Interactions between fentanyl and 2,5-dimethoxy-4-methylamphetamine: Ventilatory effects in nonhuman primates

Increasing interest in the therapeutic potential of psychedelics, combined with expanding availability, decreasing perceived risk, and widening efforts toward decriminalization, underscore the need to investigate potential consequences that might emerge with their use, including interactions that occur when psychedelics are taken in combination with other drugs such as opioids. This study examined effects of 2,5-dimethoxy-4-methylamphetamine (DOM) on fentanyl-induced ventilatory depression in rhesus monkeys (n = 6) using head plethysmography. Fentanyl (0.001-0.1 mg/kg) and DOM (0.01-0.32 mg/kg) were studied alone and in pairwise mixtures. Fentanyl alone dose-dependently decreased tidal volume while DOM alone had no effect. However, in a majority of monkeys, combining DOM with fentanyl reduced ventilation to a greater extent than the same doses of fentanyl alone. Taken together with previous studies, these data suggest that, although DOM as well as other serotonergic hallucinogens fail to enhance other abuse-related effects of opioids, they might exacerbate opioid-induced ventilatory depression, which would increase risk for overdose. Whether ventilatory effects of DOM-fentanyl mixtures extend to combinations of other opioids and other drugs with similar pharmacological properties remains unclear. SIGNIFICANCE STATEMENT: Growing interest in psychedelics underscores the need to understand risks associated with their use, including interactions with other drugs. In this this study, 2,5-dimethoxy-4-methylamphetamine enhanced the ventilatory effects of fentanyl, revealing a novel potential adverse effect of psychedelics.