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Onlinesonoramo
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Non-hallucinogenic psychedelics: scientists close in on compound * 2
    #27285112 - 04/28/21 02:04 PM (9 days, 1 hour ago)

Non-hallucinogenic psychedelics: scientists close in on compound

Discovery could accelerate development of easy-to-use treatments for mental health conditions



Natalie Grover
Wed 28 Apr 2021 11.00 EDT

Original story in The Guardian

Researchers have identified a psychedelic that doesn’t trigger hallucinations, a key discovery that could allow scientists to accelerate the development of easy-to-use treatments for mental health and neurological conditions.

Researchers are racing to harness the therapeutic potential of psychedelics for poorly treated conditions such as depression and PTSD. While antipsychotics typically work by altering brain chemistry, psychedelics appear to promote neural plasticity, essentially allowing the brain to rewire itself.

But the psychedelics being tested as treatments currently require supervision before, during and after administration, due to their hallucinogenic properties. Critics also worry that the medical use of psychedelics could promote the recreational use of these drugs.

A non-hallucinogenic psychedelic could be a Goldilocks compound – just right. But finding one, at the moment, is an onerous proposition involving protracted animal testing, said David Olson, an assistant professor in the department of chemistry at the University of California, Davis.

With his colleague Lin Tian, an associate professor at the school of medicine, he engineered a sensor that glows in the presence of a hallucinogenic compound when it interacts with a serotonin receptor, according to a study published in the journal Cell. This receptor is the target of both psychedelic drugs and classic antipsychotic medicines.

Using their sensor, the researchers have homed in on hallucinogenic and non-hallucinogenic psychedelics. Of particular interest is a previously unstudied non-hallucinogenic compound, AAZ-A-154, that has so far produced encouraging results in animal studies, similar to the impact seen with hallucinogenic psychedelics, said Olson, adding that the drug is now undergoing safety testing before being taken into early stage human trials.

The importance of the hallucinogenic effects in the therapeutic properties of psychedelics is highly debated; some scientists think they are essential to the compounds’ perceived therapeutic benefit. If that’s the case, then the sensor can be really useful for drug discovery efforts to identify new hallucinogenic psychedelic compounds, added Olson.

But non-hallucinogenic compounds are a particularly seductive notion, he said, because they could allow for medicines to be self-administered the way aspirin is. “If you undergo a psilocybin [the psychoactive component in magic mushrooms] therapy session, you have to go to the doctor to prepare yourself for the session, then be in the medical setting for at least eight hours, and then go back for some follow-up.”

The sensor could also help pharmaceutical companies with a broad portfolio of compounds, said Tian, “to really see whether a drug can target the serotonin receptor and what their hallucinogenic potential is”.

Psychedelic research has so far resulted in regulatory approvals of a ketamine-derived depression treatment, clinical trials testing the potential of psilocybin in magic mushrooms, and the estabishment of psychedelic research centres at Imperial College London and Johns Hopkins University.


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Onlinesonoramo
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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: sonoramo] * 1
    #27285117 - 04/28/21 02:08 PM (9 days, 1 hour ago)

There are two obvious things missing from this story:

  • Who are these people who are so worried about "recreational" use, and why are they worried? Maybe the first mental health need that ought to be addressed is irrational fear of psychedelics.
  • The real story is the psychedelic "sensor." This has potential to enable an explosion of new psychedelic (active, fun, recreational, entheogenic, ceremonial) compounds.


I want to know how hard it would be for amateur investigative chemists to discover new psychedelics!


Edited by sonoramo (04/28/21 02:10 PM)


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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: sonoramo] * 3
    #27285401 - 04/28/21 06:45 PM (8 days, 21 hours ago)

I laughed when I read that they were worried about recreational use, then I saw what you wrote. The language used and the puritanical idea that if such things have no medical application then they are to be demonised are so deeply ingrained, that it is hard to have a logical conversation/discussion.

I think these people desperately need this to be produced as soon as possible to treat their anxiety and irrational fear of another human being deciding to have an experience that they cannot control.


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InvisibleQM33
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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: Zanderman]
    #27285493 - 04/28/21 07:57 PM (8 days, 19 hours ago)

Ide like to see psychedelics for neuro plasticity popularized. I think lions mane has similar properties with NGF,I've often wondered the difference..

