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Progesterone, Testosterone, Allopregnanolone Are Serotonin Antagonists

haidut

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This study shows that some of the gonadal steroids act in a manner similar to the drug ondansetron - i.e. antagonize the 5-HT3 "receptor". While pregnenolone sulfate was not antagonistic to 5-HT3, taking pregnenolone metabolizes mostly into progesterone and allopregnanolone. So, it seems like a viable option for people who cannot take ondansetron to take pregnenolone. I can't see info on the dosage but pregnenolone in daily doses of 100mg+ is known to cause constipation, and that is a classic sign of 5-HT3 antagonism. Needless to mention pregnenolone does not have the side effects on the heart that drugs like ondansetron cause even in low doses.

http://www.ncbi.nlm.nih.gov/pubmed/9731711

"...Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and progesterone, may also act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT3) receptor in whole-cell voltage-clamp recordings of HEK 293 cells stably expressing the 5-HT3 receptor. Functional antagonistic properties at this ligand-gated ion channel could also be shown for 17alpha-estradiol, 17alpha-ethinyl-17beta-estradiol, mestranol, R 5020, testosterone, and allopregnanolone but not for pregnenolone sulfate and cholesterol. An antagonism at the 5-HT3 receptor could further be observed with the aromatic alcohol 4-dodecylphenol but not with phenol or ethanol. Thus, the modulation of 5-HT3 receptor function by steroids or alcohols is dependent on their respective molecule structure."

And here are some studies showing that progesterone, a major metabolite of pregnenolone, increases constipation.

http://www.ncbi.nlm.nih.gov/pubmed/22284724
http://www.ncbi.nlm.nih.gov/pubmed/21481100
 

answersfound

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haidut said:
post 79740 This study shows that some of the gonadal steroids act in a manner similar to the drug ondansetron - i.e. antagonize the 5-HT3 "receptor". While pregnenolone sulfate was not antagonistic to 5-HT3, taking pregnenolone metabolizes mostly into progesterone and allopregnanolone. So, it seems like a viable option for people who cannot take ondansetron to take pregnenolone. I can't see info on the dosage but pregnenolone in daily doses of 100mg+ is known to cause constipation, and that is a classic sign of 5-HT3 antagonism. Needless to mention pregnenolone does not have the side effects on the heart that drugs like ondansetron cause even in low doses.

http://www.ncbi.nlm.nih.gov/pubmed/9731711

"...Steroid hormone action involves binding to cognate intracellular receptors that, in turn, bind to respective response elements and thus modulate gene expression. The present study shows that the gonadal steroids, 17beta-estradiol and progesterone, may also act as functional antagonists at the 5-hydroxytryptamine type 3 (5-HT3) receptor in whole-cell voltage-clamp recordings of HEK 293 cells stably expressing the 5-HT3 receptor. Functional antagonistic properties at this ligand-gated ion channel could also be shown for 17alpha-estradiol, 17alpha-ethinyl-17beta-estradiol, mestranol, R 5020, testosterone, and allopregnanolone but not for pregnenolone sulfate and cholesterol. An antagonism at the 5-HT3 receptor could further be observed with the aromatic alcohol 4-dodecylphenol but not with phenol or ethanol. Thus, the modulation of 5-HT3 receptor function by steroids or alcohols is dependent on their respective molecule structure."

And here are some studies showing that progesterone, a major metabolite of pregnenolone, increases constipation.

http://www.ncbi.nlm.nih.gov/pubmed/22284724
http://www.ncbi.nlm.nih.gov/pubmed/21481100

Why would anyone take more than 100 mg if you get constipation? Wouldn't this create more problems? When I asked Ray about pregnenolone and constipation he said that the only reason it would cause constipation is from impurities in the supplement. I'd like to go over 100 mg daily, given that Ray has recommended up to 150 mg....
 
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ddjd

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While pregnenolone sulfate was not antagonistic to 5-HT3, taking pregnenolone metabolizes mostly into progesterone and allopregnanolone. So, it seems like a viable option for people who cannot take ondansetron to take pregnenolone. I can't see info on the dosage but pregnenolone in daily doses of 100mg+ is known to cause constipation, and that is a classic sign of 5-HT3 antagonism. Needless to mention pregnenolone does not have the side effects on the heart that drugs like ondansetron cause even in low doses.
what do you think could be the reason why pregnenolone converts to progesterone much more than allopregnanolone? i feel like when i take pregnenolone its not as good as when i take 5adhp so maybe somethings blocking conversion
 

ddjd

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Why would anyone take more than 100 mg if you get constipation? Wouldn't this create more problems? When I asked Ray about pregnenolone and constipation he said that the only reason it would cause constipation is from impurities in the supplement. I'd like to go over 100 mg daily, given that Ray has recommended up to 150 mg....
does ray not think it has an anti serotonin effect then. I personally dont notice any anti serotonin effects from either progesterone or pregnenolone, but 5aDHP works every time
 

Sativa

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pregnenolone in daily doses of 100mg+ is known to cause constipation, and that is a classic sign of 5-HT3 antagonism.
I am dubious about this. The common terpenes limonene & pinene are also 5-HT3 antagonists, perhaps someone can try a large dose to verify the constipation claims...

btw, 5-HT3 is the nausea receptor, activating it = nausea.
Alcohol activates it.

