Bit of an idea for possible CURE. Has some weight to it.

[propat45]

He was on such low doses of both Keppra and flunarizine that it's hard to imagine that those medications reduced his symptoms so drastically.  I'm more inclined to believe that he got better with time.

[Fawkinchit]

asdf

[propat45]

No need to be a complete douche-bag. 

 

I read that the starting dose for flunarizine is 10 mg and he's taking 1 mg.  He's also taking 50 mg of Keppra which is really small. 

 

It seems like Survey is attributing the reduction of his symptoms to the combination of Keppra and flunarizine.  He's taking a tenth of the starting dose of flunarizine and about 1/30 the dose of Keppra recommended in the study which is 1500 mg.  I hope these meds do work.  However, it's such a small amount that I feel there has to be other factors involved in how he got better.

[LarryC]

You could be right Skunk44. Alot depends on how long he has had it. But low doses may help some in specific combinations.

 

No need to be a complete douche-bag. 

 

I read that the starting dose for flunarizine is 10 mg and he's taking 1 mg.  He's also taking 50 mg of Keppra which is really small. 

 

It seems like Survey is attributing the reduction of his symptoms to the combination of Keppra and flunarizine.  He's taking a tenth of the starting dose of flunarizine and about 1/30 the dose of Keppra recommended in the study which is 1500 mg.  I hope these meds do work.  However, it's such a small amount that I feel there has to be other factors involved in how he got better.

[Jay1]

Could be placebo too.... It really does have strong powers, including feelings of symptoms returning, when stopping the drug. Amazing how the brain works.

[Fawkinchit]

asdf

[onedayillsailagain]

It really has nothing to do with the Keppra, he may not even realize this himself, he states that his visuals came back after going off Flu, pretty obvious whats the main driving factor there.

 

The only problem that I am having with this is I cant find the connection between 5ht2a receptors and calcium pumps. He stats its 5ht2a -> NMDA -> Calcium Channel, but I cant find anything to support this.

I think perhaps he might be referring to some LSD-LTP induced excitotoxicity:

 

I began to think about the fact that LSD after ingested begins by agonizing the 5-HT2a receptor, which then agonizes NMDA receptors, which is thought to largely account for the perceptional changes. Then the path gets murky, but I wondered if in the case of HPPD excitotoxicity occurred at some point (NMDA receptor overload) which works by overloading calcium channels.

5-HT2a------->NMDA---------->excitotoxicity (calcium ions)

I wondered if somehow in the case of HPPD if this cycle was still going on and if trying to block it at one of those receptors might help. I began with a 5-HT2a antagonist, Pizotifen and it had no effect. I then moved on to an NMDA antagonist, Namenda, which helped a little to calm me down, but ultimately did not move the needle. Then I read Ghormeh's post on this web site about visual symptoms being reduced by a calcium channel blocker called flunarizine and gave it go.

 

Exactly how LSD produces its effects is unknown, but it is thought that it works by increasing glutamate release in the cerebral cortex

Seems that glutamatergic excitotoxicity is what happens with LSD ingestion, be it direct or indirect. 

 

Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by Glutamatergic Storm.

His reasoning is actually not strange: http://www.nature.com/npp/journal/v26/n5/pdf/1395848a.pdf

Basically the idea was, that changes (neural or genetic, maybe in the form of LTP, doesn't really matter for now) had occured which caused chronic glutamatergic (and thus ionic calcium) excitotoxicity. Hyperexcitability (convulsant activity of substantial degree, as seen in HPPD) tends to involve this as well: http://en.wikipedia.org/wiki/Epilepsy#Pathophysiology.

 

However, levetiracetam binds to a synaptic vesicle glycoprotein, SV2A, and inhibits presynaptic calcium channels. This is believed to impede impulse conduction across synapses.

