Mechanisms of GLP-1 in Modulating Craving and Addiction: Neurobiological and Translational Insights

Abstract

Substance use disorders (SUDs) remain a major public health challenge, with existing pharmacotherapies offering limited long-term efficacy. Traditional treatments focus on dopaminergic systems but often overlook the complex interplay between metabolic signals, neuroplasticity, and conditioned behaviors that perpetuate addiction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have recently emerged as promising modulators of reward-related brain circuits. This review synthesizes current evidence on the role of glucagon-like peptide-1 (GLP-1) and its receptor in modulating craving and substance-seeking behaviors. We highlight how GLP-1 receptors are expressed in addiction-relevant brain regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), where their activation influences dopaminergic, glutamatergic, and GABAergic neurotransmission. In addition, we explore how GLP-1 signaling affects reward processing through gut-brain vagal pathways, hormonal crosstalk, and neuroinflammatory mechanisms. Preclinical studies demonstrate that GLP-1RAs attenuate intake and relapse-like behavior across a range of substances, including alcohol, nicotine, and cocaine. Early-phase clinical trials support their safety and suggest potential efficacy in reducing craving. By integrating findings from molecular signaling, neurocircuitry, and behavioral models, this review provides a translational perspective on GLP-1RAs as an emerging treatment strategy in addiction medicine. We propose that targeting gut-brain metabolic signaling could provide a novel framework for understanding and treating SUDs.

Keywords: GLP-1 receptor agonist; addiction; craving; dopamine; gut–brain axis; mesolimbic pathway; neuroinflammation; reward circuitry; semaglutide; substance use disorder; synaptic plasticity; vagal signaling.

Figure 1

Biased agonism at the GLP-1 receptor and spectrum of downstream signaling. GLP-1RAs can differentially recruit β-arrestin-dependent and Gαs-cAMP-PKA-dependent pathways, producing distinct transcriptional programs within neurons. Rather than acting as binary switches, these pathways exist on a continuum of activation, with specific GLP-1RAs favoring one signaling arm over the other. β-arrestin not only turns off GPCR signaling by blocking G proteins but also steers the receptor to activate gene transcription and support long-term cellular changes. This agonist bias can shape the balance between neuroplastic, metabolic, and behavioral effects, offering opportunities for pathway-selective drug design.

Figure 2

Dual gut–brain pathways for glucagon-like peptide-1 (GLP-1) receptor signaling and behavioral modulation. Nutrient-triggered GLP-1 is secreted from enteroendocrine L-cells in the distal small intestine and colon, reaching the brain via two main routes: (1) activation of vagal afferent fibers that project to the Nucleus Tractus Solitarius, (NTS), and (2) entry into the bloodstream, where it can access central structures such as the area postrema (AP), a circumventricular organ lacking a complete blood–brain barrier (BBB). Some GLP-1s enter the bloodstream through local capillary beds, but inhibition by dipeptidyl peptidase-4 (DPP4) in the vascular endothelium limits their half-life to 1–2 min (1a). Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide and liraglutide, mimic and amplify the exogenous pathway. Central GLP-1R activation in mesolimbic and mesocortical circuits, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), modulates dopaminergic, glutamatergic, and GABAergic signaling, thereby reducing reward sensitivity, craving, and substance-seeking behaviors, while also enhancing satiety and impulse control.

Figure 3

Glucagon-like peptide-1 (GLP-1) reduces appetite via pro-opiomelanocortin (POMC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) activation and dampens reward signaling through alpha-melanocyte-stimulating hormone (α-MSH)-driven GABAergic inhibition of the paraventricular nucleus (PVN) to ventral tegmental area (VTA), as well as direct modulation of VTA dopaminergic neurons and nucleus accumbens (NAc) glutamatergic tone. Glucose-dependent insulinotropic polypeptide (GIP) promotes phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT)/mammalian target of rapamycin (mTOR)-mediated synaptic plasticity, which may enhance top-down control over reward. Glucagon signaling in the PVN increases sympathetic output and norepinephrine (NE), while activation in brown adipose tissue (BAT) promotes thermogenesis via lipolysis and Uncoupling Protein 1 (UCP1). Resulting weight loss and reduced reward sensitivity are interconnected through a bi-directional association that may reinforce healthier behavioral patterns.