# Repurposing Metformin as a Treatment for Cocaine Use Disorder

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2024 · $52,664

## Abstract

PROJECT SUMMARY
Cocaine use disorder (CUD) is a chronic relapsing disease that leads to neuroadaptations in energy homeostasis
after repeated drug exposure. There is currently no FDA-approved treatment that lowers the risk of relapse in
CUD. Reported annual deaths involving cocaine have nearly quintupled in the United States from 4,939 in 2013
to 24,538 in 2021, making this a major public health concern. Despite recent scientific advances elucidating
critical neuronal circuitry and biological conditions that drive cocaine-seeking behaviors, the development of
interventions to disrupt the repeating cycle of addiction has proved more difficult. The operant behavioral model
of drug self-administration, extinction, and cue-induced reinstatement emulates cue priming and drug craving in
patients in recovery experiencing settings, cues, or memories associated with past drug use. Craving and relapse
of cocaine seeking is driven by glutamatergic (Glu) neurotransmission in the NAcC, observed in both humans
and animal models. Clinically, susceptibility to cocaine relapse is notably higher in female patients with reports
of stronger craving to cocaine-paired cues. This significant sex difference, also reflected in animal models of
CUD, represents an obstacle in treatment development that yields therapeutic benefit across sexes. Our lab has
demonstrated that metformin (MET), an FDA-approved Type II Diabetes (T2D) treatment, has pre-clinical
promise in reducing cue-induced cocaine reinstatement after a period of withdrawal when administered
intracranially in both female and male rats. My own preliminary data shows that systemic metformin reduces the
conditioned rewarding effects of cocaine in male rats. In T2D, MET improves glucose management in part
through activation of adenosine monophosphate activated protein kinase (AMPK), which when phosphorylated,
restores the intracellular ratio of AMP to ATP in response to environmental stressors. AMPK is decreased in the
nucleus accumbens core (NAcC) after chronic exposure to cocaine, with MET-induced increases in AMPK
activity thus providing a promising putative mechanism of action. Still, it remains unknown how oral MET is
biodistributed to the NAcC and how it may impact critical Glu circuitry underlying cocaine relapse events. This
study will explore the therapeutic potential of MET by defining central pharmacodynamics and pharmacokinetics
of oral MET in the NAcC. This proposal tests the hypotheses that oral administration of MET will: 1) have a more
robust effect in reducing cue-induced cocaine-seeking behavior after self-administration in male rats as
compared to female rats, 2) reduce cue-induced reinstatement via activation of AMPK, and 3) augment Glu
neurotransmission in the NAcC reducing the signal to noise of cue-associated glutamate transmission as
measured by in vivo fiber photometry. The goal of the proposed work is to provide significant evidence that
supports the potential repurposing of MET as a treat...

## Key facts

- **NIH application ID:** 10936529
- **Project number:** 5F30DA059988-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Edith Hernandez
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $52,664
- **Award type:** 5
- **Project period:** 2023-09-27 → 2027-09-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936529

## Citation

> US National Institutes of Health, RePORTER application 10936529, Repurposing Metformin as a Treatment for Cocaine Use Disorder (5F30DA059988-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10936529. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*