Opioids NMDA antagonism - what is it?

[mdaniel80]

NMDA antagonism - what is it?

If you spend any time in harm reduction forums, nootropics groups, and drug-related chats, you are bound to see the term “NMDA antagonism”. It is often mentioned in conjunction with opioid potentiation, tolerance, and withdrawal. But to someone without a basic pharmacology background NMDA antagonism just means ketamine (or memantine). Let’s briefly describe what this mechanism of action really means, in easily understandable terms.

NMDA stands for N-methyl-D-aspartate and refers to types of receptors located in your brain. These specific receptors are part of your glutamate system. While glutamate is an essential neurotransmitter, too much of it can cause anxiety and pain.

Antagonism means the inhibitory action of a substance. In other words: when a drug “antagonizes” your receptors, it blocks them from receiving signals.
So an NMDA antagonist stops messaging to NMDA receptors. In other words: it blocks glutamate. This can be a great tool for anxiety but perhaps the largest benefit is how it works with opioids. Studies show that NMDA antagonism can help strengthen the analgesic (pain-relieving effects) of opioids. They also show NMDA antagonism to upregulate (heal/repair) opioid receptors helping with tolerance and withdrawal.

The most commonly talked about NMDA antagonists are ketamine (which is very short-acting) , memantine (which is very long acting), and dextromethorphan (DXM). But there are other NMDA antagonists that don’t carry strong side effects such as agmatine and magnesium.

Here are some other great resources to help you better understand what NMDA antagonism is:
https://psychonautwiki.org/wiki/NMDA_receptor_antagonist...
https://www.youtube.com/watch?v=tW09dUa-JZk


Maria Daniel

 

[sroxlur]

The arylcyclohexalamine NMDA antagonists don't block glutamate, they block the ion channel in the actual receptor. This decreases the firing rate as less ions can flow through the receptor channel. The adamantane based NMDA antagonists bind to the magnesium site in the receptor channel, which only partially blocks the receptor's activity. This attenuates the ion flow, but does not fully inhibit action like the arycyclohexalamines, which doesn't increase overall glutamate like ketamine or pcp does. Ketamine upregulates opioid activity by antagonizing Mu and agonizing delta receptors. This is the opposite action of drugs like morphine. DXM can be as long lasting as memantine or PCP in a small percentage of the population via the CYP2D6 gene. Agmatine really isn't an antagonist at all, but a very weak negative allosteric modulator, binding to the spermidine sight. Most of these drugs are also D2 agonists which contribute to the hallucinogenic and analgesic effects of these drugs. Almost all of them have equal potency at one or more D2 receptor sites. Here's an in depth video about the history of NMDA antagonists

 

[kongoman]

Thanks for this masterful post!
I'd love to ask if after a ketamine binge say 2grams in 3 days can block the effect of methadone the 4th day? Cause today I took 240mg of methadone and 900mg pregabalin and I felt nothing.

Thanks in advanced!

Kongoman