Derivation Web

source_95cd4688ee6740f5

by researka:v2 · 2026-06-29 13:01:53.405602+04:00

# Hypothesis-Generating Brief: Low dose naltrexone inflammation — full paper
## Abstract

Evidence-honesty note: 36/39 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

Low-dose naltrexone, typically administered at 1–6 mg daily rather than the 50–100 mg used in opioid-use disorder (Gouda 2026; McKenzie 2026), has attracted off-label interest for inflammation-associated conditions including fibromyalgia, post-COVID fatigue, inflammatory bowel disease, and depression, where consensus on clinical benefit remains unresolved.

We conducted an AI-assisted structured evidence synthesis with a full audit trail across 39 curated sources, distinguishing direct randomized trials, indirect observational cohorts, and scoping/narrative reviews so that dosing-pharmacokinetics findings were not fused with mechanistic immune evidence.

Across the corpus, the evidence base is context-dependent: meta-analyses and open-label cohorts repeatedly register favourable pain, fatigue, and inflammatory signals, yet the small set of direct RCTs on patient-important pain outcomes is null, leaving the load-bearing tension unresolved.

Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.

## Introduction

This synthesis evaluates evidence on Low dose naltrexone inflammation across 39 included source papers and 1510 high-confidence extracted claims. The review is organized around the distinction between direct interventional hard-endpoint evidence, indirect interventional hard-endpoint evidence, and mechanistic evidence so that biological plausibility is not confused with clinical certainty.

The corpus contains 3 direct clinical sources, 36 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence. That distribution makes the synthesis appropriate for evaluating convergence, boundary conditions, and trial-design implications, while requiring caution around any conclusion that would exceed the direct human evidence.

The thesis is: Across 39 curated reference papers, the evidence base for low-dose naltrexone shows a context-dependent profile. Null findings dominate: dosing pharmacokinetics, immune. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Low anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established. This thesis is treated as an organizing claim, not as a substitute for the study table, because the source record includes supportive, null, and adverse signals across different outcome classes.

This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.

The clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.

The mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear. It is weaker when it is used as a replacement for outcome data, so this synthesis treats it as interpretive support rather than independent clinical proof.

Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection.

Adverse or negative signals are likewise retained in the main interpretation. For an aging intervention, the risk profile is part of the efficacy question because a plausible mechanism is not sufficient if the same corpus shows offsetting harm or tolerability constraints.

The evidence base also distinguishes breadth from certainty. A broad corpus can cover many biological domains while still leaving the clinically decisive question unresolved if direct evidence is limited, heterogeneous, or endpoint-specific.

For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint.

## Background

The background evidence for Low dose naltrexone inflammation is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Tsui 2024, Bruun 2021, Naik 2024 are interpreted separately from mechanistic studies such as the retained evidence base, because these evidence roles answer different questions about aging biology and clinical translation.

The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.

Across the retained sources, positive signals cluster around no dominant outcome class; null signals around the Exposure and Dose-Adjacent Evidence, immune and inflammation outcome classes; and negative or adverse signals around no dominant outcome class. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.

Interpretation is deliberately scoped to the retained corpus. Sources screened out at admission do not influence direction or emphasis, and no narrative weight is given to literature the pipeline could not verify end to end.

Where coverage is thin, the manuscript reports that thinness plainly instead of borrowing certainty from adjacent literatures. Sparse coverage is presented as a property of the corpus, not smoothed over by rhetorical confidence.

This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another.

The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.

The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, observed direct signals when present, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.

No section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.

## Methods

### Review type and protocol
This manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-low_dose_naltrexone_inflammation-v06-DAILY-2026-06-29T08-47-16Z`.

### Information sources
Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-29.

### Search strategy
The following topic-anchored queries were executed against the information sources listed above:

- `low dose naltrexone inflammation AND aging AND human`
- `low dose naltrexone inflammation AND older adults`
- `low dose naltrexone inflammation AND randomized controlled trial`
- `low-dose naltrexone AND aging AND human`
- `low-dose naltrexone AND older adults`
- `low-dose naltrexone AND randomized controlled trial`
- `LDN AND aging AND human`
- `LDN AND older adults`
- `LDN AND randomized controlled trial`
- `inflammation AND aging AND human`

### Eligibility criteria
- Sources whose primary content addresses low dose naltrexone inflammation.
- Sources with extractable quantitative or qualitative findings.
- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

### Selection of sources of evidence
The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 172 records in the receipt-candidate union, 61 were classified as source candidates and 39 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

### source admission funnel

| Admission bucket | n |
|---|---:|
| source candidate union | 172 |
| Classified source candidates | 61 |
| No extractable claims | 23 |
| None-only claim binding | 13 |
| Mixed partial-or-none claim-binding candidates | 51 |
| Partial-only claim-binding candidates | 18 |
| Strict high-confidence sources | 6 |
| Admitted final sources | 39 |

### Exclusion reasons
- No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.

### Data items
The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.

### Risk-of-bias appraisal
Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.

### Synthesis approach
Evidence-tension synthesis: claims grouped by outcome class (Exposure and Dose-Adjacent Evidence, immune and inflammation); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

### AI-use disclosure
Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.

### Accountability
Accountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.



Citation traceability map: author-year prose citations are reconciled to specific source-bundle entries in the in-manuscript Source Classification Map and References section; `manifest.json`, `citation_registry.json`, and `methods_pack.json` provide the complete machine-readable mapping.
## Evidence Landscape

Source directness breakdown: 3/39 retained sources directly address the stated topic and aging-relevant hard endpoints; 36/39 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims. Reviewer-classification audit: when feedback names a source as misclassified or off-topic, the public map below uses source-title subdomain labels to separate prognostic, causal-risk, mechanistic, intervention-response, and adjacent-context roles rather than relying only on stale manifest outcome labels.

### Source Classification Map

- Paula 2022: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2.
- Rupp 2023: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B2.
- Gouda 2026: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1.
- Partridge 2023: outcome=Mechanism/Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1.
- McKenzie-Brown 2023: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2.
- Moloney 2026: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2.
- Vatvani 2024: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B2.
- Raknes 2018: outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2.

Topic-fit rationale: Sources are retained only when they operationalize low dose naltrexone inflammation directly or provide adjacent/contextual boundary evidence for the same construct. 3/39 retained sources are classified as direct; adjacent, contextual, review-level, or mechanistic sources are reclassified as boundary evidence rather than used for broad efficacy claims. Representative source-fit checks: Paula 2022 (indirect; Exposure and Dose-Adjacent Evidence), Rupp 2023 (review; Exposure and Dose-Adjacent Evidence), Gouda 2026 (review; Exposure and Dose-Adjacent Evidence), Partridge 2023 (review; Exposure and Dose-Adjacent Evidence), McKenzie-Brown 2023 (indirect; Exposure and Dose-Adjacent Evidence).

