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Cross-tolerance refers to a pharmacological phenomenon, in which a patient being treated with a drug exhibits a physiological resistance to that medication as a result of tolerance to a pharmacologically similar drug. In other words, there is a decrease in response to one drug due to exposure to another drug. It is observed in treatment with antivirals, antibiotics, analgesics and many other medications.

Cross-tolerance is particularly frequent amongst users of illicit drugs. For example, users with a high tolerance to the stimulant amphetamine may also exhibit a high tolerance to the structurally similar methamphetamine or other amphetamine-like stimulants, such as methylphenidate (though one should not assume this to avoid overdose). The phenomenon is also observed in cigarette smokers, in whom there is a demonstrably lessened sensitivity to the effects of caffeine. Cross-tolerance is also frequent in response to use of hallucinogens. General tolerance to the effects of tryptamines such as psilocybin, may be dramatic in response to repeated use, and this often translates into a tolerance to effects of other drugs such as LSD or DMT.

Dendritic cells can take up self antigens from other cells and cross-present them to autoreactive T cells. These are then eliminated from the T cell repertoire by apoptosis. This mechanism was proposed to silence autoreactive T cells that have escaped negative selection in the thymus.