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Mike

Nuplazid, A new, novel medication, give it a look

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This is interesting....

 

Was browsing some medical things today and came across this med that came out recently.  It made me think it may be beneficial to this underserved area due to its unique mechanism of action.  

It's essentially an add on antipsychotic BUT it doesn't work like any other antipsychotic on the market.  It targets 5HT2A almost exclusively as an inverse agonist and to a much lower extent at 5HT2C.  You guys probably know that LSD, psychedelics, ect, target 5HT2A as an agonist, this is essentially a down regulator at that site in other words calming overexcitability.  That's kind of simplifying it but it look interesting and nothing else seems to help much other than time.  The side effect profile is suppose to be low because it does not effect dopamine receptors that cause Parkinsonism, Tardive dyskinesia.  Its used to treat hallucinations in Parkinson's because it doesn't mess with dopamine.  

I know there's some people on this board that know about all the pharmacology and this looks like it's hitting where it needs to, and a new avenue, there is no other inverse agonist on the 5HTA2 receptor on the market, might be worth a shot, best of luck to all of you, give it a look.

https://en.m.wikipedia.org/wiki/Pimavanserin

 

https://en.m.wikipedia.org/wiki/Inverse_agonist

 

https://en.m.wikipedia.org/wiki/5-HT2A_receptor

 

http://www.parkinson.org/find-help/blogs/whats-hot/april-2016

^^^^^ bullet points sum up above link ^^^^^

 

Best

Edited by Mike
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This is a related drug "in the model of" the drug mentioned above that has not made it through the drug approval pipeline yet, probably a couple more years if not fast tracked.  I bring it up because the chart on this website kind of simply explains the mechanism of this new class.  It is literally described as ....

 

"The candidate, nelotanserin, targets the 5HT2A receptor for serotonin in cells from the central nervous system. Its activation is the basis of psychedelic drugs such as LSD. Nelotanserin does the opposite, blocking its activity to reduce hallucinations in patients with DLB and PDD."

 

With a diagram.

 

Give it a look.

 

http://labiotech.eu/axovant-sciences-bermuda-dementia/

 

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Edited by Mike
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Looks interesting, for sure. Wonder how long it will take to come to market?

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Nuplazid is already available in the US, seems interesting, was reading some more about it.  It's a new class of antipsych that fills a need none of the others were.  Previous post is from another drug with a similar profile in the pipeline.  This was from another website that explained how it worked and in way, why maybe others are having difficulty treating symptoms.

 

Dr Kremens: NUPLAZID is a selective serotonin inverse agonist. To understand this, you have to understand how receptors in the brain work. Many receptors in the brain are capable of initiating signals even when they are not being stimulated, even when you don’t have an agonist bound to that receptor. Signaling can occur without an agonist; that is called basal activity. If you have an agonist, that stimulates a receptor and increases the activity of that receptor. Then there are drugs called antagonists. Antagonists block the agonist, but they permit the ongoing basal activity. Then you have inverse agonists. Inverse agonists suppress basal activity. So, with NUPLAZID, you are suppressing the basal activity of some serotonin receptors in the brain. It’s thought that the effect of NUPLAZID is a result of a combination of an inverse agonist and antagonist activity at serotonin receptors.
- See more at: http://www.ajmc.com/journals/supplement/2016/understanding-the-burden-and-management-of-hallucinations/a645-article/P-4#sthash.O13qeyGg.dpuf

 

 

 

 

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Thanks for this. Sounds like it's worth a shot. I hope people give this a try and report back. Would love to hear their experience good or bad. It would probably tell us a lot about what exactly is going on with that receptor, if anything. 

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I'd try it in a heartbeat.

I was thinking of trying Remeron because it antagonizes 5ht2a and is different than the typical SSRI but I'd try this first if I could get my hands on it.

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Also Remeron has a high affinity for blocking 5ht2a and is unlike other antidepressants.

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I haven't looked into this in quite awhile but this to me is very interesting.  In other words they seem to be implying is that inverse agonist bring down the basal activity, think of basal activity as "baseline activity".  