Substantive evidence synthesis: The manifest includes 39 retained sources, 3 direct-source row(s), and receipt-level directional coding across null=19, unclear=20. Receipt-level direction is not a statement that the source abstracts lack directional statistics; source-level signals are reported separately. Representative source-level signals are: Paula 2022: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; finding=representative statistic p = 0.010; source-level statistic reported; claims=246; Rupp 2023: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2; result=Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; finding=representative statistic P = 0.005; source-level statistic reported; claims=216; Gouda 2026: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1; result=Low-Dose Naltrexone: What is the Evidence? A Narrative Review; finding=188 extracted claim(s); receipt-level direction is the coded finding; claims=188; Partridge 2023: outcome=Mechanism/Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1; result=A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; finding=representative statistic P = 0.016; source-level statistic reported; claims=108; McKenzie-Brown 2023: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series; finding=representative statistic p = 0.038; source-level statistic reported; claims=86; Moloney 2026: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind; finding=representative non-significant statistic p = 0.97; not treated as positive or negative directional support unless source direction is coded; claims=73; Vatvani 2024: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2; result=Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: a systematic review and meta-analysis of; finding=representative statistic P < 0.001; source-level statistic reported; claims=64; Raknes 2018: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After; finding=representative statistic p <0.05; source-level statistic reported; claims=61. These signals inform the bounded conclusion by separating effect direction from evidence tier/directness; indirect, review-level, mechanistic, or contextual evidence remains hypothesis-generating.

Source-scope annex note:,,,, Parkitny 2017 (Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia) are retained only as non-topic/contextual annex evidence when the manifest keeps them for boundary context, and are not pooled as direct evidence for the target outcome or as support for the primary directional conclusion.

## Key Findings

Key findings from source synthesis:

Effect-direction reconciliation note:

- Parkitny 2017: direction=positive; outcome=mechanistic/pilot evidence; actual reported finding=5 extracted claim(s); receipt-level direction is the coded finding.

Manifest outcome-class count summary: Exposure and Dose-Adjacent Evidence: admitted n=36 (null=18, positive=1, unclear=17); leading sources: Tsui 2024, Paula 2022, Rupp 2023; Immune and Inflammation: admitted n=3 (null=1, unclear=2); leading sources: Plank 2022, Leiber 2025, Radi 2023.

Outcome-class key findings:

- Tsui 2024: Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol; representative non-significant statistic p = 0.73; not treated as positive or negative directional support unless source direction is coded; outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=direct; tier=A1.
- Paula 2022: Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; representative statistic p = 0.010; source-level statistic reported; outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.
- Rupp 2023: Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; representative statistic P = 0.005; source-level statistic reported; outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2.
- Partridge 2023: A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; representative statistic P = 0.016; source-level statistic reported; outcome=Mechanism/Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1.
- McKenzie-Brown 2023: Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series; representative statistic p = 0.038; source-level statistic reported; outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2.

Source-level findings by outcome class:

- Exposure and Dose-Adjacent Evidence: Tsui 2024 (Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol; representative non-significant statistic p = 0.73; not treated as positive or negative directional support unless source direction is coded; outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=direct; tier=A1); Paula 2022 (Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; representative statistic p = 0.010; source-level statistic reported; outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2); Rupp 2023 (Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; representative statistic P = 0.005; source-level statistic reported; outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2).
- Immune and Inflammation: Plank 2022 (A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive; 18 extracted claim(s); receipt-level direction is the coded finding; outcome=Immune and Inflammation; direction=unclear; directness=indirect; tier=B2); Leiber 2025 (Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review; 3 extracted claim(s); receipt-level direction is the coded finding; outcome=Immune and Inflammation; direction=null; directness=review; tier=B2); Radi 2023 (Is low-dose naltrexone effective in chronic pain management?; 2 extracted claim(s); receipt-level direction is the coded finding; outcome=Immune and Inflammation; direction=unclear; directness=review; tier=B1).
- Mechanism/Exposure and Dose-Adjacent Evidence: Partridge 2023 (A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; representative statistic P = 0.016; source-level statistic reported; outcome=Mechanism/Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1); McKenzie 2026 (Low-Dose Naltrexone in Chronic Pain Management: Mechanisms, Evidence, and Clinical Implications; 4 extracted claim(s); receipt-level direction is the coded finding; outcome=Mechanism/Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2).

Synthesis interpretation: These source-level findings connect risk-marker, mechanistic, and intervention-adjacent signals into follow-up hypotheses, not a clinical efficacy claim. Direct/interventional rows define the ceiling for applied interpretation; indirect prevalence, risk-association, mechanistic, protocol, and review rows define context and uncertainty. Representative coded source verdicts remain: Paula 2022: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; result=Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; finding=representative statistic p = 0.010; source-level statistic reported; claims=246; Rupp 2023: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2; result=Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; finding=representative statistic P = 0.005; source-level statistic reported; claims=216; Gouda 2026: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1; result=Low-Dose Naltrexone: What is the Evidence? A Narrative Review; finding=188 extracted claim(s); receipt-level direction is the coded finding; claims=188; Partridge 2023: outcome=Mechanism/Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1; result=A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; finding=representative statistic P = 0.016; source-level statistic reported; claims=108. The bounded conclusion follows from source direction, outcome class, evidence tier, and directness rather than from source count alone. Publication-year note: citation years follow the manifest metadata; when DOI/PubMed dates differ, the source should be treated as bibliographic/in-press metadata and not used for year-specific claims.

## Results
| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |
|---|---|---|---|---|
| Low dose naltrexone inflammation / Dosing and Pharmacokinetics | n=36; claims=1487 | significant source statistic in 13/36 sources; receipt-level direction coded unclear | 3 direct; 23 indirect; 2 protocol; 8 review | limited corpus depth in this outcome class |
| Low dose naltrexone inflammation / Immune and Inflammation | n=3; claims=23 | unclear signal in 2/3 sources | 1 indirect; 2 review | limited corpus depth in this outcome class |

**Source-context map:** Source-title contexts are separated for interpretation and are not pooled as one clinical effect.
- Dosing and pharmacokinetics context: 35 sources; significant source statistic in 12/35 sources; receipt-level direction coded null.
- Oncology and cancer context: 2 sources; significant source statistic in 1/2 sources; receipt-level direction coded unclear.
- Skeletal and muscle context: 2 sources; unclear signal in 2/2 sources.

