Theory on the Visual Effects of Psychedelics

[SpunkySkunk347]

I've believed in this theory for a while, but I don't know how accurate it is. I was wondering if I could get someone to support/dismiss the validity of this theory.

Short version:
5-HT2a pathways in the visual cortex are usually only activated while sleeping, and they help "blend together" information the brain received throughout the day so the brain can review and prioritize information.
This is why 5-HT2a psychedelics (LSD, psilocybin, DMT, etc) have the visual effect of making things appear to "morph", "stretch", and "swirl around".

Long Version:
Among the various receptor types which psychedelics bind to for their psychoactive effects, the 5-HT2a receptors are perhaps the most commonly associated with psychedelics, and attributed as the source of visual effects from LSD, psilocybin, and most other psychedelics).

But on a larger neuronal scale, what role do 5-HT2a prominent neuronal pathways play in the brain? And how does this result in perceived visual alterations during a psychedelic experience?

Here is what I think is a possible answer:

In the visual cortex (as well as nearby connected regions or other associated regions), the natural function of 5-HT2a pathways is to help the process of developing memories during periods of sleep.

The 5-HT2a pathways have the task of "comparing" pieces of visual information (which were presumably collected throughout the day before sleep) with other pieces of visual information.

During sleep, the brain receives little to no fresh visual stimulation. Instead, the brain replicates old visual information and projects this into the visual cortex. The brain selects old visual information based on things like: whether or not the mind feels like it has a good enough understanding of the information in question; the relevancy of the old visual information to possible events in the near future; unconscious knowledge; etc.

Then, when the 5-HT2a pathways are activated, they begin blending/mixing together all of the information present in the brain's artificial simulation.
By blending together a particular strand of information with other strands of information, the brain is then able to make neurological preparations for expected near-future events.

Why have a cognitive blending pot?
Perhaps the brain has a mechanism for prioritizing the replenishment of neurotransmitter storage vesicles, and sleep provides an opportunity to do this. In a sense, the brain "specializes" itself to best meet possible near-future events (like during the following day).

Or maybe the brain uses the "incoherence" from the metaphorical blending pot, and makes deductions from it to narrow down upon possibly useful information. In a sense, it might be a high-powered form of self-reflection/introspection, but it only becomes efficient in the absence of incoming stimulation (such as while sleeping).

Why couldn't the brain do all of this when its awake? Just take a look at psychedelics. When 5-HT2a pathways are forcefully activated (via ingestion of psychedelics like LSD or psilocybin), the brain begins "mixing"/"blending" together the current information in the visual cortex (as opposed to the self-projected simulation of artificial visual information). Things in the vision begin to start "morphing" and "stretching", and the mind becomes unable to focus. If this was happening constantly on a daily basis, an individual's survival odds would be greatly reduced (especially back in ancient times); hence, we evolved so that 5-HT2a pathways naturally only have high activity during periods of sleep or boredom.

Perhaps 5-HT2a pathways are also active while awake, but psychedelics trigger an action potential as soon as the drug binds to the receptor, and the neuronal pathways become de-synchronized - causing the mind to leave a normal cognitive equilibrium.

All of this explains the distinct nature of visual hallucinations during a psychedelic experience; why things appear to "morph", "stretch", or "swirl around". It also explains why psychedelics cause introspective and enlightening experiences.

I first thought of all of this while thinking about the effects of zolpidem - which doesn't have any 5-HT2a affinity by itself, but its affinity for GABAnergic can indirectly trigger 5-HT2a activity in the brain. But why? Then I thought that perhaps Zolipdem will trick the brain into thinking that its already in deep sleep, and maybe 5-HT2a pathways are the most active in periods of deep sleep.

