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Is HPPD actually the opposite of psychedelic action?

M

Memantine

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So serotonergic psychedelics excite inhibitory interneurons(5-HT2A at the soma and GABAergic at the synapse) including in the pyriform cortex, the claustrum and in layer 4 of V1 causing inhibition of pyrimidal cells in the visual pathways which results in peceptual distortions.

I hypothesize that these inhibory interneurons get over excited in response to psychedelics which results either in neuronal cell death, deafferentation or a long tem/permanent down-regulation of 5HT2A receptors. This would result in the long term/permanent loss of inhibitory input on pyrimidal cells.

Any opinions/thoughts on this?
 
My wild adventure of a life

I find your post very interesting considering I recently learned about HPPD. I would say that I agree with you on the long term/permanent loss of inhibitory input on pyramidal cells based on first hand experience.

I accidentally ingested liquid LSD as a kid. I was maybe 7 or 8. I can't remember exactly. I found it in my older brother's room. This was by far the worst experience of my life. For one, being a little kid and not understanding the things I was feeling and seeing was traumatizing. I vividly remember everything though I will spare any details for my peace of mind as well as anybody else. I can however tell you that for months after I would still see hallucinations mainly at night time.

I have been reflecting on how life was around that time and afterwards.I was disruptive in Kindergarten to where they wanted to hold me back from going to 1st. My parents had that option or send me to 1st and see how I do. Maybe I was younger than 7 or 8 after all? I had a tutor for like 3 days a week and still ended up being held back. That did wonders for my self esteem and confidence right? I started to get the hang of it though soon enough. I did really good in middle school despite feeling different than everybody. I had a hard time relating to other students and didn't talk much. This allowed me to focus on the schoolwork. It wasn't easy as I found myself distracted or daydreaming in class. My parents explained things to me and helped with homework. I was a pretty smart kid as long as I was interested in the subject.

My grades were so good I was able to go to a high school where I took college classes too. After 5 years I could have a high school diploma and an associates degree. I managed to fuck it up though. I became so stressed out from all the work and just wanted to relax and have some fun. I started drinking heavily and partying all the time. I was kicked out of school for failing too many classes and wouldn't be able to graduate with my class on time.To make a long story short I felt empty inside throughout school and was socially awkward. I had no idea why either. Alcohol helped me open up until it dragged me way down.

Anyways I believe I suffer from PSTD, ADD, BPD, and maybe depression. I have never been diagnosed though. So yea, I think psychedelics either caused these things or made them worse. I'm considering going to either a therapist or psychiatrist but unsure of telling them about this. Could there be legal repercussions after all these years like child abuse or endangerment? Well, I just wanted to share my story. I don't believe they would have studies for the effects of psychedelics on the developing brain. They should scan and study my brain to see if they find anything interesting. ;)
 
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Memantine said:
So serotonergic psychedelics excite inhibitory interneurons(5-HT2A at the soma and GABAergic at the synapse) including in the pyriform cortex, the claustrum and in layer 4 of V1 causing inhibition of pyrimidal cells in the visual pathways which results in peceptual distortions.

I hypothesize that these inhibory interneurons get over excited in response to psychedelics which results either in neuronal cell death, deafferentation or a long tem/permanent down-regulation of 5HT2A receptors. This would result in the long term/permanent loss of inhibitory input on pyrimidal cells.
Click to expand...

Several Q about your proposal:

* How would excitation of interneurons by 5-HT2A lead to their death? 5-HT2A is modulatory and while it certainly could increase excitability, something else would still have to excite the GABAergic interneurons. If you believe that the main effect of 5-HT2A in V1 is to increase GABAergic inhibition, then you are describing a situation where their excitatory drive would likely decrease (because GABA tends to reduce recurrent network activity).

* Why would loss of some GABAergic interneurons cause HPPD symptoms, but not visual deficits? The GABAergic interneurons in V1 play a very specific and well-defined role in visual processing, and their loss should result in very predictable deficits (which would be much more profound than HPPD symptoms).

* As an alternative to neuronal loss, you brought up the possibility of 5-HT2A downregulation on the interneurons. But if that is true, then shouldn't blocking 5-HT2A with an antagonist induce HPPD-like symptoms in humans?

* HPPD symptoms are similar to some hallucinogen effects. So in your hypothesis, you are predicting that the same visual symptoms that occur in a situation where there is 5-HT2A activation/GABA neuron excitation (acute hallucinogen effects) can also occur in a situation where you think 5-HT2A is downregulated and GABA neuron excitation is reduced (HPPD)? That seems inconsistant.

