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5-HT2a Antagonists: A complete cure for HPPD?

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HPPD seems to be caused by substances of all types that cause excessive 5-HT2a agonism (such as psychedellics, serotonin drugs, and high-dose SSRI). This 5-HT2a agonism leads to severe down-regulation of the 5-HT2a receptors in the visual cortex (among other places), and this leads to severe overexcitation of the neurons and hence visual anomalies.

 

Research has shown that 5-HT2a agonists can provide temporary relief from visual symptoms (which would be expected, as the overload of 5-HT2a activation supercedes their downregulation), but can cause further 5-HT2a down-regulation and thus don't serve much benefit in the treatment of HPPD.

 

Now research has also shown that 5-HT2a antagonists cause exacerbations of HPPD visual symptoms, but this would be expected; as the already down-regulated 5-HT2a receptors are receiving even less activation than before. But, over time, the lack of activation of 5-HT2a receptors (due to the antagonists) would cause a significant upregulation in the 5-HT2a receptors; back to their normal level. This means that after a period use of the antagonists the 5-HT2a receptors will return to their natural level of activation, and the visual symptoms should subside; even though during treatment the visual symptoms would be exacerbated, it would eventually lead to complete remission.

 


Articles (use Google for more):

 

5-HT2a antagonist causing HPPD symptoms in someone without HPPD:

http://www.erowid.org/archive/rhodium/pharmacology/risperidone.palinopsia.html

 

http://en.wikipedia.org/wiki/Antidepressant

"While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2A receptors, suggesting it is too simplistic to say serotonin is a happy hormone. In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again - the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behavior. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance."

 

Notice the bolded text. This effect of 5-HT2a receptors is analagous to the effect it has on the visual system. With HPPD-downregulated 5-HT2a receptors, our visual system continues to search for visual information (is disinhibited), and very rarely receives the "saturation signal" from the 5-HT2a receptors. This causes the visual anomalies. Using 5-HT2a antagonists would understimulate them and cause them to upregulate themselves to normal levels, causing a normal amount of "saturation signals" in the visual cortex and eliminating any visual anomalies.

 

 

Further evidence:

 

Many people with HPPD verify remission of the most debilitating visual symptoms over time, leaving them with only a light case of visual snow. This would be expected, as their 5-HT2a receptors begin to upregulate themselves to approach their normal range, the severe visual symptoms disappear; however, they may only upregulate themselves to the bottom of their normal activation range which would leave a light speckling of visual snow and not a complete natural remission, as most anecdotal evidence shows; and an extremely light level of visual snow is considered a normal occurrence, even people not affected by HPPD can see it if they concentrate very hard and look for it. This 5-HT2a antagonist treatment would allow the 5-HT2a receptors to upregulate even beyond the bottom level of the normal range, to a level where the visual snow becomes virtually invisible.


Anecdotal reports, even on these very forums, show exacerbation of visual symptoms while on 5-HT2a antagonists, followed by a strong reduction in visuals after their discontinuance. Had these cases been treated in an intelligent manner with supporting actions, it is very likely they would have received a complete remission of all symptoms.

 

 

Any input from knowledgeable others?

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Why the disbelief? Just the lack of a precedent?

Well, firstly putting something bold and exciting like 'a complete cure for HPPD' (full stop) in the title with no evidence is disappointing. I was expecting to read a case of someone being cured.

 

Anecdotal reports, even on these very forums, show exacerbation of visual symptoms while on 5-HT2a antagonists, followed by a strong reduction in visuals after their discontinuance. Had these cases been treated in an intelligent manner with supporting actions, it is very likely they would have received a complete remission of all symptoms.

It would be good if you could link to some of these reports and elaborate what you mean by an intelligent manner of treatment.

5-ht2a receptors have been discussed extensively on this forum, I do not recall seeing any great success in solely tackling these. I personally think tackling the serotonergic system alone is too simplistic, why can be inferred from a different idea I wrote about recently, it contradicts yours somewhat; http://hppdonline.com/index.php?/topic/2280-why-nmda-antagonism/ . I also don't have evidence though (I will be guinea pigging myself as soon as possible).