Despite the extremely low dosing, it can't simply be said that Keppra isn't doing anything for him. As he said himself though; he hasn't tried Flunarizine without Keppra, so perhaps you are right. But it could be that because they both interact with calcium transmission, they're working synergistically. Also from his report, it seems that such a low dose was effective for him. Yes, might be placebo. But honestly I think that if he didn't have a profound sustainable revitalizing epiphany of some sorts, he would've been smart enough to know that it was an isolated incidence of placebo, subsequently he would probably haven't gone through the trouble of posting his results. He's obviously tried various things, and would know how to discern between placebo and actual effect.

Hate to be talking in the third person though, so maybe @Survey could join the discussion?

[propat45]

Starting dose for what?? Hypertension? Oh! Ok.

 

Sibelium (flunarizine) is indicated in:

 

-Prophylaxis of classic (with aura) or common (without aura) migraine

[Fawkinchit]

I think perhaps he might be referring to some LSD-LTP induced excitotoxicity:

 

 

Seems that glutamatergic excitotoxicity is what happens with LSD ingestion, be it direct or indirect. 

 

His reasoning is actually not strange: http://www.nature.com/npp/journal/v26/n5/pdf/1395848a.pdf

Basically the idea was, that changes (neural or genetic, maybe in the form of LTP, doesn't really matter for now) had occured which caused chronic glutamatergic (and thus ionic calcium) excitotoxicity. Hyperexcitability (convulsant activity of substantial degree, as seen in HPPD) tends to involve this as well: http://en.wikipedia.org/wiki/Epilepsy#Pathophysiology.

 

Despite the extremely low dosing, it can't simply be said that Keppra isn't doing anything for him. As he said himself though; he hasn't tried Flunarizine without Keppra, so perhaps you are right. But it could be that because they both interact with calcium transmission, they're working synergistically. Also from his report, it seems that such a low dose was effective for him. Yes, might be placebo. But honestly I think that if he didn't have a profound sustainable revitalizing epiphany of some sorts, he would've been smart enough to know that it was an isolated incidence of placebo, subsequently he would probably haven't gone through the trouble of posting his results. He's obviously tried various things, and would know how to discern between placebo and actual effect.

Hate to be talking in the third person though, so maybe @Survey could join the discussion?

 

Yah that would great if he would, he has some substantial research and evidence. Obviously intelligent.

 

Sibelium (flunarizine) is indicated in:

 

-Prophylaxis of classic (with aura) or common (without aura) migraine

 

 You missed the whole point of the response. Good job bro!

[Fawkinchit]

asdf

[propat45]

Yah that would great if he would, he has some substantial research and evidence. Obviously intelligent.

 

 

 You missed the whole point of the response. Good job bro!

 

I just wanted to add to the discussion.  You're clearly an asshole.

[Fawkinchit]

In the rat cerebellum, the protein(5ht2a receptors) has also been found in the Golgi cells of the granular layer,^[19] and in the Purkinje cells. --->

 

Purkinje cells, or Purkinje neurons(/pərˈkɪndʒiː/ pər-kin-jee), are a class of GABAergic neurons located in thecerebellar cortex. They are named after their discoverer ---->

 

People with cerebellar ataxia may initially present with poor balance, which could be demonstrated as an inability to stand on one leg or perform tandem gait. As the condition progresses, walking is characterized by a widened base and high stepping, as well as staggering and lurching from side to side.

 

 

Interesting line of connections there, symptoms of hppd sometimes have been known to exhibit balance disorders, seems to be linked to cerebellum purkinje neurons.

[Fawkinchit]

This is a whole list of connections that might possibly link to symptoms of HPPD in other disorders. Feel free to do research on all these to see what you can find.

 

5-HT_2A is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotoninergic terminal rich areas, including neocortex(mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle. Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes,^[8][9][10] by enhancingglutamate release followed by a complex range of interactions with the 5-HT_1A,^[11]GABA_A,^[12] adenosine A₁,^[13] AMPA,^[14] mGluR_2/3,^[15] mGlu5,^[16] and OX₂receptors.^[17][18] In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer,^[19] and in the Purkinje cells.^[20][21]

In the periphery, it is highly expressed in platelets and many cell types of thecardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT_2A mRNA expression has been observed in humanmonocytes.^[22]

[Fawkinchit]

This is probably a piece of gold right here.

