GABA receptors and Sedative/Hypnotics ("Sleep Meds")

[BilZ0r]

Have you tried busprione?

Also, if we were to believe some researchers, we might think that anxiety was a hippocampal thing, so alpha5beta3gamma2/3 selective benzos would be good, but they would also be very amnesic.

 

[Dope_User]

No, I haven't...and I wasn't really looking for anything (anxiolytic med) to try, I was just merely interested in whether or not (and how) a potent anxiolytic benzo could be made that lacked most, if not all, of the sedative/hypnotic properties common to most benzos. Originally, I was interested in getting information about Lunesta, as I was considering giving that a try to for my insomnia, but then the thread topic kinda of changed to be more about the mechanisms of action of benzos and many aspects of the GABA system (including what effects "tinkering" with it will have).

Here's a new question for you:
What is a relatively long-lasting benzodiazepine which is mainly an anxiolytic and has the least sedative/hypnotic properties?
Conditions:
1. It has to be available for Rx in the US.
2. Don't say Klonopin/clonazepam (I've tried it and it doesn't have a strong enough anxiolytic effect and it is a little bit too sedating for me; although not extremely sedating.).
3. Comments on Valium/diazepam are welcome (I'm under the impression this is now mainly Rx'd as a muscle relaxant and I'm not sure how strong of an anxiolytic effect it has in comparison to "newer" benzos. I also know nothing about how sedating it is.).
4. Xanax, for me, is the best anxiolytic benzo with the least amount of sedation; therefore, Xanax XR seems like it would be exactly what I'm looking forward. Please comment and let me know if you agree. Unfortunately, I find it HIGHLY unlikely that my psychiatrist will switch my Klonopin Rx to Xanax XR but this will be what I ask for first.
5. Lastly, what would you consider most similar in terms of high anxiolytic effect/low sedative effect and (relatively) long half-life to Xanax XR (when my Dr. says he won't Rx it)?

Again, feel free to ask for any clarification on what exactly I'm looking for here...thanks.

 

[Vaya]

Xanax XR was good at what it did for me, but strung out a bit more sedation over a much longer period of time and became a problem for me, so I switched to Xanax instant release which works a lot more effectively, although it does not have a long half-life.

Aside from this, Xanax XR is looked favorably upon by many psychiatrists due to the cutting edge nature of its anti-abuse time release formula. I think you'd have no problem switching from an instant release benzo to Xanax XR.

 

[Dope_User]

Thing is, I take Klonopin 1 mg twice daily AS NEEDED. I was on it for awhile daily (for probably just less than a month while waiting for other psychiactri drugs to "kick in"). My Rx is almost gone (no refills left) and I'm sure my Dr. would have no problem writing another script for it...although I think he might wonder why I wanted to switch and asking for "Xanax XR" by name, I have a feeling the Dr. would just hear "Xanax" and associate it with abuse as I've never actually been prescribed Xanax (in any form) before.

Thing is, I just started my Spring semester at school. I went to school last fall but took off one semester before that and the semester before that, I ended up withdrawing from school due to severe depression, GAD, panic disorder, insomina, and later found out I was bipolar...gotta go shovel snow (expected up to 2 FEET in Northern NJ) so I'll edit this is a a bit.

 

[BilZ0r]

Is it just because of curiosity that your limiting this to benzos?

 

[Vaya]

gotta go shovel snow (expected up to 2 FEET in Northern NJ) so I'll edit this is a a bit.

Philadelphia, here. I feel your pain

 

[Dope_User]

No BilZ0r, feel free to add comments/information about ANY drug, I personally just don't know of any other than benzos ('cept for a few sleep aids, Ambien, Sonata) that have any affects of the GABA system. So whatever you were think, please do share. I already take 60 mg Cymbalta/day and 300 mg Lamicatal/day for depression and hypomania, respectively (diagnosed as bipolar with anxiety)...and I only take the Klonopin as needed and I have an Rx for ProSom/estazolam 2 mg pills (2 per night) but that takes too long to kick in and lasts too long...don't sleep well at all with 2 mg, and if I take 4 mg, it still takes 4 hours to fall asleep then I don't wake up for 12+ hours. Specifically asked my psychiatrist, "Is there anything like ProSom that kicks in faster and wears off sooner?" Asked twice, at two different appointments actually and he said "No" both times. Once he said I could try Doral (another older benzo, forget generic name) but it seemed to have a similar time of onset and half life, so I figured I wouldn't bother. I figured asking for Halcion might make me sound like a druggie...but then again, I may just bring in that Benzo Comparison Chart...'cept it doesn't have ProSom/estazolam on it. It be great if someone had a very detailed comparison chart of just the sedative/hypnotic benzos, relative strengths, time of onset, time to peak plasma concentrations, half-life, average duration of action, main use (obviously sedative/hypnotic) as well as other uses (anxiolytic, myorelaxant, anti-convulsant), etc. Anyone have a chart like that - or at least a benzo comparison chart that has estazolam on it? Thanks.

