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. 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 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 system. The two systems interface thus the term “Neuroendocrine“. Consequently, I’ll keep this as basic as I can (author’s note on completion – it was not easy!).
One more issue that I frequently see is the assumption that all Neuroendocrine Cancers are hormonal via Serotonin which is patently not correct. 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’. However, the misuse of the term by doctors, advocate organisations and patients, spreads the myth that anyone with Neuroendocrine Cancer has carcinoid syndrome and/or oversecretes serotonin, leading to unnecessary testing and potentially unnecessary treatment. This adds somewhat to the issue I intend to cover below.
Serotonin and NETs
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 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. However, it 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! Tryptophan cannot be manufactured in the body, it must be brought in via diet. 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 but it’s also involved in generating melatonin, and vitamin B6 (nicotinamide). Additionally, a small amount of Tryptophan is converted to B3 (Niacin) – the importance of this will be described later. Changes in the level of serotonin in the brain can alter mood. Melatonin is important for sleep and vitamin B6 is essential for energy metabolism
While serotonin cannot cross the blood-brain barrier, tryptophan 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. Just to emphasise that NET dietitians do not say to avoid foods containing tryptophan other than at the time of marker testing (see below andnutrition Blog 4). 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 (see Serotonin and the Brain section below).
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).
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. 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 TPH which will disrupt the manufacturing of tumour-derived serotonin. Read about Telotristat Ethyl (XERMELO)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 and some big assumptions are being made fuelled by ‘patient forum speculation”. Unfortunately badly moderated patient groups allow these assumptions to go unchallenged and hence they turn into myths. The issue with depression anxiety and rage in human beings has an overlap with low levels of serotonin in the brain but the assumption in Neuroendocrine Cancer that “it’s the hormones” causing it is an obvious one to make but far from logical. Why? Because any human being can have these issues and of course hormones are involved. It follows that people with Neuroendocrine Cancer can also succumb to these mental conditions in the same way.
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. Serotonin is separately manufactured in the brain (5-10%) and in the gastrointestinal tract (90-95%). The serotonin in the brain must be manufactured in the brain, 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 (a precursor to serotonin) in the brain might be contributing to low levels of serotonin in the brain. This can happen to anyone. To clarify that, I researched the reasons why there could be low serotonin in the brain. We already discussed that serotonin is thought to have a good influence on mood, emotion and sleep.
Antidepressants can boost serotonin in the brain?
It’s thought that antidepressants such as Serotonin SSRIs work by increasing serotonin levels in the brain, the word “thought” is used intentionally because scientists don’t really know for sure how they work, they were discovered by accident. Serotonin is a neurotransmitter (a messenger chemical that carries signals between nerve cells in the brain). 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. Another way to explain that is that antidepressants work by interacting with the brain’s neurotransmitter mechanisms. They’re thought to work by increasing the levels of specific neurotransmitters in the brain, usually by preventing them from being broken down and reabsorbed into the neurons, meaning they linger in the synapses longer, causing more activity, so “compensating” for the reduced overall levels. Antidepressants make the remaining neurotransmitters work twice as hard, so overall activity is more “normal”, so to speak.
So tryptophan or peripheral serotonin are not really involved in the workings of Selective Serotonin Reuptake Inhibitors (SSRI) and anti-depressant drugs with similar purposes. It’s also worth confirming that antidepressants such as SSRI do not contain any serotonin or it’s precursors, i.e. they do not work as supplements.
Despite the scientific explanation above, it’s too simplistic to say that depression and related mental health conditions are always caused by low serotonin levels (in the brain), but a rise in serotonin levels (in the brain) is said to be able to improve symptoms and make people more responsive to other types of treatment, such as Cognitive Behaviour Therapy (CBT). It’s a big challenge because there isn’t a general consensus from the scientific world about what actually causes depression and the interaction with antidepressant medication.
It’s also too simplistic to suggest that NET patients get depression and anxiety directly due to all the “hormones” these tumours produce (ergo the assumptions I mentioned above which permeate patient groups unchallenged). Of course hormones (or to be more precise, neurotransmitters) are probably involved in depression and anxiety but these neurotransmitters aren’t there just for NET Patients or just there for NET tumours to oversecrete, they have a significant job in the human body (gut and brain) for every single human being on the planet and things can go wrong for every single human being on the planet, you don’t need a NET for this effect. It’s also known that there’s a lot of interaction and knock on effects between the actions of different hormones and neurotransmitters that can have an effect on levels.
If you are one of the millions of people taking anti-depressants, please see the section below on Serotonin Syndrome.
Tryptophan and Serotonin – the smiling assassins?
