33 replies to this topic

[Area-1255]

Symptoms / Signs of Too Much Serotonin / Excess Serotonin

{SPECIFICS, EASY TO READ, CITED}

{click above link to go to original article page}

 



Due to being increasingly displeased with the difficulty in finding such information to the average user, I have compiled a well cited guide on determining if you may have TOO MUCH SEROTONIN.

One VERY important thing to remember, is that excessive serotonin production is NOT the only way to have high serotonin, and often...excessive serotonin is due decreased breakdown of serotonin and it's metabolites. This can occur when using SSRI's along with other medications or supplements that impact the breakdown of serotonin, such as MAO-A inhibitors (ST.John's Wort), Syrian Rue, Nutmeg etc

With nutmeg, it is unlikely you will get enough of a toxic effect from using a little of the whole spice, HOWEVER, if you are using teaspoon after teaspoon of nutmeg excessively, then EATING other foods that increase serotonin, like bananas and turkey - then you have an increased risk of developing serotonin syndrome.

KEEP IN MIND, that the symptoms related to serotonin syndrome represent a SEVERE excess of serotonin which often requires immediate care / CRISIS management.

TOO MUCH serotonin is describing a PERSISTENT, but NOT SEROTONIN-SYNDROME qualified excess. Therefore, this article is NOT describing serotonin syndrome, but too much serotonin* over time - where it relates to borderline health issues.

This article is ideal for those who suspect out of balance serotonin, but not so much serotonin that it becomes toxic as in an acute CRISIS. 
Some symptoms of high serotonin mirror those of low glutamate- NMDA function. 

 

 SENSORY EFFECTS

• Over-Sensitivity to sounds, especially loud noises. Excessive jumpiness or even anxiety in response to sudden sounds or movements(1) (2).
• Visual distortions, height / depth alteration, hallucinations(3) (4).
• Words may appear out of place, or your perception of what you are reading may be entirely different. { e.g reading the third line thinking its the second} (5)
• Sensitivity changes to light, sedation or no response to darkness(6) (7) (8) (9). 
• Lack of pain sensation, or HYPO Algesia, some individuals with high serotonin display such a lack in pain perception/sensitivity that it mirrors the effects of those under the influence of PCP. Pain asymbolia can be misdiagnosed as high serotonin(10) (11).
• Tinnitus, ringing in ears(12)(13).
• Vertigo. Dizziness. Room spinning(14) (15).

                  BEHAVIORAL / MENTAL EFFECTS

• Delirium. Usually including abnormal forms of panic or worry along with various disperceptions(16)(17)
• Depersonalization. Feeling out of place, out of body, or that events or surroundings are surreal(18)(19).
• Frequent or occasional episodes of psychosis, paranoia, pathology changes, and obsessional behavior(20)(21).
• Religious delusions and religious over-engagement. (some cult leaders are hypothesized to have elevated, but not toxic levels of serotonin)(22).
• Unexplained agitation or inner restlessness(23). 
• Dystonia, tic-like behaviors, punding; repetitive behaviors(24) (25)(26) (27).
• Frequent crying episodes in children, unwarranted panic or extreme anxiety(28).
• Low/Absent Libido(29)
• Emotional Anhedonia / Apathy / Blunt AFFECT (30) (31) (32) (33) (34)
• Jittery, nervous hands, tremors, impatient(35) (36) (37).
• Depression , despair, lack of motivation(38) (39). 
• Reading/Comprehension deficits(40).
• Feeling as though people are reading your thoughts. (Low glutamate sign due to high serotonin)

 

 

 

 

 

OTHER EFFECTS OF HIGH SEROTONIN ;   PERSISTENT NAUSEA, DIARRHEA, HEADACHES, OVER-EXCITABILITY OR UNDER-EXCITABILITY, DECREASED CURIOSITY, DECREASED LABILITY, DECREASED SENSE OF SMELL.

 

 

Edited by Area-1255, 03 May 2015 - 11:24 PM.

[OneScrewLoose]

Studies:
1: Simply goes over the relation between startle response and some serotonin receptors. Antagonists attenuate the response. This isn’t automatically a good thing, you’d hope to get startled if you noticed a bear right behind you. Nothing about excess serotonin here.
 
2.Same principles as 1. And from the study itself:
 
 

The impact of PCPA on the startle response is not commensurate with the extent to which it depletes 5-HT (8). This indicates that the effect of PCPA on startle amplitude in adult rats does not reflect the magnitude of 5-HT involvement in tonic inhibition of the ASR. The relatively small and inconsistent effect of PCPA may relate to the dual role of 5-HT in modulating the ASR, acting both to increase and attenuate response amplitude, and the generalized depletion of 5-HT in the spinal cord and brain that occurs with PCPA. PCPA would be expected to attenuate both effects, each acting to oppose the other. The overall impact of PCPA could vary then, if the relative contribution of 5-HT facilitation and inhibition of the ASR varied with experimental conditions.

So, serotonin levels don’t seem to correlate strongly with the startle response. This directly contradicts your hypothesis.
 
3. None of these give any evidence that high levels of endogenous serotonin cause any problems. In fact, it lists some antipsychotics as causing these problems, which tend to block serotonin receptors like 5HT2a. That’s an anti-serotoninergic effect.
 