 

From the way this doctor describes it :

 

Dr Kremens: NUPLAZID is a selective serotonin inverse agonist. To understand this, you have to understand how receptors in the brain work. Many receptors in the brain are capable of initiating signals even when they are not being stimulated, even when you don’t have an agonist bound to that receptor. Signaling can occur without an agonist; that is called basal activity. If you have an agonist, that stimulates a receptor and increases the activity of that receptor. Then there are drugs called antagonists. Antagonists block the agonist, but they permit the ongoing basal activity. Then you have inverse agonists. Inverse agonists suppress basal activity. So, with NUPLAZID, you are suppressing the basal activity of some serotonin receptors in the brain. It’s thought that the effect of NUPLAZID is a result of a combination of an inverse agonist and antagonist activity at serotonin receptors.
- See more at: http://www.ajmc.com/journals/supplement/2016/understanding-the-burden-and-management-of-hallucinations/a645-article/P-4#sthash.O13qeyGg.dpuf

 

so even if your antagonizing the receptor your still activating it in a sense, antagonism returns it to it "baseline".  But if it's stuck being hyperactive so to speak, inverse agonism depresses it, it's different, a lower baseline.  The "volume" is what needs to be lowered.

 

 

Edited by Mike
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Been looking all of this up again I guess for whatever reason.  A doctor apparently treated this condition with a VERY LOW DOSE of Zyprexa.  I'm talking 2.5 mg or lower, not even therapeutic.  Apparently when he went higher he got an opposite effect, doesn't sound like many people were helped by Zyprexa, quite the opposite, but not sure they were on a low dose.  He even wrote a book about it the condition if that means anything, The Post-LSD Syndrome.

http://www.blogtalkradio.com/powerful-patient/2012/04/13/curing-the-post-lsd-syndrome

 

Ketaserin is an older hypertensive agent, also sold as a gel that is related to Nuplazid(primavanserin).  It seems to come up a lot when researching this area.  It seems like researchers are aware of its LSD blocking capabilities and effects on seretonin, however, it's only I guess shown to stop the effects of lsd when taken prior to ingestion??? Though I have never heard of anybody using it for this condition before this article was recently published.  Not sure about availability.

https://www.theverge.com/2017/1/26/14388034/lsd-acid-neuroscience-trip-meaning-research-science

Edited by Mike
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This is fascinating. Has anybody here read that book? In the descriptions I've found online he doesn't refer to it as HPPD, only "Post-LSD Syndrome." Also, the symptoms listed aren't in line with what we have. They mention depression, sleeplessness, etc., but no visual disturbances -- at least not in the summaries I read. 

Also, has anybody tried Ketaserin or Nuplazid? Both seem promising but perhaps difficult to get ahold of. Here's an interesting thread on this subject: 

http://hppdonline.com/index.php?/topic/2294-5-ht2a-antagonists-a-complete-cure-for-hppd/#comment-18303

Lastly, did anybody else have a profound sense of meaning shortly after getting HPPD? I haven't thought much of it until reading all this stuff, but I remember in the first few weeks after getting HPPD having an absolutely revelatory sense of understanding about the world and how life was only worth living when there was meaning involved -- essentially all the stuff you're supposed to have happen while tripping, except this was weeks later. Clearly there was something going on with those same receptors that induce meaning into the world, I just don't know what exactly. 

Edited by K.B.Fante
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I'vd just noticed that Trazodone is also a 5th2a anti angonstic.

I tried that, with no success, unfortunatly.

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This is a drug that dasitmane and I sort of was looking at in 2013 i think. 

dasitmane was always saying ht2a inverse agonists.  So I found Acadia.  I bought the stock at $2.60 at dasitmane's advice.  A family member thought I was crazy so I didn't buy as much as I wanted.  Uggh.   We need someone to get on it and see.  Right now I think it is only for Parkinsonian psychosis but soon will be an add-on for schizophrenia I believe. 

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Maybe the drug company will get greedy and push to have it as an add on for MDD and it'll be the next Abilify handed out like candy. 

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It will definitely get used for all sorts of stuff at some point if it is a good drug.  IDK.  

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For what it's worth, I contacted the authors of the recent North Carolina study about whether they think HPPD could be a result of a permanent sealing of the lid on the seratonin receptor and one of them said he thinks its highly unlikely. In fact, he specifically said he thinks there's no way it's even possible. Instead, he suggested the visual cortex could have become "sensitized" given our visual disturbances and the fact this area of the brain has a high number of 5-HT2A receptors. 

He sorta sounded like he was just spitballing, but I guess it's something. Still doesn't tell us much. 

