Serotonin

From the gut to the raphe nuclei: serotonin's many receptors and roles — in mood, sleep, appetite, impulse control and perception — and why the 'chemical imbalance' story of depression is too simple.

Serotonin, or 5-hydroxytryptamine (5-HT), was first identified in the 1940s as a substance in blood serum that constricted blood vessels — hence the name, from "serum" and "tone". It was soon found in the brain.

Mostly in the gut

Surprisingly, around 90% or more of the body's serotonin is made in the gut, by enterochromaffin cells in the intestinal lining, where it helps regulate digestion. Blood platelets carry serotonin too. Serotonin in the blood doesn't cross the blood-brain barrier, so the brain makes its own.

A small source, a huge reach

Brain serotonin comes from neurons in the raphe nuclei along the midline of the brainstem. Their axons reach almost every part of the brain and spinal cord. There are at least 14 serotonin receptor subtypes, nearly all metabotropic (5-HT3 is the exception, an ion channel), which is one reason serotonin's effects are so varied.

What it does

Serotonin influences mood and emotional processing, sleep–wake cycles (it is also the precursor of melatonin), appetite, impulse control and patience, pain processing, body temperature and nausea. Psychedelic drugs such as psilocybin and LSD act mainly as activators of the 5-HT2A receptor, while anti-nausea drugs such as ondansetron block 5-HT3.

SSRIs and the chemical-imbalance debate

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac, approved in the US in 1987), block the transporter that clears serotonin from synapses. They are effective for many people with depression and anxiety disorders. But SSRIs raise serotonin within hours while their mood benefits usually take weeks, and a 2022 umbrella review found no consistent evidence that depression is caused by low serotonin. Most researchers now see depression as involving many factors — neural circuits, stress, plasticity, inflammation, life circumstances — with serotonin drugs possibly working by encouraging adaptive brain changes rather than "topping up" a deficit.