A new multinational study involving researchers from Pontificia Universidad Católica – Argentina, University of Toronto – Canada and Saveetha University, Chennai – India has found that melatonin supplements can aid in relieving and treating certain Long COVID symptoms. Being a cheap generic supplement that is easily available, the study team suggested that melatonin can easily be included in Long COVID treatment protocols.
The study findings review were published in the peer reviewed journal: Biomolecules.
Mechanism of Action of Melatonin Relevant to Long COVID Treatment
Melatonin is an ancient molecule. This methoxyindole is found in all forms of life that express aerobic respiration; melatonin’s primary function is cytoprotection, displaying anti-inflammatory, antioxidant, and immunostimulant effects [29,30] which together endow it with highly potent neuroprotective properties .
The anti-inflammatory action of melatonin involves a variety of mechanisms . One of them is Sirtuin-1 induction, which decreases the polarization of macrophages toward a proinflammatory profile . Suppression of nuclear factor (NF)-κB activation [34,35] and stimulation of nuclear erythroid 2-related factor 2 are also detected after exposure to melatonin .
Melatonin reduces proinflammatory cytokines (tumor necrosis (TN)F-α, interleukin (IL)-1β, IL-6, and IL-8) and increases anti-inflammatory cytokines such as IL-10 [33,37].
The antioxidant and scavenging effects of melatonin on free radicals in both the cytoplasm and the cell nucleus are mainly independent of receptors . To fulfill this, melatonin not only acts as a free radical scavenger but also gives rise to a cascade of molecules with high antioxidant activity.
It also acts as an indirect antioxidant, enhancing the production of antioxidant enzymes while inhibiting that of prooxidant enzymes . In addition, some antiapoptotic and cytoprotective effects are seen under ischemia, presumably due to melatonin’s stabilizing activity of the mitochondrial membrane .
A distinguishing hallmark of viral infection is the shift of cellular metabolism from the oxidative phosphorylation pattern taking place in the mitochondria to glycolysis occurring mainly in the cytoplasm (Warburg’s effect) . The main phenomenon responsible for the change in the oxidation of mitochondrial glucose is the positive regulation of cytoplasmic pyruvate, which is often accompanied by the increase in the hypoxia-inducible factor-1α (HIF-1α), and of NF-κB and other transcription factors promoting inflammation .
Because of this, M2 anti-inflammatory macrophages in COVID-19 patients are converted into M1 proinflammatory cells, therefore triggering a cytokine storm. Thus, melatonin can reduce the damage resulting from sepsis mediated by COVID-19 through different mechanisms, i.e., by reversing the Warburg-type metabolism and transforming proinflammatory M1 macrophages into anti-inflammatory M2 macrophages , by mitigating the production of HIF-1α , by suppressing NF-κB , and by inhibiting NLRP3 inflammasome .
Circulating secreted phospholipase-A2 (Group IIA) correlated with the severity of COVID-19 disease ; hence, cyclooxygenase inhibition by melatonin [48,49] is another potential mechanism by which the methoxyindole may inhibit viral infection.
As shown by several meta-analyses, the chronobiotic/hypnotic properties of melatonin are useful in patients with sleep disorders by synchronizing the circadian apparatus, decreasing sleep onset latency, and increasing total sleep time [50,51,52]. A significant role of melatonin treatment in adult insomnia was the conclusion of several recent expert consensus reports [53,54,55,56].
In addition, melatonin reduces the need for sedation in ICU patients [57,58,59,60,61,62]. These chronobiotic/hypnotic effects of melatonin are obtained at a daily dose range of 2–10 mg .
It may well be true that higher doses of melatonin would be more beneficial in the COVID pandemic condition. For example, in a retrospective cross-sectional study of a closed population of 110 old adult patients treated with a mean melatonin daily dose of 46 mg for at least 12 months prior to the availability of COVID-19 vaccination, there was no death in the face of a lethality rate of 10.5% in the local population of elders suffering acute COVID-19 disease .
Indeed, animal studies support the use of high doses of melatonin to prevent infection in murine COVID-19 models . From several animal studies, the human equivalent dose HED) of melatonin was calculated by allometry for a 75 kg adult . Allometry is commonly employed for determining initial doses used in Phase I human clinical drug trials .
