Did you know that triptans are the grand-children of a fungus? 

That’s right. The story of the triptans starts with a fungus that grows on the rye plant. This fungus, Claviceps purpurea, attaches to the rye and forms a shape that resembles the foot of a hen, called an ergot in French. Have you heard the term rye ergot before? That’s where it comes from.

What’s the story of the rye ergot? 

In medieval times, people were eating quite a bit of rye. If the rye was rotten, there was ergot on it.  If you eat the fungus, two things can happen: you can start having hallucinations, and you may develop gangrene in your feet! 

Why is the ergot causing hallucinations and gangrene? 

The ergot is called an alkaloid. It can bind serotonin receptors. If you mildly stimulate serotonin receptors in the brain, you can treat depression. If you stimulate them too much, you hallucinate. For example, another product that acts on serotonin is LSD. 

The gangrene was caused by the stimulation of serotonin receptors on blood vessels. The constriction was so severe that the flesh would become necrotic. People affected had terrible pains and could not stand on their feet. Some people would describe this as “St. Anthony’s fire”. Interestingly, people who were affected sometimes left for a pilgrimage. This was very effective, as it usually took them away from the rotten bread! 

It sounds like this fungus is dangerous?

The rye ergot was known to be  a potent substance. Once physicians observed that the rye ergot, or Claviceps, could constrict blood vessels, they thought about using it to stop bleeding. In the 18^th century, a paste of rye ergot was used to stop uterine bleeding after childbirth. That was very innovative! 

Eventually, scientists tried to understand WHY the ergot could constrict blood vessels. Studies on the rye ergot eventually led to the discovery of serotonin in the 1940s. If you look closely, the name serotonin means «substance from the blood that increases the tone of the blood vessels. The role of serotonin in the brain was understood later. 

How did the rye ergot inspire the design of triptans?

Now that physicians understood that the rye ergot could constrict blood vessels, it made a lot of sense to use it to treat migraine. Migraine was thought to be caused by the dilation of blood vessels. Making them constrict to relieve the pain was sensible. Ergotamine was discovered in 1918 and is used up to this day in certain countries. Ergotamine was strong and effective for migraine, but was linked to high blood pressure and risks of heart problems and stroke. Severe cases of ergotism could still lead to gangrene. Researchers decided to find a way to stimulate serotonin in a milder, or more specific way, to avoid these risks. 

When was the first triptan used? 

The search for a drug that could mimic the benefits of ergotamine without its side effects started in the The search for a drug that could mimic the benefits of ergotamine without its side effects started in the 1970s. Sumatriptan was discovered by Glaxo and marketed in the USA in 1993. It was a revolution for people with migraine. Nothing before had been SO effective in treating migraine attacks. At the end of the 1980s, migraine was still seen as a neurosis. There were many psychoanalytical theories. Attacks were seen as the expression of a psychiatric release. Sumatriptan challenged this vision, as the relief was rapid and suggested a biological, neurological cause more than a psychiatric one. After that, six other triptans were created and marketed.  

Can triptan cause gangrene or other vascular problems? 

Triptans should not be used in people with a history of coronary heart disease. They do constrict the coronary arteries. They also constrict the cranial arteries that bring blood to our skin and head structures. Until recently, scientists believed that triptans could constrict the brain’s blood vessels. That would cause a risk of stroke, and triptans are contra-indicated in a person who had a stroke. But recent evidence suggests that triptans do NOT constrict the brain blood vessels much. 

How do triptans work to relieve the migraine pain? 

We do not know exactly yet. Remember that the use of ergotamine was based on an observation (ergotamine constricts blood vessels) and a theory of migraine (migraine is caused by dilated blood vessels). 

Our understanding of migraine has changed now. We know that migraine pain probably comes from the cranial blood vessels. We also know that triptans act on serotonin receptors inside the brain and may influence their neurologic role, not the role of the blood vessels. Last but not least, new treatments acting on serotonin but with NO action on blood vessels are effective in treating migraine attacks. The first medication of this new class, called lasmiditan, should be available in Canada soon.

The story of triptans reminds us of a few things about nature and chemistry

• It’s not because something exists in nature that it is safe. Natural toxins can be powerful and deadly. 
• Many medications have been inspired by natural substances. Usually, creating a drug inspired by a plant involves the scientific understanding of which product in the plant is active and then the design of a chemical compound that can be fabricated and studied safely. 
• Chemical substance is a term that can be used for natural and synthetic products.

Fun Fact: 

Even if we have focused on the role of serotonin on the brain and blood vessels, 90% of the serotonin in the human body, is stored in the gut. In the digestive tract, serotonin plays an important role in motility.

REFERENCES

Eadie MJ. Ergot of rye-the first specific for migraine. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2004;11(1):4-7.

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