Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following
exposure to a traumatic experience. An estimated 12 million U.S. adults are presently affected by this
disorder. Current treatments include psychological therapies (e.g., exposure-based interventions) and
pharmacological treatments (e.g., selective serotonin reuptake inhibitors (SSRIs)). However, a significant
proportion of patients receiving standard-of-care therapies for PTSD remain symptomatic, and
new approaches for this and other trauma-related mental health conditions are greatly needed. Psychedelic
compounds that alter cognition, perception, and mood are currently being examined for their efficacy
in treating PTSD despite their current status as Drug Enforcement Administration (DEA)-
scheduled substances. Initial clinical trials have demonstrated the potential value of psychedelicassisted
therapy to treat PTSD and other psychiatric disorders. In this comprehensive review, we
summarize the state of the science of PTSD clinical care, including current treatments and their shortcomings.
We review clinical studies of psychedelic interventions to treat PTSD, trauma-related disorders,
and common comorbidities. The classic psychedelics psilocybin, lysergic acid diethylamide
(LSD), and N,N-dimethyltryptamine (DMT) and DMT-containing ayahuasca, as well as the entactogen
3,4-methylenedioxymethamphetamine (MDMA) and the dissociative anesthetic ketamine, are
reviewed. For each drug, we present the history of use, psychological and somatic effects, pharmacology,
and safety profile. The rationale and proposed mechanisms for use in treating PTSD and traumarelated
disorders are discussed. This review concludes with an in-depth consideration of future directions
for the psychiatric applications of psychedelics to maximize therapeutic benefit and minimize
risk in individuals and communities impacted by trauma-related conditions.