Pharmacology Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs

[paracelsius]

Thx for the link. Makes you wonder whether Salvinorin A is biased towards beta-arrestin. I dont know but one thing is sure: Salvinorin A is very selective for kappa. So whether canonical beta-arrestin and/or more downstream signalling are responsible for Salvia trip and G-pathways for dysphoria of kappa opioids is yet to be seen.

I find this compound interesting. why would a plant make a very specific psychoactive compound? Usually plants makes compounds like this to fight natural predators. Could it be the mint is producing it to make its predators trip and leave it alone! may be just pure coincidence, the compound is psychoactive in humans...It just doesnt look like anything and I mean anything endogenous yet it is highly potent!. At least if it looks like some endogenous compound one might expect it to mimic its effect.... but it doesnt... so who knows why the mint is producing it?

 

[ecstacylover]

That is right. As far as 5HT2A functional selectivity and “hallucinogenic” effects are concerned, it seems G-pathway but not beta-arrestin is required, so far as “hallucinogenic effects” are assessed by the standard head-twitch response in rodents.

Arrestin2 is required for a normal HTR to LSD and 5-HT. It's not required for the HTR to DOI, 5-HO-NMT, or 5-MeO-DMT (actually, arrestin2 KO increases the HTR to 5-HO-NMT & 5-MeO-DMT). Gq KO reduces the HTR to DOI, but fails to eliminate it. Oh and speaking of the cAMP pathway, DOM's HTR is suppressed by Gs inhibitors while being amplified by both cAMP analogs and PDE4 inhibitors.

And HTR is just the model which best predicts if a compound will be psychedelic in humans. To me that says that the intracellular pathway(s) which produce HTR are the same ones which produce psychedelic effects in humans. It's probably unproductive to read into it any more than that. Especially when you consider that a lot of psychedelics have biphasic dose-HTR curves, whereas the psychedelic experience in humans is generally a monotonically increasing function of dose. Or take CB1 agonists, which suppress HTR in rodents, but are one of the strongest amplifiers of psychedelic experiences in humans. There's other weird results too, like GABA-A PAMs potentiating the HTR, which possibly are due the HTRs biphasic nature (e.g. administration on the descending arm of the HTR curve might be expected to suppress it).

The problem is which downstream signalling is involved PIP or cAMP or whether selectivity for activating one or the other is relevant to the head-twitch.

The aforementioned KO results suggest that there's multiple, discrete modes of 2A signaling that can produce HTR. One pathway probably proceeds through Gq family proteins leading to PIP2 depletion and inactivation of the various PIP2-gated voltage-gated channels. Some minimal level of efficacy might be required along this pathway, otherwise the increased rate of PIP2 breakdown might be compensated for by re-synthesis and lateral diffusion.

As for how the cAMP levels would be modulated, it's not even clear. There's some in-vitro evidence that arrestin1 is necessary for adenylyl cyclase activation, while arrestin2 inhibits adenylyl cyclase in the absence of Gi activation. If this holds true in cortical pyramidal cells, then arrestin1 recruitment by 2A would have the effect of lowering cAMP, while arrestin2 recruitment would increase cAMP. Although DOI, psilocin, LSD, and lisuride all seem to preferentially recruit arrestin2. There do seem to be differences in the manner in which LSD and DOI recruit arrestin, as compared to the non-psychedelics ergotamine and lisuride, LSD and DOI produce less receptor internalization in HEK-293 cells (which appears to be an arrestin-mediated process). Additionally, LSD but not lisuride activates Src, which could be due to differential arrestin recruitment (the Gonzalez-Maeso lab suggested this was due to LSD-specific Gi activation, but it seems they only inferred this from the fact that Src is usually activated by Gi).

The biggest problem with the HTR though, is that it's a function of way too many variables. Since HTR is an intrinsic function of cortical pyramidal cells (cortical 2A rescue is sufficient to rescue HTR, although technically the promoter does rescue 2A in the claustrum as well), why not isolate that process? Even a cursory voltage ramp reveals significant differences in LSD's modulation of voltage-gated channels, relative to lisuride. Once we know which channels specifically are the biggest contributors to these differences, we can work backwards to understand the 2A-dependent signaling pathways modulating them in these cells.

I’ve seen ppl trying tease out “the hallucinations” of 2A agonism without affecting other good effects like antidepressant...etc (which the OP paper claim). Like with tabernanthologs of dave olsen or the work of Gonzalez-Maeso or also Scott Thompson in maryland. Sure 2A is required for head-twich (ie “mice hallucinating”) but not required for antidepressant. Shown by using either 2a KO rodents or a 2a antagonist... now dave olsen claims synaptogenesis resulting from brain grow factors BDNF stimulation (ie grow rat brain and make’em smarter and stop worrying!!) of tabernanthologs or other non-hallucinogenic tryptamines like 6-MeO-DMT as mechanism of AD.

There's also lots of ketamine research which suggests BDNF is the major player in AD effects. Personally I think ketamine will be much more acutely efficacious in this regard, because it not only increases activity-dependent BDNF release, but also increases BDNF transcription and translation (and acts as a TRKB PAM). So especially when using on consecutive days you have potentially this positive feedback loop where you are increasing BDNF release but also reloading it for the next day (and all the while increasing its activity at the TRKB receptor).

 

[Mjäll]

Thx for the link. Makes you wonder whether Salvinorin A is biased towards beta-arrestin. I dont know but one thing is sure: Salvinorin A is very selective for kappa. So whether canonical beta-arrestin and/or more downstream signalling are responsible for Salvia trip and G-pathways for dysphoria of kappa opioids is yet to be seen.