 

Newer findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT_2A–mGlu2 and not by monomeric 5-HT_2A receptors.

 

The mGluRs perform a variety of functions in the central and peripheral nervous systems: For example, they are involved in learning, memory, anxiety, and the perception of pain.^[3] They are found in pre- and postsynaptic neurons in synapsesof the hippocampus, cerebellum,^[4] and the cerebral cortex, as well as other parts of the brain and in peripheral tissues.^[5]

 

Like other metabotropic receptors, mGluRs have seven transmembrane domainsthat span the cell membrane.^[6] Unlike ionotropic receptors, metabotropic glutamate receptors are not ion channels. Instead, they activate biochemical cascades, leading to the modification of other proteins, as for example ion channels.^[7] This can lead to changes in the synapse's excitability, for example by presynaptic inhibition ofneurotransmission,^[8] or modulation and even induction of postsynaptic responses.

[Fawkinchit]

Wow this is awesome

 

Golgi cells areinhibitory interneurons found within the granular layer of the cerebellum. They were first identified as inhibitory by Eccles et al. in 1964.^[1] It was also the first example of an inhibitory feed back network, where the inhibitory interneuron was identified anatomically.

 

This ties in with the inhibitory feedback that I was talking about in the beginning of this thread, that there may have been damage to these inhibitory cells, and the brain now lacks the ability to modulate anxiety!

 

The question now just remains, do hallucinogens cause damage and burn out of these cells through excitotoxicity or are they turned off through receptor triggers.

 

Personally im leaning towards excitotoxic burnout.

[Fawkinchit]

Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitterglutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by Glutamatergic Storm.

 

In post #414 you can see that 5ht2a receptors effect glutamate release, and AMPA receptors, this means that the everstimulation of the receptor will cause an over abundance of the release of glutamate, causing overexcitotoxicity and the death of selective inhibitory neurons. That basically seems to be it guys. All the connections seem to be made.

[onedayillsailagain]

Damn.. nice find qaiphyx!

So then one could try and go about modulating metabotropic glutamate receptors or gene expression (which would probably prove to be extremely difficult).
One thing that keeps coming back is the excitotoxicity though. Seeing as this would be easier to treat, I'd expect that taking the right combination of supplements/medications would be enough to reduce symptoms. Maybe this is partly the reason why Keppra works so well for some:
 

The anti-epileptic action of LEV may be partially due to a reduction of glutamate-induced excitotoxicity and an enhancement of the GABAergic inhibition as observed with the inhibitory effect on the 40 mM KCl-evoked glutamate overflow.

http://www.ncbi.nlm.nih.gov/pubmed/17408599

And it of course inhibits pre-synaptic calcium channels.

On mitochondrial damage and excitotoxicity from wikipedia:

Increased extracellular glutamate levels leads to the activation of Ca2+ permeable NMDA receptors on myelin sheaths and oligodendrocytes, leaving oligodendrocytes susceptible to Ca2+ influxes and subsequent excitotoxicity. One of the damaging results of excess calcium in the cytosol is initiating apoptosis through cleaved caspase processing. Another damaging result of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release reactive oxygen species and other proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium.

It would seem to be that supporting mitochondrial function, by example, would be beneficial in mitigating excitotoxicity.. Or anything that could limit or reverse the excitotoxic damage really:
 

Exposure of cultures to MKC-231 (Coluracetam) for 12 – 24 hr ameliorated glutamate cytotoxicity. MKC-231 reduced cytotoxicity induced by ionomycin, a calcium ionophore, but did not affect the cytotoxicity induced by S-nitrosocysteine, a nitric oxide (NO) donor. These findings suggest that MKC-231 protects against glutamate neurotoxicity by suppressing the NO formation triggered by Ca²⁺-influx.

http://www.ncbi.nlm.nih.gov/pubmed/9541286

I'll look into this later, but it's definitely interesting, thank you!