 

[Sl1pp3Ry]

I studied a bit of pharmacology, neurobiology, and psychology in my time and while I am no expert or have any real clout in scientific circles, I do believe there is some credence to your theory and it could be worthy of further exploration. I don't know whether you are in school or not but you could pursue possible clues and answers through library or laboratory research if you have the means and ability.
Biologically, your theory seems fairly sound and I am fascinated with the connection you made with ambien having a secondary effect on 5-HT2a receptors through stimulation of GABA activity; thereby mimicking a deep sleep state in the brain. Interestingly, if you stay awake while on a high enough dosage of zolpidem you will literally dream while awake...a truly funky experience.
Overall, it seems to be very well thought out and I wish I could add more of a pharmacological perspective but I am somewhat far removed from my college studies. I do know that 5-HT2a receptors are crucial in the processing of information stored throughout the day into short term memory during sleep within the hippocampus and cortical regions. Their function seems vital for proper hippocampal activity and processing when it comes to the coding, storage, and retrieval of information related to tasks involved with learning and memory. Again, its increased activity during sleep and REM in particular provide evidence to lend support in the receptors role in processing of information through dreams.
However, I do believe that theory provides little evidence for psychedelics as means to any substantial long term enlightenment; thereby ending mass conflict, war, and free market capitalism. The very essence of our existence is survival. whether on an individual or global scale. In order to survive and adapt we have to be able process mass amounts of information given off by our surrounding environment in real time. The big difference being instead of avoiding predators that could eat us we are desperately trying to avoid the effects of financial, environmental, and global terror crises that plague us on a daily basis. Psychedelics impede our ability to accurately process information in a timely fashion in the short term and can have disastrous long term consequences when abused. While stimulation of 5-HT2a receptors during sleep is beneficial because of the lack of sensory stimuli, it is disorientating and induces hallucinations while awake because there is an overload of activity going on in the visual cortex. Of course, this is why we all have come to love Lucy to some degree and when taken in a controlled setting lol.
Deep introspection and enlightenment, in my estimation, does not come from any drug but how you are able to process the combined sum of your life experiences and relate them to your current and expected future situations in life. Introspection comes from within and while it may be facilitated through the administration of substance, such as LSD, it can never be achieved through that alone. I think your theory has larger implications on the role of the 5-HT2a receptor and its function in processing sensory stimuli in wake vs. sleep models when it comes to learning and memory than it does on the attainment of any sort of introspection. This, of course, is just my humble opinion. I really enjoyed reading the theory though, it is fairly well thought out and deserves some more attention. Kudos!

 

[acetylcholine]

Biologically, your theory seems fairly sound and I am fascinated with the connection you made with ambien having a secondary effect on 5-HT2a receptors through stimulation of GABA activity;

Interestingly, if you stay awake while on a high enough dosage of zolpidem you will literally dream while awake...a truly funky experience.

Only some people who stay awake after taking zolpidem, and possibly other Z drugs, report hallucinations. I wonder if people that do experience such hallucinations will have them diminished or stop completely if put on a 5-HT2A antagonist such as mirtazapine? Such drugs do appear to greatly attenuate the hallucinogenic and psychotomimetic effects of classic psychedelics.

 

[inverse_agonist]

Enriched expression of serotonin 1B and 2A receptor genes in macaque visual cortex and their bidirectional modulatory effects on neuronal responses.

Watakabe et al.
Cereb Cortex. 2009 Aug;19(8):1915-28
http://www.ncbi.nlm.nih.gov/pubmed/19056862

To study the molecular mechanism how cortical areas are specialized in adult primates, we searched for area-specific genes in macaque monkeys and found striking enrichment of serotonin (5-hydroxytryptamine, 5-HT) 1B receptor mRNA, and to a lesser extent, of 5-HT2A receptor mRNA, in the primary visual area (V1). In situ hybridization analyses revealed that both mRNA species were highly concentrated in the geniculorecipient layers IVA and IVC, where they were coexpressed in the same neurons. Monocular inactivation by tetrodotoxin injection resulted in a strong and rapid ( h) downregulation of these mRNAs, suggesting the retinal activity dependency of their expression. Consistent with the high expression level in V1, clear modulatory effects of 5-HT1B and 5-HT2A receptor agonists on the responses of V1 neurons were observed in in vivo electrophysiological experiments. The modulatory effect of the 5-HT1B agonist was dependent on the firing rate of the recorded neurons: The effect tended to be facilitative for neurons with a high firing rate, and suppressive for those with a low firing rate. The 5-HT2A agonist showed opposite effects. These results suggest that this serotonergic system controls the visual response in V1 for optimization of information processing toward the incoming visual inputs.

