What is the deal with Etizolam's upregulation of benzodiazepine receptors?

[Vastness]

Primary question is in the thread title - what is going on here? I have read it various places but I do not really understand fully how an agonist can have this affect.

I know there are different types of benzodiazepine receptors (subunits? someone correct my terminology if needed, please!) and the various ~benzodiazepines (for purposes of discussion I'm including thienotriazolobenzodiazepines in this class) have different binding affinities for a given set of receptor subunits. So I'm presuming that etizolam does not upregulate every receptor type that it binds to - it just happens to have this paradoxical effect on a very specific group of receptors, either as a direct consequence of the binding activity or as a result of some kind of "downstream" feedback mechanism which is harder to quantify.

Anyway, I would just love if someone could shed some light on this for me! Both in hard scientific terms of the relative binding affinities of etizolam to each receptor subunit as they compare to, say, a more classical benzo, diazepam or alprazolam perhaps - as well as, if possible, or known, which receptors are upregulated and why this happens.

Given that this weird shit happens with etizolam, is it possible that somewhere down the line in a more enlightened future of ultra-high-specificity AI-driven drug production we could have complementary benzodiazepine derivatives - for example - or perhaps even for other classes of drug - with almost perfectly opposing actions in terms of their upregulation/downregulation of the subunits of the receptor groups they exert their action at, such that we could have long term therapies alternating 2 such yin/yang variations of a similar chemical to counter the brain's tendency to try to develop tolerance to any exogenous agents?

Any answers or speculation welcome! Thanks in advance.

 

[Vastness]

No one has a clue? Usually would try not to bump, but, I'm on a bunch of benzos and I really wanna know! Hopefully there are some sciencey types online! :D

 

[vecktor]

Etizolam like all benzodiazepines is not an agonist at the orthosteric site, it is an allosteric modulator of GABA, what is known as the BZD site of the GABA A receptor. Agonists at the benzodiazepine site should be called benzodiazepine site agonists to avoid this confusion. The receptor is an ion channel and a pentamer made of 5 subunits and the exact subunits that make the receptor can vary. So the whole pharmacology is way more complex than say a GPCR receptor.

There is very limited animal data showing Etizolam causes tolerance more slowly than other benzodiazepines however this is tolerance specifically to the anticonvulsant effects which is a poor overall marker, chemical induced convulsions are dependent on the receptor that the convulsant such as pentylenetetrazole act on so changes in receptor density and sub type will effect the convulsant activity directly. There is very limited evidence that Etizolam causes a shift in the subtypes of receptor being expressed, much of the research was done by a manufacturer of Etizolam.

Etizolam is probably not very special at all, instead it is the manufacturer and drug developer trying to tell a plausible story to get the drug approved. The main advantage of etizolam over other older drugs is that it is fairly rapidly metabolized and excreted with a short half life and doesn't accumulate.
Benzodiazepines are deadly dull, dreary compounds which cause organic brain damage.

AI drug design is a device to extract money from gullable investors and burn it. Anyone who has been around the industry long enough has seen many fads come and go with not much to show for it, combichem delivered virtually nothing, fragment based discovery and HTS likewise now there is AI design and that will deliver very little too. The main issue with AI design is garbage in garbage out. The only drug discovery scheme that has consistently delivered novel drugs across many fields is natural product discovery, but that is unfashionable and expensive.

 

[Wilson Wilson]

As the above post states, there is basically no real evidence for etizolam causing less tolerance than any normal benzo. There was one study claiming it has reverse tolerance that came from Italy - where etizolam is a scripted drug - and I'm pretty sure that research was funded by a pharma company selling the stuff.

Independent research has not replicated those results because it's frankly bollocks. I like etizolam but the fact is it causes just as much tolerance as any normal benzo and the fact it's a thieno doesn't really change much at all about its mechanism of action. It is for all intents and purposes a benzo.

If you look at the etiz threads here on BL you will see people taking insane doses like 10mg or even 20mg of etizolam even if it's the only GABAergic drug they use. Reverse tolerance my arse.

