Serotonin deficiency is quite common and learning the serotonin deficiency symptoms can give you an idea whether you have a shortage of this neurotransmitter. Let’s explore what is serotonin, its effects on the brain, gut, hormones, the immune system, and how important is treating serotonin deficiency in MS.
Serotonin Protects the Brain Against Inflammation, Degeneration, and May Suppress Autoimmune Response
Serotonin, Mood, and Cognition
3. Serotonin & The Gut/Gut-Brain Axis — The Impact on Gut Microbiome and Its Involvement In Leaky Gut
4. Serotonin Controls Appetite and Sleep-Awake Cycle
5. Serotonin, Other Neurotransmitters, and Hormones
6. Serotonin Deficiency and MS- Could Serotonin Deficiency Be A Secret Cause?
7. How to Increase Serotonin Levels —Naturally or With Meds – Read This Article
Serotonin is best known as the neurotransmitter in the brain that makes you feel happy, playful and self-confident. Plays a key role in mood, memory, sleep, and cognition. The popular SSRI antidepressants specifically target serotonin deficiency, thus helping (to a certain degree) to treat depression. However, the benefits of serotonin go well beyond emotions. It is involved in a wide variety of physiological functions such as eating, sleep, digestive health, hormones, and the immune system.
Let’s see. Do you have some of the following serotonin deficiency symptoms?
Low serotonin mental/emotional symptoms
feeling depressed or angry for no reason
winter blues /low moods associated with lack of sunlight
loss of enjoyment in favorite activities, hobbies, relationships, foods, or life in general
feeling less confident
feeling overwhelmed with ideas to manage
feeling dependent on others
less calm, less focused
more worried than usual
unable to feel in the here and now
troubles getting a restful, deep sleep (sometimes night sweats); night owl tendencies, sleepy in the morning
desire to spend more time alone
more sensitive
Obsessive (often negative) thoughts or OCD
craving carbs and/or salt
b) Low serotonin physical symptoms
digestive: diarrhea or constipation, SIBO/IBS; nausea, weight gain, difficulty swallowing, dry mouth
neurological: migraines or headaches, blurred vision, tingling, “pins and needle” sensation, dizziness, tremor
cardio-vascular: palpitations, changes in blood pressure, increased heart rate
genitourinary : low sex drive, premature ejaculations (men), premature orgasm (women), PMS , excessive bleeding during menses, PMS
allergies
muscle and joint pains
Notes: not all symptoms must be present in a case of serotonin deficiency; These symptoms can result from serotonin deficiency or a breakdown in the serotonin transmission pathways (aka serotonergic system). Other conditions may cause some of these symptoms.
Excess serotonin symptoms
Too much serotonin is not good either. It can happen after using SSRI antidepressants for a long time. Taking estrogen pills (ie oral contraceptives) can also raise the activity of serotonin receptors and the amounts of serotonin in the brain. Symptoms of serotonin excess (mild forms) include shyness, feeling nervous, very sensitive to criticism or fear of being disliked.
Severe cases of serotonin excess are seen in serotonin syndrome, which can develop when two or more drugs are combined (for example antidepressant plus migraine medication), or when there are other changes in the treatment plan (a new drug that interferes with serotonin or increased dosage of old meds)
Serotonin syndrome can be life threatening and symptoms include: confusion, agitation, dilated pupils, headaches, abnormal changes in blood pressure and/or temperature, heavy sweating, shivering, rapid heart rate, digestive symptoms such as nausea, vomiting and diarrhea and loss of muscle coordination. Symptoms like high fever, unconsciousness, irregular heartbeats and seizure require medical attention asap.
Serotonin is made from the amino acid tryptophan
Tryptophan → 5 HTP→ Serotonin (5 HT) → Melatonin
Technical: 5-HT is synthesized from L-tryptophan in two steps which are catalyzed by tryptophan hydroxylase (TPH). TPH regulates 5-HT in the CNS and the peripheral tissues. Cofactors: making L-Try into 5HTP depends on iron, riboflavin, and vitamin B6. Folate is needed to make 5HTP into 5HT.
There are 14 serotonin receptors identified, each one having specific roles and actions. Some receptors work synergistically, while others have opposite effects in the body’s tissues, therefore I will discuss the effects of serotonin in general.
Serotonin receptors are found in the central nervous system, but as well as the heart, blood vessels, musculoskeletal and endocrine systems. Serotonin will, therefore, act on all these tissues.
