DXM and Neuron Death

[embryo923]

Is DXM basically an excitotoxin when used at recreational doses and does NMDA receptor stimulation cause neuron or cell death?

For example, this is from an article about Glutamate:

If the concentration level rises, then neurons become too excited and don’t fire in a normal manner. Glutamate becomes an excitotoxin when it is in excess; meaning it overstimulates brain cells and nerves and results in neurological inflammation and cell death.

http://www.holistichelp.net/blog/how-to-increase-gaba-and-balance-glutamate

 

[Zilpe]

DXM is an NMDA receptor antagonist which means it prevents stimulation of NMDA from glutamate. In this sense it's neuroprotective. However, it's possible that there could be rebound excitotoxicity after the NMDA antagonist leaves the system. Additionally there are some general (see the debate about Olney's lesions for example) concerns about NMDA antagonists and neurotoxicity but afaik the mechanism is unknown.

 

[embryo923]

DXM is an NMDA receptor antagonist which means it prevents stimulation of NMDA from glutamate. In this sense it's neuroprotective. However, it's possible that there could be rebound excitotoxicity after the NMDA antagonist leaves the system. Additionally there are some general (see the debate about Olney's lesions for example) concerns about NMDA antagonists and neurotoxicity but afaik the mechanism is unknown.

Thanks, great reply. Yeah I have read up on Olney's lesions and am putting all of it together to understand it as well as I can. I guess there is no reason for drug companies to invest in the research to learn about these things?

 

[white55]

It's a potential danger with all dissos, luckily a tiny benzo dose at the end of the trip seems to prevent it.

 

[Cotcha Yankinov]

DXM is an NMDA receptor antagonist which means it prevents stimulation of NMDA from glutamate. In this sense it's neuroprotective.

I'd like to add that NMDA antagonists tend to inhibit GABA interneurons, thus increasing downstream glutamate release that binds onto other glutamate receptors that aren't blocked and can still mediate excitotoxicity or potentially unwanted changes in genetic expression

 

[embryo923]

It's a potential danger with all dissos, luckily a tiny benzo dose at the end of the trip seems to prevent it.

Well is good to know! Because I religiously take 1.5-2mg of Klonopin once I begin to comedown off the DXM. So this would help prevent the rebound excitotoxicity?

 

[Zilpe]

I'd like to add that NMDA antagonists tend to inhibit GABA interneurons, thus increasing downstream glutamate release that binds onto other glutamate receptors that aren't blocked and can still mediate excitotoxicity or potentially unwanted changes in genetic expression

Sigma-1 agonism can also lead to some glutamate release which in the case of ibogaine can cause tremor and associated degeneration of motor cells but I haven't heard of DXM causing tremor

Interesting. I didn't know that. It seems that the mechanisms of drug activity are really much more complicated than simple receptor binding. Still, am I correct in thinking that downstream glutamanergic excitotoxicity from NMDA antagonists is something that is only hypothetically possible rather than something we have any actual evidence of? In terms of DXM specifically it hits a bunch of other receptors so it's certainly possible there's some other mechanism that causes excitotoxcicity but the original post was referring specifically to NMDA antagonism, for which I assume a rebound effect would be more of a concern than downstream activity.

 

[Cotcha Yankinov]

I personally wouldn't worry too much about downstream glutamatergic excitotoxicity from NMDA antagonists but it seems that the glutamate release can cause changes in expression of things like parvalbumin and GAD67 in parvalbumin positive GABA interneurons. This may be particularly appreciable with ketamine that has some pro-glutamate metabolites (hydroxynorketamine) that seem to play a role in its efficacy for depression.

Supposedly the changes in parvalbumin/GAD67 expression may underlie both some of the pro-psychotic and anti-depressant effects. Some people with schizophrenia/bipolar seem to already have issues with parvalbumin/GAD67, so this could certainly be a situation where there is more concern with some people than others. Maybe decreased GAD67 expression means that the inhibitory neurons hold even less inhibition over other neurons and this could have implications for long term use related excitotoxicity.

I'm not sure how many of the psychoactive effects are really due to the downstream glutamate release however, supposedly a lot of the psychoactive effects of NMDA antagonists are due to inhibitory interneuron inhibition -> monoamine release, in which case I would expect a lot less trouble with excitotoxicity. I think its more so the glutamate release in the cortex that helps with depression though.


There is that one MRI study of ketamine abusers that showed a lot of deleterious effects (I believe it was from China). I don't know exactly what explains those effects but I hope its not excitotoxicity - I hope that the atrophy and abnormalities seen are essentially the byproduct of the brain being in a K-hole regularly for years. In that sense some of the issues may be like muscle atrophy, in a "use it or lose it" sense.

 

[Img_9999]

Yeah, the subjects in that chinese study were using daily, and in pretty high amounts if I remember correctly.

 

[embryo923]

So any deleterious effects form ketamine would likely also occur from frequent and heavy DXM use I assume?

 

[Cotcha Yankinov]

I think ketamine and DXM may have some risks in common but maybe some risks aren't shared between the two. However, by and large the anecdotal reports are that chronic NMDA antagonist abuse can carry heavy adverse effects