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Adrienne Dellwo

Autoimmunity to Serotonin in Chronic Fatigue Syndrome

By May 23, 2013

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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.

Researchers say serotonin autoimmunity could be part of the underlying pathology of the condition, and their results provide support for ME/CFS being a neuro-immune disorder.

What it Means

In autoimmunity, your immune system basically gets confused and identifies a healthy, normal part of your body as a foreign invader that should be destroyed. It then treats it like a virus or bacteria, creating specialized cells that seek it out and try to get rid of it. This response leads to inflammation and a host of other problems.

Serotonin has long been believed to play a role in ME/CFS. In your brain, it's a neurotransmitter, which means it transports certain messages from one brain cell to the next. In the rest of your body, it's a hormone. The highest concentration of serotonin is in your digestive system, where it plays important roles.

Another known factor of ME/CFS is chronic immune system activity. Bascially, it's in high gear all the time, as if it's fighting an active illness. Autoimmunity could help explain this.

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May 23, 2013 at 9:50 am
(1) Rachael says:

The neurotransmitter responsible for putting the brake on excessive serotonin in the body is dopamine. I believe that people with ME/CFS have too much serotonin in their system because of a lack of, or dysregulation of the neurotransmitter dopamine in the brain.

Too much serotonin causes the immune system to become up-regulated; hyper-responsive. The immune system’s reaction to bacteria found in the intestinal tract of ME/CFS patients is extreme because of elevated serotonin. It is not reacting to the serotonin, but it is over-reacting to the bacteria caused by having too much serotonin in the gut which is up-regulating the body’s immune response.

Most people wouldn’t have the same reaction to foreign substances (eg bacteria, chemicals etc) as do ME/CFS sufferers. Their higher dopamine concentrations calm an overactive immune response, unlike ME/CFS sufferers.

May 23, 2013 at 10:56 am
(2) sam says:

To rachel: so why do they put cfs patients on serotonin antidepressants? Im confused! Great article – progress is being made! Whoop whoop

May 23, 2013 at 11:27 am
(3) Rachael says:

sam: For many ME/CFS sufferers, including myself, serotonin antidepressants, or SSRI’s make our symptoms much, much worse. Have you heard of Serotonin Syndrome? Excess serotonin activity produces a spectrum of specific symptoms including cognitive, autonomic, and somatic effects. The symptoms may range from barely perceptible to fatal.

Antidepressant drugs like SSRIs have been shown to boost immune uptake. Some researchers are speculating that these drugs that boost serotonin might boost immunity to the point that they can actually trigger autoimmune diseases. For the “CFS” sufferers serotonin antidepressants work for, I am guessing they don’t have ME/CFS an autoimmune/neuroimmune illness.

May 23, 2013 at 12:24 pm
(4) MissyD says:

I tried to make a comment earlier, but it didn’t show up. Am I being censored? I hope not. I read this study a saying that our bodies are attacking our serotonin, lowering its levels. That would explain why doctors and psychiatrist mistake CFS/ME for depression, and why for some of us, antidepressants give us some relief. I am interested in your thesis that we have excess serotonin. Rachel, could you please direct me to the research that support this? I am very interested ( and quite confused) with this whole serotonin thing. Thanks. Oh, one more thing, I am really grateful that researchers are finally really doing some work on our illness.

May 23, 2013 at 3:07 pm
(5) Yvette says:

I think it’s pretty clear that not everyone diagnosed with ME/CFS has the same disorder.

May 23, 2013 at 3:37 pm
(6) Rachael says:

MissyD: It’s been years and years (over 25 + years with ME/CFS) of research that has led me to this conclusion. I’ve read not one study, but countless papers. Through experimentation with over-the counter antihistamines and raising my depleted dopamine levels, I have taken myself from completely and utterly incapacitated to living a pretty normal life. For me, it was trial and error, being observant of myself and connecting-the-dots that has enabled me to get back to living a somewhat normal life. The one thing I am sure of though is that increasing serotonin makes my ME/CFS much, much worse.

Here’s one paper from biopsychiatry that might be of interest to you.