4.
 

Depending on which situation is considered, the pharmacological hypotheses underlying the symptoms are completely different. Psychostimulants-induced hallucinations result from increased dopamine transmission and hyperactivation of dopamine D2 receptor (D2R). Furthermore, “dissociative anesthetics” drugs induce complex schizophrenia-like clinical pictures, including hallucinations, that result from the blockade of glutamate NMDA receptors (NMDAR). Lastly, psychedelics act by stimulating the serotoninergic 5HT2A receptor (5HT2AR). In schizophrenia, although antipsychotic blocking studies suggest that hallucinations result from D2R hyperstimulation, there are also numerous arguments for NMDAR dysfunction, which may be a potential and specific hallucinatory mechanism.

So we have one serotoninergic mechanism here, the very obvious notion that psychedelics cause hallucinations. There is no evidence here that high endogenous serotonin can cause any of these effects. In addition, SRIs and MAOIs don’t cause this effect, despite greatly increasing 5HT levels. This is because there is a vast difference between increasing a neurotransmitters level and agonizing one of its receptors. Just look at the difference between increasing acetylcholine and agonizing the alpha-4-beta-2 receptor, the main target of nicotine in tobacco.

5. Same study as 3.
 
6.
 

The reduction of serotonin levels in flies kept in constant darkness may provide scientists with insight into the etiology and treatment of SAD, a mood disorder related to reduced sunlight during winter. “People with seasonal affective disorder will respond to medications such as Prozac to increase serotonin,” says Sehgal. “Patients also respond to light therapy. We now believe that light is also increasing serotonin-perhaps this is why both of these treatments are effective.”

The exact opposite of your hypothesis.
 
7. This isn’t even a study, it’s an article. Check out this magnificent gem:
 

Even worse, eating too serotonin-boosting foods, while it might feel good for a short time, can lead to a worse crash later on. That’s why a candy bar or a soda are so much worse for us…

Holy shit, candy and soda increase serotonin? Where can I get that study?
 
8.
 

Our results indicate that the 5-HT7 receptor subtype plays a major role in mediating the effects of 5-HT on photic responses of SCN cells in the hamster.

 
Yup, some systems are in our brain are going to regulate photic response. I guess somehow this means we should lower serotonin as much as possible.
 
9.
 

The pineal, serotoninergic and pigmented neurons are associated with light-dependent sleep/arousal, serving as a biological clock with a circadian rhythm. This rhythm is maintained by melatonin which serves to recognise the 'dark' phase. The neural network that responds to seasonal variations in day/night length has not been identified. The present study demonstrates that melanocytes in human skin respond to changes in the duration of UV exposure, and can serve as a biological calendar. These responses are mediated by two indoleamines, serotonin and melatonin. Higher melatonin levels correspond to long nights and short days (short UV pulse), while high serotonin levels in the presence of melatonin reflect short nights and long days (long UV exposure). This response recapitulates the sleep/arousal patterns in animals exposed to large variations in day/night cycle that cause changes in coat colour from pure white in winter to complete repigmentation in summer.

 
All it says is the serotonin plays an integral role in our biological clock and circadian rhythm…so clearly we need to lower it as much as possible?
 
10.
 

The tail flick assay was used to evaluate pain perception in mice treated acutely with either of the two classical antidepressant drugs (AD) imipramine or amitriptyline, or the atypical antidepressant iprindole. A sustained hypoalgesic effect, sensitive to the opiate antagonist naloxone, was detected for the AD used in this study. Administration of the aminopeptidase inhibitor bestatin or the enkephalinase blocker thiorphan made subeffective doses of AD hypoalgesic. This synergistic effect was reversed by naloxone. The antinociceptive action of the AD wore off in mice rendered tolerant to morphine by subcutaneous implantation of a pellet of the opiate. Subchronic treatment with p-chlorophenylalanine did not alter the effect of AD on pain perception, but in animals whose serotonin (5-HT) receptors were blocked by methysergide AD did not produce any change in pain threshold. It was concluded on the basis of these findings that short-chain opioids and 5-HT appear to have a role in the hypoalgesic effect of either classical or atypical AD.

So, the mu antagonist, naloxone, alone blocked the effects, and blocking 5HT receptors had no effect…this is a clear implication of the direct effect serotonin alone has on pain perception, right???...
…
…
I can’t do this anymore, can’t go through any more. I think anyone reading this gets the picture. You have absolutely no evidence that normal, endogenous, high-levels of serotonin can be problematic. And the fact that some drugs can increase serotonin too high? That goes without saying.

Edited by OneScrewLoose, 04 May 2015 - 05:50 AM.

[Area-1255]

It seems you have found your place arguing with me on this forum. Yet in the last three discussions I've proved you wrong and you no longer responded.

 

Additionally, here you are taking excerpts out of context and trying to make it look like I am saying to LOWER serotonin as much as possible here..which is not what I am saying at all. Several studies IN ADDITION to what I've already posted directly elaborate on the HARMFUL effects of excess serotonin...

 

TONS of people will undoubtedly agree with me.

Here's a few, and then I will deal with your other statements.

