Table 5.

Randomized controlled trial designs and participants

Citation(s)	Study Design	Study Participants
MDMA
ADRENERGIC AGENTS
Hysek et al. 2012c * Hysek and Liechti 2012	DB, placebo-controlled, within-subjects, counterbalanced, crossover (> 10-day washout) 1. Carvedilol 50 mg + MDMA 125 mg 2. Carvedilol 50 mg + PBO 3. PBO + MDMA 125 mg 4. PBO + PBO Carvedilol/PBO p.o. given 1 h prior to MDMA/PBO p.o	N = 16, healthy 8F, 8 M Mean age 24.2 ± 2.2 1 had used ecstasy previously CYP2D6 metabolism: 9 extensive, 6 intermed, 1 poor
Hasler et al. 2009 * Hysek et al. 2010	DB, placebo-controlled, within-subjects, counterbalanced, crossover (14-day washout) 1. Pindolol 20 mg + MDMA 1.6 mg/kg 2. Pindolol 20 mg + PBO 3. PBO + MDMA 1.6 mg/kg 4. PBO + PBO Pindolol/PBO p.o. given 1 h prior to MDMA/PBO p.o	N = 16, healthy 100% male Mean age 25 ± 4 (range 20–36) 2 had used ecstasy previously
Hysek et al. 2012a * Hysek and Liechti 2012	DB, placebo-controlled, within-subjects, counterbalanced, crossover (10- to 14-day washout) 1. Clonidine 0.15 mg + MDMA 125 mg 2. Clonidine 0.15 mg + PBO 3. PBO + MDMA 125 mg 4. PBO + PBO Clonidine/PBO p.o. given 1 h prior to MDMA/PBO p.o	N = 16, healthy 8F, 8 M Mean age 25.4 ± 4.9 2 had used ecstasy previously CYP2D6 metabolism: 8 extensive, 7 intermed, 1 poor
Hysek et al. 2013 * Hysek and Liechti 2012	DB, placebo-controlled, within-subjects, counterbalanced, crossover (≥ 7-day washout) 1. Doxazosin XL 8 mg + MDMA 125 mg 2. Doxazosin XL 8 mg + PBO 3. PBO + MDMA 125mg 4. PBO + PBO Doxazosin mesylate XL 4 mg/PBO p.o. × 1 day, then 8 mg/PBO × 2 days During testing days, Doxazosin XL/PBO given 16 h prior to MDMA/PBO p.o	N = 16, healthy 8F, 8 M Mean age 25.8 ± 3.3 CYP2D6 metabolism: 13 extensive, 2 intermediate, and 1 poor
ANTIPSYCHOTICS
Liechti and Vollenweider 2000b * Liechti et al. 2001	DB, placebo-controlled, within-subjects, counterbalanced, crossover (≥ 10-day washout) 1. Haloperidol 1.4 mg + MDMA 1.5 mg/kg 2. Haloperidol 1.4 mg + PBO 3. PBO + MDMA 1.5 mg/kg 4. PBO + PBO Haloperidol/PBO i.v. given 10 min prior to MDMA (mean 100 mg) p.o	N = 14, healthy 5F, 9 M 1 had used ecstacy previously Mean age 26 (range 21–38) Scoring > 2 standard deviations from mean normative values on the Neuroticism scale of the Freiburger Personality Inventory was exclusionary
NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS
Schmid et al. 2015 * Steuer et al. 2016	DB, placebo-controlled, crossover (≥ 10-day washout) 1. Bupropion XR 300 mg + MDMA 125 mg 2. Bupropion XR 300 mg + PBO 3. PBO. + MDMA 125 mg 4. PBO + PBO Bupropion XR 150 mg/PBO p.o. daily × 3 days, then 300 mg/PBO × 4 days During testing days, Bupropion XR/PBO given 2 h prior to MDMA/PBO p.o	N = 16, healthy 8F, 8 M, 100% white Mean age 23.3 ± 2.2 6 had used ecstacy once previously CYP2D6 metabolism: 13 extensive, 3 intermediate, and 0 poor
NMDA ANTAGONISTS
