Direct Serotonin Agonists/Antagonists

Serotonin (5-HT) is involved in gut secretion, motility, and sensation. Motility is a term that describes the movement of food through the GI tract. Sensation refers to physical feelings. Serotonin receptors in the GI tract appear to be a good target for treating IBS symptoms. Currently two therapies are Food and Drug Administration (FDA) approved for the treatment of IBS-C and IBS-D.

Tegaserod (Zelnorm®) works on the nerves and smooth muscles of the GI tract. It increases gut movement and intestinal secretions. In multiple studies it has been shown to improve pain and bloating. An increase in the number of bowel movements has also been shown.


Tegaserod is only approved for women with IBS-C under the age of 65. The women must also have no history of ischemic cardiovascular events or more than one cardiovascular risk factor. The most common side effects associated with tegaserod include headaches (migraines), dizziness, back or joint pains. Abdominal symptoms may also occur and include pain, nausea/vomiting, and diarrhea.

Tegaserod was first approved by the FDA for the treatment of overall IBS-C symptoms. The drug was voluntarily removed from the market in 2007. This was due to finding a small but increased risk of cardiovascular events such heart attack, stroke, and transient ischemic attacks. In April 2019, the FDA approved the re-introduction of tegaserod for women < 65 with IBS-C as previously described after subsequent studies failed to identify a major link between the drug and increased risks for cardiovascular events in this population.


Alosetron (Lotronex ®) delays gut movement and reduces pain. It was first approved by the FDA for the treatment of overall symptoms of IBS-D in women. This drug was withdrawn from the market by the FDA in 2001. Alosetron was found to cause increased rates of severe constipation and ischemic colitis (decreased blood flow to the colon). The FDA re-introduced this drug in 2002 under a Risk Evaluation and Mitigation Strategy (REMS) program. Now, only women with severe IBS-D symptoms can be approved for this drug.

To qualify, other conventional treatments must have been tried and failed and symptoms must limit quality of life. More recent studies have shown that rare cases of serious complications of constipation and ischemic colitis may still occur. Despite this it appears safe when prescribed within a small therapeutic window (0.5-1.0 mg twice-per-day). It should not be used as a first-line drug to treat IBS-D.

Adapted IFFGD Publication #101 revised and updated by Douglas A. Drossman, MD, Drossman Gastroenterology PLLC, Chapel Hill, NC and IFFGD Publication: Current Pharmacologic Treatments of Irritable Bowel Syndrome by Tony Lembo, MD and Rebecca Rink, MS, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA.

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IFFGD is a nonprofit education and research organization. Our mission is to inform, assist, and support people affected by gastrointestinal disorders.

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