SavedAdd your journal

Journals / Ankara Üniversitesi Eczacılık Fakültesi Dergisi / 2026 / Cilt: 50 Sayı: 3

PSYCHOPHARMACOLOGICAL EFFECTS OF CAFFEINE: IMPLICATIONS FOR NEUROPROTECTIVE USE

KAFEİNİN PSİKOFARMAKOLOJİK ETKİLERİ: NÖROPROTEKTİF KULLANIMA İLİŞKİN ÇIKARIMLAR

Meryem Nezlioğlu(Erciyes Üniversitesi)0009-0002-6041-5702
Ayşe Kübra Karaboğa Arslan(ERCIYES UNIVERSITY, FACULTY OF PHARMACY)0000-0002-4689-0657
Pages
772–796
Publication Date
2026-09-19
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Although its potential therapeutic effects on neurodegenerative diseases are promising, its impact on cognitive functions and mood remains controversial.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:Objective: Caffeine, a purine alkaloid known as 1,3,7-trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, is a widely consumed psychostimulant globally.
📊
Key Findings & Data:While moderate consumption is generally safe, excessive intake carries significant risks.
💡
Conclusion & Impact:Although its potential therapeutic effects on neurodegenerative diseases are promising, its impact on cognitive functions and mood remains controversial.
🔬Design:Review & Systematic Survey
📍Scope:Comprehensive Sample
⚙️Variables:Kafein · nöroprotektif · nörotransmiter

Abstract

Objective: Caffeine, a purine alkaloid known as 1,3,7-trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, is a widely consumed psychostimulant globally. This comprehensive review aims to explore the multifaceted effects of caffeine on human physiology. In this context, it delves into the pharmacokinetic properties of caffeine, encompassing its absorption, distribution, metabolism, and elimination processes, as well as its pharmacodynamic mechanisms, such as its effects on adenosine receptors, modulation of neurotransmitter systems, and influence on cellular signaling pathways. Furthermore, it evaluates the neurological impacts of caffeine, its potential benefits on cognitive functions, possible protective effects against neurodegenerative diseases, and adverse effects that may arise from excessive consumption. This review aimed to elucidate the complex interactions and potential therapeutic applications of caffeine, thereby providing a valuable contribution to the scientific literature. Result and Discussion: Caffeine has complex effects on human health. While moderate consumption is generally safe, excessive intake carries significant risks. The pharmacokinetic and pharmacodynamic properties of caffeine highlight the importance of individual differences and genetic polymorphisms. Caffeine exerts psychostimulant effects through various mechanisms by influencing neurotransmitter systems. Although its potential therapeutic effects on neurodegenerative diseases are promising, its impact on cognitive functions and mood remains controversial.

Özet

Amaç: Kafein, 1,3,7-trimetilksantin veya 3,7-dihidro-1,3,7-trimetil-1H-pürin-2,6-dion olarak bilinen bir pürin alkaloitidir. Bu kapsamlı derleme, dünya genelinde yaygın olarak tüketilen bir psikostimülan olan kafeinin, insan fizyolojisi üzerindeki çok yönlü etkilerini incelemeyi amaçlamaktadır. Bu bağlamda, kafeinin absorpsiyon, dağılım, metabolizma ve eliminasyon süreçlerini kapsayan farmakokinetik özellikleri ile adenozin reseptörleri üzerindeki etkileri, nörotransmiter sistemlerindeki modülasyonu ve hücresel sinyal iletim yolları üzerindeki etkileri gibi farmakodinamik mekanizmalarını ayrıntılı olarak ele almaktadır. Ayrıca, kafeinin nörolojik etkileri, bilişsel fonksiyonlar üzerindeki potansiyel faydaları, nörodejeneratif hastalıklar üzerindeki olası koruyucu etkileri ve aşırı tüketiminin neden olabileceği olumsuz etkileri de değerlendirilmektedir. Bu derleme, kafeinin karmaşık etkileşimlerini ve potansiyel terapötik kullanımlarını aydınlatarak, bilimsel literatüre değerli bir katkı sağlamayı hedeflemektedir. Sonuç ve Tartışma: Kafeinin insan sağlığı üzerinde karmaşık etkileri vardır. Günde 400 mg’a kadar (yaklaşık 4 fincan kahveye denk) tüketimi genellikle güvenli kabul edilirken, bu miktarın üzerindeki dozlar veya yüksek miktarlı tek seferlik alımlar ciddi riskler taşımaktadır. Kafeinin farmakokinetik ve farmakodinamik özellikleri, bireysel farklılıkların ve genetik polimorfizmlerin önemini vurgulamaktadır. Kafein, nörotransmiter sistemleri etkileyerek çeşitli etki mekanizmaları aracılığıyla psikostimülan etki gösterir. Nörodejeneratif hastalıklar üzerindeki potansiyel terapötik etkileri umut verici olsa da, bilişsel fonksiyonlar ve ruh hali üzerindeki etkileri hala tartışmalıdır.

