| |

Received: 5 November 2021    Revised: 14 December 2021    Accepted: 14 December 2021

DOI: 10.1111/jpi.12782

REVIEW

Safety of higher doses of melatonin in adults: A systematic

review and meta-­analysis

Zoe Menczel Schrire1,2,3,4   | Craig L. Phillips4,5  | Julia L. Chapman1,2,3,4  |

Shantel L. Duffy2,3,4,5  | Grace Wong4  | Angela L. D’Rozario1,2,3,4  | Maria Comas4  |
Isabelle Raisin6  | Bandana Saini4,5  | Christopher J. Gordon4,5  |
Andrew C. McKinnon1,2,3  | Sharon L. Naismith1,2,3  | Nathaniel S. Marshall4,5  |
Ronald R. Grunstein4,5,7  | Camilla M. Hoyos1,2,3,4
1
Healthy Brain Ageing Program, Faculty of Science, School of Psychology, The University of Sydney, Sydney, New South Wales, Australia
2
Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
3
Brain & Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
4
Woolcock Institute of Medical Research, Centre for Sleep and Chronobiology, University of Sydney, Sydney, New South Wales, Australia
5
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
6
University Library, The University of Sydney, Sydney, New South Wales, Australia
7
Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

Correspondence
Camilla M. Hoyos, Charles Perkins Abstract
Centre, The University of Sydney, Level Melatonin is commonly used for sleep and jetlag at low doses. However, there is
2, Building D17, Johns Hopkins Drive,
less documentation on the safety of higher doses, which are being increasingly
Camperdown, NSW 2050, Australia.
Email: camilla.hoyos@sydney.edu.au used for a wide variety of conditions, including more recently COVID-­19 preven-
tion and treatment. The aim of this review was to investigate the safety of higher
Funding information
CMH and ALD are funded by an
doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases
NHMRC-­ARC Dementia Research from inception until December 2019 with convenience searches until October
Development Fellowship (APP1104003 2020. Randomised controlled trials investigating high-­dose melatonin (≥10 mg)
and GTN1107716 respectively). ZMS
is funded by the Centre of Research in human adults over 30 years of age were included. Two investigators indepen-
Excellence to Optimise Sleep in dently abstracted articles using PRISMA guidelines. Risk of bias was assessed by
Brain Ageing and Neurodegeneration
a committee of three investigators. 79 studies were identified with a total of 3861
(CogSleep CRE) Scholarship. RRG is
principally funded by the Australian participants. Studies included a large range of medical conditions. The meta-­
National Health and Medical Research analysis was pooled data using a random effects model. The outcomes examined
Council (NHMRC) via a Project
were the number of adverse events (AEs), serious adverse events (SAEs) and
Grant (GTN1004528), NHMRC
Senior Principal Research Fellowship withdrawals due to AEs. A total of 29 studies (37%) made no mention of the pres-
GTN1152945, RRG), NHMRC ence or absence of AEs. Overall, only four studies met the pre-­specified low risk
Centre for Research Excellence and
NeuroSLEEP (GTN1060992, RRG).
of bias criteria for meta-­analysis. In that small subset, melatonin did not cause
SLN and CLP are funded by NHMRC a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or with-
Boosting Dementia Leadership drawals due to AEs (0.93 [0.24, 3.56], p = .92), but did appear to increase the risk
Fellowships (SLN GTN1135639, CLP

Registration: PROSPERO Registration CRD42019105147.

© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

J Pineal Res. 2022;72:e12782.  wileyonlinelibrary.com/journal/jpi   |  1 of 21

https://doi.org/10.1111/jpi.12782
 |
2 of 21       SCHRIRE et al.

GTN1139625). ACM is supported by the

NHMRC Centre of Research Excellence
to Optimise Sleep in Brain Ageing and
Neurodegeneration (CogSleep). NSM’s
time was funded by a salary from the
University of Sydney
of AEs such as drowsiness, headache and dizziness (1.40 [1.15, 1.69], p < .001).
Overall, there has been limited AE reporting from high-­dose melatonin studies.
Based on this limited evidence, melatonin appears to have a good safety profile.
Better safety reporting in future long-­term trials is needed to confirm this as our
confidence limits were very wide due to the paucity of suitable data.

KEYWORDS
dementia, drug-­related side effects and adverse reactions, melatonin, meta-­analysis,
preventative medicine, safety

1  |  I N T RO DU CT ION safety.14 Importantly, during the COVID-­19 pandemic,

Melatonin is one of the most commonly used supplements
among both adults1 and children.2 Lower doses of imme-
diate and sustained release (0.5–­5  mg) are indicated for
the treatment of jetlag, delayed sleep-­wake phase disor-
der3 and elderly insomnia.4 These doses are reported to be
well tolerated with limited adverse, withdrawal or ‘hang-
over’ effects, and with limited safety concerns or interac-
tions with medications.5 Indeed, there has been increased
uptake, particularly through individuals’ self-­medication
of melatonin as a dietary supplement in the United States
without the need for a doctor's prescription, with over
3  million American adults (1.3%) reporting melatonin
use within the past 30  days in 2012. This figure is dou-
ble the figure observed in 2007.1 In other countries such
as Norway where melatonin is not available without pre-
scription, there has also been a significant growth in the
number of prescriptions in both adults6 and children7,8
between 2004 and 2011.
Beyond its sleep and chronobiotic properties, mela-
tonin is a potent antioxidant9 and has the ability to cross
the blood-­brain barrier,10 with suggested anti-­amyloid
properties. Due to this, melatonin has been increasingly
investigated in many varying conditions, including can-
cer, cardiometabolic conditions and neurodegenerative
diseases at higher doses, where there is less documenta-
tion of its safety. Doses ranging from 30 to 100  mg are
being suggested or tested for effectiveness in a range of
conditions and ages, including ocular ischaemic syn-
drome (NCT04005222), feeding intolerance in preterm
infants (NCT04304807), renal protection (NCT03725267),
sepsis (NCT02319265) and the prevention and treatment
of neurodegeneration11 and cancer.12 Furthermore, mel-
atonin has been proposed as a potential candidate for
the prevention and treatment of COVID-­19.13 Current
trials in this area are testing a range of oral doses of
2–­30  mg/day (NCT04474483, NCT04353128). Currently,
the dosage label on supplemental melatonin may not be
accurate, and with increased use, this could have impli-
cations for clinician and patient confidence as well as
poison control calls for melatonin ingestion by children
increased by 70% and supplanted analgesics as the most
frequently ingested substance during the pandemic pe-
riod, which was linked to the increase in sales, use and
ease of accessibility. Hence, it is vital to thoroughly inves-
tigate its safety.15
Here, we aimed to investigate, using a systematic re-
view and meta-­analysis, the safety of melatonin in ran-
domised controlled trials using doses ≥10 mg (PROSPERO
Registration CRD42019105147). We also aimed to exam-
ine the proportion of papers that did not mention safety
in any capacity. We chose to only review studies where the
average age was ≥30 years as this was an arbitrary cut-­off
for the lower bound of the target population for poten-
tial prophylactic melatonin supplementation in instances
such as dementia prevention.
2  |  MATERIALS AND METHOD S
2.1  |  Search strategy and data sources
A systematic search for randomised controlled studies
investigating the effect of melatonin in any condition
was conducted (authors: IR, GW) using the following
databases: Medline, Scopus, Embase and PsycINFO. The
search terms are included in Supporting Information.
Both searches used the same search terms.
The search strategy was discussed and agreed upon by
the multidisciplinary team informally, although an official
protocol was not prepared.
The primary search was undertaken in December 2018,
and a secondary search was conducted in December 2019.
Convenience searches were regularly conducted after this
date until October 2020. No limits were used in any data-
base. Papers in other languages were translated to English.
After exporting articles into EndNote,16 duplicates were
removed. Additionally, reference lists of relevant review
articles were searched for potential missed publications.
The search was conducted using the Preferred Reporting
SCHRIRE et al.
Items for Systematic Reviews and Meta-­analyses (PRISMA)
statement and documented using the PRISMA flow chart.17
This systematic review was prospectively registered on
PROSPERO (CRD42019105147). Our primary study aim was
to document the safety outcomes of higher doses (≥10 mg)
of melatonin interventions in randomised controlled trials
(RCTs) with any comparator, in adults 30 years or older, an
arbitrary cut-­off of when melatonin could be introduced as a
public health intervention for long-­term prophylaxis of dis-
eases such as dementia. Second, we wanted to determine the
dose and duration of higher doses (≥10  mg) of melatonin
treatment that have been used in past RCTs in adults. This
dose was also used as an arbitrary cut-­off as a high dose that
may be used for prophylactic purposes. Third, we aimed
to examine the proportion of papers that did not mention
safety in any capacity.
2.2  |  Study selection and data extraction
The titles and abstracts of articles were all independently
reviewed by at least two out of a pool of six reviewers (CH,
ZMS, JC, SD, MC, GW). Disagreements about abstract in-
clusion or exclusion were resolved by consensus or by a
3rd reviewer (CP). Safety data were our outcome of inter-
est, but we did not apply this at the abstract sorting stage
because many clinical trials only mention their safety data
in the full-­text results.
The inclusion criteria for the systematic review were
as follows:
1. Population: any original data in any human with a
sample mean age above 30  years.
2. Intervention: Any form of melatonin supplementation
≥10 mg per day.
3. Comparison: RCT with any comparison arm, for exam-
ple placebo, no treatment, another drug, or intervention
[eg comparative medication] or melatonin <10 mg.
4. Outcome: studies measuring all outcomes were in-
cluded, regardless of whether they mentioned safety
data.
5. Timeframe: No limits on minimum and maximum
length of study.
Studies that met these criteria then proceeded to full-­
text review. Full-­text articles were independently reviewed
by at least two out of a pool of four reviewers (ZMS, CH,
AD, JC), and disagreements were resolved by consensus
or via a third adjudicator (CP). The characteristics, mea-
surements and outcomes of the selected studies were in-
dependently extracted by two investigators (ZMS, ACM)
into two templates. Details of the templates and how these
were filled out are detailed in Supporting Information.
     |  3 of 21
2.3  |  Risk of bias
Risk of bias was assessed by a committee of three inves-
tigators (ZMS, NM, CH) using the revised Cochrane Risk
of Bias tool (RoB 2.0) for interventional studies18 (Table
S2). Risk of bias was evaluated only in studies where ad-
verse events could be quantified. The RoB 2.0 comprises
five domains, including the randomisation process, devia-
tion from intended interventions, missing data, measure-
ment of the outcome, selective outcome reporting and
‘other sources of bias’. The tool also provides guidance
for when information on the domains is not mentioned.
Studies were classified as high risk of bias overall if they
had a high risk of bias in any one category or if they had
medium risk of bias in multiple categories, with discretion
from the authors.
2.4  |  Statistics
An exploratory meta-­analysis was completed on all studies
that reported adverse events, were low and medium risk of
bias and had a treatment period of at least 3 months. The
analysis was performed on studies of 3 months or longer
duration because if melatonin is to be used as a potential
prophylactic for chronic disease, longer term safety data
are required. Studies with high risk of bias were excluded.
Analysis was completed using Review Manager (Version
5.3) using the Mantel-­Haenszel statistical method and risk
ratio effect measure. Forest plots were created using the
mean difference method for a pooled mean effect and 95%
confidence interval using random effects model.19 The
person week (weeks of trial, multiplied by the sample size
in each group) was used as the denominator, as we were
investigating number of adverse events, not percentage of
participants that experienced any adverse events. Where
no adverse events occurred, one adverse event was added
to both arms. Inter-­study heterogeneity was evaluated by
the I-­squared statistic with the percentage of the variabil-
ity in effect estimates that is due to heterogeneity rather
than sampling error. These were interpreted as I2 < 40%:
heterogeneity unimportant, 40%–­60%: moderate heteroge-
neity, 60%–­75%: substantial heterogeneity, >75%: consid-
erable heterogeneity.20 Forrest plots (Figure 2) and funnel
plots (Figure S1) were also created.
3  |  RESULTS
3.1  |  Study selection
The primary search identified 4561 records from Medline
(1203), Embase (2069), PsycINFO (97) and Scopus (1192).
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4 of 21       SCHRIRE et al.
After duplicate removal, there were 2486 articles for title
and abstract screening. Following this, the full-­text arti-
cles were examined for eligibility and 254 continued to
the general full-­text review stage. Data extraction was
completed on 79 articles (see Figure 1). The study char-
acteristics and outcomes are summarised in Table  1.
Fifteen studies lasted 3  months or longer.21–­35 Fourteen
of the studies were in healthy populations24,36–­48 with the
remaining studies encompassing physical, mental, acute
and chronic medical conditions including cancer, demen-
tia and depression. Melatonin was used for both disease
treatment, such as in tardive dyskinesia, and for symptom
management, such as for pain and sleep disturbances.
Eleven studies used a dose of 100  mg or over of mela-
tonin, to as high as 3  g/day.24,31,36–­40,46,48–­50 Populations
with more serious diseases such as Huntington's
Disease,49 cancer51–­54 and fibromyalgia55 often reported
more varied side effects. Expected adverse events such
as tiredness and headache were reported in both healthy
populations and those with more serious diseases such
as acute respiratory failure and tardive dyskinesia. With
the exception of 5 slow release and 2 immediate release,
no other studies detailed the formulation of melatonin;
however, many of the studies predate the first licensing
of slow-­release melatonin (Circadin) in 2007.56 Of those
that stated administration route, the majority were oral
as 57 were PO, 1 enteral, 4 IV, 2 nasogastric tube, 2 sub-
lingual, 1 oral gargle, 1 compress and 1 transdermal.
3.2  |  Adverse events
Of the 79 studies, 29 (37%) did not provide any informa-
tion on AEs. Table  2 summarises the numbers of AEs,
SAEs and withdrawals due to AEs. Across the studies in-
cluded in the review, there were approximately 913 AEs
in 2114 participants taking to melatonin, most commonly
tiredness, fever, headache and diarrhoea (see Table S5 for
details). However, these side effects were also present in
the control groups, with 708 AEs reported from a total of
2258 participants. AEs were occasionally reported as the
number of participants who experienced an AE, or the
percentage of participants who reported at least one AE.
The duration of treatment did not appear to influence
whether AEs were reported.
Fifty-­six SAEs were identified among participants tak-
ing melatonin and 67 SAEs among the control groups.
Due to the inclusion of terminally ill populations, deaths
were included as SAEs depending on the context of the
study. Serious adverse events were often part of the nat-
ural prognosis for that condition, such as anaemia51 and
anorexia in cancer patients.54,57
3.3  |  Risk of bias
Forty-­eight studies were evaluated for the risk of bias
(Table S6). One study35 was assessed as having a low
risk of bias across all domains. We overrode the overall
bias status from medium to low bias for an additional
three studies47,50,58 as they only scored medium bias on
the trial registration category, and all studies were per-
formed prior to the requirement of registration. Results
were mixed for the other domains of the studies, and
20 studies were determined to be a high risk of bias
overall .22,23,26,27,29,32,41,51,53,57,59–­70
3.4  |  Meta-­analysis
The four studies we deemed to be at low and medium risk
of bias were included in the meta-­analysis, as we did not
want bias to affect the result of the systematic review and
only wanted to include high-­quality research. The stud-
ies totalled 204 participants exposed to melatonin and 197
participants exposed to control. For SAEs, the RR was 0.88
[95% CI: 0.52, 1.50], I2 = 0%, z = 0.47, p = .64 (Figure 2).
For AEs, the risk ratio was 1.40 [95% CI: 1.15, 1.69], with
I2 = 21%, z = 3.43, p = .0006 (Figure 2). For withdrawals
due to AEs, the risk ratio was 0.93 [95% CI: 0.24, 3.56],
I2 = 0%, z = 0.10, p = .92 (Figure 2). Thus, melatonin was
shown to increase the risk of AEs, but not SAEs or with-
drawals due to AEs. The results were unaffected in a sen-
sitivity analysis including high risk of bias studies (data
not shown).
4  |  DISC USSION
Overall, we found that ≥10  mg melatonin does not in-
crease the frequency of SAEs across a range of clinical
conditions. While this finding matches the current wide-
spread belief that melatonin is generally safe,71,72 which
is mirrored in the literature,73–­75 the width of our confi-
dence limits demonstrates that more high-­dose studies are
warranted for a more accurate conclusion to be drawn.
Importantly, we found that ≥10  mg doses of melatonin
increase the likelihood of AEs and that there was marked
variability in the quality of safety data collection and re-
porting in the trials conducted to date. This may indeed
reflect the general opinion of the overall safety of mela-
tonin leading to less stringent collection and/or reporting
of AEs. Interestingly, the reporting was more thorough in
larger, longer duration trials with higher doses possibly
due to the more recent adoption of standards around re-
porting quality.76
SCHRIRE et al.
F I G U R E 1   PRISMA flowchart
4.1  |  Comparison to other studies
Previous reviews and meta-­analyses reporting safety
have been restricted to specific clinical indications or
have mainly included lower doses of melatonin, rather
than incorporating all clinical conditions and focussing
on higher doses as presented here.72,77–­80 These reviews
generally support the ongoing view that melatonin is
     |  5 of 21
safe. Our finding of more AEs with melatonin could
have resulted from the exclusion of some studies using
extremely high doses aged under 30 years, which did not
show an increase of AEs in melatonin groups. An ex-
ample included a 4-­week study of 100 mg/day in young
athletes with no adverse events attributable to the active
treatment.81 We also acknowledge that the finding of in-
creased AEs in melatonin arms was based on only four
T A B L E 1   Studies arranged by indication—­cancer, surgery, cardiovascular and miscellaneous
|

Melatonin dose, route of

Author, year, Study design, Sample size, sex, age administration, formulation, time
6 of 21      

country duration Population (mean) of dosing Comparison

Cancer
Brackowski, Parallel, 14 d Metastatic solid tumour 14, NR, NR 40 mg, PO, (+TNF 0.75 mg, IV), No treatment (+TNF 0.75 mg, IV)
1994, Poland patients evening
Cerea, 2003, Italy Parallel, 9 w with Metastatic colorectal cancer 30, 13M, 65 (37–­82) median 20 mg, PO + 125 mg/m2 irinotecan No treatment + (125 mg/m2
option for 3 w (IQR) (CPT-­11), IV, Dark phase of the irinotecan (CPT-­11), IV)
extension in day
non-­responsive
participants
Del Fabbro, 2013, Parallel, DB, 1:1 Advanced lung or 73, 46M 20 mg, PO, capsule, nightly Placebo, PO, capsule
US ratio, 28 d gastrointestinal cancer MEL: 62 (32–­86)
(planned CON: 59 (36–­76)
for 8 w but
stopped trial
after interim
analysis at 4 w
due to futility)
Ghielmini, 1999, CO, DB, 21 d Inoperable lung cancer 28, 15M, 60 median (42–­69) 40 mg, PO, capsule + chemotherapy, Placebo, PO,
Switzerland (starting 8:00 PM capsule + chemotherapy
2 d before
chemotherapy)
Kouhi Habibi, Parallel, DB, Rectal cancer 60, 40M, 53.58 (7.41) 20 mg, PO, capsule, 45 min prior to Placebo, PO, capsule
2019, Iran 5 D/W totalling radiotherapy at 11:00 AM
28 D
Lissoni, 1990, Repeated CO, Metastatic renal cancer 5, 2M, 58 (median) IL-­2 + 10 mg MEL, PO, 8:00 PM IL-­2 alone
Italy 33 × 5 d
Lissoni, 1992a, Parallel, Advanced cancer 30, 18M, 64 (36–­73) IL-­2 OD+: IL-­2 OD
Italy 6 d/w × 4 w 10 mg MEL, PO, 8:00 PM IL-­2 OD
50 mg MEL, PO, 8:00 PM
Lissoni, 1992b, Parallel, cycles Non-­small cell lung cancer 63, 53M 10 mg, PO, 7:00 PM Supportive care
Italy consisting of MEL: 61 (39–­78)
21 D MEL, CON: (42–­74)
7 d rest, until
progression of
disease
SCHRIRE et al.
T A B L E 1   (Continued)

