Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use

cs3000

Most or maybe all anti psychotics have activity inhibiting serotonin receptors

when receptors coupled to g proteins are activated G proteins on the inside of the cell surface separate and exert their effects

the 5ht2a receptor specifically through g alpha protein causes hallucinations & psychosis

a supersensitive coupling of 5-HT2AR to Gαi1 as opposed to Gαq has been identified in the postmortem brain samples of schizophrenia patients.

impressive research,

after a while chronic anti-psychotics can increase HDAC 2 probably as they lose effect, @CrumblingCookie , This isnt a default feature of people with psychosis though by the looks of it,

the increase of HDAC2 binds the mGlu2 receptor promoter, and that inhibition increases a measure of psychosis in animals,

mglu2 activation can eliminate serotonin head twitch response (a sign of psychosis / hallucination), counters things at 5ht2a recpeptor

Activation of mGlu2 is well known to repress cellular, electrophysiological and behavioral responses that require the 5HT2A receptor. . Similarly, drugs that activate the mGlu2 receptor have potential for the treatment of schizophrenia, whereas 5HT2A agonists, such as hallucinogenic compounds, result in the opposite effect.
Taken together, these data suggest that the decreased density of 5HT2A binding sites by chronic treatment with atypical antipsychotic drugs results in a compensatory mechanism of repressive chromatin structure at the promoter region of the mGlu2 gene, with consequently less inhibitory effects of the mGlu2 receptor on 5HT2A-regulated pathways and behaviors.
Taken together, our findings indicate that increased expression of HDAC2 in mouse frontal cortex results in behaviors that are associated with impaired mGlu2 function.
Since activation of the mGlu2 receptor abolishes the head-twitch response induced by hallucinogens25,36, these findings correlate with the lower expression of mGlu2 in mice over-expressing HDAC2 in frontal cortex.
These data indicate that HDAC inhibitors stimulate mGlu2 promoter activity in vitro as well as in vivo in mouse frontal cortex.
We also observed that adjunctive SAHA abolishes the repressive histone modifications induced at the mGlu2 promoter by chronic atypical antipsychotics, which augments the behavioral effects induced by atypical and glutamate antipsychotics. Overall, our findings support the hypothesis that compensatory epigenetic events at the mGlu2 promoter may be responsible for the high incidence of patients that do not benefit from conventional therapy with atypical antipsychotic drugs, and provide a biochemical explanation for the clinical association of pharmacological inhibition of HDACs with improved schizophrenia treatment
5HT2A and mGlu2 interact through specific transmembrane domains to form a G protein-coupled receptor (GPCR) heterocomplex in mouse and human frontal cortex25. The signaling properties of this receptor heterocomplex have been proposed to be necessary for therapeutic-like effects of atypical antipsychotic drugs
These results suggest that the 5HT2A receptor is involved in treating the psychotic symptoms of schizophrenia, and that down-regulation of 5HT2A receptor binding sites by chronic atypical antipsychotic drugs may be one of the mechanisms underlying their therapeutic effects.
Remarkably, only chronic clozapine induces changes in histone acetylation at the 5HT2A promoter that correlate with its transcriptional repression. Although further investigation is needed to understand the mechanisms and consequences of this interesting finding, it is tempting to speculate that these histone modifications at the promoter of the 5HT2A gene may account for the enhanced antipsychotic properties of clozapine.

^ This part seems contradictory?
but for the rest below,
one potent HDAC inhibitor is sodium butyrate

also https://doi.org/10.3109/15622975.2011.585663 (5ht2a lowered a little from sodium butyrate, but mrna expression and its in the hippocampus, i think frontal cortex is more relevant here)

Here we show that chronic atypical antipsychotics down-regulate the expression of mGlu2, an effect that is associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurs in concert with a 5-HT2A receptor-dependent up-regulation and increased binding of HDAC2 to the mGlu2 promoter.
Viral-mediated over-expression of HDAC2 in frontal cortex decreases mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior.
Conversely, HDAC inhibitors prevent the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augment their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target to improve schizophrenia treatment.
https://pmc.ncbi.nlm.nih.gov/articles/PMC3431440/
we observed that atypical antipsychotics induce increased expression of HDAC2, and not HDAC1 or HDAC4, in frontal cortex of schizophrenic subjects, with no effect seen in untreated schizophrenic subjects

