zuclopenthixol (clopixil) use and 1p-LSD

[haflerhecker]

Hi, I am currently receiving intramuscular injections of clopixil every 2 weeks as an inpatient on a psychiatric ward due to paranoid schizophrenia. I am being released in around 3 weeks, with the depot injection being managed in the community, and am wondering about the use of 1p-LSD as a shamanic / recreational tool. I have 10 tabs waiting for me at home (what I would consider a "lifetime supply" taking the doses sparingly over the coming years). As an antidopaminergic drug, is the clopixil likely to interfere with the traditional psychedelic experience (whatever that may be - YMMV!) or have significant side effects with the other drugs I am planning on using (MMB-Chiminaca, EG-018, MXP and 3F-Phenmetrazine, also to be used in moderation)? I have read that antipsychotics can be used to kill a trip in process so was wondering if a constant dose within my system is likely to produce dulled effects. For the record, I am aware that I could be "stretching my sanity" when it comes to the realm of voice hearing and other psychotic symptoms / delusions but I already "suffer" from mild HPPD from previous pseudo-acid experiences so pushing at the margins of this is not really a huge concern. I am planning on researching the Bahai'i faith and "becoming one with the universe" is part of my plan, so to speak! Would appreciate any input that the community here could give. Thanks in advance.

 

[haflerhecker]

Hi, I am currently receiving intramuscular injections of clopixil every 2 weeks as an inpatient on a psychiatric ward due to paranoid schizophrenia. I am being released in around 3 weeks, with the depot injection being managed in the community, and am wondering about the use of 1p-LSD as a shamanic / recreational tool. I have 10 tabs waiting for me at home (what I would consider a "lifetime supply" taking the doses sparingly over the coming years). As an antidopaminergic drug, is the clopixil likely to interfere with the traditional psychedelic experience (whatever that may be - YMMV!) or have significant side effects with the other drugs I am planning on using (MMB-Chiminaca, EG-018, MXP and 3F-Phenmetrazine, also to be used in moderation)? I have read that antipsychotics can be used to kill a trip in process so was wondering if a constant dose within my system is likely to produce dulled effects. For the record, I am aware that I could be "stretching my sanity" when it comes to the realm of voice hearing and other psychotic symptoms / delusions but I already "suffer" from mild HPPD from previous pseudo-acid experiences so pushing at the margins of this is not really a huge concern. I am planning on researching the Bahai'i faith and "becoming one with the universe" is part of my plan, so to speak! Would appreciate any input that the community here could give. Thanks in advance.

Edit: I am also prescribed procyclidine, promethazine, co-codamol, ibuprofen and B vitamins although I can't see these having any significant contraindications - anybody think differently?

 

[serotonin2A]

Zuclopenthixol acts as a 5-HT2A antagonist, the primary site responsible for 1P/LSD effects. So the effects of hallucinogens will be inhibited to some degree. The chronic blockade would also cause desensitization of 5-HT2A, so even if you could somehow magically remove all the zuclopenthixol from your system, the response to 1P-LSD would still be blunted.

 

[Cotcha Yankinov]

Chronic blockade would cause desensitization? Are we speaking of an inverse agonist? I know you once said 5HT2A is strange though.

Also, wouldn't the brain cells downstream of the 5HT2A compensate if 5HT2A is being blocked?

 

[serotonin2A]

^ 5-HT2A regulation is atypical compared to other GPCRs. Most 5-HT2A antagonists cause desensitization -- they act as biased agonists, selectively activating the second messenger pathways that are responsible for desensitizing and/or internalizing 5-HT2A.

 

[Cotcha Yankinov]

So this desensitization would only be true of ligands that are not binding to the orthosteric site like a regular antagonist (which I understand is not the site that mediates any signal transduction, but can just block a real ligand from binding to the allosteric site?)

I have seen a some ligands disproportionately reported as 5HT2A inverse agonists compared to their other serotonin receptor efficacy so I guess this explains things.

Any comment on why selective 5HT2A inverse agonists (ketanserin) aren't on the market (Pimavanserin aside)? I heard chronic SSRI administration for depression works to some degree by down regulating 5HT2A - wouldn't you think we would search for a much faster solution in form of a selective 5HT2A inverse agonist?