 

http://www.livestron...much-serotonin/

http://www.drugwatch.com/prozac/

https://uniteforlife...otonin-dangers/

Studies:
1: Simply goes over the relation between startle response and some serotonin receptors. Antagonists attenuate the response. This isn’t automatically a good thing, you’d hope to get startled if you noticed a bear right behind you. Nothing about excess serotonin here.
 
2.Same principles as 1. And from the study itself:
 
 

The impact of PCPA on the startle response is not commensurate with the extent to which it depletes 5-HT (8). This indicates that the effect of PCPA on startle amplitude in adult rats does not reflect the magnitude of 5-HT involvement in tonic inhibition of the ASR. The relatively small and inconsistent effect of PCPA may relate to the dual role of 5-HT in modulating the ASR, acting both to increase and attenuate response amplitude, and the generalized depletion of 5-HT in the spinal cord and brain that occurs with PCPA. PCPA would be expected to attenuate both effects, each acting to oppose the other. The overall impact of PCPA could vary then, if the relative contribution of 5-HT facilitation and inhibition of the ASR varied with experimental conditions.

So, serotonin levels don’t seem to correlate strongly with the startle response. This directly contradicts your hypothesis.
 
3. None of these give any evidence that high levels of endogenous serotonin cause any problems. In fact, it lists some antipsychotics as causing these problems, which tend to block serotonin receptors like 5HT2a. That’s an anti-serotoninergic effect.

 

 

You just defeated yourself with your own statement...yes, anti-psychotics block the type 2 serotonin receptors...but HAVE ZERO AFFINITY FOR THE 5-HT5A, which is the one that CAUSES INCREASED AMPLITUDE AND OCCURRENCE OF STARTLE..therefore your statement is NULL. OF COURSE THE EFFECT WILL BE OPPOSITE...because by blocking the type 2 RECEPTORS , and PLUS, many anti-psychotics block the 1B AUTORECEPTORS now we have MORE SEROTONIN SHIFTING TO THE 5AR which CAUSES THE STARTLE...

 

But, that's not it...there are other receptors involved with the startle reflex, non serotonin receptors such as ALPHA-1-ADRENERGIC, what you aren't taking into account is that LONG-TERM EXPOSURE TO HIGH SEROTONIN OFTEN DE-SENSITIZED THE 1AR autoreceptors..leading to more 5AR agonism - Which again..does what?  CAUSES THE STARTLE...additionally, lowered/downregulated 1AR's results in HIGHER ADRENALINE...therefore this SUPPORTS MY HYPOTHESIS yet AGAIN, that high serotonin by both adrenergic pathways and serotonergic pathways...by FEEDBACK. Increases that response.

 

BUT...you are dealing in absolutes here, and it seems you are one of the pro-serotonin MANIACS that may even work for the drug companies...or maybe you just like to argue. Dealing in absolutes when I am simply saying that too much of anything is bad..that includes serotonin!!

 

Depending on which situation is considered, the pharmacological hypotheses underlying the symptoms are completely different. Psychostimulants-induced hallucinations result from increased dopamine transmission and hyperactivation of dopamine D2 receptor (D2R). Furthermore, “dissociative anesthetics” drugs induce complex schizophrenia-like clinical pictures, including hallucinations, that result from the blockade of glutamate NMDA receptors (NMDAR). Lastly, psychedelics act by stimulating the serotoninergic 5HT2A receptor (5HT2AR). In schizophrenia, although antipsychotic blocking studies suggest that hallucinations result from D2R hyperstimulation, there are also numerous arguments for NMDAR dysfunction, which may be a potential and specific hallucinatory mechanism.

So we have one serotoninergic mechanism here, the very obvious notion that psychedelics cause hallucinations. There is no evidence here that high endogenous serotonin can cause any of these effects. In addition, SRIs and MAOIs don’t cause this effect, despite greatly increasing 5HT levels. This is because there is a vast difference between increasing a neurotransmitters level and agonizing one of its receptors. Just look at the difference between increasing acetylcholine and agonizing the alpha-4-beta-2 receptor, the main target of nicotine in tobacco.

5. Same study as 3.
 
6.
 

The reduction of serotonin levels in flies kept in constant darkness may provide scientists with insight into the etiology and treatment of SAD, a mood disorder related to reduced sunlight during winter. “People with seasonal affective disorder will respond to medications such as Prozac to increase serotonin,” says Sehgal. “Patients also respond to light therapy. We now believe that light is also increasing serotonin-perhaps this is why both of these treatments are effective.”

The exact opposite of your hypothesis.
 
7. This isn’t even a study, it’s an article. Check out this magnificent gem:
 

Even worse, eating too serotonin-boosting foods, while it might feel good for a short time, can lead to a worse crash later on. That’s why a candy bar or a soda are so much worse for us…

Holy shit, candy and soda increase serotonin? Where can I get that study?
 
8.
 

Our results indicate that the 5-HT7 receptor subtype plays a major role in mediating the effects of 5-HT on photic responses of SCN cells in the hamster.

 
Yup, some systems are in our brain are going to regulate photic response. I guess somehow this means we should lower serotonin as much as possible.
 
9.
 

