Misc Can NMDA antagonists cause physiological dependence?

[Swimmingdancer]

I was watching some documentary about methadone withdrawal and a doctor on it said that one of the reasons methadone withdrawals are worse than other opioids is because of it's NMDA antagonism. He seemed to imply that constantly taking an NMDA antagonist causes a dependence, so essentially you are going through opioid withdrawal and NMDA antagonist withdrawal when you stop methadone after long-term use. Is this true? Anyone know anything about the topic of whether or not NMDA antagonism can cause a physiological dependence and therefore withdrawal syndrome?

 

[bluedolphin]

I found Ketamine physically non-addictive. MXE would leave me a little less motivated and lazy feeling upon discontinuing periods of prolonged use, which is similar to minor withdrawl from other weaker stimulants. MXE has also been shown to have more going on besides NDMA antagonism.

In any case my extensive abuse of Ketamine with no physical withdrawls leads me to conclude that a large tolerance does not mean there will be withdrawls.

 

[Znegative]

I'm not an expert in regards to NMDA antagonists by any means, but from what I know, I would think that the NMDA antagonist properties in racemic methadone would actually cause it to be less addictive, or more realistically (since we all know methadone is pretty damn addictive), that it causes methadones narcotic properties to stay more or less effective at the same dose. I have noticed that methadone does seem to produce a consistant effect in a way that other opiates don't, but I sometimes wonder if that's because of the NMDA antagonism, or if it has to do with the long half life (I bring this up because I've found buprenorphine works similarly in this way).

 

[sekio]

NMDA antagonists like e.g memantine, ketamine are generally considred to be only psychologically addictive. I don't think there's such thing as a ketamine withdrawal syndrome. (or memantine withdrawal)

MXE is also a serotonin reuptake inhibitor, which explains the withdrawals some may get from that. I think in methadone's case the problem is the ridiculously long half life, not any agonism.antaonism at other receptors.

 

[Swimmingdancer]

I don't think methadone provides a consistant effect. If you are on the same dose for a long period of time, you can feel effects from the methadone (some euphoria depending on the person and dose, anxiolysis, sedation, analgesia, etc) for the first little while, and then it gets to the point where all that dose does is alleviate withdrawals. At least this has happened to everyone I've spoken to who took methadone in stabile maintenance doses for more than a few months. Tolerance definitely does build to methadone, in my opinion/experience it actually builds quite quickly, perhaps because of it's long half-life (your brain/body gets used to constantly having it). Tolerance may build slightly more slowly than to other opioids, at least it is theorized to, but it's pretty hard to compare them.

Now, there have been studies saying that some NMDA antagonists seem to slow the progression of tolerance (and therefore, they presume, dependence), but that doesn't give any info on whether they would make withdrawals easier when one stops taking something that has NMDA antagonist properties.

One would think that if you long-term constant antagonism of NMDA, that the brain/body would compensate, like it tends to do, by causing tolerance to the NMDA antagonism. Then when it is no longer there you might have super-sensitive receptors or excess glutamate or something. I was having trouble finding any research to back up this theory though UNTIL I started looking at alcohol withdrawal. Alcohol is an NMDA antagonist and the role of NMDA in alcohol withdrawal has been well studied. There is evidence that the hyperexcitability of NMDA receptors upon withdrawal from chronic alcohol use is due to an increase in number of NMDA receptors resulting from adaptation to the long lasting inhibition of activity of the channel. This causes symptoms such as agitation, tremors and seizures. Giving NMDA antagonists (such as ketamine or memantine) to people withdrawing from alcohol has been shown to reduce general negative symptoms, psychosis, depression, cravings, cognitive problems, etc.

Methadone doesn't have as strong an NMDA antagonism as alcohol, but it makes sense to me that one could extrapolate that tolerance to the NMDA antagonizing effects of methadone would contribute to withdrawal symptoms upon cessation.

 

[crazycatman]

I have no idea if this is actually true, but here is my theory about physical addiction (the kind you get with benzos, opiates, things like that). As long as your taking a substance often enough that there is always some in your brain, your brain will adapt to it's presence (neurotransmitter levels, receptor concentrations, ..). This will lead to addiction because one you stop and the drug has left your system, the adaptations will remain and until the brain reverses them you will experience problems. Depending on what exactly the drug does the symptoms will differ (this is why anything that affects the gaba system can be really dangerous to just quit and may cause seizures).

However if you take enough time between doses that drug levels in the brain drop to 0 and stay that way for long enough, you shouldn't get actual physical addiction. For example, ghb has a really short half life. So if you take just one dose per day (maybe even two but that's pushing it) you should not have any problems just stopping (at least I never did), because for most of the day you won't have enough in your body to cause your brain to adapt. But if you start dosing 24/7 and just stop, you will get withdrawals (just check the many threads here or on other boards). On the other hand, even the short half life benzos have relatively long half lives and stay in your body very long. This is why they can cause problems even when taken only a few times per week (not huge problems but still). Same thing with alcohol, lots of teenagers (in my country anyway) binge drink on the weekends and stay sober during the week. What they are doing isn't healthy but I wouldn't call it physical addiction.

As far as mental addiction... well that's totally different. If something made you feel good, you are going to miss it and want more for a long long time. I haven't had any ghb for a year or so, but would be happy to have access to it again. Especially since I know my limits in regards to dosing frequency and physical addiction.

Now I know that this didn't answer your actual question about physical addiction to NMDA antagonists, but just consider it food for thought. (to the mods, feel free to delete this post if it's gone too far offtopic)

 

[Captain.Heroin]

You aren't going to feel good after coming off of prolonged NMDA antagonist usage.