I find this compound interesting. why would a plant make a very specific psychoactive compound? Usually plants makes compounds like this to fight natural predators. Could it be the mint is producing it to make its predators trip and leave it alone! may be just pure coincidence, the compound is psychoactive in humans...It just doesnt look like anything and I mean anything endogenous yet it is highly potent!. At least if it looks like some endogenous compound one might expect it to mimic its effect.... but it doesnt... so who knows why the mint is producing it?

To scare them away?

Kappa opioid receptor seems pretty close to a fear receptor (haven't tried myself)

Probably many other animals have simpler relationship to fear and don't get insightful trips and shit

 

[fastandbulbous]

Thx for the link. Makes you wonder whether Salvinorin A is biased towards beta-arrestin. I dont know but one thing is sure: Salvinorin A is very selective for kappa. So whether canonical beta-arrestin and/or more downstream signalling are responsible for Salvia trip and G-pathways for dysphoria of kappa opioids is yet to be seen.

I find this compound interesting. why would a plant make a very specific psychoactive compound? Usually plants makes compounds like this to fight natural predators. Could it be the mint is producing it to make its predators trip and leave it alone! may be just pure coincidence, the compound is psychoactive in humans...It just doesnt look like anything and I mean anything endogenous yet it is highly potent!. At least if it looks like some endogenous compound one might expect it to mimic its effect.... but it doesnt... so who knows why the mint is producing it?

Well, evolution doesn't create compounds without them being for a specific purpose. The fact that salvinorin A is deactivated by stomach acid sort of implies (well to me!) that it is there to discourage herbivores, which hold the plant material in their mouth for a much longer period of time (in humans, Salvinorin A is dependant upon buccal absorption).
Not good for a herbivore (usually not an apex predator or eqiv), to have no fuckin' idea about sensory input, as they tend to get eaten!

 

[paracelsius]

Arrestin2 is required for a normal HTR to LSD and 5-HT. It's not required for the HTR to DOI, 5-HO-NMT, or 5-MeO-DMT (actually, arrestin2 KO increases the HTR to 5-HO-NMT & 5-MeO-DMT). Gq KO reduces the HTR to DOI, but fails to eliminate it. Oh and speaking of the cAMP pathway, DOM's HTR is suppressed by Gs inhibitors while being amplified by both cAMP analogs and PDE4 inhibitors.

And HTR is just the model which best predicts if a compound will be psychedelic in humans. To me that says that the intracellular pathway(s) which produce HTR are the same ones which produce psychedelic effects in humans....

So HTR is not really indicative of “hallucinogenic effects” only of 5HT2A activation in rodents. If I undertand, it is necessary but not sufficient for a compound to have hallucinogenic effect, is that right? From that paper you mention, yes NMTs do not require arrestin2 to induce HTR unlike serotonin since arrestin2-KO still retains HTR with NMTs. Now serotonin is not hallucinogenic (at least high doses of its 5HTP precursor) and still induces HTR via arrestin2-Akt-src-PI3K pathway which is not required for NMTs to induce same response. Since NMTs activation of 2A promote recruitment of Ga, does that mean then G but not arrestin is mediating the hallucinogenic effects (not HTR) and that functionally G selective compound would have “psychedelic effects”?

Because activation of either pathways (arrestin2 or GTPase) elicits HTR, one leading to hallucinogenic response but not the other since NMTs are hallucinogenic in humans (Shulgin actually described the psychoactive effect of 100mg insufflated NMT). In other words, activation of both arrestin2 and GTPase pathways leads to HTR but only the latter leading to “hallucinogenic response” in rodents (and humans)?

Interesting you mention monoalkyltryptamines and that paper. I always thought monoalkyltryptamines like N-methyltryptamine NMT, N-methylserotonin (aka norbufotenin), norpsilocin or even synthetics like NET are just different psychedelics altogether. For one the effects of mushroom high in baeocystin (N-methyl homolog of psilocybin) are just different. Actually there is a debate now whether N-monoalkyltryptamines in natural sources (like norpsilocin in mushroom) and norbufotenin ie N-methylserotonin in the Bufo toad secretions contribute to the effects of natural extracts v isolated compounds. According to this paper here,

https://dx.doi.org/10.1021/acs.jnatprod.9b0106

ABSTRACT: A general synthetic method was developed to access known tryptamine natural products present in psilocybin producing mushrooms. In vitro and in vivo experiments were
then conducted to inform speculations on the psychoactive properties, or lack thereof, of the natural products. In animal models, psychedelic activity by baeocystin alone was not evident using the mouse head twitch response assay, despite its putative dephosphorylated metabolite, norpsilocin, possessing potent agonist activity at the 5-HT2A receptor.

So according to above paper, 4-hydroxyNMT (norpsilocin, the dephosphorylated “active” metabolite of baeocystin) does not induce HTR in rodents, unlike psilocin and is actually more potent than psilocin as 2A agonist. Though it could be for pharmacokinetic reasons (can’t cross BBB) as suggested by the authors and/or it gets metabolized by MAOs before reaching the brain. But baeocystin (norpsilocin precursor) was actually reported as psychoactive as psilocybin in humans (cf Gratz)! And norpsilocin isomer N-methylserotonin does induce HTR according to that paper you mention. I don’t see what would make N-methylserotonin crosses BBB but not the isomeric norpsilocin (they have pretty much similar physico-chemical properties) tho could be MAOs deactivating the latter but not the former. But if anything though I would actually expect the opposite, ie norpsilocin to be more resistant to MAOs: 4-hydroxylated tryptamines are in general more resistant to MAOs than 5-OH tryptamines cf Psilocin v isomeric 5-Hydroxy-DMT ie Bufotenin). Would be interesting to see whether norpsilocin induces HTR or not in the presence of MAOIs.