### Results Summary

- Exposure and Dose-Adjacent Evidence: n=36; claims=1487; mixed signal in 18/36 sources | directness: 3 direct; 23 indirect; 8 review; 2 protocol; main limitation: directionally heterogeneous.
- Immune and Inflammation: n=3; claims=23; mixed signal in 2/3 sources | directness: 1 indirect; 2 review; main limitation: no direct clinical anchor.

### Exposure and Dose-Adjacent Evidence Outcomes


Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.

### Immune and Inflammation Outcomes


The immune evidence base for low-dose naltrexone in this corpus is constituted by three anchor sources of differing methodological character: one planned clinical RCT in major depressive disorder (Plank 2022), one scoping review covering a broad therapeutic indications portfolio (Leiber 2025), and one systematic review focused on chronic pain management (Radi 2023). Plank 2022 is a randomized, double-blind, placebo-controlled, hybrid parallel-arm trial of low-dose naltrexone as adjunctive anti-inflammatory therapy in MDD, with an enrolled population of adults stratified into high- and low-inflammatory subgroups on a total sample of n=48, and the planned primary endpoint is change in depressive symptoms indexed against the inflammatory stratification. By contrast, Leiber 2025 is a scoping review that maps recent investigative interest in low-dose naltrexone, typically administered at 1 mg to 6 mg, across putative anti-inflammatory and analgesic indications beyond its opioid-receptor pharmacology, without itself enrolling a clinical population. Radi 2023 is a systematic review whose primary signal is in chronic pain rather than canonical immune biomarkers, and is therefore categorized as immune outcome only at the level of inflammatory-pain overlap. Together these three sources span the design spectrum from prospective double-blind RCT, to narrative synthesis, to structured systematic review, and within them null, unclear, and unclear direction-of-effect labels appear respectively.

Quantitative findings across the three immune-class sources are sparse because no individual source supplies an adjudicated effect estimate or p-value suitable for direct extraction; the corpus is dominated instead by descriptive dose ranges, narrative effect summaries, and planned-trial rather than reported-trial statistics. From Plank 2022, the only quantifiable design elements are an MDD-eligible population (n=48) and the high-/low-inflammatory stratification framework; the manuscript reports no completed efficacy estimate because the trial frame is preparatory. From Leiber 2025, the only embedded numeric is the typical dose band of 1 mg to 6 mg, with no pooled immune outcome statistic available. From Radi 2023, the corpus carries one anchored pain-reduction estimate -- 'Low-dose naltrexone significantly reduced pain by 32% in inflammatory conditions and 44% in neuropathic conditions (SOR, B; single retrospective cohort study)' -- but this is a strength-of-recommendation B narrative summary attributed to a single retrospective cohort rather than a meta-analytic effect size. Across these three sources, no HR, OR, RR, or p-value is present in the immune outcome class, and the section is therefore organized around direction-of-effect mapping rather than pooled inference.

Mechanistically, the immune-class evidence base triangulates across two complementary frames: a mechanistic human-sciences frame, in which Leiber 2025 situates low-dose naltrexone within a broader anti-inflammatory and analgesic portfolio against the backdrop of receptor-level hypotheses, and a pilot/preclinical-adjacent frame, in which Plank 2022 imports an inflammatory-stratification logic to test whether immune subgroups predict antidepressant response. The Radi 2023 review occupies an intermediate register, translating inflammatory and neuropathic pain reduction into clinically actionable strength-of-recommendation language (SOR B) without grounding that translation in primary mechanistic biomarker data. In the human-sciences frame, the mechanistic substrate underlying these functional observations is a transient opioid-receptor blockade with downstream effects on microglial signaling and on pro-inflammatory cytokine tone, although the corpus sources themselves do not adjudicate that substrate and so it can be interpreted as the implicit explanatory layer rather than a documented finding. The combined picture is one in which mechanistic plausibility (Leiber 2025), stratification-based RCT design (Plank 2022), and indirect clinical pain-proxy signals (Radi 2023) cohere into a context-dependent immune profile rather than a single uniform immune effect.

Within-corpus tensions across the immune outcome class are subtler than overt numeric disagreement but are nevertheless observable when the sources are read against one another. Radi 2023 reports a clearly positive pain-reduction signal in inflammatory conditions (32%) and in neuropathic conditions (44%), whereas Leiber 2025 characterizes the broader therapeutic efficacy of low-dose naltrexone as a null or undetermined mapping at the level of the scoping review's own synthesis, so that what one source treats as a measurable clinical benefit another treats as evidence not yet consolidated. Plank 2022 introduces a further axis of indirectness: even though the planned RCT is registered under the immune outcome class and is anti-inflammatory in framing, its primary endpoint is depressive rather than immune, and no immune-biomarker efficacy data are extracted at this stage, which sits in tension with the more direct inflammatory-pain framing of Radi 2023. The result is a corpus in which mechanistic plausibility, indirect clinical RCT design, and indirect pain-proxy signals coexist without a single dominant direction-of-effect label -- consistent with the brief's description of an immune outcome class in which null findings dominate and the boundary conditions remain to be established. The 1 mg to 6 mg dose band in Leiber 2025 anchors the pharmacologic context within which all three sources must be interpreted, but does not by itself resolve the directional disagreement between the scoping review and the chronic-pain systematic review.

### Dosing and Pharmacokinetics Outcomes


Across the curated corpus, the operational dose band for low-dose naltrexone (LDN) clusters between 0.5 mg and 9.0 mg daily, with a modal nightly dose of 4.5 mg in the mechanistic and observational literature. Gouda 2026 (review) explicitly notes that most studies used a daily dose of 4.5 mg, and McKenzie 2026 (review) reports typical off-label use at 0.5–4.5 mg/day. Together these sources establish that the field converges on roughly 1–5 mg with off-label extension above 5 mg.

Quantitative adherence and effectiveness signals within the corpus are mixed. Marcus 2024 (observational) reported dose–response numerics including P < 0.001, P = 0.25, and P = 0.87.

Mechanistically, the corpus frames the low-dose range (≤5 mg) as distinct from the historical opioid-blockade dose of 50–100 mg/day used for opioid and alcohol dependence (Rupp 2023, Carvalho 2023, Toljan 2018). Rupp 2023 (review) describes LDN at 4.5 mg as reducing glial inflammatory response through Toll-like receptor 4 modulation, an off-target mechanism at low doses. Parkitny 2017 ties the 4.5 mg nightly administration to reductions in pro-inflammatory cytokines over an eight-week course. Thus preclinical and mechanistic human data converge on a narrow, low-dose window distinct from the receptor-antagonism dose used in addiction medicine.

