Research shows first direct evidence of weight-loss drug influence on brain signals linked to food cravings
A pioneering study tracking brain activity in patients taking the weight-loss drug tirzepatide has uncovered distinctive neural patterns associated with food preoccupation, offering the first direct evidence of how incretin-based therapies modulate reward circuitry in humans. The research reveals a specific low-frequency brain signal that precedes intense food cravings and demonstrates how pharmacological intervention may temporarily suppress this biomarker.
First direct measurement of GLP-1 drug impact on human reward circuitry
Researchers at the University of Pennsylvania have conducted a groundbreaking investigation into the neurophysiological effects of tirzepatide, examining brain activity directly within the nucleus accumbens – a critical hub of the brain’s reward system. The study, published in Nature Medicine on 17 November 2025, represents the first time scientists have monitored the real-time impact of an incretin-based therapy on human mesolimbic circuitry using intracranial electroencephalography.
The investigation centred on three participants with severe treatment-resistant obesity and loss-of-control eating behaviours who had undergone implantation of deep brain stimulation devices as part of an ongoing clinical trial. The researchers identified a consistent delta-theta frequency band (≤7 Hz) signal in the ventral nucleus accumbens that preceded episodes of intense food preoccupation across all participants during initial monitoring phases.
Temporary suppression observed during tirzepatide treatment
The case study focused particularly on a 60-year-old woman with type 2 diabetes who began taking tirzepatide for glucose management four months before surgical implantation of the recording device. Following dose escalation to 12.5 mg per week, the participant experienced a remarkable absence of severe food preoccupation episodes during months two through four after surgery, with only minimal occurrences recorded.
During this quiescent period, the characteristic delta-theta band biomarker became indistinguishable from baseline control states in both brain hemispheres – a stark contrast to the elevated signals typically associated with food craving states. “The delta-theta band power during severe food preoccupation states was indistinguishable from that of control states in both the left hemisphere and right hemisphere,” the authors reported. Concurrently, the participant achieved a 7% reduction in body weight, decreasing from 138 kg to 128 kg.
Biomarker re-emergence precedes breakthrough cravings
However, during months five through seven – despite continued maximum dosing at 15 mg per week – the delta-theta oscillatory pattern re-emerged with significant intensity. “The delta-theta band power from severe food preoccupation states was significantly higher than that of control states in the left hemisphere and right hemisphere,” the researchers documented. This biomarker resurgence preceded a breakthrough in food preoccupation episodes, which increased to seven per month.
The temporal relationship between biomarker emergence and behavioural change proved particularly striking. Supplementary analysis suggested approximately a seven-week lag between the return of aberrant neural activity and the most severe manifestation of food preoccupation symptoms, potentially indicating a unique pharmacological profile for tirzepatide.
Neural oscillations reflect heightened craving propensity
The study builds upon preliminary findings from two additional participants who received responsive deep brain stimulation targeting the same delta-theta biomarker. In both cases, therapeutic stimulation successfully suppressed the neural signature and corresponded with reduced food preoccupation episodes, validating the signal as a meaningful indicator of craving states.
“We propose that the effects of an incretin-based therapy (tirzepatide) on food preoccupation may be associated with modulation of aberrant activity within this key hub of human mesolimbic circuitry,” the authors concluded. The findings suggest the delta-theta power may represent a state of heightened propensity for food preoccupation rather than simply tracking individual episodes.
Implications for treatment optimisation strategies
The discovery of this electrophysiological biomarker raises intriguing possibilities for optimising incretin-based therapies. While the invasive nature of intracranial monitoring limits immediate clinical scalability, the low-frequency characteristics of the signal suggest potential accessibility through non-invasive recording methods. The authors note parallels with Parkinson disease research, where beta band signals detectable via scalp EEG have successfully guided treatment protocols.
Casey Halpern, corresponding author and professor of neurosurgery at the University of Pennsylvania, emphasised the translational potential: the findings “could provide the foundations of developing such a biomarker-based approach for tirzepatide administration for dysregulated eating.”
Study limitations and future research directions
The investigators acknowledge several important caveats. As a single uncontrolled case study, generalisation to broader populations – particularly those without compulsive eating components – remains uncertain. The research could not determine whether tirzepatide’s effects resulted from direct action within the nucleus accumbens or identify which specific incretin receptor (GLP-1 or GIP) mediated the observed changes.
Additionally, analysing electrophysiological data without tirzepatide use proved impossible, as the medication formed part of the participant’s ongoing diabetes management. The possibility that other confounding factors – including post-operative recovery, time since surgery, or unrelated behavioural changes – contributed to the observed patterns cannot be definitively excluded.
Despite these limitations, the study provides unprecedented insights into how pharmacological interventions may engage reward circuitry to influence eating behaviours. The research suggests that biomarker-guided approaches could eventually help identify when therapeutic tolerance develops and inform optimal dosing strategies for managing food preoccupation.
The preliminary nature of these findings necessitates further controlled investigation, particularly examining whether similar patterns emerge with other incretin-based therapies and across more diverse patient populations. Nevertheless, this first-in-human demonstration of nucleus accumbens modulation by tirzepatide marks a significant advance in understanding the neurobiological mechanisms underlying both obesity and its pharmacological treatment.
Reference
Choi, W., Nho, Y.-H., Qiu, L., et. al. (2025). Brain activity associated with breakthrough food preoccupation in an individual on tirzepatide. Nature Medicine. https://doi.org/10.1038/s41591-025-04035-5
