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The clinical toxicology of caffeine: A review and case study
Open accessAbstract
Caffeine is a widely recognized psychostimulant compound with a long history of consumption by humans. While it has received a significant amount of attention there is still much to be learned with respect to its toxicology in humans, especially in cases of overdose. A review of the history of consumption and the clinical toxicology of caffeine including clinical features, pharmacokinetics, toxicokinetics, a thorough examination of mechanism of action and management/treatment strategies are undertaken. While higher (i.e., several grams) quantities of caffeine are known to cause toxicity and potentially lethality, cases of mainly younger individuals who have experienced severe side effects and death despite consuming doses not otherwise known to cause such harm is troubling and deserves further study. An attempted case reconstruction is performed in an effort to shed light on this issue with a focus on the pharmacokinetics and pharmacodynamics of caffeine.
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“However, excessive caffeine consumption (1~1.5 g/day) can cause caffeine poisoning (caffeinism), which includes symptoms such as anxiety, agitation, insomnia, and gastrointestinal disorders.”
From Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human (2020) · cites this paper as [12]
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LC-MS/MS method for rapid and accurate detection of caffeine in a suspected overdose case
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Bhatti, F., Xiao, D., Jabegu, T., Huang, X., Witherspoon, E., Dong, P., Lei, S., Shen, J., & Wang, Z. (2023) · Advanced Composites and Hybrid Materials · doi:10.1007/s42114-022-00614-z · Cited by 10
Association of Caffeine Consumption and Brain Amyloid Positivity in Cognitively Normal Older Adults
Zheng, Y., Sun, J., Shi, L., Su, S., Chen, X., Wang, Q., Huang, Y., Wang, Y., Zhu, X.-M., Que, J., et al. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-220591 · Cited by 10
“As for the amount of caffeine consumed daily, noteworthily, excessive caffeine consumption can cause caffeine poisoning, the symptoms of which include anxiety, agitation, insomnia, gastrointestinal disorders, and mental disorders [45].”
BackgroundBougrine, H., Ammar, A., Salem, A., Trabelsi, K., Jahrami, H., Chtourou, H., & Souissi, N. (2024) · Brain Sciences · doi:10.3390/brainsci14030280 · Cited by 13
“However, the potential negative side effects of CAF consumption, particularly at the doses taken to enhance performance, have received relatively little attention [8,27].”
BackgroundAhmed, W. H., Boulet, N., Briot, A., Ryan, B. J., Kinsella, G. K., O’Sullivan, J., Les, F., Mercader, J., HENEHAN, G. T. M., & Carpéné, C. (2021) · Molecules · doi:10.3390/molecules26133831 · Cited by 10
“Moreover, many pharmacokinetics stud‐ ies performed with caffeine or caffeine‐containing beverages have reported human plasma Cmax levels varying between 10 μM [45–47] and 50 μM [41].”
BackgroundTreatment of Lethal Caffeine Overdose with Haemodialysis: A Case Report and Review
Gahona, C. C. T., Bharadwaj, A. K., Shah, M., Bhagat, U., Sterman, P., & Vasquez, W. (2022) · The Journal of Critical Care Medicine · doi:10.2478/jccm-2022-0019 · Cited by 10
“Rhabdomyolysis has been associated with the calcium release from the sarcoplasmic reticulum of skeletal and cardiac muscle [16-17].”
BackgroundMethodInfluentialQush, A., Al-Khatib, H. A., Rachid, H., Al-Tamimi, H., Al-Eshaq, A., Aladwi, S. A., Yassine, H. M., & Kamareddine, L. (2023) · Microbes and Infection · doi:10.1016/j.micinf.2023.105149 · Cited by 9
Development of Personalised Immediate-Release Gel-Based Formulations Using Semi-Solid Extrusion
Aina, M., Baillon, F., Sescousse, R., Sanchez‐Ballester, N. M., Bégu, S., Soulairol, I., & Sauceau, M. (2024) · Gels · doi:10.3390/gels10100665 · Cited by 11
Caffeine as a Modulator in Oncology: Mechanisms of Action and Potential for Adjuvant Therapy
Rembiałkowska, N., Demiy, A., Dąbrowska, A., Mastalerz, J. A., & Szlasa, W. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136252 · Cited by 11
“A review by Willson et al. identified ventricular fibrillation as the most common cause of death, with coronary artery spasms also suggested as a cause in myocardial infarction cases [96].”