As for 'Serotonin Antagonists'...
I feel this concept is overly superficially hastily simplified & employed on this forum... not all serotonin system activation is witch-hunting-ly 'bad' (at least, not for well-kept balanced metabolisms) ...but anyway, it's interesting to bear in mind that - substances that activate the serotonin 5-HT1A site, lead to a dampening/inhibition of all other serotonin sites.

So, a serotonin 5-HT1A activator, acts as a broad serotonin antagonist! (gasp)
with some glutamate inhibition (aka nmda antagonism) thrown in too...

PS. activating the serotonin 5-HT2A site triggers BDNF (haidut has mentioned it's core importance. estrogen kills BDNF levels).
BDNF is akin to brain anabolic neuron food aka neurogenesis, & anti-cortisol action.
 
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Hans

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I am dubious about this. The common terpenes limonene & pinene are also 5-HT3 antagonists, perhaps someone can try a large dose to verify the constipation claims...

btw, 5-HT3 is the nausea receptor, activating it = nausea.
Alcohol activates it.

As for 'Serotonin Antagonists'...
I feel this concept is overly superficially hastily simplified & employed on this forum... not all serotonin system activation is witch-hunting-ly 'bad' (at least, not for well-kept balanced metabolisms) ...but anyway, it's interesting to bear in mind that - substances that activate the serotonin 5-HT1A site, lead to a dampening/inhibition of all other serotonin sites.

So, a serotonin 5-HT1A activator, acts as a broad serotonin antagonist! (gasp)
with some glutamate inhibition (aka nmda antagonism) thrown in too...

PS. activating the serotonin 5-HT2A site triggers BDNF (haidut has mentioned it's core importance. estrogen kills BDNF levels).
BDNF is akin to brain anabolic neuron food aka neurogenesis, & anti-cortisol action.
Yeah the 5-HT1A is the auto-receptor and methylene blue and zinc are two such agonists for example.
Haidut posted a study on his website the other day that there is a new anti-depressant drug being developed with very little action except being an antagonist to the 5-HT2A receptor and much weak antagonism to the 5-HT2C receptor.
If 5-HT2A contributes to depression, why do psilocybin and LSD have anti-depressant properties when they potently active the 5-HT2A receptors? Maybe moderate 5-HT2A activation, as with elevated serotonin, contributes to depression, but major action, as with LSD, has anti-depressant activities if done right. The reason I say if done right is that if someone is not "lead" through the experience, healing cannot take place. LSD, MDMA, psilocybin, etc., create an environment for healing, but is not healing on its own.
BTW, I find your posts very interesting.
 

Sativa

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...there is a new anti-depressant drug being developed with very little action except being an antagonist to the 5-HT2A receptor and much weak antagonism to the 5-HT2C receptor.
If 5-HT2A contributes to depression, why do psilocybin and LSD have anti-depressant properties when they potently active the 5-HT2A receptors?
It sounds as if you assume that those designing the new anti-depressant have any idea what they are doing, or what kind of a system they are designing a new drug for.
Generally, it's advisable to make your own interpretations of raw data, instead of taking second third hand interpretations as truth. That way, you avoid being mislead or misinformed by idiotic or close-minded/limited thinking - as exhibited by many scientific researchers & pharmaceutical drug developers.
The most important error most of them make is assuming that what they know is true.

For some direct insight, from nature herself, look at the pharmacology of Albizia julibrissin aka Tree of Happiness. It is, as the name suggests...
Albizia is a HT1A & HT2C agonist aka activator. It is a potent euphoric anti-depressant. I make a potent extract of this botanical...
 
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Sativa

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Throw your buckets out the window, dopamine activates the serotonin HT2A site!

Activation, internalization, and recycling of the serotonin 5-HT2A receptor by dopamine

Like serotonin, dopamine also induces HT2A receptor-internalization in these cells, although at significantly higher concentrations than serotonin. Interestingly, if the receptors are first sensitized or ‘‘primed’’ by subthreshold concentrations of serotonin, then dopamine-induced internalization occurs at concentrations 10-fold lower than when dopamine is used alone. Furthermore, unlike serotonin-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by serotonin, does not depend on PKC.
...
Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-HT2A receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders.
~source: http://www.pnas.org/content/103/41/15248.full.pdf (also attached)
 

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Sativa

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Effect of HT2A / HT2C agonist/antagonist on the all-important BDNF levels (ps BDNF is partially anti-estrogen)

5-HT2A receptor-mediated regulation of BDNF mRNA in the hippocampus and the neocortex.

