Off-label and investigational drugs in the treatment of gambling disorder: a critical review

Gambling disorder or pathological gambling is a psychiatric disorder with severe and wide-ranging consequences for the affected individual and their surroundings. While no pharmacological treatment has yet been officially approved for treatment, various drugs have been investigated to date. An electronic literature search was conducted in PubMed to identify open-label trials, randomized controlled trials, meta-analyses, other reviews and case reports. In addition, the ClinicalTrials.gov registry was reviewed to identify recent advancements, investigational drug candidates, and ongoing or forthcoming clinical research related to this topic. In this review we summarize and compare Fluvoxamine, Paroxetine, Sertraline, Citalopram, Bupropion, Nefazodone, Naltrexone, Nalmefene, Naloxone, Lithium, Valproate, Topiramate, Olanzapine, N-acetylcysteine, Disulfiram, Acamprosate, Memantine, Amantadine, Gabapentinoids, Modafinil, GLP-1 receptor agonists and Ketamine/Esketamine. From the above-mentioned substances, many have shown promising results in the treatment of gambling disorder, particularly opioid antagonists. However, the small number of studies on the respective drugs, as well as inconsistent designs and contradictory results, limit the significance and clinical applicability of the findings. Here we discuss the most promising drugs, neurobiological pathomechanisms of gambling disorder and potential methodological designs for future studies on this topic.