🔖

Cite This Article

Nezlioğlu, M., Arslan, A. K. K. (2026). PSYCHOPHARMACOLOGICAL EFFECTS OF CAFFEINE: IMPLICATIONS FOR NEUROPROTECTIVE USE. Ankara Üniversitesi Eczacılık Fakültesi Dergisi, Cilt: 50 Sayı: 3, 772–796. https://doi.org/10.33483/jfpau.1679029

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (169)

  1. Rodak, K., Kokot, I., Kratz, E.M. (2021). Caffeine as a factor influencing the functioning of the human body-Friend or foe?. Nutrients, 13(9), 3088. [CrossRef]
  2. Willson, C. (2018). The clinical toxicology of caffeine: A review and case study. Toxicology Reports, 5, 1140-1152. [CrossRef]
  3. Reddy, V.S., Shiva, S., Manikantan, S., et al. (2024). Pharmacology of caffeine and its effects on the human body. European Journal of Medicinal Chemistry Reports, 10, 100138. [CrossRef]
  4. Grzegorzewski, J., Bartsch, F., Köller, A., et al. (2022). Pharmacokinetics of caffeine: A systematic analysis of reported data for application in metabolic phenotyping and liver function testing. Frontiers in Pharmacology, 12, 752826. [CrossRef]
  5. Alasmari, F. (2020). Caffeine induces neurobehavioral effects through modulating neurotransmitters. Saudi Pharmaceutical Journal, 28(4), 445-451. [CrossRef]
  6. Kolahdouzan, M., Hamadeh, M.J. (2017). The neuroprotective effects of caffeine in neurodegenerative diseases. CNS Neuroscience & Therapeutics, 23(4), 272-290. [CrossRef]
  7. Ruggiero, M., Calvello, R., Porro, C., et al. (2022). Neurodegenerative diseases: Can caffeine be a powerful ally to weaken neuroinflammation? International Journal of Molecular Sciences, 23(21), 12958. [CrossRef]
  8. Sharma, V., Sharma, A., Verma, K., et al. (2023). A comprehensive review on pharmacological potentials of caffeine. Journal of Applied Pharmaceutical Sciences and Research, 6(3), 16-26. [CrossRef]
  9. Krishna Sri, P.S.B.J., Padmavathy, S. (2018). A short review on the effect of functional group in methylxanthine (caffeine) class of drugs. Biochemistry & Pharmacology (Los Angel), 7(4), 100257. [CrossRef]
  10. Fakioğlu, M., Kalpaklı, Y. (2022). Mechanism and behavior of caffeine sorption: Affecting factors. RSC Advances, 12(41), 26504-26513. [CrossRef]
  11. Rivers, W. H. R., Webber, H.N. (1907). The action of caffeine on the capacity for muscular work. Journal of Physiology, 36(1), 33-47. [CrossRef]
  12. Chaugule, A.A., Patil, H.H., Pagariya, S., et al. (2019). Extraction of caffeine. International Journal of Advanced Research in Chemical Science (IJARCS), 6(9), 11-19.
  13. Faudone, G., Arifi, S., Merk, D. (2021). The medicinal chemistry of caffeine. Journal of Medicinal Chemistry, 64(11), 7156-7178. [CrossRef]
  14. McLellan, T.M., Caldwell, J.A., Lieberman, H.R. (2016). A review of caffeine’s effects on cognitive, physical and occupational performance. Neuroscience & Biobehavioral Reviews, 71, 294-312. [CrossRef]
  15. Saimaiti, A., Zhou, D.D., Li, J., et al. (2023). Dietary sources, health benefits, and risks of caffeine. Critical Reviews in Food Science and Nutrition, 63(29), 9648-9666. [CrossRef]
  16. Panagiotou, M., Meijer, M., Meijer, J.H., et al. (2019). Effects of chronic caffeine consumption on sleep and the sleep electroencephalogram in mice. Journal of Psychopharmacology, 33(1), 122-131. [CrossRef]
  17. Rhee, J., Kim, R., Kim, Y., et al. (2015). Maternal caffeine consumption during pregnancy and risk of low birth weight: A dose-response meta-analysis of observational studies. PLoS One, 10(7), e0132334. [CrossRef]
  18. Alhowail, A., Aldubayan, M. (2020). Mechanisms underlying cognitive impairment induced by prenatal caffeine exposure. European Review for Medical and Pharmacological Sciences, 24(22), 11909-11913.
  19. Qian, J., Chen, Q., Ward, S.M., et al. (2020). Impacts of caffeine during pregnancy. Trends in Endocrinology & Metabolism, 31(3), 218-227. [CrossRef]
  20. Ruiz-Moreno, C., Lara, B., Salinero, J.J., et al. (2020). Time course of tolerance to adverse effects associated with the ingestion of a moderate dose of caffeine. European Journal of Nutrition, 59(7), 3293-3302. [CrossRef]
  21. Alstadhaug, K.B., Ofte, H.K., Müller, K.I., et al. (2020). Sudden caffeine withdrawal triggers migraine-a randomized controlled trial. Frontiers in Neurology, 11, 1002. [CrossRef]
  22. Redondo, B., Vera, J., Molina, R., et al. (2020). Short-term effects of caffeine intake on anterior chamber angle and intraocular pressure in low caffeine consumers. Graefe's Archive for Clinical and Experimental Ophthalmology, 258(3), 613-619. [CrossRef]
  23. Murray, A., Traylor, J. (2023). Caffeine Toxicity. StatPearls Publishing, Treasure Island, FL.
  24. Cappelletti, S., Piacentino, D., Sani, G., et al. (2015). Caffeine: Cognitive and physical performance enhancer or psychoactive drug? Current Neuropharmacology, 13(1), 71-88. [CrossRef]
  25. Cappelletti, S., Piacentino, D., Fineschi, V., et al. (2018). Caffeine-related deaths: Manner of deaths and categories at risk. Nutrients, 10(5), 611. [CrossRef]
  26. Seifert, S.M., Seifert, S.A., Schaechter, J.L., et al. (2013). An analysis of energy-drink toxicity in the National Poison Data System. Clinical Toxicology, 51(7), 566-574. [CrossRef]
  27. Tsuji, T., Morita, S., Saito, T., et al. (2020). Serum potassium level as a biomarker for acute caffeine poisoning. Acute Medicine & Surgery, 7(1), e568. [CrossRef]
  28. Mukhiddinovna, I.M. (2023). High caffeine exposure increases ovarian estradiol production in immature rats. Journal of Healthcare and Life Science Research, 2(3), 8-11.
