When less is more, NMDA antagonist desirability

[Neuroprotection]

this is just an observation I have made from hearing peoples experiences and I want to know what you all think.
Is it true that NMDA antagonist drugs with Low potency and especially very short half life tend to have much higher recreational value. for example, the very weak and short-acting NMDA antagonist nitrous oxide is very pleasant to most who try it and they will likely want to repeat the experience. on the other hand, the more powerful NMDA antagonist ketamine still has many fans but also quite a few who dislike it. on the extreme end of the spectrum, we have phencyclidine A long acting and extremely powerful NMDA antagonist which is generally aversive to most people from what I’ve heard. despite having similar structures, I’ve read that the way phencyclidine binds to the NMDA receptor makes it A blocking agent 10 times more powerful than ketamine. meanwhile, ketamine which is widely enjoyed by many is not only much less potent than phencyclidine, but also has a much shorter half life (about 2.5 hours).

Does anyone else agree?
Has anyone noticed similar trends with other classes of drugs?

 

[SpiralusSancti]

this is just an observation I have made from hearing peoples experiences and I want to know what you all think.
Is it true that NMDA antagonist drugs with Low potency and especially very short half life tend to have much higher recreational value. for example, the very weak and short-acting NMDA antagonist nitrous oxide is very pleasant to most who try it and they will likely want to repeat the experience. on the other hand, the more powerful NMDA antagonist ketamine still has many fans but also quite a few who dislike it. on the extreme end of the spectrum, we have phencyclidine A long acting and extremely powerful NMDA antagonist which is generally aversive to most people from what I’ve heard. despite having similar structures, I’ve read that the way phencyclidine binds to the NMDA receptor makes it A blocking agent 10 times more powerful than ketamine. meanwhile, ketamine which is widely enjoyed by many is not only much less potent than phencyclidine, but also has a much shorter half life (about 2.5 hours).

Does anyone else agree?
Has anyone noticed similar trends with other classes of drugs?

We who love NMDA antagonists usually like even those that we don’t really love.

 

[Neuroprotection]

We who love NMDA antagonists usually like even those that we don’t really love.

Oh yes, I can imagine that. if you’re really into a certain drug class then maybe you can enjoy The more potent chemicals. however, I was speaking more generally about people who might not know much about drug mechanisms or those who aren’t really Psychonauts.

 

[Skorpio]

Nitrous has a pretty different mechanism than the arylcyclohexylamines. It impinges on a plethora of ion channels, making its effects more complex (and the euphoria is different than other disso euphoria).

 

[SpiralusSancti]

Nitrous has a pretty different mechanism than the arylcyclohexylamines. It impinges on a plethora of ion channels, making its effects more complex (and the euphoria is different than other disso euphoria).

What about differences in build up of tolerance? I rarely hear about perma-tolerance with nitrous. I definitely noticed that certain type of tolerance builds up but pretty much gets back to 0 after pause. Almost like with nitrous perma-tolerance seems to be more like a gradual change in effects, in very nature of trip, that could be 100% psychological but somehow I doubt it isn’t also neurological.

 

[Skorpio]

What about differences in build up of tolerance? I rarely hear about perma-tolerance with nitrous. I definitely noticed that certain type of tolerance builds up but pretty much gets back to 0 after pause. Almost like with nitrous perma-tolerance seems to be more like a gradual change in effects, in very nature of trip, that could be 100% psychological but somehow I doubt it isn’t also neurological.

Yeah, there are a lot of non-NMDA antagonist sides of the nitrous high, and tolerance will vary depending on what targets are being hit. It could be that the mechanisms of tolerance for arylcyclohexylamines are occurring at circuit levels, rather than second messenger levels. This would produce more of a perma tolerance, as changes to circuitry are going to be more likely to persist after long periods of abstinence (where homeostatic changes to second messenger signaling is more dynamic, and prone to reversal given time).

 

[Neuroprotection]

Nitrous has a pretty different mechanism than the arylcyclohexylamines. It impinges on a plethora of ion channels, making its effects more complex (and the euphoria is different than other disso euphoria).

Thanks for that, I’d forgotten about the other ion channel targets of nitrous oxide. but what about the differences between ketamine and phencyclidine. is it true that PCP is generally aversive, whilst ketamine is more rewarding? if so, would you say this is due to the huge difference in potency at the NMDA receptor?

 

[Skorpio]

Thanks for that, I’d forgotten about the other ion channel targets of nitrous oxide. but what about the differences between ketamine and phencyclidine. is it true that PCP is generally aversive, whilst ketamine is more rewarding? if so, would you say this is due to the huge difference in potency at the NMDA receptor?

I'm not really sure if that initial statement holds true. I have avoided PCP (not like it's been available) and close PCP analogs, as I feel they would be rather addictive for me. Everything I hear about these drugs (mainly from practised drug users albeit), is that they are much more manic, and have much more powerful euphoric effects than ketamine. I fear they would be a good match for my self control, as I do have a fondness for dissociatives.


