Drugs That Increase the Risk of Serotonin Syndrome (2023)

What is the most important information I should know about serotonin medications?

  • Serotonin medications can cause unwanted side effects if more than one serotonergic drug is used simultaneously or if the prescribed dose is exceeded.
  • To avoid this risk, talk to your healthcare provider about all substances, medications, and supplements you are taking, and always take your medicines as prescribed.

Serotonin is a neurotransmitter, a type of chemical messenger. It plays an important role in regulating various body functions and feelings. Neurotransmitters act as communication agents between different brain cells.

There are several different substances, including medications and supplements, that can increase serotonin levels in the brain. Because serotonin levels may impact mood and anxiety levels, serotonin drugs are sometimes prescribed to treat mental health conditions.

While medications may that help balance serotonin levels can help you relieve these symptoms, it is essential to be aware of how these serotonin medications affect the body and how they may interact with other substances.

This article explores some medications that can increase serotonin levels in the brain. It also discusses the potential risks of interactions when taking more than one type of serotonin drug.

This list is not meant to be all-inclusive. To avoid increasing your risk of side effects, including serotonin syndrome, tell your healthcare provider about all drugs and dietary supplements you are taking. If you develop symptoms of serotonin syndrome, seek immediate medical attention.

Serotonin Syndrome: What Happens If You Have Too Much Serotonin?

Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin in the brain. Reuptake is a process in which neurotransmitters in the brain are reabsorbed, deactivated, or recycled for future use.

When serotonin reuptake is inhibited, more serotonin is available in the brain. This leads to an increase of serotonin levels, resulting in improved mood, decreased anxiety, and inhibition of panic.

SSRIs are considered the first-line treatment for conditions such as depression and panic disorder. SSRI medications include:

  • Celexa (citalopram)
  • Lexapro (escitalopram)
  • Luvox (fluvoxamine)
  • Paxil (paroxetine)
  • Prozac (fluoxetine)
  • Trintellix (vortioxetine)
  • Viibryd (vilazodone)
  • Zoloft (sertraline)

SSRIs are approved for the treatment of a variety of mental health conditions, including generalized anxiety disorder (GAD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and social anxiety disorder (SAD).


SSRIs are antidepressant medications that work by blocking the reuptake of the neurotransmitter serotonin. This results in increased serotonin levels in the brain, which can improve mood and reduce anxiety.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

SNRIs inhibit the reabsorption of both serotonin and norepinephrine in the brain. Norepinephrine is a neurotransmitter that influences sleep and alertness. It is believed to be correlated to the fight-or-flight stress response.

Some SNRIs include:

  • Cymbalta (duloxetine)
  • Effexor (venlafaxine)
  • Fetzima (levomilnacipran)
  • Pristiq (desvenlafaxine)
  • Savella (milnacipran)


Triptans are a class of drugs commonly used to treat migraine or cluster headaches. They act on serotonin receptors in the brain, thereby affecting serotonin levels.

Examples of triptans include:

  • Amerge (naratriptan)
  • Axert (almotriptan)
  • Frova (frovatriptan)
  • Imitrex (sumatriptan)
  • Maxalt and Maxalt-MLT (rizatriptan)
  • Relpax (eletriptan)
  • Zomig and Zomig ZMT (zolmitriptan)

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are named after the drugs’ three-ringed molecular structure. Prior to the introduction of SSRIs in the late 1980s, TCAs were the medication of choice for the treatment of major depressive disorder, panic disorder, and other anxiety disorders. TCAs are also used to treat certain pain syndromes and nocturnal enuresis (bedwetting).

It is believed that TCAs function by increasing levels of norepinephrine and serotonin in the brain.

Examples of TCAs include:

  • Elavil (amitriptyline)
  • Tofranil (imipramine)
  • Sinequan (doxepin)
  • Anafranil (clomipramine)

TCAs are used less frequently today in the treatment of depression because they tend to produce more unwanted side effects compared to SSRIs.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are a class of antidepressants believed to increase levels of norepinephrine, serotonin, and dopamine (another neurotransmitter) in the brain. They are effective for the treatment of the major depressive disorder, panic disorder, and other anxiety disorders.

