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.
