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A recent clinical trial found that a single dose of ketamine tends to increase morning cortisol levels in patients experiencing major depression and suicidal thoughts. Published in the Journal of Affective Disorders, the research provides evidence that this specific hormonal boost persists for at least 24 hours after treatment. These findings offer an informative look into how ketamine might interact with the body’s stress response systems to rapidly reduce suicidal ideation.
Cortisol is a primary hormone produced by the adrenal glands to help the body manage stress. In healthy individuals, cortisol levels naturally peak in the early morning to help the body wake up and prepare for daily activities. Within the first thirty minutes of waking, people typically experience an additional spike in this hormone. This specific morning spike is known as the cortisol awakening response. It is closely linked to how a person reacts to stress, their general mood, and their cognitive function throughout the day.
Severe depression is frequently associated with a dysregulated stress response system. People suffering from severe depressive episodes often display abnormal morning cortisol patterns, either producing too much or too little. Chronic psychosocial stress and poor health outcomes frequently accompany these hormonal imbalances.
“The overall clinical trial was conducted to address the gap in treatments for suicidality,” said Michael Grunebaum, a researcher at Columbia University Medical Center and the New York State Psychiatric Institute. “The goal of the saliva cortisol study component was to explore the stress hormone system as a potential biomarker of ketamine’s therapeutic effects.” A biomarker is a measurable biological indicator, like a hormone level, that can tell scientists if a treatment is working or how a disease is progressing.
Ketamine is an anesthetic medication that has gained widespread attention in psychiatry for its rapid antidepressant properties. Studies show it provides rapid relief from suicidal thoughts, often within hours of administration. Scientists wanted to explore if this rapid relief relates to how the drug influences morning cortisol levels and the specific morning cortisol spike. By measuring these hormonal shifts, researchers aim to uncover the underlying biological mechanisms that make ketamine effective.
To test this, researchers designed a randomized controlled trial involving 80 adults between the ages of 18 and 65. All participants were currently experiencing an episode of major depressive disorder. They also scored a four or higher on a clinical assessment for suicidal ideation, indicating severe and active suicidal thoughts. The participants were voluntarily admitted to an inpatient research unit.
The study participants were randomly assigned to receive a single, forty-minute intravenous infusion of either ketamine or midazolam. The ketamine was administered at a subanesthetic dose, which is a lower amount than what is typically used for surgical anesthesia, of 0.5 milligrams per kilogram of body weight. Midazolam, a sedative medication acting as the control treatment, was given at a dose of 0.02 milligrams per kilogram. The researchers utilized midazolam as a control to mimic the immediate sedative effects of ketamine, helping to keep participants unaware of which specific medication they received.
To track hormonal changes, the research team collected saliva samples from the participants before the infusion and exactly 24 hours later. On each day, participants provided one saliva sample immediately upon waking up. They provided a second sample exactly thirty minutes later to measure the morning cortisol spike. The participants had to follow strict guidelines to ensure accurate readings, including fasting overnight and refraining from brushing their teeth before using the specialized cotton saliva collection tubes.
The final analysis focused on 63 participants, comprising 31 people from the ketamine group and 32 from the midazolam group. Some participants were excluded because they did not adhere strictly to the saliva sampling procedures, provided an insufficient quantity of saliva, or dropped out of the study. The researchers controlled for several potential confounding variables during their analysis. They accounted for the exact time of cortisol sampling, tobacco use, caffeine intake, and any stable psychiatric medications the participants were taking at the time.
The researchers found a measurable difference in waking cortisol between the two treatment groups. Participants who received ketamine experienced an absolute increase in their morning waking cortisol levels 24 hours after the infusion. The data, which was normalized using a logarithmic scale for statistical purposes, showed that waking cortisol in the ketamine group rose from a pre-infusion average of 0.42 to a post-infusion average of 0.80.
The midazolam control group experienced no such increase in waking cortisol. Their normalized scores shifted slightly downward from a pre-infusion average of 0.97 to 0.77 after 24 hours. The findings for the ketamine group held up even after researchers adjusted their statistical models to account for baseline cortisol levels.
Grunebaum explained the specific timing of this hormonal shift. “The main takeaway is that levels of the stress hormone cortisol increased 24 hours after ketamine treatment which coincides with ketamine’s peak clinical effects on reducing suicidal thoughts and depressive symptoms in suicidal depressed inpatients,” he told PsyPost. “This cortisol increase was many hours after acute dissociative effects of ketamine typically resolve (usually within an hour).”
The research team then looked for relationships between this rising waking cortisol and clinical symptoms. “The apparent effect of ketamine on waking cortisol at 24 hours post-treatment was statistically significant and a moderate effect size,” Grunebaum said. “This cortisol increase had a small to medium, nonsignificant correlation with decreased suicidal thoughts.”
An effect size is a statistical concept that measures the strength or magnitude of a relationship between two variables, rather than just whether a relationship exists. “Understanding the practical significance of these effects requires more research,” he added. The increase in waking cortisol did not correlate with any changes in overall depression severity.
The authors also analyzed the cortisol awakening response, which is the proportional change between the immediate waking sample and the subsequent thirty-minute sample. Neither the ketamine group nor the midazolam group exhibited a noticeable increase or decrease in this specific morning spike after their respective infusions.
When combining the data from both drug groups, the researchers noted a 12 percent decrease in the cortisol awakening response that loosely tracked with general improvements in depression scores. This association was suggestive of a relationship between mood and the morning cortisol spike. However, after applying strict statistical corrections for running multiple comparisons, this specific correlation was not statistically significant.
An increase in a stress hormone like cortisol is not inherently harmful. However, finding this specific elevation in this patient population was unexpected. “Depression has been traditionally thought to be associated with hyper-cortisol states, thus finding an increase in cortisol coincident with decreased depression and suicidal thoughts in this study was somewhat surprising,” Grunebaum noted.
“It suggests that increased cortisol, if not excessive or prolonged, may enhance stress resilience in depression and merits additional research,” he added. In the context of severe depression, a moderate restoration of morning cortisol levels might actually help improve reaction time and executive functioning.
The study design prevents any firm conclusions regarding a direct chain of events. “The results are preliminary and exploratory and mainly serve as a justification for further research on ketamine’s effects on the stress-response system in stress-sensitive illness such as depression and suicidality,” Grunebaum said. The data indicates that waking cortisol increases after ketamine treatment, but it remains unknown if this hormonal shift directly causes the reduction in suicidal thoughts.
Relying on only two saliva samples per morning provides a somewhat restricted snapshot of a person’s hormone profile. A more frequent sampling method over several hours would capture a more precise curve of the morning cortisol spike. The researchers also lacked detailed objective monitoring of sleep quality and circadian rhythms.
Ketamine influences sleep patterns and circadian cycles, and improved sleep might independently alter morning cortisol levels. Future studies with continuous sleep tracking are needed to untangle how resting patterns, hormonal changes, and rapid antidepressant effects interact. Looking ahead, the team aims to build on these early findings. “Our research group plans further research into potential preventive effects of ketamine on the stress-response system in depression and suicidality,” Grunebaum said.
The study, “Increased morning cortisol after ketamine treatment for suicidal depression: Exploratory report from a randomized trial,” was authored by Tse-Hwei Choo, Hanga C. Galfalvy, John G. Keilp, Ainsley K. Burke, J. John Mann, and Michael F. Grunebaum.