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If anything, if you have a good relationship with your doctor and you explain it to them, you may be able to get a free 30 day sample pack.  It is being tested as an add on for psychiatric problems as well but when it gets through trials is anybodies guess, it may be another year or so until it is officially labeled as such.  I guess it's something you have to ask your doctor if it being covered for right now.  Chances are, it will become a wildly popular medication due to the fact that it lowers the amount of other psych meds that people have to take thus lowering the side effect profile, and it has been used in research settings for quite some time.  Hopefully if it's remarkably effective, it will not need to be used very long term.  Maybe paired up with klonopin or something.

Edited by Mike
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Also kind of wonder about the low dose of Zyprexa or antipsych meds the one doctor had success with, whether that actually holds up or if they act differently when not causing so much stimulation.

Edited by Mike
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Yeah trazadone is an antagonist, this med is an inverse agonist, it's different.  It's mechanism is to lower the activity or hyperactivity of 5ht2a receptors.

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8 hours ago, Mike said:

Also kind of wonder about the low dose of Zyprexa or antipsych meds the one doctor had success with, whether that actually holds up or if they act differently when not causing so much stimulation.

I'm getting on 2.5 mg Zyprexa soon. Probably this week.

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Interesting tidbit about Remeron:

"A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson's disease psychosis (PDP).[42]This is in alignment with recent findings that inverse agonists at the 5-HT2Areceptors are efficacious in attenuating the symptoms of Parkinson's disease psychosis. As is supported by the common practice of prescribing low-dose quetiapine and clozapine for PDP-doses too low to antagonise the D2receptor, but sufficiently high doses to inversely agonise the 5-HT2Areceptors."

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I think the bigger thing there might be the low dose of antipsych's.  It seems like it's kind of mixed if remeron an inverse agonist at 5ht2a.  A lot of pages say it's an antagonist.  I think if people would have gotten better off remeron it would have been found by now.   Think it helps to a point.  Not trying to bring you down.  Sure some records on this page.

Edited by Mike
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Got a feeling if the low dose antipsych deal worked, it would take a some time, just throwing that out there.  Your trying to get the over activity at 5ht2a down, that's basically the premise and what the guys in North Carolina were trying to tell you and maybe what the guy that wrote the post led syndrome book wrote.  

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It's essentially less is more.  When you start increase the dosage of these drugs you start activating all these other receptors and they interact and start bouncing off each other.  For lack of a better example,  I guess kind of like finding a "goldilocks zone".   Kind of like slowly bringing the train to a halt as opposed to slamming the brakes and having the wheels fall off.  

 

Also, just hypothetically, I wonder if there's kind of a "breaking point" so to speak, were you keep enough "pressure" on the point(5ht2a), and Things start to normalize.  Like if you take X antipsych at a low dose for a month or two or maybe even longer that then it starts to "slow the train down"  like a crest or something, then maybe like a cool down period so it gets use to being in a normal state.  Everybody probably has a different I guess "goldilocks zone" so to speak and you have to "hit the brakes" a different amount of time for whatever person.  But hypothetically, your trying to take an amount lower than the amount that causes extrapyrimadal side effects(or I guess very minimal).  That I imagine would be a good indicator because if your activating other receptors, I.e. Dopamine.  I guess one good thing is that if anything, most people with this are in a relative steady state(you don't have Parkinson's), but I'm not a doctor but if you have other Health problems, you should not ignore them, just throwing that out there.  If anybody listened to the podcast by the doctor that wrote the "Post Lsd Syndrome" book, he was using the lowest possible dose of Zyprexa(2.5 mg) of all things and sometimes that was too much so people I guess cut them in half if you can, half to listen again sometime.  Was reading though that Zyprexa effects 5ht2a and 5ht2c,ect at a much higher level than dopamine, which may be why the guy that wrote the "post lsd" book got more benefit from it than others.  Maybe an easier way to find a middle ground with it.

But I guess the thing about Nuplazid is it bypass having to do most of this because it doesn't mess with a lot of other receptors other than 5ht2a(strongly) and much less more 5ht2c, it just may be a challenge of getting a script and even then getting it paid for.  I know they have free 30 day sample packs out. I guess nobody knows how long it would take to work if it did since nobody's given it a real run yet, might take awhile might not, everybody's different.  I would think if you had a good relationship with your doc and you showed him some literature a light would go off in their head.

 

Either way both avenues are worth exploring.  Yeah so in short.

Nuplazid 

or

Low dose antipsych in a "goldilocks zone"

 

good luck

 

 

Edited by Mike
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