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There is constant discussion about the effects of serotonin-producing tumours and issues of depression, anxiety, and ‘rage’. However, it’s a really complex issue for laypeople and I have no intention of trying to resolve it in this article. However, it’s clear to me from listening and reading these discussions in patient forums for many years, that most of the discussion appears to be based on years of unsubstantiated and unmoderated debate inside patient forums without professional input. This is not an attempt to bash patient leaders and forum administrators, because a full understanding of these issues needs a much wider moderation. I’ve spent a considerable time researching and analysing what science is known and I can tell you now that the behaviour of serotonin in the human body is not entirely tied down. I can also tell you that trying to work this out as a layperson is like walking through treacle but it does need to be explained in layman’s terms if possible. There’s a lot of science behind it and some of this science is not 100% confirmed, and some of it is theoretical based on scientific opinion. This is therefore an opinion post and not the professional input I referred to above.
It’s about Serotonin, right?
What do we know? This is an extract from my original article Serotonin – the NET Effect, which is really focused on Serotonin in relation to Neuroendocrine Tumours (NETs). 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 gastrointestinal tract (gut) serotonin (sometimes known as 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 or normal levels in the brain. It’s also possible to have high serotonin levels manufactured in the brain – that is known as Serotonin Syndrome, which is unrelated to NETs; and will be covered below. Worth noting that serotonin measurements via blood are only measuring gut serotonin. Also, worth noting that serotonin levels fluctuate throughout the day and any blood draw for serotonin is a snapshot. Thus, why measuring the serotonin metabolite 5HIAA is a better test and indication of elevated serotonin levels in the gut.
How Serotonin is made
Serotonin is not something in food (as some sites wrongly claim (including some NET sites)), it is manufactured in the body, mainly from an amine called L-tryptophan which is found in food. In the body it is converted to 5-hydroxytryptophan (5-HTP) before being converted to serotonin (5-HT). My simple way of thinking about such things as outlined above is that low levels of 5-HT (a metabolite of L-Tryptophan) in the brain might be contributing to low levels of serotonin in the brain. But unlike serotonin which cannot pass through the BBB, 5-HTP can, and this is how serotonin is manufactured by converting 5-HTP in the brain. It follows that if you cut off or reduce the flow of L-tryptophan and its metabolites, it can reduce serotonin levels and potentially make you very unhappy. And for those who are now thinking of supplementing brain serotonin levels via 5-HTP supplements, I advise great care, particularly if you are taking anti-depressant medications such as SSRI/SNRI or other serotonergic drugs – see Serotonin Syndrome section below.
Serotonin and Carcinoid Syndrome
Certain types of NETs can produce an excess of serotonin (but also other hormones such as bradykinin, histamine, and prostaglandins). These tumours were once called ‘carcinoid tumours’ but this misnomer has been made obsolete via up-to-date and pragmatic descriptions of Neuroendocrine Neoplasms via the International Agency for Research on Cancer (IARC) publication of Classification of Tumours (WHO Blue Books).
Excess levels of these hormones can sometimes result in a diverse set of symptoms called carcinoid syndrome. When these tumours occur in the digestive tract, the substances they produce are released into a blood vessel that flows directly to the liver (portal vein), where enzymes destroy them. Therefore, tumors that originate in the digestive tract generally do not normally cause symptoms of carcinoid syndrome unless the tumors have spread to the liver. If the tumours have spread to the liver, the liver is unable to process the substances before they begin circulating throughout the body. Depending on which substances are being released by the tumours, the person will have the various symptoms of carcinoid syndrome. Neuroendocrine tumours of the lungs, testes, and ovaries also cause symptoms because the substances they produce bypass the liver and circulate widely in the bloodstream. Given the description above, clearly the over-secretion of serotonin remains within the area of the gut (peripheral) and does not cross into the brain. Although this blog post is essentially about serotonin, it’s worth mentioning that this is only one hormone among many related to several hormonal syndromes related to NETs.
