Abstract: Metamphetamine (METH) has been the most popular drug of abuse in Japan for more than 50 years, resulting in serious health and social issues. Most adult abusers in Japan consume only METH; multiple-substance abusers are rare. This unusual aspect of drug abuse makes it possible to observe clearly the sequential alteration of psychiatric symptoms induced by METH without modification by other illegal drugs. Clinical investigation reveals three core characteristics of METH abuse: (1) progressive qualitative alteration in mental symptoms from a nonpsychotic to a prepsychotic to a severely psychotic state; (2) enhanced vulnerability to relapse of psychosis; and (3) very long duration of the vulnerability to relapse. These findings indicate that the phenomenon of sensitization to METH develops during abuse and plays a key role in the susceptibility to and onset of psychosis and in the refractory process. Molecular findings using animal sensitization models may facilitate a better understanding of, and open the way for innovative therapies for, METH psychosis and also chronic schizophrenia.