Serotonin is one of the major neurotransmitters in the brain, and is most well-known for its role in mood. But it is also heavily involved in many other important bodily functions, such as digestion! For this reason, low levels of serotonin – or “serotonin deficiency” as it is sometimes called – has been associated with a wide range of different potential symptoms related to physical and mental well-being. What are these signs, and how are they related to serotonin? Read on to learn more!
What Is Serotonin Deficiency?
Serotonin is synthesized from the amino acid tryptophan by a short metabolic pathway consisting of two enzymes.
In the first step, the “raw material” (metabolic precursor) tryptophan is converted to 5-hydroxytryptophan (also known as 5-HTP) by the enzyme tryptophan hydroxylase.
In the second step, 5-HTP is converted to serotonin (5-HT) by the enzyme aromatic amino acid decarboxylase [1].
Serotonin is produced in the platelets of the blood and cells of the gut, and is then distributed throughout the body to exert its effects.
Serotonin produced outside of the brain cannot directly cross the blood-brain barrier, although tryptophan and 5-HTP can. Therefore, the latter two compounds are what produce serotonin within the brain itself.
Any disruption of these mechanisms or damage to serotonin receptors can lead to a decrease in overall serotonin effects in the body.
When serotonin levels are lower than normal, this is known as “serotonin deficiency”, and can result in a variety of symptoms including impaired body functions and even psychological disorders [2].
You can learn more about serotonin and its effects in this post, whereas in this post we’ll be focusing more on the potential causes and consequences of serotonin deficiency.
Potential Causes
There are a very large number of factors involved in the production and action of serotonin throughout the body and brain, which means that there are a very large number of different factors that can potentially play a role in how much serotonin a person has, or how much of it is available to the different biological systems that rely on it.
So, keeping in mind that this is not a fully exhaustive list, here are a few of the factors that could potentially cause or contribute to low serotonin levels (or reduced serotonin activity):
- Inherited defects that decrease BH4 (tetrahydrobiopterin), a metabolic cofactor required for the production of serotonin [3]
- Mutations in the TPH1 and TPH2 genes, which metabolize tryptophan and are ultimately responsible for the production of serotonin [4]
- Mutations in the SPR gene, which codes for a key enzyme in serotonin production (sepiapterin reductase) [5]
- Mutations in serotonin receptor genes, such as 5HT1A, 5HT1B, and 5HT2c [6]
- Mutations in the serotonin transporter gene (SERT/SLC6A4), which takes serotonin into the cells [7]
- Mutations in the MAOA gene, an enzyme which is responsible for breaking down serotonin and other important neurotransmitters in the brain [7]
Potential Effects of Serotonin Deficiency
1) May Disrupt The Biological Clock
Serotonin is highly involved in helping regulate the body’s “biological clock”, or circadian rhythm – which in turn affects many other bodily functions and cognitive processes. For this reason, abnormal levels of serotonin could theoretically affect the circadian rhythm [8].
For example, some animal studies have reported that depleting serotonin in mice leads to significant disruptions in their circadian rhythm, which in turn can significantly affect their ability to get enough high-quality sleep [8, 9].
Not only may serotonin affect the overall amount of sleep an animal gets, but it can also affect exactly when they sleep. For example, another study reported that serotonin-depleted mice slept more during the day than at night [9]. Once again, this abnormal sleep behavior suggests a disruption in their overall circadian rhythm.
However, much more research will still be needed to figure out exactly how much these initial findings in animals might apply to humans as well.
2) May Affect Sexual Preference
Interestingly, a few animal studies have reported that serotonin deficiencies may have an effect on sexual preference and behavior – at least in mice.
For example, one study reported that when animals were depleted of serotonin (such as by being given drugs, or put on tryptophan-deficient diets), this increased bisexual mating behaviors (male-on-male sex) [10].
Some researchers have proposed that this effect on sexual preference may have to do with a change in the ability of the mice to smell pheromones. The treated serotonin-deficient males still had a sense of smell, but seemed to gravitate toward other male pheromones [10].
In a similar study, female mice with serotonin deficiency were reported to prefer females as sexual partners over males [11].
