Tolerance, Drug

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Tolerance, Drug


Tolerance is a decrease in the effects of a drug dose following repeated administrations. Tolerance is central to the definition of chemical dependence to some drugs (e.g., alcohol, heroin, painkillers), with theorists assigning to tolerance, or the mechanisms that produce tolerance, an important role in the genesis and maintenance of addictive drug use. Drug tolerance can be a symptom of physical dependence and a contributing factor to the severity of the physical and psychological dependence on a drug. For example, as drug users develop tolerance, they have to progressively increase their level of consumption to achieve the high they used to feel with lower doses during their initial stages of experimentation with the drug. Tolerance can be described as a homeostatic mechanism, or an organisms adaptive response to foreign substances. Unfortunately, tolerance may decrease the effectiveness of medication regimes, as in the treatment of chronic pain, epilepsy, or depression.

Drug tolerance has been studied as either pharmacological (physiological) or learned (psychological) phenomena. Pharmacological tolerance models distinguish between dispositional (or pharmacokinetic) and functional (or pharmacodynamic) tolerance. Dispositional tolerance refers to an organisms increased ability to metabolize and distribute the drug in the body. Thus, with increased dispositional tolerance, more of the drug must be taken to reach a specific concentration at the receptor sites. On the other hand, functional tolerance defines changes in neural functioning that result in dose-response decrements at the receptor site (i.e., the receptor responds less to a given concentration of a drug). Functional tolerance that develops to the effects of the first or second drug administration is called tachyphylaxis or acute tolerance. Functional tolerance that persists after prolonged exposure is called acquired or chronic tolerance.

Psychological or learning models distinguish between operant (or instrumental) and associative (or classically conditioned) drug tolerance. Operant tolerance defines the acquisition of specific skills or responses that compensate for the disruptive effects of a drug on task performance. For example, with other influencing variables being equal (e.g., genetic sensitivity to alcohol), operant tolerance theory predicts that a person who habitually drinks and drives should make fewer mistakes while driving under the influence of a relatively high dose of alcohol than a person with the same level of alcohol-use history who rarely drinks and drives.

Associative or classically conditioned models of drug tolerance posit that environmental stimuli reliably paired with drug delivery become conditioned stimuli that elicit conditioned responses that reduce drug effects. Perhaps the most influential of the associative tolerance models is Shepard Siegels compensatory response model. In the 1970s and 1980s, Siegel conducted a number of highly influential studies to test a theory that predicted that conditioned stimuli can produce conditioned responses that are opposite to, and thus cancel or compensate for, the effects of drugs. The compensatory response model of tolerance has been used to explain why some heroin addicts may die from a heroin overdose despite having developed very high tolerance to the effects of the drug. Although overdoses are often a result of mixing heroin with other drugs, many overdose deaths appear to result from a sudden loss of tolerance. Noting that many heroin overdose deaths occurred after the drug was consumed in a new setting or a new set of circumstances, Siegel reasoned that tolerance to heroin must be partially conditioned to the environment where, and manner in which, the drug is usually taken. Therefore, taking the drug in a new environment would eliminate the presence of conditioned tolerance and lead to overdosing.

An important characteristic or difference between pharmacological and learned drug tolerance is their differential resistance to extinction following detoxification or discontinuation of a given drug administration regime. Associative drug tolerance can be maintained or remembered for long periods of time, whereas nonassociative tolerance disappears rapidly in the absence of a drug administration regime. This characteristic of associative drug tolerance has been linked to the construct of drug craving. Like tolerance effects, cravings can be elicited by environmental stimuli (e.g., the sight of a lit cigarette for the smoker), a phenomenon that can occur even after years of abstinence (as often reported by smokers). That is, craving and tolerance can be conceptualized as memories associated with drug effects. Future research examining the physiological mechanisms underlying the development of learned tolerance will be invaluable for the development of drug addiction treatments, as well as the creation of medications partially resistant to pharmacological and learned tolerance effects.

SEE ALSO Addiction; Medicine; Pharmaceutical Industry; Smoking


Cepeda-Benito, Antonio, and Paul Short. 1997. Morphines Interoceptive Stimuli as Cues for the Development of Associative Morphine Tolerance in the Rat. Psychobiology 25: 236240.

Ramsay, Douglas S., and Stephen C. Woods. 1997. Biological Consequences of Drug Administration: Implications for Acute and Chronic Tolerance. Psychological Review 104: 170193.

Siegel, Shepard. 1975. Evidence from Rats that Morphine Tolerance is a Learned Response. Journal of Comparative and Physiological Psychology 89 (5): 498506.

Siegel, Shepard. 2005. Drug Tolerance, Drug Addiction, and Drug Anticipation. Current Directions in Psychological Science 14 (6): 296300.

Tiffany, Stephen T., David J. Drobes, and Antonio Cepeda-Benito. 1992. Contribution of Associative and Nonassociative Processes to the Development of Morphine Tolerance. Psychopharmacology 109 (12): 185190.

Antonio Cepeda-Benito