I am not saying you are incorrect but I think your argument needs more substantiating. 

This is relevant to your idea, http://www.ncbi.nlm.nih.gov/pubmed/9720968

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This is the general idea about the mechanism behind HPPD, yes. But wouldnt it be simple just try an antagonist in, let say, five people? We would know instantly if this is the way. It should have a profound effect on HPPD if the theory that everything starts with 5-HTP2A and is the cause of most of the symptoms.

As dr A said, the most probably way to find a cure is for people on this board trying new meds, backed by different theories about the cause of HPPD to give some credit in what to try.

So, i believe the progress in search of a cure or symptom relief is up to ourselves. Thats why it so important to post about what we try and why in the pharm section. Imo, we need more Guinea pigs. There is too much talk and to little trials.

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This is the general idea about the mechanism behind HPPD, yes. But wouldnt it be simple just try an antagonist in, let say, five people? We would know instantly if this is the way. It should have a profound effect on HPPD if the theory that everything starts with 5-HTP2A and is the cause of most of the symptoms.

As dr A said, the most probably way to find a cure is for people on this board trying new meds, backed by different theories about the cause of HPPD to give some credit in what to try.

So, i believe the progress in search of a cure or symptom relief is up to ourselves. Thats why it so important to post about what we try and why in the pharm section. Imo, we need more Guinea pigs. There is too much talk and to little trials.

Yeah, I don't really understand why some people are so hesitant to guinea pig.. I would rather keep trying new meds with some decent research / ideas behind them with the risk of things getting temporarily worse than not trying at all because of the possibility of negative effects. That I've had this for nearly three years now is bad enough, it can't really get worse, the damage is done. I mean as long as you're not just blindly taking meds, what the hell? Hands up here if anyone has some good ideas and not willing to test on themselves.. I volunteer myself :)

Also, it's kind of ironic that probably quite a few people didn't really give a shit when taking far more dangerous substances, yet now prospectively treating themselves have decided 'oh, well chemicals got me here, I fucked up, I shouldn't take substances unless they're 99% safe now'. I think this is cognitive dissonance to the max and is simply giving up.

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Thanks for putting that in perspective Syntheso. Anyway: Intracranial stem cell injections! Not willing to try that myself, so have a go at that! Haha just kidding, but indeed it would be nice if people would be more ready to guinea pig. Problem is though that it would require some basic knowledge of pharmacology to do it safely, but then again as you said yourself; quite the ironic plot twist. Luckily we already have quite a few people who are trying things, so I guess we can be grateful for that. I'd like to see more people giving non-invasive brain stimulation a try though.. I repeat: non-invasive. At worst you'll have a mild headache, a little fatigue, but other than that you won't feel any worse, and it actually poses quite the good potential if done properly IMO. Then again, finances can be a limiting factor, also generally speaking it's not that readily available as medication, though I think it's actually far more advanced in the US than it is in the EU. Either way, it's definitely worth a shot for those hesitant to try medications (though I suppose from that point of view, zapping your skull with electricity would call upon a sort of "Requiem For A Dream" scenery in the mind's eye).

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Thanks for putting that in perspective Syntheso. Anyway: Intracranial stem cell injections! Not willing to try that myself, so have a go at that! Haha just kidding, but indeed it would be nice if people would be more ready to guinea pig. Problem is though that it would require some basic knowledge of pharmacology to do it safely, but then again as you said yourself; quite the ironic plot twist. Luckily we already have quite a few people who are trying things, so I guess we can be grateful for that. I'd like to see more people giving non-invasive brain stimulation a try though.. I repeat: non-invasive. At worst you'll have a mild headache, a little fatigue, but other than that you won't feel any worse, and it actually poses quite the good potential if done properly IMO. Then again, finances can be a limiting factor, also generally speaking it's not that readily available as medication, though I think it's actually far more advanced in the US than it is in the EU. Either way, it's definitely worth a shot for those hesitant to try medications (though I suppose from that point of view, zapping your skull with electricity would call upon a sort of "Requiem For A Dream" scenery in the mind's eye).

