Serotonin syndrome occurs from a combination of drugs, supplements or foods that increase serotonin to unsafe levels. It can result in confusion, fever, involuntary muscle spasms, seizures or even death. Although somewhat rare, serotonin syndrome is a serious medical condition and anyone consuming products that alter serotonin levels should be aware of the symptoms. Read on to learn more.

What Is Serotonin Syndrome?

Serotonin is an important chemical found in the brain and other parts of the body. Serotonin helps to transmit messages that regulate bodily functions such as behavior, mood, body temperature, digestion, blood flow and breathing. Many antidepressants work by altering the levels of serotonin in the brain [R].

Serotonin syndrome occurs when someone has too much serotonin in their system –– either from an overdose of one drug or as a result of combining multiple drugs that increase serotonin levels. This can be extremely dangerous and result in many serious complications ranging from mild (confusion, diarrhea, shivering) to severe (delirium, seizures, comas) [R].

Although some people may be more susceptible to serotonin syndrome and the severity may vary, anyone with elevated levels of serotonin will experience symptoms. Even one dose of a serotonin-altering drug can result in serotonin syndrome [R].

Serotonin Syndrome Symptoms

Since serotonin activates many receptors throughout the body, an excess of it in the bloodstream can have a wide range of effects. These vary from mild to life-threatening[R].

Too much serotonin in the brain can cause [R]:

  • Confusion
  • Agitation
  • Increased sensitivity to stimuli (hypervigilance)
  • Restlessness
  • Anxiety
  • Fever

The effects on the heart and blood vessels include [R]:

By acting on the gut, excessive serotonin can lead to [R]:

It can also cause [R]:

  • Excessive sweating
  • Muscle spasms or an increased muscle tone
  • Pupil dilation
  • Shivering
  • Tremor (rhythmic shaking)

Life-threatening symptoms include [R] :

  • Delirium
  • Metabolic acidosis
  • Rhabdomyolysis (break down of muscle tissue that releases a toxic protein)
  • Very high body temperature (over 41 C)
  • Coma

The most indicative symptoms of serotonin syndrome can be repetitive, involuntary muscle contractions  [R].

How Long Does Serotonin Syndrome Last?

Symptoms generally begin 6-8 hours after taking medication that changes the levels of serotonin in the body and comes on quite intensely. If treated properly, mild symptoms generally disappear within 24-72 hours, but it can last up to 3 days. More severe cases require hospitalization and may take longer to recover [R, R, R].

Serotonin Syndrome Long-Term Effects

The duration of serotonin syndrome symptoms is completely dependent on how long the offending drug stays in your system. There are generally no long-term effects once it’s properly treated. However, if left untreated, severe serotonin syndrome can lead to death. After recovery,  it’s important to reassess all current medications to prevent serotonin syndrome from occurring again [R].

Serotonin Syndrome Causes

OTC and Prescription Drugs

OTC and Prescription Drugs

An overdose of a single drug that increases serotonin levels or combining two drugs, even at correct doses, can potentially lead to serotonin syndrome.

1) Anti-Depressants and Anti-Anxiety drugs

Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) are drugs commonly prescribed for depression and anxiety. They work by prolonging the activity of serotonin in the brain (preventing it from being transported out of the synapse).

Antidepressants and anti-anxiety drugs are the most frequently implicated drugs in Serotonin Syndrome and include [R]:

  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluoxetine (Prozac)
  • Paroxetine (Paxil, Pexeva)
  • Sertraline (Zoloft)
  • Vilazodone (Viibryd)
  • Fluvoxamine (Luvox)
  • Venlafaxine (Effexor)
  • Clomipramine (Anafranil)
  • Imipramine (Tofranil)
  • Vortioxetine (Trintellix, Brintellix)
  • Trazadone

2) Monoamine oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) are drugs used to help various mood disorders and Parkinson’s disease. They work by blocking monoamine oxidase, which breaks down several neurotransmitters found in the brain, including serotonin. This results in more serotonin available to act on the brain.

Misuse of MAOIs or combination with other drugs that increase serotonin can lead to serotonin syndrome. These include but are not limited to [R, R]:

  • Selegiline
  • Linezolid
  • Bifemelane
  • Moclobemide
  • Pirlindole (Pirazidol)
  • Toloxatone (Humoryl)

3) Linezolid (Zyvox)

Linezolid is an antibiotic commonly used to treat bacterial infections that are resistant to other antibiotics (such as streptococci, VRE and MRSA). Linezolid can also slightly block the breakdown of serotonin (by blocking MAO).