A key point is that single neurons often express more than one kind of serotonin receptor. Under natural conditions, serotonin acts at all of those receptors simultaneously. The net effect of serotonin is not hallucinogenic. If it were, SSRIs would be psychedelic. Psychedelics create an unnatural condition in which 5-HT2A receptors are being selectively stimulated.

Watakabe et al. found that DOI enhanced the activity of slow-firing neurons and suppressed the firing of fast-firing neurons. If the cells with a fast rate are supposed to have a fast rate and the slow cells are supposed to be firing slowly, DOI is lowering the signal-to-noise ratio. V1 neurons normally respond to things like bars at particular orientations moving through their receptive fields. Hubel and Wiesel received a Nobel Prize for figuring that out:

http://www.youtube.com/watch?v=IOHayh06LJ4

You could imagine how adding noise to your edge, shape, movement, and color detection systems would cause geometric hallucinations. Here's a talk by Jack Cowan about that, which has so much math in it that I can't pretend I know what he's talking about:

http://www.archive.org/details/redwood_center_2006_02_14_cowan

 

[PsychedelicPeptide]

This is probably pretty important:

(Full text can be downloaded free http://www.jneurosci.org/cgi/content/full/23/26/8836)
J Neurosci. 2003 Oct 1;23(26):8836-43.
Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex.

González-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC.

Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract

Most neuropharmacological agents and many drugs of abuse modulate the activity of heptahelical G-protein-coupled receptors. Although the effects of these ligands result from changes in cellular signaling, their neurobehavioral activity may not correlate with results of in vitro signal transduction assays. 5-Hydroxytryptamine 2A receptor (5-HT2AR) partial agonists that have similar pharmacological profiles differ in the behavioral responses they elicit. In vitro studies suggest that different agonists acting at the same receptor may establish distinct patterns of signal transduction. Testing this hypothesis in the brain requires a global signal transduction assay that is applicable in vivo. To distinguish the cellular effects of the different 5-HT2AR agonists, we developed an assay for global signal transduction on the basis of high throughput quantification of rapidly modulated transcripts. Study of the responses to agonists in human embryonic kidney 293 cells stably expressing 5-HT2ARs demonstrated that each agonist elicits a distinct transcriptome fingerprint. We therefore studied behavioral and cortical signal transduction responses in wild-type and 5-HT2AR null-mutant mice. The hallucinogenic chemicals (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and lysergic acid diethylamide (LSD) stimulated a head-twitch behavioral response that was not observed with the nonhallucinogenic lisuride hydrogen maleate (LHM) and was absent in receptor null-mutant mice. We also found that DOI, LSD, and LHM each induced distinct transcriptome fingerprints in somatosensory cortex that were absent in 5-HT2AR null-mutants. Moreover, DOI and LSD showed similarities in the transcriptome fingerprints obtained that were not observed with the behaviorally inactive drug LHM. Our results demonstrate that chemicals acting at the 5-HT2AR induce specific cellular response patterns in vivo that are reflected in unique changes in the somatosensory cortex transcriptome.

 

[onmyway]

wow, i would love to know which genes are being up/down regulated by lsd.

is there a proposed mechanism for how different ligands have different downstream effects at metabotropic receptors? i understand that with ionotropic receptors different ligands will generally effect how often a channel is open by binding different regions on the receptor. but with g coupled, once it is "on" i thought the signal cascade would carry on the same regardless of how it got activated?

 

[inverse_agonist]

More about different ligands activating different signaling cascades here:

http://www.ncbi.nlm.nih.gov/pubmed/16803859

 

[SpunkySkunk347]

key point is that single neurons often express more than one kind of serotonin receptor. Under natural conditions, serotonin acts at all of those receptors simultaneously. The net effect of serotonin is not hallucinogenic. If it were, SSRIs would be psychedelic. Psychedelics create an unnatural condition in which 5-HT2A receptors are being selectively stimulated.

