78 replies to this topic

[OneScrewLoose]

Trazodone isn't strictly an SSRI - it's also a strong alpha-1-blocker, which is the main reason why it has a sedative effect. Most anti-psychotics also potently block alpha-1-adrenergic receptors - which is again, the main reason for their sedative effects. The antihistamine effect amplifies the adrenergic blockade effects...

Trazodone has part of that property...

 

Serotonin really doesn't alleviate insomnia...in fact, it can cause it...the only time serotonin has a specific anti-insomnia effect is when it converts into melatonin.

 

 

'Serotonin' doesn't do anything per se. It depends on what part of the brain it's working on and what receptors. What you like to specify a little? Be aware that an antagonist doesn't necessarily do the opposite of an agonist. 5HT2c antagonism increases dopamine in the Ventral Tegmental Area. Although agonism can lower the dopamine, 5HT2c agonism is also hallucinogenic and a component of psychedelics like acid along with 5HT2a agonism. Mu (endorphin/opioid) agonists cause analgesia and pleasure. Mu antagonists don't cause pain or dysphoria. Unless you are addicted to opiates, they don't really seem to change much. H1 antagonists will knock you out. H1 agonists will not wake you the hell up.

 

Trazodone's primary mode of sedation is H1 antagonism, not alpha 1 antagonism.

 

 

 

With that being said, serotonin does have anxiolytic / calming properties via 5-HT1A autoreceptors - the reasons are more complicated than most think. Autoreceptors reduce the activity of a neurotransmitter, therefore serotonin 1A inhibits itself, therefore producing a decrease in serotonergic excitation at other receptors. 

 

So it's actually the DECREASE in serotonin via autoreceptor activation that produces less anxiety....

 

Also 5-HT1A is negatively coupled to adenylate cyclase and it has diverse effects on neuropeptides, the other anxiolytic effect probably has to do with 5-HT1A being present on oxytocinergic neurons. 

 

Therefore 5-HT1A receptor activation is just about the only serotonin receptor that alleviates anxiety. It does so by.

 

• Reducing serotonin at other receptors.
• Increasing oxytocin releasee

 

 

 

Jeeee-sus. OK, here we go. First of all, not all 5HT1A receptors are autoreceptors, there are post-synapatic ones too. The effect of autoreceptors on the release of a neurotransmitter can be extraordinarily complicated. Look up the drug amisulpride and see how it's effect on dopaminergic transmission changes with the dose. It effects D2 receptors, which tend to be auto receptors. Oh yeah, btw. You'd think that activating D2 receptors would relieve schizophrenia, as they are autoreceptors, and reduce dopaminergic activity, right? Well, it's much more complicated than that. It turns out that D2 antagonists, and the later discovered 5HT2a antagonists, are what work. D2 agonists like pramipexole can make schizophrenia worse.

To assume that the decrease in anxiety from 5HT1A activation is due to reduced serotonin is jumping the gun. The newest SSRIs, sometimes called atypical SSRIs, are vilazodone and vortioxetine. They are both strong SSRIs. Vilazodone is a partial 5HT1a agonist and vortioxetine is a bit weaker on the SSRI side and is a full 5HT1a agonist (well, nearly full). They seem to be potent anxiolytics, much more so than standard SSRIs. According do your hypothesis, this shouldn't be the case. If all it took were 5HT1a agonism, than Buspar would be the most effective anxiolytic out there. But it's not prescribed often because for most people, it just doesn't work.

I'm trying to not be a dick-ish, but you need to hold off on making these extrapolations from limited data. Start with a hypothesis and build from there, find more data to support it, and in your case, look for contradictory data and confounding variables. This shit is super complicated, and needs to be approached as such. Do not do this:
 

 

HOWEVER, these receptors can easily become de-sensitized if you stimulate them too much, leading to nullification of this effect and thus lack of anxiolytic effect from serotonin....this is one of the hypothesis of violent criminals, they no longer respond to the autoreceptors of serotonin thus there are no brakes and serotonin is flooding the brain leading to erratic behavior.

 

 

That is a whopping conclusion that would need a lot of data and sources to back it up. Large amounts of serotonin as a result of SRIs do not seem to cause erratic behavior, but rather numbness. Ironically, SRAs (Serotonin Releasing Agents), seem to do the opposite (see the complexity?). One gene associated with some criminal behavior seems to be the "Warrior Gene", which reduces the amount of MAOA-I in the system. This increase a lot of neurotransmitters, including serotonin, dopamine and norepinephrine. We know very little about what genes and neurotransmitters cause criminal behavior, unfortunately.

Another example of how paradoxical this can be is Amphetamines vs. Intuniv for ADHD. Both help with ADHD. However, amphetamines increase norepinephrine, and Intuniv decreases it. It seems that with amphetamines, the norepinephrine increase aids in focus. With the Intuniv, the decrease in NE seems to help the brain's attention not be pulled away by random stimuli. allowing the person to concentrate on what's on task. The difference seems to be in what parts of the brain the increase or reduction of NE occurs.

I don't want to be disrespectful, but it may seem like it a little. I'm just trying to be as straight-forward as possible. These things complicated and need to be treated as such. You need to use doubt as your foundation of research, not assuredness.

I'm hesitant to post this yet, but I am working on a Youtube channel sharing a lot of what I know. All the videos are drafts, and I was planning to improve before I posted. But would you be interested in seeing it?

Edited by OneScrewLoose, 28 April 2015 - 01:23 AM.

[Area-1255]

You do realize I have a blog of over 200 articles and write about this stuff every day, right?
I'm also a university graduate and well-respected member of many scientific communities, not just this one...
I'm just informing you because it appears, you're not aware of this...nor of this information that I have compiled.
 
 

Trazodone's primary mode of sedation is H1 antagonism, not alpha 1 antagonism.

 If that's the case, then why is it that some people DO NOT respond to anti-histamines in terms of their sedative effects?

