Participants received TS-161 50-100 mg capsule orally once daily for three weeks. TS-161 is a mGlu2/3 receptor antagonist prodrug.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Number of participants who met remission criteria at any time point after intervention. Remission was defined as Montgomery-Asberg Depression Rating Scale (MADRS) total score ≤10 after intervention. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

Number of participants who met response criteria at any timepoint after intervention. Response was defined as a ≥50% reduction from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

The Hamilton Depression Rating Scale (HDRS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. HDRS is a widely used observational rating measure of depression severity. The HDRS contains 21 items, but four questions are not added to the numerical total score. The first 17 items are scored on a 3 (0-2) or 5 (0-4) point scale, with total score range between 0 and 52. Scores of 0-7 are considered normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. For each crossover period, the HDRS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal HDRS total score means were calculated using a linear mixed model regression that controlled for baseline HDRS and allowed treatment differences to vary by time point.

The Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. HAM-A is a widely used observational rating measure of anxiety severity. This scale was administered to assess the severity of anxiety and its improvement during the course of therapy. The scale consists of 14 items. Each item is rated on a scale of 0 to 4, with total score range between 0 and 56. A higher score represents greater symptom severity. Total score <17 indicates mild severity, 18-24 mild to moderate severity, and 25-30 moderate to severe severity. For each crossover period, the HAM-A was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal HAM-A total score means were calculated using a linear mixed model regression that controlled for baseline HAM-A and allowed treatment differences to vary by time point.

The Snaith-Hamilton Pleasure Scale (SHAPS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The SHAPS is a 14-item self-report measure of hedonic or pleasurable experiences or the lack of hedonic experiences (e.g., interests, social interactions, or sensory experiences) in adults and for assessment of any changes. Each item is rated on a scale of 1 to 4 (1 = definitely agree or strongly agree, 4 = strongly disagree) with total score range between 14 and 56. Lower scores indicate greater levels of anhedonia. For each crossover period, the SHAPS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal SHAPS total score means were calculated using a linear mixed model regression that controlled for baseline SHAPS and allowed treatment differences to vary by time point.

The Temporal Experience of Pleasure Scale (TEPS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The TEPS is an 18-item self-report measure of consummatory and anticipatory experiences of pleasure or lack of pleasure (i.e., anhedonia) in adults and for the assessment of any changes. Each item is rated on a scale of 0 to 6 (0 = very true for me, 6 = very false for me) with total score range between 0 and 108. Lower scores indicate greater levels of anhedonia. For each crossover period, the TEPS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal TEPS total score means were calculated using a linear mixed model regression that controlled for baseline TEPS and allowed treatment differences to vary by time point.

The Positive and Negative Affect Schedule (PANAS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The PANAS is a questionnaire that assesses both positive and negative affect and consists of 20 items, 10 measuring positive affect (e.g., "excited") and 10 measuring negative affect (e.g., "upset"). Each item is rated on a scale of 1 to 5 (1 = very slightly or not at all, 5 = extremely) with a total score ranging between 10 and 50 for each affect subscale. Higher scores indicate higher levels of positive or negative affect depending on the subscale. For each crossover period, the PANAS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal total score means were calculated for the positive affect using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

The Positive and Negative Affect Schedule (PANAS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The PANAS is a questionnaire that assesses both positive and negative affect and consists of 20 items, 10 measuring positive affect (e.g., "excited") and 10 measuring negative affect (e.g., "upset"). Each item is rated on a scale of 1 to 5 (1 = very slightly or not at all, 5 = extremely) with a total score ranging between 10 and 50 for each affect subscale. Higher scores indicate higher levels of positive or negative affect depending on the subscale. For each crossover period, the PANAS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal total score means were calculated for the negative affect using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

The Clinician Administered Dissociative States Scale (CADSS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The CADSS is a 28-item clinician-rated assessment of dissociative states in the moment and contains both subjective and objective items. Items are rated on a scale of 0 to 4 (0 = not at all, 4 = extreme) with total score range between 0 and 112. A higher score indicates more severe dissociation. For each crossover period, the CADSS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal CADSS total score means were calculated using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

The Brief Psychiatric Rating Scale (BPRS) mean total score at 230 minutes, 1 and 21 days following the first treatment administration. The BPRS is an 18-item clinician-rated scale that evaluates symptoms and behaviors that are characteristic of schizophrenia (e.g., hallucinations, unusual thought content). Each item is rated on scale of 1 (symptom not reported or observed) to 7 (very severe), with a total score range between 18 to 126. Higher scores indicate more severe symptoms of psychosis. For each crossover period, the BPRS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1 and 21 days days following the first dose. Estimated marginal BPRS total score means were calculated using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

