Although use of methamphetamine (MA) by smoking is the fastest growing method of administration, very limited data are available describing the effects of smoked MA. Using a murine inhalation exposure system, we explored the pulmonary effects of low-dose acute inhalation exposure to MA vapor (smoke). Inhalation of MA vapor resulted in transiently reduced pulmonary function as measured by transpulmonary resistance (RL), dynamic compliance (Cdyn), and whole body plethysmography (WBP) compared to unexposed controls. These changes were associated with an approximately 34% reduction in serotonin (5-HT) metabolism to 5-hydroxyindolacetic acid (5-HIAA) and a nearly 40% reduction in monoamine oxidase A (MAO-A) activity in the lung. Pretreatment of mice with a selective serotonin reuptake inhibitor completely ablated the MA-induced changes in pulmonary function confirming a key role for the 5-HT transporter (SERT) and the serotonergic system in this effect. Immunofluorescent staining of mouse lung tissue confirmed high expression of SERT in airway epithelial cells. Using a mouse airway epithelial cell line LA-4 and purified human MAO-A, it was demonstrated that MA impedes 5-HT metabolism through direct inhibition of MAO-A activity in vitro. Together these data demonstrate that low-dose exposure to MA results in reduced pulmonary function mediated via SERT and subsequent perturbation of 5-HT metabolism in the lung. This supports a role for the serotonergic system in MA-mediated pulmonary effects.