Table 1.

Psychedelic Substances in the Treatment of PTSD: Therapeutic Rationale, Administration, Setting, and Evidence

Substance	Therapeutic rationalea	Administration	Setting	Evidence
MDMA	• Increases release of serotonin, dopamine, norepinephrine, oxytocin, prolactin, vasopressin, and cortisol. • Serves as a catalyst to psychotherapy. • Increases fear extinction. • Reduces amygdala activity. • Reopens critical period for social reward learning. • Reduces fear response and shame. • Increases openness and interpersonal trust. • Increases emotional empathy. • Improves processing traumatic memories.	• Route of administration: oral. • Dose: 75–125 mg. • Duration of action: 4–8 h. • Administration at start of therapy session. • Multiple administrations (typically 3 sessions) spaced 1 mo apart.	• Clinical but aesthetically pleasant room. • Presence of 2 therapists. • Use of music to deepen and support therapeutic process. • Embedded within psychotherapeutic treatment (nondirective). • Multiple nondrug preparation and integrative sessions.	• Sustained reduction of PTSD symptoms. • Phase 2 RCT (n = 105) completed in 2016. • Phase 3 RCT expected to be completed in 2021. • Other indications: alcohol use disorder and social anxiety (in autistic adults).
Ketamine	• NMDA receptor antagonist. • Rapid (temporary) symptom reduction. • May serve as a catalyst to psychotherapy. • Increases synaptic plasticity. • Facilitates fear extinction and blocks memory reconsolidation. • May increase receptivity to therapeutic interventions. • May improve ability to process traumatic memories.	• Route of administration: i.v., i.m., intranasal, oral. • Dose: typically 0.50 mg/kg over 40 min. • Duration of action: 40–70 min. • Administration at start of treatment, beginning of therapy session, after memory retrieval, or without psychotherapy (depending on rationale). • Single or multiple administrations spaced days to weeks apart.	• Clinical room with no to minimal attention to aesthetics. • Psychological support varies from minimal support from nurse/psychiatrist to extensive support from psychotherapist. • Virtually no use of music. • Currently not embedded within psychotherapeutic framework. • No nondrug preparation and integrative sessions.	• Rapid (temporary) reduction of PTSD and depressive symptoms. • 1 RCT (n = 41) completed in 2014. • Multiple RCTs ongoing. • Increasing evidence for treatment of depression. • Other indications: anesthesia, depression, suicidality, alcohol and opiate addiction.
Classical psychedelics	• 5-HT2A receptor agonists. • Serve as a catalyst to psychotherapy. • Increase synaptic plasticity. • Can reduce amygdala reactivity during emotional processing. • Increase insightfulness and introspection. • Increase divergent thinking and mindfulness-related capacities. • May reduce avoidance. • Can increase emotional empathy. • Can induce emotional breakthrough experiences. • May resolve existential distress. • May increase access to traumatic memories.	• Route of administration: oral. • Dose: 10–25 mg (psilocybin), 50–200 μg (LSD). • Duration of action: 4–12 h. • Administration at beginning of therapy session. • Single or multiple administrations (typically not more than 3) spaced weeks to months apart.	• Clinical but aesthetically pleasant room. • Presence of 2 therapists/guides. • Use of music to deepen and support therapeutic process. • Often embedded within psychotherapeutic treatment (nondirective). • Multiple nondrug preparation and integrative sessions.	• No RCTs in PTSD. • Extensive psychotherapeutic use of LSD and psilocybin during first wave (1950–1970) of research with psychedelics. • Used in treatment of concentration camp syndrome in 1960s and 1970s. • Recent evidence from studies in other indications with high effect sizes. • Other indications: depression, substance use disorders, end of life anxiety, and obsessive-compulsive disorder.
Cannabinoids	• Target the endocannabinoid system (e.g., CB1 and CB2 receptors). • Symptom management (insomnia and nightmares). • May serve as a catalyst to psychotherapy. • May increase fear extinction (decreased fear extinction with chronic use). • May improve ability to process traumatic memories.	• Route of administration: oral, sublingual, or inhaled (vaporized or smoked). • Dose: varying dosages and different ratios of THC/CBD. • Duration of action: 3–8 hours. • Daily administration in case of symptom management.	• Take-home prescription. As such, used in a variety of settings. • Depending on symptoms, used throughout the day or just before sleep.	• 1 small RCT (n = 10) with nabilone completed in 2015. • Multiple RCTs with medical cannabis ongoing. • Other indications: symptom management for multiple nonpsychiatric indications, e.g., multiple sclerosis and oncology (pain, cachexia, and nausea).

Abbreviations: CB1 and CB2, cannabinoid 1 and 2 receptors; CBD, cannabidiol; 5-HT2A, serotonin 2A receptor; LSD, lysergic acid diethylamide; MDMA, 3,4-Methylenedioxymethamphetamine; NMDA, N-methyl-D-aspartate; PTSD, posttraumatic stress disorder; RCT, randomized controlled trial; THC, tetrahydrocannabinol.

^aTherapeutic rationale based on both (pre)clinical research and clinical observations.