There are several case reports of serotonin syndrome caused by Linezolid, especially when taken with other drugs that alter serotonin such as SSRIs or other MAOIs [R, R, R, R, R, R].

4) Migraine medications (Triptans)

Triptans are usually the first medication doctors will prescribe to patients with moderate to severe migraines. Triptans also activate serotonin receptors in the brain and present a risk for serotonin syndrome, especially when used in combination with opioids or antidepressants [R, R, R, R, R].

Triptans include:

  • Almotriptan (Axert)
  • Amerge (naratriptan)
  • Rizatriptan (Maxalt)
  • Sumatriptan(Imitrex)
  • Zolmitriptan (Zomig)

5) Opioids

Opioid prescriptions for pain relief and opioid abuse have been on the rise in the U.S. Some opioids prolong serotonin actions (by blocking reuptake), which results in more serotonin in the brain. Opioids can cause serotonin syndrome, especially when combined with other serotonin-altering drugs [R, R, R].

Opioid drugs include, but are not limited to:

6) Buspirone (Buspar)

Buspirone is commonly used to improve anxiety and in combination with other antidepressants for mood disorders. It activates serotonin receptors. Overdose can cause serotonin toxicity on its own or in combination with other antidepressants [R, R, R].

7) Lithium

Lithium has been used for more than 50 years to improve symptoms of bipolar disorder. Lithium increases the sensitivity of the brain to serotonin (via receptors), meaning less serotonin is required for the same effect. Some cases of serotonin syndrome have been reported from the combination of lithium with other drugs (tramadol, amitriptyline, sodium valproate) [R, R, R].

8) Anti-nausea medications

Metoclopramide (Reglan) is commonly used for stomach issues such as heartburn, nausea, vomiting, and indigestion. Two cases have been reported of patients with serotonin syndrome caused by taking a combination of metoclopramide and antidepressants [R, R].

Any nausea medication that interacts with serotonin receptors can put you at risk for serotonin syndrome. Other medications that impact serotonin include:

9) Dextromethorphan

Dextromethorphan is a cough suppressant found in many over-the-counter medications such as Robitussin, Delsym, NyQuil, and Dimetapp. Dextromethorphan can prolong the action of serotonin in the brain (blocks the reuptake).  

In one case report, a 63-year-old depressed woman experienced serotonin syndrome after taking dextromethorphan-promethazine cough syrup for two weeks in combination with the antidepressant, escitalopram (Lexapro) [R, R].

10) CYP inhibitors

Cytochrome P450 enzymes, such as CYP2D6 and CYP3A4 help to break down and remove many drugs, including SSRIs, from the body. By blocking these enzymes, concentrations of SSRIs can dangerously increase. Some HIV drugs (antiretrovirals), antifungals, and antibiotics inhibit CYPP 450 enzymes and may lead to serotonin syndrome when taken in combination with SSRIs [R, R, R].

These include:

  • HIV medications: ritonavir [R]
  • Drugs for yeast infections: fluconazole [R]
  • Antibiotics: ciprofloxacin [R]

11) Allergy medications (diphenhydramine)

In one case study, a patient got serotonin syndrome after taking tramadol for neck pain in combination with diphenhydramine for seasonal allergies [R].

Recreational Drugs

Recreational drugs

1) Ecstasy (MDMA)

Methylenedioxymethamphetamine (MDMA) is the active component in ecstasy or “molly”. MDMA increases serotonin levels in the brain (by blocking reuptake). An overdose of MDMA can cause serotonin syndrome by itself or in combination [R, R, R, R, R].

Methylone is a street drug similar in structure to MDMA that is sometimes sold as “Ecstasy”.  It is also known as “MDMC” or “M1”. There is a case report of lethal serotonin syndrome in a healthy 24-year-old girl after taking “ecstasy” containing methylone [R].

The amount of serotonin in the brain does not always directly correlate to the severity of serotonin syndrome. Severe serotonin syndrome has occurred in people with relatively low serotonin levels. Other factors such as ambient temperature or physical activity may also play an important role [R].