Additionally, you can't make that statement without a reference, and here's something for ya, the pharmacology of trazodone based on the values/Chart below CLEARLY states that it's affinity is HIGHER for the alpha-1-receptor than the H1R.

http://i57.tinypic.com/nmhwzt.jpg

 

http://www.pharmacor...lamines_7_1.php

http://www.ncbi.nlm..../pubmed/2879204

 

The above links state not only similarities between drugs that interact with the receptor , but clearly stating that alpha-1-blockade produces a STRONG sedative effect, that is ADDITIONAL and may be stronger than the anti-histamine property in that contrast.

 

As far as all the serotonin mumbo jumbo nonsense , well here's a study confirming what I've said.

YOU SAY BUSPAR would be the most EFFECTIVE ANXIOLYTIC if it were ALL ABOUT THAT, I clearly said it WASN'T JUST ABOUT THE AUTORECEPTORS, but if you actually READ, I stated it has to do with OXYTOCIN as well..so you took it out of context and didn't read everything I had to say earlier in the thread and in my other threads...

 

Well, that takes care of that..next time study a little more before you come against an esteemed member and graduate.

 

Psychopharmacology (Berl). 2000 Sep;152(1):55-66.

The selective serotonin (5-HT)1A receptor ligand, S15535, displays anxiolytic-like effects in the social interaction and Vogel models and suppresses dialysate levels of 5-HT in the dorsal hippocampus of freely-moving rats. A comparison with other anxiolytic agents.

Dekeyne A1, Brocco M, Adhumeau A, Gobert A, Millan MJ.

Author information

 

Abstract

RATIONALE:

The benzodioxane, S15535, possesses low intrinsic activity and marked selectivity at 5-HT1A receptors, hippocampal populations of which are implicated in anxious states.

OBJECTIVE:

Herein, we examined its potential anxiolytic actions in relation to its influence upon extracellular levels of 5-HT in the dorsal hippocampus of freely-moving rats. Its effects were compared with those of other anxiolytic agents: the 5-HT1A agonists, buspirone and 8-hydroxy-2-(di-n-propylamino)-tetralin HBr (8-OH-DPAT), the 5-HT2C antagonist, SB206,553 and the benzodiazepine, diazepam.

METHODS:

Potential anxiolytic actions were evaluated in the Vogel conflict paradigm (increase in punished responses) and the social interaction (SI) test (increase in active SI) in rats. Extracellular levels of 5-HT were determined by microdialysis.

RESULTS:

In analogy to diazepam. S15535 increased punished responses in the Vogel test. This action was dose dependently expressed over a broad (16-fold) dose range. Buspirone and 8-OH-DPAT were likewise active, but yielded highly biphasic dose-response curves. SB206,553 was dose dependently active in this model. In the SI test, S15535 similarly mimicked the anxiolytic-like effect of diazepam and was active over a broad dose range. Buspirone and 8-OH-DPAT again showed biphasic dose-response curves, as did SB206,553. In both the Vogel and SI tests, the anxiolytic-like effects of S15535 were abolished by the selective 5-HT1A receptor antagonist, WAY100,635, which was inactive alone. S15535 exerted its anxiolytic-like effects with a more pronounced separation to motor-disruptive doses than the other drugs. Finally, S15535 suppressed dialysate levels of 5-HT in the dorsal hippocampus, an action abolished by WAY100,635. Buspirone, 8-OH-DPAT and diazepam, but not SB206,553, also reduced 5-HT levels.

CONCLUSION:

Likely reflecting its distinctive ability to selectively and preferentially activate pre- versus postsynaptic 5-HT1A receptors, S15535 suppresses hippocampal 5-HT release and displays marked anxiolytic-like effects over a broad dose range in the relative absence of motor perturbation.

PMID:   11041316   [PubMed - indexed for MEDLINE]  

 

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Trazodone isn't strictly an SSRI - it's also a strong alpha-1-blocker, which is the main reason why it has a sedative effect. Most anti-psychotics also potently block alpha-1-adrenergic receptors - which is again, the main reason for their sedative effects. The antihistamine effect amplifies the adrenergic blockade effects...

Trazodone has part of that property...
 
Serotonin really doesn't alleviate insomnia...in fact, it can cause it...the only time serotonin has a specific anti-insomnia effect is when it converts into melatonin.

 
 
'Serotonin' doesn't do anything per se. It depends on what part of the brain it's working on and what receptors. What you like to specify a little? Be aware that an antagonist doesn't necessarily do the opposite of an agonist. 5HT2c antagonism increases dopamine in the Ventral Tegmental Area. Although agonism can lower the dopamine, 5HT2c agonism is also hallucinogenic and a component of psychedelics like acid along with 5HT2a agonism. Mu (endorphin/opioid) agonists cause analgesia and pleasure. Mu antagonists don't cause pain or dysphoria. Unless you are addicted to opiates, they don't really seem to change much. H1 antagonists will knock you out. H1 agonists will not wake you the hell up.
 
Trazodone's primary mode of sedation is H1 antagonism, not alpha 1 antagonism.
 
 
 

 

With that being said, serotonin does have anxiolytic / calming properties via 5-HT1A autoreceptors - the reasons are more complicated than most think. Autoreceptors reduce the activity of a neurotransmitter, therefore serotonin 1A inhibits itself, therefore producing a decrease in serotonergic excitation at other receptors. 
 
So it's actually the DECREASE in serotonin via autoreceptor activation that produces less anxiety....
 
Also 5-HT1A is negatively coupled to adenylate cyclase and it has diverse effects on neuropeptides, the other anxiolytic effect probably has to do with 5-HT1A being present on oxytocinergic neurons. 
 
Therefore 5-HT1A receptor activation is just about the only serotonin receptor that alleviates anxiety. It does so by.

• Reducing serotonin at other receptors.
• Increasing oxytocin releasee

 
 
Jeeee-sus. OK, here we go. First of all, not all 5HT1A receptors are autoreceptors, there are post-synapatic ones too. The effect of autoreceptors on the release of a neurotransmitter can be extraordinarily complicated. Look up the drug amisulpride and see how it's effect on dopaminergic transmission changes with the dose. It effects D2 receptors, which tend to be auto receptors. Oh yeah, btw. You'd think that activating D2 receptors would relieve schizophrenia, as they are autoreceptors, and reduce dopaminergic activity, right? Well, it's much more complicated than that. It turns out that D2 antagonists, and the later discovered 5HT2a antagonists, are what work. D2 agonists like pramipexole can make schizophrenia worse.

To assume that the decrease in anxiety from 5HT1A activation is due to reduced serotonin is jumping the gun. The newest SSRIs, sometimes called atypical SSRIs, are vilazodone and vortioxetine. They are both strong SSRIs. Vilazodone is a partial 5HT1a agonist and vortioxetine is a bit weaker on the SSRI side and is a full 5HT1a agonist (well, nearly full). They seem to be potent anxiolytics, much more so than standard SSRIs. According do your hypothesis, this shouldn't be the case. If all it took were 5HT1a agonism, than Buspar would be the most effective anxiolytic out there. But it's not prescribed often because for most people, it just doesn't work.

I'm trying to not be a dick-ish, but you need to hold off on making these extrapolations from limited data. Start with a hypothesis and build from there, find more data to support it, and in your case, look for contradictory data and confounding variables. This shit is super complicated, and needs to be approached as such. Do not do this:
 
 

 

HOWEVER, these receptors can easily become de-sensitized if you stimulate them too much, leading to nullification of this effect and thus lack of anxiolytic effect from serotonin....this is one of the hypothesis of violent criminals, they no longer respond to the autoreceptors of serotonin thus there are no brakes and serotonin is flooding the brain leading to erratic behavior.

 
 
That is a whopping conclusion that would need a lot of data and sources to back it up. Large amounts of serotonin as a result of SRIs do not seem to cause erratic behavior, but rather numbness. Ironically, SRAs (Serotonin Releasing Agents), seem to do the opposite (see the complexity?). One gene associated with some criminal behavior seems to be the "Warrior Gene", which reduces the amount of MAOA-I in the system. This increase a lot of neurotransmitters, including serotonin, dopamine and norepinephrine. We know very little about what genes and neurotransmitters cause criminal behavior, unfortunately.

Another example of how paradoxical this can be is Amphetamines vs. Intuniv for ADHD. Both help with ADHD. However, amphetamines increase norepinephrine, and Intuniv decreases it. It seems that with amphetamines, the norepinephrine increase aids in focus. With the Intuniv, the decrease in NE seems to help the brain's attention not be pulled away by random stimuli. allowing the person to concentrate on what's on task. The difference seems to be in what parts of the brain the increase or reduction of NE occurs.

I don't want to be disrespectful, but it may seem like it a little. I'm just trying to be as straight-forward as possible. These things complicated and need to be treated as such. You need to use doubt as your foundation of research, not assuredness.

I'm hesitant to post this yet, but I am working on a Youtube channel sharing a lot of what I know. All the videos are drafts, and I was planning to improve before I posted. But would you be interested in seeing it?
[/quote]

 

Edited by Area-1255, 28 April 2015 - 03:01 AM.

[Area-1255]

Also there are 5 main factors in determining how a receptor will impact anxiety etc or any other neurological behavioral response.

 

• Positive/Negative Coupling to adenylate cyclase.
• Autoreceptor permeability / ratio's .
• CO-LOCALIZATION with other neuro-receptors.
• Effects on neuropeptides; oxytocin , substance P etc
• Rate firing and mean number of receptors, as well as REGION of distribution.

 

E.G , 5-HT1A receptors interact with neuropeptides and have autoreceptor variability...the post-synaptic receptors tend to be ANXIOGENIC(!), autoreceptors are ANXIOLYTIC...which also concurs with my conclusions.

 

5-HT6 receptors are CO-LOCALIZED with GABAergic neurons which essentially means when they are activated, GABA is activated as well.(!)
 

Edited by Area-1255, 28 April 2015 - 03:52 AM.

[OneScrewLoose]

Yes, it does have a higher affinity for a1, I did indeed notice that. Silly me, I must not be respected in enough communities because I can't seem to find a1 blockers being consistently prescribed for their sedative properties like H1 antagonists are. Perhaps you have them confused with a2 agonists?

What university and communities, btw?

And you're clearly mixing correlation and causation. All you've shown is that 5HT1a antagonism correlates both with reduced serotonin output and reduced anxiety. You have done absolutely nothing to show that the reduction in serotonin is what is causing the reduced anxiety. So your hypothesis, that lowered serotonin causes reduced anxiety or other benefits, has zero proof, only correlates. 

[Area-1255]

Yes, it does have a higher affinity for a1, I did indeed notice that. Silly me, I must not be respected in enough communities because I can't seem to find a1 blockers being consistently prescribed for their sedative properties like H1 antagonists are. Perhaps you have them confused with a2 agonists?

What university and communities, btw?

And you're clearly mixing correlation and causation. All you've shown is that 5HT1a antagonism correlates both with reduced serotonin output and reduced anxiety. You have done absolutely nothing to show that the reduction in serotonin is what is causing the reduced anxiety. So your hypothesis, that lowered serotonin causes reduced anxiety or other benefits, has zero proof, only correlates. 

Wrong, did you even read what I had cited, the compound and the other sources clearly state that autoreceptor activation suppressed serotonin levels and thus reduced anxiety by that MOA.

 

This is also CONSISTENT with a basic understanding of G-Protein coupled receptors...when cyclic AMP (a major second messenger) is elevated, it usually leads to more GLUTAMATE, NORADRENALINE and other excitory transmitters..and GUESS WHAT?

3 out of 7 receptors of the serotonin family are POSITIVELY COUPLED = more cyclic AMP. (!)

5-HT2A,3A,5A , all lead to enhanced glutamate through other mechanisms such as IP3 and co-localization with glutamatergic receptors...which means the TYPE 1 family is pretty much the only receptor group with the opposite action

[Area-1255]

. 

 

Edited by Area-1255, 28 April 2015 - 03:58 AM.

[OneScrewLoose]

Wrong, did you even read what I had cited, the compound and the other sources clearly state that autoreceptor activation suppressed serotonin levels and thus reduced anxiety by that MOA.

No, it said that the compound (other drugs tested on 5HT1a autoreceptors actually produced biphasic responses, if you read the whole study), surpressed serotonin levels AND reduced anxiety. It gave no causal link between the two.

