Severe withdrawal associated with dependence from recreational substituted amphetamine use can be a difficult for a user to cope with. Long-term use of certain substituted amphetamines, particularly methamphetamine, can reduce dopamine activity in the brain.Psychostimulants that increase dopamine and mimic the effects of substituted amphetamines, but with lower abuse liability, could theoretically be used as replacement therapy in amphetamine dependence, but studies of D-amphetamine, 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 substituted amphetamine use can produce reverse tolerance; however,in humans, there is no systematic evidence of the development of behavioral sensitization to amphetamine-type drugs after acute or chronic drug treatment when used in a low or therapeutic dose range (i.e., is not abused recreationally). The absence of observed sensitization development in humans (compared to that observed in rodents) may be explained by variations in drug metabolism or different mechanisms of action of amphetamine-type drugs in humans versus rats.
^Malenka RC, Nestler EJ, Hyman SE (2009). "15". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 370. ISBN9780071481274. "Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons."
^Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res Rev60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC2731235. PMID19328213. "Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006)."