Hah, if I didn't think there is an easier way I would do that, but I reckon there probably is. Give me 6-12 months and if nothing comes up I'm game  ;) 

Yeah indeed, you do, but it's all online, and you can buy books cheaply, so worth the shot to get better. You're right, it's good that quite a few people are, but not enough IMO. I'll be trying BS when my headset arrives, need to do a fair bit of reading though !

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Yeah, I don't really understand why some people are so hesitant to guinea pig.. I would rather keep trying new meds with some decent research / ideas behind them with the risk of things getting temporarily worse than not trying at all because of the possibility of negative effects. That I've had this for nearly three years now is bad enough, it can't really get worse, the damage is done. I mean as long as you're not just blindly taking meds, what the hell? Hands up here if anyone has some good ideas and not willing to test on themselves.. I volunteer myself :)

Also, it's kind of ironic that probably quite a few people didn't really give a shit when taking far more dangerous substances, yet now prospectively treating themselves have decided 'oh, well chemicals got me here, I fucked up, I shouldn't take substances unless they're 99% safe now'. I think this is cognitive dissonance to the max and is simply giving up.

 

I think you're being completely unfair there. I say well done to those of have learnt from their past mistakes and now are being very careful what they put into their body in case they make things worse, either temporarily, or permanently. I also salute those who are willing to take a few risks for the benefit of the community. 

 

There are are also limiting factors such as access to open doctors and financial constraints. 

 

There is no right or wrong way to tackle this disorder. Everyone makes their own decisions and different things will work for different people. 

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I think you're being completely unfair there. I say well done to those of have learnt from their past mistakes and now are being very careful what they put into their body in case they make things worse, either temporarily, or permanently. I also salute those who are willing to take a few risks for the benefit of the community.

There are are also limiting factors such as access to open doctors and financial constraints.

There is no right or wrong way to tackle this disorder. Everyone makes their own decisions and different things will work for different people.

Perhaps I am being unfair, but I see lots of people beating themselves up on the point that they made a mistake. I think those people are being unfair on themselves. As such, they sort of give up - give up on the prospect of getting better and the future, trying out new things, doing personal research, and instead only accept what their doctor prescribes. I don't consider my usage of drugs in the past a mistake, it was part of my life and I wouldn't change it. I wouldn't change getting HPPD. It sucks, but it's what happened, I, we, were unfortunate. We didn't choose our disorder in the same way that bipolar people don't choose theirs. I would give away both my legs for it to go away now, but I wouldn't change having it. I do hope it will go away, I am confident it will in my lifetime, if not in the next year, but whatever happens it will be an important lesson. Anyway, the point of what I wrote was not to slag people off, and I didn't prescribe a right or wrong to the way to tackle the disorder. I simply set forward a personal view and it was more my intention to encourage people to be more active and fight the bloody thing, albeit my expression was quite blunt.

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Perhaps I am being unfair, but I see lots of people beating themselves up on the point that they made a mistake. I think those people are being unfair on themselves. As such, they sort of give up - give up on the prospect of getting better and the future, trying out new things, doing personal research, and instead only accept what their doctor prescribes. I don't consider my usage of drugs in the past a mistake, it was part of my life and I wouldn't change it. I wouldn't change getting HPPD. It sucks, but it's what happened, I, we, were unfortunate. We didn't choose our disorder in the same way that bipolar people don't choose theirs. I would give away both my legs for it to go away now, but I wouldn't change having it. I do hope it will go away, I am confident it will in my lifetime, if not in the next year, but whatever happens it will be an important lesson. Anyway, the point of what I wrote was not to slag people off, and I didn't prescribe a right or wrong to the way to tackle the disorder. I simply set forward a personal view and it was more my intention to encourage people to be more active and fight the bloody thing, albeit my expression was quite blunt.

 

I actually agree with a lot of this second post and it is similar to my outlook, even though I don't think it is completely relevant to your original post in relation to being a guinea pig for medications. I can totally understand why people would want to be really careful what they put in their body after acquiring HPPD. 

