Serotonin Antagonists: Uses, most common brand names, and safety information

Medically reviewed by  Jamie Winn, PharmD

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The first 5-HT3, or serotonin receptor antagonist to be approved for use by the FDA was ondansetron. It took almost 10 years of development and testing before it was approved in 1991. These new selective 5-HT3 receptor antagonists marked a significant improvement in the treatment of nausea and vomiting.

Certain serotonin antagonists are used in the treatment of depression, insomnia, and mood disorders. When used for these conditions, they are classified as serotonin antagonist and reuptake inhibitors (SARIs) and include Desyrel (trazodone).

The list below includes FDA-approved serotonin antagonists and their pricing:

List of Serotonin Antagonists

Some other medications that have serotonin antagonist activity but may not be classified in this drug class include:

• Remeron (mirtazapine)
• Seroquel (quetiapine)
• Risperdal (risperidone)
• Trintellix (vortioxetine)
• Lotronex (alosetron)

What are serotonin antagonists?

5-HT3 receptor antagonists are a class of prescription drugs best known as antiemetics used for the treatment or prevention of nausea and vomiting due to chemotherapy, radiation therapy, or surgery. 5-HT3 (5-hydroxytryptamine) is an abbreviation for serotonin.

First-generation 5-HT3 receptor antagonists examples include Zofran (ondansetron) and Sancuso (granisetron). These medications can affect other serotonin receptors in your body which may lead to an increased incidence of side effects and drug interactions.

Currently, Aloxi (palonosetron) is the only second-generation 5-HT receptor antagonist available. It has significant activity at only 5-HT3 receptors which helps its effectiveness at preventing emesis (vomiting) for longer periods when compared to first-generation medications.

Serotonin antagonist and reuptake inhibitors (SARIs) are typically used as antidepressants. They are also used for anxiety and sleep, due to their sedative properties. Examples include Serzone (nefazodone) although it is rarely used because it has a high risk of liver toxicity.

How do serotonin antagonists work?

Cells that line your gastrointestinal tract release serotonin when they are damaged by chemo or radiation therapy. After being released, the serotonin binds to receptors in your stomach and transmits impulses through the central nervous system (CNS) to an area of your brain known as the vomiting center. Once there, serotonin activates other nerves that trigger your vomit reflex. 5-HT3 receptor blockers reduce nausea and vomiting through the binding and inhibition of the serotonin receptors involved in this process.

SARIs act by binding to 5-HT2A receptors and blocking the reuptake of neurotransmitters such as serotonin, histamine, norepinephrine, and dopamine. These chemicals are thought to play a role in mood, emotions, and energy.

What conditions are serotonin antagonists used to treat?

Serotonin antagonists are used in several conditions, including:

• Nausea/vomiting treatment and prophylaxis
• Chemotherapy-induced nausea/vomiting
• Postoperative nausea/vomiting
• Radiation-induced nausea/vomiting
• Nausea/vomiting during pregnancy, severe or refractory (off-label)

Are serotonin antagonists safe?

The use of serotonin antagonists is relatively safe and effective when taken as prescribed. Before beginning treatment with serotonin antagonists, tell your healthcare provider if you have any of the following:

• Are taking Prozac (fluoxetine) or antipsychotics as it can increase your risk of arrhythmias
• Liver impairment or elevated liver enzymes
• Bowel obstruction
• Are taking the dopamine receptor agonist Apokyn (apomorphine)
• Are taking medications or supplements that increase serotonin such as selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), or other antidepressants
• Pregnant, plan on becoming pregnant or are breastfeeding

What are the common side effects of serotonin antagonists?

The adverse effects you experience from serotonin antagonists will depend on several factors including the medication and dose. Some common side effects of serotonin antagonists include:

• Headache
• Fatigue
• Constipation
• Drowsiness
• Dizziness
• Agitation
• Anxiety
• Tingling
• Rash
• Itching
• Diarrhea
• Urinary retention
• Fever
• High blood pressure (hypertension)
• Low blood pressure (hypotension)

Serotonin antagonists can sometimes cause more serious side effects, including:

• Severe allergic reactions
• Serotonin syndrome when taken with other serotonergic medications
• Increased risk of arrhythmias
• Increased liver enzymes
• Slow heart rate (bradycardia)

This is not a complete list of side effects and we encourage you to consult with your healthcare provider for medical advice about any possible side effects.

Who should not take serotonin antagonists?

You should not take serotonin antagonists if you are taking apomorphine or have a known hypersensitivity to any ingredients in the product’s formulation.

What antihistamines block serotonin?

The antihistamine cyproheptadine blocks serotonin and can be used as a treatment for serotonin syndrome. Other antihistamines, including the first-generation Benadryl (diphenhydramine), may inhibit the reuptake of serotonin and slightly increase serotonin levels.

What are some natural serotonin antagonists?

While these claims cannot always be verified, some supplements that are thought to naturally increase serotonin include:

• L-tryptophan
• 5-HTP (5-hydroxytryptophan)
• Lysine
• B vitamins
• SAM-e (s-adenosyl methionine)
• Probiotics
• Omega-3 fatty acids
• St. John’s wort

How long does it take serotonin antagonists to work?

Serotonin antagonists such as Zofran (ondansetron) will typically start working to reduce nausea/vomiting within 30 minutes but can take up to 2 hours before you see its full effects.

SARIs can have an immediate effect on insomnia and anxiety but it may take 2 to 4 weeks for you to see an improvement in the symptoms of depression.

How much do serotonin antagonists cost?

Serotonin antagonists are very expensive with an average cost of up to $5,000 per year.

You can purchase serotonin antagonists for $49 per month from NiceRx if eligible for assistance. Prices at the pharmacy vary by location, strength, and quantity, as well as your insurance status.

Related resources for serotonin antagonists

• https://www.drugs.com/drug-class/5ht3-receptor-antagonists.html
• https://www.ncbi.nlm.nih.gov/books/NBK513318/
• https://www.rxlist.com/how_do_antiemetic_selective_5-ht3_antagonist_work/drug-class.htm
• https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/2046-4053-2-46
• https://healthinfo.healthengine.com.au/5-ht3-receptor-antagonists-serotonin-blockers
• https://pubmed.ncbi.nlm.nih.gov/1833888/