Don't SSRIs usually have a an antagonistic effect on 5-HT2 receptor subtypes?
And where do you get the idea that 5-HT will act on all receptor types simultaneously? I understand a single neuron can have multiple 5-HT receptor subtypes on it at the same time, but one type is usually more prevalent depending on the region of the brain.
And the "net effect of serotonin is not hallucogenic"? You make it sound like Serotonin is only responsible for one set of neurological mechanisms.

Sorry if I just misinterpretted what you said.

The information you've contributed still seems to support the idea that 5-HT2a pathways are active during sleep.
Perhaps the 5-HT2a pathways are prioritized to become activated during periods of low stimulation, such as sleep?

I still believe that 5-HT2a receptors (and perhaps most of the other 5-HT receptor pathways in the visual cortex) play a core role in visual memory processing, visualization, and also responsible for the dream experience during periods of sleep.

 

[inverse_agonist]

SSRIs bind to the serotonin transporter, rather than any particular serotonin receptor. This would be expected to increase the levels of extracellular serotonin everywhere that there are serotonin transporters. There would be more serotonin around to bind to all types of serotonin receptors. When people take SSRIs, they don't start tripping, so the net effect of increased serotonin release is not hallucinogenic.

Serotonin is released from a set of nuclei in the brainstem called the raphe nuclei, which project all over the brain. The raphe nuclei are more active during wakefulness than during sleep, and they seem to suppress slow-wave and REM sleep:

http://www.ncbi.nlm.nih.gov/pubmed/20153670

Under normal circumstances, there is less serotonin around during sleep, and therefore less activity at 5-HT2A receptors. It makes sense when you think about it. Psychedelics keep people up all night, instead of putting them to sleep.

Strictly speaking, there is no such thing as a "5-HT2A pathway." There are fibers from the raphe nuclei in many areas, but these fibers don't always (usually?) synapse with anything in particular. They simply release serotonin into the extracellular space, where it serves as a modulator. Serotonin receptors are often found at extrasynaptic sites. This is called "volume transmission," and it is not uncommon in the brain. 5-HT2A receptors have a widespread distribution in the brain, although they are enriched in visual cortex:

http://www.ncbi.nlm.nih.gov/pubmed/7796165

Psychedelics are interesting, but they do not explain everything that is interesting.

 

[SpunkySkunk347]

I thought the 5-HT transporter (which SSRIs bind to) was located at the synapse on the presynaptic neuron?

You're making me very confused about everything I thought I previously knew about neuronal mechanisms.

Edit: I also distinctly remember reading articles which illustrated that SSRIs (as well as SNRIs) had higher/lower affinity for particular 5-HT subtypes than others -- and certain SSRIS/SNRIs actually had antagonistic effects on the 5-HT2a subtype. Hence, why medications such as Zoloft had been resorted to in emergency room settings for halting the effects of 5-HT2a agonists like LSD.

Or - in more layman terms - when someone came in to the emergency room having a bad trip on acid, and the protocol benzodiazepine sedation had failed, they gave the patient zoloft to make him stop tripping.

There is so many more variables at play than what you make it seem like. If what you were saying was true, then wouldn't SSRIs share similar effects with MDMA?

 

[SpunkySkunk347]

Under normal circumstances, there is less serotonin around during sleep, and therefore less activity at 5-HT2A receptors. It makes sense when you think about it. Psychedelics keep people up all night, instead of putting them to sleep.

Psychedelics bind to many different receptors (not just 5-HT receptors) such as dopaminergic and adrenoreceptors.

You can't make such a sweeping generalization as "Psychedelics are 5-HT agonists. Psychedelics keep people awake. Therefore, 5-HT is also responsible for keeping people awake." Its a logical fallacy for starters.

I am almost entirely convinced that you are pretending to know more about neurology than you actually do.
Please don't do this; it puts a huge roadblock in the path of people who are actually trying to learn legitimate information.

 

[SpunkySkunk347]

Only some people who stay awake after taking zolpidem, and possibly other Z drugs, report hallucinations. I wonder if people that do experience such hallucinations will have them diminished or stop completely if put on a 5-HT2A antagonist such as mirtazapine? Such drugs do appear to greatly attenuate the hallucinogenic and psychotomimetic effects of classic psychedelics.

