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

[ecstacylover]

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.

AMPAr activation might be needed, but that doesn't mean it's the upstream event by which ketamine/DXM are triggering RAAD response. It's not even surprising that AMPAr block suppresses RAAD response when you consider that synaptic upscaling requires insertion of additional AMPA receptors, which would be masked by AMPAr antagonists.

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?).

mTOR activation may be necessary for ketamine, but it's probably downstream of increased BDNF-TRKB signaling. The classical pathway for mTOR activation proceeds through PI3K-AKT, with PI3K generally being activated by receptor tyrosine kinases (e.g. TRKB). TRKB can also couple to ERK activation, and inhibitors of both ERK and PI3K can prevent ketamine's activation of mTOR—which is what you would expect if the mTOR effects were downstream of TRKB.

Personally I think some initial increase in activity-dependent BDNF release is necessary, as this would explain why NBQX occludes ketamine-mediated increases in both p-mTOR and BDNF protein levels within hippocampus. This activity-dependent increase in TRKB activity could lead to an increase in mTOR activity, which would synergize with the EEF2K inhibition provided by spontaneous NMDAr block to increase local dendritic synthesis of BDNF and other synaptic proteins (leading of course to synaptic upscaling and/or synaptogenesis).

Oh and btw, the AMPK activator metformin was found to impair the sustained but not the rapid AD response to ketamine (as well as that of scopolamine), although the authors suggested this wasn't due to AMPK's inhibition of mTOR.

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??

Tabernanthalog produces AD effects in FST and no HTR, so probably 2A agonists can produce therapeutic effects in the absence of strong psychoactivity. It's already been said, but humans are much more complex so the subjective effects of psychedelics can probably produce therapeutic effects over and above that of neuroplasticity alone. There was a study showing correlation of psilocybin's therapeutic benefits in cancer patients with mystical experience questionnaire scores (which in turn are a function of dose). Or take single high-dose psilocybin, which leads to significant increase in the personality domain of openness even at 1 year follow-up.

Would be nice if some studies examined the effect of 2A activation on mTOR activity, as I don't think there's any published data on it.

 

[paracelsius]

Oh and btw, the AMPK activator metformin was found to impair the sustained but not the rapid AD response to ketamine (as well as that of scopolamine), although the authors suggested this wasn't due to AMPK's inhibition of mTOR.

That is interesting. Isn’t the same metformin drug that increases life-span of C.elegans worms and mice (but not rats!) and hyped as anti-aging, “fountain-of-youth” drug by Silicon Valley? So it antagonizes RAAD effects of ketamine presumably via inhibition of mTOR1 complex (independent of AMPK)? Interesting because on the other hand, AMPK- independent inhibition of mTOR1 complex is presumed to be behind anti-aging effects of metformin!

.......In support of the idea that metformin treatment modulates certain downstream cellular effects by blocking mTORC1, both metformin and canonical mTOR1 inhibitors have similar molecular effects, decreasing translation of mRNAs encoding cell-cycle and growth regulators...... doi:10.1016/j.tem.2019.07.015

So mTOR1 activation (by 2A agonists or NMDArs) elicits ketamine-like anti-depressant effects while its inhibition elicits anti-aging effects presumably via decrease translation and growth factors as mentioned by these authors. Wonder if the same happen with synaptogenesis, ie if blocking mTOR1 complex may lead to decrease synaptogenesis but also increase survival of neurons....Interesting!

Tabernanthalog produces AD effects in FST and no HTR, so probably 2A agonists can produce therapeutic effects in the absence of strong psychoactivity. It's already been said, but humans are much more complex so the subjective effects of psychedelics can probably produce therapeutic effects over and above that of neuroplasticity alone. There was a study showing correlation of psilocybin's therapeutic benefits in cancer patients with mystical experience questionnaire scores (which in turn are a function of dose). Or take single high-dose psilocybin, which leads to significant increase in the personality domain of openness even at 1 year follow-up.

Would be nice if some studies examined the effect of 2A activation on mTOR activity, as I don't think there's any published data on it.

