Melatonin and Long COVID: What Research Suggests

Melatonin is best known as a sleep aid, but researchers are studying whether it might help with long COVID symptoms beyond sleep disturbances. The hormone has anti-inflammatory, antioxidant, and immune-modulating properties that could theoretically address some of the underlying mechanisms of long COVID. Here’s what research suggests about melatonin for post-viral symptoms.

This article examines why researchers are interested in melatonin for long COVID, what studies have found so far, and important safety considerations.

Why Researchers Are Looking at Melatonin for Long COVID

Long COVID symptoms include cognitive issues like memory loss and brain fog, chronic fatigue, myalgia, and muscular weakness resembling ME/CFS. Many of these symptoms overlap with conditions that melatonin has been studied for.

Recent research highlights circadian rhythm disruption and melatonin dysregulation as overlooked drivers of persistent symptoms. Reduced melatonin impairs cytokine suppression, antioxidant defense, and mitochondrial protection, which can fuel inflammation and oxidative stress.

Melatonin is a cytoprotective hormone with anti-inflammatory, antioxidant, and immunoregulatory activity. It has been shown to impair viral infections, maintain circadian rhythms, and shows effectiveness against diabetes and cardiovascular diseases.

Melatonin’s Multiple Mechanisms Beyond Sleep

Melatonin exhibits oncostatic, anti-inflammatory, antioxidant, and anti-aging properties. It’s not just a sleep hormone—it plays roles in various metabolic pathways and governs multiple physiological processes.

Melatonin acts as an indirect antioxidant by enhancing production of antioxidant enzymes while inhibiting prooxidant enzymes. It also has antiapoptotic and cytoprotective effects under conditions of cellular stress, likely due to its stabilizing activity on mitochondrial membranes.

The fact that melatonin works through multiple pathways is important for long COVID, which appears to involve multiple underlying mechanisms rather than a single problem.

Addressing Inflammation and the Cytokine Storm

Melatonin may prevent inflammation by decreasing release of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, while stimulating production of the anti-inflammatory cytokine IL-10.

Studies found that levels of pro-inflammatory indicators such as IL-1β, TNF-α, and nitric oxide were lower in people administered melatonin compared to control groups.

Melatonin can transform proinflammatory M1 macrophages into anti-inflammatory M2 macrophages, suppress NF-κB activation, and inhibit NLRP3 inflammasome. These mechanisms could reduce the ongoing inflammation that characterizes long COVID.

Oxidative Stress and Mitochondrial Function

By increasing expression of nuclear factor erythroid 2-related factor 2 activity, melatonin helps restore balance between reactive oxygen species and antioxidants. This modulation could potentially reduce neuroinflammation and symptoms in long COVID patients with cognitive disturbances.

Research on COVID-19 has identified mitochondrial dysfunction among the mechanisms that can be alleviated by providing melatonin. Mitochondrial problems are thought to contribute to the profound fatigue many people with long COVID experience.

Melatonin may help alleviate symptoms like fatigue and cognitive impairment by improving mitochondrial function, reducing oxidative damage, and restoring energy production.

Effects on Sleep and Circadian Rhythms

Melatonin’s chronobiotic and hypnotic properties are useful in patients with sleep disorders by synchronizing the circadian apparatus, decreasing sleep onset latency, and increasing total sleep time. Multiple meta-analyses support its effectiveness for sleep issues.

COVID-19 patients with insomnia who received prolonged-release melatonin exhibited improvements in their sleep, reduced delirium episodes, shorter hospitalization, and shorter duration of therapy with non-invasive ventilation.

Better sleep can improve other symptoms. Poor sleep worsens fatigue, cognitive function, mood, and pain perception—all common long COVID complaints.

Potential Effects on Brain Fog and Cognitive Function

Melatonin treatment increases clearance of amyloid beta peptides in the brain through the glymphatic system. It preserves slow-wave sleep, during which this clearance process increases considerably.

Research shows melatonin is effective in attenuating microglial production of proinflammatory cytokines. Melatonin therapy consistently improves sleep and cognitive performance in early stages of cognitive decline.

The ability of melatonin to regulate circadian rhythms and sleep patterns has been shown to improve cognitive function in patients with memory issues.

What Studies in Acute COVID Showed

Most research has focused on melatonin during acute COVID-19 rather than long COVID specifically. However, these studies provide context for understanding potential mechanisms.

A Cleveland Clinic study in 2020 found that melatonin usage was associated with a 28% reduced likelihood of a positive COVID-19 test. This was an observational study examining existing medical records.

Research suggests that people with COVID-19 who were given melatonin in addition to standard treatment may recover more quickly. However, high-quality studies remain limited.

