What is caffeine tolerance?

Updated: Jun 14, 2018
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Nicholas Lorenzo, MD, CPE, MHCM, FAAPL  more...
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In reference to a drug, the term tolerance denotes an acquired change in responsiveness after repeated exposure to the drug. Tolerance can be considered in 2 ways, as follows:

  • Tolerance might indicate that the dose necessary to achieve the desired euphoric or reinforcing effects increases with time, thus encouraging increased consumption of the drug

  • Tolerance to the aversive effects of high doses of the drug may occur, also leading to increased consumption of the drug over time

Tolerance to many behavioral effects of caffeine has been observed in mice, cats, and squirrel monkeys treated regularly with methylxanthine. Tolerance to caffeine-induced locomotor stimulation, cerebral electrical activity, reinforcement thresholds for electrical brain stimulation, schedule-controlled response maintained by presentation of food, and electric shock and thresholds for seizures induced by caffeine or N -methyl D-aspartate (NMDA) has been described.

In animals, development of tolerance to caffeine is rapid, is usually insurmountable, and shows cross-tolerance with the other methylxanthines, though not with other psychomotor stimulants such as amphetamines and methylphenidate. On the first 2 days after caffeine discontinuance, depression of locomotor activity is noted, with a return to baseline values on day 3 (consistent with a withdrawal syndrome).

Although the exact mechanism underlying the development of tolerance to caffeine remains unclear, tolerance to behavioral effects of caffeine in animals does not seem to involve adaptive changes in adenosine receptors but may result from compensatory changes in the dopaminergic system as a result of chronic adenosine receptor blockade.

In humans, tolerance to some physiologic actions of caffeine can occur. This is the case for the effects of caffeine on blood pressure, heart rate, diuresis, plasma adrenaline and noradrenaline levels, and renin activity. Tolerance usually develops within a few days. Tolerance to some subjective effects of caffeine, such as tension-anxiety, jitteriness, nervousness, and the strength of drug effect, has been shown.

Conversely, although tolerance to the enhancement of arithmetic skills by caffeine has been documented, evidence of tolerance to caffeine-induced alertness and wakefulness is limited. These effects are paralleled by the lack of tolerance of cerebral energy metabolism to caffeine; in one animal study, in that acute administration of 10 mg/kg caffeine induced the same metabolic increase whether the rats were exposed to previous daily treatment with caffeine or with saline for 15 days.

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