Technical: Serotonin is produced by the CNS and regulates cognitive and endocrine functions, stress reactivity, circadian rhythm, and sleep. Outside the CNS, serotonin is present in platelets, lymphocytes, monocytes, macrophages, mast cells, pulmonary neuroendocrine cells, enterochromaffin cells of the gut, and in some other cell types. There are 14 serotonin receptors identified so far [1]. Serotonin-1A and 2A subtypes play a key role in the regulation of serotonergic neurotransmission, emotions, and behavior. These two receptors are also expressed on immune cells and receptor activation seems to be both immunostimulatory and suppressive [2].
2A. Serotonin Protects the Brain Against Inflammation, Degeneration, and May Suppress Autoimmune Response
Serotonin plays a critical role in the function of the central nervous system. During the early stage of brain development, this neurotransmitter acts as a growth factor, having a huge impact on brain structure. Serotonin interacts with brain BDNF (which is important for creating new neurons) and works closely with other neurotransmitters (ie GABA, glutamate and dopamine) [3]. Serotonin deficiency has been directly implicated in depression, brain degeneration and inflammation [4], which explains why these problems often coexist (although other neurotransmitters and factors are involved in the development of depression, neuroinflammation, and neurodegeneration)
Some studies suggest that serotonin may also suppress autoimmunity, and treatment with SSRI have a neuroprotective role in MS [5]. Serotonin is seen as a mediator of bidirectional interactions between the nervous system and the immune system[6].
2B. Serotonin, The Mood and Cognition
Serotonin has antidepressants qualities, There are many receptors for serotonin in the frontal lobe, which is strongly affected in depression. Serotonin is not the only neurotransmitter involved in depression but is certainly an important one.
Low tryptophan (the precursor of serotonin) levels are associated with increased irritability and aggressive behavior, while supplementation with tryptophan is useful for managing mild to moderate depression [7]. Low serotonin levels also correlate with increased risk of suicide [8]. Research studies found that boosting serotonin has a positive impact on self-direction (feeling more responsible versus blaming, increased feeling of purpose and being resourceful), being more cooperative, more sociable and less likely to argue [9].
Depression linked with serotonin deficiency occurs for no reason, out of the blue. A person with serotonin deficiency simply can’t enjoy life, food, hobbies, relationships anymore. Depression and other serotonin deficiency symptoms can also have a seasonal pattern. The symptoms aggravate when there is lack of sunlight because sunlight stimulates the synthesis of serotonin [10].
Depressed moods from dopamine deficiency derive from lack of motivation to do enjoyable things. If a person with dopamine deficiency would get motivated enough to go to a party, he/she would enjoy it. Someone with serotonin deficiency would go to that party, but unable to enjoy it as before.
Serotonin plays a key role in cognition. Receptors are found in brain regions involved in learning and memory (ie cortex, amygdala, and hippocampus)
Technical: 5-HT2A/2C or 5-HT4 agonists or 5-HT1A or 5HT3 and 5-HT1B antagonists prevents memory impairment and promotes learning in situations involving a high cognitive demand. Receptor antagonists for 5-HT2A/2C and 5-HT4 or agonists for 5-HT1A or 5-HT3 and 5-HT1B generally have opposite effects [11].
Serotonin pathway dysfunctions area also linked with OCD[12].
Serotonin And The Gut/ Gut-Brain Axis
The gut, not the brain — is the biggest producer of serotonin. It is estimated that 90-95 percent of the body’s serotonin is made in the digestive tract, playing a key role in the physiology of the gut (motor and secretory function, as well as pain sensation). The most important serotonin receptors in these processes are 5HT3 and 5HT4.
Immune cells regulate serotonin production. Inflammation of the gut is associated with an increased number of immune cells and impairments in the serotonin-producing cells (in the gut these cells are called enterochromaffin cells), and low serotonin levels in the gut.
An abnormal number of enterochromaffin cells and serotonin deficiencies are seen in inflammatory bowel disease (IBD) as well as in IBS [13].
Serotonin deficiency can be a big issue in MS and virtually all autoimmune diseases. Autoimmune diseases are strongly associated with altered gut microbiome and increased intestinal permeability (aka leaky gut). Both can be improved by correcting serotonin deficiency, as the serotonergic system is under the influence of the gut flora (microbiome) and also regulates intestinal permeability. Supplementation with 5-HTP was found to decrease intestinal permeability [14].
Serotonin is a neurotransmitter and hormone. In the gut, it acts as a neurotransmitter in the enteric nervous system (just like in CNS). As a hormone, serotonin links the brain with the gut and has effects throughout the body, with an impact on bone density and metabolism.
Technical : differences CNS vs Gut: The peripheral endocrine synthesis pathway is different from the central and enteric neuronal pathways by the utilization of tryptophan hydroxylase type 1 instead of type 2 The breakdown of serotonin is via monoamine oxidase and aldehyde dehydrogenase to 5HIAA (similar to CNS), while in the periphery glucuronidation also plays a key role [15],[16].
