Melatonin effects

Golombek, D. A., Pevet, P. Cardinali, D. P. (1996). Melatonin effects on behavior possible mediation by the central GABAergic system. Neurosci. Biobehav. Rev. 20, 403-12. 

Jean-Louis G, von Gizycki H, Zizi F (1998) Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. J Pineal Res 25 177-183... 

Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S (2003) Double blind study of melatonin effects on the sleep-wake rhythm, Cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 70 334-341... 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Melatonin produces its effects via the GPCR, ML-1. A second lower affinity form, ML-2, has been described on the basis of binding data. Activation of melatonin receptors can inhibit DA release in the retina. 

Arendt, J, Middleton, B, Stone, B and Skene, D (1999) Complex effects of melatonin Evidence for photoperiodic responses in humans Sleep 22 625-635. 

Antihistamines such as diphenhydramine are known for their sedating properties and are frequently used over-the-counter medications (usual doses 25-50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.43 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is an herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance and thus may be a viable option for patients with a history of substance abuse. 

Non-REM parasomnias usually do not require treatment. If needed, low-dose benzodiazepines such as clonazepam can be prescribed for bothersome episodes. Clonazepam reduces the amount of sleep time spent in stages 3 and 4 of non-REM sleep, where most non-REM parasomnias occur. For treating RBD, clonazepam 0.5 to 2 mg at bedtime is the drug of choice, although melatonin 3 to 12 mg at bedtime also may be effective. Patients with RBD also should have dangerous objects removed from the bedroom and cushions placed on the floor to reduce the chance of injury from breakthrough episodes. 

Recent studies in a model of ischemic stroke suggest that the acute neuro-protective effect of melatonin involves activation of the phosphatidylinositol-3-kinase/Akt pathway, whereas ERK-1/2 and c-Jun N-terminal kinase-1/2, in addition to Akt signaling, appear to be involved in its long-term effects (Kilic et al. 2005). These results indicate that melatonin can interact with multiple cellular pathways to produce its diverse physiological effects. Moreover, MTi and MT2 receptors can interact with divergent signaling pathways, as shown by their ability to... 

Effects of exogenous melatonin administration on human sleep... 

A reduced endogenous melatonin production seems to be a prerequisite for effective exogenous melatonin treatment of sleep disorders. A recent metaanalysis of the effects of melatonin in sleep disturbances, including all age... 

In contrast, another meta-analysis undertaken by Brzezinski et al., using 17 different studies involving 284 subjects, most of whom were older, concluded that melatonin is effective in increasing sleep efficiency and reducing sleep onset time (Brzezinski et al. 2005). Based on this meta-analysis the use of melatonin in the treatment of insomnia, particularly in aged individuals with nocturnal melatonin deficiency, was proposed. 

Phase-shifting by melatonin is attributed to its action at MT2 receptors present in the SCN (Liu et al. 1997). The chronobiological effect of melatonin is due to its direct influence on the electrical and metabolic activity of the SCN, a finding that has been confirmed both in vivo and in vitro. The application of melatonin directly to the SCN significantly increases the amplitude of the melatonin peak, thereby suggesting that in addition to its phase-shifting effect melatonin directly acts on the amplitude of the oscillations (Pevet et al. 2002). However, this amplitude modulation seems to be unrelated to clock gene expression in the SCN (Poirel et al. 2003). 

A number of studies have investigated the potential of melatonin to alleviate the symptoms of jet lag. Melatonin has been found to be effective in 11 placebo-controlled studies in reducing the subjective symptoms of jet lag such as sleepiness and impaired alertness (Arendt 2005). The most severe health effects of jet lag occur following eastbound flights, since this requires a phase advancement of the biological clock. In a recent study, phase advancement after melatonin administration (using 3 mg doses just before bedtime) occurred in all 11... 

A number of clinical studies have now made use of the phase advancing property of melatonin for treating delayed sleep phase syndrome (DSPS). Melatonin, at a 5 mg dose, has been found beneficial in advancing the sleep onset time and wake time in DSPS subjects (Dahlitz et al. 1991 Nagtegaal et al. 1998 Kayumov et al. 2001). Melatonin was found to be effective when given five hours before its endogenous onset or seven hours before sleep onset. 

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