Does Serotonin Create or Fix Problems?

Remy

Administrator
I have never done well with any antidepressants...or any supplements designed to increase serotonin like 5-HTP. It made me wonder why, so I started googling. It turns out that we don't really seem to understand serotonin very well. And that antidepressant drugs probably work by reducing inflammation, not by increasing serotonin.

Dr Ray Peat (who is another story all on his own) is one of the few that has anything to say about high serotonin levels. I find this particularly interesting:

In hibernating animals, the stress of a declining food supply causes increased serotonin production. In humans and animals that don’t hibernate, the stress of winter causes very similar changes. Serotonin lowers temperature by decreasing the metabolic rate. Tryptophan and melatonin are also hypothermic. In the winter, more thyroid is needed to maintain a normal rate of metabolism.
I have a theory that the fatigue in MECFS could be related to some sort of a hibernation syndrome gone wrong...due to increased adenosine levels. So if that is true, it stands to reason that those with MECFS could also have increased serotonin, low metabolic rate, and low thyroid. Sound familiar?

High serotonin also decreases learning and alertness and stimulates the adrenals to produce cortisol and aldosterone. Too much stimulation of the adrenals for too long may eventually lead to the lowered cortisol and altered circadian rhythm seen in so many of us.
 

Remy

Administrator
Here is a report on a study that links serotonin to an autoimmune response in people with MECFS...

Research Brief
A new study on chronic fatigue syndrome (ME/CFS) suggests that an autoimmune reaction to the neurotransmitter serotonin damages serotonin-sensitive brain cells. Researchers also concluded that high levels of bacteria move through intestinal membrane in people with ME/CFS, which is known to play a role in autoimmunity.
Researchers compared serotonin antibodies in people with ME/CFS, those with chronic fatigue who don't meet ME/CFS criteria, and healthy controls.
They found that autoimmune activity against serotonin was more than four times what it was in chronic fatigue, and twelve times higher than in healthy people.
Serotonin autoimmunity was linked to more severe hyperalgesia (pain amplification,) fatigue, brain fog, autonomic symptoms, sadness, and flu-like symptoms.
 

Who Me?

Well-Known Member
Me either. Never had luck with them or really anything that works on the brain. Pretty much all of them was like I was on speed.

When I did try them, early in my illness i was taking the standard dose. Whether subclinical doses now would work? I did recently try a low dose SSRI and although I had no problems with it and almost seemed like I had a bit more mentally clarity, it totally messed up my gut.

When I googled it it seems too much serotonin in the gut can cause dire rear, bloating, cramps etc.
 

ShyestofFlies

Well-Known Member
I have moderate to severe mdd and several other mental illnesses, I have tried several seratonin based meds, some made me sick, some did nothing- for any symptoms of any disorders, only a few worked- and when they do they do not help my fatigue or pain levels. From all my research it is clear we have very little understanding of how seratonin works, it is just the first thing that had any positive effect on anything and is now a cheap solution to just give a try for most diseases, so we throw it at it and cross our fingers.
 

Remy

Administrator
so we throw it at it and cross our fingers.
This reminds me something a doctor once said to me...that SSRIs and their ilk work like a hammer to a watch (our brain) meaning that they cause massive damage. Our brains, being the remarkable agents of plasticity and regeneration that they are, often are able to put themselves back together and do work better, correcting the original dysfunction in the process. But not always.

Hopefully someday we will not be reliant on hammer approaches when it comes to our exquisitely complex brains.
 

weyland

Well-Known Member
So if that is true, it stands to reason that those with MECFS could also have increased serotonin, low metabolic rate, and low thyroid. Sound familiar?
The problem is that the evidence seems to point towards there being low serotonin in ME, possibly due to shunting of tryptophan to kynurenine production caused by inflammatory cytokines.

The migraine-like headaches, gastric mobility problems, etc. seem to go along with the low serotonin theory.

I agree we do have increased adenosine levels (mine was slightly elevated) probably due to increased purinergic signalling going on as part of an ongoing immune response.
 

Remy

Administrator
The problem is that the evidence seems to point towards there being low serotonin in ME, possibly due to shunting of tryptophan to kynurenine production caused by inflammatory cytokines.

The migraine-like headaches, gastric mobility problems, etc. seem to go along with the low serotonin theory.

