Biological function

Melatonin is an indoleamine secreted mainly by de pineal gland in a circadian manner in the absence of light (Bonmati-Carrion & Tomas-Loba, 2021). It shows several physiological roles in the brain, including the regulation of circadian rhythms and reducing oxidative stress, showing also anti-proliferative, anti-inflammatory, and anti-cancer effects (Chen et al., 2020; Ghorbaninejad et al., 2020; Kopustinskiene & Bernatoniene, 2021). Melatonin acts via receptor-dependent and independent pathways, it modulates several signal transduction steps and supports the healthy state of mitochondria, preventing potential impairments of cellular energy supply (Kopustinskiene & Bernatoniene, 2021).

Clinical relevance

Melatonin dysfunction is frequently associated to deviations in amplitudes, phasing, and coupling of circadian rhythms, which can lead to sleep disorders. Melatonin secretion decreases during aging and are also reduced in several medical conditions, such as dementia, mood disorders, severe pain, cancer and diabetes type 2. Furthermore, the anti-inflammatory properties of melatonin might help with neurological disorders and ischemias (Hardeland, 2012; Kopustinskiene & Bernatoniene, 2021).

Melatonin supplementation is well tolerated even at high doses (1–5 mg) and could serve as a potential adjuvant remedy in many degenerative and infectious diseases and for sleep regulation (Kopustinskiene & Bernatoniene, 2021).

The effects of melatonin supplements are dependent on the type of formulations used by the patients, since this affects the pharmacokinetics of melatonin in the human body. There are several melatonin receptor agonists on the market, such as ramelteon and tasimelteon, which are FDA-approved for the treatment of insomnia (Morini et al., 2017; Savage et al., 2020). In any case, more research is needed to understand which formulations are the most appropriate to achieve therapeutic effects.

Sleep disorders

A recent review of clinical trials investigating the effects of melatonin on sleep quality found that melatonin supplementation shows positive effects on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) in adults  (Fatemeh et al., 2021).

In another recent review, melatonin shows to be effective in improving sleep-onset difficulties (Baglioni et al., 2020).

COVID-19

Melatonin has been shown to have antiviral properties against several viral infections which are accompanied by neurological symptoms. The beneficial properties of melatonin relate to its properties as a potent antioxidant, anti-inflammatory, and immunoregulatory molecule and its neuroprotective effects (Wongchitrat et al., 2021). In fact, high doses of melatonin might favorably modulate the immune response and neuroinflammation caused by SARS-CoV-2 (Romero et al., 2020).

Due to its neuroprotective properties, melatonin might be effective to control cognitive decay in minimal cognitive impairment, so it could help with the neurological sequels of SARS-CoV-2 infection. Also, melatonin supplementation might be an adjuvant capable of augmenting the efficacy of anti-SARS-CoV-2 vaccines (Cardinali et al., 2020).

Melatonin use has been shown to reduce cardiac damage by blocking the CD147 protein activity. Melatonin is proposed to prevent severe symptoms, reduce symptom severity and the adverse effects of the other antiviral drugs in COVID-19 patients (Sehirli et al., 2020).

Also, melatonin can be effective in critical care patients by reducing their vascular permeability and anxiety, inducing sedation, and improving their quality of sleep (Kleszczyński et al., 2020).

Cancer

The World Health Organization classified in 2007 night shift work as a probable carcinogen due to circadian disruption. The antioxidant, immunomodulatory, pro-apoptotic, antiproliferative, and anti-angiogenic properties of melatonin are considered to play a relevant role as antitumor agent.  Some epidemiological studies linked light at night, which implies melatonin suppression, with a higher incidence of different types of cancer like liver and prostate cancer (Bonmati-Carrion & Tomas-Loba, 2021; Fernández-Palanca et al., 2021).

A review on the anticancer properties of melatonin against breast cancer suggest that it can suppress breast cancer phases including initiation, promotion, and progression, via the MT1 receptor. The production of melatonin is reduced during the fifth and sixth decades of life, the same period where the incidence of breast cancer increases. Authors suggest a causal relationship between the reduction in melatonin production in the pineal gland and the incidence of breast cancer which increases with age (Hill et al., 2013).

Periodontitis

Many studies showed that the melatonin levels in gingival crevicular fluid, saliva, serum of patients suffering from chronic periodontitis is lowered (Meenakshi & Malaiappan, 2020). Melatonin might help with periodontal regeneration since it reduces inflammation, inhibits cell proliferation and regulates differentiation of pulp cells. Melatonin increased odontoblast activities, resulting in the differentiation in the dental pulp and might help promoting periodontal wound healing (Vaseenon et al., 2021).

Diabetes mellitus

Melatonin deficiency and its effects in intermediary metabolism via resynchronization of the circadian rhythms has been associated with metabolic dysregulations. Melatonin plays a role regulating insulin secretion and its supplementation successfully improved glucose homeostasis, energy balance, and overall health in diabetes mellitus (Wajid et al., 2020).

