Too Much Serotonin

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So I am pretty sure that I have a major problem with too much serotonin. I have almost every symptom of serotonin syndrome. It seems to go into overdrive with any stressor of any type. When I crash from exertion or get triggered by a stressor, my neck and face get red. My muscles tense, fasciculate and burn...mostly in my quads. I have significant muscle wasting in my quads. I just saw a neuromuscular specialist and she's running tests but in my gut I feel it is serotonin.

So far other symptoms are:
Insomnia
Vivid nightmares/dreaming like I am awake
Muscle rigidity/ tremors
agitation/anxiety/ restlessness

I have always had really bad rxns to SSRIs....my symptoms ramp up immediately and I have had to discontinue at very low doses. I got checked out for carcinoid tumor with a 24 hr urine 5-Hydroxyindoleacetate. It was borderline high but in range and the endocrinologist was unimpressed.
On a OAT Test 5-Hydroxyindoleacetate was high and Kynurenate was bordeline high.
If I take a benzo, it immediately calms me and improves all symptoms esp muscles etc. Obviously that is not a long term answer.
Has anyone found anything that can help lower serotonin?
I'm really struggling here. The neurologist wants me to trial Mirtazapine for sleep but I'm thinking that will increase serotonin. Although MOA is different than SSRIs. I don't want to throw more gas on the fire. Any help/input is appreciated!
 
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Second star to the right ...
Like all meds, whether OTC or prescription, it has some drawbacks .... it can cause the usual expectd side effects of all antihistamines from insomnia to dizziness and blurry vision to drowsiness to constipation, and all the stops in between, but the possible side effects from long term use are a little more attention-focusing, including hyperglycemia, diabetes, liver damage, immune system suppression, weight gain, general edema, and hypertension ....

Everything's a trade off, which is really, really irritating ...
 

halcyon

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It's kind of a medical urban legend that SSRIs increase serotonin, at least initially. The reality is that they actually tank serotonin initially due to over-activating pre-synaptic 5-HT autoreceptors (Palaniyappan et al., 2018).
Palaniyappan et al. said:
Administered acutely, SSRIs initially suppress 5-HT reuptake at somatodendritic (presynaptic) sites facilitating autoreceptor activation and reduced serotonin transmission. In due course, desensitisation of these autoreceptors enhances serotonin neurotransmission. Mirtazapine, being an α2-adrenergic antagonist, reduces autoreceptor (heteroreceptor) feedback at the somatodendritic site directly. This potentially enhances serotonin transmission at a quicker pace. Thus, it could be predicted that a combination of both medications could induce a more rapid and robust antidepressant effect than each medication administered alone.
So your acute reactions to SSRIs may actually be due to too little rather than too much serotonin (and mirtazapine may help with this). Also, one of the most highly replicated findings in ME patients is an excessive sensitivity of post-synaptic 5-HT receptors, a situation that should be caused by inadequate serotonin availability over time, rather than too much. Elevations of 5-HT metabolites might argue against that though in your case (though it makes it difficult to differentiate between body and CNS 5-HT as the source).

Most of the rest what I'll say is entirely supposition, so take with a grain of salt. I believe that the symptoms of too much and too little serotonin are actually almost identical. I believe that I experience wild swings of serotonin availability, both down and up, due to migraine and ME, and also due to experience with 5-HT agonists and SERT inhibitors, and I can tell pretty clearly when this is happening based on symptoms. I also have several mutations that cause lowered activity of the enzymes that break down catecholamines (COMT V158M + MAO-A R297R), so I think that I have trouble clearing synapses if there are relatively sudden increases in serotonin availability, and the symptoms of this are almost indistinguishable from what I believe is low serotonin due to acute migraine or post-exertional inflammation induced IDO activity from ME. You may want to look into these mutations too if you have genetic data available.
 
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It's kind of a medical urban legend that SSRIs increase serotonin, at least initially. The reality is that they actually tank serotonin initially due to over-activating pre-synaptic 5-HT autoreceptors (Palaniyappan et al., 2018).


So your acute reactions to SSRIs may actually be due to too little rather than too much serotonin (and mirtazapine may help with this). Also, one of the most highly replicated findings in ME patients is an excessive sensitivity of post-synaptic 5-HT receptors, a situation that should be caused by inadequate serotonin availability over time, rather than too much. Elevations of 5-HT metabolites might argue against that though in your case (though it makes it difficult to differentiate between body and CNS 5-HT as the source).