The pineal, serotoninergic and pigmented neurons are associated with light-dependent sleep/arousal, serving as a biological clock with a circadian rhythm. This rhythm is maintained by melatonin which serves to recognise the 'dark' phase. The neural network that responds to seasonal variations in day/night length has not been identified. The present study demonstrates that melanocytes in human skin respond to changes in the duration of UV exposure, and can serve as a biological calendar. These responses are mediated by two indoleamines, serotonin and melatonin. Higher melatonin levels correspond to long nights and short days (short UV pulse), while high serotonin levels in the presence of melatonin reflect short nights and long days (long UV exposure). This response recapitulates the sleep/arousal patterns in animals exposed to large variations in day/night cycle that cause changes in coat colour from pure white in winter to complete repigmentation in summer.

 
All it says is the serotonin plays an integral role in our biological clock and circadian rhythm…so clearly we need to lower it as much as possible?
 
10.
 

The tail flick assay was used to evaluate pain perception in mice treated acutely with either of the two classical antidepressant drugs (AD) imipramine or amitriptyline, or the atypical antidepressant iprindole. A sustained hypoalgesic effect, sensitive to the opiate antagonist naloxone, was detected for the AD used in this study. Administration of the aminopeptidase inhibitor bestatin or the enkephalinase blocker thiorphan made subeffective doses of AD hypoalgesic. This synergistic effect was reversed by naloxone. The antinociceptive action of the AD wore off in mice rendered tolerant to morphine by subcutaneous implantation of a pellet of the opiate. Subchronic treatment with p-chlorophenylalanine did not alter the effect of AD on pain perception, but in animals whose serotonin (5-HT) receptors were blocked by methysergide AD did not produce any change in pain threshold. It was concluded on the basis of these findings that short-chain opioids and 5-HT appear to have a role in the hypoalgesic effect of either classical or atypical AD.

So, the mu antagonist, naloxone, alone blocked the effects, and blocking 5HT receptors had no effect…this is a clear implication of the direct effect serotonin alone has on pain perception, right???...
…
…
I can’t do this anymore, can’t go through any more. I think anyone reading this gets the picture. You have absolutely no evidence that normal, endogenous, high-levels of serotonin can be problematic. And the fact that some drugs can increase serotonin too high? That goes without saying.

You didn't link any of this..and also, a TON of this was fabricated, or taken out of context, or both..and no one is going to take you seriously when you pull that crap!

[AMx Workshop]

 

I can’t do this anymore, can’t go through any more. I think anyone reading this gets the picture. You have absolutely no evidence that normal, endogenous, high-levels of serotonin can be problematic. And the fact that some drugs can increase serotonin too high? That goes without saying.

actually yer studies make no sense buddy. i totally agree with area. when i took 5-htp i felt like complete sh**. i had no emotion. i felt lethargic but loud noises woke me up.  i wanted to sleep but never could. felt tired but slightest noise fucked me. so i believe his research is legit. whatever you posted is just bullshit and only for your own profit. 

 

also if u try rebute about that make no sense. bc even when i ate turkey i feel same way so it obvious that it is serotonin cus its the only thing similar on both end with 5-htp and with turkey which have high tryptophan. so it make sense what he saying.

[Yunasa]

ditto. serotonin is bullshit used for marketing profits on ssri's ..its no good except in very very small amounts.

i took my daughter off of the prozac when she no longer was getting to sleep at night and was waking up sick and feeling like she had no will to do anything. she said she felt like she was dying every day!

btw, this one screw loose seems like a real prick!

 

 

I can’t do this anymore, can’t go through any more. I think anyone reading this gets the picture. You have absolutely no evidence that normal, endogenous, high-levels of serotonin can be problematic. And the fact that some drugs can increase serotonin too high? That goes without saying.

actually yer studies make no sense buddy. i totally agree with area. when i took 5-htp i felt like complete sh**. i had no emotion. i felt lethargic but loud noises woke me up.  i wanted to sleep but never could. felt tired but slightest noise fucked me. so i believe his research is legit. whatever you posted is just bullshit and only for your own profit. 

 

also if u try rebute about that make no sense. bc even when i ate turkey i feel same way so it obvious that it is serotonin cus its the only thing similar on both end with 5-htp and with turkey which have high tryptophan. so it make sense what he saying.

 

 

Edited by Yunasa, 04 May 2015 - 07:30 AM.

[DeadBrain]

how do u explain that both SSRIs AND 5-HTP separately made me feel like shit? and when my serotonin is on the low side of normal i feel optimal and healthy? you didn't prove area wrong on anything. u LOST! 

 

…
I can’t do this anymore, can’t go through any more. I think anyone reading this gets the picture. You have absolutely no evidence that normal, endogenous, high-levels of serotonin can be problematic. And the fact that some drugs can increase serotonin too high? That goes without saying.

 

[Area-1255]

I honestly think he's just lonely. Likes to argue. Always the same argument on his side.

 

how do u explain that both SSRIs AND 5-HTP separately made me feel like shit? and when my serotonin is on the low side of normal i feel optimal and healthy? you didn't prove area wrong on anything. u LOST! 

 

…
I can’t do this anymore, can’t go through any more. I think anyone reading this gets the picture. You have absolutely no evidence that normal, endogenous, high-levels of serotonin can be problematic. And the fact that some drugs can increase serotonin too high? That goes without saying.

