the risk of heart attacks and strokes in patients with a history of cardiovascular disease. Frequently encountered side effects are: dry mouth, paradoxically increased appetite, nausea, strange taste in the mouth, upset stomach, constipation, trouble sleeping, dizziness, drowsiness, menstrual cramps/pain, headache, flushing, or joint/muscle pain. In a 2016 Cochrane review, sibutramine was found to substantially increase blood pressure and heart rate in some patients, in the updated review in 2021 sibutramine was not included since the drug had been withdrawn from the market. When used, regular blood pressure monitoring needed to be performed. The following side effects are infrequent but serious and require immediate medical attention: cardiac arrhythmias, paresthesia, mental/mood changes (e.g., excitement, restlessness, confusion, depression, rare thoughts of suicide). Symptoms that require urgent medical attention are seizures, problems urinating, abnormal bruising or bleeding, melena, hematemesis, jaundice, fever and rigors, chest pain, hemiplegia, abnormal vision, dyspnea and edema. Currently, no case of pulmonary hypertension has been noted. (Fenfluramine, of the 1990s "Fen-Phen" combo, forced excess release of neurotransmitters—a different action. Phentermine was uninvolved in the rare—but clinically significant—heart issues of fenfluramine.) Interactions Sibutramine has a number of clinically significant interactions. The concomitant use of sibutramine and monoamine oxidase inhibitors (MAOIs, such as selegiline) is not indicated, as it may increase the risk of serotonin syndrome, a somewhat rare but serious adverse drug reaction. Sibutramine should not be taken within two weeks of stopping or starting an MAOI. Taking both sibutramine and certain medications used in the treatment of migraines—such as ergolines and triptans—as well as opioids, may also increase the risk for serotonin syndrome, as may the use of more than one serotonin reuptake inhibitor at the same time. The concomitant use of sibutramine and drugs which inhibit CYP3A4, such as ketoconazole and erythromycin, may increase plasma levels of sibutramine. Sibutramine does not affect the efficacy of hormonal contraception. Pharmacology Pharmacodynamics Sibutramine is a serotonin–norepinephrine reuptake inhibitor (SNRI) that, in humans, reduces the reuptake of norepinephrine (by ~73%), serotonin (by ~54%), and dopamine (by ~16%), thereby increasing the levels of these substances in synaptic clefts and helping enhance satiety; the serotonergic action, in particular, is thought to influence appetite. Older anorectic agents such as amphetamine and fenfluramine force the release of these neurotransmitters rather than affecting their reuptake. Sibutramine's mechanism of action is similar to tricyclic antidepressants, and it has demonstrated antidepressant effects in animal models of depression. It was