Whether benefits during acute infection translate to long COVID treatment is a separate question that needs direct study.

The Gap in Long COVID-Specific Research

Researchers explicitly state that although many reports indicate melatonin’s positive impact on COVID-19 patients, clinical trials specifically focusing on effects in long COVID are needed.

The optimal dosing and efficiency of melatonin for managing neuropsychiatric and cognitive symptoms of long COVID should be assessed through proper trials.

Preliminary data suggest that melatonin supplementation and chronotherapy may restore circadian alignment, rebalance immunity, and mitigate disease progression, although robust large-scale trials remain limited.

We have theoretical mechanisms and some supportive evidence, but we’re missing the controlled trials specifically testing melatonin in people with established long COVID.

Possible Application to ME/CFS Symptoms

Melatonin is known to exhibit therapeutic activity against various symptoms of ME/CFS, including oxidative stress, proinflammatory state, mitochondrial dysregulation, and disruption of the gut barrier.

Since many people with long COVID meet criteria for ME/CFS, and the conditions share underlying mechanisms, research on melatonin in ME/CFS may be relevant. However, ME/CFS is notoriously difficult to treat, so caution about expectations is warranted.

Safety Considerations and Recent Concerns

A 2025 study presented at the American Heart Association found that long-term melatonin use was associated with higher risk of heart failure diagnosis and hospitalization in people with chronic insomnia who used it for more than a year.

This study examined over 130,000 adults and found those taking melatonin long-term had increased heart failure risk and doubled all-cause mortality over five years. However, the study cannot prove cause-and-effect. Worse insomnia, depression, or use of other medications might explain the association.

Many studies of long-term melatonin use have shown no difference in side effects between melatonin and placebo. Melatonin at low to moderate doses (5 mg daily or less) appears safe for short and long-term use based on existing research.

The heart failure finding is new and needs confirmation, but it raises questions about very long-term use, especially at higher doses.

Common Side Effects

The most common side effects are drowsiness and headaches. Many people experience vivid dreams and nightmares while taking melatonin.

At higher doses, some people experience dizziness, nausea, or other side effects. Short-term use of melatonin supplements appears safe for most people, typically defined as one to two months.

There is no scientific evidence that melatonin supplements can help prevent COVID-19 infection. U.S. guidelines for COVID-19 prevention do not include melatonin.

Quality Control Issues

A 2023 study published in JAMA found that 88% of melatonin gummies were inaccurately labeled. The actual quantity of melatonin ranged from 74% to 347% of the labeled amount.

This makes it nearly impossible to know exactly what dose you’re taking. Some products contained CBD that wasn’t listed on the label.

Melatonin as a dietary supplement is not subject to the same quality control and regulatory scrutiny as medicines. There’s risk of poor quality control resulting in inaccurate dosing and formulation.

Special Populations and Precautions

Exogenous melatonin may harm some groups, including nursing mothers. Because of uncertain long-term endocrine consequences, prolonged or high-dose usage should be avoided without medical supervision.

Melatonin might have effects similar to birth control, potentially making it more difficult to become pregnant. It’s best avoided during pregnancy or when trying to conceive until more is known.

People taking blood thinners, diabetes medications, immunosuppressants, or medications metabolized by certain liver enzymes should consult healthcare providers before using melatonin.

What Experts Are Calling For

Researchers urge the research community to explore melatonin’s potential as a therapeutic option for long COVID across various geographical settings.

A review specifically calls for action from the research community, suggesting melatonin could be used as potential therapy in post-COVID syndrome.

Researchers recommend clinical trials to explore the use of melatonin as a treatment for long COVID symptoms, noting that despite its properties, it hasn’t been promoted as a therapeutic option, possibly due to being non-patentable.

The Bottom Line

Melatonin has biological properties that theoretically could help with long COVID symptoms, particularly sleep disturbances, cognitive issues, and fatigue. It addresses multiple mechanisms thought to underlie long COVID: inflammation, oxidative stress, mitochondrial dysfunction, and circadian disruption.

However, we lack specific clinical trials testing melatonin in people with established long COVID. The evidence is theoretical and extrapolated from studies in acute COVID, other conditions, and general mechanisms.

For sleep problems specifically, melatonin has established evidence. For other long COVID symptoms, we’re waiting for proper research.

Recent concerns about long-term use and heart failure risk add uncertainty, though the evidence is preliminary. Short-term use at low to moderate doses appears safe for most people.

If you’re considering melatonin for long COVID symptoms, discuss it with your healthcare provider. They can help assess whether it’s appropriate for your situation, suggest appropriate dosing, and monitor for potential issues.