Table 1.

Negative valence systems.

Condition/Measures	Design	N, age	Psychedelic/dose	Clinical/neurobiological outcomes	References
Treatment-resistant depression (TRD) MADRS, 5D-ASC, ASRS, EBI; EQ-5D-3L, GAD-7, HAM-D-17, MGH-ATRQ, MINI, MSI-BPD, PANAS, QIDS, QIDS-SR-16, SDS, STAR-C, STAR-P, WSAS	Randomized, double-blind	n = 233 94% no prior psilocybin experience	Psilocybin 1 mg (n = 79), or 10 mg (n = 75) or 25 mg (n = 79)	−6.6 points on change from baseline in MADRS total scores in 25 mg vs. the 1 mg dose at week 3 (p < 0.001) 25 mg group: 36.7% showed response at week 3, 29.1% were in remission at week 3, 24.1% were sustained responders at week 12 Serious treatment emergent adverse events: 6.3% in 25 mg, 8.0% in 10 mg, 1.3% in 1 mg. 12 patients reported suicidal behavior, intentional self-injury, and suicidal ideation (≥1 month post-psilocybin)	(8), unpublished
Major depressive disorder (MDD) QIDS-SR-16, BDI-1A, HAM-D-17, MADRS, FS, STAI, BEAQ, WSAS, SHAPS, WEMWBS, SIDAS, PRSexDQ, EBI, LEIS, PTCS	Double-blind, randomized, controlled	59 MDD (20F) 41 yrs (30 psilocybin, 29 escitalopram group)	Two psilocybin 25 mg po 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) Or two psilocybin 1 mg 3 weeks apart plus 6 weeks of daily escitalopram po	No significant difference between groups in QIDS, mean (±SE) changes in the scores from baseline to week 6 were −8.0 ± 1.0 points in the psilocybin group and −6.0 ± 1.0 in escitalopram group Psilocybin decreased network modularity, or increased flexibility, of executive networks compared to the escitalopram group	(5, 42)
MDD GRID-HAMD, QIDS-SR, BDI, PHQ, C-SSRS, HAM-A, STAI	Randomized waitlist control trial (randomized immediately or after an 8-week delay) Antidepressant free	24 MDD (16F) 39.8 yrs (12.2)	Psilocybin (20 mg/70 kg and 30 mg/70 kg) Separated by 1.6 (mean) weeks	Significant decrease in GRID-HAMD and QIDS-SR scores at weeks 1 and 4 in the immediate treatment group compared to delayed treatment group Psilocybin increased cognitive flexibility for at least 4 weeks post-treatment (not correlated with antidepressant effects) Glutamate and N-acetylaspartate were decreased in the ACC at 1 week Greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility Baseline dFC from the ACC predicted improvements in cognitive flexibility Greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility	(4, 83)
Treatment-resistant depression (TRD) QIDS, BDI, STAI-T, SHAPS, MADRS, GAF, 11D-ASC, RRS BOLD fMRI Emotional Faces Images Task Cerebral blood flow (CBF)	Open label Antidepressant free	12 TRD (6F) 42.6 yrs (8 additional males at 6-month follow-up)	Psilocybin (10 and 25 mg 7 days later)	Significant reduction in depressive and anxiety symptoms and improvement in anhedonia scores from baseline to 1 week and 3 months 3-months: seven (58%) met criteria for response (BDI) 6-months: significant reductions in depression and anxiety symptoms (QIDS, BDI, STAI-T) Increased amygdala responses to emotional stimuli 1 day post-psilocybin, increased responses to fearful and happy faces in the right amygdala post-treatment. Right amygdala increases to fearful vs. neutral faces were predictive of clinical improvements at 1-week Decreases in CBF in the temporal cortex, including the amygdala (decreased amygdala CBF correlated with reduced depressive symptoms) Increase in FC between the amygdala and vPFC to occipital-parietal cortices during face processing Decreased vPFC-right amygdala FC in response to fearful and neutral (but not happy) faces associated with levels of rumination at 1 week (RRS) Emotional face recognition faster at follow-up in TRD but not controls and significantly correlated with a reduction in anhedonia Reduction of depressive symptoms at 5 weeks associated with high scores of acutely experienced pleasurable self-dissolution and by low scores for dread of ego dissolution Qualitative; change from disconnection to connection, and from emotional avoidance to acceptance	(6, 7, 40, 84–88)
