The N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg²⁺ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

The NMDA receptor is ionotropic, meaning it is a protein which allows the passage of ions through the cell membrane. The NMDA receptor is so named because the agonist molecule N-methyl-D-aspartate (NMDA) binds selectively to it, and not to other glutamate receptors. Activation of NMDA receptors results in the opening of the ion channel that is nonselective to cations, with a combined reversal potential near 0 mV. While the opening and closing of the ion channel is primarily gated by ligand binding, the current flow through the ion channel is voltage-dependent. Specifically located on the receptor, extracellular magnesium (Mg2+) and zinc (Zn2+) ions can bind and prevent other cations from flowing through the open ion channel. A voltage-dependent flow of sodium (Na+), calcium (Ca2+), and potassium (K+) ions into and out of the cell is made possible by the depolarization of the cell, which displaces and repels the Mg2+ and Zn2+ ions from the pore. Ca²⁺ flux through NMDA receptors in particular is thought to be critical in synaptic plasticity, a cellular mechanism for learning and memory, due to proteins which bind to and are activated by Ca²⁺ ions.

Activity of the NMDA receptor is blocked by many psychoactive drugs such as phencyclidine (PCP), alcohol (ethanol) and dextromethorphan (DXM). The anaesthetic and analgesic effects of the drugs ketamine and nitrous oxide are also partially due to their effects at blocking NMDA receptor activity. In contrast, overactivation of NMDAR by NMDA agonists increases the cytosolic concentrations of calcium and zinc, which significantly contributes to neural death, an effect known to be prevented by cannabinoids, mediated by activation of the CB1 receptor, which leads HINT1 protein to counteract the toxic effects of NMDAR-mediated NO production and zinc release. As well as preventing methamphetamine-induced neurotoxicity via inhibition of nitric oxide synthase (nNOS) expression and astrocyte activation, is seen to reduce methamphetamine induced brain damage through a CB1-dependent and independent mechanisms, respectively, and inhibition of methamphetamine induced astrogliosis is likely to occur through a CB2 receptor dependent mechanism for THC. Since 1989, memantine has been recognized to be an uncompetitive antagonist of the NMDA receptor, entering the channel of the receptor after it has been activated and thereby blocking the flow of ions.

Overactivation of the receptor, causing excessive influx of Ca²⁺ can lead to excitotoxicity which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases. However, hypofunction of NMDA receptors (due to glutathione deficiency or other causes) may be involved in impairment of synaptic plasticity and could have other negative repercussions. The main problem with the utilization of NMDA receptor antagonists for neuroprotection is that the physiological actions of the NMDA receptor are essential for normal neuronal function. To be clinically useful NMDA antagonists need to block excessive activation without interfering with normal functions. Memantine has this property.