Milnacipran hydrochloride (Savella) is a serotonin and norepinephrine reuptake inhibitor used to treat major depressive disorders. Milnacipran hydrochloride is an enantiomer of milnacipran, which is used to treat fibromyalgia. Milnacipran hydrochloride and milnacipran have been associated with a low rate of transient elevations in serum aminotransferase levels during treatment and with rare instances of clinically apparent acute liver injury with jaundice.

In rat prefrontal cortex, Milnacipran (10 and 30 mg/kg, p.o.) was found to dose-dependently increase extracellular levels of NA and 5-HT. In antidepressant animal behavioral models, Milnacipran (30 and 60 mg/kg, p.o.) significantly reduced immobility time in the forced swim test in rats. Similarly, in animal models of anxiety, Milnacipran (30 and 60 mg/kg, p.o.) notably decreased immobility time in the conditioned fear stress test. In freely moving guinea pigs' hypothalamus, treatment with Milnacipran (10 mg/kg and 40 mg/kg) resulted in a 57% and 47% reduction in the NA metabolite MHPG respectively. Furthermore, Milnacipran (<40 mg/kg, i.p.) increased extracellular levels of NA and 5-HT in the hypothalamus of freely moving guinea pigs in a dose-dependent manner.

Over 80% of Milnacipran is excreted in the urine primarily in its unchanged form and as glucuronide conjugates, with less than 10% metabolized through CYP3A4 enzyme-mediated N-deethylation. At high concentrations, Milnacipran can inhibit certain ligand-gated ion channel receptors, including 5-HT3A (IC50: 185 μM), NMDA (IC50: 58.4 μM), and nACh (IC50: 14.3 μM) receptors.