Hallucinations and Visual Disturbances?

[nAON]

Hey, I was curious if anyone had any info regarding the neuroscience of tripping. I'm aware of the pharmacology of drugs that interfere with vision, but this doesn't really give any info regarding the processes that underlie it, eg. in the visual cortex. Anyone got some vague insight?

 

[serotonin2A]

There have been a few attempts to model the visual effects of serotonergic hallucinogens. It appears that the geometric form constants people see are produced in primary visual cortex. That region of the brain is unstable, and if you increase the spontaneous activity past a certain level then the network of cells becomes destabilized, resulting in spontaneous patterns of neuronal fring that correspond to the form constants. The models do not explain all aspects of the geometric hallucinations but the results are still pretty impressive.

There are upwards of 10 studies you can find about this, but here are two of the most important ones:
http://www.ncbi.nlm.nih.gov/pubmed/486593

http://www.ncbi.nlm.nih.gov/pubmed/11860679

The geometric hallucinations are a more general phenomenon (they can be induced by epilepsy, migraine, flickering light, etc) and other papers have tried to model them in those specific contexts.

No one is really sure what causes visual hallucinations that are more scenic/complex. But one possibility is that higher-level visual areas are destabilized by the same mechanism. These would be areas that process things like form, spatial relationships, object recognition, motion, visual memories, and integrate visual and non-visual perception. Hallucinogens have been shown to alter the orientation tuning (i.e, the specific stimuli they respond to) of some cells in visual cortex. It's not too difficult to imagine what would happen if something similar occurs in cells that respond to faces.

 

[nAON]

Cheers for the links, will give them a read.

Regarding complex scenes - I was reading recently about cortical feedback and predictive coding, whereby a topdown signal of what's 'expected' from the visual scene is fed into early visual cortex, and the signal sent upstream is just the error mismatch rather than actual retinal input. Perhaps this process can be disrupted, wrong signal sent down and error not computed?

Would be interesting to know how such a range of pharmas, ie. opiates, NMDA-blockers, anticholinergics, dopaminergics, etc. can all induce hallucinations and whether it's via a similar mechanism or not.

p.s. don't have access to the 2nd link, any chance you could re-up the pdf?

 

[Zilpe]

If I had to hazard a guess I'd say that the visual disturbances found with psychedelics are caused by an upset in the systems governing perception (visual cortex). Whereas the type of hallucination found in something like schizophrenia is a disorder of cognition. For example thinking you're talking to someone when there's noone in the room indiciates a pretty severe disturbance in the understanding of your surroundings, requiring your brain to actually construct an independent theory of mind to simulate a conversational partner, whereas seeing the wall breath seems more like a failure to integrate sensory data appropriately. This distinction is clearly seen by how people react to hallucinations.

 

[serotonin2A]

Cheers for the links, will give them a read.

Regarding complex scenes - I was reading recently about cortical feedback and predictive coding, whereby a topdown signal of what's 'expected' from the visual scene is fed into early visual cortex, and the signal sent upstream is just the error mismatch rather than actual retinal input. Perhaps this process can be disrupted, wrong signal sent down and error not computed?

Would be interesting to know how such a range of pharmas, ie. opiates, NMDA-blockers, anticholinergics, dopaminergics, etc. can all induce hallucinations and whether it's via a similar mechanism or not.

p.s. don't have access to the 2nd link, any chance you could re-up the pdf?

There is no reason to assume at this point that the complex hallucinations produced by serotonergic hallucinogens are identical to the effects of anticholinergics, dopaminergics, NMDA antagonists, etc.

I'll try to post the second PDF.

Top down effects probably contribute but they have many more functions than just predictive coding. They play a major role in controlling activity in association cortices.

 

[nAON]

If I had to hazard a guess I'd say that the visual disturbances found with psychedelics are caused by an upset in the systems governing perception (visual cortex). Whereas the type of hallucination found in something like schizophrenia is a disorder of cognition. For example thinking you're talking to someone when there's noone in the room indiciates a pretty severe disturbance in the understanding of your surroundings, requiring your brain to actually construct an independent theory of mind to simulate a conversational partner, whereas seeing the wall breath seems more like a failure to integrate sensory data appropriately. This distinction is clearly seen by how people react to hallucinations.

Funny you mention that - one of the key measurable symptoms of schizophrenia seems to be problems in perceptual organization, ie. integration of information in the visual cortex combined with shitty top-down (attention etc.) (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122298/)

How this links to higher cortex function, hallucinating coherent conversations etc., im not sure.

