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Natural Dissociatives?

dopamimetic

dopamimetic

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There is a natural equivalent for almost any drug class. Stimulants -> Khat & Coca, Opiates (obvious), Psychedelics -> DMT & Psilocybin, Cannabis (obvious), GABAergics -> Ethanol, maybe Mulungu, etc ... but is there any naturally occurring dissociative / NMDA antagonist besides that strange Salvia, which doesn't act over glutamate? Or are they really a man-made 'invention'? Okay, alcohol acts on NMDAR's too, but I wouldn't exactly consider that a dissociative .. :)
 
Probably not the answer you're looking for, but I think there's still debate over whether non-polar gases which act as dissociatives/anesthetics exert their effects through the NMDA system or not, so basically things like noble gases (xenon in particular), nitrous oxide, volatile alkanes (4-6 carbon chain) could fit the criteria of being dissociatives and "natural" I guess. I don't know of any NMDA antagonists found in plants though. I'm sure there could be some we're not aware of yet.

Salvia is a kappa opioid agonist.

Also, do you mean every recreational drug class? Because maybe I'm mistaken, but most antipsychotics, antidepressants and things like that are synthetic.
 
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Yes, sorry, I've meant recreational drugs ... in German the term 'drug' is often used for recreational / 'abused' drugs while prescription things are 'medicines' ...

But there are natural antidepressants (St. John's worth), antipsychotics (have to look for, but there are plant-synthesized molecules that have some dopamine antagonistic properties - not as strong as the clinically used ones, but I really think that dopamine antagonism was the wrong way to go for psychosis treatment then too..), even antibiotics etc.. most structures are more or less derivates from natural / plant origins if I'm right, only very recently we are into designing truly novel compounds ...

Thinking of the dissociatives, a strange fact is that often the dextro-enantiomers of opiates are NMDA antagonists. DXM, d-Methadon, DXO, and so on ... don't know about d-Morphine, that one has histamine releasing and anti rheumatic properties, possibly seizurogenic at higher dosages but no clue if it's an NMDA antagonist too..

Yeah, the kappa agonist thing is really interesting and confusing indeed. Dissociatives & opioids (or NMDA and mu receptors, to be exact) seem to be somewhat interconnected but I don't understand yet how ...
 
dopamimetic said:
Yes, sorry, I've meant recreational drugs ... in German the term 'drug' is often used for recreational / 'abused' drugs while prescription things are 'medicines' ...

But there are natural antidepressants (St. John's worth), antipsychotics (have to look for, but there are plant-synthesized molecules that have some dopamine antagonistic properties - not as strong as the clinically used ones, but I really think that dopamine antagonism was the wrong way to go for psychosis treatment then too..), even antibiotics etc.. most structures are more or less derivates from natural / plant origins if I'm right, only very recently we are into designing truly novel compounds ...

Thinking of the dissociatives, a strange fact is that often the dextro-enantiomers of opiates are NMDA antagonists. DXM, d-Methadon, DXO, and so on ... don't know about d-Morphine, that one has histamine releasing and anti rheumatic properties, possibly seizurogenic at higher dosages but no clue if it's an NMDA antagonist too..

Yeah, the kappa agonist thing is really interesting and confusing indeed. Dissociatives & opioids (or NMDA and mu receptors, to be exact) seem to be somewhat interconnected but I don't understand yet how ...
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The same thing with "drug" and "medicine" here, it gets confusing and is redundant in my opinion. Also, as I said I could be mistaken and turns out I was about antipsychotics et al being exclusively synthetic or semi-synthetic.

I've actually been thinking about the same interesting fact that d-morphinans are NMDA antagonists. What makes you think though that NMDA and opioid receptors are interconnected? I'm also quite interested.
 
