Table 2.

Studies describing effects of melatonin in patients with RBD.

Authors, Year [Ref]	Study Setting/Design	Type of Study	Main Findings	Level of Evidence
Kunz and Bess, 1997 [32]	One patient with RBD treated with melatonin	Single case report	The first description of improvement of RBD with 3 mg/day of melatonin (significant reduction of motor activity during sleep measured by actigraphy and improvement in REM-sleep atonia by PSG)	III (NA)
Kunz and Bess, 1999 [33]	Six consecutive RBD patients were treated over 6 weeks with 3 mg of melatonin 30 min before bedtime. Clinical and PSG evaluation	Open-label trial	Dramatic clinical improvement in five of six patients within a week up to the end of treatment. Normalization of the percentage of REM sleep, a significant reduction of REM sleep without muscle atonia, a significant reduction of stage shifts in REM, and a significant reduction in epochs considered to be movement time in REM by PSG.	III (NA)
Takeuchi et al., 2001 [34]	15 PSG confirmed RBD patients treated with 3–9 mg/day of melatonin. Clinical and PSG evaluation, measurement of blood melatonin levels	Open-label trial	Marked, moderate, and mild improvement in 3, 9, and 1 patients, respectively. Two patients did not report improvement. Significant reduction of tonic REM activity in PSG after treatment with melatonin, with other PSG parameters remaining unchanged.	II (NA)
Boeve et al., 2003 [35]	14 patients with secondary RBD treated with 3–12 mg/day of melatonin because of lack of response to (n = 6) or severe side-effects with clonazepam (n = 2), cognitive impairment (n = 6), or presence of severe obstructive sleep apnoea (n = 1) and narcolepsy (n = 1)	Open-label trial. In 7 patients, melatonin was used as add-on therapy to 0.5–1 mg/day of clonazepam	Symptomatic control in 6 patients, significant improvement in 4, initial improvement with further worsening in 2, lack of improvement in 1, and increased severity of RBD in 1. Effective melatonin doses: 3 mg (n = 2), 6 mg (n = 7), 9 mg (n = 1), and 12 mg (n = 2) Side-effects in 5 patients resolved with decreasing doses (2 with morning headaches or sleepiness and 1 with delusions/hallucinations. Eight patients continued experiencing therapeutic improvement after 12 months of therapy	II (NA)
Anderson et al., 2008 [36]	Single case report	Single case report	Description of improvement of RBD in a patient diagnosed Alzheimer’s disease with 10 mg/day of melatonin (nearly complete resolution with no further episodes of self-injury or injury to his wife)	III (NA)
Kunz and Mahlberg, 2010 [37]	Eight male RBD patients treated with 3 mg of melatonin vs. placebo. Clinical (CGI-I) and PSG evaluation	Two-part, randomized, double-blind, placebo-controlled cross-over study	Significant improvement in CGI-I and reduction of the number of 30-s REM sleep epochs without muscle atonia during melatonin treatment. The number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I, while patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (melatonin treatment).	I (>50%)
McCarter et al., 2013 [21]	Description of a series of 45 RBD patients, (60% reported RBD-associated injury before treatment); 25 of them were treated with melatonin	Retrospective cohort study	RBD VAS and RBD injuries and falls from the bed significantly improved with melatonin (more than with clonazepam); 28% of patients discontinued clonazepam because of side-effects	II (NA)
Lyashenko et al. [38]	30 PD patients with PSG confirmed RBD. Treatment with 3–6 mg of melatonin ad bedtime for 4 weeks.	Open-label trial	84% of patients reported improvement of RBD symptoms	II (NA)
Schaefer et al., 2017 [39]	Four patients with RBD and concomitant obstructive sleep apnoea syndrome. Treatment with 2 mg of prolonged-release melatonin. Clinical and PSG evaluation.	Open-label study	Important clinical improvement. Non-significant changes in the percentage of REM sleep without atonia (attributed to the lack of therapy for obstructive sleep apnoea syndrome).	II (NA)
Kunz et al., 2017 [40]	A 72-year-old man diagnosed with Parkinson’s disease with reduced striatal DAT developed a typical RBD confirmed by PSG. Treatment with 2 mg of prolonged-release melatonin.	Single case report	Video-assisted PSG confirmed the diagnosis of RBD in 2012. Gradual improvement of clinical signs of RBD in 6 months and normalization of REM sleep with atonia two years later. Normalization of further DAT scans.	III (NA)
Jun et al., 2019 [41]	30 patients with PSG-confirmed iRBD. Treatment with prolonged-release 2 mg/day of melatonin, 6 mg/day of melatonin, or placebo 30 min before bedtime.Assessment with CGI-I and RBDQ-KR. The secondary outcomes included PSQI, ESS, SFRHS2 scores, as well as a sleep diary	A four-week, randomized, double-blind, placebo-controlled pilot study	Non-significant differences in the proportions of patients with a much or very much improved CGI-I score among the study groups. Non-significant differences in RBDQ-KR, PSQI, ESS, and SFRHS2, as well as in the sleep diary, among the groups.	I (>50%)
Gilat et al., 2020 [42]	30 PD patients with RBD. Treatment with 4 mg of prolonged-release melatonin or matched placebo at bedtime. Weekly diary or RBD incidents and adverse events.	Randomized, double-blind, placebo-controlled, parallel-group trial with an 8-week intervention and 4-week observation pre- and post-intervention	No differences between groups in events/week Similar adverse events between groups (mild headaches, fatigue, and morning sleepiness in 4 patients on melatonin and 5 on placebo).	II (>50%)
Sunwoo et al., 2020 [27]	Assessment of “treatment” response (“presence or absence of any improvement in dream-enacting behaviours or unpleasant dreams after treatment”) in 123 iRBD patients treated with clonazepam (n = 40), melatonin (n = 56), and clonazepam associated with melatonin (n = 27).	Retrospective review of medical records	Ninety-six (78.0%) patients reported improvement in their RBD symptoms during a mean follow-up period of 17.7 months RBDQ-KR, PSQI, SCOPA-AUT, and KVSS scores, as well as the frequency or excessive daytime sleepiness, did not significantly differ between responders and non-responders. Depression was significantly more frequent in non-responders.	II (NA)
Kunz et al., 2021 [43]	209 consecutive iRBD patients (171 patients had taken 2 mg of melatonin at 10–11 pm for ≥6 months, 13 had taken such for 1–3 months, and 25 used mixed treatments). Clinical evaluations with CGI and a newly developed RBD symptom severity scale (Ikelos-RS)	Single-centre, observational cohort study	RBD symptom severity gradually improved over the first 4 weeks of treatment and remained stably improved (mean follow-up 4.2 ± 3.1 years) The initial response was slowed to up to 3 months in patients taking beta-blockers or antidepressants and in patients with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, RBD symptoms remained stably improved. When administered for only 1–3 months, RBD symptoms gradually returned.	II (NA)

CGI, clinical global impression; CGI-I, clinical global impression-improvement; DAT, dopamine transporter; ESS, Epworth Sleepiness Scale; iRBD, idiopathic or isolated REM sleep behaviour disorder; KVSS, Korean version of sniffin’ stick; NA, not applicable; PSG, polysomnography; RBD REM, sleep behaviour disorder; RBDQ-KR, RBD Questionnaire-Korean version; PSQI, Pittsburgh Sleep Quality Index; REM, rapid eye movements; SCOPA-AUT, Scales for Outcomes in Parkinson’s Disease Autonomic; SFRHS2, Short Form Health Survey version 2; VAS, visual analogue scale.