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 Tumour (NET) patients who have serotonin-producing tumours. To a certain extent, that’s true but statement such as “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 – the human body is extremely complex.
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 to the role/location of the serotonin, e.g. neurotransmitter is concerned with the central nervous system and the brain (the neuro in neuroendocrine), whereas chemical and hormone are essentially synonymous with the endocrine systems. Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).
One more issue I frequently see is the assumption that all NETs regardless of grade and stage oversecrete Serotonin which is patently incorrect. Serotonin is only one hormone involved in Neuroendocrine Cancer and is almost exclusively associated with the group of tumours once known by the ancient and misnomer term ‘carcinoid‘ thus the term ‘carcinoid syndrome’. Moreover, the bulk of the incidence of carcinoid syndrome is centred around stage 4 midgut NETs, all other locations capable of being a true serotonin secreting NET are very small in numbers. However, the misuse of the term by doctors, advocate organisations and patients, spreads the myth that anyone who is ‘symptomatic’ with Neuroendocrine Cancer has carcinoid syndrome and/or oversecretes serotonin, leading to unnecessary testing, worry, confusion and potentially unnecessary treatment. The pancreas is a classic example as there are over 6 other hormonal syndromes possible and while carcinoid syndrome is possible, it is not the legions of pancreatic NET people you see in groups thinking they have carcinoid syndrome. Flushing and diarrhea can happen in other NETs or for non-NET reasons. This adds to the issue I intend to cover below.
Serotonin, NETs and Carcinoid Syndrome
One thing which is widely accepted and agreed…… Serotonin is definitely involved in Neuroendocrine Tumours, particularly 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 typical 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 one is tachykinins (Substance P). According to a recent study from Europe, there is currently, insufficient evidence to link histamine, bradykinin, kallikrein, prostaglandins, motilin, and other putative mediators to Carcinoid Syndrome.
However, Serotonin does appear to be guilty in causing carcinoid syndrome diarrhoea, desmoplasia, and carcinoid heart issues.
How does Serotonin get into our bodies?
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 from Tryptophan (often known as L-tryptophan) which is an amino acid (protein building blocks). L-tryptophan is called an “essential” amino acid because the body can’t make it on its own, it must be acquired from food. This makes Tryptophan very interesting as that brings in one of the missing pieces of the jigsaw – food! It follows that there is no serotonin in food (incorrectly stated on many websites), it is only manufactured in the body via the complicated process just described. In simplistic terms, after absorbing Tryptophan from food, our bodies convert it to 5-HTP and then to serotonin. Additionally, a small amount of Tryptophan is converted to B3 (Niacin) – the importance of this will be described later. 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).
The confusing bit – brain Serotonin
While serotonin cannot cross the blood-brain barrier (BBB), tryptophan and 5-HTP can, and once there, almost all of it is converted to serotonin, unlike peripheral serotonin where only a small percentage is used to generate serotonin. When you look at the role of tryptophan in the manufacture of brain serotonin, this might have an adverse effect if there is insufficient tryptophan generated and/or available (see Serotonin and the Brain section below). BUT ……. brain serotonin has nothing to do with carcinoid syndrome.
Tryptophan and Serotonin – the smiling assassins?
It should also be noted that the precursors to serotonin, tryptophan and 5-HTP, does pass through the BBB and it is therefore possible that tryptophan depletion in the gut and brain can lead to less availability of serotonin in the brain. There are two potential issues:
1. Tryptophan depletion can be caused by dietary restrictions i.e. lack of tryptophan foods. When tryptophan stores are low in the brain, they cannot be converted to serotonin. which may then cause lower availability of serotonin needed to carry out its brain function of regulating mood etc. It follows that foods containing tryptophan might be important for those with consistently elevated gut serotonin levels (except when testing 5-HIAA when they are omitted from diet during testing 5-HIAA. See brain serotonin section below for some of the contraindications of taking 5-HTP or Tryptophan supplements if also taking anti-depressants – always consult your NET Specialist in such matters.
2. The over-secretion of serotonin can lead to less availability of tryptophan. In carcinoid syndrome, functioning tumour cells indirectly depress niacin (B3) production by diverting tryptophan metabolism towards making serotonin and away from niacin. Malnourishment and diarrhea, frequently present in carcinoid syndrome patients, reduce the availability of niacin by decreasing the amount ingested and absorbed. In extreme cases, the decreased availability of niacin eventually results in very low niacin levels responsible for the development of a skin condition called pellagra. For this reason, many NET Dietitians recommend a Vitamin B3 supplement for those at risk.
Due to a number of advancements in diagnosis and treatment, in particular, the introduction of somatostatin analogues which help with hormone regulation, these issues are less common but NET patients with highly elevated 5-HIAA should remain vigilant to the possibilities. The pharmacokinetics of Telotristat Ethyl (XERMELO) are quite interesting though. Tryptophan in food enters the body and serotonin is created by a biochemical conversion process that 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. This is the process exploited by Telotristat Ethyl (XERMELO) which is a drug 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 TPH1 which will disrupt the manufacturing of tumour-derived serotonin (i.e. body or peripheral serotonin). Brain serotonin remains unaffected.
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).
5-HIAA should not be confused with the less reliable ‘serum serotonin’ test. I know many people also test for raw serotonin but many NET specialists say it’s an unreliable test given that serotonin levels are really just a ‘snapshot’ at one time and serotonin is known to spike throughout the day. Some doctors may test both. Your doctor will normally request measurement of 5-HIAA in a 24-hour urine collection in the first instance, with serotonin measurement being reserved for cases where the 5-HIAA result does not help. The 5-HIAA blood version is also snapshot but it’s still reliable because the serotonin has taken time to convert to 5-HIAA and so spikes of serotonin have been smoothed out to produce an accurate result.
It’s extremely hard to diagnose a serotonin imbalance in the brain because there’s no way to accurately test the amount. Blood serotonin levels don’t necessarily reflect the levels in your brain. It also has to be remembered that serum serotonin and 5-HIAA are not absolute tests, they are simply indicators of a potential problem.
I intentionally did not mention the other common test (Chromogranin A) or other markers as although there can sometimes be a correlation and rises and falls, they are measuring different things, but you can read about in my Testing for Markers blog.
Read more about 5HIAA by clicking here or on the picture below.
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 and as most assumptions made in groups are misplaced, I wrote a totally separate article here focussed on brain serotonin. See “Serotonin – it’s a no-brainer!“
Summary
I did say it was a difficult jigsaw!
Disclaimer
I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.
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Ronny, Have been on Somatuline gel since 1993. ( first three times/day then long acting release) Have only just found your info. Any other long term users? M Roberts
Yes thousands of people!
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.
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
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!
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.
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!
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..
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
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.
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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.
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.
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Great question and a technical one. I have not seen any pre 5HIAA test instructions saying to preclude them. Going slightly technical, brain and peripheral stores of serotonin are maintained within their own areas and do not cross into each other, the blood brain barrier prevents this. https://ronnyallan.com/2016/09/08/serotonin-the-net-effect/
One of your best, Ronny. Thank you
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?
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.
I have read that excess serotonin can also cause agitation. I immediately calmed down when my tumors were removed. Lanreotide is helping also
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.
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.
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.