Most of the rest what I'll say is entirely supposition, so take with a grain of salt. I believe that the symptoms of too much and too little serotonin are actually almost identical. I believe that I experience wild swings of serotonin availability, both down and up, due to migraine and ME, and also due to experience with 5-HT agonists and SERT inhibitors, and I can tell pretty clearly when this is happening based on symptoms. I also have several mutations that cause lowered activity of the enzymes that break down catecholamines (COMT V158M + MAO-A R297R), so I think that I have trouble clearing synapses if there are relatively sudden increases in serotonin availability, and the symptoms of this are almost indistinguishable from what I believe is low serotonin due to acute migraine or post-exertional inflammation induced IDO activity from ME. You may want to look into these mutations too if you have genetic data available.
Woah! Thank you for this but this is way above my head...and my brain is not as clear as it once was. I always thought serotonin syndrome was most common upon initiation of SSRIs? I'm not sure how to determine if I have too high or too low serotonin then. OR maybe what you are saying is I could have swings of high and low? Obviously I have a problem with serotonin. I felt like the facial flushing and muscle symptoms were more indicative of high serotonin. I have some genetic data from a Genesight test. I am a poor metabolizer of CYP2D6, so I react poorly to many meds including SSRIs in general. My ME was initially triggered by an adverse rxn to Triamcinolone and my symptoms started immediately after an injection. My COMT is homozygous for the Val allele (VAL/VAL). I thought this meant low dopamine? Does it have any influence on serotonin also? I have debated trying LDAbilify to see if it balances neurotransmitters but was wary of making my sleep worse than it already is.
 

halcyon

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I always thought serotonin syndrome was most common upon initiation of SSRIs?
The very first thing that happens with a SERT inhibitor (I assume within minutes/hours) is that serotonergic synapses are flooded with serotonin when neurons fire. This then increasingly activates the postsynaptic receptors on the receiving side, but also activates the autoreceptors on the sending side. This causes the sending neuron to believe that it is releasing too much serotonin, so this then causes reduced serotonin release (as described above). Then, and this part is unclear to me, for some time after (the several weeks that it is described for SSRIs to "kick in", I assume), both sides seem to undergo adjustments of receptor densities and probably also the amount of serotonin that the presynaptic neuron releases changes as well ("enhances serotonin neurotransmission", also as described above). This is really handwavy, I'm sorry, I've not really found a better description of how this all works, though I'm sure one is out there somewhere.

I'm not sure how to determine if I have too high or too low serotonin then. OR maybe what you are saying is I could have swings of high and low?
I guess I'm saying that I see one or the other as equal possibilities, or yes, possibly both are happening. If a neurotransmitter is not being released in large enough amounts, then the receiving side of the synapse will sprout extra receptors to try to make up for the lower signal. If you then take something that acutely increases the signal, it can overwhelm the receiver and seem like there's too much, when it's really the sensitivity that's too high due to there normally not being enough signal. I don't think there really is a good way to determine this. Looking at metabolites (or platelet concentrations, HDRI offers this test, there may be others) are the only way I'm aware of, but they are indirect and so don't really tell you exactly what is going on. One of the things I have wondered about is if SERT inhibitors might actually cause increased degradation of serotonin and thus actually lower serotonin levels in folks that aren't able to synthesize enough (like I believe ME patients aren't able to, based on the evidence I mentioned above). Once synthesized and released, I believe the two major fates of serotonin are the recycle bin (SERT) or the trash bin (MAO-A). If you gum up the recycle bin, it seems like it would cause the majority of serotonin to then be destroyed instead of reused. This could possibly then show up as an increase in serotonin metabolites, but not because there was too much serotonin, but because you're destroying too much serotonin instead of recycling it.

Honestly, this just brings up another medical urban legend, the idea that SSRIs even work at all, which the evidence points to them not really working at all in most cases (see the attached or this paper).

I am a poor metabolizer of CYP2D6, so I react poorly to many meds including SSRIs in general.
Yeah that's definitely problematic as many if not most SSRIs and TCAs are metabolized by 2D6, and several actually also inhibit 2D6 thus slowing down their own metabolism. Fluvoxamine and citalopram seem to have the least effect on 2D6, but they are both metabolized by it. What I've learned the hard way with these drugs is that they have to be used in literal baby doses to start. My doctor often starts me on doses that are half what she would give to a child, no joke.

My COMT is homozygous for the Val allele (VAL/VAL). I thought this meant low dopamine? Does it have any influence on serotonin also?
COMT does not contribute at all to serotonin metabolism to my knowledge; MAO-A is the enzyme that metabolizes serotonin. Yes, it looks like you have the polymorphism that causes increased enzyme activity of COMT. I don't want to assume too much about your aims in taking SSRIs, however you might think about looking into either amitriptyline (which has a minimal effect on SERT and serotonin, and mainly effects NET, but is metabolized by 2D6) or even selegiline/l-deprenyl (specifically the EMSAM formulation). The latter is an MAO-B inhibitor and so increases dopamine mainly and has no effect on MAO-A/serotonin at low doses (but does at high doses). Also, selegiline is not metabolized by 2D6.
 