* The explainations you proposed indicate that patients suffering from HPPD should show some degree of insensitivity to the visual effects of hallucinogens, because they either show loss of GABAergic interneurons (which you believe are responsible for mediating the acute response to hallucinogens) or the neurons no longer express 5-HT2A receptors. How do you reconcile that with the fact that HPPD patients exhibit normal responses to hallucinogens?
 
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While I'm no way an expert, I see HPPD as a result of learning, synapses that were active during the trip becoming hard coded. Seems HPPD occurs mainly after bad trips that could be seen as a trauma. Don't think there is actual cell death, the result can be equally impacting though.
 
Several Q about your proposal:

* How would excitation of interneurons by 5-HT2A lead to their death? 5-HT2A is modulatory and while it certainly could increase excitability, something else would still have to excite the GABAergic interneurons. If you believe that the main effect of 5-HT2A in V1 is to increase GABAergic inhibition, then you are describing a situation where their excitatory drive would likely decrease (because GABA tends to reduce recurrent network activity).
One proposed etiology of this disorder is that LSD causes a destruction of inhibitory interneurons that are seroto-nergic at the soma and GABAergic at the terminals (5,6). This hypothesis is supported by the partial responsiveness of HPPD to treatment with GABA agonists such as benzodiazepines.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096346/#i1524-5012-7-1-37-b6


* Why would loss of some GABAergic interneurons cause HPPD symptoms, but not visual deficits? The GABAergic interneurons in V1 play a very specific and well-defined role in visual processing, and their loss should result in very predictable deficits (which would be much more profound than HPPD symptoms).
Perhaps because other aspects of visual processing are mediated by receptors other then 5-HT2A, glutamate for example. Serotonergic hallucinogens tend to distort reality while NMDA antagonist tend to eliminate the external world. But to be honest I really do not know.

* As an alternative to neuronal loss, you brought up the possibility of 5-HT2A downregulation on the interneurons. But if that is true, then shouldn't blocking 5-HT2A with an antagonist induce HPPD-like symptoms in humans?
Actually it does in some people:Posthallucinogen-like visual illusions (palinopsia) with risperidone in a patient without previous hallucinogen exposure: possible relation to serotonin 5HT2a receptor blockade.http://www.ncbi.nlm.nih.gov/pubmed/10721882
Also from personal experience I can say that some of the 5-HT2A antagonists I used exacerbated my HPPD acutely. For example: Risperidone, Pipamperone, Hydroxyzine and Mirtzapine. While a low dose of Psilocybin seemed to impove my vision acutely.

* HPPD symptoms are similar to some hallucinogen effects. So in your hypothesis, you are predicting that the same visual symptoms that occur in a situation where there is 5-HT2A activation/GABA neuron excitation (acute hallucinogen effects) can also occur in a situation where you think 5-HT2A is downregulated and GABA neuron excitation is reduced (HPPD)? That seems inconsistant.
https://www.erowid.org/archive/rhodium/pharmacology/visualdistortions.html According to this guy there are some kind of parallel circuits from the claustrum and layer 6 of V1 that are responsible for the end-inhibition of layer 4 of V1 that require a specific firing patern in order to funcion properly. In theory both 5-HT2A blockade and activation would then disrupt this parallel firing pattern.

* The explainations you proposed indicate that patients suffering from HPPD should show some degree of insensitivity to the visual effects of hallucinogens, because they either show loss of GABAergic interneurons (which you believe are responsible for mediating the acute response to hallucinogens) or the neurons no longer express 5-HT2A receptors. How do you reconcile that with the fact that HPPD patients exhibit normal responses to hallucinogens?
Maby because only small parts of the visual pathways are damaged/changed leaving the majority of 5-HT2A containing neurons intact.






I know this hypothesis is probably not conclusive and might only count for a part of the visual deficits of HPPD.
 
It would surprise me if HPPD could be reduced to one or two neurotransmitter systems, however straightforward you consider SE psychedelic action to be. Not only the relatively 'normal' response of people with HPPD to psychedelics (apart from their probable liability to worsen their case of HPPD) suggests a more pervasive problem but also the fact that other drugs like (most of all perhaps) cannabis can be detrimental in a case of HPPD.