There's also lots of ketamine research which suggests BDNF is the major player in AD effects. Personally I think ketamine will be much more acutely efficacious in this regard, because it not only increases activity-dependent BDNF release, but also increases BDNF transcription and translation (and acts as a TRKB PAM). So especially when using on consecutive days you have potentially this positive feedback loop where you are increasing BDNF release but also reloading it for the next day (and all the while increasing its activity at the TRKB receptor).

As for AD effects of ketamine and non-hallucinogenic tryptamines like tabernathologs or 6-MeO-DMT presumably via stimulation of (unknown receptor?) -> BDNF-> synaptogenesis, well this paper the other day from the Olsen lab it looks like 5HT2A activation is essential for tryptamines to show AD effects including non-hallucinogenic tryptamines. Now the question is whether activation of 2A by tryptamines leading to AD response is independent from that leading to “hallucinations”. In other words is AD response likely mediated via 2A-arrestin2-Akt-src-PI3K -> synaptogenesis->AD? At least with tryptamines 2A agonists since ketamine is not 5HT2a agonist as far as I know (correct me if I am wrong).

 

[paracelsius]

Well, evolution doesn't create compounds without them being for a specific purpose. The fact that salvinorin A is deactivated by stomach acid sort of implies (well to me!) that it is there to discourage herbivores...

that make perfect senses.. and then herbivore predators develop enzymes to deactivate the compound and eat the plant..so I guess eventually the plant will develop another compound to ward off predators...then the predators will develop another enzymes to eat the plant.. then the plant.....and so forth and so on (fascinating how evolution works).

Here is another fascinating case of evolution: the cedar tree of Alaska (Nootka tree from the name of the natives where it is found) well that tree literally tells predator insects “Go fck yourself”, by chemical communication. See, this tree produces a compound (Nootkatone a ketonic terpene) that is a potent octopaminergic. Octopamine is for insects what adrenergic/dopaminergic is to vertebrates: so this compound is a potent insects stimulants just like a pure d-meth injected for humans. Once insects try to colonize it, the tree will release the compound getting the predators insects utterly stimulated to the point of literally vibrating and dropping from the tree..problem solved! no one got killed!

 

[Fertile]

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

I thought an image would be much more telling than a bunch of SMILES, IUPAC or IChi texts.

As you can see, the N of the pyrrole portion of an indolve overlays the 5-MeO of 2,5-dimethoxy-4<something> PEAS.

It's also worth noting that the double-bond is important. 5/6APB is more potent than the 5/6MAPB counterparts because the O/N is planer to the benzene ring.

So that explains why 5-MeO indoles are so much more potent (and other effects make them toxic - best avoided) AFAI know nobody had made the 6-APB homologue of indoles - but that might be synthetic complexity.

So IS it a surprise that 6-methyl indoles are avtive since 5-methoxy-6-methyl amphetamine was detected in Italy in the 90s in dose-units of 141mg (mean.

So, going further, no surprise that 2-(8-methylbenzo[1,2-b:4,5-b']difuran-4-yl)ethan-1-amine (2-(8-Methylfuro[2,3-f][1]benzofuran-4-yl)ethanamine) is known, WO2022006186 - PHENALKYLAMINES AND METHODS OF TREATING MOOD DISORDERS
In short, the insoles and the PEAs are very closely related in their binding and action.

I admit I forget the name but their are NBome derivatives of both PEAS and tryptamines which is another god clue to the fact that they bind in the same manner.

Now what interests me is IF it's possible to produce an N-bom derivative of aminorex and it is possible. Well, some idiot made 2,5-diemthoxy-4-bromo aminorex.... which amazingly wasn't active. No surprise there because it's a 5HT2a ligand.

BUT what is more interesting, it if it's possible to use the N-bomb route as a methodology to provide boarderline 5HT2a ligands (active but lacks sufficient affinity to be active at practical doses. So if anyone can suggest compounds with mild activity but require a LOT, maybe it's worth considering.

I will finish with the common question 'why is 4-hydroxy DMT active but 5-hydroxy DMT is not. The reason is simple, the H of the hydroxy will form a hydrogen-bond with the amine function so that it can assume a form that makes it active. I have indeed considered if their are better alternatives but nature does a great job.

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

Sorry for my crappy drawing but you get the idea.

It's SUCH a pain that production if 6-methyl indoles is such a pain. Because trust me. It's a very special class of compound. It has all of the warmth of things like psilocin but it releases dopamine as well as serotonin so the subjective effects really ate excellent, You see, the 6-methyl acts like the p-Me of PEAs so it's a little like p-TAB but because of the serotonin, you do not need LOTS of dopamine.

Over 2 years I researched over 100 compounds and 70 were dumped within 2 days because of the cost... or rather cost per dose. U-47700 was more costly because (1R,2R)-N1,N1,N2-trimethylcyclohexane-1,2-diamine (CAS: 67198-26-9) but at £60/g and the other 2 precursors being off-the-shelf, it all worked out.

BUT anyone making it will know that (1R,2R)-N1,N1-dimethylcyclohexane-1,2-diamine is the intermediate that is N-methylated BUT one only has to look at related compounds with groups in place of the N-methyl. I mean, Take a look at the most active form of allylprodine (3R,4S) (z23 M) and then try replacing the N-methyl with an N-allyl. Their are 4 isomers of allylprodine, only 2 of U-47700 so presuming one is x.7M, the other is x23 and you wind up with 12.5M.

