What is tolerance?

Background and Basic Principles

For millennia, humans have sought to counteract the effects of harmful substances by taking small amounts of the substance and then gradually increasing its levels. This practice is called mithridatism, named for Mithridates VI, the former ruler of Pontus who, after his defeat by the Romans in 63 bce, tried to commit suicide by taking poison. However, because he had built up immunity to diverse poisons by years of incremental exposure to them, the poisons did not end his life and he had to resort to demanding he be killed with a sword. Mithridatism can be effective if the substance does not pass through the body too quickly or accumulate to dangerous levels; it works because tolerance to the drug has been established.

Tolerance is influenced by diverse variables, including type of drug, dosage level, frequency of administration, environmental circumstances, psychological factors, and the drug user’s physiology. Tolerance may develop to some effects of a drug; however, little or no tolerance may occur to other effects. Although tolerance normally develops slowly, it sometimes occurs after only one or a few administrations, a phenomenon called tachyphylaxis. The effects of tolerance may accrue to other, usually closely related, drugs, through cross-tolerance.

Drug tolerance typically dissipates when exposure to a drug is limited or stopped. Conversely, with reverse-tolerance, or sensitization, in which a drug’s effectiveness progressively increases with repeated administration, the effect often persists long after a drug is discontinued.

Tolerance Mechanisms

The complexity and diversity of tolerance phenomena indicate that multiple factors underlie its occurrence. Three main mechanisms of tolerance have been identified, two are physiological and one is more psychological. Metabolic tolerance (also known as dispositional tolerance) involves increased levels of enzymes in the body to metabolize a drug; subsequently, the level of the drug in the body decreases. Metabolic tolerance will diminish all effects of a drug because the amount of the drug throughout the body is lowered.

Cellular-adaptive tolerance (also known as pharmacodynamic or physiological tolerance) is the second main physiological mechanism of tolerance. Cellular-adaptive tolerance involves diverse adjustments by the body to restore its predrug functioning; this results in decreased drug effects. Essentially, cellular-adaptive tolerance is marked by the body’s compensatory actions to reestablish the homeostasis (the normal physiological stability) disrupted by the introduction of a drug.

The compensatory processes can work at multiple levels. For example, an appetite-suppressing drug may lose its effectiveness at the cellular level because its blocking action at neuronal receptors is diminished. This diminishment occurs because, postsynaptically, more receptors are being produced and, presynaptically, more neurotransmitter is being produced. Conversely, for an appetite-suppressing drug that works by increasing neurotransmitter levels at neuronal receptors, the number of receptors and the amount of neurotransmitter produced may be decreased (a process called down-regulation). The body may also compensate for the drug in other ways, such as by producing more ghrelin, a hormone that stimulates appetite, or by increasing activity in regions of the hypothalamus that stimulates appetite.

Environmental and psychological factors almost always alter the effectiveness of a drug through a third tolerance mechanism known as behavioral tolerance. Behavioral tolerance works through a variety of conditioning (learning) and psychological processes. Respondent (also called classical) conditioning, in which two stimuli are paired repeatedly and in which the response to one stimulus is eventually elicited by the other stimulus, was demonstrated by Ivan Pavlov (in the early twentieth century). The environment in which the drug is administered is a stimulus that is usually conditioned to the effects of the drug. What typically is conditioned is the body’s attempt to resist the drug. Thus, the environment elicits compensatory actions that cause a drug to be less effective; tolerance, controlled by environment, develops. This can have dangerous consequences for a drug addict who has developed tolerance to lethal doses of a drug consistently taken in a particular setting. If the person takes the drug in a novel setting, the conditioned tolerance is absent; the loss of this tolerance may result in a fatal overdose.

Operant conditioning, in which the frequency of a behavior is determined by its consequences, also plays a role in tolerance development. Research by Muriel Vogel-Sprott and colleagues in the 1990s demonstrated that when people are rewarded for resisting the effects of a drug, they develop tolerance more rapidly than those who are not rewarded. Conversely, withholding a reward may prevent tolerance from developing. For example, amphetamine causes loss of appetite in diverse species; however, if the drug is administered to a hungry animal that is not given the opportunity to eat after being given the drug, tolerance to the appetite-suppressive effects of the drug will not evolve. Thus, whether or not tolerance develops depends on the conditions in which a drug is administered.

Bibliography

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