I remember that while taking zolpidem while also on clonazepam, the psychedelic-esque effects of zolpidem were almost non-existent.
Zolpidem still produced effects of memory impairment, and an overall impairment in functioning, but no "stretching, morphing" hallucinations.

Yet, while taking clonazepam while also on standard psychedelics (such as psilocybin or LSD), the visual effects were uninhibited. Clonazepam (for me at least) seemed to have an indifferent impact on the visual effects of psychedelics. Although, clonazepam did reduce the anxiety of psychedelic experiences.

I think I did read somewhere that clonazepam does indeed block out many of the hallucinatory effects of zolpidem - by some indirect mechanism, and not by direct removal of zolpidem from its binding site.

 

[whitemilk661]

Edit: I also distinctly remember reading articles which illustrated that SSRIs (as well as SNRIs) had higher/lower affinity for particular 5-HT subtypes than others -- and certain SSRIS/SNRIs actually had antagonistic effects on the 5-HT2a subtype. Hence, why medications such as Zoloft had been resorted to in emergency room settings for halting the effects of 5-HT2a agonists like LSD.

Or - in more layman terms - when someone came in to the emergency room having a bad trip on acid, and the protocol benzodiazepine sedation had failed, they gave the patient zoloft to make him stop tripping.

There is so many more variables at play than what you make it seem like. If what you were saying was true, then wouldn't SSRIs share similar effects with MDMA?

Link to the articles?

I know psychiatrists are now treating treatment resistant depression with 5-HT2a antagonists, atypical antipsychotics such seroquel and risperidone.

I've never heard that ssri's are antagonists of that receptor...

 

[The Smoking Man]

I think it's more likely tied to how 5-HT2a is implicated in memory formation (http://learnmem.cshlp.org/content/10/5/355.full), and therefore, synaptic plasticity. That means it's no coincidence that NMDA and anticholinergics also cause visual anomalies, which impede memory formation, and therefore affects synaptic plasticity. The difference would be that 5-HT2a activation causes an overload of activity and the rest of the brain can't keep up with it, while the CNS depressant hallucinogens stop the brain from achieving a consistent, stable perception. I'm sure there's a better way of wording it than that.

Link to the articles?

I know psychiatrists are now treating treatment resistant depression with 5-HT2a antagonists, atypical antipsychotics such seroquel and risperidone.

I've never heard that ssri's are antagonists of that receptor...

I don't know about SSRI's, but some TCA's have antagonistic action at 5-HT2a, while some others have agonistic action, according to Wikipedia.

 

[whitemilk661]

What's the difference between a partial agonist, and a full agonist?

I only know a few full agonists of the 5HT2a receptor. One, Bromo-Dragonfly apparently kills humans fairly easy above therapeutic levels.

 

[The Smoking Man]

What's the difference between a partial agonist, and a full agonist?

I only know a few full agonists of the 5HT2a receptor. One, Bromo-Dragonfly apparently kills humans fairly easy above therapeutic levels.

A partial agonist will only cause activity up to a certain % of maximum possible activity. A full agonist causes activity up to the maximum possible activity. Partial agonists are antagonistic relative to full agonists. Something along those lines, anyway. Also, I remember Hofmann saying in "LSD - My Problem Child" that LSD is less potent than serotonin itself, so it's relatively antagonistic compared to serotonin.

 

[SpunkySkunk347]