 

[nAON]

There is no reason to assume at this point that the complex hallucinations produced by serotonergic hallucinogens are identical to the effects of anticholinergics, dopaminergics, NMDA antagonists, etc.

I'll try to post the second PDF.

Top down effects probably contribute but they have many more functions than just predictive coding. They play a major role in controlling activity in association cortices.

Ah, I meant them separately - I think serotonergic hallucinations seem to be a pretty distinct group, with the geometric patterns, whereas the others I listed seem to be more 'reality bending' hallucinations, when you start seeing scenes that aren't there rather than just an overlay.

 

[nAON]

Did some more reading into 5HT-2A, and one paper summarised the effects as inhibition of neurones with high firing rates, and excitation of spontaneously-firing neurones in V1.

Though there's also that whole business of 5-HT2A linking with mGlu2, and I wonder if this gets involved with long-range glutamatergic signalling across visualcortex rather than just spontaneous patterns occuring low-level?

 

[rolodex propaganda]

Did some more reading into 5HT-2A, and one paper summarised the effects as inhibition of neurones with high firing rates, and excitation of spontaneously-firing neurones in V1.

Though there's also that whole business of 5-HT2A linking with mGlu2, and I wonder if this gets involved with long-range glutamatergic signalling across visualcortex rather than just spontaneous patterns occuring low-level?

It is worth noting human neuroimaging can present images very similar to what is seen in CEVs. Thought identification is a very new interesting field of study. Images are recreated from thoughts using technology like MRI.

I don't think this is the case but can't rule it out, so I will play devil's advocate here:

How do we know the effects are caused directly by the psychedelics binding to serotonin receptors? Could it be possible that the binding and blockade of the receptors, which prevents serotonin from binding, causes serotonin to behave differently, perhaps binding more to other receptors? Maybe the visual effects come only indirectly from the psychedelic, and are the direct effect of serotonin's altered behavior.

If that is the case, the effects have nothing to do with 5-HT2A, but rather the blocking of 5-HT binding to 5-HT2A. Perhaps for all we know, the effects come from serotonin binding to receptors it would not normally bind with... since the normal binding sites are partially blocked?

 

[serotonin2A]

How do we know the effects are caused directly by the psychedelics binding to serotonin receptors?

Because the visual effects are blocked by 5-HT2A antagonists.

Could it be possible that the binding and blockade of the receptors, which prevents serotonin from binding, causes serotonin to behave differently, perhaps binding more to other receptors? Maybe the visual effects come only indirectly from the psychedelic, and are the direct effect of serotonin's altered behavior.

If that is the case, the effects have nothing to do with 5-HT2A, but rather the blocking of 5-HT binding to 5-HT2A. Perhaps for all we know, the effects come from serotonin binding to receptors it would not normally bind with... since the normal binding sites are partially blocked?

Binding doesn't work that way because only a small percentage of serotonin is bound to its receptors at any given time. So the binding of serotonin to its receptors doesn't prevent it from interacting with other sites. The only thing that would make serotonin interact with a different set of receptors is raising the concentration.

Actually, many psychedelics reduce the firing of serotonergic neurons and reduce release, which is inconsistant with your proposal.

Depletion of serotonin or destruction of the serotonergic system doesn't prevent the actions of serotonergic hallucinogens in animals.

 

[nAON]

Should also note that a receptor complex forming with mGlu2 is necessary for psychoactive effects, 5HT2A alone won't do it. Also you get drugs like Lisuride which are seemingly identical to LSD by their binding profile, but isn't psychoactive due to different GPCR and epigenetic signalling pathways recruited.

Though agree that imaging will hopefully shed more light in the coming years, hopefully we get realtime singlecell on psychedelics soon

 

[endotropic]

Should also note that a receptor complex forming with mGlu2 is necessary for psychoactive effects, 5HT2A alone won't do it. Also you get drugs like Lisuride which are seemingly identical to LSD by their binding profile, but isn't psychoactive due to different GPCR and epigenetic signalling pathways recruited.

Though agree that imaging will hopefully shed more light in the coming years, hopefully we get realtime singlecell on psychedelics soon

I don't believe for a second high dose lisuride lacks psychedelic activity, despite the dogma.

 

[serotonin2A]

I don't believe for a second high dose lisuride lacks psychedelic activity, despite the dogma.

How high are you talking about? They have gone as high as a few mg in patients. You can't really go any higher because it is a strong dopamine agonist. That means it is at least 100-fold less active than LSD, but it has the same affinity as LSD for 5-HT2A.

