Serotonin – the NET effect

A team of researchers from Case Western Reserve University School of Medicine have used high-powered microscopes for the first time to view serotonin activating its receptor

Background

I’d never heard of Serotonin until I was diagnosed with Neuroendocrine Cancer in 2010.  It is frequently discussed, often with contrasting views from the respondents. One common assumption/question is that it is responsible for many things that can go wrong with Neuroendocrine Cancer patients who have serotonin-producing tumours. “It’s the hormones” is an easy assumption to make or an easy answer to give in response to a complex set of circumstances.  It’s difficult to get a definitive answer and the science behind the behaviour of our hormones isn’t really 100% tied down.

You may see serotonin referred to as a ‘neurotransmitter’, a ‘chemical’ and a ‘hormone’ – this is complex but it is my understanding that it can add context in respect the role/location of the serotonin, e.g. chemical and hormone are essentially synonymous and are endocrine related whereas neurotransmitter is concerned with the nervous system (the neuro in neuroendocrine) and the brain (more on this below). Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).

Serotonin and NETs

One thing which is widely accepted and agreed…… Serotonin is definitely involved in Neuroendocrine Tumours, in particular, those resulting in carcinoid syndrome which can manifest as a number of symptoms including but not limited to flushing and diarrhea.  Although serotonin is one of the main ‘hormones’ released in excess by certain NETs (mainly midgut), it is not thought to be the main culprit behind some of the symptoms produced by Carcinoid Syndrome.  For example, flushing, the most common symptom (and a cardinal one) is thought to be caused by a number of hormones/peptides – too many to list but the main ones are histamine (particularly foregut), tachykinins (Substance P), bradykinins, prostaglandins …….. and I’m sure serotonin’s in there too!  It does, however, appear to be massively guilty in causing carcinoid syndrome diarrhoea, desmoplasia, and carcinoid heart issues.

Where does Serotonin come from?

Serotonin’s technical name is 5-hydroxyltryptamine (5-HT).  It is converted from 5-Hydrotryptophan (5-HTP) which is also known as oxitriptan. 5-HTP is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of serotonin (…..and melatonin) from tryptophan. Tryptophan is interesting as that brings in one of the missing pieces of the jigsaw – food!  Tryptophan cannot be manufactured in the body, it must be brought in via diet. There is no serotonin in food, it is only manufactured in the body.

Tryptophan in food enters the body and serotonin is created by a biochemical conversion process which combines tryptophan (essentially a protein) with tryptophan hydroxylase (TPH), a chemical reactor. I suspect other substances might be involved in that process.  There are two forms of tryptophan hydroxylase – TPH1 and TPH2, which are encoded on two independent genes. TPH1 is linked to peripheral serotonin while TPH2 is related to brain serotonin.

While serotonin cannot cross the blood-brain barrier, tryptophan can, and once there, almost all of it is converted to serotonin. Unlike, peripheral setotonin where only a small percentage is used to generate serotonin. Just to emphasise that NET dietitians do not say to avoid foods containing tryptophan other than at the time of marker testing (see below and nutrition Blog 4). When you look at the role in brain serotonin, this might have an adverse effect. 

Are you happy with your serotonin?

Serotonin Inhibitors

The introduction of Somatostatin analogues (SSAs) such as Octreotide and Lanreotide, help reduce the secretion of “tumour-derived serotonin”  by binding to its receptors on the outside of the cell.  If you ever wondered why receptors are important, please check out my blog on this subject (click here).

I mentioned tryptophan hydroxylase (TPH) above and that is actually very interesting as this is how Telotristat Ethyl (XERMELO) is able to help with the symptoms of Carcinoid Syndrome diarrhea (not adequately controlled by SSAs) or where patients are unable to be treated by somatostatin analogues for whatever reason. It’s a potent inhibitor of TPH which will disrupt the manufacturing of tumour-derived serotonin. There is also evidence that it can help reduce the effects or halt the growth of the fibrosis leading to carcinoid heart disease.  Slight digression but useful to aid/enhance understanding at this point.  Read about Telotristat Ethyl here.

Serotonin and the Brain

There is constant discussion and assumption that serotonin-producing tumours are somehow causing depression, anxiety and rage.  Not as simple as that, it’s way more complicated.  Certain NETs can overproduce serotonin in the gut but the issues concerning depression and anxiety are normally associated with low levels of serotonin in the brain.