Melatonin dose, route of

Author, year, Study design, Sample size, sex, age administration, formulation, time
SCHRIRE et al.

country duration Population (mean) of dosing Comparison

Lissoni, 2007, Parallel, every day Advanced non-­small cell lung 100, 61M 20 mg PO + chemotherapy, during the Chemotherapy alone
Italy until disease cancer patients MEL: 65 (49–­72) dark period of the day Chemotherapy +
progression CON: 66 (52–­73) 5-­methoxytryptamine
Chemotherapy +
5-­methoxytryptamine: 67
(51–­74)
Onseng, 2017, Parallel, DB, Neck cancer patients 39, 26M 20 mg/10 ml, oral gargle and 20 mg, Placebo, PO, oral gargle single dose,
Thailand double dummy, receiving concurrent MEL: 47.3 (9.24) PO, capsule, suspension 15 min capsule 5 D/w × 7 w
Oral gargle chemoradiation CON: 49.6 (8.11) prior to irradiation, capsule after
1 d, capsule 9:00 PM
5 D/w × 7 w
Persson, 2005, Parallel, open Untreated advanced 23, 14M 18 mg (6 × 3 mg), PO, capsule, Fish oil 30 ml (15 ml in morning
Sweden label, 4 w gastrointestinal cancer MEL: 69 (10) evening and 15 ml evening, 4.9 g
MEL or fish oil patients CON: 66 (9) eicosapentaenoic acid and 3.2 g
followed by 4 w docosahexaenoic acid), mixture
together
Rassmussen, CO, DB, 7 d Stage IV cancer patients (any 72, 23M, 1: 65 (35–­84), 2: 62 20 mg, PO, capsule, 1 h prior to sleep Placebo, PO, capsule
2015, type) (33–­89)
Denmark
Sookprasert, Parallel, DB, 6 mo Non-­small cell lung cancer 151, 104M 20 mg, PO, capsule; 10 mg, PO, Placebo, PO, capsule
2014, MEL 20 mg: 56.3 (8.8) capsule, after 9:00 PM
Thailand MEL 10 mg: 56.8 (9.4)
CON: 55.6 (11.5)
Zhao, 2010, Parallel, 42 D (split Lung cancer patients 65, 57M, 55 median (40–­75 15 mg (3 × 5 mg), PO, Chemotherapy (lung cancer), no
China into 2 × 21 for range) capsule + chemotherapy, 8:00 PM treatment (healthy controls)
blood taking
time)
Cardiometabolic
Celinski, 2011a, 3-­arm parallel, H-­pylori-­ +ve with gastric and 42, NR, 28–­50 5 mg BD + 20 mg omeprazole BD 20 mg omeprazole BD+:
Poland 21 d duodenal ulcers Placebo;
250 mg Tryptophan BD
Celinski, 2011b Parallel, 21 d H-­pylori −ve with idiopathic 42, NR, 28–­50 5 mg BD + 20 mg omeprazole BD, 20 mg omeprazole BD+:
Poland gastric or duodenal morning and night Placebo
    

chronic ulcers 250 mg Tryptophan BD

| 
7 of 21

(Continues)
T A B L E 1   (Continued)
|

Melatonin dose, route of

Author, year, Study design, Sample size, sex, age administration, formulation, time
8 of 21      

country duration Population (mean) of dosing Comparison

Celinski, 2014, Parallel, 14 m Non-­alcoholic fatty liver 74, 23M, 1:34.2 (7.6) 2 × 5 mg MEL, PO, tablet + 300 mg 300 mg phospholipid TID PO,
Poland disease 2: 36.2 (5.8) phospholipid TID tablet+:
3: 29.3 (9.6) No treatment
2 × 500 g Tryptophan
Chojnacki, 2017, Parallel, 6 mo Statin-­treated 60, 19M, 47–­68 5 mg BD, 7:00 AM and 9:00 PM Placebo
Poland hyperlipidaemia
Dominguez-­ Parallel, DB, 1 d Revascularisation for ST-­ 146, 101M 12 mg IV + 2 mg intracoronary, Placebo
Rodriguez, elevation myocardial MEL: 57.3 (10) IV 60 min before PCI and
2017, Spain infarction CON: 58.4 (9.4) intracoronary within 60 s after
restoring blood flow to the infarct
related artery
Dwaich, 2016, Parallel, DB, 5 d CABG patients 45, 36M 20 mg, PO, OD Placebo
Iraq 10 mg MEL: 52.3 (6) 10 mg, PO, OD
20 mg MEL: 53.9 (6.1)
CON: 52.5 (3.6)
Ekeloef, 2017, Parallel, DB, 1 d ST-­elevation myocardial 48, 38M 50 mg MEL, 10 ml intracoronary and Placebo, 10 ml
Denmark infarction patients MEL: 61.7 (95% CI: 56.2–­66.9) 490 ml IV, infusion of either MEL intracoronary + 490 ml IV
CON: 64.0 (95% CI: or placebo was started
59.4–­68.7) Immediately after pPCI with a flow
rate fixed at 80 ml/h for 6 h
Gonciarz, 2010, Parallel, 2:1 ratio Non-­alcoholic steatohepatitis 42, 26M 5 mg BD, 9:00 AM and 9:00 PM Placebo
Poland (MEL: PLAC), MEL: 41.5 (4.0)
24 w CON: 40.8 (3.6)
Haghjooy Parallel, triple-­ CABG patients 58, 26M 10 mg, PO, tablet, before sleeping Placebo, PO, tablet
Javanmard, blind, 1 m MEL: 58.1 (9.8)
2013, Iran CON: 60.1 (9.2)
Herrera, 2001, CO, 1 d Chronic haemodialysis 9, 5M (39 ± 16) and 4F 6 × 3 mg, PO, tablet, 8:00 AM in 6 × placebo, PO, tablet
Venezuela (37 ± 15) fasting state
Hernandez-­ Parallel, every 8 h High probability of 37, 4M 5 × 10 mg 8 h apart (total 50 mg), Placebo, sublingual
Velazquez, for 24 h choledocholithiasis MEL: 35.3 (17.3) sublingual, 10 h prior to procedure
2016, Mexico CON: 36.3 (15.3)
Kucukakin, Parallel, DB, Open abdominal aortic-­ 52, 38M 50 mg, IV, +10 mg PO, capsule, IV Placebo, IV, infusion + placebo, PO,
2010a, Infusion for aneurysm repair or MEL: 66 (10) starting from the first incision, PO capsule
Denmark 2 h. Capsules aortobifemoral bypass CON: 65 (11) at 10:00 PM
for 3 d surgery patients
SCHRIRE et al.
TABLE 1  (Continued)