It should also be noted that the precursor to serotonin, tryptophan, 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, it cannot be converted to serotonin. which may then cause lower availability of serotonin needed to carry out it’s 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 5HIAA when they are omitted from diet during testing (read more here). See below for some of the dangers 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 B supplement (e.g. B Complex)
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 5HIAA should remain vigilant to the possibilities.
Cancer Emotions – the hormonal effect
There’s an assumption in the NET world that over secreting tumours and their associated syndromes (in particular, serotonin secreting tumours) are responsible for all the hormonal problems encountered by those patients. However, there are many emotions that come with any cancer diagnosis or traumatic experience. For example “Cancer anger” is said to be a normal response to fear, despair and grief – a range of feelings which cancer brings into our lives. This is relevant to ALL cancers It can show as frustration, irritability, emotional withdrawal or aggression. You can feel it whether you have been diagnosed (with any cancer or serious illness) or you are a relative or friend. Cancer anger can happen at any stage of the illness, even years after treatment.
Many people suffer from depression, anxiety and anger but they do not all have serotonin-producing tumours or any other Neuroendocrine Syndrome. In cancer patients, 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. It follows that the anger some NET patients claim is related to NETs is the same anger described above.
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).
5HIAA should not be confused with the less reliable ‘serum serotonin’ which is a different test and can be affected by a number of things including the use of anti-depressants (read here about this – a paid article but I wanted you to see the headline). I know many people also test for raw serotonin but many NET specialists to say it’s a unreliable test given that serotonin levels are really just a ‘snapshot’ at one time and serotonin is known to spike throughout the day. Your doctor will normally request measurement of 5HIAA 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. Urine 5HIAA is preferred because it is more stable and, since it is collected for 24 hours, there is more chance of identifying increased 5HIAA concentrations than excess serotonin that is only released intermittently. The 5HIAA blood version is also snapshot but it’s still reliable because the serotonin has taken time to convert to 5HIAA and so spikes of serotonin have been smoothed out to produce an accurate result.
It’s 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 5HIAA are not absolute tests, they are simply indicators of a potential problem. 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 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.
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. 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.
What a shame the name of this medical condition has been taken – this would have been a great replacement for carcinoid syndrome. However, let me start by saying that Serotonin Syndrome has absolutely nothing to do with Neuroendocrine Cancer or carcinoid syndrome. But I add it here as an add-on to hopefully clear up confusion (and overlap) between the symptoms of carcinoid syndrome and serotonin syndrome.
Serotonin syndrome can occur when you increase the dose of such a drug or add a new drug to your regimen. Certain illicit drugs and dietary supplements also are associated with serotonin syndrome. Serotonin syndrome is a potentially serious negative drug reaction. If you take different prescribed medications together, you may end up with too much serotonin in your body. The types of medication that could lead to serotonin syndrome include those used to treat depression and migraine headaches, and manage pain. Too much serotonin in the brain can cause a variety of mild to severe symptoms. These symptoms can affect the brain, muscles, and other parts of the body.
You may have symptoms within minutes or hours of taking a new medication or increasing the dose of an existing medication. The symptoms may include:
– muscle spasms
– muscle rigidity
– rapid heartbeat, or tachycardia
– high blood pressure
– overactive reflexes, or hyperreflexia
– dilated pupils
In more severe cases, the symptoms may include:
– irregular heartbeat
Examples of drugs and supplements associated with serotonin syndrome include (but not limited to):
Antidepressants such as selective serotonin reuptake inhibitors (SSRIs), e.g. Celexa and Zoloft.
Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as Effexor.
Tricyclic antidepressants, such as nortriptyline and amitriptyline.
Monoamine oxidase inhibitors (MAOIs), such as Nardil and Marplan.
Illegal drugs can also have some effect, these include: LSD, ecstasy (MDMA), cocaine and amphetamines.
Herbals supplements have been associated including St. Johns wort and gingseng.
Illicit drugs, including LSD, Ecstasy, cocaine and amphetamines.Read more of this from Mayo Clinic here.
If you have carcinoid syndrome symptoms and elevated serotonin / 5HIAA levels, always double check with your specialists if you are taking or prescribed any of the above just to be sure there is no conflict. Some of the side effects are spookily similar to many things I see in my private Facebook group.
Remember, Serotonin Syndrome has nothing to do with Neuroendocrine Cancer or Carcinoid Syndrome. I include this section because I looked at the statistics of people prescribed SSRIs. An example from USA – the report from the Centers for Disease Control and Prevention’s National Center for Health Statistics found that 11 percent of Americans over the age of 12 takes an antidepressant, with about 14 percent taking the medication for more than 10 years. It follows that many people with NET will be taking SSRIs regardless of whether they had a NET or not.