One striking feature of LSD, mescaline, and related psychedelic drugs is tolerance, which is a loss of typical drug effects after repeated doses. In brief, with daily doses the duration and intensity of effects rapidly diminish to the point where no subjective effects are perceived. After 200 micrograms per day of LSD, there is simply no detectable drug effect on the third or fourth day. After three or four days without LSD, the full initial effects can be triggered by the same dose that has been ''tolerated.'' Thus tolerance develops and dissipates rapidly. When subjects are tolerant to LSD, the usual dose of mescaline required for a trip is also no longer effective. This is called cross-tolerance. It is readily seen with similar dosage schedules of psilocybin, LSD, and mescaline. There is no cross-tolerance with the nonhallucinogenic stimulant drug amphetamine. Thus, there must be some common mechanism of action among the psychedelic drugs beyond their structure and similar array of mental effects.

Tolerance is seen both in humans and laboratory animals. The lack of pupil enlargement is a common sign of tolerance. In animals, some drug effects show tolerance and some do not. For example, a heightened sensitivity of rats to mild electric shock persists after daily doses and does not show tolerance. Such persisting drug effects during pe riods of tolerance have not been studied in humans. How and why a psychedelic drug loses and regains its potency in this fashion is not yet understood, but there is no withdrawal discomfort after stopping a psychedelic drug when it has been taken over several days. This differs from the classic effects described for opioid drugs, where an uncomfortable withdrawal with drug cessation requires more drug for relief. Such physical drug withdrawal phenomena are not found with psychedelics.

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