 

Back to the subject of the thread - I'd also be interested to see evidence of 5HT2a antagonists making symptoms worse. We've all read about the agonists making things worse but I've not yet seen any reports of antagonists doing the same. I'm not even sure how many people have tried antagonists.

 

Anyone tried pizotifen? I know one person has: http://hppdonline.com/index.php?/topic/888-70-95-reduction-of-symptoms-keppraflunarizine/?hl=pizotifen

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I apologise, I was hasty before. I'm quite interested in trying an anti-serotonergic approach, I see the potential for it to be palliative.

Any thoughts about what available antiserotonergic drugs would be best to try? As OP mentions 5-HT2a receptors make sense as the primary target.



5-HT2A antagonists[edit source | editbeta]


This is interesting;



 

The influence of antiserotonergic agents on the action of dopaminergic drugs.

Abstract

The effect of drugs blocking serotonin receptors: cyproheptadine, methysergide, and methergoline, and of serotonin synthesis inhibitor, p-chlorophenylalanine on the stereotyped behavior and number of rearings of the rats receiving apomorphine, amphetamine, nomifensine and 1,3-dimethyl-5-aminoadamantane was investigated. The blockade of serotonin receptors potentiates behavioral effects of dopamine agonists. It is concluded that central serotonin may play an inhibitory role, antagonistic to that of catecholamines.



Edit: Found some Cyproheptadine 15 x 4mg for £2.29, ordered. If anyone else wants to give it a whirl, let me know I'll send you the site (trusted vendor I have used a lot)

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I apologise, I was hasty before. I'm quite interested in trying an anti-serotonergic approach, I see the potential for it to be palliative.

Any thoughts about what available antiserotonergic drugs would be best to try? As OP mentions 5-HT2a receptors make sense as the primary target.

5-HT2A antagonists[edit source | editbeta]

This is interesting;

 

Edit: Found some Cyproheptadine 15 x 4mg for £2.29, ordered. If anyone else wants to give it a whirl, let me know I'll send you the site (trusted vendor I have used a lot)

 

That's one of the ones I was going to suggest. The migraine dosage seems to be 4mg three times daily; I would try doing that, and experimenting with the amount of dosage at once (seeing if 8mg makes a difference over 4mg). This may require higher doses than normal, as we're trying to upregulate the receptors.

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That's one of the ones I was going to suggest. The migraine dosage seems to be 4mg three times daily; I would try doing that, and experimenting with the amount of dosage at once (seeing if 8mg makes a difference over 4mg). This may require higher doses than normal, as we're trying to upregulate the receptors.

Yeah agreed. I haven't yet looked into how potent it is as an antiserotonergic, but potentially quite a bit more than the usual dose to harness that aspect. I don't mind about its antihistamine effects, I have high-ish histamine and take antihistamines anyway. I have ALCAR to counteract the anticholinergic properties and/or Coluracetam. I'll send you a link to the vendor I was talking about.

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What about, given that people have been negatively affected by serotonin agonists/SSRI's, the idea that HPPD = too much serotonin; serotonin toxicity/serotonin syndrome. I know some people on the board have been diagnosed with that and I'm pretty sure it's been discussed a few times already. I don't understand why SSRI's would have such negative effects in HPPD if there was a lack of serotonin. They only inhibit serotonin being absorbed by the presynaptic cell, they don't agonise the 5-HT receptors... so I don't really see a potential to 'overdo it'. Maybe I'm missing something but it seems that SSRI's would only worsen things in the case of serotonin toxicity. I know they have affinity for other receptors, but these are only weak.  Can anyone shed some light on that thought? I will post something more detailed on this later if poss.

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I think it may depend on what SSRI in particular. Paxil for example has anticholinergic effects, albeit not as bad as Scopolamine for instance.
Which are the most common SSRI's reported to have adverse effects? I did Prozac for a while, and I didn't experience any effects.
Are you suggesting that HPPD may be a case of serotonin syndrome/too much serotonin? I have some thoughts on that which I'll try to add later.
Funny; because I tried Tianeptine, which is a Selective Serotonin Reuptake Enhancer, and albeit not a fair trial, the first week I noticed some benefits such as anxiolysis. I quit after week 2 however, because I didn't notice any benefits past ~day 3-6 and wrote it off as placebo, plus I tend to be impatient and I was going to try something else. Hardly can this be seen as useful data though, considering the improper trial.