2) LSD

LSD strongly activates serotonin receptors. It can raise serotonin to unsafe levels, especially when used in combination with other drugs and antidepressants [R, R, R, R].

3) Cocaine

Cocaine increases serotonin levels in the brain (blocks reuptake). There are no reports of cocaine causing serotonin syndrome by itself, but the risk increases when combined with other drugs that increase serotonin levels [R, R].

Supplements

Supplements

1) St John’s Wort

St. John’s Wort is an herbal medicine that has been used to help with depression for centuries and has been clinically proven to work better than placebo and as well as prescribed antidepressant drugs. However, St. John’s Wort can interact negatively with many medications, including SSRIs, and may cause serotonin syndrome on its own or in combinations [R, R, R, R, R, R].

2) S-adenosyl-L-methionine (SAMe)

SAMe improved depressive symptoms in several trials, and also in patients that were not responsive to traditional SSR’s (DB-RCT of 73 patients). SAMe can significantly raise serotonin production, so it may pose a risk for serotonin syndrome if taken at a high dose or in combination with other drugs [R, R, R, R, R].  

3) Ginseng

Ginseng has been shown in the clinical trial (DB-RCTs) to lower depression in menopausal women. However, ginseng increases serotonin in the brain (especially in the hippocampus), posing a risk for serotonin syndrome when taken in high quantities or in combination with other drugs that affect serotonin levels [R, R, R, R, R].

4) L-tryptophan

L-tryptophan directly increases the production of serotonin. If taken at too high a dose, or in combination with another drug that increases serotonin levels (such as a monoamine oxidase inhibitor, MAOI), there is a risk of serotonin syndrome [R].

5) Folate

Folate may improve mood and is involved in serotonin production in the brain. Folic acid (synthetic folate) stimulates brain serotonin receptors. While folate supplements may be a  useful natural alternative for depression, they pose a small risk for serotonin syndrome in combination with drugs that raise serotonin levels [R, R, R, R].

Foods

Foods

Serotonin syndrome caused by food is highly unlikely, as the active compounds in these foods are found at relatively low levels when ingested in standard amounts. However, it’s important to be aware of which foods have the potential to increase serotonin levels, especially if consuming large amounts for therapeutic purposes.

1) Turmeric (Curcumin)

Turmeric contains high levels of curcumin, which has been used to improve mood in human patients in clinical trials. In mice, curcumin increases serotonin levels and should be used with caution when taking other drugs that increase serotonin [R, R, R, R].

2) Saffron

Saffron reduced depression in patients in several clinical trials (DB-RCTs) similar to taking SSRIs.  Studies in rats suggest that Saffron interacts with the serotonin system, so it could potentially influence serotonin syndrome [R, R, R, R, R, R].

3) Nutmeg

Nutmeg extract improved depression and anxiety in mice. A study in rats suggests this effect may be due to increasing the levels of serotonin in the hippocampus, a part of the brain that’s connected to emotional regulation. Because Nutmeg can increase serotonin levels, it has the potential to contribute to serotonin syndrome [R, R, R].

4) Tryptophan-rich foods

Foods high in tryptophan should be avoided when at risk for serotonin syndrome as tryptophan directly increases serotonin production. These include turkey, chicken, soy, eggs, pumpkin seeds, peanuts, and some cheeses [R].

5) Folate-rich foods

Because folate may boost serotonin production, folate-rich foods could potentially contribute to serotonin syndrome. These include leafy green vegetables, beans, legumes, nuts, and fortified bread and cereals [R].

Drug Interactions

Cytochrome P450 enzymes are found in the liver and help to break down and remove toxins and drugs from the body. CYP3A4 is one of these enzymes, which metabolizes 45-60% of commonly prescribed drugs, including SSRIs. When SSRIs are taken in combination with another drug that blocks CYP3A4, the level of SSRI in the bloodstream can become dangerously high and possibly lead to serotonin syndrome [R, R].

For example, there is a case study of a 46-year-old HIV patient suffering serotonin syndrome after using a combination of drugs that increase serotonin and drugs that block CYP3A4 (escitalopram, ritonavir, and esomeprazole).  [R, R].

Some drugs that increase serotonin levels also have long half-lives, which means they remain in the body for a very long time. Fluoxetine has been reported to remain in the system for up to 5 weeks after consumption [R].