If you are smart enough to resolve, it's going to be x23.

 

[fastandbulbous]

that make perfect senses.. and then herbivore predators develop enzymes to deactivate the compound and eat the plant..so I guess eventually the plant will develop another compound to ward off predators...then the predators will develop another enzymes to eat the plant.. then the plant.....and so forth and so on (fascinating how evolution works).

Here is another fascinating case of evolution: the cedar tree of Alaska (Nootka tree from the name of the natives where it is found) well that tree literally tells predator insects “Go fck yourself”, by chemical communication. See, this tree produces a compound (Nootkatone a ketonic terpene) that is a potent octopaminergic. Octopamine is for insects what adrenergic/dopaminergic is to vertebrates: so this compound is a potent insects stimulants just like a pure d-meth injected for humans. Once insects try to colonize it, the tree will release the compound getting the predators insects utterly stimulated to the point of literally vibrating and dropping from the tree..problem solved! no one got killed!

Nature always comes up with the best methods: OK, maybe not the fastest, but worth waiting for!!

 

[fastandbulbous]

So HTR is not really indicative of “hallucinogenic effects” only of 5HT2A activation in rodents. If I undertand, it is necessary but not sufficient for a compound to have hallucinogenic effect, is that right? From that paper you mention, yes NMTs do not require arrestin2 to induce HTR unlike serotonin since arrestin2-KO still retains HTR with NMTs. Now serotonin is not hallucinogenic (at least high doses of its 5HTP precursor) and still induces HTR via arrestin2-Akt-src-PI3K pathway which is not required for NMTs to induce same response. Since NMTs activation of 2A promote recruitment of Ga, does that mean then G but not arrestin is mediating the hallucinogenic effects (not HTR) and that functionally G selective compound would have “psychedelic effects”?

Because activation of either pathways (arrestin2 or GTPase) elicits HTR, one leading to hallucinogenic response but not the other since NMTs are hallucinogenic in humans (Shulgin actually described the psychoactive effect of 100mg insufflated NMT). In other words, activation of both arrestin2 and GTPase pathways leads to HTR but only the latter leading to “hallucinogenic response” in rodents (and humans)?

Interesting you mention monoalkyltryptamines and that paper. I always thought monoalkyltryptamines like N-methyltryptamine NMT, N-methylserotonin (aka norbufotenin), norpsilocin or even synthetics like NET are just different psychedelics altogether. For one the effects of mushroom high in baeocystin (N-methyl homolog of psilocybin) are just different. Actually there is a debate now whether N-monoalkyltryptamines in natural sources (like norpsilocin in mushroom) and norbufotenin ie N-methylserotonin in the Bufo toad secretions contribute to the effects of natural extracts v isolated compounds. According to this paper here,

So according to above paper, 4-hydroxyNMT (norpsilocin, the dephosphorylated “active” metabolite of baeocystin) does not induce HTR in rodents, unlike psilocin and is actually more potent than psilocin as 2A agonist. Though it could be for pharmacokinetic reasons (can’t cross BBB) as suggested by the authors and/or it gets metabolized by MAOs before reaching the brain. But baeocystin (norpsilocin precursor) was actually reported as psychoactive as psilocybin in humans (cf Gratz)! And norpsilocin isomer N-methylserotonin does induce HTR according to that paper you mention. I don’t see what would make N-methylserotonin crosses BBB but not the isomeric norpsilocin (they have pretty much similar physico-chemical properties) tho could be MAOs deactivating the latter but not the former. But if anything though I would actually expect the opposite, ie norpsilocin to be more resistant to MAOs: 4-hydroxylated tryptamines are in general more resistant to MAOs than 5-OH tryptamines cf Psilocin v isomeric 5-Hydroxy-DMT ie Bufotenin). Would be interesting to see whether norpsilocin induces HTR or not in the presence of MAOIs.


As for AD effects of ketamine and non-hallucinogenic tryptamines like tabernathologs or 6-MeO-DMT presumably via stimulation of (unknown receptor?) -> BDNF-> synaptogenesis, well this paper the other day from the Olsen lab it looks like 5HT2A activation is essential for tryptamines to show AD effects including non-hallucinogenic tryptamines. Now the question is whether activation of 2A by tryptamines leading to AD response is independent from that leading to “hallucinations”. In other words is AD response likely mediated via 2A-arrestin2-Akt-src-PI3K -> synaptogenesis->AD? At least with tryptamines 2A agonists since ketamine is not 5HT2a agonist as far as I know (correct me if I am wrong).

Yohimbine produces a HTR in rodents, but it is far from psychedelic in humans

 

[paracelsius]

As for AD effects of ketamine and non-hallucinogenic tryptamines...

another thing I forgot to mention: tho both ketamine (and similar dissociatives) and tryptamines AD effect is presumably via stimulation of BDNF, the effect of ketamine last at most a week or 2 before returning to baseline, while that of tryptamines like psilocybin may last up to 8 months in humans (cf Griffiths)! So probably different mechanisms are involved (that maybe converge on BDNF stimulation and neurogenesis. The mechanism of the long-lasting effect of a single dose of psychedelics is the million dollars question.

I will finish with the common question 'why is 4-hydroxy DMT active but 5-hydroxy DMT is not. The reason is simple, the H of the hydroxy will form a hydrogen-bond with the amine

Not quite. That model (H-bond N and 4-OH) was challenged recently (was proposed by Dave Nichols years ago to explain why 4-OH sub are more resistant to MAOs than 5-sub). The structure of serotonin, psilocin, LSD, lisuride and other "non-hallucinogenic" bound to 5HT2aR was solved recently by Chinese (cf this Science paper: "Structure-based discovery of non-hallucinogenic psychedelics: DOI: 10.1126/science.abl8615"
It shows clearly psilocin binds to the receptor in extended conformation not the folded one you show involving H-bond between N and 4-OH)!

