Serotonin syndrome occurs from a combination of drugs, supplements or herbs 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 about the causes, symptoms, and treatment.
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 [1].
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) [2].
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 [2].
Symptoms
Warning: serotonin syndrome is a potentially fatal condition and requires urgent medical treatment. If you’ve used psychoactive drugs/herbs/supplements and noticed any of the symptoms described below, seek medical help ASAP.
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 [2].
Too much serotonin in the brain can cause [2]:
- Confusion
- Agitation
- Increased sensitivity to stimuli (hypervigilance)
- Restlessness
- Anxiety
- Fever
The effects on the heart and blood vessels include [2]:
- Rapid heart rate
- Blood pressure spikes
By acting on the gut, excessive serotonin can lead to [2]:
- Diarrhea
- Nausea
- Vomiting
It can also cause [2]:
- Excessive sweating
- Muscle spasms or an increased muscle tone
- Pupil dilation
- Shivering
- Tremor (rhythmic shaking)
Life-threatening symptoms include [2] :
- Delirium
- Metabolic acidosis
- Rhabdomyolysis (the breakdown 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 [2].
How Long Does It 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 [2, 3, 4].
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 [4].
Serotonin Syndrome Causes
Interactions between multiple drugs and supplements that impact serotonin levels are the most common cause of serotonin syndrome. Make sure to consult your doctor and let them know about all drugs and supplements you are using or considering.
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) Antidepressants 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.
Antidepressants and anti-anxiety drugs most frequently implicated in serotonin syndrome include [5]:
- 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 [2, 6]:
- Selegiline
- Bifemelane
- Moclobemide
- Pirlindole (Pirazidol)
- Toloxatone (Humoryl)
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 [7, 8, 9, 10, 11].
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 [12, 13, 14, 15, 16].
They include:
- Almotriptan (Axert)
- Naratriptan (Amerge)
- 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 [17, 18, 5].
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 [24, 25, 5].
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) [26, 27, 28].
8) 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 [29, 3].
Any nausea medication that interacts with serotonin receptors can increase the risk of serotonin syndrome. Examples include:
- Granisetron (Kytril, Sancuso)
- Ondansetron (Zofran) [30]
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) [31, 32].
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 drugs inhibit CYP 450 enzymes and may lead to serotonin syndrome when taken in combination with SSRIs [33, 34, 35].
Examples include:
- HIV medications: ritonavir [36]
- Drugs for yeast infections: fluconazole [37]
- Antibiotics: ciprofloxacin [38]
For example, a 46-year-old HIV patient suffered serotonin syndrome after using a combination of drugs that increase serotonin (antidepressants) and a drug that blocks CYP3A4 (anti-HIV): escitalopram, ritonavir, and esomeprazole [36, 39].
11) Allergy Medications
In one case study, a patient got serotonin syndrome after taking tramadol for neck pain in combination with diphenhydramine for seasonal allergies [40].
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 [41, 42, 43, 44, 45].
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 [46].
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 [47].
2) LSD
LSD strongly activates serotonin receptors. It can raise serotonin to unsafe levels, especially when used in combination with other drugs and antidepressants [48, 49, 50, 25].
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 [51, 52].
Herbs and Supplements
1) St. John’s Wort
St. John’s Wort is an herbal medicine that has been used to help with depression for centuries, with clinically proven efficacy. However, St. John’s Wort can interact negatively with many medications, including SSRIs, and these combinations may cause serotonin syndrome [53, 54, 55, 56, 57, 5].
2) S-Adenosyl-L-Methionine (SAM-e)
SAMe improved depressive symptoms in several trials, and also in patients that were not responsive to traditional SSRI’s. SAM-e can significantly raise serotonin production, so it may, in theory, pose a risk for serotonin syndrome if taken at a high dose or in combination with other drugs [58, 59, 60, 61, 62].
3) Ginseng
Ginseng has been shown in clinical trials to lower depression in menopausal women. It 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 [63, 64, 65, 66, 67].
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 potential risk of serotonin syndrome [68].
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 in combination with serotonergic drugs.
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 [69, 70, 71, 72].
2) Saffron
Saffron reduced depression in patients in several clinical trials similar to taking SSRIs. Studies in rats suggest that saffron interacts with the serotonin system, so it could potentially influence serotonin syndrome [73, 74, 75, 76, 77, 78].
3) 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 [68].
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 that may contribute to 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 may be more prone to developing serotonin syndrome [79, 80, 81].
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 [82, 81].
Serotonin Syndrome Prevention & Treatment
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 several supplements known to improve mood but do not interact with the serotonin system. These can be safely combined with traditional antidepressant or antianxiety medications.
Examples include but aren’t limited to:
- Omega-3/fish oil3 [83, 84, 85, 86, 87, 88, 89].
- Vitamin D [90, 91, 92, 93, 94, 95].
- Kava [96, 97, 98, 99, 100].
- Magnesium [101, 102, 103, 104].
- Theanine [105, 106, 107].
There are also many natural methods that boost moods such as yoga, meditation, sunlight exposure, and exercise.
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 of treating serotonin syndrome is to discontinue the 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 sometimes benzodiazepines [35, 2].
In very severe cases of serotonin syndrome, cyproheptadine, may be administered. Cyproheptadine is traditionally used as an antihistamine but also blocks serotonin receptors [19, 108].
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.
It’s crucial to make the correct diagnosis because the treatments differ – NMS treatment can sometimes include drugs that would worsen serotonin syndrome [109].
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 [109, 110].
