GABA type B receptors are metabotropic receptors that regulate inhibitory signaling in the brain and are considered a promising therapeutic target in alcohol use disorder. Yet robust human biomarkers of target engagement and receptor sensitivity have been lacking, hindering the development of mechanism-based treatments. The researchers set out to test whether TMS-derived measures and hormone release could fill that gap.

Each of the 31 healthy volunteers received baclofen 30 mg, baclofen 60 mg, and placebo across three sessions in a crossover design. The investigators assessed long-interval intracortical inhibition (LICI), short-interval intracortical inhibition, and intracortical facilitation with paired-pulse TMS at baseline and again roughly 60 minutes after dosing. Baclofen blood concentrations and plasma growth hormone levels were also measured.

Baclofen produced dose-dependent increases in growth hormone release, confirming that the drug engaged GABA type B receptors in the neuroendocrine system. This peripheral marker validated that participants were receiving an active pharmacological challenge rather than a sub-threshold dose.

The critical finding emerged in the cortical measure. In light drinkers, baclofen at 30 mg potentiated LICI, and a similar potentiation appeared at 60 mg, suggesting a plateau had been reached. In heavy drinkers, the pattern was strikingly different: the 30 mg dose potentiated LICI to a degree comparable with light drinkers, but the response was absent at 60 mg despite comparable baclofen blood concentrations and pharmacokinetics.

This dissociation, a preserved response at lower agonist stimulation but a reduced response under stronger stimulation, points to altered GABA type B receptor function associated with heavy alcohol use. Because drug exposure was similar between groups, the difference is unlikely to reflect absorption or metabolism, and instead suggests a change in receptor sensitivity.

The effects were selective. Baclofen did not consistently modulate short-interval intracortical inhibition or corticospinal excitability, indicating the observed changes were specific to GABA type B receptor-mediated inhibition rather than a general shift in cortical excitability.

The authors argue that LICI and growth hormone release provide complementary biomarkers, indexing central and peripheral GABA type B receptor engagement respectively. Together, they may support translational development of mechanism-based treatments for alcohol use disorder, allowing researchers to verify that candidate drugs actually engage their target and to detect receptor sensitivity differences in patient groups.

The study’s limitations are worth noting. It enrolled healthy volunteers rather than individuals diagnosed with alcohol use disorder, and it examined acute single doses rather than chronic treatment. The heavy-drinker group was defined by drinking behavior, and the crossover design, while efficient, involved short exposure periods. Even so, the trial demonstrates a practical path from laboratory biomarker to clinical pharmacology, showing that a TMS protocol can reveal receptor-level differences between heavy and light drinkers under a controlled drug challenge.

Subject of Research: Altered GABA type B receptor sensitivity in heavy drinkers measured with a TMS-based biomarker and baclofen challenge

Article Title: Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial

Article References: Montemitro, C., Donahue, D., Costumati, A., Maruottolo, F., Terezza, S., Sjoberg, C., Perini, I., Roman, M., Kugelberg, F. C., & Heilig, M. (2026). Altered GABAB receptor sensitivity in heavy drinkers indexed using a TMS-based biomarker: a randomized controlled experimental medicine trial. Translational Psychiatry, 16(1), Article 582. https://doi.org/10.1038/s41398-026-04530-4

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04530-4

Keywords: GABA B receptor, baclofen, transcranial magnetic stimulation, alcohol use disorder, cortical inhibition, biomarker, growth hormone, experimental medicine, heavy drinking, randomized controlled trial, Translational Psychiatry, Altered