A single subanesthetic intravenous dose of ketamine increases morning waking cortisol levels in patients with major depressive disorder and suicidal ideation, according to a clinical trial published in the Journal of Affective Disorders. Researchers at Columbia University Medical Center and the New York State Psychiatric Institute found that this hormonal boost persists for at least 24 hours after treatment, offering new biological data on how the rapid-acting antidepressant interacts with the body’s stress response systems.
Clinical Trial Design and Patient Demographics
The randomized controlled trial involved 80 adults aged 18 to 65 experiencing an episode of major depressive disorder and active suicidal thoughts. According to study author Michael Grunebaum and his colleagues, participants were voluntarily admitted to an inpatient research unit and randomly assigned to receive a single 40-minute intravenous infusion of either ketamine at 0.5 milligrams per kilogram or midazolam at 0.02 milligrams per kilogram. Midazolam served as a control treatment to mimic immediate sedative effects and maintain participant blinding.
Did you know?
Cortisol is a primary adrenal hormone that naturally peaks within the first thirty minutes of waking, a phenomenon known as the cortisol awakening response. In this trial, researchers tracked this morning spike alongside waking levels using saliva samples collected before treatment and exactly 24 hours later.
Hormonal Findings 24 Hours Post-Infusion
Out of the initial cohort, final analyses focused on 63 participants—31 in the ketamine group and 32 in the midazolam group—after excluding individuals who missed saliva collection protocols or dropped out. Researchers controlled for confounding variables such as sampling time, tobacco use, caffeine intake, and stable psychiatric medications. Normalized data showed that waking cortisol in the ketamine group rose from a pre-infusion average of 0.42 to 0.80 after 24 hours. By comparison, the midazolam control group exhibited a slight downward shift from 0.97 to 0.77.
According to Grunebaum, the timing of this increase coincides with ketamine’s peak clinical effects on reducing suicidal thoughts and depressive symptoms. While the absolute increase in waking cortisol demonstrated a statistically significant moderate effect size, it showed only a small, nonsignificant correlation with decreased suicidal thoughts and did not correlate with overall depression severity scores. Neither treatment group exhibited a significant change in the cortisol awakening response, though pooled data revealed a 12 percent decrease loosely tracking general mood improvements.
Implications for Stress Resilience and Future Research
The discovery of elevated cortisol alongside reduced depressive symptoms challenges traditional models associating severe depression with hyper-cortisol states. Grunebaum noted that a moderate restoration of morning cortisol, if not excessive or prolonged, may enhance stress resilience in patients with depression. However, because the study relied on two saliva samples per morning and lacked objective sleep tracking, the authors emphasized that these exploratory findings warrant further investigation to determine exact causal mechanisms.
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Frequently Asked Questions
What is cortisol and how does it relate to stress?
Cortisol is a key stress hormone produced by the adrenal glands that helps the body manage stress. In healthy individuals, it naturally spikes in the early morning.
Why was midazolam used as a control in the ketamine trial?
Midazolam is a sedative medication given to mimic the immediate sedative effects of ketamine, which helps keep study participants unaware of which specific drug they received.
Does increased cortisol mean ketamine is harmful?
Not necessarily. Researchers suggest that a moderate, non-excessive increase in morning cortisol following treatment may actually support stress resilience in patients with severe depression.
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