I think most people believe that isoLSD, which has the same stereochemistry as lisuride, is inactive. So I'm not sure why lisuride would be different.

 

[endotropic]

How high are you talking about? They have gone as high as a few mg in patients. You can't really go any higher because it is a strong dopamine agonist. That means it is at least 100-fold less active than LSD, but it has the same affinity as LSD for 5-HT2A.

I think most people believe that isoLSD, which has the same stereochemistry as lisuride, is inactive. So I'm not sure why lisuride would be different.

Even normal doses of Lisuride cause hallucinations as a common side effect, so I'm very surprised those hallucinations don't turn into full blown psychedelic reactions at supra-therapeutic doses. Could I take a look at those high dose studies you're referring to?

Does iso-LSD have high affinity 5-HT2A agonist activity like lisuride as well? I can't find much info on that one.

 

[sekio]

Even normal doses of Lisuride cause hallucinations as a common side effect,

I was under the impression that it was non-hallucinogenic - the now infamous PLoS one human receptorome study used it as one of their "inactive" compounds... it apparently does things like block the effects of LSD, so that's a head scratcher.
James Kent actually did a cool poster (PDF) on the mechanistic aspects of 5ht2a induced hallucinations & visual disturbances. It's pretty dense but an excellent read.

 

[endotropic]

I was under the impression that it was non-hallucinogenic -

If I was a betting man (and I am) I wouldn't put money on that claim.

Check out this clinical trial for example:

Psychiatric side effects (including nightmares, isolated visual hallucinations and toxic confusional states) were the dose-limiting factor in six patients.

Dose limiting means those side effects became intolerable before any other toxicity. Now I'm not saying those are for sure 5-HT2A mediated effects, but in any case those are hallucinogenic reactions. You can find plenty of other clinical trials with similar reactions. Psychiatric disturbances are also listed on product documentation as common side effects.

 

[serotonin2A]

Even normal doses of Lisuride cause hallucinations as a common side effect, so I'm very surprised those hallucinations don't turn into full blown psychedelic reactions at supra-therapeutic doses. Could I take a look at those high dose studies you're referring to? Does iso-LSD have high affinity 5-HT2A agonist activity like lisuride as well? I can't find much info on that one.

Those "common" side effects of lisuride occur in Parkinsons patients who show the same response to bromocriptine, and many of those patients experience spontaneous visual hallucinations. I'm sure you will agree that bromocriptine is not a hallucinogen.

I'll have to dig up the citations on high dose lisuride, but they are from studies of migraine and tumor patients who did not experience any hallucinations from lisuride.

Iso-LSD doesnt bind but that is kind of my point, that it is strange that lisuride binds at all given its inverted stereochemistry. There are other examples of nonhallucinogenic 5-HT2A agonists such as ergotamine.

 

[serotonin2A]

If I was a betting man (and I am) I wouldn't put money on that claim.

Check out this clinical trial for example:



Dose limiting means those side effects became intolerable before any other toxicity. Now I'm not saying those are for sure 5-HT2A mediated effects, but in any case those are hallucinogenic reactions. You can find plenty of other clinical trials with similar reactions. Psychiatric disturbances are also listed on product documentation as common side effects.

Here are some citations. Dopamine agonists can cause hallucinations in patients with advanced Parkinsons disease. It has nothing to do with lisuride being hallucinogenic. In fact, about 30% of the patients experience spontaneous visual hallucinations.

These trials were conducted in patients without severe neurological impairments and they did not experience hallucinations:

http://www.ncbi.nlm.nih.gov/pubmed/6782153

http://www.ncbi.nlm.nih.gov/pubmed/6874328

http://www.ncbi.nlm.nih.gov/pubmed/3249509

There are a few other trials with similar outcomes. I think the highest single p.o. dose given in a trial to a non-Parkinsonian subject was slightly over 2 mg and there were no hallucinations reported. I don't think higher doses could be given because the side-effects would be intolerable.

 

[nAON]

I wonder, would a drug like MDA induce its visuals through 5HT2A? Because the subjective effects seem pretty distinct

 

[serotonin2A]

I wonder, would a drug like MDA induce its visuals through 5HT2A? Because the subjective effects seem pretty distinct

Excellent question! There is a good deal of evidence that increased glutamate activity is a downstream effect of 5-HT2A effects, and the visual effects of hallucinogens are one possible consequence. Glutamate nerve endings express 5-HT1B/1D heteroceptors that inhibit glutamate release. So potentially by releasing massive amounts of serotonin, MDA may somewhat "modulate" its actions at 5-HT2A.