Im gonna edit this post in a bit adding more to the psychosis + serotonin part https://cs3001.substack.com/publish/post/155553845

Would be good to find something potent at lowering 5ht2a activity without big sides like crushing histamine/acetylcholine/dopamine. or something activating mglu2

NoeticJuice

@cs3000 said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

Would be good to find something potent at lowering 5ht2a activity

Nuciferine, found in blue lotus (both Nelumbo nucifera and Nymphaea caerulea), might work. At least blue lotus was effective as an antipsychotic for the person in this post:

53 days no psychosis thanks to blue lotus

Some people like to make tea from blue lotus, but nuciferine is not water soluble. Here's how the OP of the linked post consumed it:

"I pulverize two flowers each night and boil it in 200ml water until the petals lose the color, add a tablespoon or two of sweet honey. The pulverized flowers also make the tea a bit thickish which I find more pleasant to consume. Also I consume all of it including the small particles of petals, if I boil the flowers whole most of the flower goes to waste I think"

According to this study, among other effects, it's an antagonist at 5-HT2A and inhibits dopamine reuptake:

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

But it decreased dopamine here:

Lotus leaf Nuciferine improves sleep and reduces the low neuronal activity and brain tissue abnormalities associated with insomnia

cs3000

@NoeticJuice thanks. dived deep into it from your thread before , got interested seeing the anti psychosis benefits with serotonin inhibition so figured it would be good for emotional state generally. and almost posted a thread but it didnt pan out ,
has a short active time in rodents (maybe in humans it could be longer) https://pmc.ncbi.nlm.nih.gov/articles/PMC4786259/#sec022

I looked through the internet for real blue lotus but it doesnt exist, the Nymphaea caerulea is a water lilly and the purple commercial kind is a different type to the ancient one, (pic commercial one)

people sell those calling it blue lotus but that doesnt have nuciferene like sacred lotus or pink lilly
https://www.researchgate.net/publication/374582027_Chemical_Composition_Market_Survey_and_Safety_Assessment_of_Blue_Lotus_Nymphaea_caerulea_Savigny_Extracts#pfc
^ thats whats in the purple kind which is probably what he had

In the current study, blue lotus concretes and absolutes were free of apomorphine and contained negligible traces of nuciferine

the dose estimate i got to for effects was probably ~50mg+ (impossible to say currently but), & best estimate i found in real lotus leaf was ~17mg nuciferine per 3g of lotus leaf (but also get a decent amount of quercetin from it too which feels nasty in my experience and long half life)
So looked around for extracts, but they're scams (dark / brown powder) pure nuciferine would be light colored
theres apomorphine but behind a medical wall & only lasts about an hour in humans

Its an interesting case report tho maybe theres something else
compounds vary a lot between samples
https://www.researchgate.net/figure/Chemical-composition-of-commercial-C-samples_tbl2_374582027
linalool the most in common & thats an agonist at 5ht1a.
i didnt notice much when i tried it before i think like 200mg diluted in some oil, wouldnt get that much in that amount he tried though. might give it a go on the lower end for longer just to see
i've got some type of lotus fook knows what it is its a redder purple, weighs 2.5g dried and looks a similar size maybe a bit smaller, guessing max 1% dry weight linalool for those purple flowers that person took would be up to 25mg

cs3000

@cs3000 said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

Found one that looks very good

Uncaria. R rhynchophylla

Will detail more on this after i finish a writeup on malate/malic acid , almost done. in people as part of a mix it lowers hallucinations,

it lowers anxiety irritability in mice and as part of a herb mix it lowers the head twitch response when given 5ht2a agonist.
Doesn't on the first day but does by day 14, lowers the 5ht2a receptor density in cortex well

https://doi.org/10.1016/j.pnpbp.2008.05.010

These findings suggest that the anxiolytic effects of Uncaria hook may involve suppressive modulation of 5-HT2A receptor function via the activation of 5-HT1A receptors.