It also specified the dorsal hippocampus as the location of reduced serotonin. As I said, these effects vary greatly depending on the part of the brain. Even if the study did demonstrate causation, this would only stretch as far as the dorsal hippocampus, and not a brain-wide reduction in serotonin.

 

 

 

This is also CONSISTENT with a basic understanding of G-Protein coupled receptors...when cyclic AMP (a major second messenger) is elevated, it usually leads to more GLUTAMATE, NORADRENALINE and other excitory transmitters..and GUESS WHAT?

wat? R U serious? cAMP is a secondary messenger, and it just that, a messenger. Like the secondary messenger p35, it as a extremely wide variety of effects depending on the receptor it was activated by:

http://en.wikipedia....phate#Functions

cAMP binds to a response element then to CREB:

http://en.wikipedia.org/wiki/CREB

As you can see, CREB is involved in a wide variety of neurotransmitters. Enkaphalins aren't exactly excitatory. BDNF is neutral. All the major secondary messengers work on many substrates and they can not be classified as simply "excititory" or "inhibitory".

[AMx Workshop]

 

Wrong, did you even read what I had cited, the compound and the other sources clearly state that autoreceptor activation suppressed serotonin levels and thus reduced anxiety by that MOA.

No, it said that the compound (other drugs tested on 5HT1a autoreceptors actually produced biphasic responses, if you read the whole study), surpressed serotonin levels AND reduced anxiety. It gave no causal link between the two.

It also specified the dorsal hippocampus as the location of reduced serotonin. As I said, these effects vary greatly depending on the part of the brain. Even if the study did demonstrate causation, this would only stretch as far as the dorsal hippocampus, and not a brain-wide reduction in serotonin.

 

 

 

This is also CONSISTENT with a basic understanding of G-Protein coupled receptors...when cyclic AMP (a major second messenger) is elevated, it usually leads to more GLUTAMATE, NORADRENALINE and other excitory transmitters..and GUESS WHAT?

wat? R U serious? cAMP is a secondary messenger, and it just that, a messenger. Like the secondary messenger p35, it as a extremely wide variety of effects depending on the receptor it was activated by:

http://en.wikipedia....phate#Functions

cAMP binds to a response element then to CREB:

http://en.wikipedia.org/wiki/CREB

As you can see, CREB is involved in a wide variety of neurotransmitters. Enkaphalins aren't exactly excitatory. BDNF is neutral. All the major secondary messengers work on many substrates and they can not be classified as simply "excititory" or "inhibitory".

 

actually i agree with area, his work is pretty pronounced..and u seem to be the type a guy who isn't satisfied even if 1000 studies are presented. sooo yea. 

 

Edited by AMx Workshop, 28 April 2015 - 05:22 AM.

[Yunasa]

 

 

Wrong, did you even read what I had cited, the compound and the other sources clearly state that autoreceptor activation suppressed serotonin levels and thus reduced anxiety by that MOA.

No, it said that the compound (other drugs tested on 5HT1a autoreceptors actually produced biphasic responses, if you read the whole study), surpressed serotonin levels AND reduced anxiety. It gave no causal link between the two.

It also specified the dorsal hippocampus as the location of reduced serotonin. As I said, these effects vary greatly depending on the part of the brain. Even if the study did demonstrate causation, this would only stretch as far as the dorsal hippocampus, and not a brain-wide reduction in serotonin.

 

 

 

This is also CONSISTENT with a basic understanding of G-Protein coupled receptors...when cyclic AMP (a major second messenger) is elevated, it usually leads to more GLUTAMATE, NORADRENALINE and other excitory transmitters..and GUESS WHAT?

wat? R U serious? cAMP is a secondary messenger, and it just that, a messenger. Like the secondary messenger p35, it as a extremely wide variety of effects depending on the receptor it was activated by:

http://en.wikipedia....phate#Functions

cAMP binds to a response element then to CREB:

http://en.wikipedia.org/wiki/CREB

As you can see, CREB is involved in a wide variety of neurotransmitters. Enkaphalins aren't exactly excitatory. BDNF is neutral. All the major secondary messengers work on many substrates and they can not be classified as simply "excititory" or "inhibitory".

 

actually i agree with area, his work is pretty pronounced..and u seem to be the type a guy who isn't satisfied even if 1000 studies are presented. sooo yea. 

 

ditto. area knows more than this idiot will ever know!!

[OneScrewLoose]

So you're expecting me accept a single study as proof that lowered serotonin is anxiolytic, brain-wide?

What the study was missing was something that would test an increase in serotonin that didn't involve a 5HT1a antagonist, like an SRI, to see if the increased serotonin abolished the anxiolytic effects of the 5HT1a agonist. Without this, it is pure correlation.

Edited by OneScrewLoose, 28 April 2015 - 05:37 AM.

[OneScrewLoose]

This was a post for another thread. Deleted.

Edited by OneScrewLoose, 28 April 2015 - 06:11 AM.

[Keizo]

Just thought I'd chime in and say that Shilajit/Fulvic Acid (both jarrow formulas, and the Pure&Fulvic also known as WuJinSan) seems to have some rather typical (to me) dopaminergic effects.

30ml of the Pure&Fulvic (6%) causes a noticeable increase in spontaneous erections, and increase in energy, for example. There is a certain feeling which is hard to describe, but it all is similar in kind to low doses of selegeline (1.25-2.5mg sublingually) or d-amphetamine (~5mg). 

2 capsules of the shilajit also had a noticeable effect, but perhaps more energizing and wakeful promoting.

 

I take about 12ml now most every day, which does not produce much noticeable immediate effect however.

I never had erection problems or anything like that, but I imagine I have increased my testosterone with a variety minerals, fats, and probably fulvic acid. Late last year I did not have the same mindset, now I am much calmer, specifically socially. We will never know (unless you fund a blood test for me. I was at 460ng/dl s-testosterone in last summer.)

Edited by Keizo, 29 August 2015 - 07:46 PM.

[gamesguru]

Concerning the ginkgo, is it more agonist or modulator?

EGb 761-induced stimulus control is significantly antagonized by the selective 5-HT1A antagonist WAY-100635

stimulus effects are mediated in part by activity at the 5-HT1A receptor.

