Tolerance is expected to develop with regular amphetamine use. When amphetamines are abused at doses well in excess of therapeutic doses, drug tolerance develops rapidly.
Severe withdrawal associated with dependence from recreational amphetamine use can be a difficult for a user to cope with. Long-term amphetamine use reduces dopamine activity in the brain. Psychostimulants that increase dopamine and mimic the effects of amphetamines while having lower abuse liability could theoretically be used as replacement therapy in amphetamine dependence, but studies of dexamphetamine, bupropion, methylphenidate and modafinil did not show reduced methamphetamine use or craving, nor any increase in sustained abstinence; more extensive trials are needed.
Some animal studies have shown that amphetamine use can produce reverse tolerance; however,in humans, there is no systematic evidence of the development of behavioral sensitization to amphetamine after acute or chronic amphetamine treatment when the drug is used in the therapeutic dose range (i.e., is not abused). The absence of observed sensitization development in humans (compared to that observed in rodents) may be explained by different amphetamine metabolism or different mechanisms of action of amphetamine in humans versus rats.