  29. Arnaud, M.J. (2011). Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man. Ed: Fredholm, B.B. Methylxanthines, Springer, Berlin, 33-91. [CrossRef]
  30. Roberts, A. (2016). Caffeine: An Evaluation of the Safety Database. Ed: Gupta, R.C. Nutraceuticals: Efficacy, Safety and Toxicity, Academic Press, San Diego, 417-434. [CrossRef]
  31. Dorne, J.L.C.M., Walton, K., Renwick, A.G. (2001). Uncertainty factors for chemical risk assessment: Human variability in the pharmacokinetics of CYP1A2 probe substrates. Food and Chemical Toxicology, 39(7), 681-696. [CrossRef]
  32. Sutrisna, E. (2016). The impact of CYP1A2 and CYP2E1 genes polymorphism on theophylline response. Journal of Clinical and Diagnostic Research, 10(11), FE01-FE03. [CrossRef]
  33. Barcelos, R.P., Lima, F.D., Carvalho, N.R., et al. (2020). Caffeine effects on systemic metabolism, oxidative-inflammatory pathways, and exercise performance. Nutrition Research, 80, 1-17. [CrossRef]
  34. dePaula, J., Farah, A. (2019). Caffeine consumption through coffee: Content in the beverage, metabolism, health benefits and risks. Beverages, 5(2), 37. [CrossRef]
  35. Zhang, Y., Liang, Y., Gu, Y. (2025). The dopaminergic system and Alzheimer’s disease. Neural Regeneration Research, 20(9), 2495-2512. [CrossRef]
  36. Matt, S.M., Gaskill, P.J. (2020). Where is dopamine and how do immune cells see it? Dopamine-mediated immune cell function in health and disease. Journal of Neuroimmune Pharmacology, 15, 114-164. [CrossRef]
  37. Shaikh, A., Ahmad, F., Teoh, S.L., et al. (2023). Targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease. Frontiers in Cellular Neuroscience, 17, 1292858. [CrossRef]
  38. Klein, M.O., Battagello, D.S., Cardoso, A.R., et al. (2019). Dopamine: Functions, signaling, and association with neurological diseases. Cellular and Molecular Neurobiology, 39(1), 31-59. [CrossRef]
  39. Ferré, S. (2008). An update on the mechanisms of the psychostimulant effects of caffeine. Journal of Neurochemistry, 105(4), 1067-1079. [CrossRef]
  40. Quarta, D., Borycz, J., Solinas, M., et al. (2004). Adenosine receptor-mediated modulation of dopamine release in the nucleus accumbens depends on glutamate neurotransmission and N-methyl-D-aspartate receptor stimulation. Journal of Neurochemistry, 91(4), 873-880. [CrossRef]
  41. Solinas, M., Ferré, S., You, Z.B., et al. (2002). Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. The Journal of Neuroscience, 22(15), 6321-6324. [CrossRef]
  42. Wang, C., Zhou, C., Guo, T., et al. (2023). Current coffee consumption is associated with decreased striatal dopamine transporter availability in Parkinson's disease patients and healthy controls. BMC Medicine, 21(1), 272. [CrossRef]
  43. Jang, M.H., Song, J. (2024). Adenosine and adenosine receptors in metabolic imbalance-related neurological issues. Biomedicine & Pharmacotherapy, 177, 116996. [CrossRef]
  44. Jacobson, K.A., Gao, Z.G., Matricon, P., et al. (2022). Adenosine A2A receptor antagonists: From caffeine to selective non-xanthines. British Journal of Pharmacology, 179(14), 3496-3511. [CrossRef]
  45. Cortés, A., Casadó-Anguera, V., Moreno, E., Casadó, V. (2016). Caffeine, Adenosine A1 Receptors, and Brain Cortex. Molecular Aspects. Ed: Preedy, V.R. Neuropathology of Drug Addictions and Substance Misuse, Academic Press, San Diego, 741-752. [CrossRef]
  46. Ribeiro, J.A., Sebastião, A.M. (2010). Caffeine and adenosine. Journal of Alzheimer's Disease, 20(Suppl. 1), S3-S15. [CrossRef]
  47. Merighi, S., Travagli, A., Nigro, M., et al. (2023). Caffeine for prevention of Alzheimer's disease: Is the A2A adenosine receptor its target?. Biomolecules, 13(6), 967. [CrossRef]
  48. Chen, J.F., Sonsalla, P.K., Pedata, F., et al. (2007). Adenosine A2A receptors and brain injury: Broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation. Progress in Neurobiology, 83(5), 310-331. [CrossRef]
  49. Schiffmann, S.N., Fisone, G., Moresco, R., et al. (2007). Adenosine A2A receptors and basal ganglia physiology. Progress in Neurobiology, 83(5), 277-292. [CrossRef]
  50. Haanes, K.A., Labastida-Ramírez, A., Chan, K.Y., et al. (2018). Characterization of the trigeminovascular actions of several adenosine A2A receptor antagonists in an in vivo rat model of migraine. The Journal of Headache and Pain, 19(1), 41. [CrossRef]
  51. Song, X., Kirtipal, N., Lee, S., et al. (2023). Current therapeutic targets and multifaceted physiological impacts of caffeine. Phytotherapy Research, 37(12), 5558-5598. [CrossRef]
  52. Ferreira, D.D., Stutz, B., de Mello, F.G., et al. (2014). Caffeine potentiates the release of GABA mediated by NMDA receptor activation: Involvement of A1 adenosine receptors. Neuroscience, 281, 208-215. [CrossRef]
