Caffeine molecular structure

For the drink, see coffee. Caffeine is a methylxanthine in coffee, tea, and cocoa. Medicine classifies it as a drug; physiologically it acts as a nutrient-like adaptogen whose effects depend on dose, meal context, and matrix (coffee vs isolated pills).[1]

I think it would be good to reconsider coffee's place in the diet and in health care.

— Ray Peat[2]

Peat listed lower thyroid disease incidence in coffee drinkers, liver protection from alcohol and acetaminophen in animal models, and anticancer effects against radiation, chemical carcinogens, viruses, and estrogens.[3]

Hormones, breast tissue, and cancer

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Caffeine synergizes with progesterone, and increases its concentration in blood and tissues.

— Ray Peat[4]

Peat wrote cystic breast disease is not caused by caffeine; caffeine's effects on cyclic AMP resemble Progesterone opposing Estrogen in breast tissue.[5] Many studies over decades showed anticancer protection, including against estrogen-driven breast changes.[6]

Caffeine stops production of free radicals by inhibiting xanthine oxidase, an important factor in tissue stress.

— Ray Peat[7]

Coffee and caffeine intake inversely associated with Parkinson disease risk (Ross et al., 2000).[8] Acute coffee lowered serum prolactin in a human crossover trial.[9]

A single dose of caffeine significantly increased 5-alpha-reductase activity in the rat diencephalon, the enzyme that converts testosterone to DHT, alongside several other centrally-acting drugs tested in the same study.[10]

Chronic low-dose caffeine raised testosterone and DHT in rats via this same 5-alpha-reductase pathway, but the same study found this was accompanied by epithelial cell proliferation and hyperplasia in the ventral prostate in most treated animals, a caution against assuming the hormone increase is unambiguously beneficial.[11] Separately, a single caffeine injection produced dose- and time-dependent increases in brain pregnenolone, progesterone, and allopregnanolone in rats, one proposed mechanism behind caffeine's stimulant and anti-anxiety effects.[12] Caffeine and caffeic acid also suppressed growth of both estrogen-receptor-positive and -negative breast cancer cell lines, with caffeine specifically reducing estrogen receptor and cyclin D1 abundance in ER+ cells.[13]

Cellular energy and mitochondrial effects

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Caffeine restored cytochrome oxidase (CcOX) activity and cardiac function in a rat sepsis model, at a dose equivalent to roughly one cup of coffee in humans; sepsis otherwise significantly impairs this terminal enzyme of the electron transport chain.[14] A separate study found caffeine upregulates cytochrome oxidase subunit expression and activity in the striatum specifically in males, via adenosine A2A receptor blockade, a proposed mechanism for caffeine's association with lower Parkinson's disease risk.[15]

Caffeine and the mitochondrial uncoupler 2,4-dinitrophenol (DNP) produced nearly identical effects on cellular metabolism in muscle cells, both inducing PGC-1alpha expression and increasing mitochondrial content and oxidative/total metabolism in a dose- and time-dependent manner.[16]

Metabolic effects, dosing, and tolerance

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A dose-response trial in athletes found 3 mg/kg and 6 mg/kg caffeine both improved endurance by about 22%, while 9 mg/kg gave no additional benefit; critically, the lowest, still fully effective dose did not raise plasma epinephrine or free fatty acids, while the two higher doses did, contradicting the assumption that caffeine's ergogenic effect requires a catecholamine/stress response.[17] Separately, a controlled human trial found that whatever acute stress response caffeine does produce (elevated blood pressure, heart rate, plasma catecholamines) develops near-complete tolerance within 1-4 days of regular use, with no detectable withdrawal effect after 7 days of use followed by discontinuation.[18]

Metabolism and practical use

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Caffeine raises metabolic rate; Peat wrote to take it with food and enough Sugar. Six hundred milligrams at once is too much unless a large meal slows absorption.[19]

Animal growth retardation from huge prenatal caffeine doses was prevented by added sucrose in experiments Peat cited; rational study design might show maternal coffee benefits through progesterone support, lower serotonin, and better uterine perfusion.[20]

As Thyroid supplementation raises temperature and pulse, large caffeine doses (800–1600 mg) may be replaceable over time; Peat suspected benefits beyond ergogenic use when free fatty acids are not rising.[21] High-dose caffeine can raise estradiol in women in epidemiology Peat discussed in email; context matters.[22]

Caffeine inhibits intestinal Iron absorption with meals, overlapping Peat's iron-limiting advice.[23] See Coffee for coffee-as-beverage nutrient content (magnesium, B vitamins, heavy-metal removal via the drip method); see also Liver, Harm reduction.