A lot of PCP's bad rap comes from its dosing method. From batch to batch potency of the ether-pcp solution used to dip cigarettes (and the likely tendency for the ether to evaporate at room temperature, thereby concentrating the solution), to the fact that people not in the know would smoke way too much, treating it like a joint, rather than taking a hit or two and then putting it out led to people taking way too much PCP. Its stimulating properties also let a person fully experience hole level experiences and be more mobile, so deranged experiences can go beyond mind movies. That said, I do think the horror stories are probably pretty rare in terms of the whole population using PCP at the time. However, the really chaotic pcp stories all do share a certain panache that other drug horror stories lack...

 

[MedicinalUser247]

Well... In my experience Nitrous Oxide's the best, Ketamine's comes in second place and PCP is not so good, but I like PCPy. The worst dissociative is that DXM stuff. I don't know why people even use the stuff because it gives you a nasty high. But people are different and like different things. I like PCPy because it makes you feel like your in a dream.

 

[Neuroprotection]

I'm not really sure if that initial statement holds true. I have avoided PCP (not like it's been available) and close PCP analogs, as I feel they would be rather addictive for me. Everything I hear about these drugs (mainly from practised drug users albeit), is that they are much more manic, and have much more powerful euphoric effects than ketamine. I fear they would be a good match for my self control, as I do have a fondness for dissociatives.


A lot of PCP's bad rap comes from its dosing method. From batch to batch potency of the ether-pcp solution used to dip cigarettes (and the likely tendency for the ether to evaporate at room temperature, thereby concentrating the solution), to the fact that people not in the know would smoke way too much, treating it like a joint, rather than taking a hit or two and then putting it out led to people taking way too much PCP. Its stimulating properties also let a person fully experience hole level experiences and be more mobile, so deranged experiences can go beyond mind movies. That said, I do think the horror stories are probably pretty rare in terms of the whole population using PCP at the time. However, the really chaotic pcp stories all do share a certain panache that other drug horror stories lack...

Interesting, thanks for that. i’ve heard that PCP can accumulate in fat tissue and already has a very long half life. Also, as you mentioned, methods of administration are often unreliable especially if the user is ignorant or reckless with drugs.
One thing that’s always interested me is why ketamine is strongly immobilising whilst PCP is not. I recently came across an article that suggested ketamine could activate a specific GABAA receptor subunit which leads to a mobilisation of the person but without interfering with the hallucinogenic affects.

 

[SpiralusSancti]

NMDA antagonists eventually lead to la-la land. Weak, strong, short or long acting, hell even stuff like booze at high doses might partly own – ops I did crazy shit again – effect to NMDA antagonism….well that last is very maybe. But push any proper NMDA anatagonist and eventually you’ll end up in la-la land, it doesn’t have to be damn PCP, it’s more than doable with a lot more “gentle” stuff.

Playing safe or being very good at avoiding what’s usually described as disso psychosis keeps them (very) friendly for some but, disso psychosis is in fact just continuation of disso effects. Like syncronicity, it’s super usual experience on dissos, push n push and you’ll start connecting everything from atoms to stars (yeah they are connected but you know what I mean).

 

[MedicinalUser247]

I'm still wondering if a half NMDA antagonist half Opiate can be designed. I wonder what that molecule would look like.

 

[Neuroprotection]

I'm still wondering if a half NMDA antagonist half Opiate can be designed. I wonder what that molecule would look like.

I’m sure some synthetic opioids have NMDA antagonist effects, with methadone being A prime example. I think the NMDA antagonism of these drugs is relatively mild but still very significant as it contributes to both enhanced effectiveness for opioid replacement and boosted analgesic affects, but simultaneously contributes to more serious side-effects like memory loss in the long-term.

 

[ecstacylover]

I'm still wondering if a half NMDA antagonist half Opiate can be designed. I wonder what that molecule would look like.

Ketamine actually has an interesting profile of activity at mu-opioid receptor/MOR, where it appears to function as a biased partial agonist with no arrestin efficacy (arrestin efficacy is tied to side-effects like constipation and respiratory depression).

The S enantiomer is much more potent as a MOR agonist, and more easily produces self-administration in rats. Despite this MOR agonism and other MOR-independent mechanisms of dopamine release, ketamine generally has ceiling effect when it comes to addiction in rodents and probably most people (as its NMDAr antagonism partially blocks the plasticity needed to rewire the NAc).

Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability - Molecular Psychiatry

Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects)...

www.nature.com

https://www.sciencedirect.com/science/article/abs/pii/S0006322322018546

Dual action of ketamine confines addiction liability - Nature

Experiments in mice show that although ketamine has positive reinforcement properties, which are driven by its action on the dopamine system, it does not induce the synaptic plasticity that is typically observed with addiction.

www.nature.com

A 2013 paper suggested had ketamine had no affinity at MOR in vitro, but the work above from Bonventura et al showed ketamine affinity for MOR in homogenized brain tissue suggesting that ketamine binds to the MOR complex in vivo, and they presented a lot of additional evidence that ketamine can directly activate MOR, and also showed that naltrexone can partially block (S)-ket self-administration.