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dissociatives / arylcyclohexylamines pharmacology

ungelesene_bettlek

ungelesene_bettlek

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dissociatives are fascinating drugs. the most important chemical class of this category are arylcyclohexylamines, with ketamine being the most prominent exponent. as far as I understand it, the action of these compounds is due to several different pathways:

NMDA antagonism is said to be mostly responsible, but how do the other pathways influence the action of arylcyclohexylamines? how do the different compounds of this class differ in their action profile? please help me to understand the psychopharmacology of ketamine and similar compounds!

one more concrete question in the end: the S-isomer of ketamine is much more active in NMDA antagonism than the R-isomer, right? but what is with the other action mechanisms? what about the opioid activity of the R-isomer?
 
Interesting conclusion that paper reaches:

Conclusion. The present study indicates that a clinically relevant concentration of ketamine interacts with μ2 opioid receptors. However, no agonist activity was observed.

But, all work does seem to agree that S-ketamine interacts 2-3X more strongly with the MOR than does R-Ketamine....
 
interesting. thank you for your replies! so are there any differences in the action profiles of the two enatiomers of ketamine, or does R-ketamine act in the same way as S-ketamine, but only much weaker?

EDIT: I was just asking myself, maybe this thread would have fittet better into advanced drug discussion?
 
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can a mod move this thread to advanced drug discussion please? my curiosity is far from satisfied, and I hope that the knowledgeable people there could probably contribute still a bit more.
 
I am still interested a lot in this topic, so I am a bit disappointed this thread didn't get more replies. so, dear mods, could you please move this thread to the "advanced drug discussion"? I really hope that it could probably more feedback there.
 
I think Trip Reports or was it PD? has a thread on this that will best answer your question. It covers a WIDE range of ketamine and PCP analogs and the subjective effects of each
 
yup

as a side thought... In that report I noticed 1-(4-hydroxyphenyl)-1-cyclohexylpiperidine(4-hydroxyPCP)has the same potency as PCP. So with all the 4-MeO-PCP going around you'd think someone would wise up and have their lab synth the 4-HO instead or atleast have another lab/someone with basic chem know how to demethylate the 4-meo, I think most of us here could handle that simple reaction;)
 
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Never Knows Best said:
You mean adder's thread in TR? http://www.bluelight.ru/vb/threads/504286-PCP-analogs-(Cumulative)
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yes, I already know this thread, it is indeed very interesting. but it doesn't really answer the main question I want to pose with this thread: how do the different pharmacological pathways of arylcyclohexylamines influence their action?

let me put this a bit differently: how would a compound feel that solely acts as NMDA antagonist, without any action on opioid receptors, sigma receptors, the dopamine system and histamine and acetylcholine receptors? is there even such a compound, or at least something that comes close to it? tiletamine perhaps...?
 
Maybe this is due to the agonist activity at dopamine receptors, in the same manner as LSD and phenethylamine psychedelics?
 
Isn't ketamine a pretty puny dopamine agonist, and aren't the effects of LSD due to 5HT agonism?
 
Nagelfar said:
R-ketamine was somewhat hallucinogenic from what I've read (and not in the manner of its S-enantiomeric NMDA activity)
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Having tried R-ketamine (which I much prefer to all other forms and types of NMDA antagonists), it is very hallucinogenic. The drawback is that you must take twice as much as the racemate Ketamine to achieve effects. I found the experiences far more lucid, with a much more psychotic (in a good way) feel to them. I would sometimes encounter a vision block on DXM where the OEV's would fully encompass my vision to the point where I could not see past it. I also had this same exact experience on R-Ketamine, and I've had one of my most profound NDE's on R-ketamine as well.

I've used racemic Ketamine for about 6 years off and on. By all routes and doses, I've yet to reach that state of experience.

I'm surprised none of the popular RC vendors have come out with simple tweaks to their flagship products in order to diversify their line up and attract new customers. You'd think with the constant revenue, they could invest in some R&D and produce enantiomer pure products at the least.
 
Nagelfar said:
R-ketamine was somewhat hallucinogenic from what I've read (and not in the manner of its S-enantiomeric NMDA activity)
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I don't think that R-ketamine is on the pharmaceutical market, or is it? so this must have been from clandestine production?

Vader said:
Isn't ketamine a pretty puny dopamine agonist, and aren't the effects of LSD due to 5HT agonism?
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you're completely right with that. only one small thing I have to add: LSD does indeed have some dopaminergic effects as well, contrary to "simple" tryptamines. most of its effects are caused by 5HT2A antagonism, though.

regarding ketamine: even though I don't think its action as dopamine agonist contributes much to its overall effects, I do think that its effects as dopamine reuptake inhibitor are significant and responsible for its stimulant properties, as well as its addictivity in some individuals. I do not have hard evidence, for this, though, it is just an educated guess.

Nachtrune said:
Memantine is a dopamine agonist too and doesn't have any significant hallucinogenic properties apart from rare cases in Alzheimer therapy. The first two, three days it feels somewhat empty and "lost" when started directly at a higher dosage (30-40 mg/d in my case), don't know if this is how plain NMDA antagonism feels, or if it's the acetylcholine antagonim or a combination of both.

But on day three the emptiness began to fade away and a calm, yet powerful and exciting stimulation (even sometimes intense music-linked euphoria) started ... something roughly comparable to moderate dosages of Methylphenidate or Amphetamine but without any "speedyness". I really wonder if this is the dopamine agonism (maybe potentiated by NMDA antagonsim) or not - many say that plain dopamine agonists don't do much and if then tolerance would build up quickly. What Memantine doesn't do.

Yes, afaik LSD (and many other psychedelics) work through 5HT agonism and not dopamine. The general opinion is that dopamine overactivity -could- lead to psychosis, but that's a different thing and I think in the average human it would need a huge increase in dopamine for that.
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thank you very much for this very informative posting, Nachtrune! :)

Nachtrune said:
Oh yes, I agree with that ... an European vendor will maybe produce 2-MeO-Ketamine soon - does anyone know what properties that compound would have?
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it is said that this compound is the closest thing to ketamine one can get.

Nachtrune said:
Somewhat off topic, maybe I'll start an own thread for that ...
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there is already a thread for 2-MeO-Ketamine: http://www.bluelight.ru/vb/threads/594944-2-MeO-Ketamine .
 
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LSD does indeed have some dopaminergic effects as well, contrary to "simple" tryptamines.
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I'm aware, by "LSD's effects" I meant "the effects of classical psychedelics in general". I think that the interesting action is serotonergic, no?
 
Vader said:
I'm aware, by "LSD's effects" I meant "the effects of classical psychedelics in general". I think that the interesting action is serotonergic, no?
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yes, you are completely right, that is what I meant. the effects of all "classical" psychedelics (i.e. simple tryptamines, lysergic acid amines, psychedelics phenethylamines and amphetamines) is mainly caused by 5HT2A agonism. but LSD is a bit peculiar by also having some dopaminergic effects.
 
ungelesene_bettlek said:
I don't think that R-ketamine is on the pharmaceutical market, or is it? so this must have been from clandestine production?
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What I read was from research and controlled studies. I can't find it now though (I tried looking before my original statement on the matter)

MyExcuse having posted above yours is an interesting colloquial account in confirmation of that idea though.

Certain "off-opioids" (e.g. Herkinorin) are "hallucinogenic" purportedly, interesting that the other handed isomer of Ketamine from its dissociative effects are not traditional opioid affective but hallucinogenic as such (again, purportedly). Leading me to think it may be from a type of mu-agonism common to the g-coupled protein which elicits a non-analgesic response from the receptor. (probably from a particular way of binding)
 
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