What is the glutamate hypothesis of ALS?

Glutamate is an amino acid that can play a variety of roles in the body. In its first role, glutamate is a building block of numerous proteins in the body and a common component of food. This role has no connection to ALS. In its second role, glutamate functions as a messenger substance (“transmitter”) between cells in the central nervous system. Nerve cells are not directly connected mechanically but are linked to one another by messenger substances. When information is transmitted from one nerve cell to a neighboring cell, neurotransmitters are released between the cells. Glutamate is one of the main neurotransmitters in the brain and spinal cord.

In ALS, it is believed that the concentration of glutamate—acting as a neurotransmitter—is elevated, leading to hyperexcitability of motor neurons in the brain and spinal cord. In the 1990s, glutamate measurements at the microscopic level (microdialysis) revealed an elevated glutamate concentration in the space between nerve cells (the “synaptic cleft”). These measurements formed the basis for the “glutamate hypothesis” of ALS. However, the hypothesis is scientifically controversial, as several repeat studies have yielded differing results. In some experiments, the findings were reproduced, while other research institutions were unable to detect any abnormal glutamate concentrations in the “synaptic cleft.”

One argument that continues to support the glutamate hypothesis today is the therapeutic effect of riluzole. Riluzole is a medication that reduces the concentration of the neurotransmitter glutamate and thereby counteracts the brain’s presumed hyperexcitability. It is important to emphasize that the different roles of glutamate (as a protein component or as a neurotransmitter) are strictly separated from one another by the blood-brain barrier. Thus, the concentration of glutamate in the body as a whole bears no relation to the level of glutamate in the synaptic cleft. Therefore, no “diet” restricting glutamate is necessary for ALS, meaning that foods containing glutamate can be consumed without concern.