The Young Mania Rating Scale (YMRS) mean total score at 230 minutes, 1 and 21 days following the first treatment administration. The YMRS is an 11-item clinician-rated scale that evaluates symptoms of mania or hypomania in adults. Each item is rated on scale from either 0-4 or 0-8, where 0 indicates a symptom is not present, and the highest score (4 or 8) indicates a symptom is extremely severe, with a total score range between 0 and 60. Higher scores indicate more severe manic/hypomanic symptoms. For each crossover period, the YMRS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1 and 21 days following the first dose. Estimated marginal total score means were calculated using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

Number of participants with suicide ideation assessed using the Columbia Suicide Severity Rating Scale (CSSRS) ideation score. The CSSRS is administered as a structured clinical interview, and a participant's responses to screening items determine which subsequent items are administered. CSSRS ideation scores can range from 0 to 5. Due to skew, CSSRS total score was dichotomized so that score of 0 indicated no suicidal ideation and score ≥1 indicated the presence of suicidal ideation. For each crossover period, the CSSRS was completed one day before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

Number of participants with suicide ideation assessed using the Scale for Suicide Ideation (SSI). SSI measures current suicidal ideation and behavior administered as a structured clinical interview, and a participant's responses to screening items determine which subsequent items are asked. A participant is asked from 5 and up to 21 items with each item rated on the scale of 0 to 2. Total scores range between 0 to 42. Due to skew, SSI total score was dichotomized so that score ≤1 indicated no suicidal ideation and score ≥2 indicated the presence of suicidal ideation. For each crossover period, the SSI was completed one day before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

Participants with major depressive disorder (MDD) were randomized to receive Placebo capsule orally once per day for three weeks.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Montgomery-Asberg Depression Rating Scale (MADRS) mean total score at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal means at 230 minutes and 1, 2, 3, 7, and 14 days following the first treatment administration were calculated using a linear mixed model regression.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Number of participants who met remission criteria at any time point after intervention. Remission was defined as Montgomery-Asberg Depression Rating Scale (MADRS) total score ≤10 after intervention. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Number of participants who met response criteria at any timepoint after intervention. Response was defined as a ≥50% reduction from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The MADRS is a 10-item clinician-rated questionnaire to evaluate depressive symptoms in adults and for the assessment of any changes to those symptoms. Each item is rated on a scale of 0 to 6 (0 = absent, 6 = severe) with total score range between 0 and 60. Higher score indicates worsening depression. For each crossover period, the MADRS was completed 60 minutes before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Hamilton Depression Rating Scale (HDRS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. HDRS is a widely used observational rating measure of depression severity. The HDRS contains 21 items, but four questions are not added to the numerical total score. The first 17 items are scored on a 3 (0-2) or 5 (0-4) point scale, with total score range between 0 and 52. Scores of 0-7 are considered normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. For each crossover period, the HDRS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal HDRS total score means were calculated using a linear mixed model regression that controlled for baseline HDRS and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Hamilton Psychiatric Rating Scale for Anxiety (HAM-A) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. HAM-A is a widely used observational rating measure of anxiety severity. This scale was administered to assess the severity of anxiety and its improvement during the course of therapy. The scale consists of 14 items. Each item is rated on a scale of 0 to 4, with total score range between 0 and 56. A higher score represents greater symptom severity. Total score <17 indicates mild severity, 18-24 mild to moderate severity, and 25-30 moderate to severe severity. For each crossover period, the HAM-A was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal HAM-A total score means were calculated using a linear mixed model regression that controlled for baseline HAM-A and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Snaith-Hamilton Pleasure Scale (SHAPS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The SHAPS is a 14-item self-report measure of hedonic or pleasurable experiences or the lack of hedonic experiences (e.g., interests, social interactions, or sensory experiences) in adults and for assessment of any changes. Each item is rated on a scale of 1 to 4 (1 = definitely agree or strongly agree, 4 = strongly disagree) with total score range between 14 and 56. Lower scores indicate greater levels of anhedonia. For each crossover period, the SHAPS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal SHAPS total score means were calculated using a linear mixed model regression that controlled for baseline SHAPS and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Temporal Experience of Pleasure Scale (TEPS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The TEPS is an 18-item self-report measure of consummatory and anticipatory experiences of pleasure or lack of pleasure (i.e., anhedonia) in adults and for the assessment of any changes. Each item is rated on a scale of 0 to 6 (0 = very true for me, 6 = very false for me) with total score range between 0 and 108. Lower scores indicate greater levels of anhedonia. For each crossover period, the TEPS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal TEPS total score means were calculated using a linear mixed model regression that controlled for baseline TEPS and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Positive and Negative Affect Schedule (PANAS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The PANAS is a questionnaire that assesses both positive and negative affect and consists of 20 items, 10 measuring positive affect (e.g., "excited") and 10 measuring negative affect (e.g., "upset"). Each item is rated on a scale of 1 to 5 (1 = very slightly or not at all, 5 = extremely) with a total score ranging between 10 and 50 for each affect subscale. Higher scores indicate higher levels of positive or negative affect depending on the subscale. For each crossover period, the PANAS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal total score means were calculated for the positive affect using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Positive and Negative Affect Schedule (PANAS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The PANAS is a questionnaire that assesses both positive and negative affect and consists of 20 items, 10 measuring positive affect (e.g., "excited") and 10 measuring negative affect (e.g., "upset"). Each item is rated on a scale of 1 to 5 (1 = very slightly or not at all, 5 = extremely) with a total score ranging between 10 and 50 for each affect subscale. Higher scores indicate higher levels of positive or negative affect depending on the subscale. For each crossover period, the PANAS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal total score means were calculated for the negative affect using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Clinician Administered Dissociative States Scale (CADSS) mean total score at 230 minutes and 1, 2, 3, 7, 14, and 21 days following the first treatment administration. The CADSS is a 28-item clinician-rated assessment of dissociative states in the moment and contains both subjective and objective items. Items are rated on a scale of 0 to 4 (0 = not at all, 4 = extreme) with total score range between 0 and 112. A higher score indicates more severe dissociation. For each crossover period, the CADSS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose. Estimated marginal CADSS total score means were calculated using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Brief Psychiatric Rating Scale (BPRS) mean total score at 230 minutes, 1 and 21 days following the first treatment administration. The BPRS is an 18-item clinician-rated scale that evaluates symptoms and behaviors that are characteristic of schizophrenia (e.g., hallucinations, unusual thought content). Each item is rated on scale of 1 (symptom not reported or observed) to 7 (very severe), with a total score range between 18 to 126. Higher scores indicate more severe symptoms of psychosis. For each crossover period, the BPRS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1 and 21 days days following the first dose. Estimated marginal BPRS total score means were calculated using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

