The Cause of HPPD and Possible Treatments.

[Fawkinchit]

Found some extremely interesting studies today that show that hallucinogens increase over excitation in the prefrontal cortex specifically of the pyramidal cells, and another study showing that there is an interaction linking these pyramidal cells along with inhibitory neurons to anxiety, which is a commonly reported symptoms of HPPD as everyone knows. It talks about a ratio in certain cases between the types of cells becoming imbalanced, though the reason cause seemingly is untraced.

I find it interesting because its likely that in HPPD these may be the specific cells that are damaged, it could also be the loss of the inhibitory cells that allow for HPPD symptoms via the pyramidal cell dysregulation.

 

https://journals.sagepub.com/doi/full/10.1177/0269881121991569

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345483/

[Fawkinchit]

I know I haven't been posting much lately, this condition is very troubling for everyone, I understand. I want to let everyone know that I am dedicated to furthering the research, understanding, and treatment for this condition, fully and to complete resolution as long as the physics of the universe will allow it. I am trying very diligently to find a way to accumulate funds for further research, because I believe its at that point. I do genuinely believe that this condition is mitochondrial in origin and damaging to neurons, whether it be microstructure or apoptosis. We need ways to do extensive research to facilitate real and known ways for resolving this. Please do not excuse my lack of posting as surrender, or any form of relinquishment. As long as I live on this earth, I will continue to find a way to resolve this. Thanks to everyone that follows my posts and supports me, and I thank everyone for their kind words.

[James91]

@Fawkinchit hey pal I'm sure I speak not on behalf of just myself when I say thankyou for your efforts and continued efforts, it's the detication of people like yourself who drive for understanding and cures that change the life of countless people for the better.

I'm not sorry if thats mushy as I feel that you (and many others out there for that matter) deserve a pat on the back. I've seen how much you do and it deserves the recongnition.

I aim to follow in such footsteps and hope I can be a part of positve change too.

[Fawkinchit]

On 10/3/2022 at 1:00 PM, James91 said:

@Fawkinchit hey pal I'm sure I speak not on behalf of just myself when I say thankyou for your efforts and continued efforts, it's the detication of people like yourself who drive for understanding and cures that change the life of countless people for the better.

I'm not sorry if thats mushy as I feel that you (and many others out there for that matter) deserve a pat on the back. I've seen how much you do and it deserves the recongnition.

I aim to follow in such footsteps and hope I can be a part of positve change too.

Thanks man! Means a lot to me

[Fawkinchit]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208100/

just posting this here for a future post so I dont lose it.

[MentholFlavoring]

Just came across this study, thought it was interesting to post. Another study that proves MDMA can cause overstimulation in GABAergic cells by 5HT2A activation and as a result cause a long-term loss of (in this case) parvalbumin interneurons. I know that this kind of neuron exists only in very small populations throughout the brain but havingunique functions, and it is very sensitive and vulnerable to overstimulation.

 

https://www.sciencedirect.com/science/article/abs/pii/S0014299915003799

"MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors"

[MentholFlavoring]

I don't want to scare anyone with this, it doesn't mean there's no hope, neurons are just processing units and others can take over their function. My own theory is that there's another deficit preventing proper re-stabilization after the initial neuronal loss.

 

Edit: this study showed that the loss happened in the dentate gyrus which is a neurogenic region (where neurogenesis takes place). Gotta read into it.

Edited November 23, 2022 by MentholFlavoring

[Fawkinchit]

On 11/23/2022 at 6:31 AM, MentholFlavoring said:

Just came across this study, thought it was interesting to post. Another study that proves MDMA can cause overstimulation in GABAergic cells by 5HT2A activation and as a result cause a long-term loss of (in this case) parvalbumin interneurons. I know that this kind of neuron exists only in very small populations throughout the brain but havingunique functions, and it is very sensitive and vulnerable to overstimulation.

 

https://www.sciencedirect.com/science/article/abs/pii/S0014299915003799

"MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors"

Wow thank you for posting this, this is a great find! I was trying to get around to making a post and some of it was going to be in regards to interneurons and the subtypes, and on how hallucinogens cause depolarization of these neurons. I was going to explain that I think Dr. Abraham may very well be right in his hypothesis of interneuron loss. So much so that I wonder if he knows that it is, and just doesn't want to say due to the overwhelming emotions it can cause patients with this condition.