^^^^ that is one study

----------------------------

\/ \/ \/ \/ this is another

Although the ginkgolides and bilobalide technically inhibit the serotonin 5-HT3A receptor, this may occur at too high a concentration to be relevant following oral supplementation. The 5-HT1A receptor appears to have its activity preserved in instances where it would normally be decreased [aging or stress]

 

 

I saw yohimbine briefly mentioned in the other thread, so I thought I may as well share this finding:

Woolley and Shaw, two investigators at the Rockefeller Institute for Medical Research, noted that LSD, harmaline, yohimbine ... all block the action of serotonin on smooth muscles.  They went on to argue that the fact that serotonin has been found int he brain suggests that th mental changes caused by the drugs are the result of a serotonin deficiency that they induce in the brain.  Woolley and Shaw concluded: "If this be true, then the naturally occurring mental disorders, for example, schizophrenia--which are mimicked by these drugs, may be pictured as being the result of a cerebral serotonin deficiency arising from a metabolic failure rather than from drug action."  They then speculated that the naturally occurring mental disorders might be treated with serotonin, and proposed combining 5-HTP with a peripheral serotonin antagonist [which does not cross the BBB] to limit activity to the cerebral and avoid cardiac fibrosis.

 

But these natural compounds tend to be pharmacologically non-selective and "dirty"... harmine reversibly inhibits MAO-A and tetrahydroharmine is a serotonin uptake inhibitor (SRI). So their net effect may be pro-sertonergic.

 

 

As for yohimbine,

In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611.
Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels.

[Blackkzeus]

Just thought I'd chime in and say that Shilajit/Fulvic Acid (both jarrow formulas, and the Pure&Fulvic also known as WuJinSan) seems to have some rather typical (to me) dopaminergic effects.
30ml of the Pure&Fulvic (6%) causes a noticeable increase in spontaneous erections, and increase in energy, for example. There is a certain feeling which is hard to describe, but it all is similar in kind to low doses of selegeline (1.25-2.5mg sublingually) or d-amphetamine (~5mg).
2 capsules of the shilajit also had a noticeable effect, but perhaps more energizing and wakeful promoting.

I take about 12ml now most every day, which does not produce much noticeable immediate effect however.
I never had erection problems or anything like that, but I imagine I have increased my testosterone with a variety minerals, fats, and probably fulvic acid. Late last year I did not have the same mindset, now I am much calmer, specifically socially. We will never know (unless you fund a blood test for me. I was at 460ng/dl s-testosterone in last summer.)

What minerals are you taking to increase testosterone?

Edited by Ed Ntuk, 30 August 2015 - 06:54 PM.

[Keizo]

...

What minerals are you taking to increase testosterone?

 

Total elemental value from powder/pills, including what is from the 1 tablet of "Two per day" from LifeExtension: ~500mg Magnesium (from magnesium bisglyicinate), ~1gram Calcium, ~30mg Zinc, ~200mcg Selenium, ~10mg Boron. 

Also 6000 IU vit. D3, 50 grams butter, half a deciliter of olive oil every other day (450 kcal), 750mg 98% resveratrol, and some "L. Reuteri plus". 

So, nothing too crazy.

There are some articles on ergo-log.com 

E.g: http://www.ergo-log....com/boron.html 

http://www.ergo-log....-synthesis.html L. reuteri (Don't know if you can buy that specific one)

http://www.ergo-log....stosterone.html shilajit

Edited by Keizo, 30 August 2015 - 08:01 PM.

[Keizo]

I just bought some Lysine because it was cheap and some people had benefits with e.g. sleep.

I now see it is a 5-ht4 antagonist... very interesting even if it is weak. In this other thread of yours you mention 5-ht4 http://www.longecity...n-in-the-brain/

 

I often get rather significant lack of motivation and a noticeable increase in social anxiety after ejaculation, which takes about 3 days to fully normalize.  I think this isn't an entirely normal response. I no longer ejaculate more than every 14 days since I wish to keep my energy levels and motivation high, etc.

If I am to believe the neurotransmitter theories thrown around I am very acetylcholine dominant (and introverted), maybe high on the serotonin scale as well. Unfortunately selegiline causes me diziness, but otherwise it helps some with social anxiety in 1.25mg sublingual doses. Shilajit / fulvic acid works with less problems in doing something similar. I would just assume these benefits are due to more dopamine,  lowered prolactin or serotonin, or heightened testosterone, in some fashion.

 

I'll just leave this regarding Lysine:  http://www.raypeatfo...opic.php?t=6004

 

Edit: I saw you mentioned it on your blog already http://area1255.blog...onin-5-ht4.html

Edited by Keizo, 13 September 2015 - 02:27 AM.

[Area-1255]

I just bought some Lysine because it was cheap and some people had benefits with e.g. sleep.

I now see it is a 5-ht4 antagonist... very interesting even if it is weak. In this other thread of yours you mention 5-ht4 http://www.longecity...n-in-the-brain/

 

I often get rather significant lack of motivation and a noticeable increase in social anxiety after ejaculation, which takes about 3 days to fully normalize.  I think this isn't an entirely normal response. I no longer ejaculate more than every 14 days since I wish to keep my energy levels and motivation high, etc.

If I am to believe the neurotransmitter theories thrown around I am very acetylcholine dominant (and introverted), maybe high on the serotonin scale as well. Unfortunately selegiline causes me diziness, but otherwise it helps some with social anxiety in 1.25mg sublingual doses. Shilajit / fulvic acid works with less problems in doing something similar. I would just assume these benefits are due to more dopamine,  lowered prolactin or serotonin, or heightened testosterone, in some fashion.

 

I'll just leave this regarding Lysine:  http://www.raypeatfo...opic.php?t=6004

 

Edit: I saw you mentioned it on your blog already http://area1255.blog...onin-5-ht4.html

Lysine does have a lot of benefits; not just with gut but also immune and heart benefits. It also counters herpes infections of all sorts; not that it would apply to all but we are talking even common cold sores...additionally; it's effects on the endocrine system are largely ANTI-CORTISOL - however, do note that LYSINE will compete with arginine for absorption - so it is best taken on an empty stomach or an hour away from food...

