Table 2.

Completed clinical trials until September 2022 and published in peer-reviewed journals

Mood disorder	Drug	Dose	Phase	Type of study	Durationa	Follow upb	NCT number	Trial design	Adjunctive treatment or monotherapy	Depressive symptoms severty scale at baseline	Population			Drug effectiveness on depressive symptoms
											N	Sex (F/M)	Mean age or range
MDD	REL-1017	25–50 mg	II	Multicenter randomized double-blind placebo-controlled trial	1 week	15–21 days	NCT03051256	3 arms REL-1017 50 (n 21) REL-1017 25 (n 19) Placebo (n 22)	Adjunctive treatment	MADRS 33.8	62	45.2%/54.8%	49.2	Reduction in depressive symptoms at week 1 MADRS: −17.4 for REL-1017 25 [P = 0.0122] [d = 0.8] vs −15.9 for REL-1017 50 [P = 0.0308] [d = 0.7] vs −8 for placebo (Primary outcome)
	AXS-05	45/105 mg	II	Multicenter randomized double-blind parallel-group trial	6 weeks	At week 7	NCT03595579	2 arms AXS-05 (n 43) Bupropion (n 37)	Monotherapy	MADRS 31.8	97	64%/38.1%	37.5	Reduction in depressive symptoms at week 6 MADRS: −17.3 for AXS-05 vs -12.1 for BUP [P = 0.013] [d = 0.5] (Primary outcome)
		45/105 mg	III	Multicenter randomized double-blind placebo-controlled trial	6 weeks	At week 7	NCT04019704	2 arms AXS-05 (n 156) Placebo (n 162)	Monotherapy	MADRS 33	327	66%/34%	42	Reduction in depressive symptoms at week 6 MADRS: −16.6 for AXS-05 vs −11.9 for placebo [P = 0.002][d = 0.38] (Primary outcome)
	Psilocybin	25 mg 1 mg	II	Randomized double-blind controlled trial	6 weeks	6 months	NCT03429075	2 arms Psilocybin + placebo (n 30) Psilocybin + escitalopram (n 29)	Adjunctive treatment and monotherapy (PAP)	QIDS-SR-16 14.5	59	33.8%/66.1%	41.2	No difference in antidepressant effect between psilocybin and escitalopram at week 6 QIDS-SR-16: −8.0 for psilocybin vs −6.0 for escitalopram [P = 0.17] (Primary outcome)
		20 mg/70 kg 30 mg/70 kg	II	Randomized waiting-list controlled trial	8 weeks (immediate treatment) 13 weeks (delayed treatment)	4 weeks	NCT03181529	2 arms Immediate treatment (n 13) Delayed treatment (n 11)	Monotherapy (PAP)	GRID-HDRS 22.8	27	67%/33%	39.8	Reduction in depressive symptoms GRID-HDRS: 8.0 at week 5 [d = 2.5], 8.5 at week 8 [2.6] for immediate treatment group [P < 0,001] GRID- HDRS: 23.8 at week 5 [d = 2.5], 23.5 at week 8 [2.6] for delayed treatment group [P < 0.001] (Primary outcome)
		25 mg	I	Randomized double-blind placebo-controlled crossover trial	2 weeks	0	NCT03912974	2 arms Escitalopram + psilocybin Placebo + psilocybin	Monotherapy (PAP)	Healthy subjects	27	47.9%/52.1%	34	Escitalopram pretreatment reduced psilocybin adverse effects [P = 0.004], fear [P = 0.004], anxiety [P < 0.05], adverse autonomic effects [P < 0.02] (Primary outcome)
	Pimavanserin	34 mg	II	Randomized double-blind placebo-controlled trial	10 weeks	4 weeks	NCT03018340	2 arms Pimavanserin (n 52) Placebo (n 155)	Adjunctive treatment	MADRS > 20	207	72.9%/27.1%	≥ 18	Reduction in depressive symptoms at week 5 HDRS-17: −11.5 for pimavanserin vs −7.5 for placebo [P = 0.003] [d = 0.63] (Primary outcome)
	Zuranolone	30 mg	II	Randomized double-blind placebo-controlled trial	2 weeks	6 weeks	NCT03000530	2 arms Zuranolone (n 45) Placebo (n 44)	Monotherapy	HDRS-17 25.2	89	62.7%/37.3%	44.3	Reduction in depressive symptoms at day 15 HDRS-17: −17.4 for zuranolone vs −10.3 for placebo [P = 0.0005] [d = 81]