 

[Vastness]

Wow, that's eye opening for sure! Guess I'm kidding myself also hoping for some kind of benzo-like drug I can take a few times a week for sleep or recreation without worrying about creeping tolerance effects... the short duration is a plus though I'd say, and it is subjectively quite enjoyable, moreso than say, diazepam, but not overly impulsive making (like xanax which I just cannot take for that reason).

Benzodiazepines are deadly dull, dreary compounds which cause organic brain damage.

Care to elaborate on this point? I thought this was somewhat up for debate.

How does this "brain damage" compare to alcohol, or other GABAergics, for example?

I often wonder if I view benzos with an unwarranted degree of wariness compared to, for example, beer. If I had 3 beers 2 nights in a row, this would be a rarity for me but I wouldn't think too much of it. On the other hand if I had 30mg diazepam, 3mg etizolam, whatever, 2 nights in a row, I'd be starting to worry about tolerance, dependence, and all that sort of negative stuff... but some of this is just drug hypochondria, surely?

 

[Wilson Wilson]

With the brain damage thing, there are studies showing that high doses (abuse level) can indeed cause a level of damage, but therapeutic doses have been shown in multiple studies over time to be fine. So unless you're on a full on bartard there's no reason benzos would cause brain damage.

As with any other drug moderation is key.

Now as for a future effective anxiolytics with less tolerance and dependence than benzos, this is still very much possible, but etizolam just ain't it. Multiple drugs are being investigated for exactly this purpose since there's a big economic incentive to do so. How recreational they end up being is yet to be seen but will be worked out very quickly once docs start handing out scripts I'm sure.

List of investigational anxiolytics - Wikipedia

en.wikipedia.org

 

[polymath]

How does this "brain damage" compare to alcohol, or other GABAergics, for example?

I think it can safely be called brain damage if the PAWS from using some drug is so bad that you're never really back to normal after quitting long term high-dose use. And experiencing the withdrawal on the street or in jail without proper treatment can actually cause the kind of excitotoxic damage that impairs your cognition permanently. Also, it's possible to get a post-traumatic stress syndrome as a result.

The "anxioselective" benzo-like compounds that only bind to alpha2 and alpha3 subunit containing GABA receptors don't seem to cause a physical dependence, but they did cause euphoria as a side effect more often than placebo in some clinical test I read.

 

[checktest]

As vecktor indicated, the claims of etizolam reverse tolerance may not be fully matched by clinical reality. Reports of abuse and dependence are still there, as well as withdrawal syndromes. Particular research models don't stand in fully for what actually happens.

Similarly, some of the early biased opioid agonists were still found to have significant abuse liability.

Betteridge's law of headlines can apply to some research as well

Can oliceridine (TRV130), an ideal novel µ receptor G protein pathway selective (µ-GPS) modulator, provide analgesia without opioid-related adverse reactions?

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to µ opioid receptor ...

www.ncbi.nlm.nih.gov

Abuse Potential of Biased Mu Opioid Receptor Agonists

G protein-biased mu opioid receptor (GPB-MOR) agonists constitute an emerging class of opioid analgesics. The first-in-class GPB-MOR agonist TRV130 (o…

www.sciencedirect.com

Theoretically [blatant speculation ahead] there could be some kind of biased agonism analog (since it is a PAM) / functional selectivity (I guess a selective PAM, though as it is an ionotropic receptor GABA-AR wouldn't be linked /operate in the same way like a GPCR would ) or particular binding populations related to subunit affinity that lead to less tolerance. E.g. preferential binding to some complexes a2b2g2 that build tolerance more slowly than say a1b2g2. Extrasynaptic / particular locations more prone to tolerance mechanisms. It isn't immediately obvious how modified chloride gradients would have similar selectivity mechanisms to, say different g-proteins with GPCR, b-arrestin or whatever. Perhaps co-receptors and localized receptors like glycine receptors, or the anchoring proteins like gephyrin are somehow altered. Exact BZD binding site changes could cause some structural variation.