The Young Mania Rating Scale (YMRS) mean total score at 230 minutes, 1 and 21 days following the first treatment administration. The YMRS is an 11-item clinician-rated scale that evaluates symptoms of mania or hypomania in adults. Each item is rated on scale from either 0-4 or 0-8, where 0 indicates a symptom is not present, and the highest score (4 or 8) indicates a symptom is extremely severe, with a total score range between 0 and 60. Higher scores indicate more severe manic/hypomanic symptoms. For each crossover period, the YMRS was completed 1440 minutes (24 hours) before intervention (baseline) and 230 minutes, 1 and 21 days following the first dose. Estimated marginal total score means were calculated using a linear mixed model regression that controlled for baseline and allowed treatment differences to vary by time point.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Number of participants with suicide ideation assessed using the Columbia Suicide Severity Rating Scale (CSSRS) ideation score. The CSSRS is administered as a structured clinical interview, and a participant's responses to screening items determine which subsequent items are administered. CSSRS ideation scores can range from 0 to 5. Due to skew, CSSRS total score was dichotomized so that score of 0 indicated no suicidal ideation and score ≥1 indicated the presence of suicidal ideation. For each crossover period, the CSSRS was completed one day before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Number of participants with suicide ideation assessed using the Scale for Suicide Ideation (SSI). SSI measures current suicidal ideation and behavior administered as a structured clinical interview, and a participant's responses to screening items determine which subsequent items are asked. A participant is asked from 5 and up to 21 items with each item rated on the scale of 0 to 2. Total scores range between 0 to 42. Due to skew, SSI total score was dichotomized so that score ≤1 indicated no suicidal ideation and score ≥2 indicated the presence of suicidal ideation. For each crossover period, the SSI was completed one day before intervention (baseline) and 230 minutes, 1, 2, 3, 7, 14, and 21 days following the first dose.

Analyses based on the intent-to-treat (ITT) population and included all randomized participants who had at least one post-baseline assessment.

Participants with major depressive disorder (MDD) were randomized to receive Placebo capsule orally once per day for three weeks.