Could well be. On the other hand, according to that Griffiths study you mention, it seems that ppl (80%+) who benefit from AD effect of psilocybin are those who've had "mystical" experience during the trip. Same clinical trial I mentioned actually showed no improvement (same as placebo) response in the sub-psychoactive group (iirc 1 mg and 10 mg psilocybin) compared to full psychoactive dose (25mg). So definately, in humans "psychoactivity" ie doses that induce "hallucinogenic effect" seems to be required for RAAD at least with psilocybin.

As for Tabernatholog and related "non-hallucinogenic" psychedelics my own take is that 5HT2A activation and resulting HTR (or lack thereof) is probably not the best model to establish relations "hallucinogenic" vs AD psychoactivity". Why I am saying that? because the parent Ibogaine and derivatives (Ibogamine, ibogaline, tabernanthine, voacangine...etc) are not really classical psychedelics. They do not significantly particularly activative 2A in therapeutic concentrations and yet are potent hallucinogens, different from classical psychedelics (they best be described as oneirogens ie dream-inducing). They have pretty complex pharmacology so the non-hallucinogenic ibogaine analogs such as tabernantholog or even simpler tryptamines such as 6-MeO-DMT may well be ..oneirogen! only way to know is human trials (I'd volunteer for that..)

 

[paracelsius]

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

Yes it does: memantine is a competitive NMDAr antagonist. It competes with Mg (a co-ligand along with glutamate) for binding to the receptor. Dizocilpine, PCP, Arylcyclohexylamines and arylethylamines are uncompetitive inhibitor. They bind to the PCP site. Yes similar to ketamine, MK801 has AD-like effects in rodents, I dont know about the phenidines.

My guess is all uncompetitive NMDA antagonists (those binding to the PCP site of the receptor) would probably have ketamine-like RAAD effects. Like ACHs, arylethyalmines..etc. Competitive antagonists like memantine, mecamyalmine..etc (those binding to the magnesium site) would probably not have ketamine-like effects. But who knows that is just my opinion. Would be nice to hear from regular users of diphenidine (or other recreational ACHs for that matter) and their experience about AD effect.

 

[Fertile]

Sorry to OT but I noted that they are now adding metformin to neuroleptics (antipsychotics) which is an admission of the dirty and dangerous action of the class.

 

[ecstacylover]

That is interesting. Isn’t the same metformin drug that increases life-span of C.elegans worms and mice (but not rats!) and hyped as anti-aging, “fountain-of-youth” drug by Silicon Valley? So it antagonizes RAAD effects of ketamine presumably via inhibition of mTOR1 complex (independent of AMPK)?

Yup, it's generally prescribed for T2D. And I interpreted the abstract as saying that metformin inhibited ketamine's late AD effect independently of AMPK-mTOR axis, although the paper is behind a paywall so I wasn't able to see why they believed metformin's AMPK-mediated mTOR inhibition had nothing to do with it.

So mTOR1 activation (by 2A agonists or NMDArs) elicits ketamine-like anti-depressant effects while its inhibition elicits anti-aging effects presumably via decrease translation and growth factors as mentioned by these authors.

I haven't really seen any papers that looked at mTOR activation in the context of 2A signaling, and the effects of 2A agonism on BDNF-TRKB do seem less robust than that of ketamine. Not saying 2A doesn't activate mTOR, as psychedelics generally activate ERK (and there's some evidence that serotonin can activate AKT via 2A), just that it hasn't really been looked as far as I'm aware.

The only thing I can really find is that chronic LSD activates mTOR and that this is necessary for enhanced social behavior (which is not observed with acute administration).

Wonder if the same happen with synaptogenesis, ie if blocking mTOR1 complex may lead to decrease synaptogenesis but also increase survival of neurons....Interesting!

Definitely makes you wonder whether some depressive phenotypes, or at least their underlying molecular causes, have adaptive benefit (e.g. via reduced growth rate of neurons) in certain circumstances.

Could well be. On the other hand, according to that Griffiths study you mention, it seems that ppl (80%+) who benefit from AD effect of psilocybin are those who've had "mystical" experience during the trip. Same clinical trial I mentioned actually showed no improvement (same as placebo) response in the sub-psychoactive group (iirc 1 mg and 10 mg psilocybin) compared to full psychoactive dose (25mg). So definately, in humans "psychoactivity" ie doses that induce "hallucinogenic effect" seems to be required for RAAD at least with psilocybin.