“…while it may be possible that SSRI drugs may restore a healthy immune function in people who are depressed and prone to infections, it is possible that they might also bolster immunity to the point that they trigger autoimmune disease.”


May 24, 2013 at 4:59 am
(7) Rach says:

The research found autoantibodies to to 5HT receptors not serotonin as you incorrectly state.

May 24, 2013 at 10:58 am
(8) Happy says:

I have ME and depression, and I am utterly reliant on my SNRI. If I miss even a single dose, I can tell immediately. Perhaps some ME patients have too much serotonin, but that is certainly not the case with everyone, and it’s certainly not supported by the study mentioned by Adrienne.

May 24, 2013 at 11:35 am
(9) Rachael says:

Just curious Happy, do you have Canadian Criteria ME/CFS? Do you have post- exertional malaise and fatigue, a loss of physical and mental stamina, rapid muscular and cognitive fatigability, malaise (flu-like symptoms) and pain worsen after exercise/exertion? Do you have a pathologically slow recovery period where it takes more than 24 hours to recover after exercise/exertion? Or does exercise generally make you feel better; give you a lift?

May 24, 2013 at 1:35 pm
(10) Steve says:

Rachael, could you elaborate on what regiment has worked for you?

May 24, 2013 at 4:20 pm
(11) Rachael says:

Steve, this is not a recommendation; what has worked for me doesn’t mean would work for you. I”ll tell you a few of the things that have helped “me” with my case of ME/CFS. I take l-tyrosine (amino acid precursor to dopamine), good quality salmon oil capsules, MSM which is a methyl donor, Vitex found in health food stores (has similar effects to that of bromocriptine, which is a dopamine agonist) and sedating antihistamines at bedtime. My goal is to raise my depleted dopamine level with supplements which in turn helps to calm my hyper-immune response. I’ve also personally found sedating antihistamines to be very beneficial in calming my immune system.

May 24, 2013 at 7:52 pm
(12) Kathy C says:

So interesting, Rachael! I’ve finally found a combination of Rx and OTC meds that allow me to sleep for at least 6 hours: Benadryl 12.5 mg, Percogesic (Tylenol 500 mg + Benadryl 12.5 mg) plus 1/2 of my sleeping pill.

When I mentioned to doctors that Percogesic helped me, they all looked at me like I was nuts.

I also take various supplements, which they also think are unnecessary.

THIS makes sense. Thanks!

May 24, 2013 at 8:10 pm
(13) Juliet Sisk says:

Thanks to everyone who is trying to help sufferers feel better ultimately regain our health. This article speaks to me because of my experience with ulcerative colitis (also an autoimmune intestinal condition). After 4 years of treatment with prednisone with only moderate results, my gastroenterologist decided to use a much stronger cancer immunopressant drug called Purineothol. The side-effects must be monitored monthly since they could have been lethal but it worked! It took 13 years but I was “in remission”. So I was taken off of the Purineothol (aka 6NP). That’s when within months, I became ill with fibromyalgia/CFS. That was 8 years ago. Interesting information in the light of this article, isn’t it……

May 24, 2013 at 10:15 pm
(14) Anne says:

Rachael, (part 1)
I completely follow you on auto immune response theory – and that CFS origination can come from several sources. For instance – I am 48 – when I was 16 I had one ovary removed – and starting menopause in mid 20′s, with other ovary/uterus/hysterectomy at 28 (sorry to be graphic, but making a point soon). Up to a few years ago, I had moderate to high-moderate CFS symptoms as I could never fully regulate by HRT the massive hormonal upheaval/dysfunction (they are now figuring some women genetically cannot fully process HRT, lucky me).

However – I did not have random swollen lymph glands, weapons grade insomnia, etc, and back then exercise could make me feel better. I think for hormonally challenged CFS, exercise causes the adrenals to compensate some hormones. continued..