TRD MADRS, HAM-D, MEQ30, BPRS+, CADSS, HRS at baseline, Day 1 (D1), D2 and D7 after dosing Serum BDNF and cortisol at D0 and D2	Randomized placebo-controlled trial Antidepressant free	29 TRD Aya = 14 (11F) 39.71 yrs (±1.26) Placebo = 15 (10F) 44.2 yrs (±11.98) 45 HCs (25F) 31.56 yrs (±9.90)	Ayahuasca 0.36 ± 0.01 mg/ml of N, N-DMT (mean ± S.D)	Significant reduction in depressive symptoms (MADRS) at D1, D2, and D7 vs. placebo Response rates significantly higher in the aya group at D7 (64 vs. 27%) Aya increased BDNF at D2 vs. placebo in both HCs and TRD but no significant differences between HC and MDD No significant differences in suicidality between aya vs. placebo Aya acutely increased salivary cortisol levels in both TRD and in HCs. 48 h after aya no difference in the cortisol awakening response between TRD and HCs Aya reduced CRP levels in both TRD (higher at baseline) and HCs compared to placebo TRD group treated with aya showed a significant correlation between larger reductions of CRP and lower depressive symptoms 48 h after aya. No significant changes in IL-6 levels	(89–93)
MDD SPECT (8 h post-dose) MADRS, HAM-D, BPRS (Anxious-Depression subscale) YMRS, CADSS Scales at 10 min before (baseline), 40, 80, 140, 180 min post-dosing and 1, 7, 14, 21 days	Open label Antidepressant free	17 MDD (14F) (3: mild, 13:moderate, 1:severe) 42.71 yrs (12.11)	Ayahuasca (2.2 mL/kg)	Significant decrease in MADRS and HAM-D (and subscales of the BPRS) across all time points No significant changes in YMRS scores Significant increases in the CADSS from 40 to 80 min Increased blood perfusion in the left nucleus accumbens, right insula and left subgenual area Significant acute (40, 80, 140, 180 min) and post-acute (1, 7, 14, 21 days) decreases in suicidality in secondary analysis using MADRS subscale among participants with baseline suicidality (n = 15)	(94, 95)
MDD HAM-D, MADRS, BPRS (Anxious-Depression subscale), YMRS Scales at 10 min before (baseline), 40, 80, 140, 180 min post-dosing and 1, 7, 14, 21 days	Open label Antidepressant free	6 MDD (4F) (2:mild, 3:moderate, 1:severe) 44.16 yrs (±13.55)	Ayahuasca (0.8 mg/mL DMT)	HAMD: significant decrease at D1, D7, D21 vs. baseline MADRS: significant decrease at 180 min, D1, D7, D21 vs. baseline BPRS-AD subscales: decrease at 140, 180 min, D1, D7, D14, D21 vs. baseline No significant changes in YMRS scores	(96)
Depression and anxiety symptoms in cancer GRID-HAM-D, HAM-A, BDI, STAI, POMS, HRS, 5D-ASC, PEQ MEQ30, M scale, BSI, MQOL, LAP-R, LOT-R, PIL, DTS, PEQ, FACIT-Sp, SROS, FMS	Randomized, double-blind, cross-over trial, counterbalanced	51 (25F) 56.3 yrs (1.4)	Psilocybin (1 or 3 mg/70 kg) and high dose (22 or 30 mg/70 kg) 5 weeks apart	Significant antidepressant and anxiolytic effects (HAMA, GRID-HAM-D) At 6 months; 83% (HAM-A) and 79% (GRID-HAM-D) met the criteria for response Significant improvements in BDI, STAI-state scale (STAI-S), STAI-T and POMS Mystical-type psilocybin experience on session day mediated therapeutic effect of psilocybin	(81)
Adjustment disorder and/or generalized anxiety in cancer HADS, BDI, STAI-S and STAI-T, BDI Outcomes assessed prior to crossover at 7 weeks, and up to 26 weeks after dosing session 2	Double-blind, placebo-controlled, crossover	29 (18F) 56.28 yrs (12.93)	Psilocybin (0.3 mg/kg) Or niacin (250 mg)	Immediate and sustained reductions in anxiety and depression symptoms (HADS, BDI, STAI-S and STAI-T) that remained significant until final follow-up. At 6.5-months: anti-depressant (BDI) or anxiolytic response rates (HAD-A) 60–80% At 4.5 yrs follow-up (16 alive, 15 participated); ~60–80% met criteria for clinically significant antidepressant or anxiolytic responses 71–100% attributed positive life changes to the psilocybin-assisted therapy and rated it among the most personally meaningful and spiritually significant experiences of their lives Reductions in suicidal ideation and loss of meaning	(82, 97, 98)