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... I have almost every symptom of serotonin syndrome. It seems to go into overdrive with any stressor of any type. When I crash from exertion or get triggered by a stressor, my neck and face get red. My muscles tense, fasciculate and burn...mostly in my quads. I have significant muscle wasting in my quads. I just saw a neuromuscular specialist and she's running tests but in my gut I feel it is serotonin.
...
Has anyone found anything that can help lower serotonin?
I'm really struggling here.
Similarly to @SlamDancin and @halcyon , I had no idea this even existed. I was always of the mindset that, with serotonin, the more the merrier. @Chardo, sorry to hear you're going through this but thanks for sharing as well... a real eye-opener for me.
 
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The very first thing that happens with a SERT inhibitor (I assume within minutes/hours) is that serotonergic synapses are flooded with serotonin when neurons fire. This then increasingly activates the postsynaptic receptors on the receiving side, but also activates the autoreceptors on the sending side. This causes the sending neuron to believe that it is releasing too much serotonin, so this then causes reduced serotonin release (as described above). Then, and this part is unclear to me, for some time after (the several weeks that it is described for SSRIs to "kick in", I assume), both sides seem to undergo adjustments of receptor densities and probably also the amount of serotonin that the presynaptic neuron releases changes as well ("enhances serotonin neurotransmission", also as described above). This is really handwavy, I'm sorry, I've not really found a better description of how this all works, though I'm sure one is out there somewhere.


I guess I'm saying that I see one or the other as equal possibilities, or yes, possibly both are happening. If a neurotransmitter is not being released in large enough amounts, then the receiving side of the synapse will sprout extra receptors to try to make up for the lower signal. If you then take something that acutely increases the signal, it can overwhelm the receiver and seem like there's too much, when it's really the sensitivity that's too high due to there normally not being enough signal. I don't think there really is a good way to determine this. Looking at metabolites (or platelet concentrations, HDRI offers this test, there may be others) are the only way I'm aware of, but they are indirect and so don't really tell you exactly what is going on. One of the things I have wondered about is if SERT inhibitors might actually cause increased degradation of serotonin and thus actually lower serotonin levels in folks that aren't able to synthesize enough (like I believe ME patients aren't able to, based on the evidence I mentioned above). Once synthesized and released, I believe the two major fates of serotonin are the recycle bin (SERT) or the trash bin (MAO-A). If you gum up the recycle bin, it seems like it would cause the majority of serotonin to then be destroyed instead of reused. This could possibly then show up as an increase in serotonin metabolites, but not because there was too much serotonin, but because you're destroying too much serotonin instead of recycling it.

Honestly, this just brings up another medical urban legend, the idea that SSRIs even work at all, which the evidence points to them not really working at all in most cases (see the attached or this paper).


Yeah that's definitely problematic as many if not most SSRIs and TCAs are metabolized by 2D6, and several actually also inhibit 2D6 thus slowing down their own metabolism. Fluvoxamine and citalopram seem to have the least effect on 2D6, but they are both metabolized by it. What I've learned the hard way with these drugs is that they have to be used in literal baby doses to start. My doctor often starts me on doses that are half what she would give to a child, no joke.


COMT does not contribute at all to serotonin metabolism to my knowledge; MAO-A is the enzyme that metabolizes serotonin. Yes, it looks like you have the polymorphism that causes increased enzyme activity of COMT. I don't want to assume too much about your aims in taking SSRIs, however you might think about looking into either amitriptyline (which has a minimal effect on SERT and serotonin, and mainly effects NET, but is metabolized by 2D6) or even selegiline/l-deprenyl (specifically the EMSAM formulation). The latter is an MAO-B inhibitor and so increases dopamine mainly and has no effect on MAO-A/serotonin at low doses (but does at high doses). Also, selegiline is not metabolized by 2D6.
Thank you! After your response, I decided to look into my genetic info further. Turns out I am SLC6A4 S/S (so short promoter of the Serotonin transporter gene) and HTR2A G/G (so homozygous for the G allele). SO the SSRI adverse reactions should not have been a surprise to my doc. I guess this lines up with what you were explaining with not recycling the Serotonin? My goal is to find something to balance me a little. Even with pacing, I crash every other day. And sleep is horrible and nightmares are traumatizing. Turns out my genes seem to not like many meds other than stimulants and benzos. I'm going to look into the emsam. Ironically its coming up with little gene interactions.
 

halcyon

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My goal is to find something to balance me a little. Even with pacing, I crash every other day. And sleep is horrible and nightmares are traumatizing.
I would definitely look into amitriptyline/nortriptyline, specifically in low doses. These can be pretty helpful for sleep and I believe they also might help blunt some of the CNS sensitivity that this disease causes. Unfortunately they can't be combined with selegiline. But if you do well with stimulants, selegiline might be better for you (amitriptyline can have some sedation effect). The main downside of selegiline is that it does (like most MAO inhibitors) have a lot of drug-drug interaction possibilities.