# Drug development of clavulanic acid, a GLT-1 activator: proof of concept for cocaine use disorder

> **NIH NIH U01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $1,777,470

## Abstract

Cocaine-related overdose deaths are rapidly rising in the U.S. An effective medication for cocaine addiction is
urgently needed. This proposal aims to determine whether clavulanic acid (CLAV) is effective in treating
cocaine use disorder. Animal studies suggest that activation of GLT-1, the dominant astroglial glutamate
transporter responsible for clearing extracellular glutamate, may provide a breakthrough approach to managing
cocaine addiction. Studies in rodents demonstrate that CLAV, a non-antibiotic component of the commonly
used antibiotic Augmentin, has short-term effects to a) increase GLT-1 activity, thus reducing extracellular
glutamate in brain areas associated with addiction, i.e., the nucleus accumbens (NAc) and its afferent limbic
region, the anterior cingulate cortex (AC), and b) inhibit the reinforcing strength of cocaine in a model of
cocaine self-administration. We have concluded an inpatient study, required by the FDA, showing that the co-
administration of CLAV and cocaine to volunteer non-treatment-seeking adults with cocaine use disorder is
associated with decreased cocaine craving and produces no serious toxicity. Using magnetic resonance
spectroscopy (MRS) at 3T, we have human pilot data demonstrating changes in brain glutamate in the AC
after the first dose of CLAV, and this is maintained for 10 days of daily CLAV dosing. We now propose two
human trials to assess the therapeutic effectiveness of CLAV: 1) We will determine whether CLAV maintains
its therapeutic effects to reduce cocaine craving when given orally once-a-day, since CLAV has a very short
half-life in the serum. Glutamate levels in the AC, measured after cessation of CLAV dosing, will be used as a
biomarker to assess whether CLAV can be dosed once daily. Resting state functional connectivity will
determine whether the AC increases target engagement with the NAc, and whether network deficits associated
with chronic cocaine use are improved by repeated CLAV. 2) In subjects who tolerate CLAV 500 mg/day, we
will determine the effects, safety and tolerability of CLAV 750 mg/day. 3) Finally, we will conduct a
randomized, placebo controlled multi-site, outpatient efficacy study of CLAV in cocaine-addicted patients
seeking treatment, using a formulation for once-daily dosing as determined in 2). If efficacy is confirmed (Go-
No Go decision point), the project will transition to our pharmaceutical company partner, VistaGen, who will be
supporting formulation development, intellectual property and regulatory strategy, as well as clinical and
preclinical development during this proposal. With VistaGen, we will schedule an FDA meeting to explore
breakthrough therapy status and discuss development plans leading to a New Drug Application submission.

## Key facts

- **NIH application ID:** 9984027
- **Project number:** 1U01DA048517-01A1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Mary F. Morrison
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,777,470
- **Award type:** 1
- **Project period:** 2020-05-15 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984027

## Citation

> US National Institutes of Health, RePORTER application 9984027, Drug development of clavulanic acid, a GLT-1 activator: proof of concept for cocaine use disorder (1U01DA048517-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9984027. Licensed CC0.

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