“Cancer anger” is a normal response to fear, despair and grief – a range of feelings which cancer brings into our lives. It can show as frustration, irritability, emotional withdrawal or aggression. You can feel it whether you have been diagnosed or you are a relative or friend. Cancer anger can happen at any stage of the illness, even years after treatment. I know that many people with cancer suffer from depression, anxiety and anger but they do not all have serotonin-producing tumours.  What they do have is a life threatening and/or life changing condition which is bound to have an effect on mind as well as body.  Hormones including Serotonin are natural substances found in the body and not just there to service NETs.

Serotonin is separately manufactured in the brain (~10%) and in the gastrointestinal tract (~90%).  The serotonin in the brain must be manufactured in the brain, it cannot be directly increased or reduced external to the brain, i.e. it cannot be directly reinforced by gut serotonin (peripheral serotonin). It follows that ‘brain serotonin’ and ‘gut serotonin’ are held in separate stores, they are manufactured in those stores and remain in those stores – there is no cross-pollination. This is managed by something called the blood-brain-barrier (BBB). Therefore, excess serotonin from NETs does not infiltrate the brain. As low-level of ‘brain serotonin’ is often linked to depression, it also follows that it’s possible to have high levels of serotonin in the gut but low levels in the brain.

My simple way of thinking about such things as outlined above, is that low levels of tryptophan in the brain might be contributing to low levels of serotonin in the brain.  To clarify that, I researched the reasons why there could be low serotonin in the brain. First, let’s dismiss any connection that the type of anti-depressant called Selective serotonin reuptake inhibitors (SSRIs) is involved. It’s thought that SSRIs work by increasing serotonin levels in the brain. Serotonin is a neurotransmitter (a messenger chemical that carries signals between nerve cells in the brain). We already discussed that it’s thought to have a good influence on mood, emotion and sleep. After carrying a message, serotonin is usually reabsorbed by the nerve cells (known as “reuptake”). SSRIs work by blocking (“inhibiting”) reuptake, meaning more serotonin is available to pass further messages between nearby nerve cells. So tryptophan or peripheral serotonin are not really involved.

It would be too simplistic to say that depression and related mental health conditions are caused by low serotonin levels (in the brain), but a rise in serotonin levels (in the brain) can improve symptoms and make people more responsive to other types of treatment, such as Cognitive Behaviour Therapy (CBT).  It’s also too simple to suggest that NET patients get depression and anxiety due to all the “hormones” these tumours produce.  Of course hormones can be involved in depression and anxiety but hormones aren’t their just for NET patients.  Cancer patients without hormone secreting tumours also get anxiety and depression so it’s possible that NET patients can get depression and anxiety in the same way.

It should also be noted that the precursor to serotonin, tryptophan, does pass through the BBB and it is therefore possible that tryptophan depletion can lead to less availability in the brain for the manufacture of brain serotonin.  Tryptophan depletion can be caused by dietary restrictions (i.e. lack of tryptophan foods) and also by the effects of certain types of tumours as excess serotonin is made leading to less availability of tryptophan.  Both could lead to low serotonin in the brain as less tryptophan gets there. It follows that foods containing tryptophan remain important in order to help maintain normal brain serotonin levels.

Measuring Serotonin levels

Measuring levels of serotonin is important in both diagnosis and management of certain NETs – although it’s probably sensible to test all potential NET patients during diagnosis when the type of tumour is not yet known.  Testing for tumour markers will differ between countries and within countries but the most common standard for testing Serotonin appears to be 5-HIAA (5-hydroxyindoleacetic acid) either via a 24-hour urine test or via a plasma version (mainly used in USA but now creeping into UK).  5-HIAA is the output (metabolite) of 5-HT (Serotonin). Not to be confused with the less reliable ‘serum serotonin’ which is a different test.

Another frequently asked question about serotonin tests is whether they are testing the amount in the brain or the gut. The answer is …… they are testing the levels in the blood. Furthermore, if you are measuring serotonin as an indicator for Carcinoid Syndrome, it has to be remembered that the majority of serotonin is in the gut, so even if serotonin levels in the brain were being measured alongside the gut levels, I don’t believe it would  influence the result in any significant way (but I have no science to back that up). It also has to be remembered that serum serotonin and 5HIAA are not absolute tests, they are not 100% sensitive, they are simply indicators of a potential problem. There are methods of measuring brain serotonin but it is very complex and beyond the purposes of this article.  However, I would just add that it is the reuptake of Serotonin in the brain (plus some other stuff) that can cause depression, not the actual level or amount in the brain.