 

[5-HT2]

On the topic of benzos, is it likely that halcion binds to or has effects on opiate receptors as well as GABA(A) receptors? This is something I often hear as an explanation of its high abuse potential. But I keep hearing different things from different people, and haven't bothered to look into the literature myself.

 

[5-HT2]

[VERY USEFUL AND INFORMATIVE STATEMENTS REMOVED BY A STUPID PARANOID MODERATOR]

Thanks again 5-HT2

^^^Hmmmm, I thought it was constructive criticism. Next time I'll try to frame it more politely and professionally instead of saying it informally the way I would to my collegaues in my lab In any case, you reposted the information most germane to the topic of this thread

 

[BilZ0r]

Didn't you get my text explaining why I did that?
Well it should be that the shorter half life benzos, and faster absorbed ones, are the ones with the most addiction liability...

And I can't find any reference that supports the idea that triazolam binds to opioid receptor... that just sounds a little silly to me...

 

[5-HT2]

^^^Sorry man, didn't check my PM's when I got on and made that post.

I always thought the halcion/opioid receptor story was somewhat of an urban legend…you hear it quite often in psychiatry/neuroscience circles though…

Here is another reference supporting alpha3 involvement in the pathophysiology of seizures:

Dynamic GABA(A) receptor subtype-specific modulation of the synchrony and duration of thalamic oscillations. Sohal VS, Keist R, Rudolph U, Huguenard JR. J Neurosci. 2003 May 1;23(9):3649-57.

 

[BilZ0r]

Oscillations eh... a PhD student in my lab cracks wood whenever he sees spontaneous or 4-AP induces oscillations in my patch-clamp recordings... that shit is a little intense for me...

 

[Dope_User]

I've heard the Halcion/Opiate Receptor "Legend" as well yet have NEVER found anything to back that up...probably because it just isn't true. Like BilZ0r said, Halcion has an extremely rapid onset of action and extremely short half life. This are too properties that will most likely make a drug more addictive or have a high abuse potential when compared to other drugs in the same class. Halcion is also quite potent when compare to other benzos, mg for mg (I've seen 1 mg triazolam is comparable to 2 mg of Xanax making it the most 'potent' benzo I'm aware of), although I don't think this necessary has any effect on it's high abuse potential. I'll make a comparison with heroin and fentanyl; fentanyl is much more potent mg for mg than heroin yet most prefer heroin. I wonder if the abuse potential of Halcion has anything to do with it being a sedative benzo. Isn't Rohypnol also marketed as a sedative benzo? I wonder if it's something about the sedative/hypnotic benzos that make people seem to prefer them over others...although if I had to guess, I'd think the more anxiolytic benzos would be the most prefered. Calling benzos "euphoric" is also a questionable statement, but I wouldn't really consider anything that makes me fall asleep (sedative/hypnotic) or prevents seizures (anti-convulsant) "euphoric." On the other hand, I really do enjoy the anti-anxiety (anxiolytic) properties of benzos and possibly even the myorelaxant properties could add to the "euphoria" of benzos...I just wonder why some of the sedative/hypnotic benzos are enjoyed by so many or have such high abuse potential, like I said, I would have guessed it would have been the anxiolytics (like Xanax). Anyone know why this may be?

EDIT: Are there any drugs that act on any opiate receptors as well as on any GABA receptors? What's ketamine mainly act on, any GABA receptors (I just saw a post a month or two ago about ketamine having some affinity for an opiate receptor, I believe the mu receptor)?

 

[BilZ0r]

ketamine is an NMDA receptors non-competative antagonist... I think it has some affinity for simga-1 opioid receptor, which I don't think they couknt as an opioid receptor anymore...

 

[Dope_User]

BilZ0r, is it the NMDA antagonism of ketamine that causes it's "euphoric" effects? I mean, there are plenty of non-euphoric NMDA antagonists out there...such as Lamictal (lamotrigine, sp?), the anti-convulsant/Bipolar med.

 

[who mE?]

Not to hijack the thread, but Ketamine is widely reported to bind to Kappa opioid receptors, and there are several reports of mu-agonism... Please do a search for a thread titled "Ketamine the Opioid" in Other Drugs by myself.

And on the subject of GABA mediated euphoria, I personally find SOME benzos to be moderately (more than mild, less than strongly) euphoric, for example Lorazepam, Alprazolam, and Diazepam, though not Midazolam or Clonazepam.

I also personally find GHB and its analogues EXTREMELY euphoric (on par with MDMA or oxycodone), and read several abstracts on The Hive (R.I.P.) regarding the idea that its euphoria was GABA-B mediated. Several reputable sources say that the "GHB receptor" is dysphoric and is pro-convulsant (although that hasn't stopped shady R.C. scammers from trying to shill GHB receptor agonists such as Hydroxy-Crotonic Acid and analogs...

I would LOVE to personally taste test a non-toxic GABA-B agonist, because I think it might just be my idea of "the perfect drug". (I know this idea probably seems silly to Bilz0r, whose statements about the fallacy of predicting effects by receptor activation I respect and am interested in reading more of)

 

[5-HT2]

Not to hijack the thread, but Ketamine is widely reported to bind to Kappa opioid receptors, and there are several reports of mu-agonism... Please do a search for a thread titled "Ketamine the Opioid" in Other Drugs by myself.