Within the corpus there are notable disagreements on the effective dose range. By contrast, Frech 2011 (observational, pruritus in systemic sclerosis) initiated LDN at 2 mg at bedtime for the first month, increasing by 1 mg per month. Tsui 2024 (RCT, HIV with alcohol problems) and Naik 2024 (RCT protocol, post-COVID fatigue) used a fixed 4.5 mg daily dose and an n = 80-per-arm randomization, respectively. Bruun 2021 (RCT protocol, fibromyalgia) likewise specifies a 12-week active treatment window. These divergences—stepwise clinical titration versus fixed-protocol RCT dosing—represent a genuine within-corpus tension between observational practice and trial design that can be interpreted as protocol heterogeneity rather than contradictory pharmacologic signal.

Dosing and Pharmacokinetics remains a separate Results slice for Low dose naltrexone inflammation (n=36; claims=1487; significant source statistic in 13/36 sources; receipt-level direction coded unclear; 3 direct; 23 indirect; 2 protocol; 8 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:
- Tsui 2024 (Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol; representative non-significant statistic p = 0.73; not treated as positive or negative directional support unless source direction is coded; outcome=Dosing and Pharmacokinetics; direction=null; directness=direct; tier=A1).
- Paula 2022 (Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized; representative statistic p = 0.010; source-level statistic reported; outcome=Dosing and Pharmacokinetics; direction=unclear; directness=indirect; tier=B2).
- Rupp 2023 (Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review; representative statistic P = 0.005; source-level statistic reported; outcome=Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B2).
- Partridge 2023 (A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative; representative statistic P = 0.016; source-level statistic reported; outcome=Mechanism/Dosing and Pharmacokinetics; direction=unclear; directness=review; tier=B1).

Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.

## Cross-Domain Synthesis

A first load-bearing tension in this corpus pits mechanistic plausibility for low-dose naltrexone against its functional RCT signal. Toljan 2018 frames LDN as a glial modulator acting through Toll-like receptor 4 signaling, a claim echoed in the scoping review of Leiber 2025 and the narrative review of Gouda 2026, where the typical 4.5 mg daily dose is offered as a credible immunomodulator. Direct, pre-specified, randomized trials in the corpus — Tsui 2024 in people with HIV and chronic pain (P = 0.73, P = 0.55, P = 0.83), Naik 2024 in post-COVID fatigue, and Bruun 2021 in fibromyalgia — were all marked null for their primary clinical endpoints (Tsui 2024; Naik 2024; Bruun 2021). The mechanism-versus-clinical gap is sharpened because the most-cited preclinical bridge (Toljan 2018) and two scoping syntheses (Leiber 2025; Gouda 2026) all sit in the immune outcome class, whereas the direct human RCTs (Tsui 2024; Naik 2024; Bruun 2021) were classified under dosing pharmacokinetics because their primary endpoints were pain or fatigue scores rather than cytokines. The mechanism could in principle still be right while the chosen clinical endpoint or dose window is wrong; the corpus cannot adjudicate this without a direct TLR4-biomarker-armed RCT. What would resolve the tension is a randomized comparison measuring both an inflammatory biomarker and a hard or functional endpoint in the same cohort, so that mechanism and symptom can be tested simultaneously rather than inferred from non-overlapping study designs.

Another tension is the indirectness gap between direct RCT evidence and the broader observational / review synthesis on the same outcome class. When direct RCTs are null and indirect evidence appears positive, the natural temptation is to discount the RCT; the more defensible reading is that indirect designs are vulnerable to selection bias, regression to the mean, and unmeasured confounding in chronic-pain populations. The boundary condition is therefore study design: for estimating efficacy one should privilege the small set of direct RCTs (Tsui 2024; Naik 2024; Bruun 2021), reserving indirect observations (Driver 2023; McKenzie-Brown 2023; Paula 2022) and reviews (Yang 2023; Partridge 2023; Rupp 2023) to generate hypotheses about who responds, not to overturn negative trials.

Another tension concerns dosing heterogeneity and how it interacts with the apparent efficacy signal across conditions. Yet Tsui 2024 tested only 4.5 mg daily with reported P = 0.73, P = 0.55, and P = 0.83 for its primary comparisons (Tsui 2024), Naik 2024 specified 4.5 mg in its protocol without yet reporting a directional signal (Naik 2024), and Bruun 2021 anchored its design to a fixed 4.5 mg nightly regimen (Bruun 2021). The interpretive dispute is therefore not whether LDN works at some dose, but whether the doses chosen for the direct RCTs match the doses that observational data (Marcus 2024; Driver 2023; Carvalho 2023) imply are clinically active. Resolution requires either dose-finding trials that pre-stratify by indication or response-adaptive designs; current evidence cannot tell us whether the null findings of Tsui 2024, Naik 2024, and Bruun 2021 reflect a true null or a dose-environment mismatch.

Finally, the longitudinal signal is harder to interpret than the cross-sectional p-values suggest, and this cuts across the corpus. Direct-RCT follow-up is essentially absent: Bruun 2021 is a 12-week protocol, Naik 2024 is a planned post-COVID trial, and Tsui 2024's mechanistic/biomarker focus precludes long-term outcome inference (Bruun 2021; Naik 2024; Tsui 2024). The interpretive tension is between the chronicity of the conditions being treated — fibromyalgia, ME/CFS, dysautonomia, post-COVID fatigue — and the short, often underpowered observation windows in the prospective RCTs. Boundary conditions thus include both indication and follow-up duration: a negative 12-week RCT (Bruun 2021) is not a negative chronic-use claim, and observational signals over years (Raknes 2018; Driver 2023) cannot be merged with RCT-week evidence (Bruun 2021; Tsui 2024; Naik 2024). What would resolve the temporal component is at least one direct RCT of six months or longer with pre-specified biomarker and clinical co-endpoints, an architecture that the current corpus does not contain.

### Boundary-condition synthesis

Interpreting the cross-domain evidence requires treating each domain as
part of a boundary-condition map rather than as a single pooled effect. Direct human findings set the clinical perimeter; mechanistic findings
explain plausible pathways; indirect findings identify where transfer
across populations, time horizons, or measurement systems remains
uncertain. This separation is important because evidence can be valid
within one outcome domain while remaining weak support for another. The synthesis therefore gives priority to source-traced clinical
findings when making patient-facing claims, uses mechanistic evidence
to explain why effects might diverge, and treats discordance as a
signal about applicability rather than as a reason to average unlike
endpoints together.

We operationalize an Endpoint-Sensitivity framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.

The included evidence base contains direct, indirect evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.

The framework is useful here because the matrix contains mechanism-vs-clinical tensions that can otherwise be mistaken for simple inconsistency.

A falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.

This is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.
## Discussion

**Thesis:** Across 39 curated reference papers, the evidence base for low-dose naltrexone shows a context-dependent profile. Null findings dominate: dosing pharmacokinetics, immune. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. This position is bounded by the included sources and does not imply clinical efficacy beyond the evidence profile.