Modulatory Effects of Caffeine on Imatinib Binding: A Molecular Docking Study Targeting CYP3A4
Amzoiu, M. O., Popescu, G. S., Amzoiu, E., Ciocîlteu, M. V., Manda, C. V., Rău, G., Greșiță, A., & Taisescu, O. (2025) · Life · doi:10.3390/life15081247 · Cited by 9
“While the caffeine-induced enhancement of binding affinity may prolong drug action, it also raises the possibility of altered clearance or unintended pharmacodynamic effects, particularly in subjects with high dietary caffeine intake [50,51].”
Popova, O. S., Ponamarev, V. S., Kostrova, A. V., & Agafonova, L. A. (2023) · International Journal of Veterinary Medicine · doi:10.52419/issn2072-2419.2023.2.142 · Cited by 9
Pill-induced esophagitis caused by ingesting excessive caffeine tablets
Miyata, J., Ito, Y., & Ito, S. (2019) · Clinical Journal of Gastroenterology · doi:10.1007/s12328-019-01055-w · Cited by 9
Ajjampur, K., & Subramaniam, A. (2020) · Australian Critical Care · doi:10.1016/j.aucc.2020.09.007 · Cited by 9
Fermented Black Tea and Its Relationship with Gut Microbiota and Obesity: A Mini Review
Nasir, N. F., Mohamad, N. E., & Alitheen, N. B. (2022) · Fermentation · doi:10.3390/fermentation8110603 · Cited by 9
Emakpor, O. L., Edo, G. I., Yousif, E., Samuel, P. O., Jikah, A. N., Zainulabdeen, K., Mohammed, A. A., Ndudi, W., Nwachukwu, S. C., Ugbune, U., et al. (2024) · OBM Integrative and Complementary Medicine · doi:10.21926/obm.icm.2402038 · Cited by 10
Serum potassium level as a biomarker for acute caffeine poisoning
Tsuji, T., Morita, S., Saito, T., Nakagawa, Y., & Inokuchi, S. (2020) · Acute Medicine & Surgery · doi:10.1002/ams2.568 · Cited by 8
Wang, Z., Xu, J., & Du, W. (2024) · Environmental Science and Ecotechnology · doi:10.1016/j.ese.2024.100437 · Cited by 8
“Adenosine receptor A1 and A2 a subtypes are mainly localized in striatopallidal GABAergic neurons of the brain [29].”
BackgroundCoffee and mental disorders: How caffeine affects anxiety and depression
Meamar, M., Raise‐Abdullahi, P., Rashidy‐Pour, A., & Raeis-Abdollahi, E. (2024) · Progress in brain research · doi:10.1016/bs.pbr.2024.06.015 · Cited by 13
Network analysis of caffeine use disorder, withdrawal symptoms, and psychiatric symptoms
Davoudi, M., Abdoli, F., Momeni, F., & Habibi, M. (2025) · BMC Psychiatry · doi:10.1186/s12888-025-06478-z · Cited by 10
Ou, H.-C., Deng, J., Yang, C., Lin, C., Mao, Y.-C., Tsai, S., & Ho, C.-H. (2021) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2021.11.049 · Cited by 8
Behl, A., Mishra, A., Sharma, G. P., & Mishra, V. (2021) · International Journal of Medical Toxicology & Legal Medicine · doi:10.5958/0974-4614.2021.00075.9 · Cited by 8
Severe caffeine poisoning successfully treated with high flow continuous hemodialysis
Kobashi, D., Kamijo, Y., Hanazawa, T., Yoshizawa, T., & Nakamura, M. (2022) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2022.05.019 · Cited by 8
Ezim, O. E., & Abarikwu, S. O. (2022) · Andrologia · doi:10.1111/and.14578 · Cited by 8
“…orally because of its basic nature (pKa = 14 at 25 C) favouring a lipophilic state in the alkaline surrounding of the small intestine as compared to the acidic nature of the stomach where it is less lipophilic and more ionized (Cyril, 2018; Ricci et al., 2017; Sepkowitz, 2013; White et al., 2016).”