	Ph-10	3.2 µg 6.4 µg	NA	Randomized double-blind placebo-controlled parallel-group trial	8 weeks	1 week	ISSN2456-9836	3 arms PH-10 6. PH-10 3.2 Placebo	Monotherapy	HDRS-17 PH10 6.4 24.7 HDRS-17 PH10 3.2 22.4	30	60%/40%	PH10 6.4 46.6 PH10 3.2 33.2	Reduction in depressive symptoms at week 8 HDRS-17: −17.80 for PH-10 6.4 [P = 0.022] [d = 0.95] vs −16.3 for PH-10 3.2 [P = 0.101] [d = 0.74] vs −10.9 for placebo (Primary outcome)
	Seltorexant	20 mg	I	Multicenter randomized double-blind placebo-controlled parallel-group trial	10 days or 28 days	2 weeks	NCT02476058	3 arms Seltorexant (n 22) Placebo (n 12) Active placebo (n 13)	Monotherapy and adjunctive treatment	IDS-C30 36.8	47	34%/66%	18–64	Reduction in depressive symptoms at day 11 HDRS-17: −5.5 for seltorexant vs −3.6 for placebo vs −4.1 for active placebo [P < 0.05] (Primary outcome)
		10 mg 20 mg 40 mg	I	Double-blind placebo-controlled four-way crossover trial	Single dose	1 week	NCT02067299	4 arms Placebo-seltorexant 10-20-40 Seltorexant 10-40-placebo-20 Seltorexant 20-placebo-40-10 Seltorexant 40-20-10-placebo	Adjunctive treatment	HDRS-17 9.35	20	60%/40%	43	Failed to improve depressive symptoms at week 1 QIDS-SR: −2.1 for Seltorexant 40 vs −0.7 for placebo
		10 mg 20 mg 40 mg	II	Multicenter randomized double-blind placebo-controlled dose-finding trial	6 weeks	2 weeks	NCT03227224	4 arms: Seltorexant 10 (n 33) Seltorexant 20 (n 61) Seltorexant 40 (n 52) Placebo (n 137)	Adjunctive treatment	MADRS ≥ 25	287	53.7%/46.3%	49.1	Reduction in depressive symptoms at week 6 MADRS: −3.1 for SLX 20 vs -1.5 for SLX 40 [P = 0.083] (Primary outcome)
TRD	AV-101	1080 mg 1440 mg	II	Randomized double-blind placebo-controlled crossover Trial	2 weeks	0	NCT02484456	2 arms AV-101-placebo Placebo-AV-101	Monotherapy	HDRS ≥ 18	19	47.4%/52.6%	41.28	Failed to improve depressive symptoms at day 15 in the HDRS [P = 0.16] [d = 0.22] (Primary outcome)
		720 mg 1440 mg	I	Randomized double-blind placebo-controlled crossover trial	3 weeks	0	NCT03583554	3 arms Placebo-AV-101 720- 1440 AV-101 720-1440-placebo AV-101 1440-placebo 720	Monotherapy	Healthy subjects	10	8.3%/91.7%	32.6	1440 mg showed consistent NMDAR blockade (Primary outcome)
	Psilocybin	10 mg 25 mg	NA	Open-label trial	2 psilocybin sessions 1 week apart	3 months	ISRCTN14426797	Single arm	Monotherapy (PAP)	QIDS 19.2	12	50%/50%	44.7	Reduction in depressive symptoms at 1 week and month 3 QIDS psilocybin 25: −11.8 at week 1 [P = 0.002] [g = 3.1] vs −9.2 at month 3 [P = 0.003] [g = 2] (Primary outcome)
PPD	Zuranolone	30 mg	III	Randomized double-blind placebo-controlled trial	2 weeks	4 weeks	NCT02978326	2 arms Zuranolone (n 76) Placebo (n 74)	Monotherapy	HDRS-17 ≥ 28.4	153	100%/0%	28.3	Reduction in depressive symptoms at day 15 HDRS-17: -17.8 for ZRN vs -13.6 for placebo [P = 0.003] [d = 0.53] (Primary outcome)
MDD and Parkinson’s disease	Pimavanserin	34 mg	II	Open-label trial	8 weeks	2 weeks	NCT03482882	Single arm	Monotherapy (n 21) adjunctive treatment (n 24)	HDRS 19.2	45	48.9%/51.1%	69.3	Reduction in depressive symptoms at week 8 HDRS-17: -11.2 for monotherapy vs -10.2 for adjunctive therapy [P < 0.0001]