Cardiovascular disorders

Melatonin shows cardioprotective properties, reducing cardiac damage and changes in cellular physiology during ischemia/reperfusion injury due to actions at mitochondrial level (Kopustinskiene & Bernatoniene, 2021).

Melatonin has been shown to control angiogenesis at both molecular and cellular levels and might have therapeutic properties associated to cardiovascular diseases such as ischemic injury and hypertension (Pourhanifeh et al., 2020; Rahbarghazi et al., 2021).

Neurological disorders

Melatonin has been shown to be neuroprotective in several neurological disorders like ischemic stroke, Alzheimer’s, Parkinson’s and Huntington's disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis and some other age-related disorders (Chen et al., 2020; Kopustinskiene & Bernatoniene, 2021; Sadanandan et al., 2020).

Melatonin shows a potent neuroprotective effect and can prevent or slow down the progression of AD. Melatonin modulates amyloidogenic APP processing and Aβ production. Additionally, melatonin ameliorates Aβ-induced neurotoxicity and probably promotes Aβ clearance. Also, melatonin has a promising effect in improving sleep quality and cognitive function (Li et al., 2020).

Melatonin secretion has been reported to be reduced in patients with autism spectrum disorders. Melatonin improves sleep latency and sleep quality in patients, and it might actually have a role in improving autistic behavioral impairments (Lalanne et al., 2021).

Rare genetic neurodevelopmental disorders like Smith-Magenis, Angelman, Fragile-X, Prader-Willi, septo-optic dysplasia, PAX6/WAGR and William’s syndromes present a range of sleep problems, particularly dyssomnias, and low nocturnal melatonin levels are commonly reported (Woodford et al., 2021).

Other medical conditions

Melatonin is present in significant amounts in the gastrointestinal tract, directly affecting its tissues and indirectly modulating the brain–gut axis, so it might also help in gastrointestinal medical conditions (Kopustinskiene & Bernatoniene, 2021)

Melatonin plays an important role in obesity by modulation of glycemic homeostasis, in addition to modulation of white adipose tissue activity, lipid metabolism, and mitochondrial activity. Additionally, melatonin increases brown adipose tissue volume and activity, and its antioxidant and anti-inflammatory properties have also been demonstrated. There appears to be a role for melatonin in adiposity reduction (Genario et al., 2021).

Melatonin levels are reduced in patients with sarcopenia and its supplementation protected the development of sarcopenia in aged rodent models (Kopustinskiene & Bernatoniene, 2021).

Melatonin may be of potential benefit in the treatment/prevention of migraine and cluster headache in adults (Liampas, Siokas, Brotis, Aloizou, et al., 2020; Liampas, Siokas, Brotis, Vikelis, et al., 2020).

Endocannabinoid System

The endocannabinoid system might play a role in the pineal gland, which is responsible for the production of melatonin, and also in the pineal sympathetic fibers. CB1 and CB2 receptors, as well as NAPE-PLD and FAAH, have been found in pineal gland cells. However, the expression of these proteins is not modulated by the circadian rhythm, with the exception of the CB1 receptor, which is significantly reduced at the end of the light phase. In summary, the pineal gland contains key players of the endocannabinoid system suggesting that endocannabinoids may be involved in the control of pineal physiology and hence, they might interact with the production or the role of melatonin (Koch et al., 2008).

A more recent study suggests that endocannabinoids are able to affect diurnal and circadian rhythms. The endocannabinoid AEA showed rhythmic changes in rat pineal glands, showing higher levels during the light-period and reduced amounts at the onset of darkness. AEA was down-regulated by norepinephrine, which is essential for melatonin biosynthesis at night. Authors suggest that AEA might exert time-dependent autocrine and/or paracrine functions within the pineal gland, and this might affect both the production and functioning of melatonin (Koch et al., 2015).

Cannabinoid synergies

A study performed in the 80’s found a highly significant increase of melatonin serum levels after THC administration in humans (Lissoni et al., 1986). In contrast, another study shows that cannabis attenuate melatonin biosynthesis by inhibiting norepinephrine-induced arylalkylamine N-acetyltransferase activity. The mechanisms underlying such effect are intracellular and there is no involvement of classical cannabinoid receptor-dependent signaling cascades (Koch et al., 2006). Furthermore, another study shows that the synthetic cannabinoid WIN55212-3 antagonizes signaling of the human MT1 receptor (Savinainen et al., 2005). The only study combining melatonin and THC administration showed that melatonin and/or vitamin C exacerbate THC-induced testicular and spermatozoid damage in rats when administered separately but ameliorate it when combined (Alagbonsi et al., 2016; Alagbonsi & Olayaki, 2018).

Due to the lack of scientific evidence and because of contradictory results on how cannabinoids affect endogenous melatonin levels on the human body, we only can say that there is an interaction between cannabinoids and melatonin, but more research is needed to understand their interaction.

Health Claims (NIH)

• Jet lag
• Delayed sleep-wake phase disorder
• Sleep disorders in children
• Anxiety before and after surgery

Health Claims (EU/EFSA)

• Melatonin contributes to the alleviation of subjective feelings of jet lag
• Melatonin contributes to the reduction of time taken to fall asleep

 

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