And although whatever the fuck they were trying in the experiments I assume to be synthesized  the idea is totally there.
That you don't have to trip out for God knows how long to be able to treat your brain well,no, to treat your brain exceptional, or what might considered now.
And I'm sure that something in nature is non hallucinic and also "psychedelic", lol.
How they use the term psychedelics is actually super crazy if you think about it, like psychedelics ARE this super medicine. Duh.
Non hallucenagenic "psychedelics", lol. Really think about that. What is a psychedelic without the "hallucenations". What do they know that we don't? Or what are they trying to do with what we've know?


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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: sonoramo]
    #27285577 - 04/28/21 09:19 PM (8 days, 18 hours ago)

Quote:

sonoramo said:
Who are these people who are so worried about "recreational" use, and why are they worried?




In an episode of Hamilton's Pharmacopeia, regarding Amanita muscaria, in what I assume were state-sponsored studies, new compounds were being compared, subjectively, to other drugs of abuse. If it seemed familiar, it would have been stricken from further development.

In theory, they don't want to bring any new epidemics to market, seeing the Hedonistic Imperative in terms of street poopers and spent needles.

Experimenters at social expense are prone to see everything in terms of social cost, seeing as how they are technically in competition with the homeless. Champagne socialism and welfare cheese are both served at the same table of public subsidies.


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Onlinesonoramo
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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: QM33]
    #27285618 - 04/28/21 09:50 PM (8 days, 18 hours ago)

Quote:

QM33 said:
... What is a psychedelic without the "hallucenations". What do they know that we don't? ...




Sub-hallucinatory doses can still produce emotional and spiritual release and even an "afterglow" period. The way I understand the research motivation is that they want to get that release without the "scary parts" and especially without the aspects of the journey that would make the journeyer want to have a sitter. Because as expensive as fancy-pants pharmaceuticals are, if they can offer most of the benefits without those scary hallucinations, that's still cheaper than paying somebody with a Ph.D. to hold your hand while you do your work.


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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: sonoramo]
    #27285634 - 04/28/21 09:56 PM (8 days, 17 hours ago)

Become accustomed to the scary, mental pictures and make friends with them, as though you are living among dangerous animals or powerful people. 

Just, not naked in the intersection.


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InvisibleQM33
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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: durian_2008]
    #27286203 - 04/29/21 09:01 AM (8 days, 6 hours ago)

I know sonoramo..

But this article makes it seem like it's common knowledge,or commonly accepted in scientific  culture thay you get these effects from "psychedelics". Psychedelics  is such a broad term as it is, and since when is it such common knowledge?


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Non-hallucinogenic psychedelics: scientists close in on compound [Re: sonoramo]
    #27289071 - 05/01/21 01:25 PM (6 days, 2 hours ago)

It seems all they have found is an non-hallucinogenic 5HT2A agonist that shows anti-depressant effects.

Psychadelics produce their effects through biased agonism/functional selectivity.They bind to and activate the 5-HT2A–mGlu2 receptor heterodimer and not just monomeric 5-HT2A receptors, additionally their binding preferentially recruits β-arrestin over activating G proteins. The former is directly responsible for the psychedelic experience, I don't know how the latter is involved exactly.

When people talk about finding a non-hallucinogenic psychedelics for psychiatric use they want ligands which share these properties but don't have hallucinogenic effects.

Which is why when some people talk about the hallucinogenic experience being intrinsic to the medical value, they mean the patient needs to experience it. But when I say I believe the hallucinogenic experience is intrinsic to the psychedelics pharmacological action, I don't think you'll be able to get that biased agonism without some degree of psychedelia. But maybe you could find one that is more mild, but still effective medicine.

From what I have seen there is no evidence that AAZ-A-154 shares the same biased agonism/functional selectivity as psychedelics. Correct me if I am wrong about that.


Edited by Holybullshit (05/01/21 01:43 PM)


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InvisibleQM33
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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: Holybullshit]
    #27289950 - 05/02/21 07:51 AM (5 days, 8 hours ago)

So all psychedelics do this?
2c,25i,dxm? The less common ones than L, mush, dmt, but less researched and potentially more harmful?


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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: QM33]
    #27290062 - 05/02/21 09:57 AM (5 days, 5 hours ago)

It's why drugs like lisuride and methysergide or even serotonin itself don't produce psychadelic effects after activating the 5ht2a receptor.

The amount of affinity for the 5ht2a-mGlu2 heterodimer or how selectively they activate the b-arrestin mediated intracellular signaling pathways may differ between ligands, but no(afaik) psychedelic binds strictly to the 5ht2a receptor and then strictly activates the same cell signalling pathways as 5-HT.

