears, and increased immobility and defaecation in the open-field test. They decreased the number of entries and time spent on the open arms of the elevated-plus maze, reduced social interaction in paired rats and increased the feeding latency in an unfamiliar environment in 48-h food-deprived rats. Lorazepam, a well known benzodiazepine anxiolytic agent, attenuated the anxiogenic effects of caffeine and yohimbine. Subchronic administration of caffeine (50 mg/kg, i.p.) for 21 days, in different groups of animals, induced a significant degree of tolerance in the elevated plus-maze test, which was statistically significant after 14 and 21 days’ treatment. Yohimbine, however, did not induce similar tolerance. When caffeine (50 mg/kg, i.p.) was withdrawn after 21 days’ administration, to a separate group of rats, significant withdrawal anxiety was observed 48 h later as noted in the elevated plus-maze test. The investigations support clinical evidence of caffeine-induced anxiety, tolerance to anxiety on continued use, and withdrawal anxiety in chronic caffeine-containing beverage users.
Postuma, R. B., Lang, A. E., Munhoz, R. P., Charland, K., Pelletier, A., Moscovich, M., … Shah, B. (2012). Caffeine for treatment of Parkinson disease. Neurology, 79(7), 651–658. https://doi.org/10.1212/WNL.0b013e318263570d
Objective: Epidemiologic studies consistently link caffeine, a nonselective adenosine antagonist, to lower risk of Parkinson disease (PD). However, the symptomatic effects of caffeine in PD have not been adequately evaluated.  Methods: We conducted a 6-week randomized controlled trial of caffeine in PD to assess effects upon daytime somnolence, motor severity, and other nonmotor features. Patients with PD with daytime somnolence (Epworth >10) were given caffeine 100 mg twice daily ×3 weeks, then 200 mg twice daily ×3 weeks, or matching placebo. The primary outcome was the Epworth Sleepiness Scale score. Secondary outcomes included motor severity, sleep markers, fatigue, depression, and quality of life. Effects of caffeine were analyzed with Bayesian hierarchical models, adjusting for study site, baseline scores, age, and sex.  Results: Of 61 patients, 31 were randomized to placebo and 30 to caffeine. On the primary intention-to-treat analysis, caffeine resulted in a nonsignificant reduction in Epworth Sleepiness Scale score (−1.71 points; 95% confidence interval [CI] −3.57, 0.13). However, somnolence improved on the Clinical Global Impression of Change (+0.64; 0.16, 1.13, intention-to-treat), with significant reduction in Epworth Sleepiness Scale score on per-protocol analysis (−1.97; −3.87, −0.05). Caffeine reduced the total Unified Parkinson’s Disease Rating Scale score (−4.69 points; −7.7, −1.6) and the objective motor component (−3.15 points; −5.50, −0.83). Other than modest improvement in global health measures, there were no changes in quality of life, depression, or sleep quality. Adverse events were comparable in caffeine and placebo groups.  Conclusions: Caffeine provided only equivocal borderline improvement in excessive somnolence in PD, but improved objective motor measures. These potential motor benefits suggest that a larger long-term trial of caffeine is warranted.  Classification of evidence: This study provides Class I evidence that caffeine, up to 200 mg BID for 6 weeks, had no significant benefit on excessive daytime sleepiness in patients with PD.
Rogers, P. J., Hohoff, C., Heatherley, S. V., Mullings, E. L., Maxfield, P. J., Evershed, R. P., … Nutt, D. J. (2010). Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption. Neuropsychopharmacology, 35(9), 1973–1983. https://doi.org/10.1038/npp.2010.71
Caffeine, a widely consumed adenosine A1 and A2A receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine. Participants were 162 non-/low (NL) and 217 medium/high (MH) caffeine consumers. In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. Caffeine intake was prohibited for 16 h before the first dose of caffeine/placebo. Results showed greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake (indeed coffee intake was higher), in the rs5751876 TT genotype group, and a reduced anxiety response in MH vs NL participants irrespective of genotype. Apart from the almost completely linked ADORA2A SNP rs3761422, no other of eight ADORA2A and seven ADORA1 SNPs studied were found to be clearly associated with effects of caffeine on anxiety, alertness, or headache. Placebo administration in MH participants decreased alertness and increased headache. Caffeine did not increase alertness in NL participants. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.
Griffiths, R. R., & Woodson, P. P. (1988). Caffeine physical dependence: a review of human and laboratory animal studies. Psychopharmacology, 94(4), 437–451.
Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been poorly characterized in laboratory animals and only moderately well characterized in humans. In humans, a review of 37 clinical reports and experimental studies dating back to 1833 shows that headache and fatigue are the most frequent withdrawal symptoms, with a wide variety of other signs and symptoms occurring at lower frequency (e.g. anxiety, impaired psychomotor performance, nausea/vomiting and craving). When caffeine withdrawal occurs, severity can vary from mild to extreme (i.e. incapacitating). The withdrawal syndrome has an onset at 12-24 h, peak at 20-48 h, and duration of about 1 week. The pharmacological specificity of caffeine withdrawal has been established. The proportion of heavy caffeine users who will experience withdrawal symptoms has been estimated from experimental studies to range from 25% to 100%. Withdrawal symptoms have been documented after relatively short-term exposure to high doses of caffeine (i.e. 6-15 days of greater than or equal to 600 mg/day). Although animal and human studies suggest that physical dependence may potentiate the reinforcing effects of caffeine, human studies also demonstrate that a history of substantial caffeine intake is not a necessary condition for caffeine to function as a reinforcer. The similarities and differences between caffeine and classic drugs of abuse are discussed.
Watson, J., Deary, I., & Kerr, D. (2002). Central and peripheral effects of sustained caffeine use: tolerance is incomplete. British Journal of Clinical Pharmacology, 54(4), 400–406. https://doi.org/10.1046/j.1365-2125.2002.01681.x
Aims It is widely held that tolerance develops to the effects of sustained caffeine consumption. This study was designed to investigate the effects of chronic, staggered caffeine ingestion on the responses of an acute caffeine challenge, during euglycaemia.  Methods Twelve healthy volunteers were randomized using a double-blind, cross-over design to take either 200 mg caffeine (C-replete) or placebo (C-naïve) twice daily for 1 week. Following baseline measurements being made, the responses to 200 mg caffeine (blood-pressure, middle cerebral artery velocity, mood and cognitive performance) were examined over the subsequent 120 min. Blood glucose was not allowed to fall below 4.0 mmol l−1.  Results After the caffeine challenge, middle cerebral artery blood velocity decreased in both conditions but was greater in the C-naïve condition (−8.0 [-10.0, −6.1] cm s−1 vs −4.9 [-6.8, −2.9] cm s−1 C-replete, P < 0.02). Systolic blood pressure rise was not significantly different in C-naïve, although this rise was more sustained over time (P < 0.04). Mood was adversely affected by regular caffeine consumption with tense aspect of mood significantly higher at baseline in C-replete 11.6 ± 0.6 C-naïve vs 16.3 ± 1.6 C-replete, P < 0.01). Cognitive performance was not affected by previous caffeine exposure.  Conclusions Overall these results suggest that tolerance is incomplete with respect to both peripheral or central effects of caffeine.