Low Serotonin and depression – correlation and causation
A common statement in NET patient forums goes along the lines of “……. it’s due to all the hormones thrashing around in my body”. That statement in many cases is almost correct. However, it’s based on an incorrect proposition because every single human uses these “hormones” to function, and they are not there just to service NET patients. It follows that these hormones do their job (or not) for every single person in the world including NET patients. The problem of depression, anxiety, anger, mood swings, etc, isn’t just the responsibility of a single hormone.
When you consider the very significant numbers of people taking anti-depressants compared to the total number of NET patients, it becomes clear that many people will succumb to these issues whether they have NETs or not – ergo, very often these emotional effects are unrelated to NETs but rather are related to the normal situations which cause people to succumb to these issues including a cancer diagnosis and follow-on issues related to treatment and prognosis. This whole area of misunderstanding is often due to the incorrect use of the term “carcinoid” and “carcinoid syndrome” to describe the cause of these issues and something that can apply to all NETs (Only around 10% of all NET patients are diagnosed with carcinoid syndrome and many of those will become non-syndromic following treatment).
Many cancer patients (all cancers) suffer from issues of anxiety and depression, but the vast majority of those cancer patients do not have a serotonin-secreting tumour!
For years, some of these issues were thought to be related to low levels of brain serotonin but this has been recently (2022) debunked via a new major study. For those who might be worried by this statement, don’t be, this does not affect the use of anti-depressant drugs (including SSRI/SNRI) which help to improve these issues, they clearly work for many people. It’s just the causal effect rather than the treatment that is being debated.
Peripheral serotonin (mainly in the gut) over-secretion – other potential effects
When NETs make large amounts of serotonin, tryptophan gets used up quicker causing deficiencies in other areas which may have an effect on some NET patients.
1. Vitamin B3 (Niacin). Tryptophan is a precursor of serotonin but also of niacin (vitamin B3). The latter is important for normal cellular metabolism. Extreme niacin deficiency can lead to severe symptoms including pellagra. In terms of surveillance, this is an unmet need and deserves to be included in those patients with highly elevated levels of 5HIAA (a metabolite of serotonin and the gold standard test). One study indicated that serotonin-producing NET patient data on niacin status was scarce. That said, I do see many NET dietitians generating awareness of this issue via NET best practices, advising supplementation where necessary. The aforementioned study concluded that serotonin-producing NET patients’ niacin deficiency was prevalent and advised that urinary N1-MN deserves to be included in their standard biochemical evaluation. Niacin supplementation normalises niacin status in most niacin deficient serotonin-producing NET patients.
2. Brain Serotonin levels. When you consider the logic above, less tryptophan available due to over-secretion of serotonin could lead to less tryptophan available to travel across the BBB to the brain for conversion to serotonin, perhaps contributing to depression and anxiety. This is a highly technical area because there are other interactions involved, for example, it’s known that carbohydrates stimulate the release of insulin, which helps to clear other amino acids from the bloodstream and helps tryptophan reach the brain. Fortunately, the introduction of somatostatin analogues in the last 20 years has for many helped to suppress the levels of serotonin thus reducing the potential for this issue to arise. Technically it should only apply to those with carcinoid syndrome (i.e. from predominately serotonin secreting tumours with evidence of over-secretion) and to invoke the tryptophan/niacin/serotonin issues above, this would need large amounts of serotonin which would mean highly elevated serotonin/5HIAA. So, this is most likely something involving a very small ratio of the NET patient population and not the swathes of all the different types of NETs who claim this is what causes their anxiety and depression and who do not have a predominately serotonin secreting NET, nor do they have highly elevated levels of serotonin/5HIAA. This paragraph also indicates a potential link between diet and low brain serotonin levels. And I repeat something from above: Serotonin measurements via blood are only measuring gut serotonin. Also, worth noting that serotonin levels fluctuate throughout the day and any blood draw for serotonin is a snapshot. Thus, why measuring the serotonin metabolite 5HIAA is a better test as it averages out the fluctuations.
