Table 8.

Overview of clinical studies of psychedelics used to treat diagnoses associated with trauma exposure.

Diagnosis Associated with Trauma Exposure	MDMA	Psilocybin	LSD	Ayahuasca	Ketamine (Focus on Ketamine-Assisted Psychotherapy (KAP))
.Major Depressive Disorder (MDD)	Dose-Response Study of MDMA-assisted Psychotherapy in People With PTSD Preliminary data showed absolute (unknown significance) decrease in BDI-II scores after treatment with MDMA in PTSD patients (PAP).	Gukasyan et al., 2022 [551] Randomized waiting-list controlled trials found 75% response in treating severe depression and 58% remission (PAP). Carhart-Harris et al., 2021 [499] Trial did not find a significant difference in antidepressant effects between psilocybin and escitalopram (based on the primary outcome measure of change in depression scores on the QIDS-SR-16.) See Appendix 1B. Davis et al., 2021 [500] Mean GRID-HAMD scores at weeks 1 and 4 in the immediate treatment group were significantly lower than the scores in the delayed treatment group, suggesting that psilocybin combined with therapy is effective in treating MDD. See Appendix 1C. (Psychedelic-only)	LSD Therapy for Persons Suffering From Major Depression (LAD) Trial completed; awaiting results (PAP) Bershad et al., 2019 [463] Microdoses of LSD (0-26 μg) in normal controls did not affect depression per POMS questionnaire score (Psychedelic-only) Grof et al., 1973 [876] LSD and dipropyltryptamine (DPT) trial in terminal cancer patients. LSD and DPT decreased symptoms of depression (PAP).	Palhano-Fones et al., 2019 [453] Trial found significant antidepressant effects of ayahuasca (measured by MADRS) when compared with placebo. See Appendix 1A. (Psychedelic-only)	Wilkinson et al., 2021 [884] 6 IV ketamine doses administered over the course of 3 weeks as a treatment for depression (n=42). 28 patients (66.7%) saw >50% reduction in depression severity by the end of the ketamine sessions. The ketamine responders were randomized to receive either cognitive behavioral therapy (CBT) or treatment as usual (TAU) for an additional 14 weeks. Greater sustained improvements in MADRS scores were noted in the CBT group. Wilkinson et al., 2017 [877] Open-label trial in which 4 ketamine infusions were administered twice a week for 2 weeks in conjunction with a 10-week course of CBT in patients with treatment-resistant depression (n=16). 50% of participants responded to the ketamine infusions, with 7 achieving symptom remission (KAP).
Substance Use Disorder (SUD)/ Alcohol Use Disorder (AUD)	Sessa et al., 2019 [770] Case report from preliminary data in current clinical trial, showed that treatment is well tolerated. Study will be expanded into a randomized placebo-controlled study (PAP).	Bogenschutz et al., 2022 [498] Double-blind RCT: heavy drinking days during the 32-week period were significantly less for psilocybin group compared with diphenhydramine group (p = .01, Hedges g, 0.52) (PAP). Bogenschutz et al., 2015 [763] Open-label trial showed a significant reduction in self-reported drinking days and heavy drinking days for 32 weeks (p < 0.05) after psilocybin (PAP).	LSD Treatment for Persons With Alcohol Use Disorder (LYSTA) Trial not yet recruiting (Psychedelic-only) Fuentes et al., 2020 [423] Summary of 7 RCTs from 1960s/70s for LSD vs. placebo on AUD, 4 of which had statistically significant effects, but not in the long term. (PAP for all except Denson & Sydiaha, 1970)	Berlowitz et al., 2019 [878] Prospective cohort study of (n=36) males with substance use disorder (SUD) or dependence. One week after treatment, participants had significant decreases in dependence severity outcomes for drug use (p < 0.001) and alcohol use (p < 0.001), psychiatric status (p < 0.001), and social/familial relationship problems (p < 0.001) (as indexed by the ASI), and improvements in substance craving (p < 0.001) (as indexed by the CEQ). Note: No control group (PAP). Barbosa et al. 2018 [879] Observational cross-sectional case control of 30 UDV members compared with 27 non-ayahuasca users. The ayahuasca group demonstrated less recent use of alcohol (p < 0.001), and greater past use of alcohol (p = 0.007) and cannabis (p = 0.001) (Psychedelic-only) Fábregas et al., 2010 [765] Observational trial with two parts: jungle-based ayahuasca users (n = 56) compared with rural controls (n = 56); urban-based ayahuasca users (n = 71) compared with urban controls (n = 59). In both studies, reductions in alcohol use and psychiatric status subscales of the Addiction Severity Index (ASI) were found among ayahuasca users at 12 months (PAP).	Grabski et al., 2022 [771] 96 participants with severe AUD were enrolled in a trial to compare ketamine to placebo and pilot ketamine combined with mindfulness-based relapse prevention therapy in increasing alcohol abstinence. Significantly greater rates of alcohol abstinence were observed in the ketamine group compared with the placebo group at 6-month follow-up. (KAP and ketamine only) Dakwar et al., 2020 [880] Participants with AUD (n = 40) were assigned to receive either IV ketamine infusion or an active control during an outpatient motivational enhancement therapy program. Compared with the control, ketamine significantly improved abstinence, time to relapse, and days of heavy drinking. (Concurrent ketamine and therapy) Dakwar et al., 2019 [773] Participants with cocaine use disorder (n = 55) were randomized to receive an IV ketamine infusion or midazolam during a 5-day inpatient stay, while also beginning a 5-week program of mindfulness-based behavioral modification. Improved rates of abstinence from cocaine were observed in the ketamine group (48.2%) over the last 2 weeks of the trial, compared with the midazolam group (10.7%). (Concurrent ketamine and therapy) Krupitsky et al., 2007 [881] 59 participants with heroin dependence were enrolled in a 2-arm RCT. All participants received psychotherapy in conjunction with IM ketamine, and were then randomized to receive either 2 sessions of addiction counseling sessions or ketamine-guided psychotherapy sessions. At 1-year follow-up, 50% of participants in the multiple ketamine infusion group were fully abstinent from heroin vs. 22.2% of the single ketamine session group (KAP).
-	-	-	-	Thomas et al., 2013 [766] Preliminary observational trial. Improvements in self-reported alcohol, tobacco, and cocaine use up to 6 months post-retreat (PAP).	Krupitsky et al., 2002 [774] 70 participants with heroin dependence were enrolled in a 2-arm RCT and randomized to a single high or low dose of IM ketamine combined with existentially oriented psychotherapy. Complete heroin abstinence rates at 1- and 2-year follow-up were 24% and 17% in the high-dose group, vs. 6% and 2% in the low-dose group (KAP).
Anxiety	Wolfson et al., 2020 [190] Trials found groups treated with MDMA had a greater mean reduction in STAI-Trait scores (measuring reduction in anxiety) compared with placebo groups at the primary endpoint; results did not reach a significant group difference (p = 0.056). See Appendix 1D (PAP). Danforth et al. 2018 [882] MDMA group showed significantly greater improvement in LSAS scores from baseline to primary endpoint compared with placebo group. A 6-month follow-up showed similar positive results. See Appendix 1F (PAP).	Yu et al., 2021 [777] Meta-analysis collated data from 5 RCTs: Significant and sustained improvement in trait anxiety (Hedges’ g = -0.71, 1 months g = -1.04, 3 months g = -0.60, 6 months g = -1.03) and significant, though time-limited, improvement in state anxiety (Hedges’ g = -0.70, 1 months g = -0.73, 3 months g = -0.47, 6 months g = -0.88) (PAP).	Holze et al., 2023 [883] (still in pre-proof): Anxiety both with and without life-threatening illness. Timepoints of measurements occurred: between sessions, 2 weeks post second session, 8 weeks post second session, 16 weeks post second session. Improvements in anxiety (global STAI d=-1.2, -1.6, -1.0, -0.87) depression (HAM-D-21 d=-1.1, -1.5, -0.60, -1.1; BDI d=-0.57, -1.1, -0.48, -0.72), general psychiatric symptomatology as compared with placebo (PAP). Gasser et al., 2014 [778] Positive trends associated with LSD-assisted psychotherapy were observed in STAI at 2-month follow-up, and state anxiety was significantly reduced. See Appendix 1E (PAP). Grof et al., 1973 [876] LSD and DPT trial in terminal cancer patients. LSD and DPT decreased symptoms of anxiety (PAP).	N/A	N/A (No clinical trials specific to KAP for anxiety-related disorders)