Sorry to derail the thread!

 

[serotonin2A]

So this desensitization would only be true of ligands that are not binding to the orthosteric site like a regular antagonist (which I understand is not the site that mediates any signal transduction, but can just block a real ligand from binding to the allosteric site?)

I don't understand what you mean -- the desensitization occurs with 5-HT2A antagonists such as clozapine, risperidone, and ketanserin, which bind to the orthosteric site.

Any comment on why selective 5HT2A inverse agonists (ketanserin) aren't on the market (Pimavanserin aside)? I heard chronic SSRI administration for depression works to some degree by down regulating 5HT2A - wouldn't you think we would search for a much faster solution in form of a selective 5HT2A inverse agonist?

5-HT2A antagonists have been investigated for several indications but it turns out that they don't work very well -- or at least not as well as existing medications. Volinaserin was found to be effective for insomnia but subjects in clinical trials didn't like it; patient satisfaction was low because volinaserin doesn't produce sedation.

 

[Cotcha Yankinov]

I'm guessing the subjects in the volinaserin trial were not drug naive? Seems like scientifically that would be flawed but as far as profit goes you would want a drug that bodes well with the patient population you are marketing to (people who have been on Z-drugs etc)?

If depression dose involve over-expression if 5HT2A receptors in humans in some instances, then do you think that is something that would slip through the animal models of depression, and you would have to skip straight to human studies, and maybe select some humans that have increased 5HT2A receptor density? Or is over expression of 5HT2A not causal of depression?

 

[Cotcha Yankinov]

Edit: sorry, I thought you were using "antagonist" in one of your earlier posts to mean inverse agonist just out of simplicity for the poster.

I thought ketanserin/Risperidone were inverse agonists. Are there orthosteric binding inverse agonists?

 

[serotonin2A]

I'm guessing the subjects in the volinaserin trial were not drug naive? Seems like scientifically that would be flawed but as far as profit goes you would want a drug that bodes well with the patient population you are marketing to (people who have been on Z-drugs etc)?

If depression dose involve over-expression if 5HT2A receptors in humans in some instances, then do you think that is something that would slip through the animal models of depression, and you would have to skip straight to human studies, and maybe select some humans that have increased 5HT2A receptor density? Or is over expression of 5HT2A not causal of depression?

I don't think it is an issue of using non-drug naive subjects. In many patients, the subjective perception of having poor sleep quality is a big part of insomnia. Volinaserin reduces the amount of time it takes to fall asleep but that doesn't translate to a subjective sense that sleep has improved.

5-HT2A density probably isn't an important causitive factor in most depression cases.

Edit: sorry, I thought you were using "antagonist" in one of your earlier posts to mean inverse agonist just out of simplicity for the poster.

I thought ketanserin/Risperidone were inverse agonists. Are there orthosteric binding inverse agonists?

There are very few 5-HT2A neutral antagonists -- virtually every drug that blocks 5-HT2A acts as an inverse agonist. However, 5-HT2A inverse agonists can also be classified as 5-HT2A antagonists, and that is what most people call them.

There is no reason why inverse agonists cannot act through an orthosteric mechanism. In fact, most 5-HT2A inverse agonists, including, clozapine and ketanserin, act on the orthosteric site.

 

[Cotcha Yankinov]

I apologize profusely - I thought he orthosteric site was the neutral antagonist binding location (an article I learned from only depicted inverse agonism at the PAM site).

In an attempt to reduce clutter I've made a new thread on 5HT2A receptors, wondering about their locations important for psychedelic experience and wakefulness. http://www.bluelight.org/vb/threads...xperience-wakefulness?p=13692245#post13692245

I'd really appreciate it if you'd look over it

 

[paranoid android]

Clopixol along with being one of the most potent D2 antagonists out there is also a 5ht2a antagonist so Psychedelics would not work while taking this drug. Everyone i know who has had it said it left them a drooling zombie basically until it worse off. Not to mention if you actually need a Typical Anti-Psychotic as heavy as zuclopenthixol taking Psychedelics may not be a great idea.