  53. Vecchio, I., Sorrentino, L., Paoletti, A., et al. (2021). The state of the art on acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease. Journal of Central Nervous System Disease, 13, 11795735211029113. [CrossRef]
  54. Souza, A.C., Souza, A., Medeiros, L.F., et al. (2015). Maternal caffeine exposure alters neuromotor development and hippocampus acetylcholinesterase activity in rat offspring. Brain Research, 1595, 10-18. [CrossRef]
  55. Sharma, M., Sharma, A., Thakur, S., et al. (2023). Discovery of blood-brain barrier permeable and orally bioavailable caffeine-based amide derivatives as acetylcholinesterase inhibitors. Bioorganic Chemistry, 139, 106719. [CrossRef]
  56. Pohanka, M. (2012). Antioxidants countermeasures against sulfur mustard. Mini-Reviews in Medicinal Chemistry, 12(8), 742-748. [CrossRef]
  57. Chen, Z.R., Huang, J.B., Yang, S.L., et al. (2022). Role of cholinergic signaling in Alzheimer’s disease. Molecules, 27(6), 1816. [CrossRef]
  58. Echeverri, D., Montes, F.R., Cabrera, M., et al. (2019). Corrigendum to "Caffeine’s vascular mechanisms of action". International Journal of Vascular Medicine, 2019, 7480780. [CrossRef]
  59. Mota-Rojas, D., Villanueva-García, D., Hernández-Ávalos, I., et al. (2023). Cardiorespiratory and neuroprotective effects of caffeine in neonate animal models. Animals (Basel), 13(11), 1769. [CrossRef]
  60. Zhong, Z., Dong, H., Zhou, S., et al. (2024). Caffeine’s neuroprotective effect on memory impairment: Suppression of adenosine A2A receptor and enhancement of tyrosine hydroxylase in dopaminergic neurons under hypobaric hypoxia conditions. CNS Neuroscience & Therapeutics, 30(12), e70134. [CrossRef]
  61. Ősz, B.E., Jîtcă, G., Ștefănescu, R.E., et al. (2022). Caffeine and its antioxidant properties-it is all about dose and source. International Journal of Molecular Sciences, 23(21), 13074. [CrossRef]
  62. Wedick, N.M., Brennan, A.M., Sun, Q., et al. (2011). Effects of caffeinated and decaffeinated coffee on biological risk factors for type 2 diabetes: A randomized controlled trial. Nutrition Journal, 10, 93. [CrossRef]
  63. Marcinek, K., Luzak, B., Rozalski, M. (2024). The effects of caffeine on blood platelets and the cardiovascular system through adenosine receptors. International Journal of Molecular Sciences, 25(16), 8905. [CrossRef]
  64. Turnbull, D., Rodricks, J.V., Mariano, G.F., et al. (2017). Caffeine and cardiovascular health. Regulatory Toxicology and Pharmacology, 89, 165-185. [CrossRef]
  65. Yilmaz, F., Aydemi, R.S., Yilmaz, B., et al. (2024). Effects of dose-dependent chronic caffeine consumption in a rat burn wound model: Histopathological and immunohistochemical evaluation. Iranian Journal of Basic Medical Sciences, 27(9), 1180-1186.
  66. Berman, N.K., Honig, S., Cronstein, B.N., et al. (2022). The effects of caffeine on bone mineral density and fracture risk. Osteoporosis International, 33(6), 1235-1241. [CrossRef]
  67. Mubarak, B., Ahmed, M., Hussein, N., et al. (2024). Vitamin D, calcium and caffeine intake relationship to bone mineral density. Arab Gulf Journal of Scientific Research, 3, 1012-1025. [CrossRef]
  68. Romualdo, G.R., Rocha, A.B., Vinken, M., et al. (2019). Drinking for protection? Epidemiological and experimental evidence on the beneficial effects of coffee or major coffee compounds against gastrointestinal and liver carcinogenesis. Food Research International, 123, 567-589. [CrossRef]
  69. Lee, S.J., Park, S.Y., Bak, S., et al. (2023). Synergistic effect of saccharin and caffeine on antiproliferative activity in human ovarian carcinoma Ovcar-3 cells. International Journal of Molecular Sciences, 24(19), 14445. [CrossRef]
  70. Anwar, M.M., Laila, I.M.I. (2022). Mitigative effect of caffeine against diclofenac-induced hepato-renal damage and chromosomal aberrations in male albino rats. BMC Complementary Medicine and Therapies, 22, 327. [CrossRef]
  71. Di Pietrantonio, D., Pace Palitti, V., Cichelli, A., et al. (2024). Protective effect of caffeine and chlorogenic acids of coffee in liver disease. Foods, 13(14), 2280. [CrossRef]
  72. Salim, S. (2017). Oxidative stress and the central nervous system. Journal of Pharmacology and Experimental Therapeutics, 360(1), 201-205. [CrossRef]
  73. Choi, E.Y., Jang, J.Y., Cho, Y.O. (2010). Coffee intake can promote activity of antioxidant enzymes with increasing MDA level and decreasing HDL-cholesterol in physically trained rats. Nutrition Research and Practice, 4(4), 283. [CrossRef]
  74. Xu, H., Gan, C., Gao, Z., et al. (2020). Caffeine targets SIRT3 to enhance SOD2 activity in mitochondria. Frontiers in Cell and Developmental Biology, 8, 822. [CrossRef]
  75. Heatherley, S.V., Hayward, R.C., Seers, H.E., et al. (2005). Cognitive and psychomotor performance, mood, and pressor effects of caffeine after 4, 6 and 8 h caffeine abstinence. Psychopharmacology, 178(4), 461-470. [CrossRef]