At least in regard to ketamine, a recent paper (N=576) had this to say: We found no evidence of a clinically significant positive or negative association between dissociation and antidepressant effect for esketamine.

As for Tabernatholog and related "non-hallucinogenic" psychedelics my own take is that 5HT2A activation and resulting HTR (or lack thereof) is probably not the best model to establish relations "hallucinogenic" vs AD psychoactivity". Why I am saying that? because the parent Ibogaine and derivatives (Ibogamine, ibogaline, tabernanthine, voacangine...etc) are not really classical psychedelics. They do not significantly particularly activative 2A in therapeutic concentrations and yet are potent hallucinogens, different from classical psychedelics (they best be described as oneirogens ie dream-inducing). They have pretty complex pharmacology so the non-hallucinogenic ibogaine analogs such as tabernantholog or even simpler tryptamines such as 6-MeO-DMT may well be ..oneirogen! only way to know is human trials (I'd volunteer for that..)

The means by which ibogaine and derivatives are hallucinogenic may be 2A-independent. Their effects on neural plasticity probably are not, as ketanserin blocks increases in dendritic complexity by both ibogaine and TBG.

Yes it does: memantine is a competitive NMDAr antagonist. It competes with Mg (a co-ligand along with glutamate) for binding to the receptor. Dizocilpine, PCP, Arylcyclohexylamines and arylethylamines are uncompetitive inhibitor. They bind to the PCP site. Yes similar to ketamine, MK801 has AD-like effects in rodents, I dont know about the phenidines.

Memantine binds to the PCP site as well, there's a crystal structure for bound MK-801 and they used MD simulation to show memantine binds at the same site. This is the same site Mg2+ binds to, and you can see that a hydrophobic collapse occurs after MK-801 or memantine binding which stabilizes the blocked state. Obviously this conformational shift wouldn't occur upon Mg2+ binding, which explains why its block is of a "flickering" nature.

Obviously there are subtle differences in memantine's block, as it fails to block NMDAr-mediated mEPSCs which is also why it fails to induce RAAD effect.

 

[SpiralusSancti]

I know this is not exactly what this thread is about but what do you think how likely we will find substance that affects smell, taste or touch perception in a way DiPT affects sound perception?

Also as far as I know reasons for unique effects of DiPT are nowhere near point of being understood and there is zero guidance in any way if someone would get on a quest to design another, what could be described as mostly auditory psychedelic. And before that coming even close to reality we’ll first have to get insanely better at predicting what will cause head twitch in mouse following possibly some rudimentary guesses about what subjective effects might have some completely novel substance but given enough time it doesn’t seem impossible some day we’ll have idea what might be somewhat similar in effects to DiPT while being molecule with unrelated structure.

 

[paracelsius]

Yup, it's generally prescribed for T2D. And I interpreted the abstract as saying that metformin inhibited ketamine's late AD effect independently of AMPK-mTOR axis, although the paper is behind a paywall so I wasn't able to see why they believed metformin's AMPK-mediated mTOR inhibition had nothing to do with it.

I haven't really seen any papers that looked at mTOR activation in the context of 2A signaling, and the effects of 2A agonism on BDNF-TRKB do seem less robust than that of ketamine. Not saying 2A doesn't activate mTOR, as psychedelics generally activate ERK (and there's some evidence that serotonin can activate AKT via 2A), just that it hasn't really been looked as far as I'm aware.

The only thing I can really find is that chronic LSD activates mTOR and that this is necessary for enhanced social behavior (which is not observed with acute administration).

Yes metformin “anti-aging”, rather its life-span-increasing effects was discovered with T2D patients, how do you call that serendipitously? Some smart doctor noticing his patients treated with metformin seem to live longer than those on other diabetes drugs! How it does that tho is the million$ question?

