Melatonin vs placebo for sleep-onset latency in primary insomnia

Overview

Melatonin vs placebo for sleep-onset latency in primary insomnia

In adults with primary insomnia, does melatonin reduce sleep-onset latency versus placebo? (Randomized placebo-controlled trials; mean difference in minutes.)

Primary outcome

Transparency (independently checkable)

26 of 26 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 0 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Melatonin vs placebo for sleep-onset latency in primary insomnia

## PICO
- **Population:** adults with primary insomnia.
- **Intervention:** melatonin (including prolonged-release / controlled-release melatonin, or Circadin).
- **Comparator:** placebo.
- **Primary outcome:** sleep-onset latency (mean difference in minutes).

## Eligibility - P/I/C/design only
Include randomized controlled trials when all of the following are true:
- The population is adults with primary insomnia, judged from the title or registry conditions.
- The randomized intervention is melatonin (any release formulation).
- The randomized comparator is placebo.
- The trial is double-blind or placebo-controlled.

Exclude records for wrong population (children, adolescents, autism or neurodevelopmental disorders, shift work, jet lag, delayed sleep-phase disorder, dementia or Alzheimer's disease, intensive-care patients, benzodiazepine withdrawal), wrong intervention, wrong comparator, non-randomized design, reviews, protocol-only reports, and secondary/circadian populations outside primary insomnia.

Eligibility is not based on whether the abstract reports the target outcome. If an otherwise eligible trial does not report sleep-onset latency as a per-arm mean and standard deviation (in the abstract or in eligible structured registry results), it is declared absent rather than substituted with another endpoint or an imputed variance.

## Outcomes
Primary outcome:
- Sleep-onset latency, including phrasings such as sleep onset latency, sleep-onset latency, sleep latency, latency to sleep onset, polysomnographic sleep latency, and subjective sleep latency.

The estimand is the mean difference (minutes) in sleep-onset latency, melatonin versus placebo. Pooling is random-effects inverse-variance on the mean difference; a single included trial is presented as that trial's own effect, not a random-effects pool.

Where a trial's structured results report the outcome for a **pre-specified subgroup** (e.g. Wade et al. report sleep-onset latency for the pre-defined age 65-80 population, a co-primary analysis, N=137 melatonin / 144 placebo), the subgroup is disclosed on the page as the analysis population rather than presented as the whole trial. The pooled value is the **unadjusted** per-arm mean difference computed from the reported per-arm change-from-baseline means and SDs; the trial's own covariate-adjusted estimate (Wade: -15.6 minutes, 95% CI -25.3 to -6.0, baseline- and age-adjusted linear regression) is noted where it differs. The per-arm means and SDs are verified against both the ClinicalTrials.gov structured posted results and the published Table 3.

## Sources and verification
- Per-arm mean and standard deviation are taken verbatim from the trial's primary report or its structured ClinicalTrials.gov posted results (the AACT-equivalent), never imputed from a figure or a Kaplan-Meier curve.
- Every pooled number is verified against the committed source span before it is pooled; where per-arm variance is not reported in accessible text or structured results, the trial is declared absent with the reason named, rather than pooling an imputed SD.

## Comparator
- Published open-access meta-analysis of melatonin for primary insomnia (sleep-onset latency), for trial-set overlap and reporting comparison only. An identical estimate on an identical trial set is arithmetic, not corroboration; the overlap is stated on the page.

Search

Source status (which adapters ran)

Citation chase: RAN_OK · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: RAN_OK · PubMed: RAN_OK · Registry-first (AACT): RAN_ERROR — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

PubMed

melatonin primary insomnia sleep onset latency placebo randomized

"melatonin"[Title] AND "primary insomnia" AND placebo AND randomized

"prolonged-release melatonin" insomnia placebo randomized sleep latency

ClinicalTrials.gov

{"cond": "primary insomnia", "intr": "melatonin"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 126 records: agreement 108/126, disagreement 14.3% (18 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Trial integrity: none of the 1 trials pooled across all outcomes on this page is retracted; 1 registered retrospectively — after enrolment began, a reporting-bias signal, not disqualifying (20712869) (checked 2026-09-12T11:20:58Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

126 records screened; 12 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['20712869'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['25862116'] recovered by the search and correctly EXCLUDED ['25862116'] by rule (same drug/design, wrong topic).

Results

Sleep-onset latency (primary)

k = 1: the 1 trial(s) named below were pooled; 11 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Adverse events

Comparator

Scope match (is this the same question?)

✓ same question. Intervention level: topic is a single agent, comparator is a single agent (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 0 of 1 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 1 are pooled but have no registry match (20712869) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT registry fields). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In adults with primary insomnia, does melatonin reduce sleep-onset latency versus placebo? (Randomized placebo-controlled trials; mean difference in minutes.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 146edbf72435); a registry-first search was screened by two independent rule screeners with adjudication (126 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. A single eligible trial contributed an extractable estimate: MD -17.4 (95% CI -28.52 to -6.28); with k=1 no between-trial heterogeneity or prediction interval is estimable. 11 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was moderate (from 1 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 146edbf72435) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

A single eligible trial contributed an extractable estimate: MD -17.4 (95% CI -28.52 to -6.28); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Risk-of-bias sensitivity. 0 of 1 pooled trials carry a risk-of-bias rating; no trial is rated high risk. a low-risk-only subpool was not estimable.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision); risk of bias is not assessed for every pooled trial (registry-derived coverage). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA 146edbf72435) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py melatonin-primary-insomnia-sol

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Parity with the published comparator

Our pooled k = 1 vs the comparable same-scope comparator k = 15 — GAP. Comparator (PLoS One 2013, PMID 23691095) sleep-onset-latency pool = 15 RCTs (verified from its heterogeneity df: Q=31.9, df=14 => k=15; WMD 7.06 min [4.37,9.75]). We pool 1 (prolonged-release melatonin 2 mg, Wade 2011 / Circadin / NCT00397189, adult primary insomnia, per-arm mean/SD from CT.gov). The comparator's pool is deliberately BROADER in scope: of its 19 included studies, 4 are delayed-sleep-phase syndrome, 1 is REM sleep behaviour disorder, and >=3 are in CHILDREN (van Geijlswijk 2010, Smits 2003, Smits 2001) - all outside our adult-primary-insomnia scope - plus multiple cross-over designs and immediate-release doses from 0.05 mg/kg to 5 mg (a different formulation/estimand than our prolonged-release pool). The exact 15 SOL forest-plot trial identities are NOT in the comparator's cached OA full text (Figure 1 row labels absent), so the remaining per-trial split cannot be completed from source; several are pre-2000 cross-over trials with no accessible per-arm data. So this is a SCOPE (formulation/population/estimand) + partial REACH gap, honestly bounded - not a like-for-like shortfall. This is one of our narrowest pools and is shown as such.