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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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Identification Of Caffeine In Extracts Of Camellia Sinensis By Liquid Chromatography
Dixit, T. (2023) · Journal of Pharmaceutical Negative Results · doi:10.47750/pnr.2023.14.s02.127 · Cited by 2
Erdős, Á. (2023) · European Journal of Mental Health · doi:10.5708/ejmh.18.2023.0008 · Cited by 4
“Even higher doses (~2000 mg/day) lead to muscle convulsions, toxic symptoms, ventricular fibrillation, cardiovascular symptoms, hallucinations, and (~3000 mg/day) death (Glaister & Moir, 2019; Willson, 2018).”
BackgroundEnjoy or quit: impact of coffee on cardiac and metabolic health
Güneş, Y., & Aktaş, G. (2024) · Cardiology Plus · doi:10.1097/cp9.0000000000000092 · Cited by 2
“Drinking caffeinated coffee may cause short-term increases in blood sugar levels due to adrenaline release, reduced insulin sensitivity, and reduced skeletal muscle glucose uptake secondary to adenosine receptor inhibition (Figure 3) [2,35,38] .”
Yamazaki, Y., Kaizaki‐Mitsumoto, A., Sato, M., Inoue, Y., Miyamoto, K., Suzuki, K., Hayashi, M., Dohi, K., & Numazawa, S. (2024) · The Journal of Toxicological Sciences · doi:10.2131/jts.49.447 · Cited by 2
“This study, as previously reported (Willson, 2018; Gahona et al ., 2022), confirmed that HD during CFF intoxication is effective in reducing blood CFF levels and found that 3–4 hr of HD reduces blood CFF by 33.2%– 77.6% ( median 58.7%).”
InfluentialUnwanted Clinical Complications Following the Consumption of Death Coffee : A Case Series
Bordbari, A., Soltani, M., Ashoori, Y., Najarcolaii, F. M., & Zakariaei, Z. (2025) · Neuropsychopharmacology Reports · doi:10.1002/npr2.70013 · Cited by 2
Torrisi, S. A., Rizzo, S., Godos, J., Grosso, G., & Leggio, G. M. (2025) · Royal Society of Chemistry eBooks · doi:10.1039/9781839166853-00388 · Cited by 2
Colombo, G., Selimi, A., Cesari, A., Pedrotti, P., & Sacco, A. (2025) · European Heart Journal - Case Reports · doi:10.1093/ehjcr/ytaf252 · Cited by 2
“2,3 Additionally, consuming 3 to 5 standard cups of coffee per day has been associated with a reduced risk of cardiovascular and chronic diseases.”
Association between coffee intake and serum α-Klotho levels in adults: a population-based study
Tang, X., Tuo, H., Cao, C., Yang, Z., Zhang, S., & Du, R. (2025) · BMC Public Health · doi:10.1186/s12889-025-23812-y · Cited by 2
“High doses of caffeine lead to this tolerance [34, 35], and further consumption does not significantly alter SαKl levels.”
Sato, S., Tampo, A., Okuda, K., Shimizu, K., Namba, H., ICHIMIYA, T., & Yamakage, M. (2021) · Journal of the Japanese Society of Intensive Care Medicine · doi:10.3918/jsicm.28_454 · Cited by 2
Determining the Efficiency and Yield of Caffeine Extraction for Robusta and Arabica Coffee Beans
Yu, Z., Reddy, A. J., & Wagh, H. (2021) · Applied Cell Biology · doi:10.53043/2320-1991.acb90013 · Cited by 2
“Figures 1,3, and 4 had peaks around 1700 cm-1 and 1500 cm-1 which indicates that the product that was collected from both the robusta and the arabica coffee was relatively pure as caffeine should have peaks around those regions as the caffeine molecule has aromatic double bonds as well as carbonyl groups [10].”
BackgroundCaffeine intake in adults with cardiovascular diseases; A cross-sectional study
Bozkır, Ç., Tuğgüm, S., Kağan, N., Nizam, B., & Alpsoy, Ş. (2022) · Nutrition and Health · doi:10.1177/02601060221105030 · Cited by 2
“Caffeine consumption and its effects on individuals as a result of consumption differ, and high amounts of caffeine intake (>400 mg) may have some acute and chronic toxicity effects in general (Nehlig, 2018; Willson, 2018).”
