High-Dose vs. Low-Dose Melatonin: The Quest for Circadian Regulation in the ICU
Delirium remains one of the most significant challenges in modern intensive care medicine, particularly among patients requiring mechanical ventilation. Characterized by an acute onset of cognitive dysfunction, fluctuating levels of consciousness, and inattention, it affects up to 80 percent of patients in the intensive care unit (ICU). The consequences are profound, ranging from increased mortality and prolonged hospital stays to long-term cognitive impairment resembling Alzheimer’s disease. Given the potential role of circadian rhythm disruption in the pathogenesis of delirium, melatonin—an endogenous hormone regulating sleep-wake cycles—has been a subject of intense research. However, the DEMEL trial, recently published in Intensive Care Medicine, provides a sobering look at whether pharmacological melatonin supplementation can truly move the needle in delirium prevention.
Highlights of the DEMEL Trial
1. The study identified that a low-dose melatonin regimen (0.3 mg) achieved a significantly better pharmacokinetic profile in critically ill patients than a higher dose (3 mg).
2. Despite achieving optimal blood levels in the low-dose group, melatonin did not reduce the incidence of delirium compared to placebo (54.4 percent vs. 55.2 percent).
3. Secondary outcomes, including sleep quality, ventilator-free days, and mortality at 28 and 90 days, showed no significant differences between the melatonin and placebo groups.
Background: The Burden of Delirium in the Critically Ill
The ICU environment is notoriously hostile to normal physiology. Constant noise, artificial lighting, frequent clinical interventions, and the underlying severity of illness combine to shatter the natural circadian rhythm. Melatonin secretion, normally triggered by darkness to signal the biological night, is often suppressed or phase-shifted in ICU patients. This disruption is hypothesized to contribute to the high prevalence of delirium. While previous small-scale studies and observational data suggested a potential benefit for exogenous melatonin in preventing delirium, high-quality, multicenter evidence has remained elusive. The DEMEL trial (Delirium and Melatonin) was designed to address this gap using a rigorous, adaptive methodological framework.
Study Design: An Adaptive, Multiarm Approach
The DEMEL trial was a multicenter, adaptive phase 2b/3 randomized, placebo-controlled, double-blind trial conducted across 20 health centers in France. The study enrolled patients who were receiving mechanical ventilation, a population at particularly high risk for delirium. The trial was structured in two distinct phases: an interim activity stage and a final efficacy stage.
In the activity stage, 75 patients were randomized (1:1:1) to receive either placebo, low-dose melatonin (0.3 mg), or high-dose melatonin (3 mg). The primary goal here was to identify which dose achieved an optimal pharmacokinetic (PK) profile—defined as reaching physiological or supra-physiological nocturnal melatonin levels without excessive daytime accumulation. Melatonin was administered enterally at 9:00 p.m. for up to 14 consecutive nights.
Based on the results of the PK analysis, the Steering Committee proceeded to the efficacy stage, comparing the most effective dose against placebo. The final primary endpoint was the percentage of patients experiencing delirium, assessed twice daily using the Confusion Assessment Method for ICU (CAM-ICU), from randomization until day 14, death, or ICU discharge.
Key Findings: Pharmacokinetics and Clinical Efficacy
The Pharmacokinetic Paradox
One of the most intriguing findings of the DEMEL trial occurred during the interim activity stage. Counterintuitively, the low-dose melatonin group (0.3 mg) demonstrated a much higher rate of optimal pharmacokinetic profiles (50 percent) compared to the high-dose group (24 percent). In the placebo group, no patients reached the target PK profile. This suggests that in the context of critical illness, higher doses of enterally administered melatonin may lead to unpredictable absorption or saturation of metabolic pathways, potentially resulting in suboptimal plasma concentrations. Consequently, the 3 mg arm was discontinued, and the 0.3 mg dose was selected for the efficacy phase.
Efficacy and Clinical Outcomes
Despite the successful selection of a dose that optimized blood levels, the clinical results were neutral. The trial randomized a total of 355 patients, with 334 included in the primary analysis. The results showed no statistical difference in delirium incidence:
– Low-dose Melatonin (0.3 mg): 54.4 percent (80/147 patients)
– Placebo: 55.2 percent (85/154 patients)
– Risk Ratio: 0.986 (95 percent CI 0.803 to 1.211)
The lack of benefit extended to all secondary clinical endpoints. There were no significant differences in sleep quality (as perceived by clinicians or measured by surrogate markers), delirium-free days, or coma-free days. Furthermore, the 28-day mortality and 90-day long-term outcomes, including quality of life and the prevalence of post-intensive care syndrome (PICS), remained comparable between the groups.
Expert Commentary: Why Did Melatonin Fail to Reduce Delirium?
The failure of melatonin to prevent delirium in the DEMEL trial raises several critical questions for the intensive care community. First, the pathophysiology of delirium in mechanically ventilated patients is multifactorial, involving neuroinflammation, neurotransmitter imbalances (such as acetylcholine and dopamine), and sedative-induced toxicity. While circadian disruption is a factor, it may not be the primary driver in this specific cohort.
Second, the timing of intervention may be crucial. Melatonin was started after the initiation of mechanical ventilation. It is possible that by the time a patient is critically ill enough to require a ventilator, the cascade of neuroinflammation leading to delirium is already too advanced for a mild chronobiotic like melatonin to reverse.
Third, the dose itself remains a point of discussion. Although 0.3 mg was superior from a PK standpoint in this study, other clinicians argue that much higher doses (e.g., 5 mg to 10 mg) might be necessary to overcome the profound physiological stress of sepsis or respiratory failure. However, the DEMEL data suggests that increasing the dose does not linearly increase the likelihood of achieving a physiological profile.
Finally, the heterogeneity of the ICU population must be considered. Delirium is a syndrome, not a single disease. A patient with alcohol withdrawal delirium may respond differently than a patient with septic encephalopathy. The DEMEL trial provides high-level evidence that a broad, non-targeted application of melatonin is not effective for the general mechanically ventilated population.
Conclusion: Moving Beyond Melatonin for Delirium Prevention
The DEMEL trial is a landmark study for its methodological rigor and its use of an adaptive design to first solve the pharmacokinetic puzzle before testing clinical efficacy. While the results are disappointing for those hoping for a simple pharmacological solution to delirium, they are essential for refining ICU protocols. Currently, clinical guidelines should continue to emphasize non-pharmacological strategies—such as the ABCDEF bundle (Assessing pain, Both Spontaneous Awakening and Breathing Trials, Choice of analgesia and sedation, Delirium monitoring/management, Early mobility, and Family engagement)—as the primary defense against delirium.
Future research may need to focus on more targeted populations or perhaps combine melatonin with other circadian-reinforcing interventions, such as bright light therapy or the minimization of nocturnal light and noise. For now, the routine use of melatonin for delirium prevention in mechanically ventilated patients is not supported by the evidence.
Funding and Trial Information
The DEMEL trial was funded by the French Ministry of Health (Programme Hospitalier de Recherche Clinique). The study is registered at ClinicalTrials.gov under the identifier NCT03524937.
References
Mekontso Dessap A, Ricard JD, Contou D, et al. Melatonin for prevention of delirium in patients receiving mechanical ventilation in the intensive care unit: a multiarm multistage adaptive randomized controlled clinical trial (DEMEL). Intensive Care Med. 2025 Jul;51(7):1292-1305. doi: 10.1007/s00134-025-08002-z. PMID: 40608082.