I agree we do have increased adenosine levels (mine was slightly elevated) probably due to increased purinergic signalling going on as part of an ongoing immune response.
I agree, it's a bit of a conundrum, probably due to less than ideal testing methods for serotonin. Every time I've had serotonin metabolites tested, they come back low...indicating low serotonin. But yet I have more symptoms of high serotonin.

Maybe it's more of a functional problem vs actual quantity. Maybe it's a receptor problem. Maybe it's a difference between gut and brain levels. I don't know. Sure wish I did!
 

Remy

Administrator
Here's more on upregulated serotonin receptors found in postviral fatigue syndrome...which also coincidentally sounds a lot like MECFS.

BMJ. 1992 Apr 18;304(6833):1010-2.
Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome.

Bakheit AM1, Behan PO, Dinan TG, Gray CE, O'Keane V.
Author information


Abstract

OBJECTIVE:

To study the dynamic function of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome.
DESIGN:

Prospective comparison of patients with postviral fatigue syndrome with two control groups.
SETTING:

Department of neurology, University of Glasgow, Southern General Hospital; department of psychiatry, St James's Hospital, Dublin.
SUBJECTS:

15 patients with postviral fatigue syndrome, 13 age and sex matched healthy subjects, and 13 patients with primary depression.
MAIN OUTCOME MEASURES:

Serum prolactin concentrations before and one, two, and three hours after administration of buspirone.
RESULTS:

Because of the effects of sex hormones on prolactin secretion data for men and women were analysed separately. There was no significant difference in baseline prolactin concentrations between patients with postviral fatigue syndrome and healthy subjects or those with primary depression. However, the percentage difference between peak and baseline values was significantly higher in patients with postviral fatigue syndrome than the control groups (one way analysis of variance: women, p = 0.003; men, p = 0.004).
CONCLUSIONS:

The results suggest upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. The buspirone challenge test may therefore be useful in distinguishing these two conditions. Larger studies are required to explore the potential value of drugs acting on central 5-hydroxytryptamine receptors in the treatment of patients with the postviral fatigue syndrome.
It's also interesting to me that certain studies have looked at using serotonin antagonists, specifically to the 5-HT3 receptor. This study used ondansetron (Zofran).

FWIW, I tried ondansetron myself for a couple of months but did not notice anything one way or another. I only used 4 mg twice a day though because that was all my insurance would cover.

Hrycaj et al.[75] investigated the efficacy of ondansetron in 20 patients with fibromyalgia using a crossover study design. The patients were asked to discontinue all medications for fibromyalgia; after a one-week wash-out period, they were given either acetaminophen 500 mg or ondansetron 8 mg orally twice daily for five days and then, after a three-day washout period, switched to the other treatment. Ondansetron treatment resulted in significant decreases in VAS scores for pain, tender-point scores, and average pain threshold. Fifty-five percent of patients were considered "responders" to ondansetron therapy, compared with 5% of patients considered responders to acetaminophen. The most common adverse effects of ondansetron were constipation and dry mouth. As ondansetron is available in a generic formulation, a prospective randomized trial might not be actively pursued.
I wonder if that is the wrong receptor to target though...the studies below specify 5-TH1A?

If we look to some of the research on channelopathies (my favorite!) we see some interesting tidbits as well...

An example of this may occur in familial migraine where impaired calcium channel function appears to be related to defective serotonin release (Chaudhuri et. al. 2000).
So back to calcium channels again...the same thing that beta blockers like verapamil target.

There is evidence of abnormal neurotransmitter activity in CFS. Response to a serotonin agonist (enhancer – busiprone) suggests hypersensitive serotonin receptors are present in CFS. CFS patients also often suffer from IBS, a problem that is possibly related to increased colonic activity due to a hypersensitive serotonin response.

Studies have suggested increased sensitivity of hypothalamic serotonin receptors (R-HTIa) (Dinan et. al. 1997), increased 5-TH1a receptor sensitivity (Bakheit et. al.1992, Cleare et. al. 1995) and reduced serotonin receptor density (Yamamoto et. al. 2004, Cleare et. al. 2005).
 

weyland

Well-Known Member
which also coincidentally sounds a lot like MECFS.
Same thing, that was just one popular term for ME in the UK at that time. Cleare found the same thing in Holmes criteria CFS patients as did Sharpe in male Oxford criteria patients.

Interesting thing is that Natelson tried something similar using l-tryptophan but only found the increased prolactin response in women for some reason.
 

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