de Sousa Fernandes Perna et al. 2014	DB, placebo-controlled, within-subjects, counterbalanced, crossover (≥ 7-day washout) 1. Memantine 20 mg + MDMA 75 mg 2. Memantine 20 mg + PBO 3. PBO + MDMA 75 mg 4. PBO + PBO Memantine/PBO p.o. given 2 h prior to MDMA/PBO p.o	N = 15, healthy 4F, 11 M Mean age 22.9 ± 1.9 (range 20–28) Mean previous ecstasy use 18.8 times
PSYCHOSTIMULANTS
Hysek et al. 2014b * Bigler et al. 2015	DB, placebo-controlled, within-subjects, counterbalanced crossover (10-day washout) 1. Methylphenidate 60 mg + MDMA 125 mg 2. Methylphenidate 60 mg + PBO 3. PBO + MDMA 125 mg 4. PBO + PBO Immediate-release methylphenidate/PBO p.o. given 1 h prior to MDMA/PBO p.o	N = 16, healthy 8F, 8 M Mean age 24.8 ± 2.6 6 had used ecstasy previously CYP2D6 metabolism: 12 extensive, 2 intermed, 1 poor, 1 unknown (Bigler et al. 2015: n = 12, 8F, 4 M, mean age 24.9)
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Liechti and Vollenweider 2000a * Liechti 2000 * Liechti et al. 2001	DB, placebo-controlled, within-subjects, counterbalanced, crossover (≥ 14-day washout) 1. Citalopram 40 mg + MDMA 1.5 mg/kg 2. Citalopram 40 mg + PBO 3. PBO + MDMA 1.5 mg/kg 4. PBO + PBO Citalopram/PBO i.v. infused over 90 min prior to MDMA/PBO (dose range 80–120 mg) p.o	N = 16, healthy 4F, 12 M Mean age 27.4 ± 4.4 (range 21–39) 3 had used ecstasy previously Scoring > 2 standard deviations from mean normative values on the Neuroticism scale of the Freiburger Personality Inventory (Fahrenberg et al., 1984) was exclusionary
Tancer and Johanson 2006	DB, placebo-controlled, within-subjects, crossover (≥ 48-h MDMA-PBO washout) 1. Fluoxetine 20 mg + MDMA 1.5 mg/kg 2. Fluoxetine 20 mg + PBO 3. PBO + MDMA 1.5 mg/kg 4. PBO + PBO Fluoxetine 20 mg/PBO p.o. daily × 5–11 days PBO pre-treatment was always tested first During testing days, Fluoxetine/PBO given 1 h prior to MDMA/PBO p.o	N = 8, recreational MDMA users (mean 28.6 times, range 4–66) 2F, 6 M, 100% white Mean age 23.9 (range 19–33) Drug or alcohol dependence in the past year -OR- lifetime recreational use of stimulants, opiates, phencyclidine, or sedative exceeding 50 times were exclusionary
Farré et al. 2007 * Pacifici et al. 2004 * Segura et al. 2005	DB, placebo-controlled, within-subjects, counterbalanced, crossover (15-day washout) 1. Paroxetine 20 mg + MDMA 100 mg 2. PBO + MDMA 100 mg Paroxetine 20 mg/PBO p.o. daily × 3 days During testing days, Paroxetine/PBO given 3 h prior to MDMA p.o	N = 12, healthy 100% male Mean age 24 years (range 19–34) Previously used ecstasy ≥ 5 times 100% extensive CYP2D6 metabolizers (Segura n = 7)
SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS
Hysek et al. 2012d * Simmler et al. 2011 * Hysek and Liechti 2012	DB, placebo-controlled, within-subjects, counterbalanced, crossover (≥ 10-day washout) 1. Duloxetine 120 mg + MDMA 125 mg 2. Duloxetine 120 mg + PBO 3. PBO + MDMA 125 mg 4. PBO + PBO Duloxetine 120 mg/PBO given 16 h & 4 h prior to MDMA/PBO p.o	N = 16, healthy 8F, 8 M Mean age 26.1 ± 6.0 Ecstasy-naive CYP2D6 metabolism: 13 extensive, 2 intermed, and 1 poor