  76. Smith, A., Sunderland, D., Christopher, G. (2005). Effects of repeated doses of caffeine on mood and performance of alert and fatigued volunteers. Journal of Psychopharmacology, 19(6), 620-626. [CrossRef]
  77. Renda, G., Committeri, G., Zimarino, M., et al. (2015). Genetic determinants of cognitive responses to caffeine drinking identified from a double-blind, randomized, controlled trial. European Neuropsychopharmacology, 25(6), 798-807. [CrossRef]
  78. Caballero, M., Núñez, F., Ahern, S., et al. (2011). Caffeine improves attention deficit in neonatal 6-OHDA lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD). Neuroscience Letters, 494(1), 44-48. [CrossRef]
  79. Ágoston, C., Urbán, R., Horváth, Z., et al. (2022). Self-medication of ADHD symptoms: Does caffeine have a role? Frontiers in Psychiatry, 13, 813545. [CrossRef]
  80. Vázquez, J.C., Martin de la Torre, O., López Palomé, J., et al. (2022). Effects of caffeine consumption on attention deficit hyperactivity disorder (ADHD) treatment: A systematic review of animal studies. Nutrients, 14(4), 739. [CrossRef]
  81. Adam, L.C., Repantis, D., Konrad, B.N., et al. (2021). Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study. Brain and Cognition, 154, 105802. [CrossRef]
  82. Fiani, B., Zhu, L., Musch, B.L., et al. (2021). The neurophysiology of caffeine as a central nervous system stimulant and the resultant effects on cognitive function. Cureus, 13(5), e15032. [CrossRef]
  83. Borota, D., Murray, E., Keceli, G., et al. (2014). Post-study caffeine administration enhances memory consolidation in humans. Nature Neuroscience, 17(2), 201-203. [CrossRef]
  84. Franceschini, S., Lulli, M., Bertoni, S., et al. (2020). Caffeine improves text reading and global perception. Journal of Psychopharmacology, 34(3), 315-325. [CrossRef]
  85. Araújo, L. F., Giatti, L., Reis, R.C., et al. (2015). Inconsistency of association between coffee consumption and cognitive function in adults and elderly in a cross-sectional study (ELSA-Brasil). Nutrients, 7(11), 9590-9601. [CrossRef]
  86. Sherman, S.M., Buckley, T.P., Baena, E., et al. (2016). Caffeine enhances memory performance in young adults during their non-optimal time of day. Frontiers in Psychology, 7, 1764. [CrossRef]
  87. Johnson-Kozlow, M., Kritz-Silverstein, D., Barrett-Connor, E., et al. (2002).Coffee consumption and cognitive function among older adults. American Journal of Epidemiology, 156(9), 842-850. [CrossRef]
  88. Cornelis, M.C., Weintraub, S., Morris, M.C. (2020a). Caffeinated coffee and tea consumption, genetic variation and cognitive function in the UK Biobank. The Journal of Nutrition, 150(8), 2164-2174. [CrossRef]
  89. Cornelis, M.C., Weintraub, S., Morris, M.C. (2020b). Recent caffeine drinking associates with cognitive function in the UK Biobank. Nutrients, 12(7), 1969. [CrossRef]
  90. Huck, N.O., McBride, S.A., Kendall, A.P., et al. (2008). The effects of modafinil, caffeine, and dextroamphetamine on judgments of simple versus complex emotional expressions following sleep deprivation. International Journal of Neuroscience, 118(4), 487-502. [CrossRef]
  91. Killgore, W.D., Lipizzi, E.L., Kamimori, G.H., et al. (2007). Caffeine effects on risky decision making after 75 hours of sleep deprivation. Aviation, Space, and Environmental Medicine, 78(10), 957-962. [CrossRef]
  92. Paiva, I., Cellai, L., Meriaux, C. (2022). Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription. The Journal of Clinical Investigation, 132(12), e149371. [CrossRef]
  93. Irwin, C., McCartney, D., Grant, G., et al. (2022). Effects of different sources of low-dose caffeine on mood/arousal and cognitive performance. Perceptual and Motor Skills, 129(6), 1672-1690. [CrossRef]
  94. Akyürek, E.G., Altınok, A., Karabay, A. (2025). Concurrent consumption of cocoa flavanols and caffeine does not acutely modulate working memory and attention. European Journal of Nutrition, 64(1), 35. [CrossRef]
  95. Chen, S.Q., Wang, Z.S., Ma, Y.X., et al. (2018). Neuroprotective effects and mechanisms of tea bioactive components in neurodegenerative diseases. Molecules, 23(3), 512. [CrossRef]
  96. Doyle, L.W., Schmidt, B., Anderson, P.J., et al. (2014). Reduction in developmental coordination disorder with neonatal caffeine therapy. The Journal of Pediatrics, 165(2), 356-359. [CrossRef]
  97. Hassanein, S.M., Gad, G.I., Ismail, R.I., et al. (2015). Effect of caffeine on preterm infants’ cerebral cortical activity: An observational study. Journal of Maternal-Fetal & Neonatal Medicine, 28(17), 2090-2095. [CrossRef]
  98. Ren, X., Chen, J.F. (2020). Caffeine and Parkinson’s disease: Multiple benefits and emerging mechanisms. Frontiers in Neuroscience, 14, 602697. [CrossRef]
