Kratom Alkaloids for the Treatment of Alcohol Use Disorder.

Alcohol use disorder (AUD) accounts for nearly 4.7% of all deaths and imposes a huge economic burden on society. Despite the magnitude of the problem, only a few Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved drugs are currently available for AUD treatment. Despite being efficacious, these drugs are not without problems, adverse effects being a major issue. That combined with medication adherence and compliance problems, the discovery of new drugs is imperative. Kratom (Mitragyna speciosa) alkaloids and some of their semisynthetic derivatives reduce alcohol intake and alcohol-induced withdrawal symptoms in animal models. These compounds act as G-protein-biased ligands at the μ-, δ-, and κ-opioid receptors, and their effect in reducing alcohol intake is mediated through the δ-opioid receptor. This article provides a critical overview of recent preclinical studies involving kratom alkaloids for AUD treatment, with a particular focus on the pharmacology and medicinal chemistry of these alkaloids. FDA/EMA approved drugs, repurposed drugs, and plant-based compounds for the treatment of AUD are briefly mentioned. Finally, important caveats and future research directions on this topic are discussed.