One study on human males reported that heterosexual and homosexual men exhibit significant differences in neurotransmitter activity, and respond differently to serotonin-increasing drugs [12]. However, the exact mechanisms responsible for these differences remain unclear, so this finding only suggests a possible link that will have to be confirmed by additional research in the future.
The results from some of these early studies might seem to suggest that serotonin levels could be related to sexual preference in humans; however, sexual preference is determined by a very large number of different factors – including many neuronal structures in the brain which are not changeable by altering serotonin – and so it remains unknown to what degree either increasing or decreasing serotonin might affect sexual preferences in the real world.
There are also some other significant limitations to take note of here. For one, we can’t extrapolate findings from animal studies directly to humans, as the underlying mechanisms and biological processes could be very different across different animal species. Secondly, many of these early studies have only been done on animals with extremely severe serotonin depletions; therefore, we also can’t predict with certainty what might happen in other animals or humans who only have a slight or moderate deficiency in serotonin.
3) May Affect the Digestive System
The contraction of muscles in the gut (peristalsis) is what causes food and liquids to move through the digestive tract.
Nearly 95% of serotonin is produced and stored in the gut. A deficiency in serotonin can, therefore, have a potentially significant effect on gut function [13, 14].
When serotonin levels are low, this can alter the magnitude and length of muscle cell signals, as well as decrease the amount of calcium released from cells. This has led some researchers to suggest that serotonin deficiency could interfere with the digestive process, and could even potentially lead to blockages in the digestive tract [15].
For example, low serotonin levels in the gut may be associated with certain gastrointestinal disorders, such as irritable bowel syndrome (IBS) – especially when the symptoms involve constipation or difficulty passing stools [16].
Altered gut flow is also one of the main clinical features of diverticulitis, a condition that has also been potentially linked to lower serotonin levels [13]. Diverticulitis occurs when the bulging sacs that appear in the lining of your large intestine, or colon, get acutely infected or inflamed.
A pilot study of 51 patients reported that patients with diverticulitis had fewer serotonin transporters (SERT) in the gut [16].
While alterations in serotonin do not appear to be responsible for the development of diverticulitis, decreased SERT expression and function might be caused by the inflammation and contribute to some of the symptoms [13].
However, the available data on serotonin’s relationship to digestive health is mixed. For example, patients with celiac disease have been reported to have increased levels of serotonin in the gut [16]. So the underlying relationship between serotonin and digestion may not as straightforward as initially believed.
In any case, much more research will be needed to confirm the above findings, as well as to determine exactly how severe a serotonin deficiency would have to be in order to produce noticeable gastrointestinal effects in the average human.
4) May Affect Blood Clotting
Serotonin plays a major role in blood clotting. This is because serotonin is stored in the blood’s platelets, where it acts as a signal to trigger the clotting process. Thus, a significant decrease in serotonin could theoretically impair blood clotting [2].
For example, certain strains of mice that are chronically deficient in serotonin show excessive bleeding from cuts, which suggests impaired blood-clotting. One study of these mouse strains reported that mutations that significantly decrease the activity of the serotonin transporter gene (SERT) may be responsible for this [17].
Additionally, treating these mice with compounds that increased their blood serotonin levels back into the normal range has been reported to reverse the impaired blood clotting, adding further preliminary evidence that serotonin levels may play a role in blood clotting in general [18].
However, these findings have still only been reported in certain very specific strains of mice, and much more research would be needed to see if these findings have any relevance to humans or other animals.
5) May Affect Immune System Function
Based on preliminary findings from a handful of early animal studies, some researchers have proposed that serotonin deficiency may be associated with suppression of the immune system.
For example, fish with low levels of serotonin were reported to show a significant reduction in their production and multiplication of various different types of immune cells, which may weaken the immune system as a whole [19, 20].
Similar, another animal study reported that mice who were depleted of serotonin showed a decrease in overall immune cell production [21, 22].
However, these early results are based solely on animal studies, so it’s not yet known for certain what the relationship between serotonin and the immune system might be in humans, and more research will be needed to determine this.
6) May Increase Cravings for Salty Foods
Preliminary findings from one animal study suggest that serotonin levels may have some impact on dietary and food preferences. According to one study in mice, serotonin depletion led to increased cravings for sodium, with serotonin-depleted mice ingesting significantly more sodium compared to a control group of mice [23].