If HPPD is a pervasive problem with proper integration of visual processing without any kind of noise in the system due to improper feedback in the signal cascades, then the relatively normal reaction to psychedelics is consistent as well as the supposition that basically any visually active drug can ultimately play a role in HPPD if that activity becomes engrained in the wetware. It also means that it's much more difficult to target and counter or mask with medication, and that most of all the advice typically given now is sound: to avoid taking psychedelic / hallucinogenic / any visually active drug.
The reason being that this is basically the only way for such a pervasive problem to heal: the balance needs to restore naturally.

If you want to investigate therapeutic possibilities for HPPD, I would personally check the effectivity of 'pervasively acting' neurogenic drugs i.e. in the category nootropics those that increase neuroplasticity. Maybe not enough is understood about the promise or risk of using nootropics that way since neuroplasticity or neurogenesis isn't a simple 'the more the better' matter, of course. But I personally would not be surprised if that particular potential while in itself neutral, depends on what you do with it much like a psychedelic.
If you take nootropics and combine it with very unhealthy practices, do negative changes to your brain and mind happen more rapidly than without such nootropics? In any case, if you rest well and capitolize on your recovery, I'd be interested in if they could speed it up, like some other forms of recovery from brain injury.
All of that would also be consistent with the idea of adaptogenics, although I really wonder if adaptogenics don't just have the exact same caveat that you shouldn't combine them with behaviors that may make your case worse at a higher rate.

^^

Good that you mention glutamate and NMDA! :) I forgot to add in my reply that I am also reminded of how nootropics apparently remedy or reverse effects from dissociatives.
Sorry, I am not versed in advanced neurochemistry to more deeply consider your proposal.
Who knows, maybe one can 'break down' that pervasive disorder of HPPD into a few correlates of those 'improper feedback loops' in visual processing, one component being like the one you propose.
 
I think everyone has good hypothesis. Mabe the solution to a illusionary paradox is to mix ideas..

Mabe HPPD can be a result of alot of things, once you start activating neurons with psychedelics low medium dose, they become ALOT more active and easy to access. So, HPPD can even be a simple traumatic disorder where emotions/memories are sent out of your brain to keep you safe from it. (logical but not complete theory) Psychedelic hallucinations are a form of language, every psychedelic users know that. The only condidtion to this theory is having a low medium trip to give you HPPD, which is rare.

Mabe other way of having HPPD is both cell death and cell overactivation but I don' thnink so. Memantine have mentioned that mabe only small parts of the circuit were messed with, how about cell disregulation (not dead not overactivate, just acting different), they start action on their own disregulating your neural pathaways,I have it and calmness and control reduce it. SO MY theory is that cells HPPD is a result of pushing neurons too far with power that they become drunk with power draining energy from other neurons disrupting neural pathways permanatly. But I think or brain can do things when we begin to regain control over the cells. How to do that? let them have energy but tell them what you want. I have been practicing and I got to control the color and shapes and intensity of my HPPD. HPPD is a communication problem betewen visual neural cells and RAM no matter how it is caused, death, life, disregulation, psychological problem etc.
Why binding to ONE explanation.
 
I was under the impression HPPD had partly to do with an un-inhibition of COMT.

But I see HPPD in a bit broader sense personally, I wouldn't just focus on the visuals. It's somewhat like schizophrenia - everyone knows it by the flamboyant symptoms like hallucinations but there's much more to it than that.
 
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The (I think first) P stands for perception, though.

That excessive or problematic use of psychedelics can certainly have an impact on mental well-being, that doesn't mean you can just all consider it HPPD. :) read the definition, it's a sensory thing.

https://www.erowid.org/chemicals/lsd/lsd_health2.shtml

And by the way, I reject that they are called flashbacks there even if its the DSM (hopefully they fixed it in DSM-V / editt: nope) - I wrote a whole bit about that in the OP or OPs of PD central threads on HPPD and flashbacks respectively: Flashbacks are much more transient episodic experiences that are more typical for PTSD and happen due to experiences, stress / trauma in other words linked to severely emotional occurrences and these are definitely not restricted to psychedelic trips but also e.g. war veterans or victims of abuse etc. Sure, reliving an experience through a flashback can bring along also re-experiencing psychedelic effects epiphenomenologically but it's rather secondary.

HPPD is a sensory disorder that while it can be triggered by stress or anxiety, it's not specific stress triggered by a unique experience but can happen from any stress - it's much more chronic and not really episodic, even if it can come and go somewhat.

As all disorders, it qualifies when it impairs functioning in life.
I personally have not had HPPD as the disorder but definitely know the type of protracted effect on the senses when tripping a LOT, i just never really bothered me and just went away again eventually. And I also unmistakenably had a flashback once - triggered by a song that I heard the previous time, immediately after coming out of a many-hours long 'white-out' / an experience of the mystical type that was my second trip ever, which shook me to my core, traumatized and ruined quite a bit for a while. The phenomena are fundamentally different and should not be confused because of apparent similarities (trip-effects while not actually on a psychedelic).

I wrote the American Psychiatric Association that writes the DSM about this. :) I wonder how they respond.
 
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Well I guess what I mean is that tinnitus and such is very common with HPPD, and I personally have had a lot of "audio abnormalities" since around the time I got visual HPPD, BUT unfortunately it's hard to say whether the same changes that caused the visuals were the cause of the audio changes or whether they just happened to occur around the same time (especially when it comes to MDMA). What I mean to say is that this maybe isn't a phenomenon that is occurring 100% in visual areas of the brain - other areas are affected. DR/DP are two other symptoms that are hard to nail down as being perceptual or whatever too but to me they do have a sensory component.

From what I've heard flashbacks are probably partially related to death of inhibitory neurons.
 
Cotcha Yankinov said:
From what I've heard flashbacks are probably partially related to death of inhibitory neurons.
Click to expand...

There isn't any evidence of cell death in HPPD. Furthermore, it would be obvious if inhibitory interneurons died. Most of the cells in V1 are organized to detect visual edges and their orientation, effects that are dependent on lateral inhibition via GABAergic interneurons. Other inhibitory interneurons in V1 are required for color vision. Loss of interneurons would produce profound deficits in visual perception, not the distortions that are characteristic of HPPD. This is well known because there are many cases of cell loss due to stroke, hypoxia, poisoning, etc that have been studied.
 
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When you say there isn't any evidence of cell death in HPPD, are you saying we should discount inhibitory cell death as a potential contributing cause of psychedelic flashbacks because we don't see increased cell death in HPPD? Makes sense. I can't remember where I heard about the inhibitory cell death thing...
 
The idea of GABAergic interneurons dying was first proposed by Henry Abraham's papers, but it was just speculation. In addition to having no supporting data, the proposal also doesn't make any sense based on how V1 neurons are known to function. Hubel and Wiesel worked out how V1 functions in the 1960s and 1970s and won a Nobel prize for their work. Treating V1 like a black box is about forty years out of date.

"One suggestion regarding the etiology of HPPD is that LSD in vulnerable persons reduces the population of 5-HT2 inhibitory interneurons modulating visual processing by excitotoxicity, thus reducing GABA efferents to glutamatergic neurons."
 
I see... Very interesting... What do you think is contributing to HPPD? COMT changes?

I'm not too sure if a hypothesis for HPPD would need to center around 5HT2A dysfunction anyways, seeing as NMDA antagonists supposedly can cause HPPD. Can MDAI and such cause HPPD? Or is it mainly 5-HT2A agonists?
 
^ Drugs that work on COMT may be useful treatments but COMT itself likely plays no role. The rationale for testing COMT inhibitors is that they can increase sensorimotor gating in individuals with COMT polymorphisms.

We know next to nothing about the causes of HPPD because it is relatively rare. The extent to which it is caused or exacerbated by drug use (some people who develop HPPD symptoms do not use hallucinogens) and anxiety (some clinicians think it is actually an anxiety disorder) is unclear. But it is known that drugs from a variety of classes can improve or worsen the symptoms. That means that the ability of COMT inhibitors to affect HPPD doesn't necessarily mean that COMT is involved in the illness. Sensorimotor gating abnormalities are usually linked to schizophrenia and there are a variety of gene polymorphisms that are known to be linked to altered sensorimotor gating, including the gene for 5-HT2A. So at this point any link to HPPD is tentative at best.
 
Do you think that already weakened sensorimotor gating in the form of some of those schizophrenia polymorphisms might predispose one to HPPD? Seeing as I just got my 23andme/promethase results back I'm curious about the particulars of those genes...

On another note, it appears that I have "one short form 5-HTTLPR", which might explain my issues with MDMA?
 
Personally, I don't think HPPD is a gating disturbance. I think it is an excitability disorder..sort of like a seizure disorder but the overexcitation doesn't spread.

What are your issues with MDMA?
 
If HPPD was a more seizure related disorder then it would explain why sodium channel antagonists help some.

I just have a lot of residual effects from having used MDMA years ago, insomnia/anxiety/DR/DP and such, but I remember seeing a couple studies concerning MDMA and tryptophan depletion where as I recall the people with the short form of the SERT gene were worse off.
 
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