Its asian uncaria R, not the south american uncaria T thats lighter colored.
(I bought a product labelled cats claw uncaria T and its actually probably asian uncaria R, i blended some crude dried dark uncaria from china and it becomes the same medium brown as what was in it. so some products are crossing over)

uncaria T should be light brown-yellow i think and uncaria R medium brown as a powder or dark as dry stems

Mauritio

@cs3000 have you ever gotten around to trying blue lotus (or whatever alternative you came up with)?

I was intrigued by this post on another thread.
And it's relatively cheap, so I'll give it a shot.

I'll probably try one of those two:

https://www.magic-mushrooms-shop.com/de/blue-lotus-extract-tincture.html

https://www.magic-mushrooms-shop.com/de/blue-lotus-nymphaea-caerulea.html#customer-reviews

NoeticJuice

@Mauritio The only source I know for real Nymphaea caerulea is Healing Herbals. At least it looks like the real one. I haven't tried it though.
https://healingherbals.store/products/egyptian-water-lily-authentic-rare-high-potency

Reddit post for more pictures of the product:
https://www.reddit.com/r/bluelotusflower/comments/1kxs7bx/blue_lotus_i_got_from_healing_herbals_a_few_days/

As cs3000 wrote in a post above, the studies on Nymphaea caerulea, Nelumbo nucifera or nuciferine won't necessarily apply to the purple blue lotus.

@cs3000 said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

people sell those calling it blue lotus but that doesnt have nuciferene like sacred lotus or pink lilly

People still get some effects from the purple flowers, and it seems like it has helped some people with psychosis and some other mental health issues, so it could still be worth trying them if you want to.

Mauritio

@NoeticJuice thanks for the reply.
If their flowers are the "real" one, their extract should be as well, right?
Maybe I'll get that, but 19$ shipping to Germany is pricey.

I hear you, but I'm mainly interested in the anti-serotonin, pro-dopamine effect @Mulloch94 describes in the post I linked above. So whatever he had , I want. Unfortunately the company he linked doesn't ship to Germany.

NoeticJuice

@Mauritio said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

If their flowers are the "real" one, their extract should be as well, right?

Not necessarily. They already had the extracts before they started selling the flowers. If I wanted to be certain about getting the real plant, I would buy the whole flowers.

@Mauritio said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

I'm mainly interested in the anti-serotonin, pro-dopamine effect @Mulloch94 describes in the post I linked above. So whatever he had , I want.

The mechanisms Mulloch94 wrote about are those of nuciferine and apomorphine, not necessarily those of the plant extract. But if you just want the same/similar subjective effects, then the product(s) you were thinking to buy could be fine.

NoeticJuice

Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes

Abstract
Dopamine D2LR-serotonin 5-HT2AR heteromers were demonstrated in HEK293 cells after cotransfection of the two receptors and shown to have bidirectional receptor–receptor interactions. In the current study the existence of D2L-5-HT2A heteroreceptor complexes was demonstrated also in discrete regions of the ventral and dorsal striatum with in situ proximity ligation assays (PLA). The hallucinogenic 5-HT2AR agonists LSD and DOI but not the standard 5-HT2AR agonist TCB2 and 5-HT significantly increased the density of D2like antagonist 3H-raclopride binding sites and significantly reduced the pKiH values of the high affinity D2R agonist binding sites in 3H-raclopride/DA competition experiments. Similar results were obtained in HEK293 cells and in ventral striatum. The effects of the hallucinogenic 5-HT2AR agonists on D2R density and affinity were blocked by the 5-HT2A antagonist ketanserin. In a forskolin-induced CRE-luciferase reporter gene assay using cotransfected but not D2R singly transfected HEK293 cells DOI and LSD but not TCB2 significantly enhanced the D2LR agonist quinpirole induced inhibition of CRE-luciferase activity. Haloperidol blocked the effects of both quinpirole alone and the enhancing actions of DOI and LSD while ketanserin only blocked the enhancing actions of DOI and LSD. The mechanism for the allosteric enhancement of the D2R protomer recognition and signalling observed is likely mediated by a biased agonist action of the hallucinogenic 5-HT2AR agonists at the orthosteric site of the 5-HT2AR protomer. This mechanism may contribute to the psychotic actions of LSD and DOI and the D2-5-HT2A heteroreceptor complex may thus be a target for the psychotic actions of hallunicogenic 5-HT2A agonists.