Examples of MAOIs include:

  • Nardil (phenelzine)
  • Parnate (tranylcypromine)
  • Marplan (isocarboxazid)
  • Emsam (selegiline)

Because of potentially dangerous interactions with certain foods, beverages, and other drugs, particularly those that influence serotonin, MAOIs are usually not considered as a first-line treatment for depression.

Other Psychiatric Medications

There are also other psychiatric medications that can influence serotonin levels in the body.

  • BuSpar (buspirone): BuSpar affects the neurotransmitters serotonin and dopamine. It acts as an agonist on serotonin receptors, which means that it increases the actions of these receptors. As a result, this medication can be useful for relieving symptoms of anxiety.
  • Eskalith (lithium): This medication is a mood stabilizer that is used in the treatment of bipolar disorder. It works by restoring the balance of neurotransmitters, including serotonin.
  • Desyrel (trazodone): Desyrel is an antidepressant medication that works by increasing the amount of serotonin available in the body.It also has sedative effects, which is why it is sometimes used to treat insomnia.

Analgesics (Painkillers)

A number of analgesic drugs can also affect serotonin levels in the body. These medications are often used to treat pain, but they are also sometimes misused and can lead to dependence and addiction. Some painkillers that act on serotonin include:

  • Codeine
  • Fentanyl
  • Tramadol

Antibiotic/Antiretroviral Medications

Some antibiotics and antiretroviral medications may also affect serotonin. This can potentially lead to drug interactions when people are taking other medications such as SSRIs or MAOIs. Because of these risks, you should always tell your healthcare provider about other medications, drugs, or supplements you are currently taking.

  • Zyvox (linezolid): Zyvox is an antibiotic that is sometimes prescribed to treat serious bacterial infections. In addition to inhibiting bacterial growth, this medication also affects serotonin. This affect can be more pronounced when Zyvox is combined with other serotonin medications.
  • Norvir (ritonavir): Norvir is an antiviral medication that is used to treat HIV infection. When combined with other medications, it works to slow the progress of the disease.

Herbal Drugs/Dietary Supplements

It is important to be aware that some herbal medicines and dietary supplements can have an effect on serotonin levels.

St. John’s Wort

St. John's wort (hypericum perforatum) is a type of flowering plant that is sometimes used as an herbal remedy, particularly to relieve symptoms of depression. It is also used for other conditions including anxiety, premenstrual syndrome (PMS), menopause symptoms, smoking cessation, and seasonal affective disorder.

Researchers are not entirely sure of exactly how St. John's wort works to elevate mood, but it is believed to increase neurotransmitter levels in the brain, including serotonin.


Ginseng is a root that is often used as an herbal supplement. Purported benefits include improved immunity, energy, and cognition. Ginseng acts on serotonin and other transmitters and also affects hormones, receptors, and signaling molecules.

Research suggests that ginseng is associated with interactions with some psychotropic medications, including SSRI and SNRI antidepressants.

Other Drugs That Affect Serotonin

There are also a number of other substances that can affect serotonin levels in the body.


Amphetamine stimulants are often prescribed to treat attention-deficit hyperactivity disorder (ADHD). These medications can also increase serotonin levels.

While usually not enough to present a risk when taken as prescribed, stimulant medications such as Adderall may increase the risk of serotonin toxicity if they are misused or are combined with other serotonin medications.


Cocaine blocks the reuptake of serotonin. This can be potentially risky if people use cocaine while they are taking antidepressants, triptans, or other medications that also increase serotonin levels.


Lysergic acid diethylamide (LSD) is a hallucinogenic drug that affects thinking and moods. These effects are the result of the impact of the drug on serotonin. The drug binds to certain receptors in the brain and changes how the brain responds to serotonin.