Neuroprotection and neuroinflammation

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Caffeine attenuates lipopolysaccharide-induced neuroinflammation in rats, supporting a protective role against endotoxin-driven damage to the blood-brain barrier implicated in MS, Alzheimer's disease, and Parkinson's disease.[24]

Screening for small molecules that raise brain NMNAT2, an enzyme with both a neuroprotective function and a "chaperone" role against the misfolded tau protein implicated in Alzheimer's, Parkinson's, Huntington's disease, and ALS, identified caffeine among 24 compounds capable of boosting the enzyme, at a human-equivalent dose of about 150-300 mg daily.[25]

Chronic caffeine treatment attenuated experimental autoimmune encephalomyelitis (an animal model of MS) in rats, consistent with caffeine and niacinamide together showing effectiveness across several autoimmune conditions.[26]

Antiviral activity

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Caffeine and related methylxanthines (including theophylline) inhibit HIV-1 replication in primary human cells by acting at the same step of the viral life cycle as the drug itself.[27]

Topical use

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Hair growth

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In organ-cultured human hair follicles, caffeine counteracted testosterone's suppression of hair shaft production, prolonging the anagen (growth) phase and stimulating hair matrix keratinocyte proliferation in both male and female follicles, with female follicles showing greater sensitivity.[28]

Weight loss

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Adding caffeine to a topical plant-extract lipolytic solution more than doubled its fat-loss efficacy in rats; the extract alone promoted lipolysis via beta-adrenergic signaling and upregulated the thermogenic protein UCP1 in subcutaneous fat.[29]

Skin cancer protection

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Topical/oral caffeine inhibits UVB-induced thymine dimer formation and sunburn lesions in mouse skin, while separately enhancing UVB-induced apoptosis of damaged, precancerous cells through both p53-dependent and p53-independent mechanisms.[30]

Gut effects

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Caffeine dose-dependently protected against ibuprofen-induced gastric mucosal damage in rats, apparently through increased gastric mucosal blood flow and suppressed neutrophil activation, rather than by simply reducing acid output.[31]

Lifespan and other findings

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Caffeine was one of six FDA-approved drugs found to protect C. elegans neurons from glucose toxicity and extend lifespan in that model, through a mechanism depending on the CBP-1 protein.[32] Theanine (found in tea) antagonizes caffeine's stimulatory effects at roughly equivalent molar doses in animal EEG studies, offering one explanation for why tea's stimulant effect differs qualitatively from coffee's.[33]

Serotonin system

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Chronic caffeine ingestion alters the density of a wide range of brain receptors, including a 26-30% increase in cortical 5-HT1/5-HT2 serotonin receptor density, a 40-50% increase in muscarinic and nicotinic receptor density, a 65% increase in GABA-A-associated benzodiazepine binding sites, and a 25% decrease in beta-adrenergic receptor density, at a dose equivalent to moderate daily human intake.[34] Caffeine also suppresses the exercise-induced rise in tryptophan hydroxylase (the serotonin-synthesizing enzyme) in the rat brain, one proposed ergogenic mechanism.[35] However, five days of high-dose caffeine in rats followed by withdrawal decreased brain serotonin (without affecting tryptophan levels), a proposed mechanism for caffeine-withdrawal depression; this is a caution specifically about sudden discontinuation after sustained high intake, not about caffeine use itself.[36] Caffeine also decreases exhaled nitric oxide, an effect that needs to be accounted for when interpreting nitric oxide measurements in respiratory research.[37]

Cardiovascular and metabolic

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Chronic caffeine intake (equivalent to regular coffee consumption) reduced salt-sensitive hypertension in rats by activating AMPK in the kidney, which inhibits the epithelial sodium channel and increases urinary sodium excretion, without affecting sympathetic nervous activity, distinguishing this long-term effect from caffeine's acute, transient blood-pressure-raising effect.[38]

Digestive and antimicrobial effects

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Caffeine and the related methylxanthine aminophylline inhibited growth of several pathogenic bacterial strains in vitro, though at concentrations higher than standard antibiotics.[39] High-dose caffeine also inhibited parathyroid hormone secretion in human parathyroid cells via reduced cAMP and protein kinase A activity, independent of any change in intracellular calcium.[40] Caffeine's effect on intestinal calcium absorption is small (each cup of coffee costs roughly 5-10 mg of calcium) and controlled balance studies find as little as 1-2 tablespoons of milk fully offsets it, meaning coffee taken with dairy carries little practical calcium cost.[41]