I feel like these two threads should be connected
"The dopamine system of healthy, highly creative people is similar to that found in people with schizophrenia"

Mauritio

@NoeticJuice said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

I feel like these two threads should be connected
"The dopamine system of healthy, highly creative people is similar to that found in people with schizophrenia"

Well, hypomania is what we want , I guess .

Mauritio

@NoeticJuice said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

The mechanisms Mulloch94 wrote about are those of nuciferine and apomorphine, not necessarily those of the plant extract. But if you just want the same/similar subjective effects, then the product(s) you were thinking to buy could be fine.

But he did get those effects (anti-serotonin and pro-dopamine) from the plant extract, so there should be some nuciferine and apomorphine in there. Or at least something that works along similar lines.

lobotomize-me

@cs3000 ketanserin

lobotomize-me

@NoeticJuice said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes

From what I understand from this thread, along with the ones NoeticJuice mentioned, we should favor keeping 5ht2a relatively higher (compared to other 5ht receptors), since it antagonizes other 5 ht receptors and also decreases agonist effects on the D2 receptor

NoeticJuice

@lobotomize-me said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

decreases agonist effects on the D2 receptor

Based on the article, it seems like some 5-HT2A agonists enhance D2-mediated effects, but that is specific to the D2 receptors that are in the same heteroreceptor complex with the activated 5-HT2A receptor.

@lobotomize-me said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

keeping 5ht2a relatively higher (compared to other 5ht receptors), since it antagonizes other 5 ht receptors

I didn't know about 5-HT2A's interaction with other serotonin receptors before this. I asked Grok about it an it gave links to these two articles.

Cross-talk between 5-Hydroxytryptamine Receptors in a Serotonergic Cell Line: INVOLVEMENT OF ARACHIDONIC ACID METABOLISM

5-HT2B and 5-HT2A receptors of 1C11*cells are coupled with a PLA2-mediated release of arachidonic acid. Moreover, activation of the 5-HT2B receptor inhibits the 5-HT1B/1D receptor function, via a cyclooxygenase dependent AA metabolite. This 5-HT2B-mediated inhibition of the 5-HT1B/1D function can be blocked by a concomitant 5-HT2A activation.

Activation of 5-HT2A/C Receptors Counteracts 5-HT1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex

Taken together, our study suggests that serotonin, via 5-HT1A and 5-HT2A/C receptor activation, regulates NMDAR functions in PFC neurons in a counteractive manner. 5-HT2A/C, by activating ERK via the β-arrestin-dependent pathway, opposes the 5-HT1A disruption of microtubule stability and NMDAR transport.

I think that, for generally healthy people, a little more 5-HT2A could be beneficial. However, it's probably a bad idea for people with psychosis. At least for people with schizophrenia, it seems like their 5-HT2A receptors function differently from the norm + the extreme reliance on the left-hemisphere mode of perceiving probably doesn't help.

@cs3000 said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

a supersensitive coupling of 5-HT2AR to Gαi1 as opposed to Gαq has been identified in the postmortem brain samples of schizophrenia patients.

NoeticJuice

A basic theory of psychosis and related phenomena:

The left hemisphere is extremely perceptually dominant.
The left hemisphere distorts what is given by the right hemisphere, leading to hallucinations, delusions and a breakdown of reality.
In a system that is dysfunctional in this way, reducing signal filtering at the thalamus acts as increasing fuel for the delusions etc., while in a person whose hemispheres are better balanced, it would instead fuel creativity.