Combining antidepressant medications and LSD has the potential to produce unwanted effects associated with serotonin toxicity.

Tell your doctor about any medications, supplements, or substances you are taking to avoid potentially life-threatening drug interactions.

Potential Serotonin Drug Interactions

Taking one or more medications that impact serotonin levels can be potentially dangerous. It can lead to a condition known as serotonin syndrome, where high serotonin levels in the brain cause symptoms such as:

  • Blood pressure changes
  • Coma
  • Confusion
  • Fever
  • Increased heart rate
  • Hallucinations
  • Nausea
  • Seizures

According to the U.S. Food and Drug Administration, there is an increased risk of serotonin syndrome due to combining selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs) with migraine headache medications called triptans.


What drugs increase risk of serotonin syndrome? ›

The drugs and supplements that could potentially cause serotonin syndrome include: Selective serotonin reuptake inhibitors (SSRIs), antidepressants such as citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle) and sertraline (Zoloft)

Which drug is least likely to cause serotonin syndrome? ›

Although counterintuitive, serotonergic agonists that have their effect directly on postsynaptic 5-HT receptors (eg, fentanyl, buspirone, LSD, triptans) are less likely to cause severe or classic serotonin toxicity as compared with drug-drug interactions or MAOIs [10].

Which antidepressants do not cause serotonin syndrome? ›

Nonserotonergic antidepressants such as mirtazapine and bupropion are possible alternatives. Most tricyclic antidepressants (e.g., amitriptyline, desipramine and nortriptyline) are also less serotonergic than SSRIs, though clomipramine and imipramine are notable exceptions.

Does gabapentin cause serotonin syndrome? ›

Research has indicated that gabapentin can cause serotonin syndrome, especially when taken with other drugs like tramadol.

Can Benadryl cause serotonin syndrome? ›

Diphenhydramine may occasionally interact with selective serotonin reuptake inhibitor (SSRI) antidepressants such as sertraline (Zoloft). We found one case report that suggests diphenhydramine affects the neurotransmitter serotonin (Cureus, Apr. 2018). This could lead to a complication called serotonin syndrome.

Does Xanax cause serotonin syndrome? ›

The main risk of a Zoloft Xanax interaction is serotonin syndrome. Because both medications work by increasing serotonin levels to improve mood and other mental health symptoms, taking them together could lead to a spike in serotonin, resulting in this condition. Symptoms of serotonin syndrome include: Agitation.

What drugs should be avoided with serotonin syndrome? ›

Pethidine, tramadol and dextromethorphan (a common ingredient in cough medicines) are opioids with a high risk of causing serotonin syndrome when used with serotonergic antidepressants. Concomitant use of these medicines with MAOIs is contraindicated due to this interaction.

What pain meds cause serotonin syndrome? ›

Opioids with serotonergic effects include the phenylpiperidine series opioids fentanyl, methadone, meperidine and tramadol and the morphine analogues oxycodone and codeine. In combination with certain serotonergic drugs, e.g. antidepressants, they can provoke serotonin syndrome.

Does ibuprofen increase serotonin? ›

Under calcium conditions ibuprofen and paroxetine significantly released more serotonin after 10 min, while all other treatments with calcium did not increase the serotonin release from platelets either after 10 or 60 min (Table 2B).

What is the safest antidepressant for SSRI? ›

Which SSRI antidepressants have the least side effects?
  1. Celexa. Overall, Celexa seems to be one of the best-tolerated SSRIs for many people. ...
  2. Lexapro. Lexapro is closely related to Celexa. ...
  3. Prozac. Prozac causes less weight gain than other SSRIs. ...
  4. Zoloft.
Mar 15, 2023

Which antidepressant has highest risk of serotonin syndrome? ›

Tricyclic antidepressants are also serotonin reuptake inhibitors, with clomipramine and imipramine being the most potent and likely the only TCAs to be involved in serotonin toxicity; other TCAs such as amitriptyline are weaker inhibitors and are thus unlikely to cause toxicity.

