I have a slightly different way of thinking than most people; I have better-developed deductive skills, the ability to see in contexts and connections. Hopefully, you will have no problem understanding this article, as I often digress from the main topic and write about the context as well.
NMDA antagonists are generally called dissociative substances.
https://en.wikipedia.org/wiki/NMDA_receptor_antagonist
The most well-known dissociative substance is the addictive ketamine . It is also called a dissociative anesthetic. Ketamine can immobilize a person, so it is suitable for restless children if the doctor needs to perform a minor surgical procedure. It also relieves pain. It only works for a short time, I think only about 10-15 minutes. A dissociative anesthetic is perceived as one that, in principle, does not cause unconsciousness.
Ketamine increases blood pressure mainly because its effect is non-selective, and it also has a certain common property with cocaine: it is an inhibitor of the reuptake of dopamine, serotonin, and noradrenaline.
The well-known "laughing gas" is also an NMDA antagonist; in addition, it increases the activity of some dopamine receptors. It is impractical for general anesthesia because it significantly stops breathing and its effectiveness is quite low; it must be administered in high concentrations with oxygen, while the threat of hypoventilation is very high. It is sometimes used mixed with other inhalation anesthetics. It is used alone only as an analgesic and is most often used by dentists (especially private ones), more or less as entertainment for patients, because the dentist has other, more practical options for pain relief.
Xenon is a general anesthetic, it is a selective NMDA antagonist with a substantially higher affinity/efficacy than nitrous oxide, it is more practical, it is not yet used in Slovakia. A comparison of nitrous oxide with xenon is here https://en.wikipedia.org/wiki/Xenon#Medical
Substances that are NMDA antagonists can cause hallucinations and out-of-body experiences. https://en.wikipedia.org/wiki/Dissociative
The possibility of habituation and addiction to NMDA antagonists can only occur if the effect of these substances is non-selective, if they also increase the activity of the dopamine receptor.
(Overall, addiction to all addictive psychoactive substances is explained by current science by only one theory: an increase in the activity of dopamine receptors (either directly or indirectly), although not all substances that increase the activity of dopamine receptors are addictive, such as LSD or Parkinson's drugs).
The term dissociation is perceived as a certain change in the state of consciousness, mainly in the positive sense of the word. If dissociation becomes pathological, then it is perceived as depersonalization or derealization , and this is already in connection with a psychiatric diagnosis. (Very unpleasant states of depersonalization are often experienced by cannabis users, which is also associated with severe depression)
NMDA receptors are very unique. As the only major receptors, they are perceived as excitatory receptors ,
(while most receptors are neither inhibitory nor excitatory). Conversely, the only major inhibitory receptors are GABA receptors.
All general anesthetics available on the Slovak pharmacological market are pharmacological GABA agonists and NMDA antagonists, except for opiates and midazolam, which, as a sedative-benzodiazepine, increases the activity of GABA receptors only.
(In addition, common anesthetics are often antagonists of muscarinic-acetylcholine or nicotinic-acetylcholine receptors, which are almost identical receptors. This has the advantage of suppressing mucus secretion in the airways, which is extremely useful for the anesthesiologist).
GABA agonist and NMDA antagonist is like alcohol – it's probably not for nothing that it was used as an anesthetic for operations in the distant past.
GABA and NMDA receptors should be, as far as I know, the most abundant receptors in the brain. Therefore, substances acting on these receptors have a stronger effect and are more significant.
Dissociatives are unique in that they are the only psychoactive substances that work by reducing receptor activity (antagonism) . All other substances, both addictive and non-addictive, work by increasing the activity of a receptor (agonism).
NMDA Receptors and Neurodegenerative Diseases
According to apparent logic, the processes in the human body should slow down in old age. But the opposite is true. As a person ages, all processes in the body accelerate, e.g., the heart starts working at a much more powerful pace, which manifests as hypertension (overall, the main factor of blood pressure is the heart), which almost everyone has in old age.
And the exact same logic applies to the brain. The most powerful working (excitatory) receptors start working even more powerfully in old age. Too high activity of NMDA receptors causes gradual self-destruction, the death of nerve cells, and this is called excitotoxicity (derived from the words excitation and toxicity).
Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are related to excitotoxicity. Alzheimer's and Parkinson's patients should take drugs that are NMDA antagonists.
In Alzheimer's disease, it can be strikingly observed that the brain of an Alzheimer's patient is reduced and shrunken.
Schizophrenia
Some symptoms of schizophrenia are similar to the effects of NMDA antagonists. According to current science, it has been found that schizophrenics have a higher level of a substance in the brain that is an NMDA antagonist https://en.wikipedia.org/wiki/Kynurenic_acid#Role_in_disease . Therefore, the NMDA theory of the origin of schizophrenia was also developed. This theory is not in conflict with the dopamine theory. By the way, a large part of psychiatrists consider schizophrenia as a set of several diagnoses at once. A schizophrenic should take a substance that is an NMDA agonist.
https://en.wikipedia.org/wiki/Glutamate_hypothesis_of_schizophrenia
Health risks
No significant health risks have been recorded with non-addictive NMDA antagonists. Only long-term use, at high frequency and in high doses, can cause permanent brain damage. In the short term, the change in nerve cells is such that they contain more water in the vacuoles. However, this quickly returns to normal after the dissociative substance wears off.
The biggest problem I see is that NMDA antagonists are very poorly scientifically researched. We know very little about them. We only know more information exclusively about ketamine and DXM.
L-phenylalanine is also an NMDA antagonist. It is a nutritional supplement available over-the-counter in pharmacies. People on the internet have written that after taking phenylalanine they had very vivid dreams https://en.wikipedia.org/wiki/L-Phenylalanine
DXM DXM is the active ingredient in cough medicines. Since these medicines are also commonly available in stores in the USA, their sale does not require a prescription. People have a lot of recreational experience with it, and it is probably the most information-rich substance available. However, it has an extremely low affinity/potency, and people use it in recreational doses of 600-1000 mg or even much more. Unpleasant short-term side effects can be significant due to its low affinity. The body's organs have a hard time coping with such a very large amount of foreign, unnatural "chemical" in the body. https://en.wikipedia.org/wiki/Recreational_use_of_dextromethorphan
Otherwise, there is also a dissociative substance with a very high affinity, but it has been very little researched. There would be no such side effect problems there.
Sigma σ receptors
It is not an opioid receptor. Addictive NMDA antagonists such as ketamine and PCP increase activity through this receptor. According to current scientific knowledge, DMT is the only substance from tryptamines (tryptamines are substances very similar to the neurotransmitter serotonin https://en.wikipedia.org/wiki/Category:Psychedelic_tryptamines ) and the only psychedelic substance that is an agonist of sigma receptors.
The antipsychotic Haloperidol is an antagonist of these receptors.
The substances Ditolylguanidine and Siramesine should be non-addictive agonists for sigma receptors and at the same time antagonists for NMDA receptors. These are little-researched substances.
A better documented substance that has the strongest effect on sigma receptors is Ibogaine. The problem with it is cardiac arrhythmias https://en.wikipedia.org/wiki/Ibogaine