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

Metabotropic γ-aminobutyric acid type B receptors (GABA B Rs) are implicated in alcohol use disorder (AUD) and represent a promising therapeutic target. However, robust biomarkers of GABA B Rs target engagement and sensitivity in humans are lacking. We examined transcranial magnetic stimulation (TMS)–derived cortical inhibition and growth hormone (GH) release as measures of GABA B R function, and whether heavy alcohol use is associated with altered responses to pharmacological GABA B R activation. In a randomized, double-blind, placebo-controlled crossover study, 31 healthy volunteers (16 heavy drinkers, 15 light drinkers) received baclofen 30 mg, baclofen 60 mg, or placebo across three sessions. Long-interval intracortical inhibition (LICI), short-interval intracortical inhibition, and intracortical facilitation were assessed with paired-pulse TMS at baseline and ~60 min post-dose. Baclofen blood concentrations and plasma GH levels were measured. Baclofen produced dose-dependent increases in GH release, confirming neuroendocrine GABA B R engagement. The LICI response to baclofen differed between groups: In light drinkers, baclofen at 30 mg potentiated LICI, and a similar potentiation was seen at 60 mg, indicating that a plateau may have been reached. In contrast, in heavy drinkers, a potentiation of LICI similar to that in light drinkers was seen at 30 mg baclofen, but was absent at the 60 mg dose despite comparable pharmacokinetics, suggesting altered GABA B R function. Effects were selective for GABA B R–mediated inhibition, with no consistent modulation of short-interval intracortical inhibition or corticospinal excitability. Acute baclofen administration reveals altered GABA B R sensitivity in heavy drinkers, with preserved responses at lower doses but reduced response under stronger agonist stimulation. LICI and GH release provide complementary biomarkers of central and peripheral GABA B Rs engagement and may support translational development of mechanism-based treatments for AUD.