How fast does serotonin syndrome happen? ›

Serotonin syndrome is diagnosed clinically and requires a thorough review of medications and a careful physical exam. Symptoms tend to develop rapidly after exposure to the precipitating drug: 30% within one hour, 60% within 6 hours, and nearly all patients with toxicity developing symptoms within 24 hours of exposure.

How do you prevent serotonin syndrome? ›

Depending on your symptoms, you may receive the following treatments:
  1. Muscle relaxants. ...
  2. Serotonin-production blocking agents. ...
  3. Oxygen and intravenous (IV) fluids. ...
  4. Drugs that control heart rate and blood pressure. ...
  5. A breathing tube and machine and medication to paralyze your muscles.
Jan 22, 2022

How can serotonin syndrome be prevented? ›

Preventing Serotonin Syndrome

The best way to prevent serotonin syndrome is to let all of your caregivers know about all of your medications before adding any new ones. If you're on any drug that increases your serotonin level, check with your doctor before taking even an over-the-counter medication or supplement.

What is the Hunter's criteria for serotonin syndrome? ›

Only a few well-defined clinical features were used in Hunter's Criteria (hypertonia, agitation, tremor, hyperreflexia, temperature and clonus). Clonus is the most important sign in the Hunter's Criteria. This neuromuscular feature was strongly associated with serotonin toxicity.

What are symptoms of too much serotonin? ›

Signs of Too Much Serotonin
  • Confusion.
  • Increased reflexes.
  • Restlessness.
  • Hallucinations.
  • Extreme agitation.
  • Fluctuations in blood pressure.
  • Increased heart rate.
  • Nausea, vomiting, and diarrhea.
Feb 24, 2023

Can too much melatonin cause serotonin syndrome? ›

Combining medication or supplements that jointly boost serotonin can cause it to accumulate and reach abnormally high levels in the body - a serious condition called serotonin syndrome, which can result in shivering, diarrhea, muscle rigidity, fever or seizures.

How rare is serotonin syndrome? ›

Researchers also found that the incidence of serotonin syndrome was 0 to 4 cases per 10,000 person-years of exposure to coprescription of triptans and SSRI or SNRI antidepressants.

Can trazodone cause serotonin syndrome? ›

Trazodone may cause a serious condition called serotonin syndrome if taken together with some medicines. Do not use trazodone with buspirone (Buspar®), fentanyl (Abstral®, Duragesic®), lithium (Eskalith®, Lithobid®), tryptophan, St.

Does Ativan cause serotonin syndrome? ›

Ativan is a drug that causes an increase in serotonin and dopamine levels in the brain. This is particularly true when it is being taken in higher than normal dosages, or when it is otherwise abused. Because of this, the risk of addiction is very high for Lorazepam.

Is anxiety caused by too much serotonin? ›

Serotonin syndrome occurs when someone has an excess of the neurotransmitter serotonin in their nervous system. The condition's symptoms generally fall into three categories: Altered mental status (irritability, agitation, restlessness, and anxiety)

Can antihistamines cause serotonin syndrome? ›

Serotonin syndrome is a reaction to commonly prescribed antidepressants, painkillers, antibiotics, antihistamines, anti-nausea medications, migraine medications, and some herbal supplements. It's more common in people who take one or more of these medications at the same time.

Can tramadol cause serotonin syndrome? ›

The use of tramadol with serotonergic medicines can increase the risk of serotonin syndrome. To reduce the likelihood of these serious reactions occurring, prescribe the lowest effective doses of tramadol and avoid its use in patients with a history of seizure disorders.

Can Wellbutrin cause serotonin syndrome? ›

Cases of serotonin syndrome have been identified in associated with bupropion, especially in overdose or when bupropion is administered with other drugs with a serotonergic effect.

