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,

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

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.

One potent HDAC inhibitor is sodium butyrate

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 (sodium butyrate could be one indirectly in this context)

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