 

5-HT4 antagonism as with very high dose Lysine goes well with 5-HT7 and / or 2A antagonism...so something like amisulpride plus a dopamine agonist and LYSINE would be very beneficial in theory.

 

As far as post--orgasm anxiety as you put it...that MOST LIKELY has to do with prolactin...if your prolactin is elevated you often feel guilty or anxious or depressed after ejac/orgasm....some will tell you this is due to a drop in serotonin...but that is not at the core of the issue as there are many people with low serotonin who do not erupt into a depression after having sex .   

 

With that being said, and all mumbo-jumbo garbage science aside, I do very much advocate for a strong sexual life - perhaps not in being a deviant per se but at least in relationships or w/e..or even with hookups.... 

 

It is a fair bet you can check your prolactin and see if they are elevated... 

[iseethelight]

Panax Ginseng is actually a serotonin reuptake inhibitor according to pubmed. http://www.ncbi.nlm....pubmed/22435351

Can you elaborate on that?

 

Also do you have a recommended brand for shilajit? Most of the brands were found to be contaminated with heavy metals and other toxins. http://www.ncbi.nlm....les/PMC3296184/

Edited by iseethelight, 23 September 2015 - 05:55 AM.

[gamesguru]

that study says ginseng also inhibits norepinephrine uptake.  Not usually a good thing.

 

green tea and ginkgo also act as modulators.

http://area1255.blog...ntagonists.html

http://www.amazon.co...CKVDQ7BYBQ44YF3

 

Dietary modulation of uptake transporters. PhD thesis, University of Leeds.
Transporters play a determinant role in creating and maintaining physiological balance within the cells. Though, not much information exists on the modulation of transporters, especially in terms of polyphenols and other dietary components. Initially, a comprehensive database was created, using the high-performance search engine Genevestigator. The database summarises the existing knowledge on selected transporters (OAT1, OAT3, OATP1A2, OATP1B1, OATP1B3, OATP4C1, MRP2, MRP3, BCRP, MCT1, MCT7 and SMCT1). The anatomical distribution of the latters was investigated in the human heart, kidney, liver and intestine. Transcriptional modulation was also assessed, in response to biological mediators, disease, chemicals and drugs. It was shown that while some transporters were modulated from a large number of conditions, others only responded to few. Interestingly, not many dietary compounds were tested, highlighting the limited knowledge existing in this area. Subsequently, expression of a transporter of interest, the organic anion transporter 3 (OAT3), was assessed in liver HepG2 cells. It was predicted, on the basis of the Ct value, that OAT3 was expressed in the cell line at low levels. Modulation of OAT3, in response to stressors (hydrogen peroxide, tert-butyl hydroperoxide and ethanol) at various concentrations and for different time lengths was assessed. It was shown that none of the stressors affected the transporter. In the same cell line, uptake of the metabolite kaempferol-3-O-glucuronide was assessed, to establish whether uptake occurred in a carrier-mediated manner or through passive diffusion mainly. Uptake resulted to be carrier-mediated, although the low Vmax of the transport, close to detection limit, did not make possible further studies to identify the transporter(s) involved in its uptake. Finally, intestine Caco-2 cells were used to assess modulation of the serotonin transporter from green tea and coffee. For the first time, it was reported that green tea and coffee acted as modulators of serotonin uptake. Whole extracts showed to act in a concentration-dependent way. Physiological concentrations of individual green tea components showed not to have a significant effect on the uptake, however significant effect was observed when using supplement concentrations (equivalent to 7 cups). Physiological concentrations of several coffee components showed to modulate serotonin uptake. Among them, ferulic acid and 5-feruloylquinic acid showed to act in a competitive manner.

Neurobiological effects of the green tea constituent theanine and its potential role in the treatment of psychiatric and neurodegenerative disorders.
Theanine (n-ethylglutamic acid), a non-proteinaceous amino acid component of green and black teas, has received growing attention in recent years due to its reported effects on the central nervous system. It readily crosses the blood-brain barrier where it exerts a variety of neurophysiological and pharmacological effects. Its most well-documented effect has been its apparent anxiolytic and calming effect due to its up-regulation of inhibitory neurotransmitters and possible modulation of serotonin and dopamine in selected areas. It has also recently been shown to increase levels of brain-derived neurotrophic factor. An increasing number of studies demonstrate a neuroprotective effects following cerebral infarct and injury, although the exact molecular mechanisms remain to be fully elucidated. Theanine also elicits improvements in cognitive function including learning and memory, in human and animal studies, possibly via a decrease in NMDA-dependent CA1 long-term potentiation (LTP) and increase in NMDA-independent CA1-LTP. Furthermore, theanine administration elicits selective changes in alpha brain wave activity with concomitant increases in selective attention during the execution of mental tasks. Emerging studies also demonstrate a promising role for theanine in augmentation therapy for schizophrenia, while animal models of depression report positive improvements following theanine administration. A handful of studies are beginning to examine a putative role in attention deficit hyperactivity disorder, and theoretical extrapolations to a therapeutic role for theanine in other psychiatric disorders such as anxiety disorders, panic disorder, obsessive compulsive disorder (OCD), and bipolar disorder are discussed.

Edited by gamesguru, 23 September 2015 - 06:23 AM.

[Area-1255]

Also do you have a recommended brand for shilajit? Most of the brands were found to be contaminated with heavy metals and other toxins. http://www.ncbi.nlm....les/PMC3296184/

1.) http://www.therootof...rootofthematter

 

2.) http://www.dragonher....asp?number=526

Edited by Area-1255, 23 September 2015 - 12:29 PM.

[iseethelight]

 

Also do you have a recommended brand for shilajit? Most of the brands were found to be contaminated with heavy metals and other toxins. http://www.ncbi.nlm....les/PMC3296184/

1.) http://www.therootof...rootofthematter

 

2.) http://www.dragonher....asp?number=526

 

 Ok. Care to elaborate on the ginseng question? Any studies backing up your claim that it decreases serotonin? We don't want people trying to decrease serotonin to increase it as this can cause serious issues.