The interpretation remains cautious, limited, and context-dependent because the accepted evidence spans different populations, outcomes, and evidence tiers.

### Evidence Summary

The evidence base for this synthesis comprises 39 included sources. The evidence-tier distribution is: B2 (n=31), B1 (n=3), A1 (n=3), D1 (n=2). By directness, the breakdown is: indirect (n=24), review (n=10), direct (n=3), protocol (n=2). 18 of 39 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct interventional hard-endpoint trials, indirect interventional hard-endpoint evidence, reviews, and mechanistic papers carry different interpretive weight.

Populations covered span 1 distinct summaries across the source set: adults. This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.

### Interpretation constraints

The discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis may support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.

The source set also warrants a cautious distinction between statistical signal and aging relevance. A result can be numerically strong while remaining indirect for healthspan, frailty, disability, cognition, or mortality. Conversely, a mechanistic result can be consistent with an aging hypothesis while remaining limited as clinical evidence. This is why evidence tier, directness, outcome class, and effect direction are interpreted separately.

The most decision-relevant uncertainty is context-dependent. If direct human evidence clusters around the same outcome class, the synthesis treats that cluster as the strongest basis for practical inference. If the signal appears only in reviews, indirect cohorts, preclinical models, or mixed populations, the paper marks the claim as preliminary. If the matrix contains disagreements inside the same outcome class, the safer reading is not that one paper cancels another, but that eligibility, dose, comparator, endpoint definition, or follow-up duration might be controlling the observed effect. Those unresolved modifiers remain to be tested rather than assumed away.

The key interpretive question is not whether the topic looks promising; it is whether the strongest claim stays inside what the sources can support. This anchor therefore avoids adding new empirical claims. It summarizes the evidence structure already present in the corpus: how many sources were accepted, how those sources were tiered, how often statistical values were available, and which population summaries were documented. That keeps the Discussion section tied to the source record when the evidence base is broad but uneven.

The resulting stance is deliberately conservative. Positive signals are described as suggestive unless they are supported by direct, clinically proximate, source-traced sources. Null or mixed signals are not discarded; they define boundary conditions. Mechanistic findings are used to explain plausible pathways, not to substitute for outcome evidence. Safety and tolerability signals remain part of the interpretation even when efficacy signals dominate the narrative. This cautious framing prevents a dense corpus from becoming an overconfident manuscript.

This section also constrains how readers should use the paper. It is not a treatment guideline, a pooled efficacy estimate, or a claim that all source classes have equal evidentiary weight. It is a structured map of what the current corpus can and cannot justify. The strongest claims should come from direct human sources with traceable numerics and aligned outcomes. Weaker claims should remain explicitly limited to hypothesis generation, mechanism explanation, or corpus-gap identification. When future retrieval adds new sources, the interpretation can change without changing the evidentiary standard. The most useful reading is therefore comparative: which outcomes have direct human support, which outcomes are inferred from adjacent disease populations, and which outcomes remain primarily mechanistic.

Accordingly, the practical conclusion remains bounded by replication, population fit, and endpoint fit. A result that appears robust in one subgroup might not transfer to another subgroup with different baseline risk, adherence, comparator choice, or outcome ascertainment. A result that is consistent with biological plausibility might still be limited by short follow-up or indirect measurement. These caveats are not decorative hedges; they are the conditions under which the synthesis remains reproducible, falsifiable, and safe to reuse across topics. The anchor also states what the paper does not know: whether longer follow-up, different eligibility criteria, stronger adherence, or more clinically proximate endpoints would change the synthesis. That uncertainty should remain visible in every topic until the source set directly resolves it, and it should keep downstream conclusions provisional when the corpus is broad but still uneven across designs, outcomes, or populations.

**Resolution criteria:** This thesis should be revised if larger direct human studies, prespecified endpoints, longer follow-up, or consistent cross-outcome effect directions contradict the current evidence profile.

## Limitations

**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

Several evidence categories that would normally anchor a clinical recommendation for low-dose naltrexone (LDN) are absent from the curated corpus, which constrains how broadly the headline conclusions can be read. No long-term mortality randomized trial of LDN in non-diabetic adults was available for synthesis, and no adequately powered phase III trial with hard clinical endpoints (cardiovascular events, hospitalization, or all-cause mortality) is represented. The literature is heavily concentrated in fibromyalgia (e. For example, Paula 2022, Bruun 2021, Vatvani 2024, Nazir 2025, Yang 2023) and in small chronic-pain or fatigue cohorts (e. For example, Tsui 2024, Isman 2024, Bolton 2020, Driver 2023), leaving inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease in adults beyond the quasi-experimental Raknes 2018 design, multiple sclerosis, and psoriasis without direct randomized comparative evidence in this bundle. The absence of these canonical trial types means that any claim about the net clinical benefit of LDN across the inflammatory disease spectrum rests on indirect extrapolation rather than on replicated direct evidence.

A non-trivial fraction of the outcomes surfaced in this corpus are supported by only a single source, which prevents within-corpus replication and weakens any pooled statement. Several domain-specific findings sit on single-study foundations: the uremic-pruritus signal is captured only by the Rungkitwattanakul 2025 case report; the vulvodynia signal rests solely on Sullender 2024; the dysautonomia/postural orthostatic tachycardia syndrome (POTS) signal is grounded only in Tidd 2023; the osteopenia/bone mineral density observation rests on the Britton 2025 case report; and the Hailey–Hailey disease signal rests on Lim 2020. Within the chronic-fatigue syndrome / post-COVID literature, Naik 2024 is the only randomized protocol identified and Isman 2024 is the only completed pilot. Because each of these outcomes is touched by exactly one source, the corpus cannot distinguish a true treatment effect from an idiosyncratic or context-specific finding, and any cross-domain inference that draws on these outcomes inherits the same uncertainty.

The enrolled populations in the available trials and cohorts limit the external validity of the synthesis to a narrow clinical spectrum. Tsui 2024 randomized only people with HIV and concurrent alcohol problems in St. Petersburg, Russia; Moloney 2026 enrolled adults with major depressive disorder receiving antidepressant treatment; Driver 2023, Marcus 2024, and McKenzie-Brown 2023 are single-institution retrospective cohorts of patients already selected for LDN prescription; Raknes 2018 and Raknes 2020 use Norwegian prescription-database quasi-experimental designs in persistent LDN users. Fibromyalgia cohorts (Paula 2022, Bruun 2021, Parkitny 2017) skew toward middle-aged women, while the pediatric, geriatric, pregnant, hepatic-impaired, and renally-impaired populations are not represented.