[onedayillsailagain]

Wwhy do I have to feel so loopy now? I thought I somehow found a way to provide an end to the cycle. Well, let me try regardless.

 

This extends the concept that cortical acetylcholine enhances neuronal signal to noise ratio. It is suggested that muscarinic receptor activation in the cortex is involved in confining the contents of the discrete self-reported conscious "stream." In the absence of cortical acetylcholine, currently irrelevant intrinsic and sensory information, which is constantly processed in parallel at the subconscious level, enters conscious awareness. This is consistent with the ability of anti-muscarinic drugs administered medically, recreationally, or ritualistically to induce visual hallucinations and other perceptual disturbances.

Acetylcholine and hallucinations: disease-related compared to drug-induced alterations in human consciousness

Relevance of S-N-R can be found here and here for those of you cognitively more competent than I am (at this moment).
So.. correct me if I'm wrong, but acetylcholine enhances signal-to-noise ratio (possibly synonymous to: "reduces neuronal noise"). Epiphany? Perhaps.

Soooo.. damnit I lost all my relevant arguments. But it basically came down to: Coluracetam (High-Affinity Choline Uptake Enhancer/ AcetylCholine biosynthesis enhancement) + PRL-8-53 (Positive Allosteric Modulator for ACh receptors / potentiates the effects of ACh) = Super cholinergic synergy + protection from excitotoxicity = probably pretty darn awesome for our case.

I got too excited and closed some pretty awesome pages by accident, and can't seem to retrieve them. Damn, damn, and damn. Hoping one of you can make use of this sparse information, and that I might be able to expand on this tomorrow.

Perhaps also of interest (although it's on retinal neurons.. but w/e): http://www.iovs.org/content/45/5/1531.full

[Fawkinchit]

Damn.. nice find qaiphyx!

So then one could try and go about modulating metabotropic glutamate receptors or gene expression (which would probably prove to be extremely difficult).

One thing that keeps coming back is the excitotoxicity though. Seeing as this would be easier to treat, I'd expect that taking the right combination of supplements/medications would be enough to reduce symptoms. Maybe this is partly the reason why Keppra works so well for some:

http://www.ncbi.nlm.nih.gov/pubmed/17408599

And it of course inhibits pre-synaptic calcium channels.

On mitochondrial damage and excitotoxicity from wikipedia:

It would seem to be that supporting mitochondrial function, by example, would be beneficial in mitigating excitotoxicity.. Or anything that could limit or reverse the excitotoxic damage really:

http://www.ncbi.nlm.nih.gov/pubmed/9541286

I'll look into this later, but it's definitely interesting, thank you!

The excitotoxicity cascade is no longer present in the brain, it is present during the influence of the hallucinogenic compounds. Once the hallucinogens are out of the blood stream the excitotoxic event ends. HPPD is a result of neuronal apoptosis(death) during the excitotoxic event. The only way to fix HPPD is through neurogenesis, the only other method of having a significant effect would be to somehow mimic the inhibitory cells such as the perkinje cells, or the golgi, which I assume would be impossible, and that would only effect anxiety and balance I believe, so visuals would still be there etc.

 

[onedayillsailagain]

qaiphyx: How do you know the excitotoxicity is no longer present? I don't have anything to support this (yet), but it could be that through genetic alterations or other mechanisms, that some kind of excitotoxic "cycle" is taking place. Hyperexcitability/pre-seizural activity, can be/is, accompanied by excitotoxicity. What use is neurogenesis when apoptosis is still taking place then? Besides, neurogenesis mainly takes place in the hippocampus, and AFAIK never in adult visual cortex. By saying that neurogenesis is the true and only fix, you're simultaneously saying that there is no fix.

If as you say the inhibitory cells are dysfunctional/damaged, then that would only trigger a cascading event of excitotoxicity I'd suppose.
Also there's enough evidence suggesting the cerebellum (where most of these cells are located) is intrinsically involved with vision, so it wouldn't only affect anxiety and balance.