Equally, perhaps there is some other channel / mechanism that isn't captured as well. Some strange orphan receptor or calcium channel action that modifies the GABA response. Like diazepam with PDE.

Personally skeptical of etizolam's claims. Maybe some of the partial /mixed PAMs like imidazenil could have better profiles, but full PAM not so sure.

Recent structural papers could bring more insight.

GABAA receptor signalling mechanisms revealed by structural pharmacology - PubMed

Type-A γ-aminobutyric (GABA_A) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without...

www.ncbi.nlm.nih.gov

Cryo-electron microscopy reveals informative details of GABAA receptor structural pharmacology: implications for drug discovery

www.ncbi.nlm.nih.gov

Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin

γ-Aminobutyric acid type A receptors (GABA[A] Rs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABA[A] Rs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled ...

www.ncbi.nlm.nih.gov

Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer - PubMed

Type A γ-aminobutyric acid (GABA_A) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system^1,2. Their dysfunction is implicated in a range of neurological disorders, including depression...

www.ncbi.nlm.nih.gov

Edit: Additional GABA/GABAR review papers (some older) and some relevant neurons
doi.org/10.1152/physrev.00015.2010
doi.org/10.1152/physrev.00017.2006
doi.org/10.1152/physrev.00007.2017

 

[Vastness]

Quite a bit to digest here, thank you everyone who posted, but just briefly:

The "anxioselective" benzo-like compounds that only bind to alpha2 and alpha3 subunit containing GABA receptors don't seem to cause a physical dependence, but they did cause euphoria as a side effect more often than placebo in some clinical test I read.

Would pyrazolam be one of these, or if not, which ones?

I always get a kick out of "euphoria" being listed as a side effect although I guess it's technically correct.

 

[Tryptamite]

What's the one professor David nut was hoping could be an alternatI've to ethanol in alcoholic beverages

 

[S.J.B.]

What's the one professor David nut was hoping could be an alternatI've to ethanol in alcoholic beverages

That was 5-methoxy-2-aminoindane.

 

[LucidSDreamr]

What's the one professor David nut was hoping could be an alternatI've to ethanol in alcoholic beverages

anything that doesn't have as brutal a hangover as alcohol, would be too addictive i think. Alcohol is a bit easier not to get addicted to because of how severely you get punished they day after using it.

 

[vecktor]

What's the one professor David nut was hoping could be an alternatI've to ethanol in alcoholic beverages

I believe it was Bretazenil that Nutt originally investigated and was trialed a few times in humans, using grant money and then dropped it when the free money dried up.

It then seems that he worked with Ezekiel Golan, Dr Zee, on the indan MEAI (5-methoxy-2-aminoindane or 5-MeO-AI or Chaperon, then parted ways, I wonder why? maybe Nutt didn't want to own Golans bodycount.
Golan then has tried to market the indan as Pace in the USA and Canada.

see https://undark.org/2019/04/03/binge-drinking-chemical-drugs/

What mysterious compound Nutt is now calling alcarelle is anyones guess, its probably not even worth wasting time trying to figure it out.
Alcarelle holdings, Nutts business entity that was supposed to develop alcohol replacements has skirted wipeout and seems it is going nowhere. The filed patent applications are still unpublished and probably will time out.

I don't generally bother to follow anything involving Nutt, it is quicker and more accurate to directly read stuff written by his owners.

 

[Wilson Wilson]

What's the one professor David nut was hoping could be an alternatI've to ethanol in alcoholic beverages

David Nutt has patented something like 100 different chemicals and is actively studying two right now as of the latest media reports. He moved away from benzo analogues and is looking at other GABAergics instead.

He's conducting the research through a private company run by him and a bunch of scientists, and since he's looking to profit from the end product he's being a bit secretive on exactly what chemical he's developing for release.