Anyways I think this link may very well be the answer we have been looking for. Great job man! And thank you. The one thing that I see is that it does say its mediated through 5HT2A, I'll have to look up whether or not MDMA acts as a 5HT2A agonist like hallucinogens, in which case I suppose its likely the end of this research.

The other article I posted is just some interneuron regeneration stem cell therapy. I can't remember at this exact moment why I have it saved with the other link, but thought it may be encouraging to post.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855184/

https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/stem.3252

Edit: I reviewed the article a little and it states

"Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT_2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region."

It looks like its primarily the glutamate that causes the parvalbumin interneuron loss, and that it somehow is dependent on 5HT2A. So it still doesn't exactly show that hallucinogens cause interneuron loss through 5HT2A receptor agonism. 5HT2A receptor agonists(Hallucinogens) method of action is the depolarization of these interneurons as it might appear, allowing for other sensory neurons to become overexcited. As far as I understand it at least.

So I would have to say its still not definitively neuronal loss yet. But I think that interneurons are a avenue to go down, to further understand the methodology of the compounds and their effects on the central nervous system.

[Fawkinchit]

If I can find a way to culture Interneurons it would be simple to test the potential for toxicity of hallucinogenic compounds. And also test for potential neurogenesis. I already have the equipment I would need I will just have to figure out a way to culture them. 

[Fawkinchit]

It appears its possible

https://www.frontiersin.org/articles/10.3389/fncel.2017.00423/full

https://www.frontiersin.org/articles/10.3389/fncel.2022.827628/full

Also more info on interneurons

https://www.sciencedirect.com/topics/neuroscience/5-ht2a-receptor

https://elifesciences.org/articles/66960

[jh875]

On 11/24/2022 at 5:20 PM, Fawkinchit said:

It looks like its primarily the glutamate that causes the parvalbumin interneuron loss, and that it somehow is dependent on 5HT2A. So it still doesn't exactly show that hallucinogens cause interneuron loss through 5HT2A receptor agonism. 5HT2A receptor agonists(Hallucinogens) method of action is the depolarization of these interneurons as it might appear, allowing for other sensory neurons to become overexcited. As far as I understand it at least.

Hppd is a condition that is in some ways similar to ptsd and in some ways different. For ptsd some research indicates that there are some autoimmune links or that it is driven or made worse by inflammation in the brain.

Injecting drugs into the brains of mice (I don't know if they used a reasonable dosage or not) is likely to cause inflammation and neurological changes. If the dosages are reasonable it is likely the mice will recover, however I am not sure if this is connected to hppd directly. The changes might be stress related.

If hallucinogens cause damage to certain brain cells (which I think is a possibility) it might be by altering how nerves fire. If you slow down or stop a neurons activation for a while  it might "gasp for air" and have a patter of activation and inactivation that is abnormal. I could see how this might be toxic for neurons or select for neurons that function in a slightly different way from normal neurons.

Like, for example, uv rays might make dark patches of skin grow larger as they aren't as effected by sun light compared to other areas of skin.

Hallucinogen flashbacks might indicate that taking hallucinogens changes gene expression, how some or all neurons function or the pattern of  connectivity in the brain. And then under certain circumstances this pattern is activated.

Stress for some people can cause a flashback I have heard.

The 5HT2A is likely a trigger for hppd I think however there may be multiple complex things going on, rather than just damaged neurons. 5ht2a receptor is present in immune cells also, so it is also likely that a hallucinogen could prevent the immune system from working properly which may prevent proper brain repair.

I think people on this forum have had mixed results with this method:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8987195/

but it may give insight it to what might be causing hppd.

Clonazepam up regulates the 5ht2a  receptor is certain parts of the brain and down regulates it in other parts.

https://cris.tau.ac.il/en/publications/clonazepam-treatment-of-lysergic-acid-diethylamide-induced-halluc

[MentholFlavoring]

Thanks man, I appreciate your excitement! I wasn't even specifically looking for it, it just came by as a coincidence.

I remember in one paper from Dr. Abraham it was mentioned specifically to not call HPPD a "loss" of neurons yet since it wasn't evident enough, instead, calling it an inhibitory "deficit" or something like that. Another interesting aspect of HPPD is DP/DR. It is known that DP/DR is a common comorbidity of HPPD. DP/DR could be caused by disturbances in frontal cortex regions, while the visual symptoms of HPPD seem to evolve mainly from the visual cortex only. It makes me think that the brain dysfunction is not be isolated only to the visual cortex, but may be more widespread in the brain.
 