I intentionally did not mention the other common test (Chromogranin A) or other markers as they are measuring different things but you can read about in my Testing for Markers blog.

Serotonin Video with myself and Dr Mike Morse

I made a video in 2019 with Dr Mike Morse sponsored by Lexicon Pharmaceuticals, Inc.  It’s all about Carcinoid Syndrome with a slant towards hormones, in particular Serotonin. Entitled “Likely Suspects: How Hormones May Lead to Carcinoid Syndrome – What People Living With Carcinoid Syndrome Need to Know”

You need to register to watch although some of you will already be registered and just need an email to login to see the this webcast. The one I’m featured in is the latest in a series on the subject and I’d like to break the record for views please! Please help me achieve this 💙 I would also love to get your feedback and sincerely hope you will find the time to listen in.  Please also find the time to complete the survey at the end.  Thanks

Click on the link here: www.CarcinoidWebcast.com

Don’t forget to press the play button and ensure your sound is turned up, particularly on mobile devices.

webcast morse allan

Summary

I did say it was a difficult jigsaw!

Thanks for reading

Ronny

I’m also active on Facebook. Like my page for even more news. I’m also building up this site here: Ronny Allan

Disclaimer

My Diagnosis and Treatment History

Most Popular Posts

Sign up for my twitter newsletter

Read my Cure Magazine contributions

Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!

patients included

Please Share this post

Tweeps – have you retweeted this tweet?

 

Author: Ronny Allan

Facebook: https://m.facebook.com/NETCancerBlog and https://m.facebook.com/RonnyAllanBlog twitter: @ronnyallan1 twitter: @netcancerblog

18 thoughts on “Serotonin – the NET effect”

  1. Ronny, I experienced extreme symptoms of anxiety, depression and anger while my Carcinoid Syndrome was going on. I am not as technical in my description of things as you but, these symptoms immediately ceased after debulking and removal of primary tumor. The doctor’s explanation of this was that my tumor was dumping serotonin into my bloodstream before the liver had a chance to clean it of the excess hormone. Once in the bloodstream, this would have impacted my brain, would it not? Maybe i am misunderstanding your explanation of the experience but it sounds to me that you are saying there are other reasons for these experiences? If so, i have to disagree, In my case there is no other explanation, I had no idea for years I had an active carcinoid tumor, my symptoms increased in severity (bouts of anger, depression, etc.,) over those years. Once located and removed my symptoms decreased/disappeared in total almost immediately. Thanks for listening.

    1. excess serotonin from tumours in the gut do not cross the blood brain barrier. Brain and Gut serotonin are manufactured separately and remain in their own stores. I cannot comment on you situation or the context of the doctor’s explanation. Sorry

  2. Hi Ronnie, I stumbled across your page when I got the result of my chromogranin A blood test (90), did the 5HIAA urine test (awaiting results) and hot called for an urgent Tektrotyd scan – ALL my symptoms point to a neuroendocrine tumour (I have felt ill for about 7 years). I have all the symptoms of carcinoid syndrome. However scan results are clear, no tumours. But I’m baffled – why is my CgA high and why do I feel so ill? Any advice to give? I wish you well in your journey – you are very inspiring!

    1. I see this a lot Lisa. Unfortunately with many cancers “tissue is the issue” and to do a biopsy (currently), you need to ‘see’ a tumour to biopsy. It’s possible you don’t have a NET as the symptoms tend to be vague and similar to many everyday conditions – I would say flushing is pretty cardinal BUT it’s not like a wet hot flash you would get in menopause nor it is sweating, it’s dry as a rule of thumb. Check out my article “I bet my flush beats yours” to see the differential diagnoses for flushing. Your CgA is not actually that high – are you taking PPIs (anti acid medications) ? That will skew CgA – a blood test called Pancreastatin is better and not affected by PPIs, if that is the case. It will be useful to see the results of the octreoscan (I had to google tektroyd!). If you have working receptors, it should light up where there is an excess secretion (but even then it needs careful interpretation). Can you let me know the results when you get it? A gallium 68 PET is the newer version of octreoscan.

