The resurgence in research on classic psychedelics has provided some evidence for their efficacy as therapeutic approaches to psychiatric, neurological, and medical conditions. Psychedelics are pharmacologically distinct compounds that induce various phenomenological effects, including hallucinogenic disturbances and nonordinary states of consciousness. When combined with selective serotonin or selective serotonin-norepinephrine reuptake inhibitors, psilocybin produced a better antidepressant response with small effect size than placebo, and esketamine showed greater antidepressant efficacy and better tolerability than the atypical neuroleptic quetiapine in treatment-resistant depression. In preliminary studies on chronic and acute pain, psychedelics showed mixed effects. They may also be useful in several other conditions, such as Parkinson’s, Alzheimer’s, brain trauma, disorders of consciousness, and medical problems like inflammatory bowel disease. Outside of trials, psychedelics may be used “compassionately” in some countries through exemptions or by licensed practitioners. Legal and regulatory issues are complex although there seems to be an ongoing expansion to access. Many uncertainties with psychedelics remain, regarding addiction, personality changes, psychoses, altered cognition, and ethical concerns. Improvements in mental symptoms may even end up in severe deterioration, especially with previous psychoses. Excessive expectations and inappropriate risk-benefit assessments may harm patients, clinicians, and potential options for psychedelic therapy.