Yohimbine produces a HTR in rodents, but it is far from psychedelic in humans

My point exactly: see lots of research on "non-hallucinogenic" (in rodents at least) use HTR to translate "hallucinogenic effects" or lack therof in humans. It really doesn't say much.

 

[Fertile]

I meant ORALLY active.

 

[ecstacylover]

As for AD effects of ketamine and non-hallucinogenic tryptamines like tabernathologs or 6-MeO-DMT presumably via stimulation of (unknown receptor?) -> BDNF-> synaptogenesis, well this paper the other day from the Olsen lab it looks like 5HT2A activation is essential for tryptamines to show AD effects including non-hallucinogenic tryptamines. Now the question is whether activation of 2A by tryptamines leading to AD response is independent from that leading to “hallucinations”. In other words is AD response likely mediated via 2A-arrestin2-Akt-src-PI3K -> synaptogenesis->AD? At least with tryptamines 2A agonists since ketamine is not 5HT2a agonist as far as I know (correct me if I am wrong).

The Olsen lab showed that tabernathalog induces spinogenesis despite its inability to produce an HTR. They also showed that 6-MeO-isoDMT induces dendritogenesis with potency comparable to 5-MeO-DMT, despite significantly reduced HTR efficacy. So yeah, the AD effects in rodents are dissociable from the HTR. Obviously humans are more complex and the psychedelic effects probably influence the therapeutic effects, independently of synaptogenesis.

And ketamine indirectly increases serotonin signaling, although its blockade of spontaneous NMDAr signaling appears to be the upstream event leading to AD effects. Much of the research on ketamine's AD mechanism has come out of the Monteggia lab, and I think they're now emphasizing the importance of synaptic upscaling in ketamine's RAAD effect. Synaptic scaling is a form of homeostatic plasticity which counters the runaway inhibition or excitation produced by Hebbian plasticity, and it's distinct from synaptogenesis. Hopefully future experiments can examine whether psychedelics also induce synaptic scaling, and determine the relative importance of synaptogenesis vs synaptic upscaling in mediating AD effects.

As for the mechanism, presumably psychedelics can increase calcium-dependent release of BDNF from dendrites via Gq activation, as well as increasing activity-dependent axonal release of BDNF. 2A also recruits the GEF kalirin-7, which activates the small GTPase Rac1. The small GTPases are important regulators of actin dynamics, and Rac1 activation facilitates spine growth. The duration of Rac1 activation is crucial, since its prolonged activation actually leads to spine shrinkage.

Duration is an important consideration in BDNF signaling as well, since prolonged TRKB activation leads to synaptic downscaling (in contrast to the synaptic upscaling produced by acute TRKB activation). This is actually how lithium produces its antimanic effects, which makes you wonder if the hypomania produced by acute and/or short-term dissociative use is due to synaptic upscaling. With extended use (at least in my personal experience), many dissociatives also produce an antimanic effect (e.g. blunted affect and alogia), which I presume is due to prolonged TRKB activation.

So HTR is not really indicative of “hallucinogenic effects” only of 5HT2A activation in rodents. If I undertand, it is necessary but not sufficient for a compound to have hallucinogenic effect, is that right? From that paper you mention, yes NMTs do not require arrestin2 to induce HTR unlike serotonin since arrestin2-KO still retains HTR with NMTs. Now serotonin is not hallucinogenic (at least high doses of its 5HTP precursor) and still induces HTR via arrestin2-Akt-src-PI3K pathway which is not required for NMTs to induce same response. Since NMTs activation of 2A promote recruitment of Ga, does that mean then G but not arrestin is mediating the hallucinogenic effects (not HTR) and that functionally G selective compound would have “psychedelic effects”?

The thing with 5-HT is that it's only ever endogenously released along predefined pathways. And 5-HT neurons only make synaptic contacts in the superficial layers of the cortex, so the 2A-expressing neurons in deeper layers will "see" much lower concentration. In the case of empathogens you would have higher 5-HT concentrations in these deeper layers, and of course these drugs have unique effects on emotions and perception. Even then though, you might not have the degree of 2A activation that can be obtained with systemically administered psychedelics. Personally I wouldn't be surprised if ICV administered 5-HT could produce psychedelic effects in humans (not considering the toxicity of off-target effects of course).

But of course 5-HT could just be giving a false positive on the HTR, fenfluramine is another example of this.

 

[paracelsius]

And ketamine indirectly increases serotonin signaling, although its blockade of spontaneous NMDAr signaling appears to be the upstream event leading to AD effects. course)...

Havent been following literature on ketamine AD lately. But last I checked, it seems NMDA antagonism is not really involved since other NMDAr antagonists do not elicit ketamine-like AD effect. On the other hand iirc ketamine metabolites (norketamine or one of its stereoisomer?) which do not not have significant NMDAr antagonism do induce AD effect similar to racemic ketamine. (or was it just gimmick from Big Pharma to by-pass fact you can’t patent ketamine and still ca$h in?? there were only clinical study iirc).
How about metabotropic AMPA antagonism -> downstream mTOR->BNDF -> synaptogenesis (dendritogenesis) hypothesis of ketamine AD? Where does stand? Have to catch up on current lit.