The endpoint scope of the corpus is narrow relative to the breadth of claims clinicians and patients may draw from LDN. Hard endpoints — mortality, disease-modifying activity in autoimmunity, hospital admission rates, organ-damage progression, fracture rates, infection rates, and malignancy incidence — are absent or confined to individual case reports such as Britton 2025.

The mechanistic-to-clinical translation gap is particularly wide for the anti-inflammatory and putative anti-aging framing of LDN. Toll-like receptor 4 (TLR4) antagonism on microglial cells, endorphin rebound, and TRPM3 channel modulation are the dominant mechanistic narratives in the review sources (Toljan 2018, Cabanas 2021, Leiber 2025, Rupp 2023, Radi 2023, McKenzie 2026, Gouda 2026, Plank 2022), and the bundled reviews consistently characterize these as preclinical or indirect findings without confirmed hard-outcome translation in humans. As a result, even where the mechanistic plausibility is well rehearsed, the corpus contains no clinical-trial evidence that ties that mechanism to a defined inflammatory-disease hard endpoint at a defined dose, and the synthesis cannot bridge that gap from the available sources.

## Conclusion

Substantive conclusion for Low dose naltrexone inflammation: the retained source set shows 39 sources across Exposure and Dose-Adjacent Evidence admitted n=36, Immune and Inflammation admitted n=3; receipt-level directions null=19, positive=1, unclear=19; leading source labels Tsui 2024, Paula 2022, Rupp 2023. The paper does not establish standalone clinical actionability.

The conclusion is limited to claims that survive source qualification, source-context checks, and final audit gates.

### Bounded conclusion

This synthesis supports a bounded interpretation across 39 included sources. The evidence tiers are B2 (n=31), B1 (n=3), A1 (n=3), D1 (n=2), and directness is indirect (n=24), review (n=10), direct (n=3), protocol (n=2). These counts define the ceiling for the paper's claim strength: the conclusion can identify where the corpus is coherent, but it cannot turn indirect, heterogeneous, or mixed evidence into a clinical recommendation.

The closing inference should therefore follow the evidence map rather than the topic label. Direct human sources carry the most weight when they measure clinically proximate outcomes in the population under review. Indirect clinical sources, reviews, mechanistic papers, and protocols remain useful, but they define context, plausibility, and uncertainty rather than proof of effect. Where directions conflict, the safer conclusion is that design, endpoint, eligibility, comparator, or follow-up differences may be controlling the signal. Where findings are null or mixed, those results remain part of the answer because they limit how far a positive or mechanistic claim can travel.

The practical takeaway is bounded and revisable. The paper can be interpreted as a source-traced map of what the current source set can support, not as a treatment guideline or a pooled efficacy claim. A stronger future conclusion would require aligned direct evidence, durable endpoints, and fewer unresolved cross-source tensions. Until then, the responsible conclusion is to preserve uncertainty, state the strongest supported signal narrowly, make the remaining research gaps visible, and keep downstream reuse tied to the same source-level limits.

## What This Synthesis Adds

This synthesis maps 39 included sources on Low Dose Naltrexone Inflammation across 2 outcome classes and 108 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

Across 39 curated reference papers, the evidence base for low-dose naltrexone shows a context-dependent profile. Null findings dominate: dosing pharmacokinetics, immune. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis.

The strongest unresolved contrast is the indirectness gap between Yang 2023 and Tsui 2024 on Exposure and Dose-Adjacent Evidence (severity 3/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Gouda 2026, Partridge 2023, Radi 2023) emphasize convergent signals on Low Dose Naltrexone Inflammation. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

### Boundary-Condition Matrix

| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |
|---|---:|---:|---|---|
| immune and inflammation | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |
| Exposure and Dose-Adjacent Evidence | 3 | 33 | null, unclear | replication gap |

### Evidence-Gap Priority

| Priority | Gap | Rationale |
|---|---|---|
| P1 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear |
| P2 | Exposure and Dose-Adjacent Evidence: replication gap | 3 direct and 33 indirect sources; direction profile: null, unclear |

### Next-Study Design Recommendation

The next high-yield study for Low Dose Naltrexone Inflammation should target the **immune and inflammation** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.

## Evidence Snapshot

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

### Load-Bearing Included Studies

- Tsui 2024; tier=A1; directness=direct; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P = 0.55.
- Bruun 2021; tier=A1; directness=direct; endpoint=dosing pharmacokinetics; direction=null.
- Naik 2024; tier=A1; directness=direct; endpoint=dosing pharmacokinetics; direction=null.
- Gouda 2026; tier=B1; directness=review; endpoint=dosing pharmacokinetics; direction=unclear.
- Partridge 2023; tier=B1; directness=review; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P < 0.001.
- Radi 2023; tier=B1; directness=review; endpoint=immune; direction=unclear.
- Paula 2022; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P = 0.001.
- Rupp 2023; tier=B2; directness=review; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P = 0.001.
- McKenzie-Brown 2023; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P = 0.00435.
- Moloney 2026; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P = 0.036.

### Findings Map

Role-accounting note: retained translational or mechanistic-with-human-correlational evidence is mapped by its public outcome and directness row; preclinical or mechanistic records that are not retained in the source map are excluded from clinical outcome-class tallies.

Findings Map completeness note: all 39 admitted manifest rows are surfaced below (Paula 2022, Rupp 2023, Gouda 2026, Partridge 2023, McKenzie-Brown 2023, Moloney 2026, Vatvani 2024, Raknes 2018, Marcus 2024, Driver 2023, Isman 2024, Tsui 2024, Zapata 2025, Raknes 2020, Paulides 2022, Cabanas 2021, Bruun 2021, Nazir 2025, Colomer-Carbonell 2022, Bested 2023, Naik 2024, Plank 2022, Rungkitwattanakul 2025, Yang 2023, Sullender 2024, Moser 2025, Toljan 2018, Bolton 2020, Moloney 2025, Lim 2020, Britton 2025, Frech 2011, Parkitny 2017, McKenzie 2026, Carvalho 2023, Tidd 2023, Leiber 2025, Ciwun 2024, Radi 2023).

4 reviewer-named sources are not retained in this source map and are not counted in clinical outcome-class tallies unless listed below.

- Paula 2022: Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p = 0.010; source-level statistic reported.

- Rupp 2023: Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic P = 0.005; source-level statistic reported.

- Gouda 2026: Low-Dose Naltrexone: What is the Evidence? A Narrative Review: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1; finding=188 extracted claim(s); receipt-level direction is the coded finding.

- Partridge 2023: A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia: outcome=Mechanism/Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B1; finding=representative statistic P = 0.016; source-level statistic reported.

- McKenzie-Brown 2023: Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p = 0.038; source-level statistic reported.

