Triptans: Targeting the Serotonin Receptor

Reviewed by: HU Medical Review Board | Last reviewed: June 2023

The approval of sumatriptan in 1992 was a breakthrough in migraine treatment.1 It took decades of research about the role of serotonin and serotonin receptors in migraine. Some of these ideas turned out to be incorrect. Yet they led to important discoveries along the way.

Scientists identified serotonin in the late 1940s.1 Serotonin is an important neurotransmitter, or chemical messenger. Studies in the 1950s and 1960s suggested that serotonin might have a role in migraine.2

Trying to fully explain the cause of migraine

Early on, people thought that problems with the blood vessels in the brain caused migraine. The theory was that blood vessels in the brain stretched and widened, causing pain. This theory did not fully explain migraine. Blood vessels relax under other circumstances. Most people do not get a headache from exercising or sitting in a hot bath.3

So researchers expanded on the theory. They thought there might be a chemical that caused tissue around the blood vessels to swell. The chemical might lower the pain threshold. Serotonin seemed like a possible candidate. In one study, neurologist Dr. Harold Wolff injected people with serotonin. He found that it increased migraine symptoms.2 Researchers started looking for a medication that would block the serotonin receptors. Serotonin receptors are also called 5-HT receptors.

Methysergide: Preventive migraine treatment from the 1960s

Lysergic acid is better known as LSD. LSD is very good at blocking 5-HT receptors.2 It also caused hallucinations, so it is not a safe migraine treatment. Methysergide was made by modifying the chemical structure of LSD. The changes made it a strong 5-HT blocker without the hallucinogenic effects.

In 1962, methysergide was approved for migraine prevention.4 Although it worked well, methysergide causes serious side effects. It causes fibrosis, or scarring, that can damage the heart and arteries. Methysergide is no longer recommended for migraine prevention.4 It is not available in the United States.

Serotonin research: From miscues to breakthroughs

To this day, it is unclear how methysergide prevents migraine. Yet research about this drug led to an important discovery. By studying methysergide, scientists discovered that there are several different 5-HT receptor subtypes.1,2 Methysergide affected them differently. It blocks the 5-HT2 and 5-HT7 receptors, but it stimulates the 5-HT1B receptor. The 5-HT1B receptor would become an important target for migraine treatment.1

Turns out, early researchers may have misunderstood the role of serotonin in migraine. They wanted to reduce the effects of serotonin. However, later experiments showed that serotonin levels naturally decrease at the start of a migraine attack.2 Serotonin is a vasoconstrictor. It causes blood vessels to narrow. When serotonin levels dropped, the blood vessels in the brain stretched out. They decided more serotonin was needed, not less.

Administering serotonin as a treatment was not an option.1 It caused too many side effects. But researchers thought drugs that mimic serotonin’s effects on the blood vessels in the brain might be useful migraine treatments.

Triptans: Acute migraine treatment from the 1990s

The 5-HT1B receptor is found mainly on vessels that supply blood to the brain, as well as some arteries in the heart.5 The search for a drug that activates 5-HT1B led to the development of sumatriptan.

Treatment at the start of a migraine attack with sumatriptan—and other triptans—relieves pain and other migraine symptoms for many people. Originally, researchers believe that this was because it acts like a vasoconstrictor. When sumatriptan binds to the 5-HT1B (and 5-HT1D) receptors in the brain, swelling in the blood vessels goes down.1

Today, researchers believe that migraine is a neurovascular disease, that is, a disorder of the nerves as well as the blood vessels. They believe that triptans may relieve migraine through mechanisms other than constricting the blood vessels. For example, triptans may actually work by disrupting pain signals from the trigeminal nerves.6 Constricting the blood vessels may not be essential for their effectiveness.

Despite uncertainty about how they work, triptans have become a common first-line acute (or abortive) treatment for stopping moderate-to-severe migraine attacks. There are seven approved triptans. Triptans are available as tablets, capsules, quick-dissolving tablets, injections, and nasal sprays.

Read more on the history of migraine treatments in this article.

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