The effects of methylphenidate on the cardiovascular system. Methylphenidate (MPH) is widely prescribed for ADHD. It is a sympathomimetic drug, so adverse cardiovascular (CV) effects would be expected. There is growing evidence that sympathomimetic amines in general are associated with an increased risk of CV events, including sudden death. This paper will review the physiological effects of MPH on the CV system, focusing on its vasoactive properties and the effects of methylphenidate on the sympathetic nervous system. Literature was sourced through MEDLINE and reviewed for all research related to the cardiovascular effects of MPH. Searches were made with the terms methylphenidate and cardiovascular with all subterms. Additional papers were found using the reference lists from other papers. Methylphenidate acts both as an inhibitor of the reuptake of dopamine (DA) and norepinephrine (NE) at noradrenergic nerve endings, and at adrenergic nerve endings (α1 receptors). Vagally mediated increases in heart rate are significantly reduced in conscious rats by methylphenidate. In vitro, methylphenidate has a direct effect on vascular muscle (rat aorta). It causes a concentration-dependent relaxation of endothelium-intact aorta with a lower potency than NE, but greater than DA. The actions of methylphenidate have been compared with selective adrenoceptor agonists (phenylephrine, NE, and isoproterenol), NE transporter (NET) blockers (nisoxetine and reboxetine), and noradrenergic receptor antagonists (propranolol, guanethidine and phentolamine), all of which cause vasoconstriction in the aorta. Some studies have found elevations in heart rate and blood pressure with administration of methylphenidate, but most studies in the absence of cardiovascular disease do not show these effects. In conclusion, a literature review confirms that MPH has sympathomimetic properties with vasoconstrictive effects both in vitro and in vivo. These effects are not mediated through adrenoceptors or the NET but appear to be via direct actions on vascular muscle. Methylphenidate has been linked to sympathomimetic effects with a potential for vasoconstriction. As many patients are exposed to sympathomimetic drugs, the possibility of a cardiovascular adverse event should be borne in mind. However, the majority of reports suggest that such an event is unlikely. Further research is required to determine the effect of methylphenidate in patients with cardiovascular disease.