Aspirin synergy

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Aspirin alone is dopaminergic only at very high doses, but combining a human-equivalent dose of about 500mg aspirin with 50-75mg caffeine produced additive dopaminergic (hyperactivity) effects lasting up to 6 hours in rats, likely via salicylate's effect on catecholamine utilization combined with caffeine's phosphodiesterase inhibition.[42] In humans, adding 64mg caffeine to 800mg aspirin significantly improved vigilance and self-reported efficiency beyond either substance alone, with no adverse mood effects detected.[43] Caffeine also increases aspirin's absorption rate and peak plasma concentration by about 25% and 17% respectively, without changing its half-life, volume of distribution, or clearance.[44]

Reproductive effects

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In a double-blind randomized trial, 100mg caffeine taken on demand before intercourse more than doubled intravaginal ejaculation latency time (from 144 to 312 seconds on average) in men with premature ejaculation, with no significant change in the placebo group.[45]

See also

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References

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  1. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  2. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  3. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  4. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  5. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  6. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  7. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  8. ↑ Ross GW, et al. "Association of coffee and caffeine intake with the risk of Parkinson disease," JAMA. 2000. PMID 10819950.
  9. ↑ Rodak K et al., "The Examination of the Influence of Caffeinated Coffee Consumption on the Concentrations of Serum Prolactin and Selected Parameters of the Oxidative-Antioxidant Balance in Young Adults: A Preliminary Report," Oxidative medicine and cellular longevity, 2022
  10. ↑ Kaneyuki T, Kohsaka M, Shohmori T. "Sex hormones metabolism in the brain: influence of central acting drugs on 5 alpha-reduction in rat diencephalon," Endocrinol Jpn. 1979;26(3):345-351.
  11. ↑ Sarobo C, Lacorte LM, Martins M, et al. "Chronic caffeine intake increases androgenic stimuli, epithelial cell proliferation and hyperplasia in rat ventral prostate," Int J Exp Pathol. 2012;93(6):429-437.
  12. ↑ Concas A, Porcu P, Sogliano C, et al. "Caffeine-induced increases in the brain and plasma concentrations of neuroactive steroids in the rat," Pharmacol Biochem Behav. 2000;66(1):39-45.
  13. ↑ Rosendahl AH, Perks CM, Zeng L, et al. "Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer," Clin Cancer Res. 2015;21(8):1877-1887.
  14. ↑ Verma R, Huang Z, Deutschman CS, Levy RJ. "Caffeine restores myocardial cytochrome oxidase activity and improves cardiac function during sepsis," Crit Care Med. 2009;37(4):1397-1402.
  15. ↑ Jones FS, Jing J, Stonehouse AH, et al. "Caffeine stimulates cytochrome oxidase expression and activity in the striatum in a sexually dimorphic manner," Mol Pharmacol. 2008;74(3):673-684.
  16. ↑ Vaughan RA, Garcia-Smith R, Bisoffi M, et al. "Effects of Caffeine on Metabolism and Mitochondria Biogenesis in Rhabdomyosarcoma Cells Compared with 2,4-Dinitrophenol," Nutr Metab Insights. 2012;5:59-70.
  17. ↑ Graham TE, Spriet LL. "Metabolic, catecholamine, and exercise performance responses to various doses of caffeine," J Appl Physiol. 1995;78(3):867-874.
  18. ↑ Robertson D, Wade D, Workman R, et al. "Tolerance to the humoral and hemodynamic effects of caffeine in man," J Clin Invest. 1981;67(4):1111-1117.
  19. ↑ "Ray Peat Email Advice Depository," Low Tox in Forum thread
  20. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  21. ↑ "Ray Peat Email Advice Depository," Low Tox in Forum thread