(a) Melatonin and brain fog
As stated above, the deficits in attention, memory, verbal processing, and problem-solving seen in patients complaining of brain fog resemble MCI, the initial phase of Alzheimer’s disease (AD) . The underlying neuroinflammation in this condition (Figure 1) could be effectively controlled by melatonin, as shown by studies in cell lines linked to AD, in which melatonin reverses abnormalities in the Wnt/β-catenin, insulin, and Notch signaling pathways, proteostasis disruption and abnormal autophagic integrity (reviewed in Refs. [67,68,69,70,71]).
In transgenic models of AD, melatonin regulates amyloid-β (Aβ) metabolism beginning with the initial phases of the pathological process (see Ref. ). From these studies, the HED of melatonin for a 75 kg adult was 2 to 3 orders of magnitude greater than those usually employed in humans.
The exact mechanism by which melatonin inhibits the production of Aβ is unknown. Via structural melatonin features independent of its antioxidant capabilities , melatonin interacts with Aβ40 and Aβ42, thus inhibiting progressive -sheet and/or amyloid fibrils and facilitating peptide clearance by increasing proteolytic degradation.
Aβ-induced neurotoxicity and cell death involve oxidative stress, and melatonin effectively protects cells against it in vitro  and in vivo [74,75]. Melatonin was found to protect against Aβ toxicity, particularly at the mitochondrial level. Melatonin effectively inhibits tau hyperphosphorylation in N2a and SH-SY5Y neuroblastoma cells by influencing protein kinases and phosphatases [76,77].
Melatonin treatment of AD transgenic mice increases Aβ glymphatic clearance [78,79]. Relevant to this, melatonin is known to preserve slow-wave sleep in patients , a phase in which the glymphatic elimination of Aβ peptides increases considerably . Thus, the correction by melatonin of sleep disruption can contribute to counteracting the failure of Aβ clearance found in AD.
Epidemiological research suggests that anti-inflammatory medication use in AD may be beneficial due to activated microglia’s decreased secretion of proinflammatory cytokines . In this respect, melatonin is very effective in attenuating the microglial production of proinflammatory cytokines induced by Aβ, NF kB, or nitric oxide .
The effectiveness of melatonin therapy in improving sleep in demented patients is supported by two meta-analyses [84,85]. In addition, the administration of melatonin in the initial stages of cognitive decline consistently improves sleep and cognitive performance (see Ref. ).
In one of our laboratories, we conducted a retrospective analysis of MCI patients who had received a daily dose of 3–24 mg of melatonin along with their usual medication. Compared to the untreated group, melatonin-treated patients significantly improved cognitive performance, Beck Depression Inventory, and quality of sleep/wake rhythm [86,87].
In a study on 40 MCI patients treated with melatonin at a daily dose of 0.15 mg/kg for 6 months, the hippocampal volume and lamina cribrosa thickness decreased significantly as compared with 39 MCI patients receiving placebo . On the other hand, the cerebrospinal fluid T-tau level of the melatonin-treated group was significantly lower compared with the untreated group.
A lower Mini Mental State Examination score, a smaller hippocampus volume, and upregulated level of tau protein were associated with significantly thinner lamina cribrosa in MCI patients, all effects counteracted by melatonin treatment . In a meta-analysis of 22 randomized controlled trials to assess the neurocognitive effects of melatonin treatment in healthy adults and individuals with AD disease and insomnia, AD patients receiving >12 weeks of melatonin treatment (2.5–10 mg daily) improved MMSE score, particularly in the mild stage of AD . Therefore, melatonin treatment could be effective in the early stages of neurodegenerative diseases, such as brain fog, in long COVID patients. Unfortunately, very little information is available on melatonin efficacy in COVID therapy, and none has been related to long COVID brain fog syndrome.
(b) Melatonin and ME/CFS
The beneficial effects of melatonin on fibromyalgia (associated commonly with ME/CFS) were first described in one of our laboratories . Since then, several studies have confirmed the initial findings (for a summary, see ref. ). A common pathogenic mechanism is suggested by the similarities among ME/CFS, fibromyalgia, and post-COVID syndrome. The multiplicity of pathophysiological abnormalities in ME/CFS patients opens the possibility of numerous potential therapeutic targets .
The several abnormalities described comprise increased oxidative stress, mitochondrial dysfunction, dysregulated bioenergetics, a proinflammatory state, the disruption of gut mucosal barriers, and autonomic nervous system disturbances related to autoimmunity  (Figure 2). The possible therapeutic options targeting these pathways include melatonin, coenzyme Q10, curcumin, molecular hydrogen, and N-acetylcysteine . Among them, melatonin is the only compound that addresses all mentioned potential targets .