Melatonin in Easing Depression and Anxiety

Apr 11, 2024 | Written by Solène Grosdidier, PharmD, PhD | Reviewed by Scott Sherr, MD and Marion Hall

Melatonin in Easing Depression and Anxiety

Melatonin is a hormone made by the pineal gland in the brain via cyclic secretion. The circadian rhythm and darkness progressively stimulate its synthesis and secretion. High concentrations levels of melatonin are observed at night, while low concentrations are observed during the day. Melatonin is well-known for its modulation of the circadian rhythm through signaling pathways involving its two G protein-coupled receptors, melatonin receptor type 1A (MT1) and 1B (MT2) [1]. However, melatonin is involved in many other mechanisms and represents therapeutic opportunities for different conditions, including anxiety and depression.

In previous articles, we've discussed melatonin supplements, supplementation, and safety, and we've also discussed its anticancer potential. In this article, we'll take a deep dive into melatonin and its links to depression and anxiety.

Melatonin and depression

Depression is one of the most frequent mood disorders in the world and the World Health Organization reported an estimated 280 million people with depression in 2019.

Although melatonin alterations have been reported in various mood disorders, including Major Depressive Disorder (MDD), its role in the pathophysiology of the disease remains unclear. Melatonin primarily interacts with MT1 and MT2, and their deletions cause an increase in anxiety-like behavior in mice [2]. In humans, single nucleotide polymorphisms in melatonin receptors are associated with a higher risk of depression [3]. In addition, melatonin receptor agonists (activators) were found to be beneficial in treating depression and other depressive mood disorders [4].

Melatonin synthesis involves acetylserotonin methyltransferase, the rate-limiting enzyme in melatonin synthesis, whose gene has been linked with susceptibility to recurring depressive disorder [3].

Although conflicting results have been published, several studies have shown that melatonin levels in patients with depression compared to healthy individuals are significantly decreased [5].

Brown and colleagues studied the melatonin concentration in the blood of seven depressed male patients with melancholia and five healthy males for 15 h. When comparing both groups, they discovered that depressed patients had a significantly lower rise in melatonin [6]. Beck-Friis and colleagues compared 32 patients with MDD with 33 healthy individuals and measured melatonin concentration in the blood over 24 h. A comparison of both groups revealed that melatonin was significantly lower in patients with abnormal cortisol secretion; at the same time, no differences were found when comparing patients with normal cortisol secretion and healthy controls [7]. McIntyre and colleagues compared the nocturnal blood concentrations of melatonin between 11 patients with MDD and 18 healthy individuals and discovered that the melatonin concentrations at midnight were significantly lower in patients with MDD [8]. Crasson and colleagues compared blood (over 15 h) and urine concentrations (over 24 h) of melatonin between 14 patients with MDD and 14 healthy individuals. A comparison of both groups showed a significantly delayed peak of melatonin in patients with MDD [9].

The effects of melatonin on depression

There is very limited evidence supporting the positive effects of melatonin supplementation for the treatment of depression in humans [10]. However, several newly published randomized controlled trials demonstrated the beneficial effects of melatonin on secondary depressive and anxiety symptoms in various patient populations.

A clinical trial study reported that melatonin impacts cognition, depressive symptoms, and sleep quality in the context of breast cancer. A total of 36 women with breast cancer were randomly assigned to receive either melatonin or a placebo for 10 days before and during the first cycle of adjuvant chemotherapy. Results showed that melatonin's neuroprotective effects were able to counteract the adverse effects of chemotherapy on cognitive function, sleep quality, and depressive symptoms [11].

