Therapeutic Potential of Peroxisome Proliferator-Activated Receptor (PPAR) Agonists in Substance Use Disorders: A Synthesis of Preclinical and Human Evidence

Targeting peroxisome proliferator-activated receptors (PPARs) has received increasing interest as a potential strategy to treat substance use disorders due to the localization of PPARs in addiction-related brain regions and the ability of PPAR ligands to modulate dopamine neurotransmission. Robust evidence from animal models suggests that agonists at both the PPAR-α and PPAR-γ isoforms can reduce both positive and negative reinforcing properties of ethanol, nicotine, opioids, and possibly psychostimulants. A reduction in the voluntary consumption of ethanol following treatment with PPAR agonists seems to be the most consistent finding. However, the human evidence is limited in scope and has so far been less promising. There have been no published human trials of PPAR agonists for treatment of alcohol use disorder, despite the compelling preclinical evidence. Two trials of PPAR-α agonists as potential smoking cessation drugs found no effect on nicotine-related outcomes. The PPAR-γ agonist pioglitazone showed some promise in reducing heroin, nicotine, and cocaine craving in two human laboratory studies and one pilot trial, yet other outcomes were unaffected. Potential explanations for the discordance between the animal and human evidence, such as the potency and selectivity of PPAR ligands and sex-related variability in PPAR physiology, are discussed.