Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial

This randomized study (n=80) found that participants with depression (MDD) and suicidal ideation (SSI/SI) who were treated with ketamine (IV, 35mg/70kg) have significantly lower SSI scores versus treatment with midazolam (another anesthetic). This effect consistently held up to 6 weeks later.


Objective: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.

Method: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).

Results: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen’s d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.

Conclusions: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.

Authors: Michael F. Grunebaum, Hanga C. Galfalvy, Tse-Hwei Choo, John G. Keilp, Vivek K. Moitra, Michelle S. Parris, Julia E. Marver, Ainsley K. Burke, Matthew S. Milak, M. Elizabeth Sublette, Maria A. Oquendo & J. John Mann


This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health


Depression is a major public health concern, affecting more than 300 million individuals worldwide, and is estimated to be responsible for $210 billion in economic burden.

Although many patients with depression showed reduced symptoms after treatment with existing pharmacotherapies, 30% to 50% of patients did not respond fully, and 10% to 30% were considered treatment-resistant.

Most current pharmacotherapies for MDD increase levels of brain monoamine neurotransmitters such as serotonin and norepinephrine, but newer ketamine-like medications exert therapeutic efficacy through effects on glutamate neurotransmission. Ketamine has high abuse liability and requires medical monitoring.

MDD has a negative public health impact and current pharmacotherapies have variable efficacy and unwanted adverse effects. Psilocybin therapy may improve or save lives.

Study Design and Participants

Participants with moderate or severe MDD episodes were eligible for this trial of psilocybin therapy. They were required to self-report no current pharmacotherapy for depression at trial screening, and to refrain from using antidepressants for at least 5 half-lives before the screening and up to 4 months after enrollment.

We recruited 870 participants using flyers, print advertisements, internet forums, social media, and the study website. 27 participants were randomized to either an immediate treatment group or a delayed treatment group, and the 4-week primary outcome assessments were completed in July 2019.

Immediate Treatment Condition

A group of 20 participants underwent 2 daylong psilocybin administration sessions at the Center for Psychedelic and Consciousness Research. The sessions were conducted 1.6 weeks apart and involved preparatory meetings with 2 session facilitators.

Psilocybin was administered in opaque gelatin capsules with approximately 100 mL water. Participants were instructed to lie on a couch in a living room-like environment and focus their attention inward.

Delayed Treatment Condition

During the 8-week delay period, participants were monitored weekly by in-person assessment or brief telephone calls. They completed the same intervention as the participants in the immediate treatment group.

Outcome Assessments

The primary outcome measure was the GRID-HAMD, which was administered by blinded clinician raters at baseline, postrandomization weeks 5 and 8 and at weeks 1 and 4 postsession 2 follow-up visits for both groups.

GRID-HAMD indicates GRID Hamilton Depression Rating Scale.

Severity of depression was assessed using the total GRID-HAMD score, and a clinically significant response was defined as 50% or greater decrease from baseline. Interrater reliability for all depression assessments was 85%.

The Beck Depression Inventory II and the 9-item Patient Health Questionnaire were used to measure depressive symptoms, and the Columbia-Suicide Severity Rating Scale was used to measure anxiety symptoms. Blood pressure and heart rate were examined before and during the psilocybin sessions.

Statistical Analysis

A previous study of psilocybin found a large effect of a high psilocybin dose on reducing GRID-HAMD scores. A repeated-measures analysis of variance was used to examine changes in the primary depression outcome (GRID-HAMD score).

The primary outcomes included a descriptive analysis of the percentage of participants who met the criterion for clinically significant response and remission in the sample, and a comparison of week 1 with week 4 GRID-HAMD scores in the immediate treatment condition group.


A total of 27 participants were randomized, of whom 24 completed the intervention as well as the postsession assessments at weeks 1 and 4. There were no statistically significant differences between conditions in terms of demographic characteristics or baseline GRID-HAMD scores.

The immediate treatment condition showed significantly lower depression scores at weeks 1 and 4 postsession-2 follow-up compared with the delayed treatment condition at weeks 5 and 8. The effect sizes were large at weeks 5 and 8.

After the psilocybin session, 16 participants at week 1 and 17 participants at week 4 had a clinically significant response to the intervention, and 14 participants at week 1 and 13 participants at week 4 met the criteria for remission of depression.

All secondary depression and anxiety outcomes showed statistically significant differences between conditions and across both conditions after entry into the active intervention period.

Participants reported challenging emotional and physical experiences, including feeling body shake or tremble, after completing at least one-half of the psilocybin sessions. Mild to moderate transient headache was reported during 16 of 48 sessions (33%) and after the subjective psilocybin effects had subsided after 14 of 48 sessions (29%).


This randomized clinical trial showed that psilocybin-assisted therapy produced substantial rapid and enduring antidepressant effects among patients with MDD, and that the therapeutic effects persisted for at least 4 weeks. Furthermore, psilocybin was found to have low potential for addiction and a minimal adverse event profile.

Psilocybin is being used to treat a variety of psychiatric conditions, and mystical-type and psychologically insightful experiences are associated with favorable outcomes. Furthermore, psilocybin may decrease negative affect and the neural correlates of negative affect, which may be a mechanism underlying transdiagnostic efficacy.

The present trial showed that psilocybin administered in the context of supportive psychotherapy produced large, rapid, and sustained antidepressant effects. Psilocybin was associated with nonserious adverse effects, and may be more acceptable to patients than widely prescribed antidepressant medications.

Strengths and Limitations

This study had some strengths, such as a randomized design, blinded clinician raters, and controlled for the possible effects of having been accepted into the trial. However, it had some limitations.

This study has some limitations, including a short-term follow-up, a small sample, and a predominantly White non-Hispanic population. Further research is needed to better assess the safety and efficacy of psilocybin therapy among patients with MDD.


Psilocybin-assisted therapy produced large, rapid, and sustained antidepressant effects among patients with MDD. Further studies are needed in larger and diverse populations.

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