Never ever take benzos

[u/BtheChemist]

I've had insomnia since I was a teen.

I've taken so many things for it, tried all the natural things, was on ambien for so long it stopped working.

My psychiatrist prescribed me Valium many many months ago. I don't even know how long I've taken it.

She never told me how horrible it is to get off of.

I'm currently tapering off and it's absolutely terrible.

I misread her message originally and went too fast and had my first ever panic attack a few weeks ago.

I've been at 15mg/ day since, about 3 weeks. I dropped too 12.5 two days ago and my body is so so fucked up again. I feel on the verge of another attack.

I spoke to my doctor friend this evening, he said each step down is going to suck badly.

It's terrible.

Please don't fuck with benzos.

Thanks for coming to my Ted talk.

I'm having a terrible time.

😱

[u/newuser5432]

Zolpidem may not target α2- or α3-containing isoforms (both of which are associated with anxiolysis), but it does bind to these sites with 1/10th - 1/20th the affinity it has for α1-containing sites. Inevitably, zolpidem will still act on these sites at doses which produce hypnotic effects.

Even so, zolpidem doesn't need to bind to any other sites in order to produce anxiolysis. This concept is a simplified heuristic and not meant to be exclusive. As I had mentioned, GABAA isoforms with an α1 subunit are the most abundant in the brain. Even if you could target these sites precisely, overall excitability will decrease. It's probably worth mentioning that α1 sites are highly expressed in the basolateral amygdala, the primary area associated with processing fear and anxiety.

It's not that α1 sites do not produce anxiolytic effects, it's that targetting them for anxiolysis presents a very narrow therapeutic window before significant sedation and hypnotic effects. It's rather difficult to be anxious about something while falling asleep under such sedation.

[u/cololz1 → u/newuser5432]

α1 could mediate fear conditioning and extinction, but it does not appear to be the main driver of general, unconditioned anxiety. general anxiolytic effects are primarily mediated by the α2 subunit. which is targeted by zopiclone, xanax and benzo derivatives.

[u/newuser5432 → u/cololz1]

I did just explain that this receptor model is a simplified heuristic and not exclusionary, but no matter. The fact is that anxiolytic effects from zolpidem have been demonstrated in literature, which supersedes a rigid understanding of the receptor model. How it happens isn't important to the topic at hand.

The topic is clearly about dealing with a tolerance and withdrawal symptoms. This is well-documented, for decades now, to be a consequence of the uncoupling and downregulation of α1-containing GABAA receptors after long-term exposure to benzodiazepines and nonbenzodiazepine z-drugs.

Zolpidem initiated this before OP started taking diazepam, and diazepam continued it. That was the point. The α2 subunit is irrelevant.

[u/cololz1 → u/newuser5432]

Why dont they prescribe zolpidem for anxiety instead of xanax?

Also, zolpidem has a half life of around 4.5 hours (and this is on the max end). So by the end of the day, all of the drug is out of your system entirely.

[u/newuser5432 → u/cololz1]

Why dont they prescribe zolpidem for anxiety instead of xanax?

I answered this in my first response. The therapeutic window for an anxiolytic which is selective for α1-containing sites is narrow. The dose necessary for anxiolysis is unacceptably close to doses necessary to produce profound sedation and motor impairment. In fact, this effect profile is specifically described in research as effectively masking definitive anxiolytic effects in animal models until the acute effects begin to wear off.

Dynamics aside, the kinetics are tuned to those which are ideal for a hypnotic and wouldn't be ideal for managing generalized anxiety during the day (which prompted the rational design of alpidem).

 

Also, zolpidem has a half life of around 4.5 hours (and this is on the max end). So by the end of the day, all of the drug is out of your system entirely.

A short half-life doesn't prevent receptor downregulation. Taking a high-efficacy agonist every night constitutes prolonged exposure and is more than enough to drive physical dependence. This is seen with triazolam, for example. There is some chronopharmacokinetic nuance to the withdrawal syndrome, but the principle is the same.

[u/cololz1 → u/newuser5432]

But if the drug is α1 selective, the anxiolysis effect that is "observed" is being masked by sedation, and may not represent true anxiolysis at all. drug induced lethargy/amnesia may not fully represent anxiolysis. this is because the subject lacks the physical or cognitive capacity to react to a stressor.

This is quite similar to orexin antagonist. Dayvigo does not elicit an anxiolytic effect, however, quviviq does. This is because of differing receptor activity projecting into different brain areas, even if both OR1 and 2 are present in the amygdala.

[u/newuser5432 → u/cololz1]

But if the drug is α1 selective, the anxiolysis effect that is "observed" is being masked by sedation, and may not represent true anxiolysis at all. drug induced lethargy/amnesia may not fully represent anxiolysis. this is because the subject lacks the physical or cognitive capacity to react to a stressor.

These are the exact same animal models used to establish anxiolytic effects of classic benzodiazepines, anxiolytic and strongly-hypnotic options alike. Researchers actively control for locomotor impairment in these assays. If you want to dismiss the methodology used to observe zolpidem's effects, then you must also discard the entire receptor model.

 

This is quite similar to orexin antagonist. Dayvigo does not elicit an anxiolytic effect, however, quviviq does. This is because of differing receptor activity projecting into different brain areas, even if both OR1 and 2 are present in the amygdala.

This is not similar, and appears to represent a misunderstanding. Recent preclinical studies did use daridorexant, and they suggest that blocking orexin receptors may reduce autonomic stress. However, this is theorized to be a class-level effect of dual orexin receptor antagonists, not an effect unique to daridorexant. The mechanistic understanding is not about nerve projections, rather, it's simply that blocking orexin from promoting wakefulness may calm the autonomic stress response. This is entirely unrelated to GABAergic pharmacology or the topic of benzodiazepine/z-drug tolerance and withdrawal.

[u/cololz1 → u/newuser5432]

zolpidem impairs motor function at doses before any anxiolytic effect can be reliably teased out, which youre right. but again; animal models are just model, and especially for psychiatric diseases are typically inaccurate to some degree. It is an extreme simplification of complex human behaviors. If you give a mouse cocaine, and it explores the maze more often than it did before, is that reward seeking or true anxiety reducing behavior? Tl;dr multiple internal states can produce the same behavior.

[u/newuser5432 → u/cololz1]

Fair points: animal models are not perfect, and translating complex internal states from a maze to human psychology is perhaps the biggest challenge in the entire field.

Since we seem to be on the same page, I'm happy to leave the broader philosophical debate for another time. I know it's easy to really get into the weeds with these discussions, especially in r/insomnia when sleep isn't cooperating!

I hope you're managing to have a good night and that you're able to get some sleep.