Can Melatonin Make You Depressed?

Can melatonin, often dubbed the ‘sleepy hormone', cause depression? Melatonin is essential for synchronising our body to the day-night cycle and is a dietary supplement used in insomnia treatment. Excess sleepiness is a symptom of depression, which begs the question of whether melatonin can cause depression through increasing sleepiness. Despite this, Melatonin is approved for the treatment of Depression, underlining the complex relationship between melatonin and depression.
Klara Hatinova

Klara Hatinova

Klara is postgraduate researcher in experimental psychology at the
University of Oxford.

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Does Melatonin Cause Depression?

Melatonin does not make you depressed, nor does melatonin cause depression. Quite the opposite – melatonin has been studied for its ability to treat depression.

What is Melatonin?

To understand whether melatonin can make you depressed, it’s crucial to understand what melatonin is.

  • Melatonin is a peptide hormone produced by the pineal gland in response to reduced light intensity, most commonly upon nightfall [1]. Thanks to this, melatonin is used as a marker of healthy circadian rhythms by measuring the melatonin released at nightfall.
  • Melatonin can also be produced by the skin, intestine, lungs or even immune cells, which has been of interest in investigating pre-symptomatic COVID-19 [2, 3].
  • Melatonin, as a dietary supplement, is used to manage insomnia. Although melatonin will not make you fall asleep, it can promote sleepiness. This property has been widely used in jetlag and shift workers [4]

Melatonin and circadian rhythms

The circadian clock is the 24-hour rhythmic cycle our body maintains independent of light-darkness. Light is a crucial Zeitgeber – a signal that can re-align the circadian clock. Without light to reset our circadian clock every day, we would wake up and go to sleep progressively later every day since the natural human circadian cycle is about 25 hours.

It is difficult to measure the circadian rhythm in humans directly, so a rise in melatonin upon dim light is a commonly used marker. This demonstrates that melatonin is clearly defined in regulating the circadian rhythm.

The pineal gland that produces melatonin is tightly coupled to the suprachiasmatic nucleus, a small nucleus tightly joined to the visual system. The suprachiasmatic nucleus gets signals from specific rods in the eyes that are sensitive to light intensity. The suprachiasmatic nucleus is the grand clock orchestrator—it tells your brain to wake up in the morning, increases your body temperature, sends signals to start digestion, increases urges to be physically active, and does the opposite in the evening to prepare for sleep [5].

What is Depression?

A depressed mood can be a short-term, natural adaptation to stress [6]. Depressed mood can be recognised through loss of interest, reduced or increased appetite, increased sleepiness, and changes to activity patterns. A depressed mood is nonetheless different to major depression, although the terms are often confused. Major depression is a psychiatric condition defined, according to the ICD-11, as a depressed mood persisting over six weeks [7]. At present, major depression is among the top three most debilitating conditions worldwide [8].

Circadian rhythms in depression: A link between melatonin and depression?

There is abundant evidence that there are disruptions of the circadian rhythm in depression, primarily in preclinical mouse and rat models [9]. Disruption to the light-dark cycle that regulates circadian rhythms has been shown to increase helplessness, despair and anxiety-like behaviour.

In healthy people, mood is regulated by the circadian clock and the time since waking up, demonstrating that melatonin can have an important role in depressed mood [10]. Diurnal patterns in mood, referring to night-day differences in mood, have also been found in patients at risk for mental health conditions, including depression [10].

To sum up, there is strong evidence that the time from waking and the circadian clock play a critical role in depression and, thereby, also major depression.

Melatonin is produced from serotonin in the pineal gland in a process controlled by the suprachiasmatic nucleus [5]. When light is turned on at night, the pineal gland stops producing melatonin and initiates its breakdown in the liver. Therefore, sleeping in a dark room and avoiding bright light is critical to good sleep [11].

Serotonin is a pivotal monoamine neurotransmitter associated with depression. It is targeted by most antidepressants and works by stabilising mood, appetite and alertness. Increased serotonin through psychedelic drugs has also been found to alleviate symptoms of depression. Likewise, depleting tryptophan, a precursor of serotonin in individuals remitted from depression, can increase depressive mood, demonstrating how important serotonin is for depression recovery [12].

So, can making too much melatonin come at the cost of reduced serotonin, causing depression?

This is likely not the case, as homeostatic and circadian mechanisms tightly control melatonin production. What is more likely is that individuals with major depression will have lower levels of melatonin since they have less serotonin to begin with. Indeed, this has been shown by several studies [13, 14]

Clinical Evidence and Therapeutic Potential of Melatonin in Depression

Clinical evidence on melatonin's role as a treatment for depression is mixed. While animal models hint at potential benefits, human trials show inconsistent results [15].

Animal studies of melatonin and depression

A group in Japan found that supplementing melatonin in mice can increase the production of serotonin throughout the day [15]. This could potentially have an antidepressant effect. Another group demonstrated, using a mouse model of depression, that melatonin could reverse depression, possibly by influencing inflammation in the brain [16, 17].

The evidence for supplementing melatonin in animal studies seems strong –can melatonin cause or treat depression in human studies?

Human studies of melatonin and depression

A review from 2017 elegantly summarised findings of different clinical studies using melatonin as an intervention in depression, finding that supplementation of melatonin was well tolerated but did not significantly increase mood [18]. These were replicated in 2022 [5].

Some studies found improvements in sleep quality, but not depressive symptoms, others found no effect [19], and other found that melatonin and an antidepressant, such as buspirone, improved depressive symptoms more than just buspirone [20].

A very old study from the 1970s found that melatonin aggravated symptoms of dysphoria []. However, the patient group this study looked at were people with Huntington’s Disease, suggesting that their results may not necessarily apply to people without Huntington’s Disease.

Agomelatine and depression: a melatonin analog

Agomelatine is a relatively new antidepressant, first discovered in 1992, which can stimulate melatonin and serotonin receptors. It has similar antidepressant efficacy to other antidepressants, including fluoxetine, sertraline and escitalopram, but with no adverse events reported to date [22].

Therefore, agomelatine could be an antidepressant that mimics melatonin and can confer the benefits of improved sleep, combined with relief from depressed mood.

This science, however, hasn’t shown demonstratable benefits of taking melatonin over antidepressants for depression.

Summary: Does Melatonin Make You Depressed?

To summarise, melatonin does not make you depressed, nor does melatonin cause depression. Quite the opposite – melatonin has been studied for its ability to treat depression.

Our understanding of melatonin's interaction with depression requires piecing together a vast, multidimensional puzzle. It’s becoming clear that melatonin could improve symptoms of insomnia, and whether it helps with depression will be highly individual.

For patients who struggle with sleep, shift work or jetlag, melatonin can be an effective strategy to reduce depressed mood. Newer antidepressants, such as agomelatine, could provide the bridge between helping alleviate circadian problems and depressive symptoms. Nonetheless, melatonin supplementation in severe major depression is unlikely to benefit individuals since melatonin has no strong support for improving mood directly.

Klara Hatinova

Klara Hatinova

Klara is a postgraduate researcher in experimental psychology at the University of Oxford. She has worked across a spectrum of hot topics in neuroscience, including her current project measuring reinforcement learning strategies in Parkinson’s disease. Previously, she studied the efficacy of psilocybin as a therapy for critical mental health conditions and examined molecular circadian rhythms of migraine disorders. She completed her undergraduate degree in Neuroscience at the University of Glasgow and participated in a year abroad at the University of California, where she worked on a clinical trial for spinal cord injury.