Then again one of the confounding factor with ketamine is that some of its metabolites are also active as Dopamine (and NE??) reuptake inhibitors (and some opioid activity too?). So yeah for sure a DRI with combined opioid activity will certainly give you an antidepressant response. So it is kind of tricky in animal models to dissociate the specific pathways involved in AD effects of ketamine.

The thing with 5-HT is that it's only ever endogenously released along predefined pathways. And 5-HT neurons only make synaptic contacts in the superficial layers of the cortex, so the 2A-expressing neurons in deeper layers will "see" much lower concentration. In the case of empathogens you would have higher 5-HT concentrations in these deeper layers, and of course these drugs have unique effects on emotions and perception. Even then though, you might not have the degree of 2A activation that can be obtained with systemically administered psychedelics. Personally I wouldn't be surprised if ICV administered 5-HT could produce psychedelic effects in humans (not considering the toxicity of off-target effects of course).

But of course 5-HT could just be giving a false positive on the HTR, fenfluramine is another example of this.

That coupled with selectivity of empathogens like MDMA to (also) activate different 5HT receptors subtypes in addition to releasing 5HT (and catecholamines).
well it seems with MDMA there is more than just transporter mediated 5HT release: it turns out activation of central 5HT2B by MDMA is required in order to induce release of 5HT in NAcc-VTA! ie induce signature entactogenic effect. Apparently MDMA do not induce 5HT release in 5HT2B KO mice....

Serotonin 5-HT2B Receptors Are Required for 3,4-Methylenedioxymethamphetamine-Induced Hyperlocomotion and 5-HT Release In Vivo and In Vitro
Doly S et al DOI:10.1523/JNEUROSCI.5723-07.2008.

Abstract....acute inhibition or genetic ablation of the 5-HT2B receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in
nucleus accumbens and ventral tegmental area. Furthermore, the 5-HT2B receptor dependence of MDMA-stimulated release of endogenous
5-HT from superfused midbrain synaptosomes suggests that 5-HT2B receptors act, unlike any other 5-HT receptor, presynaptically
to affect MDMA-stimulated 5-HT release....

Who would’ve thought? I always thought 5HT2B receptors are just associated with cardiac valves morphology..Their central function has been less appreciated.

 

[paracelsius]

I meant ORALLY active.

communication issues: important qualifier "orally". I thought you were implying intrinsic activity at 5HT2a and "active" as in "active conformation" ie the one that binds and activates the receptor. But yeah could be the reason why 4-OH subs are better protected from MAOs than 5-subs allowing the former oral activity but not the latter. iirc Nichols showed that actually pKa of the dimethylamino is dramatically reduced in 4-OH-tryptamines v 5-OH... could be why 4-subs are orally active? or might simply be that MAOs just dont tolerate substituents at 4-position of the indole as opposed to 5 @fastandbulbous know more about MAO selectivity...

 

[Neuroborean]

Dissociatives reduce sensory input to zero, so brain is just left with internal feedback loops.

Could you develop more this idea?

 

[Fertile]

So my information is old. But look at PEAs ans tryptamines next to each other to see how the amines end up in the same relative 3D space in both:

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

I hope the above gets others thinking. I co-responded with Nichols for a long time and HE was excited by the addition of a methyl in the same spot on the LSD (and analogue) compounds. But he was totally fair - 'if you can work out a route, we WILL make it' but the synthesis was impossible.

I like Nichols a lot. I gave him all my work on the ring-substituted aminorex class (you can induce increase in extracellular monoamines BUT you cannot get selective 5HT2a activity. So we made the p-Me, m-methyl, m-methoxy-p-methyl )and a 2:1 mix of p-Me to m-Me was truly amazing. My wife has had a LOT of MDMA but she was welded to the floor until I put on some Neu! when she got up and did a 'tree dance' for 15 minutes.

Later we made the benzofurans (like 5-APB & 6-APB) but they weren't as good as the p-Me/m-Me mix.... so their WAS a fine difference in the space beyond the meta & para.

Didn't make any of the p-halo analogues. A few people said that p-F was good. Likely increase in serotonin activity makes it good, but the duration and suspect toxicity put us off.

FINALLY we bothered to read the WHOLE of the patent. Example 14 is 3,4-MD Aminorex. It's not a case of 'IF', just 'WHEN'. None of the precursors are controlled so it's easy to obtain (for about $3500/Kg) of the 2-amino-1-(2H-1,3-benzodioxol-5-yl)ethan-1-ol is VERY cheap and easy to make from piperonal. Now you might argue that piperonal is controlled, but OFTEN the law will treat the SAME compound depending on it's purpose.

Finally, while 7-methyl DMT is active, 'the rules' say larger groups are inactive.... but I see no research suggesting this.

I will conclude by sayiny that while 4MAR can be cyclized using KOCN but with aminorex, you just end up with a substituted urea but I feel sure someone will do some more work to find another simple route. After all, what is ACTUALLY happening is the urea and hydroxyl form a ring and throw out ammonia.

https://ibb.co/S7pYWFr

Now I HAVE devoted time to this, but if someone finds a trivial way to produce aminolysis. If so. a HUGE array of substituted aminorex compounds could be sold it kit form. If carefully managed, the ONLY 'producer' and 'distributor' is the end user. I don't mean this as being cowardly, but if suddenly their are just SO MANY people caught making 2-3g of the stuff for their night out, I feel that the CPS would not suggest that it's in the public interest.

Last of all - a 3 pipe problem. Phenylacetylcarbinol is rapidly becoming the leading source of ephedrine and potentially meth. Reductive amination with methylamine yields ephedrine, with ammonia (or ammonia donating compounds like ammonium formide or formamide) will yield PPA or optical isomers thereof.