Here's the website of his company if you're curious:

About – ALCARELLE

Alcarelle - our aims Great things happen when we relax and socialise with our friends, family and community. And having a drink together is part of our social c

alcarelle.com

 

[Tryptamite]

I was thinking of non-benzo z drug pagoclone

Pagoclone - Wikipedia

en.m.wikipedia.org

 

[Wilson Wilson]

I was thinking of non-benzo z drug pagoclone

Pagoclone - Wikipedia

en.m.wikipedia.org

I think this is one of the ones he moved away from for primarily this reason:

The abuse potential of pagoclone has been assessed as being similar to, or slightly less than that of diazepam and it would also be expected to be somewhat safer due to its relatively weaker sedative effects, but development of pagoclone as a commercial drug would still be unlikely due to concerns about abuse.

Note that the study used as a source in the Wiki article is from 2005.

Wouldn't mind trying that stuff if it ever popped up on the RC market though.

 

[Tryptamite]

I believe I have seen it for sale. Possibly in kg amounts from China but also through more "typical" clearnet rc vendors.

I would try it too.

Apparently one specific sub unit of gaba a (say a3) I's responsible for alcohol addiction. I think it surely must be more than that as alcohol affects more than just gaba a.

 

[Wilson Wilson]

I believe I have seen it for sale. Possibly in kg amounts from China but also through more "typical" clearnet rc vendors.

I would try it too.

Apparently one specific sub unit of gaba a (say a3) I's responsible for alcohol addiction. I think it surely must be more than that as alcohol affects more than just gaba a.

Interesting...

And yeah I am highly sceptical that one single GABA subreceptor is responsible for alcohol addiction. Since the withdrawal from alcohol is similar to benzos GABA definitely plays a part, but the mechanism of action is far more complex with it also affecting serotonin via 5-HT3, being an NMDA antagonist, acting as a calcium channel blocker like pregabalin, and increasing dopamine, endorphins, and a shitload more things.

The pharmacology of ethanol is not actually fully understood yet despite being widely used for so long but it's a very "dirty" drug that hits a lot of receptors. This is why it can be said with so much confidence, in fact I'm pretty sure Prof Nutt said so himself, that if alcohol was invented today it'd be a Class A drug. Only reason it's legal is social acceptability in Western cultures, not safety profile. Likewise the only reason opium and cannabis are illegal is because they are associated with foreign cultures (opiates, of course, do have risks, but opium was not initially made illegal in the US, UK, Canada, Australia, etc on that basis - indeed, Britain was happy to go to war with China twice to keep selling it opium, and back home opium, morphine, heroin were OTC at any pharmacy).

Demonstrates just how arbitrary drug laws are. 100% political.

 

[copium7777]

Pretty sure that it's not true. Etizolam seems to cause tolerance or maintain it for me at least.

 

[dopamimetic]

I believe I have seen it for sale. Possibly in kg amounts from China but also through more "typical" clearnet rc vendors.

Yeah, tried it some time ago ... honestly I found it pretty boring, but so are benzos and booze too so guess I am the wrong person for this. More clear than either of them though, more like a benzo that doesn't impair cognition or sedate so much.. Had a nonlinear dose-response curve and blacking out is apparently possible, as reports of others suggest. The pure substance seems to be of pink color.

There's another benzo mimetic of which I unfortunately don't recall the name, think it was like "-faxine", that is supposed to induce less tolerance than usual for the price of having a slight possibility of being toxic to the liver. I'll post the name when I find it.

Have personal experience with pregabaline, over at least 3 months (maybe too less of time though for real conclusion), higher-than-recommended 900mg and it was very easy to discontinue gradually. I would chose that for getting off benzos.

Edit: It's called Etifoxine.

Studies suggest is as effective as lorazepam as an anxiolytic, but has fewer side effects.[7]

Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxietylike behaviors. The non-benzodiazepine anxiolytic compound etifoxine (...) is devoid of benzodiazepine-related side effects, such as sedation, amnesia, myorelaxation, tolerance and dependence [9-12] (...)

Source here.