This column is the sixth in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first 3 columns in this DDI series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs, how to recognize such DDIs, strategies for avoiding and/or minimizing adverse outcomes from such DDIs, and pharmacokinetic considerations concerning DDIs in psychiatric practice. The fourth and fifth columns in this series presented a pair of parallel tables, one of which outlined the primary, known mechanism(s) of action of all commonly used psychiatric medications and one of which summarized major types of pharmacodynamic DDIs based on mechanism of action. Clinicians can use these 2 tables together to predict pharmacodynamically mediated DDIs. This sixth column in the series discusses some key issues related to pharmacodynamic interactions involving commonly used psychiatric medications. The column first discusses 3 types of pharmacological agents that deserve special mention because of the widespread types of pharmacodynamic DDIs they can have with psychiatric and other medications: ethanol, opioids, and monoamine oxidase inhibitors, with a special focus on hypertensive crises and serotonin syndrome with monoamine oxidase inhibitors. The column also discusses DDIs in terms of effects on the cardiovascular system, including QTc prolongation, blood pressure and heart rate regulation, increased risk of bleeding and abnormal bleeding, and valvular heart disease, and on the central nervous system, including increased sedation, respiratory depression, body temperature regulation, and tardive dyskinesia. The overall goal of this series of columns is to present a simple way of conceptualizing neuropsychiatric medications in terms of their pharmacodynamics and pharmacokinetics to allow prescribers to take these facts into consideration when they need to use more than 1 drug in combination to optimally treat a patient.