Mazindol Immediate-Release/Sustained-Release (IR/SR): A 50-Year Legacy of Multifaceted Mechanisms and Emerging...

Mazindol, an imidazo[2,1-a]-isoindole anorectic from the 1970s, has recently re-emerged as a candidate therapy for disorders of arousal and reward dysregulation, due to its unique multimodal receptor profile. Despite its 1999 withdrawal from US/EU markets, off-label narcolepsy efficacy spurred immediate-release/sustained-release (IR/SR) development. Clinical trials demonstrate mazindol IR/SR efficacy, reducing excessive daytime somnolence and cataplexy in narcolepsy and attention-deficit/hyperactivity disorder (ADHD) severity symptomatology, with mild adverse events (e.g., dry mouth). Preclinical studies demonstrate potent monoamine transporter inhibition (dopamine, norepinephrine, serotonin) with minimal dopamine release, reducing abuse liability compared with amphetamines. Novel interactions orexin-2, 5-HT_1A, and mu-opioid receptors suggest reward modulation, low abuse potential, and utility in polydrug dependence (e.g., fentanyl-cocaine co-use). This review, covering the period 1970-2025, emphasizes the potential for repositioning mazindol, including its potential utility in managing opioid-stimulant co-dependence and attention-related disorders, and underscores its relevance for future therapeutic repurposing. Although this is a narrative review, we conducted targeted searches of PubMed, Scopus, and ClinicalTrials.gov from this period of time, using terms including "mazindol," "narcolepsy," "ADHD," and "substance use disorder."