 

 

[OneScrewLoose]

Yeah, serotoninergic drugs can increase serotonin beyond a certain point, but you're putting forward, if I understand correctly, that you can have a natural, too-much "across the board" levels of serotonin. You have shown no evidence that this exists, just extrapolations from SRIs and other serotoninergic drugs.

[Area-1255]

Yeah, serotoninergic drugs can increase serotonin beyond a certain point, but you're putting forward, if I understand correctly, that you can have a natural, too-much "across the board" levels of serotonin. You have shown no evidence that this exists, just extrapolations from SRIs and other serotoninergic drugs.

You can certainly have too much natural serotonin as well, as in the cases of overmethylation/low histamine...GABA deficiency can provoke serotonin neurons to overfire, and producing too much dynorphin can cause downstream excess of serotonin. None of these necessarily have to do with medications or drugs that one would take.

 

There's also serotonin transporter mutations that are present in some families; which result in higher levels of serotonin in the synapse and essentially a natural "SSRI" constantly in their system. 

 

I've shown not JUST in this article that this can happen, but also in my histamine related articles and in my articles regarding methylation and regarding mutations. All of which are not only cited, but highly regarded.

[Area-1255]

Also keep in mind that other major publications such as the neuro-endocrine role of serotonin have also established the same conclusions stated in this thread/article and by it's other citations.

[stan08]

Thank you for providing this information.  It seems to confirm that I was taking too many supplements that increase serotonin levels as I've been experiencing most of the signs/symptoms you list.

[Tubzy]

Great article Area! I'm not a fan of serotonin especially how it is overly expressed by everyone. I like GABA better =)

[DeadBrain]

high copper = high serotonin and norepinephrine..common issue me thinks.

[Area-1255]

high copper = high serotonin and norepinephrine..common issue me thinks.

Yes, common issue especially in URBAN, lower class America where copper piping and factories exist. Tends to perpetuate biPolar and thrill seeking behavior...when you have high copper, noradrenaline is used in much different ways...which leads to a high serum level but basically the brain doesn't get that much out of it and there's more NET around..which leads to ups and downs, drug use and risky behavior...contrary to popular belief, you don't need low adrenaline to become a thrill seeker, you can actually have high NE but high transporters which lead to it being used up to quickly.

[aarfai]

Have to agree with Area on this. Great thread!

[addx]

No offense, but what's the difference between the common SSRI side-effect list and this thread?

[shaister]

Isn't emotional blunting associated with high serotonin?

 

Though can you explain that somehow 5-htp allowed me to experience my emotions again for a few seconds?

 

Don't say 5-HT1A receptor please, I know nothing about the science of this stuff.

 

I don't even know how I got emotional blunting, and it seems related to the activation of 5-Ht1A since I've token MDMA lots of times.

But It may have been from the combination of Valium with BK-MDMA. I can't remember.

[Area-1255]

Isn't emotional blunting associated with high serotonin?

 

Though can you explain that somehow 5-htp allowed me to experience my emotions again for a few seconds?

 

Don't say 5-HT1A receptor please, I know nothing about the science of this stuff.

 

I don't even know how I got emotional blunting, and it seems related to the activation of 5-Ht1A since I've token MDMA lots of times.

But It may have been from the combination of Valium with BK-MDMA. I can't remember.

Depends on what you define as "emotions"...trust me, I've heard a lot of people for w/e reason think or bring across as emotions as equating to specific parameter's such as empathy and / or motivation..which isn't exactly the same.

MDMA acitvates mainly the 5-HT2A family of serotonin receptors, those are the classically stimulating serotonin subtypes but they also lead to more hostility and agitation ..

 

Hence in receptor expression and in rate of time or experience of user in tell, it varies between person how MDMA will affect you and once may be one effect others may get more of an aggressive effect over time whereas others may not.

[shaister]

I'm defining "emotions" as when your heart consciousness is intact, and you can feel who you are. Unfortunately my dialogue may not be exact, because I haven't experienced what I tried to describe for quite sometime.

 

I might try an H3 Antagonist, because this possibly is oxytocin blunting.

[Area-1255]

I'm defining "emotions" as when your heart consciousness is intact, and you can feel who you are. Unfortunately my dialogue may not be exact, because I haven't experienced what I tried to describe for quite sometime.

 

I might try an H3 Antagonist, because this possibly is oxytocin blunting.

That might help...perhaps along with a DRI?

[β-Endorphin]

What always confuses me is why SSRI and SRAs have such a very different effect on emotions and perception. For example, MDMA tends to cause intense positive emotions, trust, openness and love. SSRIs however tend to cause emotional blunting, increased depression(during the first few weeks), and unpleasant side effects. Of course, its different for everyone but you get my point. Wouldn’t SRAs be worse than SSRIs(More emotional blunting, worsened depression etc.) if the culprit was high serotonin levels? I’m not disagreeing with you or your studies, I’m just not sure how this fits in to our current knowledge.

 

What do you think is happening here? I have a few(unproven) theories.

 

Perhaps serotonin activates its autoreceptor(Feedback mechanism) very strongly. Strong enough that SSRIs or precursor loading serotonin activates the serotonin autoreceptors so strongly that it actually reduces net serotonin release/receptor activation. This would explain why SSRIs tend to blunt emotions and worsen depression during the initial few weeks of treatment(as the extracellular serotonin release is reduced initially but increases later on as the autoreceptor downregulate).