Melatonin dose, route of

Author, year, Study design, Sample size, sex, age administration, formulation, time
SCHRIRE et al.

country duration Population (mean) of dosing Comparison

Kucukakin, Parallel, DB, 1 d Laparoscopic 44, 0M 10 mg (in 25 ml ethanol/saline Placebo (in 25 ml ethanol/saline
2010b, cholecystectomy female MEL: 45 (20–­67 median solution), IV, infusion starting at solution), IV
Denmark patients range) surgical incision and lasted 30 min
CON: 57 (23–­69 median
range)
Madsen, 2017, Parallel, DB, 12 w Acute coronary syndrome 252, 196M 25 mg, 1 h prior to bedtime Placebo
Denmark MEL: 62.9 (11.3)
CON: 62.1 (10.8)
Nickkholgh, Parallel, DB, 1 d Major liver resection patients 50, 28M 50 mg/kg body weight (dissolved Placebo, nasogastric tube
2011, MEL: 59 (10) in 250 ml milk with 3.5% fat
Germany CON: 56 (11) content), via nasogastric tube, after
intubation for general anaesthesia
on the day of surgery
Ostadmohamma, Parallel, DB, 12 w Diabetic haemodialysis 60, 38M 10 mg (2 × 5 mg), PO, capsule, 1 h Placebo, PO, capsule
2020, Iran patients MEL: 65.6 (13.1) prior to bedtime
CON: 64.1 (8.2)
Rahbari-­Oskoui, CO, DB, 4 w Essential hypertension 40, 11M, 48.9 (9.9) 24 mg (sustained release, PO, 30 min Placebo
2019, United prior to going to bed)
States
Raygan, 2019, Parallel, DB, 12 w Diabetic patients with 60, 27M 10 mg (2 × 5 mg), PO, capsule, 1 h Placebo, PO, capsule
Iran coronary heart disease MEL: 67.7 (11.4) prior to bed
CON: 65.3 (10.1)
Shafiei, 2018, Parallel, open CABG patients 88, 39M 20 mg over 24 h (3 × 5 mg tablets 24 h Placebo
Iran label, 4 doses MEL: 62.0 (8.8) prior then 1 × 5 mg tablet 1 h prior N-­acetyl cysteine
of MEL within CON: 61.6 (7.7) to surgery, starting 24 h before and
24 h, Placebo N-­acetyl cysteine: 57.7 (11.2) ending with 1 h before operation)
unclear
Healthy
Anderson, 1993, CO, DB, 14 d Healthy adult men 12, 12M, 32 (26–­52) (range) 100 mg, PO, capsule, 4:00 PM Placebo, PO
UK
Cagnacci, 1997, CO, DB, 1 d Postmenopausal women 7, 0M, 54–­62 100 mg, PO, capsule, 8:00 AM Placebo, PO, capsule
US
    
| 
9 of 21

(Continues)
T A B L E 1   (Continued)

Melatonin dose, route of

|

Author, year, Study design, Sample size, sex, age administration, formulation, time
10 of 21      

country duration Population (mean) of dosing Comparison

Chiodera, 1998, CO, 1 d Healthy men 18, 18M, 27–­36 12 mg, PO Placebo, PO
Italy Expt1: 30 min prior to ITT 6 mg MEL, PO
test (n = 6)
Expt2: 30 min prior to ANG
II test (n = 6)
Expt3: after withdrawal basal
blood sample (n = 6)
Comperatore, CO, DB, 9 d Army aviation unit 29, 29M, 24–­41 10 mg, PO, 30 min prior to bed Placebo, PO
1996, US
D'Anna, 2017, Parallel, open Women in menopausal 40, 0M 3 g/d MEL + 2 g myo-­Ins/d, before 2 g myo-­Ins BD
Italy label, 6 mo transition MEL:49.1 (1.7) sleeping
CON: 48.7 (1.5)
Emser, 1993, CO, DB, 1 d Healthy 13, 5M, 22–­48 10 mg, PO, 4:00 PM Placebo
Germany
Hoffmann, 1999, CO, open label, 1 d Healthy males 15, 15M, 20–­35 10 mg in two forms, Between 8:00 and 5 mg MEL
Germany 8:30 AM
Jorgensen, 1998, CO, DB, 2–­5 d Emergency medicine 20, 16M, 32 (25–­40) 10 mg, sublingual, tablet, morning Placebo, sublingual, tablet
US physicians after each night shift
Kirby, 1999, US Parallel, DB, 5 d Healthy women 20, 0M, 18–­39 10 mg, 1:00 PM Placebo
Naguib, 2006, Parallel, DB, 1 d Ventilated awake patients 200, 83M 0.2 mg/kg, PO, 3 ml solution, 50 min Placebo, PO + 3 ml solution
United States (Status 1 ASA) MEL + propofol: 32.4 (19.9) prior to propofol or thiopental
MEL + thiopental: 34.9 (8.9) anaesthetic induction
CON + propofol: 34.4 (8.9)
CON + thiopental: 31.6 (10.9)
Paccotti, 1987, CO, DB, 1 d Healthy males 6, 6M, 23–­32 100 mg, PO, 8:00 AM and 8:00 PM 1 mg MEL
Italy Placebo
Scheuer, 2016, CO, DB, 1 d Healthy 22, 7M, median 32 (24–­53) 12.5%, transdermal, topical, within No treatment
Denmark 40 min of sun exposure at 1:22 PM Placebo, transdermal, topical
0.5%, transdermal, topical
2.5%, transdermal, topical
Valcavi, 1987, CO, 1 d Healthy males 8, 8M, 20–­37 1000 mg (2 × 500 mg), PO, 60 and Placebo + GRF, PO + IV,
Italy 30 min before administration of Placebo + saline, PO + IV
GRF or saline
Neurological
SCHRIRE et al.
TABLE 1  (Continued)

Melatonin dose, route of

Author, year, Study design, Sample size, sex, age administration, formulation, time
SCHRIRE et al.

