Amphetamine (AMPH) exerts effects on the metabolic and the cardiovascular systems. The melanocortin system is a key central regulator of both metabolic and cardiovascular function. Here we show that the melanocortin system is critical for AMPH-induced anorexia, energy expenditure, tachycardia and hypertension. AMPH excited proopiomelanocortin (POMC) neurons, significantly increased α-melanocyte stimulating hormone (αMSH) secretion from the hypothalamus, elevated blood pressure and heart rate, increased BAT thermogenesis and reduced both food intake and body weight. In melanocortin 4 receptor deficient (MC4R KO) mice, AMPH still significantly increased αMSH secretion although metabolic and cardiovascular effects were significantly attenuated. Central serotonergic and noradrenergic systems are responsible for melanocortin-dependent effects of AMPH because antagonism of either or both of these neurotransmitter systems attenuated AMPH-induced αMSH secretion as well as AMPH-induced metabolic and cardiovascular effects. We propose that AMPH increases serotonergic activation of POMC neurons, and reduces the noradrenergic inhibition of POMC neurons, thereby disinhibiting them. Together these presynaptic mechanisms result in increased POMC activity, increased αMSH secretion and increased activation of MC4R pathways that regulate both the metabolic and cardiovascular systems