Does Adderall cause serotonin syndrome? ›

Adderall has a direct impact on the brain's serotonin levels. Serotonin syndrome can happen when the brain cannot regulate the body's functions because of an excess of serotonin. Use of Adderall with other drugs, such as antidepressants or illegal drugs such as MDMA, can increase the risk of serotonin syndrome.

Does Tylenol increase serotonin? ›

Recent studies confirmed bulbospinal serotonergic pathway involvement in acetaminophen analgesia and acetaminophen-induced serotonin increases in the central nervous system.

Does acetaminophen affect serotonin? ›

Acetaminophen has been shown to influence cognitive and affective behavior possibly via alterations in serotonin function.

What supplements should not be taken with antidepressants? ›

John's wort, garcinia cambogia, L-tryptophan (or 5-HTP) and SAMe (S-adenosyl-methionine) supplements with your antidepressant. Consumer Labs says they can increase your risk of experiencing serotonin syndrome.

What is the mildest safest antidepressant? ›

SSRIs are usually the first choice medicine for depression because they generally have fewer side effects than most other types of antidepressant.

What is the number 1 prescribed antidepressant? ›

What are the most common antidepressant medications? Sertraline, also known by the brand name Zoloft, used for multiple mental health and mood disorders, is the most prescribed antidepressant dispensed to U.S.

What is the safest antidepressant for long term use? ›

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. They can ease symptoms of moderate to severe depression, are relatively safe and typically cause fewer side effects than other types of antidepressants do.

Which SSRI has the highest fatality rate? ›

Within the SSRIs, citalopram had a higher case fatality than the other SSRIs (1.1, 95% CI 0.8–1.4 v.

What blood tests are done for serotonin syndrome? ›

The serotonin test measures the level of serotonin in the blood. Blood is drawn from a vein (venipuncture), usually from the inside of the elbow or the back of the hand. A needle is inserted into the vein, and the blood is collected in an air-tight vial or a syringe. Preparation may vary depending on the specific test.

Does Benadryl lower serotonin? ›

Diphenhydramine inhibits post-synaptic reuptake of serotonin.

How obvious is serotonin syndrome? ›

Serotonin syndrome may not be obvious to recognize, presenting the opportunity for rapid progression and severe complications. Additionally, it can be difficult to predict which patients are at risk for developing serotonin syndrome.

Can serotonin syndrome go unnoticed? ›

Serotonin syndrome is not often reported. However, this condition is thought to be commonly overlooked and may therefore be underdiagnosed.

Should I worry about serotonin syndrome? ›

However, severe serotonin syndrome can be life-threatening and if you experience any of the symptoms below you should seek emergency treatment immediately: Irregular heartbeat. High fever (>103 F/40 C) Seizures.

How can I reduce serotonin syndrome naturally? ›

Read on to learn about different ways to relieve symptoms of mood disorders like depression and potentially increase serotonin naturally.
  1. Adjust your diet. ...
  2. Get more exercise. ...
  3. Bring in the bright light. ...
  4. Take certain supplements. ...
  5. Try massage therapy. ...
  6. Try mood induction. ...
  7. Manage emotions and stress levels.

Can 5mg of Lexapro cause serotonin syndrome? ›

Common side effects of Lexapro include nausea, sexual side effects, and insomnia. For some people, these go away as your body gets used to the medication. More serious side effects of Lexapro are rare. These include suicidal thoughts or behaviors, abnormal bleeding, and serotonin syndrome.

What does the beginning of serotonin syndrome feel like? ›

In the early stages of serotonin syndrome people may experience mild serotonin syndrome, which causes symptoms such as tremors, dizziness, and headache.

What drains serotonin? ›

Certain drugs and substances such as caffeine, alcohol, nicotine, NutraSweet, antidepressants, and some cholesterol-lowering medications deplete serotonin and other neurotransmitter levels. Hormone changes cause low levels of serotonin and neurotransmitter imbalances.