One again, however, more research in humans will be needed to confirm this early finding.
7) May be Involved in Anorexia Nervosa
Some psychiatric research suggests that serotonin may be centrally involved in many of the behavioral and psychological symptoms associated with eating disorders, such as anorexia (anorexia nervosa).
However, this relationship is very tricky to study, as diet is one of the main determining factors of serotonin levels in the brain – and eating disorder patients typically have very restricted and limited diets that result in very low intake of the “raw ingredients” (metabolic precursors) that their bodies need in order to actually produce serotonin and other important neurotransmitters. Therefore, it’s hard to know to what extent eating disorder symptoms might be initially caused by low serotonin levels, versus how much of the low serotonin levels seen in eating disorder patients are actually caused by their poor diets, rather than playing a direct role in causing these disorders themselves [24].
However, a few human studies have reported that giving anorexic patients supplements of tryptophan may help partially alleviate their symptoms and disordered eating behaviors. This is at least some preliminary evidence in favor of the idea that serotonin might be causally involved in eating disorders somehow [24].
Nonetheless, much more follow-up research will be needed to better understand the potential relationship between serotonin levels and the development of eating disorders.
8) May Contribute to Migraines
Serotonin appears plays a role in the onset of migraines, although the exact mechanisms are still unknown.
According to some researchers, low serotonin levels in the brain, or underlying deficiencies in tryptophan, may be one of the biological factors that potentially trigger headache attacks in migraine patients [25]. Nonetheless, more research will be needed to explore this potential relationship further.
Potential Negative Effects on the Brain
Some lines of research have also identified a number of potential links between low serotonin levels and various psychiatric disorders and other brain-related functions or conditions.
However, note that none of the information below should ever be used to replace conventional medical treatment! If you ever believe that you might be suffering from some of the symptoms related to the disorders below, make sure to talk to your doctor, who will help officially diagnose any conditions you might have, as well as work with you to determine the best course of treatment for your specific needs and circumstances.
9) May Contribute to Depression
A review of several studies reported that increasing serotonin could help treat depression [26].
Other studies have shown that serotonin deficiency may cause a relapse in patients with depression, but otherwise probably does not affect healthy people [27].
10) May Contribute to Anxiety Disorders
According to some animal studies, activity in serotonin 5HT1A receptors may contribute to anxiety disorders. For example, mice lacking these receptors have been reported to show increased signs of anxiety [28].
11) May Contribute to Stress
One animal study has reported that mice with altered serotonin transporter (SERT) or 5HT1A receptor genes were more susceptible to stress (specifically, stress caused by the presence of predators, such as cats) [29].
The authors of this study have even speculated that this might suggest a link between these serotonin mechanisms and the development of PTSD – however, much more additional research will be needed to fully flesh out this potential connection, and for now, it’s just an interesting theory.
12) May be Involved in ADHD
While ADHD is typically treated with medications that target the dopamine system, there is at least some preliminary evidence that serotonin might play a role as well.
For example, supplementing with tryptophan – the metabolic precursor of serotonin – has been reported to reduce ADHD symptoms. Relatedly, variations in the serotonin 5HT1B receptor gene have been associated with increased susceptibility to ADHD [30, 31].
13) May Contribute to OCD
Some researchers believe that serotonin may be involved in the development of obsessive-compulsive disorder (OCD), although the precise mechanisms behind its potential role in this condition are still unclear.
It has been proposed that serotonin may be specifically related to the “obsessional” symptoms involved in OCD, which serotonin-based drugs could theoretically target and treat. For example, one early study reported that SSRIs alleviated OCD symptoms significantly better than placebo, which may suggest some involvement of serotonin [32]. However, much more research will still be needed to explore this potential connection further, and it’s not possible to come to any firm conclusions yet.
14) May Contribute to Panic Disorder
Panic disorders involve both psychological symptoms (such as feelings of panic or anxiety) as well as physical symptoms (such as increased heart rate).
One preliminary study has reported that SSRIs may have an effect on panic disorder symptoms, specifically by enhancing the brain’s ability to control heart rate and keep it “in check” [33]. However, the research behind this connection is still in a very early stage, and the mechanisms potentially responsible for these effects are still unclear.
15) May Contribute To Social Phobias
Some studies linked serotonin deficiency to social phobia.