Abbreviations: ASI: Addiction Severity Index, AUD: Alcohol use disorder, BDI-II: Beck Depression Inventory Second Edition, CBT: Cognitive Behavioral Therapy, CEQ: Creative Experiences Questionnaire, DPT: Dipropyltryptamine, GRID-HAMD: GRID Hamilton Rating Scale for Depression, HAM-D-21: Hamilton Depression Rating Scale (HAM-D) (21-item), IM: Intramuscular, IV: Intravenous, KAP: Ketamine-assisted psychotherapy, LAD Study: LSD Therapy for Persons Suffering From Major Depression, LSD: Lysergic acid diethylamide, LSAS: Liebowitz Social Anxiety Scale, LYSTA Study: LSD Treatment for Persons With Alcohol Use Disorder, MADRS: Montgomery-Asberg Depression Rating Scale, MDD: Major depressive disorder, MDMA: 3,4-methylenedioxy-methamphetamine, PAP: Psychedelic-Assisted Psychotherapy, POMS: Profile of Mood States, PTSD: Post-traumatic stress disorder, QIDS-SR-16: Quick Inventory of Depressive Symptomatology (16-Item) (Self-Report), RCT: Randomized controlled trial, STAI: State-Trait Anxiety Inventory, SUD: Substance use disorder, TAU: Treatment as usual, UDV: União do Vegetal.