BUT given the edited section above, this commonly given reason for some anxiety/depression/behavioural issues must now be questioned in light of new research suggesting that low levels of brain serotonin are not the cause of anxiety and depression issues. e.g. invented conditions such as so-called ‘carcinoid rage’ must also now be debunked.
Depression and Anxiety – it’s the hormones, right?
The natural assumption for NET patients to suspect over-secreting hormones is understandable. However, it must be remembered that “hormones” (neurotransmitters) can be involved in depression and anxiety but it’s the action of other substances that puts them ‘out of whack’ which often causes the effects. Moreover, it must be recognised that these hormones aren’t there just for NETs to oversecrete, they have a regular job in the human body (gut and brain) for every single human being on the planet. It’s also known there’s a lot of interaction and knock-on effects between the actions of different hormones and neurotransmitters that can also have an effect on levels. It follows that NET patients are capable of getting depression and anxiety issues in the same manner.
There are many emotions that come with cancer. For example, “Cancer anger” is said to be a normal response to fear, despair, and grief – a range of feelings that 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. I know that many people with cancer suffer from depression, anxiety, and anger but they do not have serotonin-producing tumours. What they do have is a life-threatening and/or life-changing condition that is bound to have an effect on the mind as well as the body. Hormones including serotonin are natural substances found in the body. It follows that the anger some NET patients claim is related to NETs is the same anger described above.
I indicated above that the prevalence of people prescribed anti-depressants for different types of depression and anxiety has a significantly higher prevalence than those with a NET and I see this in patient forums. Many ask about a connection between taking these medications alongside treatment for NET including any impact on their hormone levels due to a syndrome. These are always difficult questions that are best left to their doctors. I guess people have noticed the word ‘serotonin’ in the main anti-depressant type called ‘Selective serotonin reuptake inhibitors (SSRIs)’. It’s thought that SSRIs work by increasing serotonin levels in the brain (but see NEW EDIT section above) because serotonin is thought to have a good influence on mood, emotion, and sleep. Serotonin is usually reabsorbed by the nerve cells (known as “reuptake”) and so SSRIs work by blocking (“inhibiting”) reuptake, meaning more serotonin is available to pass further messages between nearby nerve cells. So, tryptophan or peripheral serotonin (serotonin not stored in the brain) are not really involved in the workings of SSRI and anti-depressant drugs with a similar method of action.
It’s also 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 to normal (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. And as I included above, new research debunks the long-standing theory that low levels of serotonin in the brain cause anxiety and depression.
To summarise, the anti-depressant paragraph above has nothing to do with NETs – this is a clinical condition significantly more prevalent than NETs. NET patients are able to be diagnosed with this issue in the same way as others without NETs and some will possibly ‘chug along’ thinking it’s part of NETs because of the lack of knowledge about how serotonin in the brain operates separately from gut serotonin. It’s also worth mentioning the issue of having too much serotonin in the brain, a dangerous condition known as Serotonin Syndrome (see below), again nothing to do with NETs but the symptoms and signs may be similar to carcinoid syndrome (and other NET syndromes) but are in fact a totally different causal effect. I cover that below as too much serotonin in the brain can have severe side effects and some patients may confuse that with various NET syndromes.
What a shame the name of this medical condition has been taken – this would have been a great replacement for the archaic 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 to 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 are 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.
- Certain other antidepressants.
- Migraine medications (triptan category), these include, almotriptan (Axert), naratriptan (Amerge), sumatriptan (Imitrex).
- Illegal drugs can also have some effects, these include: LSD, ecstasy (MDMA), cocaine and amphetamines.
- Herbals supplements have been associated, including St. Johns wort and ginseng.
- Illicit drugs, including LSD, Ecstasy, cocaine and amphetamines.
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.
This study here confirms the risk of antidepressants in NET patients is low but concludes that doctors should watch for any worsening of symptoms to those prescribed. Read more here.
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 take 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.
Read more about Serotonin Syndrome from Mayo Clinic click here.
Remember, I am NOT telling you to stop taking anti-depressants or other anxiety-related meds.
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.
Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional.
Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.
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