4 replies to this topic

[Galaxyshock]

Are there any GABAB PAMs available? So they would work like benzos but at the metabotropic GABAB receptors instead of GABAA.

 

A quick search reveals that GABAB is a new target for drugs to treat addictions to alcohol etc. but I wonder if they are also possibly superior anxiolytics compared to GABAA ligands. I've always responded better to GABAB agonists like Phenibut, Gotu Kola and Ashwagandha. Benzos surely work for me too but tolerance comes quite quickly and they aren't as practical as GABAB ligands to use as "day-time tranquilizers". Tolerance and possible withdrawals are of course a concern if taking any strong GABAergics but I'm thinking only using them as needed and possibly switching between GABA A and B ligands could be a way to avoid tolerance.

 

Of the herbals, I suspect Licorice could be a GABAB ligand, but possibly just an agonist instead of being a positive allosteric modulator. I'll have to research more.

[Galaxyshock]

Wikipedia GABAB receptor page lists a few PAMs but they are all research compounds:

 

PositiveAllosteric Modulators
CGP-7930[20][21]
BHFF
Fendiline
BHF-177[22]
BSPP
GS-39783[23]

→ source (external link)

 

No surprise that some of them have shown to potentiate direct agonists like Baclofen.

[Daniel Cooper]

Unfortunately I suspect that anything that works on any neuroreceptor as an agonist or PAM is potentially and even likely to build tolerance. 

 

Tolerance to phenibut is widely reported and the withdrawals from that drug are notoriously wicked, so GABAB seems as problematic in this regards as GABAA.

 

It seems like all these types of drugs have been something of a fool's errand. Maybe down the road gene editing will be able to permanently fix someone with intractable anxiety or depression. But the older I get the more I conclude that these psych pills we have today just don't work long term.

 

 

Edited by Daniel Cooper, 21 February 2024 - 04:06 PM.

[Galaxyshock]

Unfortunately I suspect that anything that works on any neuroreceptor as an agonist or PAM is potentially and even likely to build tolerance. 

 

Tolerance to phenibut is widely reported and the withdrawals from that drug are notoriously wicked, so GABAB seems as problematic in this regards as GABAA.

 

It seems like all these types of drugs have been something of a fool's errand. Maybe down the road gene editing will be able to permanently fix someone with intractable anxiety or depression. But the older I get the more I conclude that these psych pills we have today just don't work long term.

 

I agree Phenibut is a rollercoaster to brutal withdrawals if taken daily. But there's something wierd about the metabotropic GABAB receptor - Phenibut and GHB are addictive agonist of the receptor yet something like Baclofen (pure GABAB-agonist) is in fact anti-addictive. Perhaps it's the other effects of those drugs - Phenibut is also a gabapentinoid and GHB of course also agonizes the GHB receptor - that make them problematic. They are rewarding which can be nice to those of us who have anhedonia, but are they really therapeutic well that's another question.

 

Good that this was brought up anyways, my hunch is that a GABAB PAM probably would be somewhat addictive similar to benzodiazepines, but also my thinking is that perhaps a protocol of taking a GABAA PAM something like twice a week and a GABAB PAM similarly twice a week would leave the person without much of a dependency, tolerance or craving to take more. But I do not know about cross-tolerance and of course GABAB PAMs are poorly studied field but an interesting idea to people suffering from general anxiety.

 

Yeah psych drugs can seem like a dead-end, but I try to remain optimistic some protocols can be invented that in fact work yet don't get the patient in trouble. 

[Galaxyshock]

Unfortunately I suspect that anything that works on any neuroreceptor as an agonist or PAM is potentially and even likely to build tolerance. 

 

I think this is only partially true, some receptors don't respond that way. I remember reading that in ADHD treatment, the dopamine D4 receptor does not downregulate in response to the medications and some of the therapeutic effects don't disappear because of that reason. Actually I found a study to support this claim.

 

Another wierd thing about the GABA-B receptor is that both agonists and antagonists of the receptor show antidepressant properties.