in rats: Methoxetamine (MXE) (0.5-5 mg·kg-1) affected motor activity in a dose- and time-dependent manner, inducing hypermotility and hypomotility at low and high doses respectively. At low and intermediate doses (0.5 and 1 mg·kg-1), MXE induced anxious and/or obsessive-compulsive traits (marble burying test), did not significantly increase sociability (social interaction test) or induce spatial anxiety (elevated plus maze test). At a high dose (5 mg·kg-1), MXE induced transient analgesia (tail-flick and hot-plate test), decreased social interaction time (social interaction test) and reduced immobility time while increasing swimming activity (forced swim test), suggesting an antidepressant effect.

It was investigated the effects of methoxetamine (MXE) on several endpoints using multiple in vitro models. These included rat primary cortical cells, human SH-SY5Y cells, human induced pluripotent stem cell (hiPSC)-derived iCell Neurons, DopaNeurons and astrocyte co-cultures, and human embryonic kidney (HEK293) cells. There were studied effects on several neurotransmitter receptors using single cell intracellular calcium [Ca2+]i imaging, effects on neuronal activity using micro-electrode array (MEA) recordings and effects on human monoamine transporters using a fluorescence-based plate reader assay. In rat primary cortical cells, 10 μM MXE increased the glutamate-evoked increase in [Ca2+]. MXE and ketamine did not affect voltage-gated calcium channels (VGCCs), but inhibited spontaneous neuronal activity (IC50 0.5 μM and 1.2 μM respectively). In human SH-SY5Y cells, 10 μM MXE slightly inhibited the K+- and acetylcholine-evoked increase in [Ca2+]i. In hiPSC-derived iCell (Dopa)Neurons, only the ATP-evoked increase in [Ca2+]i was slightly reduced. Additionally, MXE inhibited spontaneous neuronal activity (IC50 between 10 and 100 μM). Finally, MXE potently inhibits uptake via monoamine transporters (DAT, NET and SERT), with IC50 values in the low micromolar range (33, 20, 2 μM respectively).