Here is a cell culture study: (@Fawkinchit this is exactly the thing you want to do, how great is that! :P)

"Ecstasy induces apoptosis via 5-HT2A-receptor stimulation in cortical neurons"
https://www.sciencedirect.com/science/article/abs/pii/S0161813X0700071X

Here is another study related to the dentate gyrus: (the dentate gyrus is a region inside the hippocampus)

"MDMA and Glutamate: Implications for Hippocampal GABAergic Neurotoxicity"
https://etd.ohiolink.edu/apexprod/rws_olink/r/1501/10?clear=10&p10_accession_num=ucin1460444662
 

Edited November 29, 2022 by MentholFlavoring

[Fawkinchit]

On 11/29/2022 at 1:47 PM, MentholFlavoring said:

 Here is a cell culture study: (@Fawkinchit this is exactly the thing you want to do, how great is that! :P)

"Ecstasy induces apoptosis via 5-HT2A-receptor stimulation in cortical neurons"
https://www.sciencedirect.com/science/article/abs/pii/S0161813X0700071X

Damn dude, that's probably it. I mean, its true, they don't state the dose, its pretty important information. I will see if I can contact any of them to find out. Thing is though it shows that over stimulation of the 5ht2a receptor is the specific cause of the neuronal loss, via free radical production.

"Cortical neurons can be broadly divided into two classes: interneurons and projection neurons. The interneurons are a varied subgroup of cells, which occupy many different cortical layers and largely utilize GABA as a neurotransmitter."

So that's probably it, see there was a study that I found once that showed DMT had no notable neurotoxicity on neurons in vitro, but they were normal neurons if I remember correctly. Maybe I will have to find the study again. But these are specifically cortical, and I bet that's not what they used in the other study. I will try and find it.

[Fawkinchit]

It seems as though it still may not be the case as the actual neurotoxicity is still via glutamate, but the glutamate release requires the serotonin receptors. So still not solid.

normal hallucinogens as far as my understanding goes do not cause increases in glutamate.

https://pubmed.ncbi.nlm.nih.gov/25936514/

[Fawkinchit]

Ok, so it would appear that its quite likely that the glutamate release is activated by 5ht2a/5ht receptors, and would pretty much solidify the neurotoxicity or any 5ht2a agonist, specific to interneurons. Here is the study that basically shows the link between glutamate and 5ht2a.

https://www.nature.com/articles/1395430

So, I think everything really came around and connected everything together finally.

5ht2a agonism increases glutamate, we know already glutamate storms are neurotoxic. The neurotoxicity is mediated through reactive oxygen species leading to mitochondrial DNA damage/failure, which is going to cause them to signal apoptosis, leading to intraneuronal loss. Interneurons are regulatory neurons and without their involvement excitatory neurons will act unregulated giving the symptoms of HPPD.

The only thing that can show otherwise at this point is if say classical hallucinogens like LSD or DMT etc do not show the same release of glutamate. But based on the study posted here I think its likely it will be the same. 

What some people may be wondering then is why do some not appear to get HPPD and others do, but in this case the answer is simple. Because eventual neuronal loss is caused by reactive oxygen species its going to be mediated through various antioxidant profiles and according to one of the studies it looks to be glutathione, people who do not appear to get HPPD realistically are still probably losing neurons, however in the case of people with HPPD they likely have altered glutathione levels, which can occur for various reasons.

Well I'll try and add some positivity for anyone reading this, cause even after studying this for 10 years now this is a pretty hard read. The positive side is, that interneurons as far as I understand are specifically close proximity neurons and have short connections, so recovery under stimulation of neurogenesis is likely to be higher than say if long distance axons were damaged/lost. To say that other neurons in the surrounding areas are not affected, I'm not sure, but when I have time I will look in to the possibility.

I think though this most likely explains the cause and etiology of HPPD. Maybe we can get the information stickied so that people understand what it is that these compounds do, and will help to prevent the future use of them.

It explains as well why benzodiazepines assist the best in the condition but do not mute the symptoms entirely, is that there are no receptors/synapses/neurons to exhibit GABA for excitatory neurons, and it is probably acting on downstream neurons that still have their interneuron connections.

Big thanks to @MentholFlavoring for find those studies.

[Lucas]

Soooo...

Do you think there's hope to recover one day ?

[Fawkinchit]

11 hours ago, Lucas said:

Soooo...