From that paper, it seems like mTOR1 play key role in anti-aging effects of metformin, the same complex presumably involved in ketamine RAAD, which is actually antagonized by metformin (the enduring effect of ketamine? Not the acute, is that right? Kind of sucks that paper is behind paywall... tempting tho to suggest inhibition of mTOR1 complex may be behind antagonism of ketamine enduring RAAD by metformin but also its anti-aging effect. How about Rapamycin effects on ketamine RAAD or anti-aging tho?

On the other hand, would be interesting to see if metformin does antagonize 2A psychedelics (“hallucinogenic” or not) enduring RAAD effects, like it does with ketamine. That may suggest mTOR1 involvement in 2A activation leading to increase dendritogenesis and enduring RAAD as well. no study has looked at mTOR1 involvement in 2A signalling RAAD??

At least in regard to ketamine, a recent paper (N=576) had this to say: We found no evidence of a clinically significant positive or negative association between dissociation and antidepressant effect for esketamine.

That is pretty solid evidence ketamine RAAD may be independant from its dissociative effects in humans! Hard to argue with numbers like this (n=576) for sure. The question now is whether NMDAR is involved at all in ketamine RAAD in humans, and other ketamine-like NMDA antagonists like MK801 as well. Lots to be learn when it comes translating from rodents to humans.
Like, how one can measure “dissociative schizophrenic psychosis” in rodents models dosed with MK801? FST for AD-like effects or HTR for 2A activation in rodents is one thing but a behavior marker indicative of rodents experiencing the equivalent of dissociative schizophrenic psychosis of MK801 in humans!?

Memantine binds to the PCP site as well, there's a crystal structure for bound MK-801 and they used MD simulation to show memantine binds at the same site. This is the same site Mg2+ binds to, and you can see that a hydrophobic collapse occurs after MK-801 or memantine binding which stabilizes the blocked state. Obviously this conformational shift wouldn't occur upon Mg2+ binding, which explains why its block is of a "flickering" nature.

Obviously there are subtle differences in memantine's block, as it fails to block NMDAr-mediated mEPSCs which is also why it fails to induce RAAD effect.

I thought memantine is a pure competitive NMDA antagonist, competing with Mg, unlike uncompetitive PCP,MK801, ketamine,ACHs, phenidines...etc that bind at allosteric PCP site. I didnt know it also bind PCP site or that the 2 sites actually overlap. No hard data, but somehow I was under the impression blockade at PCP site but not Mg (or glutamate or glycine sites) may be required for RAAD effects, at least with MK801. But that also lead to...well dissociative schizophrenic psychosis effects of MK801! I mean binding at PCP site. On the other hand, like with ketamine, the two effects might be mediated by different different pathways altogether.

Havent look at MK801-NMDA crystal structure and mode of inhibition ie via hydrophobic collapse and blocking of the channel preventing Ca release. Yes some ion channels blockers act via this mechanism (hydrophobic collapse) but mostly they just “sit” on the channel pore and block ions trafficking, at least with lots of nicotinic cholinergic channels blockers I’ve seen.

 

[paracelsius]

The means by which ibogaine and derivatives are hallucinogenic may be 2A-independent. Their effects on neural plasticity probably are not, as ketanserin blocks increases in dendritic complexity by both ibogaine and TBG.

Which somehow make me suggesting that HTR is probably not the best indicator to describe the presence (or absence) of "hallucinogenic" effects of this class of non-classical psychedelics in rodents. I mean the HTR may be absent but not the "hallucinations". I've seen some evidence that most "hallucinogenic" (and anti-additive) effects of Ibogaine is due to blockade of nicotinic cholinergic alfa3beta4 channels in the medial habenula/interpedencular nuclei. So it may interesting to look at the effects of ibogalogs on those channels here is a recent review https://doi.org/10.1021/acs.jmedchem.2c01562 (behind paywall.. kind of frustrating . may be somebody can post a link)

 

[ecstacylover]

How about Rapamycin effects on ketamine RAAD or anti-aging tho?

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 enhances the response to IV ketamine.

Rapamycin robustly increases lifespan in rodents and I believe there's an upcoming clinical trial in dogs, which could show that it slows mammalian aging across species. The basic idea is that mTOR controls cell growth (like it literally causes cells to increase in size, as opposed to replication-mediated increases in organismal size), and that this it at odds with maintenance. The lack of a shut-off valve leads to an unhalted developmental program and insufficient maintenance, which show up as aging.

no study has looked at mTOR1 involvement in 2A signalling RAAD??

