Repurposing anti-inflammatory medications for alcohol and substance use disorders

Alcohol and substance use disorders (AUD, SUD) have diverse systemic and neuroinflammatory mechanisms. Existing approved pharmacotherapies for AUD/SUDs are incompletely effective with complex polysubstance use patterns complicating treatment. Some SUDs lack any approved pharmacotherapies, and where treatments exist, inaccessibility and/or high costs of medication presents additional obstacles. Recent findings support the repurposing of several promising compounds, FDA-approved for other conditions, to reduce harmful alcohol and/or drug use to help fill these gaps. Importantly, these drugs are also nearing patent expiration which will offer increased accessibility and future affordability for patients.

Decades of data show that alcohol and drug use alter cellular energy homeostasis and increase proinflammatory signaling that drives continued substance use. We highlight preclinical studies showing that anti-inflammatory compounds FDA-approved to treat other conditions effectively reduce harmful behaviors (i.e. use, craving) in animal models for AUD and SUD [1–4]. Emergent clinical findings provide further support for advancing these drugs [1, 5, 6]. We focus on apremilast, approved for psoriatic arthritis, plaque psoriasis, and oral ulcers associated with Behcet disease, and a group of drugs approved for treatment of type 2 diabetes (T2D; e.g., exenatide, semaglutide, liraglutide, metformin) and obesity (e.g., semaglutide, liraglutide). While the proximal targets of these drugs diverge, they converge on anti-inflammatory signaling.

Apremilast is known as a phosphodiesterase 4 inhibitor that elevates cAMP, but it also rebalances pro- and anti-inflammatory factors. Apremilast curtailed excessive drinking in a spectrum of AUD animal models, including binge-like drinking and dependence-induced escalation of drinking [1]. In a double-blind, placebo-controlled proof-of-concept study, apremilast reduced drinks per day and heavy drinking days in non-treatment-seeking individuals [1].

Semaglutide, liraglutide, and exenatide are glucagon-like peptide-1 (GLP-1) receptor agonists known to suppress neuroinflammation. Metformin has numerous molecular targets/functions including augmenting GLP-1 levels and reducing oxidative stress and inflammation. Semaglutide reduced binge-like alcohol drinking in mice and rats [2]. Liraglutide lowered cue-induced, drug-primed, and stress-induced reinstatement of heroin seeking following self-administration in rats [3]. Metformin likewise reduced cue-induced cocaine-seeking in a rat model [4]. Exenatide in combination with nicotine replacement therapy improved rates of abstinence and reduced post-cessation weight gain in a pilot randomized controlled trial with prediabetic and/or overweight smokers [5]. In a double-blind, placebo-controlled study, exenatide similarly reduced alcohol intake and number of heavy drinking days in a secondary analysis based on BMI in a subgroup of obese, treatment-seeking patients [6]. The highlighted findings and a growing body of preclinical research provides support for these drugs across AUD and SUD, highlighting their exciting potential for treating polysubstance use disorder.

These data support continued pursuit of anti-inflammatory drugs as harm reduction therapy for AUD and SUDs. Additional studies, largely beyond the scope of this feature, suggest that these drugs may improve a wide variety of other symptoms associated with AUD/SUD. We highlight recent findings for these compounds not only because they converge on anti-inflammatory processes, but because adoption of such affordable pharmacotherapies can increase accessibility and equity of treatment, improve quality of life, reduce family and work burdens, and reduce loss of life for people with AUD and/or SUD.

Author contributions

ARO and SMS contributed equally to writing and editing this submission.

Competing interests

The authors declare no competing interests.