Preclinical research in psychedelics drugs has dramatically increased within the last decade focus on its therapeutic potential in psychiatric disorders. Observational data and animal studies have demonstrated a potent anti-addictive effect of psychedelic alkaloids ibogaine (Ibo), and its metabolite noribogaine (Nor); however, the underlying mechanism remains under study. We hypothesized that the anti-addictive property of both psychedelics can be related to an antidepressant-like effect, since ibogaine and noribogaine inhibit the serotonin transporter, and ibogaine increased the brain-derived neurotrophic factor RNAm levels in the rat prefrontal cortex. We evaluated the behavioral effects (dose- and time-dependence) induced by a single dose of Ibo and Nor administration (20 and 40 mg/kg i.p.) by the rat forced swim test. A correlation between plasma and brain concentrations of Ibo and Nor and the behavioral response was performed. Ibo and Nor induced a dose- and time-dependent antidepressant-like effect without changes of motor activity. A correlation between plasma and brain concentrations and behavior was found. Notably, that behavioral effect was not reproduced by an equivalent dose of the classic selective serotonin reuptake inhibitor fluoxetine (40 mg/kg, i.p., single injection). Our results suggest a polypharmacological mechanism underpinning the antidepressant-like effects of Ibo and Nor, and we propose that this effect can collaborate to its anti-addictive property.