Caffeine and coffee tolerance.

To the Editor: Corti et al1 recently reported that habitual coffee drinkers display different degrees of caffeine tolerance, depending on the route of caffeine administration. Although the participants did not display elevated systolic blood pressure after consumption of caffeinated coffee, they did after intravenous caffeine administration. In both conditions, the amount of caffeine administered was selected to result in similar plasma levels of the drug. The authors concluded that “tolerance to coffee does not appear to be related to caffeine” (p. 2939). We suggest that the difference in tolerance expression after oral and intravenous caffeine may be another demonstration of the situational specificity of tolerance. Results of research with a variety of species, including humans, indicate that drug tolerance is modulated not only by experience with the drug but also by experience with both exteroceptive and interoceptive drugassociated stimuli.2 That is, drug tolerance is more pronounced in the presence of the usual drug predictive cues than in the presence of alternative cues. Habitual coffee drinkers have prior experience with salient exteroceptive cues, such as the taste and odor of the coffee, signaling the effects of caffeine; thus, it is not surprising that they are more tolerant to the drug administered in the presence of these cues (ie, in coffee) than in the absence of these cues (ie, intravenously). The finding is similar to an earlier report that tolerance to alcohol is more pronounced when the drug is consumed in a beverage previously associated with alcohol (beer) than when the same amount of alcohol is consumed in a novel beverage (blue and peppermint flavored).3 Additionally, among the stimuli that comprise the drugpredictive cues are those cues inherent within the administration procedure (eg, route of administration or early weak drug effects, experienced immediately after administration, that signal the later larger drug effect). When a drug-experienced, and drugtolerant, organism experiences a drug via a new route of administration, the expected level of tolerance frequently is not observed. Thus, in humans, changing from oral to transdermal opiate administration may result in a loss of tolerance.4,5 Similarly, in rats, changing from intraperitoneal to intravenous morphine administration or from gradual intravenous morphine administrations to a rapid intravenous administration results in a disruption of the display of tolerance (research reviewed elsewhere2). Coffee drinkers experience the effects of caffeine after interoceptive cues inherent to the oral route of administration. Evaluating tolerance after administration via a different route (intravenous) is tantamount to altering the usual predrug cues, which results in a disruption of tolerance. Finally, caffeine administered in coffee is self-administered. In contrast, intravenous caffeine is administered by the experimenter—not the participant. If a drug is self-administered (rather than passively received), interoceptive response-initiating (or response-produced) cues are paired with the drug effect. Results of many experiments indicate that greater tolerance is displayed to a self-administered drug than to the same dose of a passively received drug. This effect of the self-administration contingency on tolerance has been demonstrated with a variety of drugs and species, including cocaine, nicotine, and alcohol in rats; phencyclidine in monkeys; and hydromorphone and alcohol in humans.2 Situational specificity of tolerance has been implicated in tolerance to a variety of effects of many drugs, including opiates, alcohol, nicotine, pentobarbital, immunoenhancing drugs, cholecystokinin, carisoprodol, haloperidol, and several benzodiazepines.2 Corti et al1 may well be the first to demonstrate situational specificity of tolerance to caffeine. Acknowledgments The authors’ research summarized in this letter was supported by grants to Dr Siegel from the US National Institute on Drug Abuse (grant DA11865) and from the Natural Sciences and Engineering and Research Council of Canada (grant 00298).