I am also intrigued by ketamine's kappa-opioid activity as I find it similar in some respects to salvia divinorum, and Salvinorin A is a potent kappa-opioid receptor agonist. Still, I would bet that its primary psychopharmacological activity is due to NMDA receptor antagonism.

I also personally find GHB and its analogues EXTREMELY euphoric (on par with MDMA or oxycodone), and read several abstracts on The Hive (R.I.P.) regarding the idea that its euphoria was GABA-B mediated.

Yeah, GHB binds to the GABA-B receptor. It also appears to bind to other sites in brain, which have been called "GHB receptors" by some, though their molecular identity is not known. Baclofen, a selective GABA-B agonist, has been reported to cause euphoria in primates, including humans.

Several reputable sources say that the "GHB receptor" is dysphoric and is pro-convulsant

Well, I don't know about the dysphoria part, but it is definitely pro-convulsant. I personally believe the pro-epileptic actions of GHB and its relatives on both convulsant and non-convulsive seizures contribute to the safety issues with it. In particular, the behavioral effects of a dose of GBL that induces nonconvulsive seizures in rodents appear to be similar to the so-called "g-coma" that humans go into upon overdosing on a nonconvulsant dose GHB.

I would LOVE to personally taste test a non-toxic GABA-B agonist, because I think it might just be my idea of "the perfect drug".

Try some baclofen, you might like it 8)

 

[BilZ0r]

The molecular identy of the GHB is known. PMID 12958178

Still, I'm very dubious of this idea that the GHB receptor is dysphoric, or more, that its part to play in GHBs effect is pointless... anyone who says that, needs to compare baclofen to GHB, and it will be blatently obvious. Sure some people find baclofen a little fun, but it's not GHB.

But isn't GHBs "pro-seizure" effect ... I mean, it's absence seizure, not tonic-clonic seizures.... baclofen does the same thing.

Now GHB receptor specific ligands increase glutamate in dialysates of the hippocampus, so that makes me nervous and actual honest-to-god seizures.


Anyway, as far as this whole, ketamine opioid thing goes, as far as I'm awear, there is only one study which looks at that (here), now I would have liked it if they had done the experiment and shown a negative result.. "Racemic ketamine inhibited the formation of cyclic adenosine monophosphate (naloxone insensitive) in a dose-dependent manner (concentration producing 50% inhibition approximately 2 mM) in all cell lines, including untransfected CHO cells" makes me very nervous. Finally, even if we assume they are correct, these affinities are around 40, 30, 270µM (mu, kappa, delta) respectively, in comparison to its 900nM NMDA affinity... i.e. they're about 100x too weak.

 

[5-HT2]

The molecular identy of the GHB is known. PMID 12958178

I stand corrected (I hadn't seen any mention of this finding in any of the previously published reviews and articles on GHB action that I've read). However, the endogenous ligand for these GHB receptors is uncertain, though it could possibly be GHB itself.

Still, I'm very dubious of this idea that the GHB receptor is dysphoric, or more, that its part to play in GHBs effect is pointless... anyone who says that, needs to compare baclofen to GHB, and it will be blatently obvious. Sure some people find baclofen a little fun, but it's not GHB.

Never tried baclofen, so I wouldn't know, but I believe you.

But isn't GHBs "pro-seizure" effect ... I mean, it's absence seizure, not tonic-clonic seizures....

GHB is used to pharmacologically model absence in rodents. I do not think it is used to model other types of epilepsy. However, large overdoses in humans can cause convulsions; I have seen it with my own eyes. Perhaps I should test what a high dose of GBL would do to a mouse…
I believe that drug-induced seizures form a continuum, with absence-like seizures at one end and tonic-clonic status epilepticus at the other.

baclofen does the same thing.

Does baclofen do the same thing as GHB? I don't think it is widely (if at all) used to pharmacologically model absence.

Anyway, as far as this whole, ketamine opioid thing goes, as far as I'm awear, there is only one study which looks at that (here), now I would have liked it if they had done the experiment and shown a negative result.. "Racemic ketamine inhibited the formation of cyclic adenosine monophosphate (naloxone insensitive) in a dose-dependent manner (concentration producing 50% inhibition approximately 2 mM) in all cell lines, including untransfected CHO cells" makes me very nervous. Finally, even if we assume they are correct, these affinities are around 40, 30, 270µM (mu, kappa, delta) respectively, in comparison to its 900nM NMDA affinity... i.e. they're about 100x too weak. [/B]

Well I've never looked at the literature myself, but from what you've presented here, it seems that the ketamine/kappa-opioid connection must be yet another internet drug myth.

 

[BilZ0r]

Does baclofen do the same thing as GHB? I don't think it is widely (if at all) used to pharmacologically model absence.

Ah, you're right, baclofen just prolongs, or worsens experimentally induced absence...