  99. Manalo, R.V.M., Medina, P.M.B. (2020). Caffeine reduces deficits in mechanosensation and locomotion induced by L-DOPA and protects dopaminergic neurons in a transgenic Caenorhabditis elegans model of Parkinson’s disease. Pharmaceutical Biology, 58(1), 721-731. [CrossRef]
  100. Costa, M.S., Botton, P.H., Mioranzza, S., et al. (2008). Caffeine prevents age-associated recognition memory decline and changes brain-derived neurotrophic factor and tirosine kinase receptor (TrkB) content in mice. Neuroscience, 153(4), 1071-1078. [CrossRef]
  101. Prasanthi, J.R., Dasari, B., Marwarha, G., et al. (2010). Caffeine protects against oxidative stress and Alzheimer's disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radical Biology and Medicine, 49(7), 1212-1220. [CrossRef]
  102. Socała, K., Szopa, A., Serefko, A., et al. (2020). Neuroprotective effects of coffee bioactive compounds: A review. International Journal of Molecular Sciences, 22(1), 107. [CrossRef]
  103. Sonsalla, P.K., Wong, L.Y., Harris, S.L., et al. (2012). Delayed caffeine treatment prevents nigral dopamine neuron loss in a progressive rat model of Parkinson’s disease. Experimental Neurology, 234(2), 482-487. [CrossRef]
  104. Xu, Q., Park, Y., Huang, X., et al. (2010). Physical activities and future risk of Parkinson disease. Neurology, 75(4), 341-348. [CrossRef]
  105. Lindsay, J., Laurin, D., Verreault, R., et al. (2002). Risk factors for Alzheimer’s disease: A prospective analysis from the Canadian Study of Health and Aging. American Journal of Epidemiology, 156(5), 445-453. [CrossRef]
  106. Eskelinen, M.H., Ngandu, T., Tuomilehto, J., et al. (2009). Midlife coffee and tea drinking and the risk of late-life dementia: A population-based CAIDE study. Journal of Alzheimer's Disease, 16(1), 85-91. [CrossRef]
  107. Sugiyama, K., Tomata, Y., Kaiho, Y., et al. (2016). Association between coffee consumption and incident risk of disabling dementia in elderly Japanese: The Ohsaki Cohort 2006 Study. Journal of Alzheimer’s Disease, 50(2), 491-500. [CrossRef]
  108. Ritchie, K., Carrière, I., de Mendonca, A., et al. (2007). The neuroprotective effects of caffeine: A prospective population study (the Three City Study). Neurology, 69(6), 536-545. [CrossRef]
  109. Postuma, R.B., Lang, A.E., Munhoz, R.P., et al. (2012). Caffeine for treatment of Parkinson disease: A randomized controlled trial. Neurology, 79(7), 651-658. [CrossRef]
  110. Liu, R., Guo, X., Park, Y., et al. (2012). Caffeine intake, smoking, and risk of Parkinson disease in men and women. American Journal of Epidemiology, 175(11), 1200-1207. [CrossRef]
  111. Palacios, N., Gao, X., McCullough, M.L., et al. (2012). Caffeine and risk of Parkinson’s disease in a large cohort of men and women. Movement Disorders, 27(10), 1276-1282. [CrossRef]
  112. Altman, R.D., Lang, A.E., Postuma, R.B. (2011). Caffeine in Parkinson’s disease: A pilot open-label, dose-escalation study. Movement Disorders, 26(13), 2427–2431. [CrossRef]
  113. Lee, J., Lee, J.E., Kim, Y. (2017). Relationship between coffee consumption and stroke risk in Korean population: The Health Examinees (HEXA) Study. Nutrition Journal, 16, 7. [CrossRef]
  114. Shao, C., Tang, H., Wang, X., et al. (2021). Coffee consumption and stroke risk: Evidence from a systematic review and meta-analysis of more than 2.4 million men and women. Journal of Stroke and Cerebrovascular Diseases, 30(1), 105452. [CrossRef]
  115. Hedström, A.K., Mowry, E.M., Gianfrancesco, M.A., et al. (2016). High consumption of coffee is associated with decreased multiple sclerosis risk; results from two independent studies. Journal of Neurology, Neurosurgery & Psychiatry, 87(5), 454-460. [CrossRef]
  116. Madeira, M.H., Boia, R., Ambrósio, A.F., et al. (2017). Having a coffee break: The impact of caffeine consumption on microglia-mediated inflammation in neurodegenerative diseases. Mediators of Inflammation, 2017, 4761081. [CrossRef]
  117. Soleimani, S.M.A., Ekhtiari, H., Cadet, J.L. (2016). Drug-induced neurotoxicity in addiction medicine: From prevention to harm reduction. Progress in Brain Research, 223, 19-41. [CrossRef]
  118. Vulin, I., Tenji, D., Teodorovic, I., et al. (2022). Assessment of caffeine neurotoxicity using novel biomarkers of neural function in SH-SY5Y cells - Is there a need for environmental concern? Chemico-Biological Interactions, 365, 110082. [CrossRef]
  119. Kang, S.H., Lee, Y.A., Won, S.J., et al. (2002). Caffeine-induced neuronal death in neonatal rat brain and cortical cell cultures. Neuroreport, 13(15), 1945-1950. [CrossRef]
  120. van Koert, R.R., Bauer, P.R., Schuitema, I., et al. (2018). Caffeine and seizures: A systematic review and quantitative analysis. Epilepsy & Behavior, 80, 37-47. [CrossRef]