So if one could introduce an amine group that would also undergo cyclization, that's 4MAR in 1. Also, L-PAC is made in large bioreactors. Usually in India so no heating nor cooling are needed. Just the occasional test and infusion of (sterile) food for the bacteria. I mean, maybe the next step is a bacteria that produces 4MAR directly?

 

[ecstacylover]

But last I checked, it seems NMDA antagonism is not really involved since other NMDAr antagonists do not elicit ketamine-like AD effect. On the other hand iirc ketamine metabolites (norketamine or one of its stereoisomer?) which do not not have significant NMDAr antagonism do induce AD effect similar to racemic ketamine. (or was it just gimmick from Big Pharma to by-pass fact you can’t patent ketamine and still ca$h in?? there were only clinical study iirc).

Memantine fails to produce a rapid AD response because although it's an NMDAr antagonist, it fails to block spontaneous NMDAr signaling. Spontaneous NMDAr signaling occurs even at resting potential in the presence of Mg2+, and is thought to be due to release of a presynaptic vesicle pool distinct from that used in evoked release.

Also, R,R-HNK levels are negatively associated with AD response to ketamine, which suggests that ketamine is the more efficacious AD (presumably due to its higher NMDAr affinity).

Personally I'm pretty bullish on NMDAr antagonism being the primary MOA, as most ACHs produce AD effects in my personal experience. Yeah it's not a double-blind clinical trial, but I don't think it's any less valuable than rodent data.

How about metabotropic AMPA antagonism -> downstream mTOR->BNDF -> synaptogenesis (dendritogenesis) hypothesis of ketamine AD? Where does stand? Have to catch up on current lit.

Spontaneous NMDAr block->disinhibition of protein translation (via increased elongation rate)->increased BDNF synthesis/release->synaptic upscaling (e.g. via AMPAr insertion) and synaptogenesis.

In most cellular contexts protein translation is rate limited by initiation rate (which is regulated by mTOR), so the increased elongation rate might be expected to have little effect in the absence of mTOR activation. However, the actual role of mTOR is a little less clear. In rodents, ICV rapamycin blocks ketamine-induced dendritogenesis in PFC as well as rapid AD effect, while IP rapamycin fails to block the rapid AD effect. In humans, pretreatment with oral rapamycin seemed to enhance the response to IV ketamine. Perhaps the latter 2 studies primarily inhibit peripheral mTOR (e.g. skeletal muscle)?

My personal opinion is that the synaptogenic effects are probably just as important as the effects on synaptic scaling, at least in certain psychological contexts. Reason being that IME phenibut blocks most of the AD-like effects of ACHs, which I imagine is due to its generalized inhibition of synaptogenesis.

That coupled with selectivity of empathogens like MDMA to (also) activate different 5HT receptors subtypes in addition to releasing 5HT (and catecholamines).
well it seems with MDMA there is more than just transporter mediated 5HT release: it turns out activation of central 5HT2B by MDMA is required in order to induce release of 5HT in NAcc-VTA! ie induce signature entactogenic effect. Apparently MDMA do not induce 5HT release in 5HT2B KO mice....

Interesting about the 5-HT2B KOs. And yeah the network effects definitely complicate things, actually many psychedelics increase cortical and striatal DA release in a similar manner (although it's 2A-dependent rather than 2B).

 

[paracelsius]

Memantine fails to produce a rapid AD response because although it's an NMDAr antagonist, it fails to block spontaneous NMDAr signaling. Spontaneous NMDAr signaling occurs even at resting potential in the presence of Mg2+, and is thought to be due to release of a presynaptic vesicle pool distinct from that used in evoked release.

True NMDA blocker memantine (or mecamylanine for that matter that was clinically trialed and failed as AD) doesnt elicit ketamine and other ACHs-like effects. But it is not only ACHs that have ketamine-like RAAD effects. Cough syrup dissociative dextrometorphan DXM is also a RAAD as good as or even better than Ketamine.

.....Dextromethorphan (DM) is an antitussive with rapid acting antidepressant potential based on pharmacodynamic similarities to ketamine........AMPA receptor activation has been shown to increase brain-derived neurotrophic factor(BDNF) expression in vitro and vivo [49,54], a pivotal downstream component for conveying rapid acting and delayed therapeutic efcacy [55,56]. Importantly, a single injection with an AMPA receptor potentiator increased BDNF mRNA expression in the hippocampus within hours [52]compared to the more chronic dosing usually required of traditional antidepressants...... doi: 10.1016/j.bbr.2015.03.024

So according to this paper it seems that DXM (and ketamine?) RAAD effect is mediated by AMPA receptors activation rather than direct blockade of NMDAr.

In most cellular contexts protein translation is rate limited by initiation rate (which is regulated by mTOR), so the increased elongation rate might be expected to have little effect in the absence of mTOR activation. However, the actual role of mTOR is a little less clear. In rodents, ICV rapamycin blocks ketamine-induced dendritogenesis in PFC as well as rapid AD effect, while IP rapamycin fails to block the rapid AD effect. In humans, pretreatment with oral rapamycin seemed to enhance the response to IV ketamine. Perhaps the latter 2 studies primarily inhibit peripheral mTOR (e.g. skeletal muscle)?

My personal opinion is that the synaptogenic effects are probably just as important as the effects on synaptic scaling, at least in certain psychological contexts. Reason being that IME phenibut blocks most of the AD-like effects of ACHs, which I imagine is due to its generalized inhibition of synaptogenesis.