Another clinical trial focused on melatonin's effects on mental health in patients treated for opioid addiction and under methadone maintenance treatment. Patients were randomized to receive either melatonin or a placebo for 12 weeks. Results showed that melatonin significantly improved sleep quality and reduced depression and anxiety symptoms compared to the placebo [12]. Similarly, an additional clinical trial reported the effects of melatonin in women with polycystic ovary syndrome. Patients were randomly assigned to receive either melatonin or a placebo for 12 weeks. Here, it was found that melatonin significantly improves sleep quality and reduces depression and anxiety symptoms compared to the placebo [13]. Finally, a last randomized clinical trial involving 60 patients with Parkinson’s disease receiving either melatonin or a placebo for 12 weeks also reported positive effects in reducing symptoms of depression and anxiety [14].

Melatonin and anxiety

Melatonin receptors MT1 and MT2 are involved in anxiety-like responses in different animal models. MT1 and MT2 are expressed in different brain areas (i.e., amygdala, hippocampus, and prefrontal cortex) responsible for fear processing [15]. The genetic deletion (knockout) of MT1 or MT2 has been found to increase anxiety-like behaviors in several rodent models [16], and melatonin agonists are known to have anxiolytic properties [17]. As such, the potential therapeutic role of melatonin in anxiety has been previously investigated.

The effects of melatonin on anxiety

In rats, sleep disturbances and sleep deprivation have been shown to induce anxiety-like behavior, and supplementation with melatonin may prevent this [18]. In humans, many studies indicate that preoperative anxiety results in worsened perioperative outcomes, such as impaired wound healing, nausea, or postoperative pain. Consequently, the therapeutic potential of melatonin in preventing anxiety has been investigated in the context of surgery [19].

In a randomized clinical trial, the effectiveness of melatonin in reducing postoperative pain and anxiety was compared to clonidine and placebo after abdominal hysterectomy. Fifty-nine patients were randomly assigned to receive either oral melatonin, clonidine, or a placebo. The results suggest that melatonin was as effective as clonidine in reducing pain intensity and analgesic consumption compared to a placebo in anxious patients. Additionally, melatonin or clonidine administration before the intervention resulted in a significant decrease in postoperative morphine consumption. However, in mildly anxious patients, no effects were observed. Overall, these findings suggest that preoperative anxiolysis with melatonin can alleviate postoperative pain and reduce morphine needs after a hysterectomy in highly anxious patients [20]. Several other clinical trials reported similar melatonin effects regarding anxiolysis related to other surgical interventions [21]. Melatonin treatment proved comparable to midazolam concerning anxiolysis in a randomized clinical trial involving 120 patients undergoing surgery. Melatonin even proved superior as it does not impair general cognition (working memory, sustained attention, and flexibility of thinking) or psychomotricity unlike midazolam [22].

Overall, a recent meta-analysis states that melatonin medication before a treatment or procedure in adults can reduce preoperative anxiety as measured 50 and 120 min following administration, but melatonin's clinical relevance in postoperative anxiety is uncertain. In addition, melatonin presents similar effects to benzodiazepines in the context of surgery [23].

Melatonin has also been tested in pediatric surgery. One randomized clinical trial involving 105 children compared the perioperative effects of melatonin, midazolam, or a placebo in addition to acetaminophen. Results showed that melatonin was as effective as midazolam in alleviating preoperative anxiety. In addition, melatonin was associated with faster recovery and a lower incidence of sleep disturbance 2 weeks after surgery [24]. Similar results regarding melatonin’s anxiolytic effects were found in another randomized clinical trial that involved a group of 80 children [25].


Melatonin appears to be associated with depression, with supplementation showing its potential to alleviate secondary depressive symptoms across various patient populations in recent literature. However, many studies have found that melatonin has limited or no effect on primary depression. As such, more research is needed to fully understand melatonin's potential in depression treatment.

Melatonin has also shown promising results in alleviating anxiety and anxiety-like symptoms, especially in the context of perioperative anxiolysis in both adult and pediatric populations.

However, if you’d like to use melatonin for what it’s best known for (i.e., helping with the timing of your circadian rhythms and sleep), then give Tro Zzz a try! It’s our buccal troche formulated for sleep that has melatonin as one of its main ingredients to help you fall asleep, stay asleep, and wake up feeling refreshed.



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