  121. Vesoulis, Z.A., McPherson, C., Neil, J.J., et al. (2016). Early high-dose caffeine increases seizure burden in extremely preterm neonates: A preliminary study. Journal of Caffeine Research, 6(3), 101-107. [CrossRef]
  122. Yu, N.Y., Bieder, A., Raman, A., et al. (2017). Acute doses of caffeine shift nervous system cell expression profiles toward promotion of neuronal projection growth. Scientific Reports, 7(1), 11458. [CrossRef]
  123. Blaise, J.H., Park, J.E., Bellas, N.J., et al. (2018). Caffeine consumption disrupts hippocampal long-term potentiation in freely behaving rats. Physiological Reports, 6(5), e13632. [CrossRef]
  124. López-Cruz, L., Salamone, J.D., Correa, M. (2018). Caffeine and selective adenosine receptor antagonists as new therapeutic tools for the motivational symptoms of depression. Frontiers in Pharmacology, 9, 526. [CrossRef]
  125. Manalo, R.V.M., Medina, P.M.B. (2018). Caffeine protects dopaminergic neurons from dopamine-induced neurodegeneration via synergistic adenosine-dopamine D2-like receptor interactions in transgenic caenorhabditis elegans. Frontiers in Neuroscience, 12, 137. [CrossRef]
  126. Owolabi, J.O., Adefule, K.A., Shallie, P.D., et al. (2021). Experimental study of pre- and postnatal caffeine exposure and its observable effects on selected neurotransmitters and behavioural attributes at puberty: Caffeine exposure and its observable effects on selected neurotranmitters and behaviour. Metabolic Brain Disease, 36(7), 2029-2046. [CrossRef]
  127. Saarinen, E.K., Kuusimäki, T., Lindholm, K., et al. (2024). Dietary caffeine and brain dopaminergic function in parkinson disease. Annals of Neurology, 96(2), 262-275. [CrossRef]
  128. Khadrawy, Y.A., Sawie, H.G., Hosny, E.N., et al. (2018). Assessment of the antidepressant effect of caffeine using rat model of depression induced by reserpine. Bulletin of the National Research Centre, 42(1), 36. [CrossRef]
  129. Kaur, N., Sharma, P., Banipal, T.S., et al. (2019). Effect of caffeine on the physicochemical properties of neurotransmitter GABA: Thermodynamic and theoretical approach. Journal of Chemical & Engineering Data, 64(9), 3919-3932. [CrossRef]
  130. Kamli, H., Shaikh, A., Bappi, M.H. (2023). Sclareol exerts synergistic antidepressant effects with quercetin and caffeine, possibly suppressing GABAergic transmission in chicks. Biomedicine & Pharmacotherapy, 168, 115768. [CrossRef]
  131. Kim, A.J., Senior, J., Chen, K. (2024). Catecholamines: Influence on healthy aging and the progression of neurodegenerative diseases. Neuroscience & Biobehavioral Reviews, 162, 105733. [CrossRef]
  132. Cui, W.Q., Wang, S.T., Pan, D., et al. (2020). Caffeine and its main targets of colorectal cancer. World Journal of Gastrointestinal Oncology, 12(2), 149-172. [CrossRef]
  133. Moustafa, F., Feldman, S.R.A. (2014). Review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology. Dermatology Online Journal, 20(5), 22608. [CrossRef]
  134. Stefanello, N., Spanevello, R.M., Passamonti, S. (2019). Coffee, caffeine, chlorogenic acid, and the purinergic system. Food and Chemical Toxicology, 123, 298–313. [CrossRef]
  135. Nabofa, E.E.W., Alada, A.R.A. (2020). Cardiovascular Effects of caffeine in rabbits involve Beta-1 Adrenergic receptor activation. Journal of Caffeine and Adenosine Research, 10(2), 84-91. [CrossRef]
  136. Goldstein, D.S., Sullivan, P., Corrales, A., et al. (2021). Multiple catechols in human plasma after drinking caffeinated or decaffeinated coffee. Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 1185, 122988. [CrossRef]
  137. Hamad, A.K.S. (2024). Caffeine and arrhythmias: A critical analysis of cardiovascular responses and arrhythmia susceptibility. Journal of the Saudi Heart Association, 36(4), 335-348. [CrossRef]
  138. Klinkenberg, I., Sambeth, A., Blokland, A. (2011). Acetylcholine and attention. Behavioural Brain Research, 221(2), 430-442. [CrossRef]
  139. Hosny, E.N., Sawie, H.G., Elhadidy, M.E., et al. (2019). Evaluation of antioxidant and anti-inflammatory efficacy of caffeine in rat model of neurotoxicity. Nutritional Neuroscience, 22(11), 789-796. [CrossRef]
  140. Nehlig, A., Daval, J.L., Debry, G. (1992). Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Research. Brain Research Reviews, 17(2), 139-170. [CrossRef]
  141. Jones, L.A., Sun, E.W., Martin, A.M., et al. (2020). The ever-changing roles of serotonin. International Journal of Biochemistry & Cell Biology, 125, 105776. [CrossRef]
  142. Simon, L.V., Torrico, T.J., Keenaghan, M. (2024). Serotonin syndrome. StatPearls Publishing, Treasure Island (FL).
  143. Bamalan, O.A., Moore, M.J., Al Khalili, Y. (2023). Physiology, serotonin. StatPearls Publishing, Treasure Island (FL).