Just some thoughts straight out of bed here.. back to the tea

[Fawkinchit]

qaiphyx: How do you know the excitotoxicity is no longer present? I don't have anything to support this (yet), but it could be that through genetic alterations or other mechanisms, that some kind of excitotoxic "cycle" is taking place. Hyperexcitability/pre-seizural activity, can be/is, accompanied by excitotoxicity. What use is neurogenesis when apoptosis is still taking place then? Besides, neurogenesis mainly takes place in the hippocampus, and AFAIK never in adult visual cortex. By saying that neurogenesis is the true and only fix, you're simultaneously saying that there is no fix.

If as you say the inhibitory cells are dysfunctional/damaged, then that would only trigger a cascading event of excitotoxicity I'd suppose.

Also there's enough evidence suggesting the cerebellum (where most of these cells are located) is intrinsically involved with vision, so it wouldn't only affect anxiety and balance.

Just some thoughts straight out of bed here.. back to the tea

 

If you go over everythimg that I have posted recently you can see that the excitotoxicity is from 5ht2a receptor activation,  its all in the notes, it goes 5ht2a agonist > 5ht2a receptor > glutamate release > excitotoxicity > neuronal apoptosis. Im sure its hard to take on and alot of people are going to just be in denial about cause brain damage seems like a dead end, but its not, neurogenesis is possible, and can be proven easily to be so, its just figuring out how.

 

Also damage to specific sites in the cerebellum is all Ive shown, im sure that there is damage to inhibitory cells also in the visual cortex, and there should be some in the lobes, 

 

Also didnt know that the cerebellum was involved with vision can you provide the information on that.

[Transform]

Here's my take: what you really want is serotonin to bind with these receptors, not some other chemical to take its place. Yeah you have agonists but a lot of them are hallucinogens.....lol........RC chemicals, dmt, lsd, mescaline etc. ...........as of right now the best things are small amounts of benzos and re-uptake inhibitors (dopamine, norepinephrine, serotonin, etc.) which leaves more neurotransmitter jumping around the cleft and binding.

Do re-uptake inhibitors make you feel at all wired or anything. Because i don't wanna get ahold of these things and spazz out like when i was sent to the insane asylom when i was on STP and a chineese man began stuffing large amounts of Zeprexa down my throat "Because i needed it" Yeah right that shit made my syptoms way worse, like pouring salt on an open wound.

 

I agree with the low dose- Benzo treatment but honestly man it only works so long.. and i don't like gulping down pills everytime my engine starts thumping and i start to hear my brain sizzle but do i have a choice? Id rather feel normal for an hour in my day than feel dissociated for 24....

[Fawkinchit]

Do re-uptake inhibitors make you feel at all wired or anything. Because i don't wanna get ahold of these things and spazz out like when i was sent to the insane asylom when i was on STP and a chineese man began stuffing large amounts of Zeprexa down my throat "Because i needed it" Yeah right that shit made my syptoms way worse, like pouring salt on an open wound.

 

I agree with the low dose- Benzo treatment but honestly man it only works so long.. and i don't like gulping down pills everytime my engine starts thumping and i start to hear my brain sizzle but do i have a choice? Id rather feel normal for an hour in my day than feel dissociated for 24....

 

 

It can be presumed that the stimulatory effect of reuptake inhibitors could make symptoms worse.

[Guest]

Just curious Qaiphyx but at one point in time in early onset more than 15 years ago, I was taking 5htp supplements and I kid you not when I say my DP/DR and anxiety levels went through the fucking roof. Considering your knowledge base, would you know the reason why this happened?

[Fawkinchit]

Just curious Qaiphyx but at one point in time in early onset more than 15 years ago, I was taking 5htp supplements and I kid you not when I say my DP/DR and anxiety levels went through the fucking roof. Considering your knowledge base, would you know the reason why this happened?

 

I could only assume that its cause its a precursor to serotonin, were you on any other meds? Were there any other supplements? BTW 15 years? Wow man im really sorry!