Taurine Detoxifies the Liver

Gray1085
Henry Vandyke Carter creator QS:P170,Q955620 Henry Gray author QS:P170,Q40319, Gray1085, marked as public domain, more details on Wikimedia Commons

Functional evolution of the pregnane X receptor
“In contrast to the data in mammals described above, the first major study to systematically compare multiple non-mammalian and mammalian PXRs found that the zebrafish PXR was not activated by a variety of bile acids and synthetic bile acid derivatives [10]. However, biliary bile salts vary significantly across vertebrate species and the bile acids found in humans, mice, and most other mammals are not found in zebrafish and some other fish [9799]. Most mammals and birds, and even the majority of present-day bony fish, convert 27-carbon cholesterol predominantly to C24 bile acids such as cholic acid and chenodeoxycholic acid, conjugated to either glycine or taurine. In contrast, the evolutionarily ‘earliest’ fish (i.e., the fish most distantly related to humans), represented now by jawless fish (lampreys, hagfish), cartilaginous fish (e.g., sharks, skates, rays) and some bony fish (like zebrafish), synthesize C27bile alcohols conjugated with sulfate (see Figure 1) [99,100]. In these ‘early’ fish, C27 bile alcohol sulfates account for nearly all biliary lipids [100]. The zebrafish does not produce any C24 bile acids and instead synthesizes 5α-cyprinol (5α-cholestan-3α,7α,12α,26,27-pentol) sulfate [101,102], a bile alcohol sulfate very similar to the bile salts found in the earliest vertebrates to evolve, the jawless fish [103,104]. The bile salt synthetic pathway leading to C27 bile alcohol sulfates is a simpler pathway than that needed to produce C24 bile acids such as cholic acid (avoiding for example the need to cleave the cholesterol side-chain) and likely represents the first bile salt synthetic pathway to evolve in vertebrates [100,102].”
The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity
Lithocholic acid (LCA) is a hydrophobic secondary bile acid that is primarily formed in the intestine by the bacterial 7α-dehydroxylation of chenodeoxycholic acid. Administration ofLCA and its conjugates to rodents is known to cause intrahepatic cholestasis (1213). Cholestasis, functionally defined as a cessation or impairment of bile flow, can cause nutritional imbalance related to malabsorption of lipids and fat-soluble vitamins and, moreover, irreversible liver damage as a result of the accumulation of toxins normally excreted in bile (14). In humans, elevated levels of LCA are found in patients suffering from chronic cholestatic liver disease (15). The potentially harmful effects of LCA and other bile acids are attenuated by two hepatic detoxification pathways, namely hydroxylation and conjugation. These reactions make the bile acid more hydrophilic and facilitate its excretion in the feces or urine. Notably, 6-hydroxylation of LCA is catalyzed by members of the CYP3A subfamily (1617).”

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