Psychedelics, used for millennia in spiritual and healing practices, have emerged as promising treatments for mental health conditions including depression, post-traumatic stress disorder (PTSD), substance use disorders and anxiety. Despite the therapeutic potential of psychedelics and their increasing use in both medical and nonmedical settings, there is a paucity of data on their cardiovascular safety. Here we review current evidence on the cardiovascular effects and safety of this unique class of therapeutic agents. The cardiovascular effects and associated risks of classic psychedelics are categorized into three areas: electrophysiological effects and arrhythmia risk, structural effects and valvular heart disease risk, and vascular effects including hypertension and ischemia risks. The Review also emphasizes crucial knowledge gaps that require further basic and clinical investigation including studies in individuals with underlying cardiovascular disease, characterization of important drug-drug interactions and studies on the safety of repetitive, long-term (including microdosing) exposure to classic psychedelics.