country duration Population (mean) of dosing Comparison

Callegari, 2016, CO, DB, 10 w Behavioural fronto-­temporal 24, 11M, 53.8 10 mg (sustained release) Agomelatine 50 mg
Italy dementia
Carman, 1976, CO, DB, case Major Primary Depression or 8, 2M Peak doses: Pt1: 1100 mg Placebo PO or IV
US series Huntington's Pt1: 66 y Pt2: 1600 mg
Pt1: 24 d Pt2: 40 y Pt3: 1200 mg
Pt2: 16 d Pt3: 44 y Pt4: 1200 mg
Pt3: 9 d Pt4: 31 y Pt5: 250 mg
Pt4: 3 d Pt5: 48 y Pt6: 50 mg
Pt5: 7 d Pt6: 47 y Pt7: 1200 mg
Pt6: 3 d Pt7: 53 y Pt8: 1200 mg
Pt7: 12 d Pt8: 39 y PO, capsule, or IV, Divided into four
Pt8: 9 d equal doses daily or IV infusions
once or twice daily
Dianatkhah, Parallel, DB, Haemorrhagic stroke 42, 21M 30 mg, nasogastric tube, nightly Control (no treatment)
2017, Iran 6–­25 d MEL: 57.7 (12.7)
(depending on CON: 52.9 (13.7)
length of ICU
stay)
Dolberg, 1998, Parallel, DB, 4 w Major Depressive Disorder 24, NR, 22–­65 5–­10 mg (slow release) + 20 mg Placebo + 20 mg fluoxetine, PO,
Israel fluoxetine, PO, capsule, 9:00 PM capsule
Dowling, 2005, 3-­way CO, DB, Parkinson's Disease 40 completed, 29M, 61.7 (8.4) 50 mg, PO, capsule, 30 min prior to Placebo, PO, capsule
US 14 d bedtime MEL 5 mg, PO, capsule
Gehrman, 2009, Parallel, DB, 10 d Alzheimer's Disease nursing 41, 13M, 82.9 (7.0) 8.5 mg (immediate release), PO, Placebo, PO, capsule
US home residents capsule + 1.5 mg (sustained
release), PO, 10:00 PM
Grunhaus, 2001, Parallel, DB, 3 m Major depressive disorder and 35, 13M 5–­10 mg (sustained release), PO, Placebo, PO, tablet
Israel electroconvulsive therapy MEL: 61.1 (10.7) tablet, 3 h before bedtime
CON: 59.6 (14.1)
Leibenluft, 1997, CO, DB, 12 w Bipolar disorder patients 5, 0M, 47.2 (3.8) 10 mg, 10:00 PM Placebo
US
Leone, 1996, Italy Parallel, DB, 14 d Cluster headache 20, 15M 10 mg, PO, evening Placebo, PO
MEL: 38.4
CON: 34.4
    
| 
11 of 21

(Continues)
T A B L E 1   (Continued)

Melatonin dose, route of

|

Author, year, Study design, Sample size, sex, age administration, formulation, time
12 of 21      

country duration Population (mean) of dosing Comparison

Sanchez-­Lopez, Parallel, DB, 6 mo Relapsing-­remitting multiple 16 25 mg, PO, capsule, 1 h prior to sleep Placebo, PO, capsule
2018, Mexico sclerosis treated with MEL: 29%M, 26–­52 range
Interferon B-­1b CON: 25%M, 29–­51 range
Shamir, 2001, CO, DB, 6 w Schizophrenia and anti-­ 24, 11M, 64.2 (14.3) 2 × 5 mg, PO, tablet, 8:00 PM 2 × placebo, PO, tablet
Israel psychotic Tardive
Dyskinesia
Singer, 2003, Parallel, DB, 8 w Alzheimer's disease and sleep 157, 56.1%F, 77.4 (8.9) 10 mg (immediate release), PO, Placebo, PO, capsule
United States disturbance capsule, 1 h prior to habitual 2.5 mg MEL (sustained release), PO,
bedtime capsule
Reproductive
Cagnacci, 1991, CO, DB, 1 d Females during early 11, 0M, 25–­35 100 mg, PO, capsule, 8:00 AM Placebo, PO, capsule, 8:00 AM
US follicular phase MEL 2.5 mg (1 mg: 8.00 AM,
0.75 mg: 10:00 AM and 12.00 PM),
PO
Cagnacci, 1995a CO, DB, 1 d 1: Females in early follicular 14, 0M 100 mg, PO, capsule, 8:00 AM Placebo, PO, capsule
phase 1: 22–­32
2: Postmenopausal females 2: 54–­62
Cagnacci, 1995b, CO, DB, 1 d 1: Females in early follicular NR, 0M 100 mg, PO, capsule, 8:00 AM Placebo, PO, capsule
US phase 1: 22–­32
2: Postmenopausal women 2: 54–­62
Fernando, 2018, Parallel, DB, dose-­ First cycle of IVF or ICSI 160, 0M 8 mg (sustained release) BD, PO, Placebo, PO, capsule, BD
Australia finding, day 2 women 16 mg MEL: 35.4 (4.4) capsule, between 8:00–­10:00 AM 2 mg MEL (sustained release), BD,
of their cycle 4 mg MEL: 35.0 (4.1) and between 8:00–­10:00 PM PO, capsule
until the night 8 mg MEL: 36.0 (4.2) 4 mg MEL (sustained release), BD,
before oocyte CON: 35.2 (4.2) PO, capsule
retrieval
Lu, 2018, China Parallel, DB, 3 mo Subinguinal varicocelectomy 54, 54M 400 mg, PO, capsule Placebo, PO, capsule
infertile male patients MEL: 32.2 (2.4)
CON: 32.8 (3.2)
Schwertner, Parallel, DB, 8 W Chronic pelvic pain and/ 40, 0M 10 mg, PO, tablet, bedtime Placebo, PO, tablet
2013, Brazil (56 D) or dyspareunia and MEL: 36.7 (6.4)
endometriosis CON: 37.6 (5.5)
Other
SCHRIRE et al.
TABLE 1  (Continued)

Melatonin dose, route of

Author, year, Study design, Sample size, sex, age administration, formulation, time
SCHRIRE et al.

