Here we show its active metabolite, desmetramadol, is as effective as morphine, oxycodone and fentanyl in eliciting G protein coupling at the human μ opioid receptor (MOR), but surprisingly, supratherapeutic concentrations spare human MOR-mediated βarrestin2 recruitment thought to mediate lethal opioid-induced respiratory depression. Here, OPRM1 is linked to respiratory depression.