 

That would also explain why SRAs are more effective for depression, they release so much more serotonin than SSRIs that they overload the autoreceptors and thus cause an initial increase in Serotonin rather than a decrease.

 

Perhaps MDMAs other mechanisms is what causes the effect(Dop and Norepi releasing agent, Serotonin agonist etc.) But much more selective Dop and Norepi releasing agents(like D-amphetamine) has a completely a different(and MUCH more subtle) effect on mood and emotions. Serotonin agonism would contribute to my previous theory as it would contribute to the overload of Serotonin autoreceptors and thus release of serotonin.

 

What are your thoughts on this?

 

Edited by β-Endorphin, 08 May 2015 - 05:31 PM.

[Area-1255]

It's about the rate and direction of serotonin efflux...as in SSRI's aren't changing the amount your body produces , they are merely 'trapping' serotonin into the synapse  - thereby enhancing levels of serotonin on multiple receptors...whereas MDMA has the ability to directly activate some serotonin receptors, plus MDMA also acts on dopamine terminals as well as on TAAR1 ; like amphetamine etc.

Serotonin has chemically opposite effects at the autoreceptors 1A,1B,1D and 5A, whereas all other receptors; 2A/2B/2C, 3A, 4A, 6 , 7  all of these receptors are stimulatory , the first group e.g type 2 family couples to IP3 and stimulates Glutamate efflux whereas the other serotonin receptors i.e 4A, 6 and 7 are positively coupled to adenylate cyclase..also increasing calcium channels and neurotransmitter release...

 

Because MDMA has direct binding effects, and given it's distinguishable differences on cAMP systems , as well as being quicker to act and being a stimulant..there are characteristic differences..also many SSRI's also have effects on sigma receptors and have effects on GABA, separate properties from their inhibition of SERT proteins etc.

 

So it's really quite simple, MDMA is a stimulant with a much different half life and rate of interaction with receptors...and additional dopaminergic properties...SSRI's lack the direct interactive effects and also do not have stimulant properties...

 

That doesn't mean that SSRI's can not stimulate the nervous system, they just don't do so in a direct manner..most of the time they are inhibitory until the 1A autoreceptors become de-sensitized..then the SSRI starts raising cAMP.

 

What always confuses me is why SSRI and SRAs have such a very different effect on emotions and perception. For example, MDMA tends to cause intense positive emotions, trust, openness and love. SSRIs however tend to cause emotional blunting, increased depression(during the first few weeks), and unpleasant side effects. Of course, its different for everyone but you get my point. Wouldn’t SRAs be worse than SSRIs(More emotional blunting, worsened depression etc.) if the culprit was high serotonin levels? I’m not disagreeing with you or your studies, I’m just not sure how this fits in to our current knowledge.

 

What do you think is happening here? I have a few(unproven) theories.

 

Perhaps serotonin activates its autoreceptor(Feedback mechanism) very strongly. Strong enough that SSRIs or precursor loading serotonin activates the serotonin autoreceptors so strongly that it actually reduces net serotonin release/receptor activation. This would explain why SSRIs tend to blunt emotions and worsen depression during the initial few weeks of treatment(as the extracellular serotonin release is reduced initially but increases later on as the autoreceptor downregulate).

 

That would also explain why SRAs are more effective for depression, they release so much more serotonin than SSRIs that they overload the autoreceptors and thus cause an initial increase in Serotonin rather than a decrease.

 

Perhaps MDMAs other mechanisms is what causes the effect(Dop and Norepi releasing agent, Serotonin agonist etc.) But much more selective Dop and Norepi releasing agents(like D-amphetamine) has a completely a different(and MUCH more subtle) effect on mood and emotions. Serotonin agonism would contribute to my previous theory as it would contribute to the overload of Serotonin autoreceptors and thus release of serotonin.

 

What are your thoughts on this?

 

[β-Endorphin]

It's about the rate and direction of serotonin efflux...as in SSRI's aren't changing the amount your body produces , they are merely 'trapping' serotonin into the synapse  - thereby enhancing levels of serotonin on multiple receptors...whereas MDMA has the ability to directly activate some serotonin receptors, plus MDMA also acts on dopamine terminals as well as on TAAR1 ; like amphetamine etc.

Serotonin has chemically opposite effects at the autoreceptors 1A,1B,1D and 5A, whereas all other receptors; 2A/2B/2C, 3A, 4A, 6 , 7  all of these receptors are stimulatory , the first group e.g type 2 family couples to IP3 and stimulates Glutamate efflux whereas the other serotonin receptors i.e 4A, 6 and 7 are positively coupled to adenylate cyclase..also increasing calcium channels and neurotransmitter release...

 

Because MDMA has direct binding effects, and given it's distinguishable differences on cAMP systems , as well as being quicker to act and being a stimulant..there are characteristic differences..also many SSRI's also have effects on sigma receptors and have effects on GABA, separate properties from their inhibition of SERT proteins etc.

 

So it's really quite simple, MDMA is a stimulant with a much different half life and rate of interaction with receptors...and additional dopaminergic properties...SSRI's lack the direct interactive effects and also do not have stimulant properties...

