Hallucinogenic GABA agonists

[mad_scientist]

Why is it that some GABA agonists have hallucinogenic side effects?

The ones for which this is most often reported are Zopiclone, Zolpidem, Nimetazepam and Muscimol, although i've heard that Lorazepam also rarely causes these effects.

With zolpiclone and zolpidem, the sedative effect is so strong that a hallucinogenic dose almost always puts you to sleep, but if you mix them with enough strong uppers then you can stay awake and notice the trippy effects. Apparantly nimetazepam produces visuals etc at recreational doses although i've never had the chance to try it yet. And with muscimol, its cited as the active hallucinogen in Amanita muscaria mushrooms, yet its pharmacology is a pretty selective GABA-a agonist.

So does this mean that one of the GABA subtypes is capable of inducing hallucinogenic effects? And if so, would it be possible to make an agonist selective for this subtype, so the sedative effects are minimised and the hallucinogenic effect maximised? Could make for an interesting compound...

 

[swilow]

GABA is such a major neural inhibitor that to subtract the sedative effects would probably stop GABA-a agonism- the inherent nature of GABA is to reduce the firing of neurons yeah?

I ould love to see a halluciogen with inherent calming qualites- but ot dissociation.

Ibotenic acid is aloso found in A. MUsucaria, maybe that is muscimol but I'm not sure.

Why is muscaria called that if it contains no muscarine?

 

[BilZ0r]

A. Muscaria does have muscarine in it, just not enough to get you that high, before the muscimol kills you.

A. Muscaria isn't that hallucinogenic. Neither are the novel benzodiazepines.
Sure you can get hallucinogenic effects off them, but it's hardly LSD.

I mean, GABA is so important in the brain, you absolutely mess with all aspects of neural processing. So it's not surprising you get altered conciousness.

I doubt a subtype selective GABA(A) modulators/agonist could be selectively hallucinogenic and not sedatory.

 

[jasoncrest]

I think I read somewhere that the hallucinogenic effect of Zolpidem/Zopiclone/Zaleplon were not fully understood, but it may be caused by some interaction with serotonin receptors....

 

[mad_scientist]

Sure you can get hallucinogenic effects off them, but it's hardly LSD.

I mean, GABA is so important in the brain, you absolutely mess with all aspects of neural processing. So it's not surprising you get altered conciousness.

I doubt a subtype selective GABA(A) modulators/agonist could be selectively hallucinogenic and not sedatory.

If I remember correctly, at least some of the visual effects from 5HT2A agonists like LSD result from inhibition of neurons in the visual cortex that recognise the edges of objects, which is why everything moves like its liquid.

Taking LSD along with GABA agonists sometimes increases the visuals, presumably it causes increased depolarisation and inhibits those visual cortex neurons more. I'm wondering if these particular GABA agonists might be having an inhibitory effect on that same area of the brain and hence producing visuals by a similar mechanism to LSD.

Obviously as you point out, none of the GABA agonist drugs I mentioned are anywhere near as hallucinogenic as proper hallucinogens like LSD, psilocin etc, but I was more wondering if it would be possible to make new ones where this effect has been maximised. I'm sure such a drug would retain sedative effects but these could be minimised, some benzos are less sedative than others.

 

[BilZ0r]

^ No one has looked to see what LSD does to the visual cortex AFAIA.

 

[THAdream]

yeh i've found it interesting that ambien has hallucinogenic properties, considering its mechanism of action. lorazepam in high doses has produced similar visual distortions, though not to the same degree. what makes lorazepam different than other benzodiazepines pharmacologically? i wondered if there was a correlation between the GABAA receptor subtypes ambien acts on, and muscimol.

 

[mad_scientist]

^ No one has looked to see what LSD does to the visual cortex AFAIA.

Ok I looked up the references, bit more complicated than I remembered...but still I'm wondering if this same area of the brain is affected by the GABA agonists to induce visuals. Would there be binding data for different GABA agonists at the various subtypes available anywhere?


Neural Computation. 2002 Mar;14(3):473-91.
What geometric visual hallucinations tell us about the visual cortex. Bressloff PC, Cowan JD, Golubitsky M, Thomas PJ, Wiener MC.

Neuroscience and Biobehavioural Reviews. 1982 Winter;6(4):503-7.
Electrophysiological studies of d-lysergic acid diethylamide in the visual system.
Foote WE.

Neuroscience Letters. 1979 Jul;13(2):147-50.
LSD's effect on neuron populations in visual cortex gauged by transient responses of extracellular potassium evoked by optical stimuli. Connors B, Dray A, Fox P, Hilmy M, Somjen G.

 

[Helios.]

Have you looked at the structures of these "Hallucinogenic GABA agonists"? They look more like elaborate tryptamine analogues.

LSD stimulates the part of the brain responsible for "seeing the light."

 

[almost-]

Some GABA-A-agonist are also 5-HT2A-agonist. ask for reference, I'm busy right now.

So if you take them with flumazenil?

Psychedelics from the pharmacy, that doesn't sound too bad.

 

[Jamshyd]

This may be off-topic, but does anyone know Zolpidem's affinity for NMDA-receptors, if it has any? The reason I asked is that I sensed with Zolpidem a dissociative "signature" that was identical to the "signature" I sense with all the classical dissociatives.