    2. Thanks for your response. I have dry flushing (no sweating) triggered by alcohol, chocolate, spicy food, stress, and sometimes is so bad I get a massive drop in blood pressure, violent vomiting, diarrhoea, immense cramping pain in right side then feel dreadful and can’t eat for 2-3 days. Keep being diagnosed with IBS but am so fatigued, B12 and vitamin D deficient, joint pain, hypoglycaemic, thyroiditis, just generally been feeling very unwell past 7 years. Seeing consultant next Wednesday so will let you know what 5HIAA result was and what scans showed. Thank you so much!

  3. I was dx’d in 2015 and Had small intestine resection. Since then my Serotonin level has been > 2000, Last test was 2250. I was wondering what the long term effects of serotonin typically are. I see things like hyper sensitivity to cold, muscle weakness, and hyper reflexivity. I have heard of Telotristat Ethyl (XERMELO) might be able to lower this. My Net Dr mentioned this back in May 2017 but my last visit in Dec 2017, made no mention of it. But did talk about PRRT and possibility of being approved early in 2018. We depend on these Net Dr’s but they are so busy, I think my Doc has been a little scattered..

    1. Hi Jeff. What was your 5HIAA score? You didn’t mention the unit of measure for serotonin, presumably the figure you gave is not normal, i.e. it’s out of range? XERMELO is approved for inadequate control of carcinoid syndrome diarrhea (this would indicate it’s for diarrhea caused by abnormal levels of serotonin rather than caused by surgery (i.e. shorter bowel etc)). Apparently it does lower 5HIAA results (the output of serotonin). Check out my article on XERMELO https://ronnyallan.com/2016/03/31/telotristat-ethyl-xermelo-an-oral-treatment-for-carcinoid-syndrome-diarrhea-not-adequately-controlled-by-somatostatin-analogues/ I would say one of the biggest long term risks of elevated serotonin is carcinoid heart disease – https://ronnyallan.com/2015/06/02/neuroendocrine-cancer-dont-break-my-heart/ however, these risks are lowered by the use of somatostatin analogues

  4. Really interesting. At oncology appointments I only have blood taken which is immediately put on ice. Do you think that’s the plasma version test you mention? Haven’t done a 24 hour urine for a while. Also Ronnie. What are your thoughts on fatigue? Disease vs treatment as the cause. It drives me crazy. Thanks.

    https://polldaddy.com/js/rating/rating.js

    1. The blood in ice is probably Chromogranin A (CgA) which is measuring tumour bulk rather than function. As for fatigue, am working on a post stay tuned. However, it’s a common problem and even doctors gave difficulty fixing it. I have some ideas.

  5. What are your thoughts on discontinuing an SSRI for 72 hours prior to the 5-HIAA test? Is it necessary to do so? My GI doctor said I didn’t need to stop them, but I’ve read conflicting information. I’d rather not have to stop them if possible, but I don’t want to mess up my test results either.


    https://polldaddy.com/js/rating/rating.js

  6. This is good stuff. I have been wondering why I wasn’t tripping over myself with happiness if my body produces too much Serotonin and why I don’t feel more sad with my Lanreotide injections. I have been curious if this injection interferes with the 5-HTP test results? Would it also interfere with a Gallium scan’s results? Should one stop injections before such tests?

    1. Thanks for commenting. I tried to put over that the two stores of serotonin in the GI tract and the brain were independent of each other, mainly to dispell the myth that the excess serotonin from NET tumours (specifically carcinoid) does not go zooming straight into the brain. I did not want to focus on serotonin issues associated with depression and treament for that (SSRIs etc) as it is even more technical (and beyond my understanding) and would perhaps complicate my focus on the specific serotonin NET issues, which in comparison are straightforward (kinda !).

      As for somatostatin analogues leading up to a Octreotide scan or Gallium 68, there is a protocol for that which I will try to find for you. Re the 5-HTP test, why do you get this? Is it a blood serum test.

  7. I have read that excess serotonin can also cause agitation. I immediately calmed down when my tumors were removed. Lanreotide is helping also

    1. Do you mean brain serotonin or gut serotonin? In respect brain serotonin, excess would not be a NET issue and I wanted to avoid discussing illnesses such as serotonin syndrome as this is not related to NETS.

      1. I suppose the agitation is from brain serotonin but it’s interesting that I feel more calm since my gut serotonin is lower. It’s still above average but lower than prior to surgery. Perhaps it’s due to some other cause.

      2. Maybe you’re feeling more calm because you’ve had treatment? If you’re also taking a somatostatin analogue, that will lower gut serotonin too.

Leave a Reply to Ron Cancel reply