• Bluelight HOT THREADS
  • Let's Welcome Our NEW MEMBERS!

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

Vastness

Moderator: PD
Staff member
Joined
Mar 10, 2006
Messages
1,384
Location
iterating through cyclic eternities
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.
 

vecktor

Bluelight Crew
Joined
Jan 17, 2006
Messages
2,003
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

Moderator: BDD, OD
Staff member
Joined
Aug 6, 2014
Messages
2,191
Location
LDN, UK
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

Moderator: PD
Staff member
Joined
Mar 10, 2006
Messages
1,384
Location
iterating through cyclic eternities
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).

vektor said:
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

Moderator: BDD, OD
Staff member
Joined
Aug 6, 2014
Messages
2,191
Location
LDN, UK
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.

 

polymath

Bluelight Crew
Joined
Nov 4, 2010
Messages
1,422
Location
Northern Europe
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

Bluelighter
Joined
Jun 9, 2013
Messages
166
Location
The Aether
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

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.




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
 
Last edited:

Vastness

Moderator: PD
Staff member
Joined
Mar 10, 2006
Messages
1,384
Location
iterating through cyclic eternities
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. 😄
 
Top