More details about the relationship between serotonin and gut microbiome
How the gut microbiome establishes early in life and changes as we age has an impact on the metabolism of tryptophan, and therefore on the serotonin pathways. There should be a balance between the use of tryptophan by gut flora and the tryptophan needed for serotonin production in CNS and enteric system. Gut flora regulates the serotonin levels mainly by the kynurenine pathway. For more details, this is a great study to read [17].
Serotonin Controls Appetite and Sleep-Awake Cycle
Serotonin reduces the appetite because improves the sensation of satiety (mechanism of action: influences the taste, the quality of food and the function of the stomach)[18]. Boosting serotonin leads to decrease consumption of carbs and increase intake of proteins [19]. Drugs that target serotonin receptors (5-HT(1B) and 5-HT(2C) receptors) are used for appetite control in treating obesity [20]. Drugs that target serotonin receptors 5-HT4 (Selective 5-HT4 agonists) can help manage constipation associated with IBS and 5-HT3 antagonists can help treat IBS associated with diarrhea.
Serotonin improves the circadian rhythm: It works as the opposite of melatonin. 5HTP is the precursor of melatonin. Tryptophan improves the quality of sleep and improves morning alertness. When tryptophan is suddenly depleted, there are REM changes seen (inhibition of REM latency and prolonged REM sleep). Depression is well-known associated with poor sleep, and antidepressants aggravate this condition (the drugs increase the sleep time, but significantly decrease the quality of deep, healthy sleep) [21]. Serotonin precursor 5 HTP can be helpful to treat sleep apnea.
Serotonin, Other Neurotransmitters, and Hormones
Serotonin works closely with estrogen. Low levels of estrogen can decrease the activity of serotonin receptors and create serotonin deficiency. The opposite is also true- taking oral contraceptives and hormone replacement therapy during menopause can cause excess serotonin — in these cases, would be a good idea to supplement with SAMe, B12 and MSM since estrogen depletes these nutrients which are needed for serotonin synthesis.
Testosterone modulates the serotonin pathways, low testosterone being associated with serotonin deficiency. A different combination: high testosterone and low serotonin levels in the brain appear to be a key component in the development of aggression [22]. Low thyroid hormones correlate with low serotonin levels. Supplementing with 5HTP (in cases of healthy thyroid) leads to increased serotonin levels [23]
Cortisol and other stress hormones cause serotonin (and dopamine) deficiency, especially during chronic stress. Serotonin activates the HPA axis via serotonin 2C receptor stimulation [24]
Serotonin works closely with other neurotransmitters. This is just an example of how they share similar effects and actions. Serotonin, along with norepi and acetylcholine modulate synaptic plasticity [25]. Serotonin also influences the levels of glutamate, GABA, and histamine [26].
Serotonin Deficiency Associated with MS And Its Impact On MS Progression
Serotonin deficiency is often seen in MS. Why? Of course, I wanted to understand why is this happening. There is no short answer, as I found several factors involved, for example:
Living at high latitude areas in the first two decades of life (a well-known risk factor to develop MS) correlates with serotonin deficiency due to lower levels of tryptophan. Remember that serotonin production is sensitive to sunlight, and serotonin is also produced in the skin. Myelin damage had been found in diseases associated with 5-HTP deficiency [27].
Serotonin pathways malfunction — for example problems with SERT (serotonin transporter) are found in MS [28], but also other conditions like IBD and IBS [29]. SERT is responsible for the reuptake of serotonin from the synaptic space. If reuptake is blocked, the cells can’t inactivate serotonin.
Not enough amounts of serotonin precursors (ie tryptophan) convert to serotonin; tryptophan gets used to create kynurenines instead of serotonin; creates a deficit in serotonin, but also more oxidative stress, excessive levels of glutamate in the brain (which is neurotoxic), along with anxiety and depression
Explanations: tryptophan follows a second pathway- called the kynurenine pathway :
Tryptophan → 5 HTP→ Serotonin (5 HT) → Melatonin
Tryptophan –> Kynurenine
More details of the kynurenine pathway here [30].The kynurenine pathway (KP) is involved in MS and other neuroinflammatory/neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and brain tumors. Some compounds (metabolites) of KP are neurotoxic, while others are protective. Overall, the kynurenine pathway seems to malfunction in MS [31]
Recent studies suggesting that abnormalities in the KP pathway are associated with the switch from early mild stages to debilitating progressive forms of MS. Furthermore, some metabolites of this pathway (ie. kynurenic acid, quinolinic acid) could be used as markers of disease progression [32].
