Low-dose ketamine tilts the cortical excitation--inhibition balance irrespective of systemic physiological response
Judith Kunze, Justus Student, Sarah Tune, Henrik Oster, Stefanie Schmidt, Harald Ihmsen, Alexander Tzabazis, Benedikt Lorenz, Carla Nau, Jonas Obleser
bioRxiv (Cold Spring Harbor Laboratory) September 21, 2026 preprint DOI: 10.64898/2026.09.17.752361 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Single-blind, placebo-controlled crossover study |
|---|---|
| Sample size | 25 |
| Population | Healthy adults |
| Interventions | Ketamine Propofol Placebo |
| Dose | low, subanesthetic doses |
| Topics | Esketamine Ketamine |
| Key points | Low, subanesthetic doses of ketamine flattened the aperiodic EEG exponent (a shift toward excitation) and raised heart rate and blood pressure, while propofol produced opposite effects; both agents reduced alpha oscillatory power. The cardiovascular response did not mediate the cortical excitation-inhibition shift, and controlling for heart rate left the ketamine effect intact and numerically stronger. |
Abstract
Non-invasive proxies of cortical excitation--inhibition (E:I) balance, are increasingly used to understand human neural dynamics; especially so the aperiodic (1/f) electroencephalographic (EEG) exponent. Ketamine, an NMDA-receptor antagonist, is thought to shift this balance toward excitation. Propofol, a GABAA-receptor agonist, should behave oppositely. Here we show that these pharmacological manipulations at low doses tilt the noninvasive read-out of E:I balance as predicted, and we demonstrate this effect to be robust against potential mediation by the ketamine-related systemic cardiovascular response. In a single-blind, placebo-controlled crossover study, 25 healthy adults received low, subanesthetic doses of ketamine, propofol, or placebo by target-controlled infusion during resting-state EEG. We further analyzed electrocardiogram (ECG) and dissociating ratings. Ketamine flattened the aperiodic exponent (i.e., a shift toward excitation) and raised heart rate and blood pressure; propofol exerted its effects in the opposite direction, while both agents reduced alpha oscillatory power. Critically, the cardiovascular response did not mediate the cortical E:I shift. Controlling for heart rate left the ketamine effect not only intact but numerically stronger, suggesting that E:I balance findings might even be underestimated when ignoring the systemic physiological response.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |