Ayahuasca prevents the reinstatement of cocaine-induced rewarding effects in C57Bl/6 mice

Abstract Ayahuasca is a psychedelic brew used for centuries in religious rituals by indigenous cultures. Recent studies suggest its potential to reduce depression and anxiety and as an alternative for treating ethanol and tobacco use disorders. However, research on its impact on cocaine use disorder remains limited. We investigated the effects of ayahuasca on the reinstatement of cocaine-induced conditioned place preference (CPP) in C57Bl/6 mice. First, we examined if ayahuasca (2.5, 7.5, 12.5 and 15 mg DMT/kg, gavage) could induce CPP. Next, using a choice-based CPP paradigm, we compared the rewarding effects of cocaine (10 mg/kg, i.p.) with a previously established rewarding dose of ayahuasca (15 mg DMT/kg). Finally, we employed a cocaine-induced reinstatement protocol to assess the potential of ayahuasca to prevent the drug-associated contextual preference reactivation. Therefore, mice were conditioned with cocaine and subsequently treated with water or ayahuasca (12.5 or 15 mg DMT/kg). Following a cocaine challenge, reinstatement of cocaine-induced CPP was evaluated. Our findings showed that while ayahuasca induced rewarding effects with the higher dose tested, these were less pronounced than those of cocaine. Moreover, ayahuasca treatment effectively reduced cocaine-induced CPP reinstatement. These findings highlight the therapeutic value of ayahuasca in the context of cocaine use disorder.