One study (DB-RCT) of 77 people diagnosed with social phobia reported that serotonin-increasing drugs significantly improved symptoms related to anxiety, depression and social phobia [34].
Additionally, one meta-analysis concluded that serotonin-increasing drugs may be better for treating social phobia than other common medications, such as benzodiazepines or antipsychotics [35].
However, the evidence is still in an early stage, and serotonin-based medications have not yet replaced these other drugs as the standard form of medical treatment.
16) May Increase Aggression
In addition to its general role in mood, serotonin has also been associated with aggressiveness or aggression-related behaviors in general.
One early animal study has reported that mice with serotonin deficiency, or who are lacking serotonin 5HT1B receptors, both tend to exhibit more aggressive behavior [36, 28].
However, it remains to be seen whether this effect translates to humans as well, so more research will be needed.
17) May Affect Memory
The serotonin transporter (SERT) is believed to be involved in recall and memory by determining the strength of serotonin signals and their interactions with other neurotransmitters [37, 38].
A recent study reported that rats who are deficient in serotonin (due to a lack of one- or both copies of the SERT gene) may have significant memory impairments, while those that were not deficient showed normally-function memory abilities [37].
However, the serotonin system in the human brain is highly complex, and might not respond the same way as a rat’s brain does. Therefore, much more research will be needed to tease out the precise effects of serotonin levels in humans before any strong conclusions can be made about this potential link.
How to Increase Serotonin Levels / Activity
Medical Drugs That Increase Serotonin
One of the drugs that are most well-known for their effects on serotonin levels is selective serotonin reuptake inhibitors (SSRIs). SSRIs are prescription antidepressants that reduce the reuptake of serotonin outside of cells, thus generally increasing serotonin availability throughout the brain [32].
It is important to note that SSRIs are serious medical drugs that can only be legally taken by prescription, and for the direct purpose of treating a specific psychiatric condition. In other words, we are not recommending SSRIs as a practical approach for boosting your own serotonin levels!
(For some “non-pharmaceutical” approaches to increasing serotonin levels, see the Complementary Approaches section, below.)
SSRIs are the “first-line” (official, FDA-approved) medical treatments for a variety of different psychological disorders including depression, social phobia, anxiety, and OCD [39]. Some examples of common SSRI medications include sertraline, fluoxetine, and paroxetine [39].
SSRI medications act primarily on the brain’s serotonin system, and generally do not strongly interact with other major neurotransmitters. The highly selective and targeted mechanisms of SSRIs are believed to be at least one of the main reasons these medications are typically reported to produce relatively fewer side-effects compared to some other common forms of antidepressants [39, 40].
Nonetheless, SSRIs may still have negative side-effects, such as nausea, lowered libido, diarrhea, anxiety, tremors, or loss of bone mass [39, 41].
As always, if you are receiving or seeking treatment for a diagnosis of a depressive disorder, always discuss any treatment options or approaches with a qualified medical practitioner first; only a medical professional has the necessary training to determine which specific medications or other treatments are the most appropriate for you.
Complementary Approaches to Increasing Serotonin
Note: make sure to have a discussion with your doctor before experimenting with any of the complementary strategies discussed in this section. This is important to avoid any potential negative interactions with other medications you’re taking, other pre-existing health conditions, or other lifestyle and dietary factors that may potentially affect your health. Only your doctor has the necessary knowledge and expertise to navigate all these potential concerns, and will work with you to come up with the optimal treatment for any health conditions you may have.
Serotonin levels can be potentially increased in multiple ways. For example, bright light exposure, exercise, and increased tryptophan intake have all been associated with relatively increased serotonin levels [42].
Moreover, carbohydrate intake – acting via insulin secretion – has been reported to lead to increased tryptophan levels, and, therefore, increased serotonin production. Conversely, dietary protein seems to have the opposite effect [43].
Serotonin itself can’t cross the blood-brain barrier and enter the brain to exert many of its effects, whereas tryptophan and 5-HTP can. Therefore, supplementing with 5-HTP and tryptophan may help boost the levels of this neurotransmitter in the brain, specifically.
For a more comprehensive list of the many different “natural” or “complementary” approaches to potentially increasing serotonin levels, check out the detailed SelfDecode post on this topic here.