What is the common cause of serotonin syndrome? ›

Serotonin syndrome most commonly occurs after a dose increase (or overdose)of a potent serotonergic drug or shortly after a second drug is added. Some of the drugs involved have very long half-lives (e.g. fluoxetine) and may have been ceased weeks before.

What increases risk of serotonin syndrome? ›

Serotonin syndrome can occur when you increase the dose of certain medications or start taking a new drug. It's most often caused by combining medications that contain serotonin, such as a migraine medication and an antidepressant. Some illicit drugs and dietary supplements are associated with serotonin syndrome.

How many people get serotonin syndrome each year? ›

About 7300 diagnosed cases of serotonin syndrome occur each year, and about 100 of these cases result in death. Drugs with serotoninergic properties have the ability to increase the level of serotonin or to act as direct agonists of postsynaptic serotonin receptors in the central nervous system (CNS).

What is the first listed diagnosis for serotonin syndrome? ›

The first report of a clinical picture consistent with what nowadays is termed SS was in 1960,4 which described the coadministration of L-tryptophan (the substrate of the rate-limiting enzyme, tryptophan hydroxylase [TPH], in the biochemical synthesis of serotonin) with a monoamine oxidase inhibitor (MAOI) inducing ...

What antidepressants are safe for serotonin syndrome? ›

The most obvious choice in this regard would be bupropion (brand name Wellbutrin), an antidepressant that affects the norepinephrine and dopamine systems, but leaves serotonin untouched. Another option would be an older antidepressant called desipramine (brand name Norpramin).

Does Wellbutrin cause serotonin syndrome? ›

Cases of serotonin syndrome have been identified in associated with bupropion, especially in overdose or when bupropion is administered with other drugs with a serotonergic effect.

Can 40 mg Lexapro cause serotonin syndrome? ›

When an individual takes a combination of medications that contain serotonin (commonly prescribed antidepressants such as Zoloft, Lexapro, both SSRIs and Effexor, an SNRI), they are at a high risk for developing serotonin syndrome.

What is a toxic amount of Lexapro? ›

The escitalopram overdose dosage ranges from 5 to 20 mg as defined by the Food and Drug Administration (FDA). However, considering that the average starting dose for this medication is 10mg, the window for overdose is probably much wider.

What medications should not be taken with Lexapro? ›

Do not take escitalopram with a monoamine oxidase (MAO) inhibitor (eg, isocarboxazid [Marplan®], linezolid (Zyvox®), methylene blue injection, phenelzine [Nardil®], selegiline [Eldepryl®], tranylcypromine [Parnate®]).

How likely is serotonin syndrome from SSRI? ›

An estimated 15% of SSRI overdoses lead to mild or moderate serotonin toxicity. Serotonergic agents used in conjunction can increase the risk for severe serotonin syndrome; an SSRI and an MAOI in combination poses the greatest risk.

What does too much serotonin feel like? ›

The condition's symptoms generally fall into three categories: Altered mental status (irritability, agitation, restlessness, and anxiety) Neuromuscular hyperactivity (tremors, shivering, muscle rigidity, and muscle spasms) Autonomic hyperactivity (rapid heartbeat, high blood pressure, sweating, and fever)

How quickly does serotonin syndrome happen? ›

Serotonin syndrome is diagnosed clinically and requires a thorough review of medications and a careful physical exam. Symptoms tend to develop rapidly after exposure to the precipitating drug: 30% within one hour, 60% within 6 hours, and nearly all patients with toxicity developing symptoms within 24 hours of exposure.

Why is bupropion not prescribed? ›

Bupropion was rarely prescribed when the presence of comorbid anxiety disorders or symptoms reflecting central nervous system activation influenced antidepressant selection.

Does trazodone cause serotonin syndrome? ›

Trazodone may cause a serious condition called serotonin syndrome if taken together with some medicines. Do not use trazodone with buspirone (Buspar®), fentanyl (Abstral®, Duragesic®), lithium (Eskalith®, Lithobid®), tryptophan, St.


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