Use of amphetamines is a global health problem associated with significant social and financial burdens. Worldwide, amphetamines are second only to marijuana and opiates, respectively, for most abused illicit drug and highest prevalence of addiction. Epidemiological data reveal that adolescent and female drug users are at higher risk to develop addiction and have worse treatment outcomes than adults or males. Drug-induced cognitive deficits and neuroadaptations, in combination with different patterns of drug-seeking, represent possible mechanisms by which heightened vulnerability to addiction may be conferred in adolescents and females. Using a rodent model, this hypothesis was tested with two specific aims: (1) by assessing the impact of exposure to amphetamines on cognitive flexibility and 5-HT2C receptor structure and function (Experiments 1, 3, 4) and (2) by examining age and sex differences in intravenous methamphetamine self-administration (Experiment 2). In Experiment 1, male and female Sprague-Dawley rats were treated with amphetamine (3 mg/kg i.p.) during adolescence or young adulthood and tested in a Pavlovian outcome devaluation task at the same age in adulthood. Subsequently, the impact of systemic 5-HT2C receptor antagonism on devaluation was tested in a separate group of amphetamine-treated rats. In Experiment 2, male and female Sprague-Dawley rats were trained to self-administer methamphetamine at 3 doses (0.02, 0.05, 0.08 mg/kg/inf) during adolescence or adulthood and, subsequently, tested for motivation to work for four doses of methamphetamine using a progressive ratio schedule of reinforcement. Rats that acquired methamphetamine self-administration at the highest dose were used in Experiments 3 and 4. In Experiment 3, rats with a history of self-administration were tested for cognitive flexibility in an operant strategy shifting task. Subsequently, in Experiment 4, immunohistochemical analysis of the brains examined colocalization of 5-HT2C receptors with parvalbumin-immunoreactive interneurons in the orbitofrontal cortex. These studies revealed complex interactions of age and sex on drug-induced changes and heightened drug-seeking in adult rats. Taken together and in the context of broader literature, this work supports the assertion that pervasive, and sometimes subtle, drug-induced changes in cognition and neurobiology along with different patterns of drug-seeking may be mechanisms of heightened vulnerability in adolescent and female users.