 

That doesn't mean that SSRI's can not stimulate the nervous system, they just don't do so in a direct manner..most of the time they are inhibitory until the 1A autoreceptors become de-sensitized..then the SSRI starts raising cAMP.

Thanks for your input and explanation, its cleared up some things for me.

 

As you’ve said, MDMA is a Triple Releasing Agent and an agonist at certain serotonin receptors, so its other mechanisms of action aside from its SRA properties probably has a lot to do with its effects. When comparing D-amp(Strong dop/norepi and weak serotonin RA) and MDMA(Strong Ser and weaker Dop/Norepi RA), MDMA is a radically different drug from D-Amp(In terms of other people’s subjective experience). The only real difference I see between them is MDMAs additional action on Serotonin. Is the Serotonin releasing agent aspect of MDMA what sets its effect aside from D-amp? If so, does that mean that High Serotonin levels are bad on their own, but when combined with high dopamine and high norepinephrine levels, High serotonin levels has a positive effect on mood?

 

Also, is high serotonin the reason that SSRIs worsen depression and cause emotional bluntness? If so, then why are SSRAs more effective than SSRIs at curing depression? Wouldn’t SSRAs increase serotonin further, worsening the issues caused by SSRIs?

 

Thanks for your help, I hope I’m not throwing too many questions at you at once.

[Area-1255]

High serotonin is negative on it's own, and  even worse with high norepinerphine...this is what leads to bipolar and manic issues...hence why cocaine aggravates bipolar..it's not so much the dopamine but the noradrenaline and serotonin....these create a hyped up atmosphere...and high serotonin causes emotional blunting moreso when sustained because the autoreceptors are sensitive to de-sensitization when exposed to high amounts of serotonin over time..then serotonin releases even more of itself, leading to overstimulation of other receptors..which leads to cortisol and ACTH excess - which then leads to adrenal burnout, which then leads to anhedonia, loss of emotional capacity etc...so it's the serotonin-induced high cortisol and high prolactin that leads to the emotional blunting and plus , dopamine drops to the ground as well.

 

The BIGGEST questions you have to ask yourself.

 

• Why do some people with low serotonin have ZERO depression and anxiety?
• Why are there such behavioral differences between one person with low serotonin and another?

THE ANSWER :: is it's not as simple as just looking at serotonin...same thing with cortisol...you can have low of both of these and feel fine DEPENDING ON THE CAUSE AND / OR ROUTINE in which got you there...or whether other 'REACTIVE' coinciding factors exist. MEANING : Say you have low serotonin but the REASON for low serotonin is undermethylation by the liver, and so therefore , by status quo of low methylation rates you would ALSO have low dopamine and norepinephrine..so is it the low serotonin causing the issues? Or the low dopamine and norepinephrine..if you look at the pathophysiology of depression, you will see it's more linked to low dopamine and such....and that serotonergic are going about it ALL WRONG.

 

THINK: why would any logical human want to go about treating depression with a substance that raises cortisol and prolactin, lowers our dopamine WHICH IS RESPONSIBLE FOR MOTIVATION, PLEASURE AND REWARD, and the same substance is sensitize to de-sensitization and downregulation anyhow..which limits clinical benefit especially given the diverse differences in each person taking a particular drug to do so.

 

ALSO CONSIDER;;; how many people who take SSRI's actually TEST for blood work and urine serotonin levels to see if they ACTUALLY HAVE low serotonin, some just go on symptoms..and these symptoms I've mentioned are NOT MEANT to get you to block serotonin just as low serotonin symptoms shouldn't advise you to raise it..always get blood work first and urine test etc for metabolites.

 

Read these articles as well.

 

http://www.theguardi...in-neurogenesis

http://mentalhealthd...more-important/

http://mindhacks.com...in-or-dopamine/

 

Thanks for your input and explanation, its cleared up some things for me.

 

As you’ve said, MDMA is a Triple Releasing Agent and an agonist at certain serotonin receptors, so its other mechanisms of action aside from its SRA properties probably has a lot to do with its effects. When comparing D-amp(Strong dop/norepi and weak serotonin RA) and MDMA(Strong Ser and weaker Dop/Norepi RA), MDMA is a radically different drug from D-Amp(In terms of other people’s subjective experience). The only real difference I see between them is MDMAs additional action on Serotonin. Is the Serotonin releasing agent aspect of MDMA what sets its effect aside from D-amp? If so, does that mean that High Serotonin levels are bad on their own, but when combined with high dopamine and high norepinephrine levels, High serotonin levels has a positive effect on mood?

 

Also, is high serotonin the reason that SSRIs worsen depression and cause emotional bluntness? If so, then why are SSRAs more effective than SSRIs at curing depression? Wouldn’t SSRAs increase serotonin further, worsening the issues caused by SSRIs?

 

Thanks for your help, I hope I’m not throwing too many questions at you at once.

 

 

Edited by Area-1255, 08 May 2015 - 07:42 PM.