Even if this theory is true, it would still only be a general, bigger-picture view. There are probably refinements and a lot more detail that could be added. For example, the information in the OP of this thread could be integrated, and more about specific brain regions could be added.

Some additional notes:

In schizophrenia, it might not just be about left-hemisphere dominance but also right-hemisphere damage/deficit.
IIRC, schizophrenics generally have reduced myelination in the brain. If their right hemispheres have less white matter than normal, then their right hemispheres, in a way, might be less right-brained than the average right hemisphere. Increasing myelination might be something worth looking into.

user2

@NoeticJuice said in Psychosis and serotonins 5ht2a receptor , HDAC and chronic anti-psychotic use:

A basic theory of psychosis and related phenomena:

The left hemisphere is extremely perceptually dominant.

The left hemisphere distorts what is given to it by the right hemisphere, leading to hallucinations, delusions and a breakdown of reality.

In a system that is dysfunctional in this way, reducing signal filtering at the thalamus acts as increasing fuel for the delusions etc., while in a person whose hemispheres are better balanced, it would instead fuel creativity.

Even if this theory is true, it would still only be a general, bigger-picture view. There are probably refinements and a lot more detail that could be added. For example, the information in the OP of this thread could be integrated, and more about specific brain regions could be added.

Some additional notes:

In schizophrenia, it might not just be about left-hemisphere dominance but also right-hemisphere damage/deficit.

IIRC, schizophrenics generally have reduced myelination in the brain. If their right hemispheres have less white matter than normal, then their right hemispheres, in a way, might be less right-brained than the average right hemisphere. Increasing myelination might be something worth looking into.

Little or no salt and meat, plus more plants, fruits, and dairy products can contribute to a person being more prone to visions ,“hallucinations”, dreams,Sunlight and EMFs can also contribute. In my experience, visions, hallucinations, and dreams are either manifestations of the body's internal agency/agency attempt, which may include stored engrams/memories from the person's past experiences, engrams/memories from other living beings/sources, that have entered the person's body in the past and have been stored, or direct receptions of information/energy from external sources, whether foods, drugs, emf, the sun, the moon, other living beings, or supernatural beings, which can include past, present, and future informations. It is not necessarily optimal in the long term to be prone to these things, as it can be associated with reduced physical/mental resilience or even damage.

Yet , once a person is in that state, visions/hallucinations/dreams can have a positive effect and lead the person towards a better internal agency and a better energetic state. Visions/hallucinations/dreams can contain elements that indicate to the person what they need to return to an optimal energetic state

NoeticJuice

@user2 I was thinking more in the context of things like schizophrenia or drug-induced psychosis.

I think visions are facilitated by the right hemisphere. In the case of visions without psychosis, while the person still remains sane, there's less distortion, so they can be better used for one's own benefit. I think it's similar for dreams.

Whatever people see from taking drugs is almost certainly distorted to a greater or lesser degree.

By the way, I don't think visions are something we should try to get. I feel like intuition is generally better.

user2

@NoeticJuice i include schizophrenia or drug-induced psychosis in my comment above

Mauritio

While looking into studies on blue lotus (Nymphaea caerulea), I found a very interesting study on a plant from the same genus called N. lotus.

It was on mice with hyperprolactemia that received different dosages of N. Lotus, while bromocriptine served as the positive control group.

Not only was it able to lower prolactin, but at the highest dose, it lowered prolactin more than bromocriptine.At that dose it even lowered prolactin below the control groups value, which didn't receive prolactinergic medication .
They gave rats an HED of 30mg of Bromo, which is a hefty dose.

On top of that it also drastically increased mices progesterone. Again, outperforming bromocriptine and even the control group.

It also lowered estradiol.

I haven't done enough research yet, but that study alone makes me really want to try N. lotus.
https://scialert.net/fulltext/?doi=ajb.2017.91.98

Mauritio

Here's another study in male animals where it had a positive impact on male reproductive health. They didn't test hormones, but numbers of offspring drastically increased in the N. Lotus group and sperm health did as well.

https://ppj.phypha.ir/browse.php?a_code=A-10-935-1&slc_lang=fa&sid=1