How Anesthesia Disrupts the Body Clock and Why Melatonin May Help Restore It

Every general anesthetic is delivered to a body that is not physiologically flat. The patient on the operating table carries a suprachiasmatic nucleus firing in its own rhythm, peripheral molecular clocks ticking in the liver, heart, and immune cells, and a pineal gland releasing melatonin on a schedule set by darkness. A new review published in Frontiers in Pharmacology pulls together mechanistic, preclinical, and clinical evidence on how anesthetic agents, surgical stress, and the perioperative environment interact with this circadian and melatonergic machinery, and asks whether the interaction can be turned into a therapeutic target. The answer that emerges is nuanced: the biology is plausible and increasingly well mapped in animal models, but the clinical evidence remains uneven, and most human trials so far have been designed in ways that cannot actually test the hypothesis they set out to probe.

The core of the review is a synthesis of how volatile and intravenous anesthetics alter clock function in rodent and cellular systems. These effects are not uniform; they depend on which agent is used and on the circadian phase at which the drug is delivered. Propofol, sevoflurane, and other anesthetics appear to interfere with the molecular oscillator at several levels. One proposed route involves GABAergic and glutamatergic modulation of the neural signals that normally entrain the master clock in the suprachiasmatic nucleus to the light-dark cycle. Another involves transcriptional and chromatin-level repression of the CLOCK-BMAL1 complex and its PER and CRY feedback partners, the core loop that generates roughly 24-hour rhythms in gene expression throughout the body. A third route is metabolic: anesthetics may couple to the clock through signaling hubs such as CaMK-CREB, AMPK, SIRT1, and GSK-3β, enzymes that link cellular energy state and post-translational modification to the timing machinery.

What makes this mechanistic picture compelling in rodents and cell culture is also what limits it. The review is explicit that none of these specific mechanisms has been confirmed in humans. Human perioperative physiology is confounded by factors that animal models cannot fully reproduce: the tissue injury of surgery itself, opioid analgesia, preoperative fasting, the inflammatory response to trauma, and the radically disrupted light-dark exposure of intensive care units and hospital wards. In patients, the effects of anesthetics on circadian biology are inseparable from these overlapping stressors, all of which independently suppress the amplitude of the melatonin rhythm, delay its nighttime onset, and promote internal desynchrony, the state in which centrally and peripherally governed rhythms drift out of alignment with one another.

Melatonin itself is the other half of the axis, and the review draws a pharmacologically important distinction that is often blurred in the clinical literature. Melatonin signals through two G-protein-coupled receptors, MT1 and MT2, and activation of these receptors produces chronobiotic effects, shifting the timing of circadian phase, as well as anxiolytic and antinociceptive effects. These receptor-mediated actions operate at the doses achievable with standard oral supplementation. By contrast, a separate body of literature attributes to melatonin mitochondrial protection, antioxidant and redox modulation, and anti-inflammatory actions. The review emphasizes that these cytoprotective effects have been described almost exclusively in animal and cellular models, and that they require substantially higher exposures than receptor-level signaling. The two arms of melatonin pharmacology are therefore distinct, and the authors argue they should not be pooled when interpreting trial results or designing new studies, because a dose that engages MT1 and MT2 signaling will not necessarily achieve the concentrations at which mitochondrial and anti-inflammatory effects have been observed in preclinical systems.

On the clinical side, the most consistently supported indication is preoperative anxiolysis in adults. Across trials, melatonin given before surgery reduces anxiety with an effect comparable to standard benzodiazepine premedication in many studies, and with a favorable side-effect profile. This is the one application where the evidence base is coherent enough to support routine consideration. Beyond the preoperative period, the picture becomes markedly less certain. Evidence for melatonin’s benefit on postoperative sleep quality, on analgesia and opioid sparing, on the prevention of postoperative delirium, and on organ protection such as myocardial or renal preservation is heterogeneous, with trials of varying quality, dosing schemes, and patient populations producing conflicting results. The overall certainty of that evidence is low, and the review does not attempt to paper over the contradictions.