I can't say I've researched all the RC's specifically, but logic would dictate that if a ligand were 5ht2a selective, and if that ligand activated the same signal transduction cascade as serotonin(not biased agonism), then that ligand could not be a psychedelic(at least not without some other action).

So the fact that they cloned a 5HT2AR for their psychlight, not the 5ht2a-mGlu2 receptor complex, and their psychlight lights up in the presence of plain ole serotonin, to me says their psychlight is detecting any and all 5ht2a agonists, but just because something is a 5ht2a agonist doesn't make it a "psychedelic" or mean it will provoke the same neurological changes as a psychedelic.


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InvisibleQM33
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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: Holybullshit]
    #27290068 - 05/02/21 10:02 AM (5 days, 5 hours ago)

Now can you put that in layman's terms?


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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: QM33] * 1
    #27290088 - 05/02/21 10:16 AM (5 days, 5 hours ago)

It seems all they have found is an non-hallucinogenic 5HT2A agonist that shows anti-depressant effects. But binding to the 5HT2A receptor does not a psychedelic make. And even once bound to the 5HT2A receptor psychadelics have a different action at that receptor than other known non-hallucinogenic ligands.

Here is a paragraph on what distinguishes lisuride from LSD.

Quote:

While lisuride has a similar receptor binding profile to the more well-known and chemically similar ergoline lysergic acid amide (LSD; N,N-diethyllysergamide) and acts as a partial agonist of the serotonin 5-HT2A receptor likewise,[5] it lacks the psychedelic effects of LSD.[1] Research suggests that the lack of psychedelic effects with lisuride arises from biased agonism of the 5-HT2A receptor. Stimulation of the 5-HT2A protomer within the 5-HT2A–mGlu2 receptor complex evokes psychedelic effects, while these effects do not occur during sole stimulation of monomeric 5-HT2A receptors. Accordingly, different G proteins are involved.[14][15] Lisuride behaves as an agonist at the 5-HT2A receptor monomer. Since it competitively antagonizes the effects of LSD, it may be regarded as a protomer antagonist of the 5-HT2A–mGluR heteromer.[16] GPCR oligomers are discrete entities and usually possess properties distinct from their parent monomeric receptors.




Lisuride is a non-hallucinogenic agonist of 5HT2A, just like AAZ-A-154, but it doesn't share the same biased agonism at the 5HT2A receptor and on top of that it actually appears to be an antagonist at the 5HT2A-mGluR heteromer.


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InvisibleQM33
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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: Holybullshit]
    #27290106 - 05/02/21 10:28 AM (5 days, 5 hours ago)

Whoa. Interesting. I'm going to be trying to keep up on this ha.
Thanks!


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Re: Non-hallucinogenic psychedelics: scientists close in on compound [Re: QM33]
    #27290129 - 05/02/21 10:41 AM (5 days, 5 hours ago)

Here, this is just from wiki, but its about the functional selectivity.

https://en.wikipedia.org/wiki/5-HT2A_receptor#Functional_selectivity

Quote:

5-HT2A-receptor ligands may differentially activate the transductional pathways (see above). Studies evaluated the activation of two effectors, PLC and PLA2, by means of their second messengers. Compounds displaying more pronounced functional selectivity are 2,5-DMA and 2C-N. The former induces IP accumulation without activating the PLA2 mediated response, while the latter elicits AA release without activating the PLC mediated response.[86]
2,5-DMA.svg 2C-N.png

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT2A agonists that produce headshakes in the mouse and those that do not, such as lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT2A agonists.[87][88] One known example of differences in signal transduction is between the two 5-HT2A agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-arrestins, more specifically arrestin beta 2.[89][90] Cyclopropylmethanamine derivatives such as (-)-19 have also been shown to act as 5-HT2A/2C agonists with functional selectivity for Gq-mediated signaling compared with β-arrestin recruitment.[91]




The bold part is especially relevant to what I have been talking about...if their "psychlight" lights up in the presence of serotonin(which it does) then it isn't detecting psychadelics(like they claim).

Now I could understand looking for a ligand with minimal capability to activate the b-arrestin signalling pathway, in hopes of avoiding hallucinogenic effects, but if that's the case to call it a "psychedelic", for me at least, it needs to retain affinity for the 5HT2A-mGluR coplex.

Because if its only binding to the 5HT2A receptor, not the receptor complex associated with psychedelic effects, and its activating the 5HT2A receptor, but not in the same way as psychedelics...what in the world makes its a "psychedelic"? The only thing it really shares in common with psychedelics is 5HT2A affinity, and the same could be said for any 5HT2A ligand, even antagonists.



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