BackgroundToxicology of pharmaceutical and nutritional longevity compounds
Kahraman, Ç., Bilecenoglu, D. K., Sabuncuoğlu, S., & Çankaya, İ. İ. T. (2023) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2023.18 · Cited by 8
Caffeine Consumption and Its Potential Health Effects on Saudi Adolescents in Jazan
Eltyeb, E., Al-Makramani, A., Mustafa, M. M. E., Shubayli, S., Madkhali, K. A., Zaalah, S. A., Ghalibi, A., Ali, S. A., Ibrahim, A. M. M., & Basheer, R. A. (2023) · Cureus · doi:10.7759/cureus.44091 · Cited by 8
“Moreover, restlessness, nervousness, and gastric pain have been observed with caffeine intoxication [9,10].”
Jovanović, D., Filipović, A., Janjić, G. V., Pašti, T. D. L., Džambaski, Z., Bondžić, B. P., & Bondžić, A. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25021033 · Cited by 8
Cardiovascular Toxicity of Energy Drinks in Youth: A Call for Regulation
Vetter, V. L., & Naim, M. Y. (2024) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2024.114224 · Cited by 8
Irimia, C. V., Yumusak, C., Ban, B., Leeb, E., Mayr, F., Schimanofsky, C., Mardare, A. I., Molnar, M. A., Teichert, C., Sariçiftçi, N. S., et al. (2025) · IEEE Journal on Flexible Electronics · doi:10.1109/jflex.2025.3539612 · Cited by 8
The Role of Xenobiotic Caffeine on Cardiovascular Health: Promises and Challenges
Campagna, R., & Vignini, A. (2025) · Journal of Xenobiotics · doi:10.3390/jox15020051 · Cited by 8
“…tartrate pharmaceutical salts. tartrate pharmaceutical Since CAF is a water-soluble compound with hydrophobic properties and low protein binding (10–35%), it easily enters and distributes within cells and tissues, being able to also penetrate the blood-brain barrier effectively [36]. salts.”
Khan, A., Abdalla, M. A., Zakhary, C. M., Rushdi, H., Hamdan, J. A., Youssef, K. N., & Khan, S. (2021) · Cureus · doi:10.7759/cureus.17783 · Cited by 8
“Hyperventilation, respiratory failure, weakness, rigidity, tremor, rhabdomyolysis, tinnitus, dizziness, diuresis, and death are also known to occur [3].”
BackgroundInfluentialCaffeine - a substance well known or still researched
Balawejder-Biśto, A., & Pyka, A. (2022) · Farmacja Polska · doi:10.32383/farmpol/155158 · Cited by 8
Premnath, S., Alalshaikh, G., Alfotawi, R. A., & Philip, M. R. (2020) · Cureus · doi:10.7759/cureus.7820 · Cited by 8
“, ≤ 400 mg) and undesirable effects generally above this level of intake [28].”
Clinical Neurobiology of Sleep and Wakefulness
Castillo, P. R. (2023) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001260 · Cited by 9
Hamdan, M., Suharto, A. P., Nugraha, P., & Islamiyah, W. R. (2024) · Narra J · doi:10.52225/narra.v4i2.826 · Cited by 7
“However, the effects of caffeine are dose-dependent and vary among individuals, in which doses of <400 mg are often associated with positive effects, whereas doses of >400 are often linked to undesirable effects [28].”
Background
Metadata
- Authors
- Willson, C.
- Corresponding author
- Willson, Cyril
- Venue
- Toxicology Reports
- Publisher
- Elsevier BV
- Published
- 2018
- Volume
- 5
- Pages
- 1140-1152
- ISSN
- 2214-7500 (ISSN-L)
- PMC
- PMC6247400
- OpenAlex
- W2899447541
- Cited by
- 289
- References
- 197
- Citations by year
- 2026: 21 · 2025: 50 · 2024: 61 · 2023: 35 · 2022: 39 · 2021: 47 · 2020: 27 · 2019: 8
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Toxicology Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Coffee research and impacts
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- caffeine, caffeine toxicity, psychostimulants, pharmacokinetics, toxicokinetics, mechanism of action, case reconstruction, young adults
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