By the way; Ketanserin seems better from an initial glance.

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I think it may depend on what SSRI in particular. Paxil for example has anticholinergic effects, albeit not as bad as Scopolamine for instance.

Which are the most common SSRI's reported to have adverse effects? I did Prozac for a while, and I didn't experience any effects.

Are you suggesting that HPPD may be a case of serotonin syndrome/too much serotonin? I have some thoughts on that which I'll try to add later.

Funny; because I tried Tianeptine, which is a Selective Serotonin Reuptake Enhancer, and albeit not a fair trial, the first week I noticed some benefits such as anxiolysis. I quit after week 2 however, because I didn't notice any benefits past ~day 3-6 and wrote it off as placebo, plus I tend to be impatient and I was going to try something else. Hardly can this be seen as useful data though, considering the improper trial.

By the way; Ketanserin seems better from an initial glance.

For sure. I was on Citalopram for 3 weeks with HPPD and can't say I noticed a difference, not that long for an SSRI though. It seems to be widely accepted on this board that SSRI's = bad for HPPD.

I'm not sure.. I would like to know. 

I am saying yes possibly, but also the OP seemed plausible IIRC. Certainly some of the effects of serotonin toxicity seem to make sense in HPPD. What's interesting though is the effect of serotonin on other neurotransmitters. More on that later. 

Edit: Doesn't look like Ketanserin is marketed.

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Any supplements or ideas on this..I got VS 4 months ago from a high dose of antibiotics and have BAD negative afterimages which seem to be a retinal issue...Mild snow and bad BFEP..Maybe time will help???

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St Johns Wort for 5ht2a Upreg?

"Pharmacopsychiatry. 1997 Sep;30 Suppl 2:113-6.
Effects of long-term administration of hypericum extracts on the affinity and density of the central serotonergic 5-HT1 A and 5-HT2 A receptors.
Teufel-Mayer R, Gleitz J.
Source
Department of Naturheilkunde, Ulm University, Germany.
Abstract
Extracts of St. John's wort, Hypericum perforatum L. (Hypericaceae), are used as a phytotherapeutic antidepressant. A number of clinical studies demonstrate that their antidepressive potency is comparable to tricyclic antidepressants (TCA). Although the therapeutic effect of hypericum extracts is well documented, very little is known about the molecular mode of action. As the improvement of the depressive symptoms with both TCA and hypericum extracts only occurs significantly after a lag phase of 10 to 14 days, it is assumed that the medication causes long-term adaptations within the central nervous system. In this context, serotonergic (5-HT) receptors are of special interest. Therefore, we investigated possible alterations in affinity and density of 5-HT1 A and 5-HT2 A receptors caused by long-term treatment of rats with St. John's wort. The brain without cerebellum and brain stem of rats, treated daily for 26 weeks with a commercially available hypericum extract (2700 mg/kg LI 160) were used for membrane preparations. Affinity (KD) and amount (Bmax) of serotonergic receptors were determined by employing receptor binding assays using 3 H-8-OH-DPAT and 3H-Ketanserin as selective radioligands for the 5-HT1 A and the 5-HT2 A receptors, respectively. We found that in hypericum-treated rats the number of both 5-HT1 A and 5-HT2 A receptors were significantly increased by 50% compared to controls, whereas the affinity of both serotonergic receptors remained unaltered. The data suggest an upregulation of 5-HT1 A and 5-HT2 A receptors due to prolonged administration of hypericum extracts. These results are consistent with a modification of the expression levels of serotonergic receptors caused by synthetic antidepressants.
PMID: 9342771 [PubMed - indexed for MEDLINE]
MeSH Terms, Substances"

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I volunteer myself after five years lol. The main issue is always going to be getting the "guinea pig" medicine from the docs. I believe a lot of people have tried just solely these? Maybe on the old board but those records are gone unfortunately. Stem cell is an interesting idea for sure but a little extreme at the moment...maybe.

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