Anxiety symptoms in cancer patients EORTC-QLQ-30, STAI, HADS, Visual Analog Pain Scale, SCL-90-R Outcomes at baseline, 1-week, 2-months, 12-months	Double-blind, randomized, active placebo-controlled pilot, then into open-label crossover	12 (4F) 51.7 yrs	LSD (200 mcg) (n = 8) Or 20 mcg with an open-label crossover to 200 mcg after initial blinded treatment (n = 4) 2–3 weeks apart	2-months: significant reductions in STAI, sustained at 12 months Qualitative follow up at 12-months: insightful, cathartic, and interpersonal experiences, accompanied by a reduction in anxiety (77.8%), increase in quality of life (66.7%)	(99, 100)
Anxiety/adjustment disorder in advanced stage cancer 5D-ASC, STAI, BDI, POMS regularly up to 6 months	Double-blind placebo-controlled cross-over trial	12 (11F) 36–58 yrs (range)	Psilocybin (0.2 mg/kg) or niacin (250 mg) 2 separate dosing sessions	Significant decreases were observed in STAI scores at 3-months follow-up, and BDI scores at 6-months All 12 participants completed the 3-month follow-up 8 completed the 6-month follow-up (two subjects died and two became too ill to continue)	(80)
Obsessive compulsive disorder (OCD) YBOCS, VAL at 0, 4, 8, and 24 h, HRS at 8 h	Open label proof-of-concept pilot Antidepressant free (failed to respond to at least 1 SSRI for 12 weeks)	9 (2F) 40.9 yrs (±13.2)	Psilocybin po (25, 100, 200, and 300 mcg/kg at 1-week intervals)	23–100% decrease in YBOCS score (no dose response)	(15)

PHQ, Patient Health Questionnaire; QIDS, Quick Inventory of Depressive Symptoms; SHAPS, Snaith-Hamilton Pleasure Scale; STAI, The State-Trait Anxiety Inventory (STAI) trait scale (STAI-T); POMS, Profile of Mood States; HAM-A, Hamilton Anxiety Rating Scale; GRID-HAM-D; HADS, Hospital Anxiety and Depression Scale; POMS, Profile of Mood States; HAM-D, Hamilton Rating Scale for Depression; MADRS, Montgomery-Asberg Depression Rating Scale; BPRS, Brief Psychiatric Rating Scale; YMRS, Young Mania Rating Scale; BHS, Beck hopelessness scale; SPECT, single photon emission tomography; CADSS, Clinician Administered Dissociative States Scale; DASS, Depression, Anxiety, and Stress Scale; DPES, Dispositional Positive Emotion Scale; PANAS-X, Positive and Negative Affect Schedule - X; 5D-ASC, 5-Dimensions Altered States of Consciousness questionnaire; CADSS, Clinician Administered Dissociative States Scale; SPECT, single photon emission tomography; HRS, Hallucinogenic Rating Scale; MEQ, Mystical Experience Questionnaire; F, female; HC, healthy controls; FC, functional connectivity; C-SSRS, Columbia-suicide severity rating scale; PFC, prefrontal cortex; vPFC, ventromedial prefrontal cortex; GAF, Global Assessment of Functioning; aya, ayahuasca; BDNF, Brain-derived neurotrophic factor; TRD, treatment-resistant depression; DMT, Dimethyltryptamine; YBOCS, Yale-Brown Obsessive Compulsive Scale; HRS, Hallucinogen Rating Scale; BPD, borderline personality disorder; BEAQ, Brief Experiential Avoidance Questionnaire; vs., versus; CRP, C-reactive protein; 11D ASC, 11 dimension altered states of consciousness questionnaire; M scale, Mysticism Scale; BSI, Brief Symptom Inventory; MQOL, The McGill Quality of Life Questionnaire; LAP-R, The Life Attitude Profile-Revised; LOT-R, Life Orientation Test-Revised; PIL, Purpose in Life test; DTS, Death Transcendence Scale; PEQ, Persisting Effects Questionnaire; FACIT-Sp, Functional Assessment of Chronic Illness Therapy; SROS, Spiritual-Religious Outcome Scale; FMS, Faith Maturity Scale; EORTC-QLQ-30, European Cancer Quality of Life Questionnaire; FS, Flourishing Scale; WSAS, Work and Social Adjustment Scale; WEMWBS, Warwick-Edinburgh Mental Well-being Scale; SIDAS, Suicidal Ideation Attributes Scale; PRSexDQ, Psychotropic-Related Sexual Dysfunction Questionnaire; LEIS, Laukes Emotional Intensity Scale; EBI, Emotional Breakthrough Inventory; PTCS, Post-Treatment Changes Scale; RRS, Ruminative Response Scale; VAL, visual analog scale; dFC, dynamics of functional connectivity; STAR-C, Scale to Assess Therapeutic Relationship – Clinician version; STAR-P, Scale to Assess Therapeutic Relationship – Patient version; MGH-ATRQ, Massachusetts General Hospital Antidepressant Treatment History Questionnaire; MINI, Mini International Neuropsychiatric Interview; MSI-BPD, McLean Screening Instrument for Borderline Personality Disorder; ASRS, Adult Self-Report Scale; EQ-5D-3L, Euro QoL-5 dimension-3 level.