[Area-1255]

 

 

Also do you have a recommended brand for shilajit? Most of the brands were found to be contaminated with heavy metals and other toxins. http://www.ncbi.nlm....les/PMC3296184/

1.) http://www.therootof...rootofthematter

 

2.) http://www.dragonher....asp?number=526

 

 Ok. Care to elaborate on the ginseng question? Any studies backing up your claim that it decreases serotonin? We don't want people trying to decrease serotonin to increase it as this can cause serious issues.

 

http://www.sigmaaldr...ax-ginseng.html (CNS/Neurological/Cognitive effects)

Edited by Area-1255, 23 September 2015 - 08:16 PM.

[iseethelight]

 

 

 

Also do you have a recommended brand for shilajit? Most of the brands were found to be contaminated with heavy metals and other toxins. http://www.ncbi.nlm....les/PMC3296184/

1.) http://www.therootof...rootofthematter

 

2.) http://www.dragonher....asp?number=526

 

 Ok. Care to elaborate on the ginseng question? Any studies backing up your claim that it decreases serotonin? We don't want people trying to decrease serotonin to increase it as this can cause serious issues.

 

http://www.sigmaaldr...ax-ginseng.html (CNS/Neurological/Cognitive effects)

 

 

That's a weak reference. There is more solid info about it increasing serotonin than decreasing. I would remove it as serotonin antagonist from your article as it is dangerous to claim so.

Edited by iseethelight, 23 September 2015 - 09:55 PM.

[Area-1255]

That's a weak reference. There is more solid info about it increasing serotonin than decreasing.

Sigma Aldrich is one of the most respected chemical suppliers and held to the highest standard. Their information is not only sourced but they have first-hand experience due to direct contract evaluations.
Oh, and , clearly, you read nothing or don't understand the terms. Read the context and lmk if you need help understanding the terms ' metabolism of ' and 'uptake ' of.

Ginseng saponins: influence on neurotransmitter uptake in rat brain synaptosomes.

Effects of Panax ginseng root on the vertical and horizontal motor activities and on brain monoamine-related substances in mice.

J Altern Complement Med.[/size] 2003 Aug;9(4):505-10.[/size]

Effect of ginseng saponins on the recombinant serotonin type 3A receptor expressed in xenopus oocytes: implication of possible application as an antiemetic.
Min KT1, Koo BN, Kang JW, Bai SJ, Ko SR, Cho ZH.


Author information
 



Abstract


OBJECTIVES:
Nausea and vomiting are the most frequently reported side-effects by patients who are given general anesthesia perioperatively and patients with cancer who undergo chemotherapy or radiotherapy. Serotonin (5-hydroxytryptamine, 5HT) type 3A receptor (5HT(3A) receptor) is known to mediate nausea and vomiting and its antagonists have been used effectively to prevent and/or reduce the incidence and severity of nausea and vomiting. However, the adverse effects on cardiac function, such as QT interval prolongation, limit their routine use by these patients. This study was designed to elucidate the effect of ginseng saponins on the recombinant 5HT(3A) receptor expressed in the xenopus oocyte.

DESIGN:
After in vitro transcription of the recombinant human 5HT(3A) receptor in the Xenopus laevis oocyte, we examined Panax ginseng saponins (total saponin [TS], panaxadiol saponin [PD] fraction, panaxatriol saponin [PT] fraction, and ginsenoside-Rb1 and -Rg1) for their ability to inhibit current flow through the 5HT(3A) receptor using the voltage-clamp technique.

RESULTS:
All saponin fractions (TS, PD, PT fraction, as well as ginsenoside-Rb1 and -Rg1) inhibited the peak current induced by the agonist 5HT on the 5HT(3A) receptor in a concentration-dependent, reversible, and voltage-independent manner. The PT fraction inhibited 5HT-induced currents in 5HT(3A) receptor more than the PD fraction; meanwhile, there was a similar degree of inhibition between ginsenoside-Rg1 and -Rb1, the main substitutes of PT fraction and PD saponin fractions, respectively.

CONCLUSIONS:
These results indicate that ginseng saponins, especially PT fraction, have substantial inhibitory effects on the recombinant 5HT(3A) receptor, suggesting that some of the specific types of ginsenoside might have an antagonistic action against 5HT(3A) receptor related to nausea and vomiting.






PMID:

 

14499026

 

[PubMed - indexed for MEDLINE]

 
 

I would remove it as serotonin antagonist from your article as it is dangerous to claim so.

I am not removing anything as it is properly cited and even anecdotes are given - are you here just to troll and argue ? 

Because if that's the case, you won't last on this forum very long.   

Edited by Area-1255, 23 September 2015 - 10:19 PM.

[iseethelight]

 

That's a weak reference. There is more solid info about it increasing serotonin than decreasing.

Sigma Aldrich is one of the most respected chemical suppliers and held to the highest standard. Their information is not only sourced but they have first-hand experience due to direct contract evaluations.
Oh, and , clearly, you read nothing or don't understand the terms. Read the context and lmk if you need help understanding the terms ' metabolism of ' and 'uptake ' of.

Ginseng saponins: influence on neurotransmitter uptake in rat brain synaptosomes.

Effects of Panax ginseng root on the vertical and horizontal motor activities and on brain monoamine-related substances in mice.

J Altern Complement Med.[/size] 2003 Aug;9(4):505-10.[/size]

Effect of ginseng saponins on the recombinant serotonin type 3A receptor expressed in xenopus oocytes: implication of possible application as an antiemetic.
Min KT1, Koo BN, Kang JW, Bai SJ, Ko SR, Cho ZH.


Author information
 



Abstract


OBJECTIVES:
Nausea and vomiting are the most frequently reported side-effects by patients who are given general anesthesia perioperatively and patients with cancer who undergo chemotherapy or radiotherapy. Serotonin (5-hydroxytryptamine, 5HT) type 3A receptor (5HT(3A) receptor) is known to mediate nausea and vomiting and its antagonists have been used effectively to prevent and/or reduce the incidence and severity of nausea and vomiting. However, the adverse effects on cardiac function, such as QT interval prolongation, limit their routine use by these patients. This study was designed to elucidate the effect of ginseng saponins on the recombinant 5HT(3A) receptor expressed in the xenopus oocyte.