Cancer-related depression and anxiety	Psilocybin	0.2 mg/kg	I/II	Randomized double-blind placebo-controlled trial	2 psilocybin sessions, several weeks apart	6 months	NCT00302744	2 arms Psilocybin Active placebo	Monotherapy (PAP)	BDI ≥ 15	12	91.7%/8.3%	36–58	Failed to improve depressive symptoms (BDI) and anxiety symptoms (STAI) at week 2 (Primary outcome) STAI reduced at month 1 [P = 0.001] and at month 3 [P = 0.03] BDI reduced at month 6 [P = 0.03]
		1 or 3 mg/70 kg 22 or 30 mg/70 kg	II	Randomized double-blind crossover trial	2 psilocybin sessions, 5 weeks apart	6 months	NCT00465595	2 arms Psilocybin 1 or 3 first (n 25) Psilocybin 22 or 30 first (n 26)	Monotherapy (PAP)	GRID-HDRS-17 22	56	49%/51%	56.3	Reduction in depressive symptoms at 6 months GRID-HDRS-17: clinical response rate of 78% for two-dose sequence group [d = 1.55] (Primary outcome) Reduction in anxiety symptoms at 6 months HAM-A: clinical response rate of 83% for two-dose sequence group [d = 1.55] (Primary outcome)
		0.3 mg/kg	I	Randomized double-blind placebo-controlled crossover Trial	2 psilocybin sessions, 7 weeks apart	6 months	NCT00957359	2 arms Psilocybin first (n 14) Active placebo first (n 15)	Monotherapy (PAP)	BDI ≥ 15	31	62.1%/37.9%	56.28	Reduction in depressive symptoms at week 7 (prior the crossover) BDI: clinical response rate of 83% for psilocybin group first vs 14% for active placebo group first [P < 0.05][d = 0.82] (Primary outcome) Reduction in anxiety symptoms at week 7 (prior the crossover) HADS: clinical response rate of 58% for PSY group first vs 14% for active placebo group first [P ≤ 0.01][d = 1.07] (Primary outcome)
		0.3 mg/kg	NA	Randomized double-blind placebo-controlled crossover trial	2 psilocybin sessions, 7 weeks apart	4.5 years	NA	2 arms Psilocybin first (n 6) Active placebo first (n 5)	Monotherapy (PAP)	NA	11	63.6%/36.4%	60.3	Reduction in suicidal ideation at 8 h [P < 0.001] and sustained for 6.5 months [P < 0.001] (Primary outcome) Reduction in LoM at 2 weeks [P = 0.005] and sustained for 6.5 months [P < 0.001], 3.2 years [P < 0.001], and 4.5 years [P < 0.001]
AIDS-related depression	Psilocybin	0.3 mg/kg 0.36 mg/kg	I	Open-label trial	1 psilocybin session	3 months	NCT02950467	Single arm	Monotherapy (PAP)	DS-II ≥ 8/32	18	0%/100%	59.2	Reduction in demoralization at week 3 DS-II: −5.78 [hp2 = 0.47] (Primary outcome)

For some studies, some data is not available (i.e. phase study, depressive symptoms severity scale at baseline, P value, effect size).

BDI, Beck Depression Inventory total score; DS-II, Demoralization Scale-II total score; GRID-HDRS, Grid-Hamilton Depression Rating Scale total score; HADS, Hospital Anxiety and Depression Scale total score; HAM-A, Hamilton Anxiety Rating Scale total score; HDRS, Hamilton Depression Rating Scale total score; IDS-C, Inventory of Depressive Symptomatology Clinician Rating total score; LoM, loss of meaning; MADRS, Montgomery-Asberg Depression Rating Scale total score; MDD, major depressive disorder; NA, not available; PAP, psilocybin assisted psychotherapy; PPD, postpartum depression; QIDS, Quick Inventory of Depressive Symptomatology total score; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Reported total score; STAI, State-Trait Anxiety Inventory total score; TRD, treatment-resistant depression.

^aRefers to the length over time of the pharmacological intervention.

^bRefers to the length of monitoring over time of participant’s health after the end of the pharmacological intervention.