http://www.nature.com/npp/journal/v27/n6/full/1395967a.html

The selective serotonin reuptake inhibitor fluoxetine consists of equal amounts of R and S stereoisomers. In this study, we investigated the pharmacologic properties of the stereoisomers using transporter and receptor binding assays and in vivo microdialysis in freely moving rats. Binding to the transporter confirmed selectivity of R- and S-fluoxetine for the 5-HT transporter versus the dopamine (DA) and norepinephrine (NE) human transporters. Receptor binding studies demonstrated significant affinity of R-fluoxetine, but not S-fluoxetine, for human 5-HT2A and 5-HT2C receptor subtypes. Functional GTPgammaS binding studies indicated that R-fluoxetine is an antagonist at 5-HT2A and 5-HT2C receptors In microdialysis studies, acute R- and S-fluoxetine increased extracellular levels of 5-HT, DA, and NE in prefrontal cortex (PFC), but R-fluoxetine caused significantly greater increases of catecholamines. R-fluoxetine increased extracellular levels of 5-HT and NE in PFC, nucleus accumbens, and hypothalamus, whereas it increased dopamine in PFC and hypothalamus, but not in DA-rich nucleus accumbens and striatum, thus indicating a regionally selective effect. The unexpected increases of extracellular catecholamines by a selective 5-HT uptake inhibitor like R-fluoxetine may be due to its antagonism of 5-HT2C receptors.

And a google search will reveal plenty more articles that talk about SSRIs' paradoxical effect of acting as antagonists on certain 5-HT receptor subtypes.

Also, after a quick search, there appears to be another thread on bluelight which discussed a similar topic not too long ago:
http://www.bluelight.ru/vb/showthread.php?t=496327
The thread addresses the question "Why don't SSRIs produce psychedelic effects?"

 

[SpunkySkunk347]

This article verifies that the various 5-HT receptor subtypes are distributed in different quantities depending on the region of the brain; In case that was in dispute.

5-HT2A, originally referred to as 5-HT2 and less commonly as 5-HT2a, receptors were among the first 5-HT receptors to be identified and, consequently, have been extensively reviewed (64,158). 5-HT2A receptors are widely distributed at varying densities throughout the brain; the highest density is in the neocortex. 5-HT2A receptors are directly coupled to a phosphoinositol second messenger system. In certain brain regions, 5-HT stimulates phospholipase A2 via a 5-HT2 mechanism.

http://www.acnp.org/g4/GN401000039/Ch039.html

Also, I'll keep looking for more information about SSRIs/SNRIs and their varying affinity for different 5-HT receptor subtypes.

If I remember correctly, it has something to do with what region of the brain the SSRI/SNRI molecules will most likely be condensed to -- different SSRIs/SNRIs end up in different regions of the brain.

Just as an example:
SSRI "A" might be more prone to end up at the middle-brain,
while SSRI "B" might be more prone to end up at the fore-brain.

I have this memory in mind of seeing a chart listing all the various SSRIs/SNRIs, and then showed ratios of their affinity for a particular 5-HT receptor subtype.

 

[atara]

Only some people who stay awake after taking zolpidem, and possibly other Z drugs, report hallucinations. I wonder if people that do experience such hallucinations will have them diminished or stop completely if put on a 5-HT2A antagonist such as mirtazapine? Such drugs do appear to greatly attenuate the hallucinogenic and psychotomimetic effects of classic psychedelics.

But everyone hallucinates on amanitas, which are true GABA-A agonists, as opposed to positive allosteric modulators.

I've never heard that ssri's are antagonists of that receptor...

He may be confused. Most SSRIs have negligible 2A activity or are low-potency antagonists, but almost all are potent antagonists at the 5-ht2c receptor, which has two functions: lowering appetite, and making you feel horrible on piperazines. This is implicated in the resultant weight gain. Conversely, mCPP, one of the piperazines, has been shown to induce weight loss:

http://www.ncbi.nlm.nih.gov/pubmed/9361339

 

[inverse_agonist]

Psychedelics bind to many different receptors (not just 5-HT receptors) such as dopaminergic and adrenoreceptors.

You can't make such a sweeping generalization as "Psychedelics are 5-HT agonists. Psychedelics keep people awake. Therefore, 5-HT is also responsible for keeping people awake." Its a logical fallacy for starters.

I am almost entirely convinced that you are pretending to know more about neurology than you actually do.
Please don't do this; it puts a huge roadblock in the path of people who are actually trying to learn legitimate information.

Look at what came just before the point about psychedelics keeping people awake: a link to a recent review of the role of serotonin in sleep. The first sentence of the abstract reads

Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches it is currently accepted that serotonin (5-HT) functions to promote waking (W) and to inhibit rapid-eye movement sleep (REMS).

The fact that psychedelics keep people up all night is consistent with that statement.