  144. Arnold, M.R., Williams, P.H., McArthur, J.A., et al. (2019). Effects of chronic caffeine exposure during adolescence and subsequent acute caffeine challenge during adulthood on rat brain serotonergic systems. Neuropharmacology, 148, 257-271. [CrossRef]
  145. Szopa, A., Doboszewska, U., Herbet, M., et al. (2017). Chronic treatment with caffeine and its withdrawal modify the antidepressant-like activity of selective serotonin reuptake inhibitors in the forced swim and tail suspension tests in mice. Effects on Comt, Slc6a15 and Adora1 gene expression. Toxicology and Applied Pharmacology, 337, 95-103. [CrossRef]
  146. Ohta, R., Sano, C. (2022). Serotonin syndrome triggered by overuse of caffeine and complicated with neuroleptic malignant syndrome: A case report. Cureus, 14(2), e22468. [CrossRef]
  147. Lee, J.B., Kim, T.W. (2019). Ingestion of caffeine links dopamine and 5-hydroxytryptamine release during half immersion in 42°C hot water in humans. Journal of Exercise Rehabilitation, 15(4), 571-575. [CrossRef]
  148. Giles, G.E., Mahoney, C.R., Brunyé, T. T. (2012). Differential cognitive effects of energy drink ingredients: Caffeine, taurine, and glucose. Physiology & Behavior, 102(4), 569-577. [CrossRef]
  149. Kahathuduwa, C.N., Dhanasekara, C.S., Chin, S.H. (2018). l-Theanine and caffeine improve target-specific attention to visual stimuli by decreasing mind wandering: A human functional magnetic resonance imaging study. Nutrition Research, 49, 67-78. [CrossRef]
  150. Kahathuduwa, C.N., Wakefield, S., West, B.D., et al. (2020). Effects of L-theanine-caffeine combination on sustained attention and inhibitory control among children with ADHD: A proof-of-concept neuroimaging RCT. Scientific Reports, 10(1), 13072. [CrossRef]
  151. Mourad, I.M., Noor, N.A., Mohammed, H.S., et al. (2021). A neurochemical and electrophysiological study on the combined effects of caffeine and nicotine in the cortex of rats. Basic and Clinical Neuroscience, 12(5), 681-692. [CrossRef]
  152. Serra, M., Simola, N., Pollack, A.E., et al. (2024). Brain dysfunctions and neurotoxicity induced by psychostimulants in experimental models and humans: An overview of recent findings. Neural Regeneration Research, 19(9), 1908-1918. [CrossRef]
  153. Aziz, N., Serafi, A.S. (2020). Psychostimulants-a boon or bane during examinations. GSC Biological and Pharmaceutical Sciences, 13(1), 010-018. [CrossRef]
  154. Ballesteros-Yáñez, I., Castillo, C.A., Merighi, S., et al. (2018). The role of adenosine receptors in psychostimulant addiction. Frontiers in Pharmacology, 8, 985. [CrossRef]
  155. Kassim, F.M., Lim, J.H.M., Slawik, S.V., et al. (2023). The effects of caffeine and d-amphetamine on spatial span task in healthy participants. PLoS One, 18(7), e0287538. [CrossRef]
  156. Ferré, S., Díaz-Ríos, M., Salamone, J.D., et al. (2018). New developments on the adenosine mechanisms of the central effects of caffeine and their implications for neuropsychiatric disorders. Journal of Caffeine and Adenosine Research, 8(4), 121-131. [CrossRef]
  157. Mckenzie, A., Meshkat, S., Lui, L.M.W., et al. (2022). The effects of psychostimulants on cognitive functions in individuals with attention-deficit hyperactivity disorder: A systematic review. Journal of Psychiatric Research, 149, 252-259. [CrossRef]
  158. Cojocaru, A., Hogea, L.M., Poroch, V., et al. (2021). Effectiveness of psychostimulant and non-psychostimulant drug therapy in the attention deficit hyperactivity disorder. Applied Sciences, 11(2), 502. [CrossRef]
  159. França, A.P., Takahashi, R.N., Cunha, R.A., et al. (2018). Promises of caffeine in attention-deficit/hyperactivity disorder: From animal models to clinical practice. Journal of Caffeine and Adenosine Research, 8(4), 131-142. [CrossRef]
  160. Perrotte, G., Moreira, M.M.G., de Vargas Junior, A., et al. (2023). Effects of caffeine on main symptoms in children with ADHD: A systematic review and meta-analysis of randomized trials. Brain Sciences, 13(9), 1304. [CrossRef]
  161. Repantis, D., Bovy, L., Ohla, K., et al. (2021). Cognitive enhancement effects of stimulants: A randomized controlled trial testing methylphenidate, modafinil, and caffeine. Psychopharmacology, 238(2), 441-451. [CrossRef]
  162. Ramírez-delaCruz, M., Esteban-García, P., Abián, P., et al. (2024). Effects of different doses of caffeine on cognitive performance in healthy physically active individuals. European Journal of Nutrition, 63(8), 3025-3035. [CrossRef]
  163. de Bem Alves, A.C., Speck, A.E., Farias, H.R., et al. (2023). The striatum drives the ergogenic effects of caffeine. Purinergic Signalling, 19(4), 673-683. [CrossRef]
  164. Gardiner, C., Weakley, J., Burke, L.M., et al. (2023). The effect of caffeine on subsequent sleep: A systematic review and meta-analysis. Sleep Medicine Reviews, 69, 101764. [CrossRef]
  165. Weibel, J., Lin, Y.S., Landolt, H.P., et al. (2021). The impact of daily caffeine intake on nighttime sleep in young adult men. Scientific Reports, 11(1), 4668. [CrossRef]
  166. Koch, G., Schönfeld, N., Jost, K., et al. (2020). Caffeine preserves quiet sleep in preterm neonates. Pharmacology Research & Perspectives, 8(3), e00596. [CrossRef]
  167. Pauchon, B., Beauchamps, V., Gomez-Mérino, D., et al. (2024). Caffeine intake alters recovery sleep after sleep deprivation. Nutrients, 16(20), 3442. [CrossRef]
  168. Ferré, S. (2010). Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine. Journal of Alzheimer’s Disease, 20(Suppl 1), S35-S49. [CrossRef]
  169. Heckman, M.A., Weil, J., Gonzalez de Mejia, E. (2010). Caffeine (1,3,7-trimethylxanthine) in foods: A comprehensive review on consumption, functionality, safety, and regulatory matters. Journal of Food Science, 75(3), R77-R87. [CrossRef]