country duration Population (mean) of dosing Comparison

Bourne, 2008, Parallel, DB, 4 d ICU ventilated patients 25, 11M 10 mg, enteral, liquid, 9:00 PM Placebo, enteral, liquid
UK acute respiratory failure MEL: 69.9 (12.0)
requiring weaning CON: 58.7 (12.5)
Capuzzo, 2006, Parallel, DB, 1 d Elderly preoperative patients 150, 69M 10 mg, PO, capsule, 90 min prior to Placebo, PO, capsule
Italy MEL: 73.2 (5.9) surgery
CON: 72.1 (5.4)
Castro, 2011, Parallel, DB, 12 w Neuroleptic-­induced Tardive 13, 9M, 59.9 (2.7, standard 20 mg, PO, capsule, nightly Placebo, PO, capsule
Venezuela Dyskinesia error)
Coiro, 1998, Italy CO, 1 d Alcoholic men Alcoholic: 9, 9M, 40–­52 12 mg, PO, 8:30 AM (30 min after Placebo, PO
CON: 9, 9M, 39–­49 cannula)
de Zanette, 2014, Parallel, DB Fibromyalgia 42, 0M, M: 47.4 (7.8) 10 mg MEL, PO, tablet + placebo, Placebo + 25 mg amitriptyline, PO,
Brazil double dummy, MEL + amitriptyline: 49.7 bedtime tablet
42 d (7.2) 10 mg MEL, PO, tablet + 25 mg
CON: 49.8 (8.9) amitriptyline, PO, tablet bedtime
El-­Sharkawy, Parallel, DB, 2 m Chronic periodontitis with 80, 41M 10 mg, PO, capsule + scaling and root Placebo, PO, capsule + scaling
2019, Egypt primary insomnia MEL: 45.6 (7.1) planning prior to randomisation, and root planning prior to
CON: 46.7 (8.3) 1 h before bedtime randomisation
Forrest, 2007, UK Parallel, DB, 6 m Rheumatoid arthritis 75, 22M 10 mg, PO, tablet, before bed Placebo, PO, tablet
MEL: 65.1 (2.1)
CON: 60.0 (1.8)
Fraschini, 1999, 4-­arm CO, DB, 1 d NR 5, 4M, 32.5 10 mg Placebo
Italy 100 mg 5 mg MEL
Ghaderi, 2019, Parallel, DB 12 w Methadone treatment 60, 54M 10 mg (2 × 5 mg), PO, capsule, 1 h Placebo, PO, capsule
Iran patients MEL: 42.5 (8.0) prior to bedtime
CON: 42.7 (9.9)
Ismail, 2009, Parallel, 1 d Cataract surgery patients with 40, 21M 10 mg, PO, tablet, 90 min prior to Placebo, PO, tablet
Saudi Arabia topical anaesthesia MEL: 72.8 (8.1) surgery
CON: 68.5 (7.9)
Moldabek, 2013, CO, 1 mo Hypothyroidism 51, NR, 45 (9 ± 1.5) 15 mg + LHT, PO, nightly L-­Thyroxine
Kazakhstan
Mowafi, 2008, Parallel, DB, 1 d Elective hand surgery with 40, 22M 10 mg, PO, 90 min prior to surgery Placebo, PO
Saudi Arabia regional anaesthesia MEL: 44.6 (11.4)
    

CON: 42.8 (12.1)

| 
13 of 21

(Continues)
 14 of 21       | SCHRIRE et al.

studies, two of which had large sample sizes (n = 252,82

Abbreviations: BD, twice daily; CO, cross-­over; COM, control; D, days; DB, double-­blind; g, grams; IQR, inter-­quartile range; IV, intravenous; M, males; MEL, melatonin; mg, milligrams; mL, millilitres; Mo, months;
n  =  15154) and investigated more life-­threatening dis-
eases (non-­small-­cell lung cancer, acute coronary syn-
drome), which led to comparatively high numbers of
adverse events in both intervention and comparator
groups. The papers did not mention if participants with
Placebo, compress

conditions such as compromised hepatic or renal func-

Comparison

tion were excluded as these can compromise drug me-

Clonidine

tabolism. The remaining adverse event numbers in both

melatonin and placebo groups were minimal, and thus,
any differences at all (significant or non-­significant)
were able to skew the results.
2 × 5 mg, PO, night before surgery and
administration, formulation, time

12:30 PM, 3:30 PM, 7:30 PM

4.2  |  Strengths and

4 × 3 mg, compress, 8:30 AM,

60 min before anaesthesia

Melatonin dose, route of

limitations of the study

The strength of the current review is that it is the first to

evaluate all RCTs investigating high doses of melatonin
in adults. Additionally, we chose to include all com-
of dosing

parators, routes of administration and study durations.

However, there were only available safety data from
placebo-­controlled trials. It could be expected that stud-
ies using active comparators may have reported similar
numbers of AEs between groups. Importantly, melatonin
NR, not reported; OD, once daily; PO, oral; TID, three times a day; UK, United Kingdom; US, United States; W, weeks.
Sample size, sex, age

is often given in practice as a substitute for medications

20, 4M, 64.4 (11.6)

with known AE profiles (eg glucocorticoids, opioids, ben-

CON: 41.4 (14.4)
MEL: 50.0 (6.9)

zodiazepines and non-­steroidal anti-­inflammatory drugs)

while additionally having a significantly more favour-
Note: References in supplementary document. Routes of administration not listed were not reported.
(mean)

able side-­effect profile, including no apparent addictive

26, 6M

potential or hangover effects.83 Unlike other reviews, we

have also chosen to include all formulations to show the
breadth of studies investigating melatonin supplementa-
ESS for chronic sinusitis and
Burning mouth syndrome

tion. However, there were no bioavailability data to make

a judgement on the effect of this. It is conceivable that dif-
ferent formulations could have different bioavailability
polyp removal

and side-­effect profiles, and this should be explored fur-

Population

ther in future research.

A limitation is that most studies had limited differ-
ences between melatonin and placebo, and small AE
numbers overall, thus causing small differences between
groups to have more impact. Specifically, there was large
CO, triple-­blind,

heterogeneity in the AE meta-­analysis and many papers

Study design,

CO, blind, 1 D

had a medium-­to-­high risk of bias. Further, we were un-

duration

able to assess the possibility of publication bias using

8 w

funnel plots as there were only four studies included. For

T A B L E 1   (Continued)

this reason, we did not statistically analyse the plots using

Egger's test. Second, while all meta-­analysed studies were
2014, Poland

over 3 months, the systematic review included a wide va-

Varoni, 2018,

Wawrzyniak
Author, year,

riety in study duration ranging from 1  day to 6  months.

Italy

This should be taken into consideration as shorter studies

country

would have more participant supervision where adverse

events may be recorded, but longer studies give more time
SCHRIRE et al.      |  15 of 21

T A B L E 2   Adverse events

Withdrawal due to
Serious adverse events Adverse events adverse events

Author MEL CON MEL CON MEL CON

Anderson, 1993 0 0 >8 0 0 0
Bourne, 2008 0 0 1 0 0 0
Brackowski, 1994 NR NR NR NR NR NR
Cagnacci, 1991 NR NR NR NR NR NR
Cagnacci, 1995a NR NR NR NR NR NR
Cagnaccib, 1995 NR NR NR NR NR NR
Cagnacci, 1997 NR NR NR NR NR NR
Callegari, 2016 NR NR NR NR 0 0
1 2 2 0 0 2 2
Carman, 1976 NR NR 41 0 0 0
Castro, 2011 0 0 3 2 0 0
Celinski, 2011a NR NR NR NR NR NR
Celinski, 2011b 0 0 NR NR 0 0
Celinski, 2014 0 0 0 0 0 0
Cerea, 2003 NR NR 22 13 0 0
Chiodera, 1998 0 0 0 0 0 0
Chojnacki, 2017 0 0 6 1 0 0
Coiro, 1998 0 0 0 0 0 0
Comperatore NR NR NR NR NR NR
D'Anna, 2017 NR NR NR NR NR NR
a a a a
de Zanette, 2014 6/21 5/21 3/21 8/21 2 2
Del Fabbro, 2013 3 2 37/38a 34/35a 3 2
Dianatkhah, 2017 5 7 NR NR NR NR
Dolberg, 1998 NR NR 3 0 NR NR
Dominguez-­Rodriguez, 2017 3 2 13 13 0 0
Dowling, 2005 0 0 1 1 0 1
Dwaich, 2016 NR NR NR NR NR NR
Ekeloef, 2017 6 6 0 0 0 0
El-­Sharkawy, 2019 0 0 3 4 0 0
Emser, 1993 NR NR NR NR NR NR
Fernando, 2018 0 1 43 4 mg –­ 51 8 mg –­ 40 0 0
Forrest, 2007 NR NR NR NR NR NR
Fraschini, 1999 0 0 0 0 0 0
Gehrman, 2009 NR NR NR NR NR NR
Ghaderi, 2019 0 0 3 0 0 0
Ghielmini, 1999 1 1 NR NR NR NR
Gonciarz, 2010 0 0 0 0 0 0
Grunhaus, 2001 NR NR NR NR NR NR
Haghjooy Javanmard, 2013 NR NR NR NR 3 5
Hernandez-­Velazquez, 2016 0 1 0 0 0 0
Herrera, 2001 0 0 1 1 0 0
Hoffmann, 1999 NR NR NR NR NR NR

