Modulation of monoaminergic neurotransmission in substance use disorders: a neuropharmacological perspective focusing on plant-derived metabolites

Substance use disorders (SUDs) pose a major global health burden, often worsened by comorbid depression and anxiety. Dysregulation of monoaminergic neurotransmission, especially dopamine, serotonin, and norepinephrine transporters, underlies the reinforcing and harmful effects of addictive drugs. Current pharmacotherapies targeting these transporters offer benefits but are limited by delayed onset, side effects, and modest efficacy against emotional and cognitive symptoms. Despite advances in structural biology, a unified framework integrating transporter structure with docking and molecular dynamics simulations remains lacking. Emerging evidence suggests that plant-derived metabolites and essential oil preparations may modulate monoamine transporters through both direct and indirect mechanisms. These includes allosteric effects, membrane interactions, ion channel modulation, and downstream signaling pathways; however, these effects require further validation. This review summarizes recent preclinical and clinical data on transporter-modulating metabolites from Hypericum perforatum L., Rhodiola rosea L., Withania somnifera , and some of the essential oils. It highlights mechanistic insights from structural biology and molecular pharmacology, suggesting that plant-derived metabolites and essential oil preparations may influence monoaminergic neurotransmission and stress-related pathways. Despite challenges in bioavailability, standardization, and clinical validation, these metabolites may offer polypharmacology for adjunctive, personalized SUDs interventions. Integrated approaches, merging structural modeling, enhanced delivery, and rigorous trials, are needed.