The influence of 5-HT receptor agonists on the expression of BDNF in brain was determined.
Administration of a hallucinogenic 5-HT2A /2C receptor agonist, but not a 5-HT1A receptor agonist, resulted in a significant but differential regulation of BDNF mRNA levels in hippocampus and neocortex.
...
The effect of the 5-HT2A /2C receptor agonist on BDNF mRNA in both the hippocampus and the neocortex was blocked by pretreatment with a selective 5-HT2A, but not 5-HT2C, receptor antagonist.
The expression of BDNF mRNA in the hippocampus is reported to be decreased by stress, raising the possibility that the 5-HT2A receptor mediates this effect.
Pretreatment with ketanserin, a 5-HT2A /2C receptor antagonist, significantly blocked the stress-induced downregulation of BDNF mRNA in hippocampus
, in support of this hypothesis.
The results of this study raise the possibility that regulation of BDNF expression by hallucinogenic 5-HT2A receptor agonists leads to adaptations of synaptic strength in the hippocampus and the neocortex that may mediate some of the acute and long-term behavioral effects of these agents.
~source: 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. - PubMed - NCBI
 
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Sativa

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This is an interesting conclusion from analyzing lots of research data...
No matter what you do to the 5-HT2C receptor, whether agonize, antagonize, or inverse agonize, you will downregulate it in the long term.

"...many varied effects of the serotonin receptors [5-HT2A is the higher-brain psychedelic receptor, while 5-HT2C is just the flu receptor that makes you feel sick... completely unrelated but classified together because of sequence homology]​

"Kudzu does this by antagonizing the 5-HT2C receptor.
This is basically the "sickness" receptor, when it turns on it inhibits the release of dopamine and norepinephrine, making you feel down, and lethargic.
Blocking it makes you energetic and euphoric.
Apparently most people have at least a medium amount of 5-HT2C activation"​

"Hey, guys, 5-HT2C is a crappy receptor to activate.
If daidzin antagonizes this receptor then it should be amazing to take.
5-HT2C isn't a psychedelic receptor, it's the illness receptor.
It turns on when you feel sick. It causes dopamine and norepinephrine release to slow down, reducing dopamine and norepinephrine levels in the body.
"​

aside: I found the above data using this google search query:
site:tapatalk.com/groups/herbsmxf/ HT2C
Ok, enough quotes from forums, here's some research paper insights:

Constitutively active 5-HT2C receptors reveal novel inverse agonist activity of receptor ligands.
http://www.ncbi.nlm.nih.gov/pubmed/7909313

Chronic mianserin or eltoprazine treatment in rats: effects on the elevated plus-maze test and on limbic 5-HT2C receptor levels.
http://www.ncbi.nlm.nih.gov/pubmed/7813563

Sertindole is a serotonin 5-HT2C inverse agonist and decreases agonist but not antagonist binding to 5-HT2C receptors after chronic treatment.
http://www.ncbi.nlm.nih.gov/pubmed/11594443

SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety.
SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. - PubMed - NCBI


Novel Actions of Inverse Agonists on 5-HT2C Receptor Systems
Novel Actions of Inverse Agonists on 5-HT2C Receptor Systems
 
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LeeLemonoil

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Everything you post is worthwhile.

I have quarrels with touting that sert-receptor a „sickness“-receptor, even if it’s used for poignant description purposes. I have profound theories about these receptors and their actions, but I won’t share them as of now in the internet because people steal your ideas like there is no tomorrow, even if there is no financial gain to make.
 

Sativa

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HT3 agonism is definitely nausea central.
as for HT2C being flu receptor, well, the downstream pharmacology seems to fit.

tbh, I am not bothered about these specifics. I prolifically use many serotonin modulating substances...
Albizia (1A & 2C agonist); Piperine (1A agonist); Agmatine, Limonene & Pinene (HT3 antagonists); Citral (HT2A agonist) as well as employing the downstream mechanisms of HT2A activation, notably AMPA agonism = BDNF(!) which is how smart drugs like piracetam and pyroglutamic acid (aka pidolic acid) work. HT2A psychoactives also trigger BDNF implying cognitive enhancing properties, eg LSD, Mushrooms (4-PO-DMT) etc
 

LeeLemonoil

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HT2A is probably also heavily imvolved in creativity, sublimation and problem solving when under existential threat. Some drop immobile by 2As action and try to appease the enemy or hope to provoke others to help.