[β-Endorphin]

 

High serotonin is negative on it's own, and  even worse with high norepinerphine...this is what leads to bipolar and manic issues...hence why cocaine aggravates bipolar..it's not so much the dopamine but the noradrenaline and serotonin....these create a hyped up atmosphere...and high serotonin causes emotional blunting moreso when sustained because the autoreceptors are sensitive to de-sensitization when exposed to high amounts of serotonin over time..then serotonin releases even more of itself, leading to overstimulation of other receptors..which leads to cortisol and ACTH excess - which then leads to adrenal burnout, which then leads to anhedonia, loss of emotional capacity etc...so it's the serotonin-induced high cortisol and high prolactin that leads to the emotional blunting and plus , dopamine drops to the ground as well.

 

The BIGGEST questions you have to ask yourself.

 

• Why do some people with low serotonin have ZERO depression and anxiety?
• Why are there such behavioral differences between one person with low serotonin and another?

THE ANSWER :: is it's not as simple as just looking at serotonin...same thing with cortisol...you can have low of both of these and feel fine DEPENDING ON THE CAUSE AND / OR ROUTINE in which got you there...or whether other 'REACTIVE' coinciding factors exist. MEANING : Say you have low serotonin but the REASON for low serotonin is undermethylation by the liver, and so therefore , by status quo of low methylation rates you would ALSO have low dopamine and norepinephrine..so is it the low serotonin causing the issues? Or the low dopamine and norepinephrine..if you look at the pathophysiology of depression, you will see it's more linked to low dopamine and such....and that serotonergic are going about it ALL WRONG.

 

THINK: why would any logical human want to go about treating depression with a substance that raises cortisol and prolactin, lowers our dopamine WHICH IS RESPONSIBLE FOR MOTIVATION, PLEASURE AND REWARD, and the same substance is sensitize to de-sensitization and downregulation anyhow..which limits clinical benefit especially given the diverse differences in each person taking a particular drug to do so.

 

ALSO CONSIDER;;; how many people who take SSRI's actually TEST for blood work and urine serotonin levels to see if they ACTUALLY HAVE low serotonin, some just go on symptoms..and these symptoms I've mentioned are NOT MEANT to get you to block serotonin just as low serotonin symptoms shouldn't advise you to raise it..always get blood work first and urine test etc for metabolites.

 

Read these articles as well.

 

http://www.theguardi...in-neurogenesis

http://mentalhealthd...more-important/

http://mindhacks.com...in-or-dopamine/

Thank you so much for clearing that up for me

 

Just to be clear, I don't support SSRIs(In Fact I'm very against them), it just always stumped me how SSRIs that supposedly increase extracellular serotonin(in studies) has little to no effect on depression versus a Serotonin releasing agent like MDMA that not only cures depression instantly, but puts the person in a warm, loving euphoria. I get it now, cortisol, acth and prolactin play a massive role in this. I didn't know that people could go on normally with low serotonin depending on the circumstances, thank you for informing me. Those articles were pretty good too, the man with the disorder living normally with low serotonin and dopamine surprised me quite a bit :O.

 

I'm pretty excited for the next round of pharmaceutical anti-depressants(Triple reuptake inhibitors). They won't cure the issue, but they're a much needed step in the right direction IMO, considering how effective cocaine is at alleviating depression(Though I imagine the antidepressants will be much weaker and have a much slower effect). There are quite a few experimental antidepressants out there right now that I hope the pharmaceutical companies look at though. Like Kappa-Opioid antagonists, Delta-mu opioid partial agonists, Enkephalinase inhibitors, NMDA agonists/co-agonists etc. etc.

 

Anyways I've gone off topic. Thank you for all your help.

[Area-1255]

One more thing. Estrogen is very important in all this..it seems that if estrogen is high and serotonin is low, it's a big issue, but if your test levels are high and serotonin is low - with estrogen being in the normal or low normal range..then low serotonin seems to have less side-effects. So estrogen's effects on gene transcription may be the real core issue in determining some of these facets as well.

 

Thank you so much for clearing that up for me

 

Just to be clear, I don't support SSRIs(In Fact I'm very against them), it just always stumped me how SSRIs that supposedly increase extracellular serotonin(in studies) has little to no effect on depression versus a Serotonin releasing agent like MDMA that not only cures depression instantly, but puts the person in a warm, loving euphoria. I get it now, cortisol, acth and prolactin play a massive role in this. I didn't know that people could go on normally with low serotonin depending on the circumstances, thank you for informing me. Those articles were pretty good too, the man with the disorder living normally with low serotonin and dopamine surprised me quite a bit :O.

 

I'm pretty excited for the next round of pharmaceutical anti-depressants(Triple reuptake inhibitors). They won't cure the issue, but they're a much needed step in the right direction IMO, considering how effective cocaine is at alleviating depression(Though I imagine the antidepressants will be much weaker and have a much slower effect). There are quite a few experimental antidepressants out there right now that I hope the pharmaceutical companies look at though. Like Kappa-Opioid antagonists, Delta-mu opioid partial agonists, Enkephalinase inhibitors, NMDA agonists/co-agonists etc. etc.

 

Anyways I've gone off topic. Thank you for all your help.

 

 

[Area-1255]

Anybody else have any experiences with ST.John's wort? Good or Bad?

Edited by Area-1255, 10 May 2015 - 08:11 PM.

[SerP3nT]

great thread area!!

[Area-1255]

great thread area!!

Thanks! Glad you enjoyed it. 

[Area-1255]

Bump for those who haven't seen this yet.