One of the most consequential points in the review concerns how clinical trials have been designed. Most studies to date have used fixed clock-time dosing, giving melatonin at, say, 22:00 or 60 minutes before surgery, without measuring the patient’s internal circadian phase or the achieved plasma concentration of the drug. This matters because melatonin’s chronobiotic effect is phase-dependent: the same dose can advance, delay, or leave unaffected the circadian clock depending on when it is given relative to the individual’s internal night. A trial that ignores circadian phase and never verifies drug exposure cannot distinguish between two very different explanations for a null result: that the mechanism itself is ineffective in surgical patients, or that the intervention was inadequate, delivered at the wrong biological time or at a dose that failed to reach the relevant compartment. The review argues that this design flaw has likely obscured real effects in the existing literature and that future trials must be phase-aware and exposure-informed.

The perioperative environment itself is a circadian disruptor of considerable magnitude. Patients scheduled for surgery are typically fasted, often receive their anesthetic at times that bear no relation to their habitual sleep-wake cycle, and are then nursed under continuous artificial light, frequently in intensive care settings where nocturnal light exposure and noise fragment sleep. Opioids suppress rapid eye movement sleep and alter the timing of nocturnal hormone release. Surgical inflammation feeds back on the hypothalamic-pituitary-adrenal axis, which in turn modulates the pineal gland. The result is a constellation of internal desynchrony that is already established before any specific pharmacological effect of the anesthetic on the molecular clock is considered. Any therapeutic strategy that targets the circadian system in surgical patients must therefore contend with this broader environmental and inflammatory context, not just with the direct actions of propofol or sevoflurane on CLOCK-BMAL1 signaling.

For clinicians, the practical takeaways are relatively modest but concrete. Preoperative oral melatonin for anxiolysis in adult patients is supported by the most consistent evidence and can be considered as an alternative or adjunct to benzodiazepine premedication, particularly in settings where respiratory depression is a concern. Beyond that, the review refrains from endorsing melatonin for postoperative delirium prevention, sleep promotion, or organ protection as standard practice, because the trials are too inconsistent and too small to support firm recommendations. What the review does offer is a framework for the next generation of studies: trials that stratify or randomize by circadian phase, that measure plasma melatonin concentrations to confirm exposure, that separate receptor-mediated from high-dose cytoprotective hypotheses, and that are adequately powered to detect the effect sizes that the preclinical literature would predict.

The broader significance of the work lies in its reframing of anesthesia as an interaction with a temporally organized biological system rather than a reversible switch applied to a physiologically neutral one. The molecular clock influences drug metabolism, immune responses, inflammatory resolution, and sleep architecture, all of which are central to perioperative outcomes. If anesthetic agents genuinely repress CLOCK-BMAL1/PER-CRY signaling and desynchronize peripheral clocks, then the timing of surgery and the design of anesthetic regimens could, in principle, be optimized to minimize circadian disruption, with downstream benefits for recovery, delirium risk, and long-term cognitive outcomes. That possibility remains speculative until the human mechanisms are confirmed, but the review makes a strong case that the question is now answerable with the right experimental design.

The circadian-melatonin axis, the authors conclude, remains a plausible perioperative target, but one whose clinical translation has been hampered more by trial methodology than by the absence of underlying biology. The mechanistic work in rodents and cells has generated specific, testable hypotheses about GABAergic entrainment, chromatin-level clock repression, and metabolic coupling through AMPK, SIRT1, and GSK-3β. What is needed now is the human evidence: phase-aware, exposure-informed, adequately powered trials that can determine whether manipulating melatonin signaling at the right biological time, at the right dose, and for the right indication can improve outcomes for surgical patients. Until those trials are done, the most defensible clinical use of melatonin in the perioperative period remains its best-established one, preoperative anxiolysis in adults, while the larger promise of chronotherapeutic anesthesia waits on better-designed evidence.

Subject of Research: Circadian and melatonin signaling mechanisms in general anesthesia and their perioperative therapeutic implications

Article Title: Circadian–melatonin signaling in general anesthesia: molecular mechanisms and perioperative implications

Article References: Mui, W.-C., Hou, Y.-C., Liao, Y.-C., & Lu, K.-C. (2026). Circadian–melatonin signaling in general anesthesia: molecular mechanisms and perioperative implications. Frontiers in Pharmacology, 17, Article 1960152. https://doi.org/10.3389/fphar.2026.1960152

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1960152

Keywords: circadian rhythm, melatonin, general anesthesia, suprachiasmatic nucleus, CLOCK-BMAL1, perioperative medicine, postoperative delirium, preoperative anxiolysis, MT1 receptor, MT2 receptor, chronotherapy, molecular clock