May 24, 2013 at 10:38 pm
(15) Anne says:

Rachael (part II) –


About 4 years ago, the game changed to what is now a viral component. HIgh CFS symptoms – Flu like, incompacitating. And exercise makes it WORSE. That didn’t happen before.This is a hallmark symptom between viral base CFS and other originations. I have tested negative for generic viruses , still looking. But am going to try tackling from immune system standpoint, after years of the hormonal angle. A major problem now is no stage 3 (deep/delta) sleep – due to long term use and functional dependence on hypnotics for any kind of sleep (Lunesta). No doubt at this point immune based sleep issue, which I can’t find a doctor in my area to listen to any theories of immune based insomnia, sigghh.. (And we’re talking Johns Hopkins, folks).

Just received a supplement box a few days ago w/inosine (which seems to be helping already w/sleep), the others haven’t tried yet – vitex, l-theanine, GLA, stinging nettle, bromelain, rhodiola. Anti histamines have always caused dehydration based headaches for me, but may be worth a try again.
Thanks -

May 24, 2013 at 10:54 pm
(16) Anne says:

Also..one more CFS component – MCS (multiple chemical sensitivety), and allergies. For me probably due to long time low DHEA levels (again problems w/supplementing hormones – most people can successfully raise levels w/ OTC DHEA)- I can only take minute amounts. Long term low DHEA levels can cause allergies/sensitivities to everything. Also I have a saying – if it has a scent, I’m in trouble, lol! Just a few minutes of exposure to most kinds of chemical smells can send me back a day energy wise. Same w/many foods- to safe guard energy reserves, I don’t eat lunch/meals during the day anymore – kicks in CF.

Anyways these are just my experience and factors to possible CFS origination factors.

May 25, 2013 at 8:30 am
(17) Dana says:

Doctors thought I was nuts when I told them that all the antidepressants they gave me made me depressed.

May 25, 2013 at 10:03 am
(18) Antihistamines, Allergies, Depression says:

“Psychiatrists have been very reluctant to accept the idea that depressions, which they know so well, may be caused by allergies to common environmental molecules such as foods, airborne particles, and chemicals in water.”

“Treatment of the allergy will, in most cases, “cure” the depression.”

“The tricyclic antidepressants are third generation antihistamines. The discovery of the antihistamines was followed by their use as tranquilizers.”

“In this communication I will summarize the evidence which supports the conclusion that a large fraction of depressions are responses to environmental molecules, and that the tricyclics are effective in many patients because of their antihistaminic properties, not because they act upon the serotonin or sympathomimetic amine pathways.”

“The close association between depression and allergies. It is rare to find one without the other; when one is relieved, so is the other.”

“I suggest neuropsychopharmacologists once more examine seriously the antihistaminic properties of the antidepressants.”

Read more: http://www.orthomed.org/resources/papers/hofdepr.htm

May 25, 2013 at 10:35 pm
(19) Gloria says:

@ Anne,
I found that my CFS started after a severe bacterial infection and got worse after a viral infection — and exercise does not help at all, but I do still try to get some “movement” in my days and try to ride my exercise bike for a short time whenever I can.
I used L’Tyrosine for a couple of years and never notice ANY difference in how I felt, but when I started on Tryptophan supplements I found that my energy really increased.
I recently realized that I have Pyrrole Disorder and since I have done a fair bit of reading, I found that I was already following the supplemental protocol for that. More info at http://www.vitalityandwellness.com.au/pyroluria and see Greg Newsome on You Tube for more info.
I wondered if many who have CFS/ Fibromyalgia have this disorder as well.

May 26, 2013 at 4:40 am
(20) Geraldine says:

Anti Depressants and Lyrica had a bad effect on me but Anti Histamines really help with sleep and are my saviour.

May 27, 2013 at 5:08 pm
(21) Geraldine says:

I forgot to say that I tested low in Dopamine and also had slightly raised ANA levels too. I have severe Endometriosis and I am allergic to Nickel and was dignosed with Infectious Mononucleosis prior to CFS all of which can be associated with ME/CFS/FMS.