Do you think there's hope to recover one day ?

Yah absolutely, however, as intricate as the brain is, I would assume there may be challenges at getting near the same architecture, or it may even be impossible to get the same architecture, especially if long distance neurons are affected. Basically, there can likely be a significant degree of recovery, but if the architecture doesn't return to complete normal, there will likely still be residual symptoms that are mild and light, or even be scarcely noticeable until say, drinking a lot of coffee. 

Ultimate goal is to find a way to recover to exact architecture. Neurogenesis in my opinion is the easy part. 

[kynerer]

It turns out that the treatment is to improve neurogenesis by increasing the level of glutathione?

[jh875]

6 hours ago, kynerer said:

It turns out that the treatment is to improve neurogenesis by increasing the level of glutathione?

It might help, I don't know. I don't think it is known why some people get HPPD and some do not. Inflammation might be part of the problem, or there could be a genetic link.

Glutathione in an antioxidant, if I remember rightly that blocks and modulates nmda receptor. NAC has been shown to be partly effective at lowering anxiety levels in number of different brain disorders.

Boosting antioxidants levels may be helpful at least partly, but I think people do get mixed results with that type of thing.

A high fiber diet boosts SCFA which can be used as fuel by the brain, and lowers inflammation.

Benfotiamine is a fat soluble form of Thiamine that can be more easily absorbed by nerves and the brain. Thiamine (depending on the dosage) acts as a nr-f2 activator with is anti-inflammatory.

[Fawkinchit]

On 12/7/2022 at 7:30 AM, kynerer said:

It turns out that the treatment is to improve neurogenesis by increasing the level of glutathione?

To explain simply, antioxidant profiles in people who get HPPD are probably lower, that's essentially my theory. Glutathione appears to be specific in this case according to the studies. In the studies listed, supplementing antioxidants reduced neuronal loss. So basically, neuronal loss is going to be dependent on dose, duration, and antioxidant levels. Its possible for people to have deficiencies in antioxidants, its actually the cause of scurvy, they lack vitamin c. Basically it appears to be a possibility that people who get HPPD, could possibly have lower or maybe even severely deficient levels of antioxidant profiles. Hence the reason that some get HPPD, and others appear not to get it. However, in both cases they both will have neuronal loss, however in the low antioxidant people, the neuronal loss will be more profuse.

If that makes sense.

It also will depend on dose and duration of use.

Once the damage is done, its not something that the antioxidants can repair as far as I know in medical literature. They're not a treatment, but rather a preventative measure.

[SteadfasttotheEnd]

On 3/28/2021 at 10:55 PM, Fawkinchit said:

So basically if anyone doesn't understand whats happening here, mitochondria have failed, producing excess free radicals, depleting neuron and astrocyte energy,  and causing excess premature oxidation of catecholamines(dopamine, noradrenaline, and adrenaline) which leads to abnormal neuronal behavior. So alleviating mitochondrial disfunction is the key to treating HPPD. Thats literally as simple as I can explain it. 

Interesting. So is the argument also that psychedelics damaged the mitochondria but if you take a supplement to fix the mitochondria, the damage can be reversed?

[Fawkinchit]

On 1/19/2023 at 6:03 AM, SteadfasttotheEnd said:

Interesting. So is the argument also that psychedelics damaged the mitochondria but if you take a supplement to fix the mitochondria, the damage can be reversed?

If per say that the neurons are not lost, then the mitochondria can repair and replenish. Unfortunately its just not known whether or not we have lost neurons.

[hff893]

Btw I just wanted to report that I'm kind of guinea-pigging your theory/regimen currently in case this might be interesting to you. Vitamin C 1g/day, Vit E 400 IU, Niacin 500mg. Have been at it for approximately one and a half months, so far no noticeable changes. Not on any medications except occasional benzo interventions.

[LonelySailor]

On 1/30/2023 at 7:12 PM, hff893 said:

Btw I just wanted to report that I'm kind of guinea-pigging your theory/regimen currently in case this might be interesting to you. Vitamin C 1g/day, Vit E 400 IU, Niacin 500mg. Have been at it for approximately one and a half months, so far no noticeable changes. Not on any medications except occasional benzo interventions.

Is it working?? 

I need some update on this theory plz 

[Sharlot]

19 hours ago, LonelySailor said:

Работает ли это??

Мне нужна некоторая информация по этой теории, пожалуйста

Hello! me too,please