Serotonin measured in the blood or urine reflects predominantly peripheral production rather than local brain serotonin levels. This is because brain serotonin is synthesised locally within serotonergic neurons in the brain and peripheral serotonin does not cross into the brain via the blood–brain barrier. Consequently, urinary serotonin concentrations alone cannot be used to determine localised brain serotonin levels or synaptic activity.

In contrast, serotonin precursors, metabolites and diversion pathway activation provide a more informative measure of overall peripheral and brain serotonin levels. 5-HIAA as an example is generated following the breakdown of serotonin peripherally and locally within the brain. After brain formation 5-HIAA diffuses into cerebrospinal fluid, enters systemic circulation, and is ultimately excreted in urine. For this reason, 5-HIAA serves as a more meaningful indicator of whole-body serotonin, alongside other analytes detailed below.

These analytes are interpreted in relation to laboratory reference ranges to determine whether levels fall within limits consistent with brain and peripheral serotonin deficiency.

• 5-HIAA is the primary end-metabolite of serotonin and reflects total serotonin breakdown.

• Tryptophan is the dietary precursor to serotonin and must cross the blood–brain barrier before being converted into serotonin within the brain. Low tryptophan availability may limit central serotonin synthesis.

• Kynurenine is formed when tryptophan is diverted away from serotonin production often in response to inflammation. Elevated kynurenine relative to tryptophan can indicate inflammatory shunting and reduced serotonin synthesis potential.

• Kynurenic acid, 3-hydroxykynurenine, and xanthurenic acid are downstream metabolites of the kynurenine pathway and reflect inflammatory activation and altered tryptophan metabolism rather than direct serotonin levels.

Urine