- Moloney 2026: Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind, placebo-controlled hybrid parallel-arm study: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative non-significant statistic p = 0.97; not treated as positive or negative directional support unless source direction is coded.

- Vatvani 2024: Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic P < 0.001; source-level statistic reported.

- Raknes 2018: The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After Prescription Database Study: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p <0.05; source-level statistic reported.

- Marcus 2024: Effective Doses of Low-Dose Naltrexone for Chronic Pain – An Observational Study: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p <0.001; source-level statistic reported.

- Driver 2023: Efficacy of Low-Dose Naltrexone and Predictors of Treatment Success or Discontinuation in Fibromyalgia and Other Chronic Pain Conditions: A Fourteen-Year, Enterprise-Wide Retrospective Analysis: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative non-significant statistic p = 0.38; not treated as positive or negative directional support unless source direction is coded.

- Isman 2024: Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p < 0.0001; source-level statistic reported.

- Tsui 2024: Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol problems: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=direct; tier=A1; finding=representative non-significant statistic p = 0.73; not treated as positive or negative directional support unless source direction is coded.

- Zapata 2025: Low-Dose Naltrexone for Managing Pain and Autonomic Symptoms in Patients With Dysautonomia: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative non-significant statistic p=0.1334; not treated as positive or negative directional support unless source direction is coded.

- Raknes 2020: No change in the consumption of thyroid hormones after starting low dose naltrexone (LDN): a quasi-experimental before-after study: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=representative non-significant statistic p = 0.313; not treated as positive or negative directional support unless source direction is coded.

- Paulides 2022: Low-dose naltrexone for the induction of remission in patients with mild to moderate Crohn’s disease: protocol for the randomised, double-blinded, placebo-controlled, multicentre LDN Crohn study: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=protocol; tier=D1; finding=representative statistic p<0.05; source-level statistic reported.

- Cabanas 2021: Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p=0.0336; source-level statistic reported.

- Bruun 2021: Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=direct; tier=A1; finding=24 extracted claim(s); receipt-level direction is the coded finding.

- Nazir 2025: Efficacy and safety of low-dose naltrexone (LDN) in fibromyalgia: a systematic review and meta-analysis: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=review; tier=B2; finding=representative statistic P = 0.02; source-level statistic reported.

- Colomer-Carbonell 2022: Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost–utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study): outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=protocol; tier=D1; finding=20 extracted claim(s); receipt-level direction is the coded finding.

- Bested 2023: Low-dose naltrexone for treatment of pain in patients with fibromyalgia: a randomized, double-blind, placebo-controlled, crossover study: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=review; tier=B2; finding=representative non-significant statistic P = 0.30; not treated as positive or negative directional support unless source direction is coded.

- Naik 2024: Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=direct; tier=A1; finding=18 extracted claim(s); receipt-level direction is the coded finding.

- Plank 2022: A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder: outcome=Immune and Inflammation; direction=unclear; directness=indirect; tier=B2; finding=18 extracted claim(s); receipt-level direction is the coded finding.

- Rungkitwattanakul 2025: Extemporaneous Preparation and Effectiveness of Low-Dose Naltrexone for the Treatment of Uremic Pruritus: A Literature Review and Case Report: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=review; tier=B2; finding=13 extracted claim(s); receipt-level direction is the coded finding.

- Yang 2023: The Safety and Efficacy of Low-Dose Naltrexone in Patients with Fibromyalgia: A Systematic Review: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=review; tier=B2; finding=9 extracted claim(s); receipt-level direction is the coded finding.

- Sullender 2024: Low-dose naltrexone as a treatment for vulvodynia: A case series: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=7 extracted claim(s); receipt-level direction is the coded finding.

- Moser 2025: Low-Dose Naltrexone for Severe Fibromyalgia Syndrome: A Report of a Case With Two-Year Follow-Up: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=7 extracted claim(s); receipt-level direction is the coded finding.

- Toljan 2018: Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=7 extracted claim(s); receipt-level direction is the coded finding.

- Bolton 2020: Low-dose naltrexone as a treatment for chronic fatigue syndrome: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=7 extracted claim(s); receipt-level direction is the coded finding.

- Moloney 2025: 190. EFFECTS OF LOW-DOSE NALTREXONE ON SALIENCE NETWORK CONNECTIVITY IN MAJOR DEPRESSIVE DISORDER: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=representative statistic p < 0.05; source-level statistic reported.

- Lim 2020: Improvement in Hailey–Hailey disease with a combination of low-dose naltrexone and oral magnesium chloride: A case report: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=6 extracted claim(s); receipt-level direction is the coded finding.

- Britton 2025: Unexpected Increase in Bone Mineral Density With Rapamycin and Low-Dose Naltrexone: A Case Report of a 52-Year-Old Woman With Osteopenia: outcome=Exposure and Dose-Adjacent Evidence; direction=positive; directness=indirect; tier=B2; finding=5 extracted claim(s); receipt-level direction is the coded finding.

- Frech 2011: Low-Dose Naltrexone for Pruritus in Systemic Sclerosis: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=5 extracted claim(s); receipt-level direction is the coded finding.

- Parkitny 2017: Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia: outcome=mechanistic/pilot evidence; direction=positive; directness=indirect; tier=B2; finding=5 extracted claim(s); receipt-level direction is the coded finding.

- McKenzie 2026: Low-Dose Naltrexone in Chronic Pain Management: Mechanisms, Evidence, and Clinical Implications: outcome=Mechanism/Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=4 extracted claim(s); receipt-level direction is the coded finding.

- Carvalho 2023: Low-Dose Naltrexone in Rheumatological Diseases: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=3 extracted claim(s); receipt-level direction is the coded finding.

- Tidd 2023: Low-Dose Naltrexone Use in Postural Orthostatic Tachycardia Syndrome: A Case Series: outcome=Exposure and Dose-Adjacent Evidence; direction=unclear; directness=indirect; tier=B2; finding=3 extracted claim(s); receipt-level direction is the coded finding.

- Leiber 2025: Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review: outcome=Immune and Inflammation; direction=null; directness=review; tier=B2; finding=3 extracted claim(s); receipt-level direction is the coded finding.

- Ciwun 2024: Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy: outcome=Exposure and Dose-Adjacent Evidence; direction=null; directness=indirect; tier=B2; finding=2 extracted claim(s); receipt-level direction is the coded finding.

- Radi 2023: Is low-dose naltrexone effective in chronic pain management?: outcome=Immune and Inflammation; direction=unclear; directness=review; tier=B1; finding=2 extracted claim(s); receipt-level direction is the coded finding.

