NMDA receptor antagonists induce a state called dissociative anesthesia, marked by catalepsy, amnesia, and analgesia.[1] Ketamine is a favored anesthetic for emergency patients with unknown medical history and in the treatment of burn victims because it depresses breathing and circulation less than other anesthetics.[2][3]Dextrorphan, a metabolite of dextromethorphan (one of the most commonly used cough suppressants in the world[4]), is known to be an NMDA receptor antagonist.
Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects and, at higher doses, begin inducing dissociation and hallucinations, though these effects and the strength thereof vary from drug to drug.[13]
Most NMDA receptor antagonists are metabolized in the liver.[14][15] Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.[16]
NMDA receptor antagonists are also under investigation as antidepressants. Ketamine has been demonstrated to produce lasting antidepressant effects after administration in a clinical setting. In 2019, esketamine, an NMDA antagonist enantiomer of ketamine, was approved for use as an antidepressant in the United States.[17] In 2022, Auvelity was approved by the FDA for the treatment of depression.[citation needed] This combination medication contains dextromethorphan, an NMDA receptor antagonist.
Olney's lesions involve mass vacuolization of neurons observed in rodents.[18][19] However, many suggest that this is not a valid model of human use, and studies conducted on primates have shown that use must be heavy and chronic to cause neurotoxicity.[20][21] A 2009 review found no evidence of ketamine-induced neuron death in humans.[22] However, temporary and permanent cognitive impairments have been shown to occur in long-term or heavy human users of the NMDA antagonists PCP and ketamine. A large-scale, longitudinal study found that current frequent ketamine users have modest cognitive deficits, while infrequent or former heavy users do not.[23]
Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2agonists such as clonidine and guanfacine are thought to most directly target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates,[24]ethanol,[25] 5-HT2Aserotonin receptor agonists,[26]anticonvulsants,[27] and muscimol.[28]
Since NMDA receptor overactivation is implicated in excitotoxicity, NMDA receptor antagonists have held much promise for the treatment of conditions that involve excitotoxicity, including benzodiazepine withdrawal, traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions,[29] and studies have started to find agents that prevent this neurotoxicity.[25][28] Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic neurotransmission, blocking them causes side-effects. These results have not yet been reproduced in humans, however.[30] Mild NMDA receptor antagonists like amitriptyline have been found to be helpful in benzodiazepine withdrawal.[31]
Simplified model of NMDAR activation and various types of NMDAR blockers.[10]
The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called "activated."
Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists block binding to neurotransmitter glutamate sites; glycine antagonists block binding to glycine sites; noncompetitive antagonists inhibit binding to NMDARs allosteric sites; and uncompetitive antagonists block binding to a site within the ion channel.[10]
Dextromethadone: (S)-enantiomer of the drug methadone that has low affinity for opioid receptors and exhibits rapid antidepressant effects in animal models.
Dizocilpine (MK-801): an experimental drug used in scientific research.[41]
Ethanol: also known as alcohol, a widely used intoxicant.
Eticyclidine: a slightly more potent dissociative anesthetic than phencyclidine but with greater nausea/unpleasant taste, that was discontinued early in its development due to these digestive complaints.
Gacyclidine: an experimental drug developed for neuroprotection and is being studied for the treatment of tinnitus.[42]
Ketamine: a dissociative hallucinogen with antidepressant properties used as an anesthetic in humans and animals, a possible treatment in bipolar disorder patients with treatment-resistant depression, and used recreationally for its effects on the CNS.[43]
PD-137889: Potent NMDA receptor antagonist with roughly 30 times the potency of ketamine. Substitutes for PCP in animal studies.
Phencyclidine: a dissociative anesthetic previously used in medicine, but its development was discontinued in the 1960s in favor of its successor ketamine due to its relatively high incidence of psychotomimetic effects. Abused recreational and legally controlled in most countries.
Remacemide: a low affinity antagonist also a sodium-channel blocker.
Rolicyclidine: a less potent analogue of phencyclidine, but seems to be seldom, if ever, abused.
Aptiganel (Cerestat, CNS-1102): binds the Mg2+ binding site within the channel of the NMDA receptor.
HU-211: an enantiomer of the potent cannabinoid HU-210 which lacks cannabinoid effects and instead acts as a potent non-competitive NMDA antagonist.[50]
Dipeptide D-Phe-L-Tyr.[54] weakly inhibit NMDA/Gly-induced currents possibly by ifenprodil-like mechanism.
Ibogaine: a naturally-occurring alkaloid found in plants of the family Apocynaceae. Has been used, albeit with limited evidence, to treat opioid and other addictions.[55][56]
Remacemide: principle metabolite is an uncompetitive antagonist with a low affinity for the binding site.[57]
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