My bad, I thought that study using chronic LSD was the only one, but I just found out the Olsen lab showed that rapamycin blocks either DOI, LSD, or DMT-mediated increased dendritic complexity in vitro.

Like, how one can measure “dissociative schizophrenic psychosis” in rodents models dosed with MK801? FST for AD-like effects or HTR for 2A activation in rodents is one thing but a behavior marker indicative of rodents experiencing the equivalent of dissociative schizophrenic psychosis of MK801 in humans!?

Some combination of tests looking at brain rhythms, memory, sensorimotor gating/PPI, impaired motor function (e.g. stereotypy or ataxia) or affective function, etc. Actually in humans both acute ketamine and memantine enhance PPI, although I suspect that chronic use will result in impaired PPI.

I thought memantine is a pure competitive NMDA antagonist, competing with Mg, unlike uncompetitive PCP,MK801, ketamine,ACHs, phenidines

I believe they're all uncompetitive/use-dependent, as there's asparagine residues in the selectivity filter (i.e. the narrowest part of the channel) which are crucial for both Mg2+ and PCP block/binding, as well as MK-801 and memantine. Considering the pH dependence of most of these blockers (potency increases w/ decreasing pH), I would imagine their protonated amine groups are engaging in some sort of H-bond interaction w/ the carbonyl oxygen on the asparagine residues. There's probably enough data out there to say this more precisely and definitively, but I'm too lazy to read structural biology.

Bit of a side note, but I always found it odd that NMDAr conducts Ca2+ and is blocked by Mg2+, considering that Ca2+ is bigger in a vacuum. The answer of course is that Mg2+ binds water more tightly and thus cannot shed its waters of hydration, which makes it effectively bigger in aqueous environments.

 

[Neuroprotection]

5-HT2A stands out in that it doesn't just activate Gq and arrestin, but can also activate G12/13, Gi, and Gs. The activation of non-canonical G proteins is likely downstream of either Gq or arrestin, as the Roth lab used BRET experiments to show 5-HT2A couples only to Gq-family members (along with a weak coupling to Gz).


The Gonzalez-Maeso lab suggested that LSD activates the Gi pathway while non-psychedelic 2A agonist lisuride does not. Furthermore, there's data suggesting that psychedelic 2A agonists activate the Gs pathway while non-psychedelic 2A agonists lisuride and tabernathalog don't.

Although there's been so much research into functional profiles of 2A agonists and it's still quite unclear which pathways (or ratio thereof) are most relevant, and the expression system is often not constant across experiments. Personally I'd be much more interested to see electrophysiology of pyramidal cells studied for all the different 2A agonists, because then you could see which ion channels are being modulated in a native system and how the ion channel fingerprint varies across the different psychedelic 2A agonists.

I’m no scientist, but this is what I understood from research on psychedelics. Normal activation of 5HT2A receptor by serotonin or non-hallucinogenic agonists modulates various neuronal ion channels and affects excitability of the neurons expressing this receptor. this is one reason why even quite high concentrations of serotonin do not cause psychedelic/ hallucinations. On the other hand, such receptor activation facilitates powerful modulation of mood and emotional states. it also affects release of other neurotransmitters, especially dopamine. psychedelics differ in that they activate 5HT2A in a particular manner, which causes it to form a heteromeric complex with a Metabetropic glutamate receptor called MGLU2. this produces dramatic changes at the circuit level including a large release of glutamate into the cortex, if I remember correctly. this excessive glutamate in certain brain regions apparently produces tremendous sensory overload, disturbances of brain information-processing, Extreme sense of awareness appearing as a state of super wakefulness on brain scans amongst many other effects.

 

[AlsoTapered]

4 billion years of evolution via trial & error. Like trying to understand how a VHS videorecorder works, purely by seeing videocassettes played...

No disrespect, but having seen you load a video, you did so with a certain amount of wonder in your eyes. It was all you could do not to lay your greasy little hands on it and rip it apart to see what makes it work.

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