  22. ↑ "Ray Peat Email Advice Depository," Low Tox in Forum thread
  23. ↑ "Caffeine: A vitamin-like nutrient, or adaptogen," Ray Peat article
  24. ↑ Brothers HM, Marchalant Y, Wenk GL. "Caffeine attenuates lipopolysaccharide-induced neuroinflammation," Neurosci Lett. 2010;480(2):97-100.
  25. ↑ Ali YO, Bradley G, Lu HC. "Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons," Sci Rep. 2017;7:43846.
  26. ↑ Chen GQ, Chen YY, Wang XS, et al. "Chronic caffeine treatment attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats," Brain Res. 2010;1309:116-125.
  27. ↑ Nunnari G, Argyris E, Fang J, et al. "Inhibition of HIV-1 replication by caffeine and caffeine-related methylxanthines," Virology. 2005;335(2):177-184.
  28. ↑ Fischer TW, Herczeg-Lisztes E, Funk W, et al. "Differential effects of caffeine on hair shaft elongation, matrix and outer root sheath keratinocyte proliferation, and transforming growth factor-β2/insulin-like growth factor-1-mediated regulation of the hair cycle in male and female human hair follicles in vitro," Br J Dermatol. 2014;171(5):1031-1043.
  29. ↑ Mori S, Satou M, Kanazawa S, et al. "Body fat mass reduction and up-regulation of uncoupling protein by novel lipolysis-promoting plant extract," Int J Biol Sci. 2009;5(4):311-318.
  30. ↑ Conney AH, Lu YP, Lou YR, Kawasumi M, Nghiem P. "Mechanisms of Caffeine-Induced Inhibition of UVB Carcinogenesis," Front Oncol. 2013;3:144.
  31. ↑ Koyama R, Kataoka H, Tanaka Y, et al. "Effect of caffeine on ibuprofen-induced gastric mucosal damage in rats," J Pharm Pharmacol. 1999;51(7):817-824.
  32. ↑ Lublin A, Isoda F, Patel H, et al. "FDA-Approved Drugs that Protect Mammalian Neurons from Glucose Toxicity Slow Aging Dependent on Cbp and Protect Against Proteotoxicity," PLoS One. 2011;6(11):e27762.
  33. ↑ Kakuda T, Nozawa A, Unno T, et al. "Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat," Biosci Biotechnol Biochem. 2000;64(2):287-293.
  34. ↑ Shi D, Nikodijević O, Jacobson KA, Daly JW. "Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain," Cell Mol Neurobiol. 1993;13(3):247-261.
  35. ↑ Lim BV, Jang MH, Shin MC, et al. "Caffeine inhibits exercise-induced increase in tryptophan hydroxylase expression in dorsal and median raphe of Sprague-Dawley rats," Neurosci Lett. 2001;308(1):25-28.
  36. ↑ Haleem DJ, Yasmeen A, Haleem MA, Zafar A. "24h withdrawal following repeated administration of caffeine attenuates brain serotonin but not tryptophan in rat brain: implications for caffeine-induced depression," Life Sci. 1995;57(19):PL285-292.
  37. ↑ Bruce C, Yates DH, Thomas PS. "Caffeine decreases exhaled nitric oxide," Thorax. 2002;57(4):361-363.
  38. ↑ Yu H, Yang T, Gao P, et al. "Caffeine intake antagonizes salt-sensitive hypertension through improvement of renal sodium handling," Sci Rep. 2016;6:25746.
  39. ↑ AL-Janabi AAHS. "Potential Activity of the Purine Compounds Caffeine and Aminophylline on Bacteria," J Glob Infect Dis. 2011;3(2):133-137.
  40. ↑ Lu M, Farnebo LO, Bränström R, Larsson C. "Inhibition of Parathyroid Hormone Secretion by Caffeine in Human Parathyroid Cells," J Clin Endocrinol Metab. 2013;98(8):E1345-E1351.
  41. ↑ Heaney RP. "Effects of caffeine on bone and the calcium economy," Food Chem Toxicol. 2002;40(9):1263-1270. PMID 12204390.
  42. ↑ Collins C, Laird RI, Richards PT, Starmer GA, Weyrauch S. "Aspirin-caffeine interaction in the rat," J Pharm Pharmacol. 1979;31(9):611-614.
  43. ↑ Lieberman HR, Wurtman RJ, Emde GG, Coviella IL. "The effects of caffeine and aspirin on mood and performance," J Clin Psychopharmacol. 1987;7(5):315-320.
  44. ↑ Yoovathaworn KC, Sriwatanakul K, Thithapandha A. "Influence of caffeine on aspirin pharmacokinetics," Eur J Drug Metab Pharmacokinet. 1986;11(1):71-76.
  45. ↑ Saadat SH, Ahmadi K, Panahi Y. "The effect of on-demand caffeine consumption on treating patients with premature ejaculation: a double-blind randomized clinical trial," Curr Pharm Biotechnol. 2015;16(3):281-287.