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Time course of tolerance to adverse effects associated with the ingestion of a moderate dose of caffeine



This study aimed to identify and describe the time course of tolerance to the most common caffeine-induced side effects.


Eleven participants took part in a crossover, double-blind placebo-controlled experimental design. In one phase, participants ingested 3 mg/kg/day of caffeine for 20 days, while in another phase, they ingested a placebo. Resting heart rate and blood pressure were measured three times per week during each 20-day phase and a quantitative survey was used to categorise the magnitude of side effects.


In the pairwise comparison with the placebo, the ingestion of caffeine increased systolic (+ 7.8 ± 10.1%, P < 0.05) and diastolic blood pressure (+ 6.4 ± 12.9% P < 0.05) for the first 8 days of ingestion, but then this effect became attenuated for both outcomes (on day 20, − 1.1 ± 4.3% and + 0.9 ± 9.6%, respectively). The ingestion of caffeine did not affect heart rate at any time point. Caffeine increased the feelings of nervousness and vigour and the rating of gastrointestinal complaints, insomnia and diuresis at several time points in the treatment (P < 0.05) and they did not disappear after 20 days of ingestion.


The daily intake of 3 mg/kg of caffeine induced a meaningful elevation in arterial blood pressure that disappeared after 8 days. However, other caffeine-induced effects such as increased nervousness and vigour, irritability, insomnia and diuresis remained after 20 days of consecutive caffeine ingestion. Although there was clear tolerance to the effect of caffeine on blood pressure, the persistence of other side effects suggests the inconvenience of maintaining a chronic caffeine intake, at least at the dose of 3 mg/kg/day.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.


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The authors wish to thank the subjects for their invaluable contribution to the study.


This investigation did not receive any funding.

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Authors and Affiliations



CRM, BL, JJS, JMO, JC: formulated the research question. CRM, BL, JJS, JC: designed the study. CRM, BL, JJS, JC : carried it out. CRM, DBS, BL, JJS, JC: analysed the data. DBS, JMO, JC: wrote the article. CRM, DBS, BL, JJS, JMO: revised the article.

Corresponding author

Correspondence to Juan Del Coso.

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All authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work.

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Ruiz-Moreno, C., Lara, B., Salinero, J.J. et al. Time course of tolerance to adverse effects associated with the ingestion of a moderate dose of caffeine. Eur J Nutr 59, 3293–3302 (2020).

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