DESIGN:
After in vitro transcription of the recombinant human 5HT(3A) receptor in the Xenopus laevis oocyte, we examined Panax ginseng saponins (total saponin [TS], panaxadiol saponin [PD] fraction, panaxatriol saponin [PT] fraction, and ginsenoside-Rb1 and -Rg1) for their ability to inhibit current flow through the 5HT(3A) receptor using the voltage-clamp technique.

RESULTS:
All saponin fractions (TS, PD, PT fraction, as well as ginsenoside-Rb1 and -Rg1) inhibited the peak current induced by the agonist 5HT on the 5HT(3A) receptor in a concentration-dependent, reversible, and voltage-independent manner. The PT fraction inhibited 5HT-induced currents in 5HT(3A) receptor more than the PD fraction; meanwhile, there was a similar degree of inhibition between ginsenoside-Rg1 and -Rb1, the main substitutes of PT fraction and PD saponin fractions, respectively.

CONCLUSIONS:
These results indicate that ginseng saponins, especially PT fraction, have substantial inhibitory effects on the recombinant 5HT(3A) receptor, suggesting that some of the specific types of ginsenoside might have an antagonistic action against 5HT(3A) receptor related to nausea and vomiting.






PMID:

 

14499026

 

[PubMed - indexed for MEDLINE]

 
 

I would remove it as serotonin antagonist from your article as it is dangerous to claim so.

I am not removing anything as it is properly cited and even anecdotes are given - are you here just to troll and argue ? 

Because if that's the case, you won't last on this forum very long.   

 

 

Troll and argue? Why the personal attack?  Why can't we focus on the matter? You seem to be quite a sensitive fellow whenever someone argues with your claims and think you're some kind of scientist who people should respect. Real scientists welcome debate and scrutinies. Anger and personal attacks are a real sign of an amateur trying to live out a fantasy online.

 

There is no sugarcoating things when people's health is at stake because of people giving out false information. Don't recommend things as an authority when you haven't researched it well enough or hold no credentials. 

 

Relax dude. So people can't call you out on incorrect information? Are you just going to ignore the fact the studies that say otherwise. Ginseng Saponins are just an isolated part of ginseng, ginseng as a whole supplement has other chemicals that will affect serotonin differently.

Edited by iseethelight, 23 September 2015 - 11:12 PM.

[Area-1255]

Don't recommend things as an authority when you haven't researched it well enough or hold no credentials.

And you like literally just signed up late last month. You are twenty posts in, and talking all kinds of garbage..and yet, haven't posted a SINGLE study to back up what YOU are saying..Ask anybody on this forum - you'll see I am highly respected. But I think you already know that - and most likely you are a former (probably banned) disgruntled member who is on here literally to start arguments. Maybe the overseers should check your IP address to see?
 
 
 
 

Troll and argue? Why the personal attack?  Why can't we focus on the matter? You seem to be quite a sensitive fellow whenever someone argues with your claims and think you're some kind of scientist who people should respect. Real scientists welcome debate and scrutinies. Anger and personal attacks are a real sign of an amateur trying to live out a fantasy online.

 And this last sentence, by definition is Ad Hominem; it is a morbid generalization holding no merit - exuming a psychological precept that can't even be applied to this current situation.. 

There is no sugarcoating things when people's health is at stake because of people giving out false information.
 
Relax dude. So people can't call you out on incorrect information? Are you just going to ignore the fact the studies that say otherwise. Ginseng Saponins are just an isolated part of ginseng, ginseng as a whole supplement has other chemicals that will affect serotonin differently.

 

You basically reiterated your statement in two different forms, then the last sentence has no citation to back it up...

Why don't you go back to your cave and curl up into a ball like you usually do. Internet tough guy.  

Edited by Area-1255, 23 September 2015 - 11:38 PM.

[gamesguru]

Selling tickets, $5

See Sigmund Frued   analyze Jason.

[Area-1255]

Selling tickets, $5

See Sigmund Frued   analyze Jason.

Sigmund Freud would proverbially chew this guy up and spit him out as a different person! 

Oh..just imagine.   

[kurdishfella]

@Area-1255 I gotta say you know your shit.

 

I have high serotonin levels I first thought I had Histapenia (not a real diagnosis) but this makes more sense to me.

 

I have all the side effects of HIGH serotonin

-Numb (no emotions)

-Socially anxious

-Depressed (weird right because high lvls of serotonin should prevent this)

-irritated/mad 

-Bad sleep

-Fatigue/no energy 

-Can't concentrate 

 

Anyway did you guys see the study that says  Social anxiety is actually caused by too much serotonin?

http://articles.merc...y-disorder.aspx

 

 

I looked trough your blog and im gonna give these supplements or whatever you wanna call them a try:

-WHITE WILLOW BARK (some guy suggested this in the comments)

-Agnus Castus

- yohimbe Bark Extract

- panax ginseng

-Shilajit

 

 

are there any specific doses or how many times a day you need to take these to keep your serotonin normal ?

 

 

atm im taking seroquel supposedly this block serotonin cant say it helps much only day 1 tho.

Edited by farshad, 07 June 2017 - 11:43 AM.

[gamesguru]

ah, area.. no longer posts here; he has been banned many times over, for breaking every rule in the book.  luckily you're talking to another titan, and the next best thing

 

without knowing too much about agnus castus, i would slim my stack down to that and shilajit.  the yohimbine and panax can be a bit harsh, and the willow bark seems to be tacked on a bit randomly imo.  it can cause ulcers and is not the first choice in either pain killing or cholesterol lowering, so so what if some guy suggested it in the comments?  especially if youre on seroquel watch out how many supplements you go taking behind your doctor's back.  your complaints seem to be part of a cluster to a larger set of anhedonic symptoms.  phenibut, ginseng, tribulus and resveratrol are reputedly effective, though they can be a bit harsh.  those four are listed in order of descending effectiveness.  you could also consider things like exercise, low tryptophan diet, bacopa, magnesium and dark chocolate, but at that point tbh it's getting a bit hopeless