Serotonin Syndrome Prevention

Being aware of serotonin syndrome and its symptoms is an important first step towards prevention. Even if you have mild symptoms, make sure to monitor them carefully and communicate with your physician. If your current medications are not helping you, consult with your doctor before increasing dosage or combining any medications.  Be sure your doctor is aware of all medications you are currently taking.

There are also several supplements that are known to improve mood but do not interact with the serotonin system. These can be safely combined with traditional antidepressant or antianxiety medications.

Deficient omega-3 levels have been associated with depression and increasing omega-3s improves depressive symptoms in clinical trials. The anti-inflammatory properties of omega-3s are likely responsible for the antidepressant effect. Supplementing with fish oil is an excellent way to help boost omega-3s [R, R, R, R, R, R, R ].

Low levels of Vitamin D are associated with an increased risk for depression and several studies have shown supplementing with Vitamin D improves depressive symptoms by increasing production of dopamine, norepinephrine, and epinephrine (increases tyrosine hydroxylase) [R, R, R, R, R, R].

Kava is an herbal extract that has been shown in clinical trials (RCTs) to improve depression and anxiety and works by strengthening GABA-A signaling (a neurotransmitter that has a calming effect) [R, R, R, R, R].

Magnesium deficiency has been associated with depression and supplementing with magnesium can improve depressive symptoms by reducing the effect of glutamate (blocks NMDA receptor) [R, R, R, R].

L-Theanine is an amino acid found in tea and some fungi. In mouse and human studies (open-label), L-Theanine reduced depressive symptoms [R, R, R, R].

There are also many other natural methods that boost moods such as yoga, meditation, or increased exposure to sunlight.

Serotonin Syndrome Treatment

There are no published clinical trials on the treatment of serotonin syndrome. Most recommendations are based on case studies or epidemiological data.

The most important component to treating serotonin syndrome is to discontinue use of whatever substance caused the episode. Patients with more severe symptoms are also generally admitted to the hospital for supportive care involving IV fluids, monitoring and benzodiazepines are often prescribed.  [R, R].

In very severe cases of serotonin syndrome, Cyproheptadine, may be administered. Cyproheptadine is traditionally used as an antihistamine but also blocks serotonin receptors [R, R].

NMS vs. Serotonin Syndrome

Neuroleptic malignant syndrome (NMS) is another rare, but very serious, adverse reaction to mood-altering drugs. The symptoms of NMS and serotonin syndrome are similar, which can make accurate diagnosis quite challenging. But it’s crucial to make the correct diagnosis because the treatments differ — NMS treatment can sometimes include drugs that would worsen serotonin syndrome [R].

Certain blood tests (creatine kinase levels, liver function, white blood cell count, and iron levels) and specific symptoms such as spasms or involuntary jerking in the legs (lower limb hyperreflexia) can help your doctor to distinguish between the two [R, R].

Limitations and Caveats

Most evidence suggests that supplementing with Vitamin D or Fish Oil (Omega-3s) can be beneficial for depression without affecting serotonin levels. It has been alternatively suggested that omega-3 fatty acids and Vitamin D may help depression by increase serotonin production and action, but there is no evidence that this could trigger serotonin syndrome [R].

Genetic Predispositions

Susceptibility to Serotonin Syndrome can depend largely and how your body processes drugs that increase serotonin. CYP P450 enzymes play a very important role in breaking down and removing drugs from the body. SNPs in CYP enzymes can determine how efficiently your body can process a drug, potentially resulting in dangerously elevated blood concentrations and triggering serotonin syndrome.

CYP2D6 is a detoxing enzyme that clears many tricyclic antidepressants and SSRIs, so it can affect serotonin levels. Over 80 variants of the CYP2D6 gene exist, and 7-10% of the European population has a version that results in a slow metabolism and more of the drug building up. People who carry  “slow” versions of this gene are at higher risk for developing serotonin syndrome [R, R, R].

Other drugs associated with Serotonin Syndrome, such as Sertraline and Norfluoxetine, are broken down by CYP3A4. CYP3A4 also has gene variants that can affect drug processing in the body. The CYP3A4*22 variant, in particular, is associated with decreased enzyme activity, which can raise drug levels and increase the risk of serotonin syndrome [R, R].

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