Abstract Objective During the last few decades, endocannabinoid system has emerged as a novel possible target for antidepressant treatment. Although the medical literature provides information on the mood-changing effects of CB1 ligands, little is known about the possible interaction between the simultaneous activation or inhibition of the CB1 receptor and administration of other agents that possess antidepressant potential. The main goal of our study was to evaluate the influence of the CB1 cannabinoid receptor ligands (oleamide – an endogenous agonist and AM251 – an inverse agonist/antagonist) on the antidepressant-like activity of biometals (i.e. magnesium and zinc). Methods The forced swim test and the tail suspension test in mice were used to determine the antidepressant-like activity. Key findings Concomitant intraperitoneal administration of per se inactive doses of oleamide (5 mg/kg) or AM251 (0.25 mg/kg) and the tested biometals (i.e. magnesium, 10 mg/kg or zinc, 5 mg/kg) shortened the immobility time of animals in the forced swim test and the tail suspension test. The observed effect was not associated with an increase in spontaneous locomotor activity of mice. Conclusions The simultaneous modulation of the cannabinoid system and supplementation of magnesium or zinc produce at least additive antidepressant-like effect.