Glp-1–associated suppression of cocaine craving following tirzepatide in undiagnosed adult ADHD

Background

Substance use disorders frequently co-occur with attention-deficit/hyperactivity disorder (ADHD), which remains underdiagnosed in adulthood and contributes to adverse clinical outcomes. In some individuals, stimulant use may represent maladaptive self-medication targeting deficits in dopaminergic and noradrenergic signalling within frontostriatal circuits, leading to impaired executive functioning, increased impulsivity and heightened internal restlessness [4,5]. Cocaine may transiently normalise these processes through inhibition of monoamine reuptake, particularly dopamine, resulting in subjective cognitive relief rather than euphoria [5].

Glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed for metabolic indications, have been shown to modulate central reward circuitry, including mesolimbic dopaminergic pathways [1]. Emerging translational evidence suggests that GLP-1 signalling may reduce reinforcement salience, attenuate cue-induced craving and decrease compulsive reward-seeking behaviours, potentially influencing substance use trajectories [2].

Case Presentation

We report a 45-year-old man with obesity (BMI 41.18 kg/m²) and cocaine use disorder, initially diagnosed with bipolar affective disorder, admitted to a psychiatric day hospital. At baseline, he presented with moderate depressive symptoms (MADRS 26) and severe anxiety (GAD-7 15), with preserved insight and no psychotic features. Pharmacological treatment included agents targeting GABAergic modulation (diazepam), glutamatergic and GABAergic balance (valproate, topiramate), and dopaminergic/noradrenergic tone (bupropion), alongside quetiapine XR.

Despite significant improvement in affective and anxiety symptoms (MADRS reduced to 12; GAD-7 to 1), intermittent cocaine use persisted and was consistently described as producing mental quietness and improved cognitive organisation. Longitudinal observation revealed no evidence of manic, hypomanic or depressive episodes, prompting diagnostic reassessment and identification of previously unrecognised adult ADHD, characterised by persistent executive dysfunction, impulsivity and dysregulated attentional control.

Tirzepatide, a dual GLP-1/GIP receptor agonist [3], was initiated for metabolic indications (2.5 mg weekly, titrated to 5 mg). Shortly after initiation, the patient reported a marked reduction in cocaine craving and compulsive drive, accompanied by a subjective decrease in reward salience associated with drug-related cues. This change was temporally associated with sustained abstinence, confirmed by serial negative toxicological screens, despite continued exposure to psychosocial triggers previously linked to relapse.

Subsequent initiation of lisdexamfetamine, enhancing synaptic dopamine and noradrenaline via prodrug-mediated release, resulted in further improvement in executive functioning, attentional regulation and emotional stability, without increased craving or relapse. Over follow-up, the patient maintained abstinence from cocaine and tobacco, with improved global functioning and interpersonal relationships. BMI decreased to 30.88 kg/m², with good tolerability and no significant adverse effects.

Conclusions

This case supports the conceptualisation of cocaine use as a maladaptive attempt to compensate for underlying dysregulation of frontostriatal dopaminergic and noradrenergic systems in undiagnosed adult ADHD. The temporal association between tirzepatide initiation and rapid suppression of cocaine craving raises the hypothesis that GLP-1 receptor–mediated modulation of mesolimbic reward pathways may reduce reinforcement salience and compulsive drug-seeking behaviour [1,2]. Although causality cannot be inferred, this observation highlights a potential mechanistic target for adjunctive intervention in addiction psychiatry and warrants systematic investigation.

References

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