Several other factors that have an important impact on serotonin levels — for example, abnormal metabolism of sugar (works both ways: imbalanced sugar levels create serotonin deficiencies, and serotonin has an important influence on insulin [33]. Inflammation, stress, hormones (ie estrogen, stress hormones cortisol and or adrenaline, thyroid hormones) [34], [35], and altered gut flora
When it comes to serotonin levels, there is a concern that a low carb diet can cause serotonin deficiency (High-glycaemic index and -glycemic load meals increase the availability of tryptophan [36]. There are even “serotonin diets” that claim to boost serotonin with a high carb low-fat foods. (I am wondering it is acknowledged that glucose increases tryptophan absorption, but fructose has the opposite effect). I believe the body (and serotonin levels) can adjust to a low carb diet without causing a serotonin deficiency. That is because a low carb diet stabilizes blood sugar levels and inflammation, both having a positive impact on serotonin. Some may need low doses of serotonin precursor 5 HTP (short term) when switching to low carb diets.
Some scientists suggest that neurological deficit in MS may be more likely due to serotonin deficiency and not the actual brain lesions. Why? A number of studies found dramatic and quick improvement of symptoms following magnet therapy (PEMF), and they think the benefits of PEMF derive from improving serotonin levels (as myelin repair can’t be achieved within a few days). There are different PEMF devices but the one that appears to be the most beneficial (and boost serotonin) use a weak magnetic field in the picotesla range.
One research paper describes a 64 years old lady with MS who suffered from weakness, gait impairment, problems swallowing, vision problems, cognitive issues, and fatigue. Two 30 minute treatment with PEMF in picotesla range lead to marked improvement: within 48 hours she no longer needed walker, and complete resolution of double vision, bladder problems, fatigue, while mood and cognition also improved [37]. More studies showed the benefits of magnetic therapy for MS here [38], [39], [40], [41].
Dr. Sandyk, M.D., M.Sc., the author of these studies suggests a close relationship between MS and the calcification of the pineal gland (this gland contains the largest amounts of serotonin). He found that 100% of people with MS have pineal calcifications, further suggesting that the MS symptoms are directly associated with serotonin deficiency. Based on his clinical experience, 60-70% of his patients with MS show marked improvement.
To me, it looks that the benefits of PEMF go way beyond a serotonin boost, as it can directly impact (decrease) proinflammatory markers, improve blood flow to the brain, promote cellular repair and much more [42]. PEMF can be a very powerful tool, and regular use can promote the formation of new brain cells (neurogenesis, in the hippocampus) [43]. The serotonergic system is affected in MS in certain areas of the brain (limbic and paralimbic regions as well as in the frontal cortex), which could (partially) explain mental-emotional symptoms seen in MS [44].
A 2008 double-blind placebo-controlled study conducted in 40 patients with MS found that improving serotonin levels with the SSRI drug fluoxetine for 24 weeks reduced the risk of new MRI lesions- more than 60% of the participants who took fluoxetine had no new lesions were only 26% of the placebo group had no new lesions. I really enjoyed the other comments from the authors: they suggest to increase serotonin naturally (with diet, spending time in direct sunlight, supplementation with nutrients that promote the production of serotonin biotin, magnesium, vitamins B-1, B-3, B-6, and B-12) [45], [46].
Serotonin as a mediator of gut-brain axis was researched for many conditions, and also specifically for MS. The conclusion: Gut microbiome influences the serotonin (and GABA and dopa) levels in the gut as well as the serotonin in the brain. Furthermore, drugs that improve serotonin levels appear to be beneficial and improve the course of the disease, in addition to having antidepressant qualities [47]. Digestive problems such as constipation, indigestion, and IBS are frequently associated with MS [48]. These digestive problems can also be due to serotonin deficiency in the gut [49], [50] -one more reason to correct a shortage of this neurotransmitter.
Overactive bladder is experienced by as many as 75% of people with MS, and again- serotonin pathways (in the brain) seem to be involved [51].
The “serotonin hypothesis” of clinical depression is currently debated. Some scientists suggest that serotonin is not as important for mood as previously thought [52]
It looks that we are going here from one extreme to another. Maybe serotonin is not as important as we thought, but we can’t ignore the benefits of healthy levels of serotonin. I think serotonin plays a key role in depression, but serotonin should be considered relative to the other key neurotransmitters (because the neurotransmitters should be in balance). Other factors such as nutrient deficiencies, gut health, hormones, metabolism, and inflammation should also be considered as they are all linked with depression.
Studies show that SSRI antidepressants can help manage depression associated with MS, and can favorably modulate the immune system in MS -decrease the inflammation [53],[54], decrease fatigue associated with MS [56], and lower the risk of stress-related relapses in MS [57].
Drugs that increase serotonin and norepinephrine can help treat neuropathic pain (tingling and numbness) [58].