Hysek et al. 2011 * Hysek and Liechti 2012	DB, placebo-controlled, within-subjects, counterbalanced, crossover (10- to 14-day washout) 1. Reboxetine 8 mg + MDMA 125 mg 2. Reboxetine 8 mg + PBO 3. PBO + MDMA 125 mg 4. PBO + PBO Reboxetine 8 mg/PBO p.o. given 12 h & 1 h prior to MDMA/PBO p.o	N = 16, healthy 8F, 8 M Mean age 25.7 ± 5.5 3 had used ecstasy previously CYP2D6 metabolism: 10 extensive, 4 intermed, 2 poor
PSILOCYBIN
ADRENERGIC & ANXIOLYTIC AGENTS
Pokorny et al. 2016	DB, placebo-controlled, randomized, within-subjects, crossover (≥ 2-week washout) A) 1. Buspirone 20 mg + Psilocybin 0.17 mg/kg 2. Buspirone 20 mg + PBO 3. PBO + Psilocybin 0.17 mg/kg 4. PBO + PBO Buspirone/PBO p.o. given once 1 h prior to Psilocybin/PBO B) 1. Ergotamine 3 mg + Psilocybin 0.17 mg/kg 2. Ergotamine 3 mg + PBO 3. PBO + Psilocybin 0.17 mg/kg 4. PBO + PBO Ergotamine/PBO p.o. given 100 min prior to Psilocybin/PBO p.o	A. Buspirone Group N = 19, healthy 9F, 10 M Mean age 24.9 ± 4.0 B. Ergotamine Group N = 17, healthy Mean age 23.8 ± 3.7
ANTIPSYCHOTICS
Keeler 1967	Placebo-controlled, crossover (2-week washout) 1. Chlorpromazine 50 mg + Psilocybin 0.2 mg/kg 2. PBO + Psilocybin 0.2 mg/kg Chlorpromazine/Placebo p.o. given once 2 h prior to Psilocybin p.o	N = 8, healthy “free from evidences of major psychopathology, had stable academic and work histories and did not conduct themselves in ways actively contradictory to conventional mores”
Vollenweider et al. 1998	Placebo-controlled, within-subjects, crossover (1-month washout) A) 1. Haloperidol 0.021 mg + Psilocybin 0.25 mg/kg 2. Haloperidol 0.021 mg + PBO 3. PBO + Psilocybin 0.25 mg/kg 4. PBO + PBO Haloperidol/PBO i.v. given 75 min prior Psilocybin/PBO p.o B) 1. Risperidone 0.5 mg + Psilocybin 0.25 mg/kg 2. Risperidone 1 mg + Psilocybin 0.25 mg/kg 3. PBO + Psilocybin 0.25 mg/kg 4. Risperidone 0.5 mg + PBO 5. Risperidone 1 mg + PBO 6. PBO + PBO Risperidone/PBO p.o. given once 90 min prior to Psilocybin/PBO p.o	A. Haloperidol Group N = 5, healthy B. Risperidone Group N = 5, healthy 7F, 8 M University staff History of “illicit drug abuse” exclusionary
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Becker et al. 2021	DB, placebo-controlled, within-subjects, counterbalanced, crossover (≥ 2-day washout) 1. Escitalopram 20 mg + Psilocybin 25 mg 2. PBO + Psilocybin 25 mg Escitalopram 10 mg/PBO p.o. daily × 7 days, followed by Escitalopram 20 mg/PBO p.o. daily × 7 days During testing days, Escitalopram/PBO given 2 h prior to Psilocybin p.o	N = 23, healthy 11F, 12 M Mean age 34 ± 10 (range 25–55) 6 had used psilocybin-containing mushrooms previously

^*Secondary or exploratory outcomes. DB double-blind, F female, h hour(s), kg kilogram, M male, mg milligram, min minute(s), PBO placebo, p.o. per os (by mouth)