While illicit use of hallucinogens, cannabinoids, and opioids has been stigmatized in the past, emerging research demonstrates therapeutic benefits from selective use of psychedelics, cannabinoid derivatives, and kappa- and mu-opioid receptor modulators in controlled circumstances for the treatment of different psychiatric conditions, including mood disorders, anxiety disorders, posttraumatic stress disorder, and schizophrenia. The role of endocannabinoids and endogenous opioids in regulation of stress response and mood will be discussed, as well as relevant receptor pharmacology. Finally, available scientific research supporting their therapeutic use will be critically reviewed.