Imo, one thing seems clear: both psychedelics 5HT2a activation and ketamine (either via NMDA or direct AMPAr or other mechanism like sigma agonism) pathways converge on mTOR stimulation leading to BDNF and synaptogenesis. I think mTOR is the key. The question is the transient nature of mTOR activation, 2-3 weeks before returning to baseline (could that be due to synaptic scaling?). Another question at least with psychedelics is the upstream pathways leading to mTOR activation and whether it can be dissociated from that leading to so-called “hallucinations”(topic of OP). Same with dissociatives actually: sub-psychotomimetic doses of ketamine do not elicit RAAD iirc. So again can the two be dissociated??

Oh btw, recent clinical data on Psilocybin trials showed the RAAD effect of single 25 mg dose Psilocybin lasts about 3 weeks, so it is similar to ketamine. Which would not be unexpected if both psychedelics and dissociatives act (downstream) via mTOR stimulation, at least the chronic AD effect (may be not the acute fast response which imo may be simply due to stimulant effect of both drugs).

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression https://www.nejm.org/doi/full/10.1056/NEJMoa2206443​

Kind of disappointing the clinical trials of psilocybin. There have been so much hype it is incredible: you’d think the holy grail of depression and any and all psychiatric conditions (just pop 25 mg pill and you good for 8-12 months!!). I mean there are more 150 clinical trials now of psilocybin.. Well I guess lots of ppl are going get disappointed and lots of companies ca$h in on the hype before reality sets in.

 

[paracelsius]

Later we made the benzofurans (like 5-APB & 6-APB) but they weren't as good as the p-Me/m-Me mix.... so their WAS a fine difference in the space beyond the meta & para.

Didn't make any of the p-halo analogues. A few people said that p-F was good. Likely increase in serotonin activity makes it good, but the duration and suspect toxicity put us off.

FINALLY we bothered to read the WHOLE of the patent. Example 14 is 3,4-MD Aminorex. It's not a case of 'IF', just 'WHEN'. None of the precursors are controlled so it's easy to obtain (for about $3500/Kg) of the 2-amino-1-(2H-1,3-benzodioxol-5-yl)ethan-1-ol is VERY cheap and easy to make from piperonal. Now you might argue that piperonal is controlled, but OFTEN the law will treat the SAME compound depending on it's purpose.

then why not the 3,4-dimethyl (I mean 3'.4'DMAR, 5-(3,4-dimethylphenyl)-2-aminooxazoline) instead of mix. if anything 3,4-dimethylmethcathinone DMMC is as good as meph and/or 3MMC! well somewher in between. it is more comparable (SAR-wise) than 5(6)APBs. the aldehyde precursor shouldnt be a problem.

then again as I keep saying the issue with aminorex is that as far as recreational effects goes, you just cant beat plain aminorex. this drug is "perfect" kind of like cocaine (you can get closer but never quite there!)... too bad Aminorex is illegal. One thing that would be interesting tho is the chiral compound, I mean the dextro or levo-AR. I havent seen any data on those. Poos patent mentions the possibility of dextro or levo since there is one chiral carbon. I think nobody has done that but I am pretty sure only one enantiomer is active (or at least more active). which one? I dont know. I'll propbably try make that one and see.

btw, have you actually tried the MDAR tho? imo it would probably be flatliner (AR is already pretty well balance DAT-NET-SERT). adding a MD would make MORE serotonergic!!! Naphthaminorex (naphthalene bioisostere of benzodioxole) was not as good well kind of like mdma but rather mellow... I suspect MDAR would be similar.

edit: wouldnt it it better to use 4MAR thread to discuss that tho...it is more relevant and fair to readers, isnt it?

 

[Skorpio]

True NMDA blocker memantine (or mecamylanine for that matter that was clinically trialed and failed as AD) doesnt elicit ketamine and other ACHs-like effects. But it is not only ACHs that have ketamine-like RAAD effects. Cough syrup dissociative dextrometorphan DXM is also a RAAD as good as or even better than Ketamine.


So according to this paper it seems that DXM (and ketamine?) RAAD effect is mediated by AMPA receptors activation rather than direct blockade of NMDAr.


Imo, one thing seems clear: both psychedelics 5HT2a activation and ketamine (either via NMDA or direct AMPAr or other mechanism like sigma agonism) pathways converge on mTOR stimulation leading to BDNF and synaptogenesis. I think mTOR is the key. The question is the transient nature of mTOR activation, 2-3 weeks before returning to baseline (could that be due to synaptic scaling?). Another question at least with psychedelics is the upstream pathways leading to mTOR activation and whether it can be dissociated from that leading to so-called “hallucinations”(topic of OP). Same with dissociatives actually: sub-psychotomimetic doses of ketamine do not elicit RAAD iirc. So again can the two be dissociated??

Oh btw, recent clinical data on Psilocybin trials showed the RAAD effect of single 25 mg dose Psilocybin lasts about 3 weeks, so it is similar to ketamine. Which would not be unexpected if both psychedelics and dissociatives act (downstream) via mTOR stimulation, at least the chronic AD effect (may be not the acute fast response which imo may be simply due to stimulant effect of both drugs).


Kind of disappointing the clinical trials of psilocybin. There have been so much hype it is incredible: you’d think the holy grail of depression and any and all psychiatric conditions (just pop 25 mg pill and you good for 8-12 months!!). I mean there are more 150 clinical trials now of psilocybin.. Well I guess lots of ppl are going get disappointed and lots of companies ca$h in on the hype before reality sets in.

Is it known if say mk801 or the phenidines have rapid antidepressant effects? I've always been under the impression that memantine blocks the channel in a functionally different manner than ketamine. I don't have any hard evidence currently so am unsure if this impression is correct