May 28, 2013 at 11:10 pm
(22) Dr. Gail Hume says:

Great article, Adrienne! This research also makes me think this could be the reason sleep is so messed up with ME/CFS. Serotonin is a precursor to melatonin and serotonin is being destoyed by the immune system. And this possibly contributes to intestinal hyperpermeability too – all that resulting inflammation from the immune response to serotonin in the gut. I also wonder about 5-HTP, the precursor to serotonin. 5-HTP was quite aggravating to me when I took it and other ME/CSF sufferers also experience this. It is truly great news that relevant research is happening!

May 29, 2013 at 2:03 pm
(23) Sharon Long says:

savella may be a better answer? My daughter has been on that for several years with pretty good success. It inhibits reuptake (increases levels) of both serotonin and norepinephrine, but affects norepinephrine levels 3x more. Perhaps that mixture is the desired balance. SNRI

May 29, 2013 at 6:48 pm
(24) Lannie says:

Great article and comments!!!!!

I became severely depressed the 2 times I tried SSRIs in an attempt to decrease pain(a rheum prescribed one known for helping FM). First attempt I lasted 72 hours, 2nd attempt only 48 hrs.

This is so interesting, I look forward to reading more on this subject!!!

Thank you Adrienne!

May 29, 2013 at 9:44 pm
(25) Molly says:

Rachael – I have similar reactions to serotonin in my system, which were described in the research of 5-HT on CFS. You mentioned increasing dopamine as being helpful. Do you know of natural and/or pescription medications that do this without raising serotonin.

May 29, 2013 at 10:21 pm
(26) Rachael says:

Molly: I’ve found things that work for me in raising my dopamine levels. This doesn’t mean it will work for you, or anyone else and this is not a recommendation. Read comment #11. L-tyrosine is an amino acid found in many health food stores. It is a precursor to dopamine.

May 30, 2013 at 1:06 am
(27) Pamela Powell says:

Rachel is absolutely correct. Long story short; nurse 45 years, cfs/ fibro 27 years, continual research & trail and error, same conclusion I found years ago & still convinced.

May 30, 2013 at 10:18 am
(28) Pamela Hoke says:

To Rachel: I have had ME/CFS for about 7 years. I take Lotronex for IBS which blocks serotonin (5HT3). I have ofter wondered if messing with the neurotransmitters might have caused the ME/CFS. After reading the article, I decided to stop taking the Lotronex. After reading the comments, it seems that blocking the serotonin might be a good thing. Please help me know what to do.
Thank you.

May 30, 2013 at 11:39 am
(29) Rachael says:

Pamela Hoke: I’m not a doctor and don’t feel it is my place to tell you what you should be doing, or not doing for “your “case of ME/CFS. We are all different and what works for one person, may have entirely different effects for another person.. As you can probably see from some of the comments, those of us with this illness are probably not all suffering from the same condition. I’m just trying to convey to others what has helped me. I hope that this information may somehow offer assistance to someone else in finding their own way.

All the best

June 2, 2013 at 7:15 pm
(30) HeyJude says:

Juliet Sisk I was on 6MP for my Crohn’s and it worked great! Then I had to go off of it because my creatine level went up which can lead to kidney failure. Around 6 months later I started having symptoms of severe fatigue, and muscle and joint pain. My GI sent me to a specialist that diagnosed me with adrenal fatigue caused from 30 plus years of being on and off of Prednisone. She said I would have to take Prednisone or Cortef the rest of my life. My Rheumy said the joint pain is from my 36 yr history of Crohn’s, and the other pain is Fibro. It’s wild that both of us developed these problems after going off of 6-MP. What are you using to treat your symptoms now? Thank you~Judy

June 4, 2013 at 10:55 am
(31) Molly says:


Just wondering….I have tried several SSRI/SNRI and I too definately have increased symptoms in my CFS – pain, depression, stiff muscles, etc..when I get off, my symptoms get much better. I also tried Wellbutrin but I got the same response from that (almost worse if you ask me). I thought this would increase dopamine? Is this something you also observed? I realize the process if very individualized but I am hoping to get some guidance on what other people have observed.

June 4, 2013 at 8:13 pm
(32) Rachael says:

Molly: What I have come to understand about myself is that I am running low of the neurotransmitter dopamine. Even though some drugs are meant to raise dopamine levels such as Wellbutrin, if you have nothing to work with (dopamine stores are running near empty – depleted/dysregulated) then you won’t attain the desired effect from such drugs.

You need a source to restore dopamine stores in the brain. That is why I take the amino acid l-tyrosine (precursor to dopamine) and other supplements in the morning to raise my low dopamine levels. When I take the eg Vitex ( a dopamine agonist) it now has something to work with to activate dopamine receptors in the brain. Hope this helps!

September 4, 2013 at 2:44 am
(33) Stephen says:

Thanks for the interesting posts Rachael. I have been unwell with CFS for 17 years and the conclusion I have come to after endless reading, research and experimentation is absolutely consistent with yours. IE- dopamine (functional dysregulation and/or effective lack of, in particular parts of the brain) is a fundamental part of the condition….and ‘further up the line’ I believe this is caused by immune dysfunction (most probably an over-active immune system) . Speculating further, I’d say any combination of genetic pre-disposition, infection and/or environmental stressor could bring this state of dysregulation about in the first place, for a given individual. Based on stats, there’s also perhaps something about being female which makes one more prone. I’m male…so that bit doesn’t follow for me, even if all the rest does!

You might have already read/be intererested in this research from the CDC last year which is consistent with these ideas re dopamine and immune system:


December 5, 2013 at 8:16 pm
(34) Marti says:

OMG Rachel…you’re article describes me! I have always suspected that I have too much Serotonin (actually it came back high on my labs and prompted me to really think about it) I think it’s “pooling” in the system and causing all the things you mention: hypersensitivity, gut issues, sleep issues (no deep sleep), hormonal issues, and especially mood issues (anxiety & depression) I too have “CFS” and I also have Methylation issues and MTHFR and MAO-A mutations. I have always had a half-theory about trying to raise my brain Dopamine levels to balance and calm the Serotonin overload. I respond horribly to ANY SSRI including Wellbitrin and not well to 5-HTP and I have tried looking for L-DOPA or Dopamine Agonists. Things like Klonopin calm the hyper brain, but i want to find something less drug-based and more supportive to Dopamine. I am going to try a few things you suggested. Thank you!

February 16, 2014 at 5:19 am
(35) Virginia says:

Hi – I found this quite interesting and would like to pick your brain about some of it. I’ve never been diagnosed with CFS but I wonder if I may have it to some degree now. A little bit of the story, the part I am willing to share online anyway, was that I went into a pretty bad depression last year (plenty of high stressors for it). I’ve never liked anti-depressants as I’ve not reacted well to them in the past (for anxiety, situational stresses) so I was loathe to go on them again. But after not being able to pick myself back up, I was finally convinced by a counselor to go on anti-depressants. I told the dr about my sensitivity and they believed it was that I was over-stressed and put me on Fluoxitine (sp?) which 3-4 days in drove me nuts – and I do mean really put me into overdrive. I got off them, and went on Sertraline, at a low dose to increase higher periodically. It never made me feel very good, I was hyper-aware of my body, over anxious, had (and still have) an irritable bowel. I lowered my dosage over a period of time and began to feel a little better, despite stress. But I now do not react well to stress, if I sleep a little poorly the night before (but in a normal time I’d have been able to function on that sleep level), I have bad muscle tension and pain and holding up something for a long period can be difficult on my arms and as I said one thing is that for a year I’ve had a very bad bowel. So I wonder if the strain of going on antidepressants triggered a trauma (along with the trauma that put me into depression to begin with). I’ve read that trauma can bring on CFS and I felt like when I was on SSRIs that I was not reacting to it the way that I should be – though the doctors cannot seem to attribute my feelings on it to anything other than my mental state and stress.

February 16, 2014 at 5:20 am
(36) Virginia says:

cont. I am just trying to make sense of a very confusing and scary situation. There is a lot more to be said on it but I don’t want to put out publicly but I’d like to make some sense out of what I’ve gone through and what I still go through and find something that will truly help me feel better.

April 15, 2014 at 11:03 am
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