(Continues)
 |
16 of 21       SCHRIRE et al.

T A B L E 2   (Continued)

Withdrawal due to
Serious adverse events Adverse events adverse events

Author MEL CON MEL CON MEL CON

Ismail, 2009 0 0 1 1 0 0
Jorgensen, 1998 NR NR 1 4 0 0
Kirby, 1999 NR NR NR NR NR NR
Kouhi Habibi, 2019, Iran NR NR NR NR NR NR
Kucukakin, 2010a 0 0 9 3 0 1
Kucukakin, 2010b 0 0 4 1 0 0
2 1 0 0 0 1 0
Leone, 1996 0 0 0 0 0 0
Lissoni, 1990 0 0 NR NR NR NR
Lissoni, 1992a 0 0 0 0 0 0
Lissoni, 1992b NR NR NR NR NR NR
Lissoni, 2007 NR NR NR NR NR NR
Lu, 2018 NR NR NR NR NR NR
Madsen, 2017 21 24 122 105 4 2
Moldabek, 2013 NR NR NR NR NR NR
Mowafi, 2008 NR NR 2 NR 0 0
Naguib, 2006 NR NR NR NR NR NR
Nickkholgh, 2011 0 2 11 18 0 0
Onseng, 2017 0 0 NR NR NR NR
Ostadmohammadi, 2020 0 0 0 0 0 0
Paccotti, 1987 0 0 4 0 0 0
Persson, 2005 NR NR 0 0 0 0
a a
Rahbari-­Oskoui, 2019 1 0 85 81 0 0
Rasmussen, 2015 7 14 NR NR 9 in both groups N/A
Raygan, 2019 NR NR NR NR NR 0
Sanchez-­Lopez, 2018 0 0 5 3 0 0
Scheuer, 2016 0 0 0 0 0 0
Schwertner, 2013 0 0 0 0 1 0
Shafiei, 2018 NR NR NR NR 0 0
Shamir, 2001 0 0 0 0 0 0
a
Singer, 2003 NR NR MEL 10 mg: CON: 69.2% , mean NR NR
74%,a # AE reports per
mean # person: 2.4 ± 2.7
AE reports 2.5 mg MEL: 79.6%a
per person: Mean # AE reports
2.0 ± 1.9 per person:
3.4 ± 3.4
Sookprasert, 2014 0 0 390 180 0 0
Valcavi, 1987 NR NR NR NR 0 0
Varoni, 2018 NR NR 20 23 2 2
Wawrzyniak 2014 NR NR NR NR NR NR
Zhao, 2010 NR NR NR NR 0 0
Note: Abbreviation: NR, not reported.
a
Total when adding number of participants reporting different AEs.
SCHRIRE et al.      |  17 of 21

(A)

(B)

(C)

F I G U R E 2   Forrest plot of (A) SAEs, (B) AEs, (C) Withdrawals due to SAEs with low and medium risk of bias over 3 months.
Populations: Castro, 2011—­Neuroleptic-­induced Tardive Dyskinesia, Madsen 2017—­acute coronary syndrome, Sanchez-­Lopez,
2018—­Relapsing-­remitting multiple sclerosis treated with Interferon B-­1b, Sookprasert, 2014—­Non-­small-­cell lung cancer

for adverse events to arise, whether they are related to the
study drug or not. However, all studies included a control
arm that they should be compared to, rather than those
of other unrelated studies. Lastly, the quality of the data
was so low that a comprehensive review of AEs and SAEs
was not possible; however, they are all listed in Supporting
Information. Reassuringly, most studies had a protocol for
administration of melatonin in the evening to avoid sleep-
iness, an otherwise common AE of melatonin.
4.3  |  Future directions and implications
Animal and pharmacokinetic studies suggest that some in-
dications for melatonin require higher doses for treatment
efficacy.84,85 The current review highlights that higher
doses of melatonin have been used across many fields.
Current trials are also investigating doses of 500 mg IV per
day to reduce the mortality of COVID-­19 patients in ICU
(NCT04568863) as well as 30 mg orally in outpatients with
COVID-­19, with a main outcome of treatment-­emergent
adverse events (NCT04474483). As such, understanding
the safety of melatonin from existing studies, especially in
higher doses and longer time periods in varying medical
conditions, is warranted and necessary. Our findings sug-
gest that increased doses and durations of treatment do
not increase SAEs compared to placebo, although it may
increase the likelihood of AEs.
Based on our findings, larger phase 3 clinical trials
using high doses of melatonin should ensure rigorous
safety data monitoring as a potentially clinically import-
ant increase in SAEs cannot be ruled out using the cur-
rent accumulated safety data. We did however find a
40% increase in AEs, but these were primarily limited to
headache, dizziness and drowsiness. All triallists should
employ rigorous safety recording and reporting in future
studies. Individuals already taking large doses of mel-
atonin should consider the lack of conclusive evidence
evaluating the benefit of treatment against risk of SAEs.
The National Institute of Health in 1996 asserted that
 |
18 of 21       SCHRIRE et al.
melatonin users are the unwitting subjects in a large-­scale
uncontrolled experiment, and urged that solid safety ev-
idence is required.86 Twenty-­five years later, the current
study still finds that additional studies in adults, using
higher doses for longer durations are needed, with com-
prehensive reporting on AEs to confirm the current wide-
spread belief that melatonin is indeed safe.
CONFLICTS OF INTEREST
There were no conflicts of interest for any of the authors.
DATA AVAILABILITY STATEMENT
The data are presented in the supplementary tables in the
paper and supplementary documents.
ORCID
Zoe Menczel Schrire  https://orcid.
org/0000-0001-9903-0899
Camilla M. Hoyos  https://orcid.
org/0000-0002-6543-4016
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