Some others develop elaborate strategies by 2a activation, be it practical or mental as in gaining new outlook on life and so forth. It all comes down to survival/phylogenetic immunity
 

Hans

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It sounds as if you assume that those designing the new anti-depressant have any idea what they are doing, or what kind of a system they are designing a new drug for.
I should have linked some studies. Here are a few:
The therapeutic role of 5-HT1A and 5-HT2A receptors in depression
"Pyramidal neurons in the prefrontal cortex are particularly enriched in 5-HT2A receptors. Their blockade may affect the function of prefrontal–subcortical circuits, an effect that probably underlies the beneficial effects of the addition of atypical antipsychotic drugs, which are 5-HT2A receptor antagonists, to SSRIs in treatment-resistant patients."

Role of 5-HT2A receptor antagonists in the treatment of insomnia
"Moreover, 5-HT2A receptor antagonists may improve clinical symptoms of depression, anxiety, and/or psychosis in specific patient populations.55,56"

Generally, it's advisable to make your own interpretations of raw data, instead of taking second third hand interpretations as truth.
I do my own research.

That way, you avoid being mislead or misinformed by idiotic or close-minded/limited thinking - as exhibited by many scientific researchers & pharmaceutical drug developers.
You clearly hold a grudge against some people here on this forum (dare I say the H word: Haidut) and have a pro-serotonin agenda. Let me just be clear. I'm all for balancing serotonin and not abolishing it out of existence. Some of the serotonin receptors do have benefits, such as boosting BDNF, but most people have excess serotonin, so lowering it, or lowering/fixing the serotonin promotors, such as excess estrogen, cortisol, low ATP, stress, etc., is a great idea.
There is evidence that 5-HT2A agonists like psilocybin, LSD, etc., are anti-depressants because it has a long term down regulatory effect on the receptor.

Furthermore, I will not be debating with you as you have a mean, belittling, childish and insecure attitude and assume that you are always right. I also do not appreciate your "lol". You linked an in vitro study while I linked an in vivo study and then you say "it's more nuanced than that" while the information is right in front of your eyes.
Yes, the body is complicated, but if you want a serious discussion, leave the lol and link some counter (in vivo) studies. I'm all for learning new things and discovering the truth.
 

Inaut

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@Hans just read your article about lowering serotonin and work outs.

Your pre-workout formula is pretty much what i do daily but wasn't really up on the proper dosages. Excited to try it out now. Thanks for sharing :) :)
 

Hans

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@Hans just read your article about lowering serotonin and work outs.

Your pre-workout formula is pretty much what i do daily but wasn't really up on the proper dosages. Excited to try it out now. Thanks for sharing :) :)
Sweet man. I find the bicarb nasty, but it's so fundamental to the formula. Keep me updated on how it works for you.
 

Sativa

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You clearly hold a grudge against some people here on this forum (dare I say the H word: Haidut) and have a pro-serotonin agenda.
what?
no, I actually look up to all of Haiduts posts, and especially adore his products. I have mimicked them myself actually!
I don't have a pro-serotonin agenda, this is your polarized interpretation. I have simply noticed people here, who perhaps are not overly familiar or experienced with neuro-pharmacology, who have been misinformed about the nature of serotonin 'receptors' and dynamics. To say I am pro-serotonin is ludicrous, since I am fundamentally aligned with Ray Peat's core principles. So please, keep your polarized hasty assumptions to yourself lol, it will save you from looking silly to others in future.
I will not be debating with you as you have a mean, belittling, childish and insecure attitude and assume that you are always right.
I wasn't looking for a debate?
Perhaps you shouldn't assume your hasty assumptions are valid; it would save you from writing things which I then nicely mention might be considered as painting you in a silly light.
 

rei

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Throw your buckets out the window, dopamine activates the serotonin HT2A site!

Activation, internalization, and recycling of the serotonin 5-HT2A receptor by dopamine

Like serotonin, dopamine also induces HT2A receptor-internalization in these cells, although at significantly higher concentrations than serotonin. Interestingly, if the receptors are first sensitized or ‘‘primed’’ by subthreshold concentrations of serotonin, then dopamine-induced internalization occurs at concentrations 10-fold lower than when dopamine is used alone. Furthermore, unlike serotonin-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by serotonin, does not depend on PKC.
...
Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-HT2A receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders.
~source: http://www.pnas.org/content/103/41/15248.full.pdf (also attached)
Do you realize this kind of activation blocks the action of the active site? So it is long-term antagonist without the signal of being continuously active (overactivation-> downregulation like LSD does). I suspect the nausea people describe when coming up on psychedelics is the overactivation phase, and the psychedelic effect comes on as the compensatory downregulation kicks in.
 

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