Yeah, darvon (dextroproxyprophene) is an opioid but novrad (levoproxyprophene) is an anti cough med. There should definitely be more research into exploring this link of opioids and NMDA antagonists; it seems too unprobabilistic to be coincidential.
 
belligerent drunk said:
I've actually been thinking about the same interesting fact that d-morphinans are NMDA antagonists. What makes you think though that NMDA and opioid receptors are interconnected? I'm also quite interested.
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There's a somewhat subjective side in that if you'd try to describe a (low-dose) dissociative experience to someone who's not experienced with drugs, it would sound much like an opioid buzz - that comfortable peaceful feeling of being covered in a warm blanket at home, the train of thoughts slowing down, some body heaviness etc. and dissociatives are good pain killers too - but the experience is somewhat qualitatively different from the opioids, I can't put it into words really.. the opioids are more numbing, changing your personality etc.. the dissociatives leave the core of one's personality untouched somewhat..

But there is also some neurological connection between NMDA and (mu) opioid receptors:

NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity.
The Mu-Opioid Receptor and the NMDA Receptor Associate in PAG Neurons: Implications in Pain Control
Ketamine – More mechanisms of action than just NMDA blockade <-- about the sensitisation of the opioid system by antagonising NMDA etc..

So probably the dissociative experience really involves endorphins to a certain degree and one could maybe see them as different / safer opioids somewhat ... at least to some extent ... or kind of yin and yang of the opioid and NMDA system? But it's very complicated thinking of the different opioid receptors that aren't fully researched yet, especially the kappa ones, as well as the sigma receptors and NMDA also has many different sub units ...

SKL said:
Reserpine/Rauwolfia serpentina, actually a rather remarkable plant.
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Reserpine was exactly what I meant but didn't remember the name ;)
 
Thanks for the info and articles! When you think about the fact that different morphinans affect NMDA and/or µ-opioid receptors; that NMDA antagonism slows/reverses/inhibits opioid tolerance and their currently known relation, the picture becomes quite interesting. I'm wondering how everything plays out between them downstream from receptor activation. I need to do some more reading on this subject, because I know little of opioid receptors despite them being my favorite drug.
 
Yeah, I forgot ... Ibogaine is the natural dissociative! ;)

220px-Ibogaine.svg.png


It's only slightly less potent at antagonising NMDA than as a kappa- and sigma-agonist, and it acts on 5-HT2a too. I've been really, really curious about Ibogaine for a long time ever since I've heard about and read experience reports (but also afraid of it, my experiences with Salvia weren't exactly fun) ... it must be one hell of a dissociative psychedelic therapeutic rollercoaster...
 
The part is finding a natural substance that doesn't have undesirable pharmacology on top of it's potential dissociative antiglutamergic effects. Apart from xenon and n2o the many natural nmda antagonists have contradictory reports of their activity and it may only be antagonistic at only particular receptors. Ibogaine has too many other effects for me to consider it a dissociative for the purpose of this discussion. Most have either agonist or antagonist activity at GABA receptors and i suppose you could come up with a balanced mix but i wouldn't want to take the risk. Many others are 5HT/DA antagonists so those are no fun.

I don't know much about synthesizing peptides. My understanding of dosing them is that absorption of them to the body and brain can vary greatly with some. It seems that histogranin (an endogenous peptide)is a true and verified dissociative as active as ketamine give or take. I assume it may not be costworthy to produce however.
 
Muscimol from amanitas is considered a dissociative by some tho I believe it's effects come from GABAA agonism.
 
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"Dissociative" effect of glaucine can be easily accounted for by VDCC blocker effect ? Gabapentin and pregabalin at least can give me detached feelings / experiences though phenibut hardly ever managed that. But higher doses of phenibut I don't really tolerate well (GABAb agonism?) compared to gabapentinoids.

I've wondered about the question of this thread and failed to come up with the great answer ibogaine even if that compound cannot be used like arylcyclohexylamines are. Thnx!

People who suggest that drugs / or some drugs are put on earth for a special purpose for humans [the arrogance] always amaze me - so many chems out there and so many similarities with pharmacophores. As someone in my country once put it: if I stand right here naked with a hard on and all you guys throw a donut at me, rest assured one or two will be hanging from my dick.
 
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