BackgroundYoon, H., Ro, Y. S., Jung, E., Moon, S. B., Park, G. J., Lee, S. G. W., & Shin, S. D. (2023) · Journal of Neurotrauma · doi:10.1089/neu.2023.0006 · Cited by 3
“24,25 26-28 Further, an interaction analysis model was used to investigate whether the effects of serum caffeine level on study outcomes were modified by the presence of concus-sive symptoms, such as loss of consciousness or post-traumatic amnesia.”
Yulikawanti, A. E. T., Phonchai, A., Janchawee, B., & Prutipanlai, S. (2024) · Journal of Analytical Chemistry · doi:10.1134/s106193482401012x · Cited by 2
Korolkiewicz, P. K., & Salloum, A. (2021) · European Journal of Clinical Nutrition · doi:10.1038/s41430-021-00944-z · Cited by 2
Lambrych, M. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-824315-2.00372-9 · Cited by 2
Caffeine, coffee, and breast-feeding
Hálek, J., Voláková, J., Wita, M., Lasák, J., & Kantor, L. (2021) · Pediatrie pro praxi · doi:10.36290/ped.2021.056 · Cited by 1
“Inhibice fosfodiesterázy a intracelulární uvolnění kalcia působí až ex trémní dávky kofeinu a zřejmě tedy nemají praktický význam (12).”
Hebert, J. F., Eiwaz, M. B., Nickerson, M. N., Munhall, A. C., Pai, A. A., Groat, T., Andeen, N. K., & Hutchens, M. P. (2023) · Military Medicine · doi:10.1093/milmed/usad142 · Cited by 1
Koffeinintoxikation in suizidaler Absicht
Uehlein, S., Schneider, R., Stahl, K., & Dechant, K. (2025) · Die Innere Medizin · doi:10.1007/s00108-025-01938-w · Cited by 1
Use of Extracorporeal Therapies to Treat Severe Caffeine Poisoning
Kohara, S., Kamijo, Y., Takai, M., Kyan, R., Hasegawa, E., & Shimane, T. (2025) · Hemodialysis International · doi:10.1111/hdi.70002 · Cited by 1
“…tract and mainly metabolized by the cytochrome P450 enzyme system (CYP1A2, 2E1, and 3A) [7] with a serum elimination half-life of 2–10 h [8], which may be extended to approximately 15 h after large or excessive consumption owing to the saturated activity of metabolic enzymes [9, 10].”
Jovanović, D., Filipović, A., Suručić, R. V., Korićanac, L., Žakula, J. J., Bondžić, B. P., & Bondžić, A. M. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.145524 · Cited by 1
Domaszewski, P., Konieczny, M., Pakosz, P., Poliwoda, A., & Skorupska, E. (2025) · Health Problems of Civilization · doi:10.5114/hpc.2025.152431 · Cited by 1
Kukongviriyapan, N., & Leethanakul, C. (2025) · Journal of Orofacial Orthopedics / Fortschritte der Kieferorthopädie · doi:10.1007/s00056-025-00611-z · Cited by 1
“While at higher concentrations, caffeine produces agonistic effects on the activation of calcium channels (ryanodine receptor) and is a nonspecific inhibitor of phosphodiesterase (PDE) enzymes [31].”
InfluentialEsposito, E., Dzyhovskyi, V., Santamaria, F., Marvelli, L., Boldrini, P., Mariani, P., Pepe, A., Ortore, M. G., Benedusi, M., Valacchi, G., et al. (2025) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.3389/jpps.2025.15553 · Cited by 1
Lại, Q. D., Nguyen, H. T., Long, N. Q., & Tran, V. T. K. (2025) · Journal of Food Science · doi:10.1111/1750-3841.70602 · Cited by 1
Kohmoto, H., Uotsu, S., Masaoka, T., Oshima, Y., Kawaguchi, T., & Ando, T. (2025) · JCEM Case Reports · doi:10.1210/jcemcr/luaf276 · Cited by 1
“By blocking adenosine receptors, it enhances sympathetic outflow and increases catecholamine release [9].”
Muranaka, K., Mutoh, J., Takada, M., Yanagita, Y., Noguchi, K., Tachibana, K., Kishikawa, N., Kuroda, N., & Wada, M. (2025) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2025.117317 · Cited by 1
Domaszewski, P. (2026) · Nutrients · doi:10.3390/nu18020328 · Cited by 1
“Caffeine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations typically observed between 30 and 120 min after ingestion [57].”
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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