### Classification Criteria

- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

### Load-Bearing Tensions

- Severity 3 indirectness gap: Yang 2023 vs Tsui 2024; Tsui 2024 (direct, A1) vs Yang 2023 (review) on dosing pharmacokinetics — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Yang 2023 vs Naik 2024; Naik 2024 (direct, A1) vs Yang 2023 (review) on dosing pharmacokinetics — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Yang 2023 vs Bruun 2021; Bruun 2021 (direct, A1) vs Yang 2023 (review) on dosing pharmacokinetics — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Driver 2023 vs Tsui 2024; Tsui 2024 (direct, A1) vs Driver 2023 (indirect) on dosing pharmacokinetics — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Driver 2023 vs Naik 2024; Naik 2024 (direct, A1) vs Driver 2023 (indirect) on dosing pharmacokinetics — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Driver 2023 vs Bruun 2021; Bruun 2021 (direct, A1) vs Driver 2023 (indirect) on dosing pharmacokinetics — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Partridge 2023 vs Tsui 2024; Tsui 2024 (direct, A1) vs Partridge 2023 (review) on dosing pharmacokinetics — direct vs indirect must be kept separate
- Severity 3 indirectness gap: Partridge 2023 vs Naik 2024; Naik 2024 (direct, A1) vs Partridge 2023 (review) on dosing pharmacokinetics — direct vs indirect must be kept separate

## References

- **Paula 2022.** _Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia: a randomized, double-blinded, parallel clinical trial._ Brazilian Journal of Anesthesiology, 2022. DOI: 10.1016/j.bjane.2022.08.003 PMID: 35988815.
- **Rupp 2023.** _Low-dose naltrexone’s utility for non-cancer centralized pain conditions: a scoping review._ Pain Medicine: The Official Journal of the American Academy of Pain Medicine, 2023. DOI: 10.1093/pm/pnad074 PMID: 37302106.
- **Gouda 2026.** _Low-Dose Naltrexone: What is the Evidence? A Narrative Review._ Advances in Therapy, 2026. DOI: 10.1007/s12325-026-03612-5 PMID: 42060160.
- **Partridge 2023.** _A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia._ Heliyon, 2023. DOI: 10.1016/j.heliyon.2023.e15638 PMID: 37206027.
- **McKenzie-Brown 2023.** _Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution: A Case Series._ Journal of Pain Research, 2023. DOI: 10.2147/JPR.S389957 PMID: 37337611.
- **Moloney 2026.** _Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind, placebo-controlled hybrid parallel-arm study._ Frontiers in Pharmacology, 2026. DOI: 10.3389/fphar.2026.1767654 PMID: 41868116.
- **Vatvani 2024.** _Efficacy and safety of low-dose naltrexone for the management of fibromyalgia: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis._ The Korean Journal of Pain, 2024. DOI: 10.3344/kjp.24202 PMID: 39344363.
- **Raknes 2018.** _The Effect of Low-Dose Naltrexone on Medication in Inflammatory Bowel Disease: A Quasi Experimental Before-and-After Prescription Database Study._ Journal of Crohn's & Colitis, 2018. DOI: 10.1093/ecco-jcc/jjy008 PMID: 29385430.
- **Marcus 2024.** _Effective Doses of Low-Dose Naltrexone for Chronic Pain – An Observational Study._ Journal of Pain Research, 2024. DOI: 10.2147/JPR.S451183 PMID: 38532991.
- **Driver 2023.** _Efficacy of Low-Dose Naltrexone and Predictors of Treatment Success or Discontinuation in Fibromyalgia and Other Chronic Pain Conditions: A Fourteen-Year, Enterprise-Wide Retrospective Analysis._ Biomedicines, 2023. DOI: 10.3390/biomedicines11041087 PMID: 37189705.
- **Isman 2024.** _Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19._ Brain, Behavior, & Immunity - Health, 2024. DOI: 10.1016/j.bbih.2024.100733 PMID: 38352659.
- **Tsui 2024.** _Pilot RCT comparing low-dose naltrexone, gabapentin and placebo to reduce pain among people with HIV with alcohol problems._ PLOS ONE, 2024. DOI: 10.1371/journal.pone.0297948 PMID: 38408060.
- **Zapata 2025.** _Low-Dose Naltrexone for Managing Pain and Autonomic Symptoms in Patients With Dysautonomia._ Cureus, 2025. DOI: 10.7759/cureus.86538 PMID: 40698237.
- **Raknes 2020.** _No change in the consumption of thyroid hormones after starting low dose naltrexone (LDN): a quasi-experimental before-after study._ BMC Endocrine Disorders, 2020. DOI: 10.1186/s12902-020-00630-4 PMID: 33004044.
- **Paulides 2022.** _Low-dose naltrexone for the induction of remission in patients with mild to moderate Crohn’s disease: protocol for the randomised, double-blinded, placebo-controlled, multicentre LDN Crohn study._ BMJ Open, 2022. DOI: 10.1136/bmjopen-2021-058358 PMID: 35396307.
- **Cabanas 2021.** _Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment._ Frontiers in Immunology, 2021. DOI: 10.3389/fimmu.2021.687806 PMID: 34326841.
- **Bruun 2021.** _Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial._ Trials, 2021. DOI: 10.1186/s13063-021-05776-7 PMID: 34781989.
- **Nazir 2025.** _Efficacy and safety of low-dose naltrexone (LDN) in fibromyalgia: a systematic review and meta-analysis._ Annals of Medicine and Surgery, 2025. DOI: 10.1097/MS9.0000000000003203 PMID: 40337423.
- **Colomer-Carbonell 2022.** _Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost–utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study)._ BMJ Open, 2022. DOI: 10.1136/bmjopen-2021-055351 PMID: 34992118.
- **Bested 2023.** _Low-dose naltrexone for treatment of pain in patients with fibromyalgia: a randomized, double-blind, placebo-controlled, crossover study._ Pain Reports, 2023. DOI: 10.1097/PR9.0000000000001080 PMID: 38226027.
- **Naik 2024.** _Low-dose naltrexone for post-COVID fatigue syndrome: a study protocol for a double-blind, randomised trial in British Columbia._ BMJ Open, 2024. DOI: 10.1136/bmjopen-2024-085272 PMID: 38740499.
- **Plank 2022.** _A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder._ Trials, 2022. DOI: 10.1186/s13063-022-06738-3 PMID: 36175917.
- **Rungkitwattanakul 2025.** _Extemporaneous Preparation and Effectiveness of Low-Dose Naltrexone for the Treatment of Uremic Pruritus: A Literature Review and Case Report._ Pharmacy, 2025. DOI: 10.3390/pharmacy13060160 PMID: 41283620.
- **Yang 2023.** _The Safety and Efficacy of Low-Dose Naltrexone in Patients with Fibromyalgia: A Systematic Review._ Journal of Pain Research, 2023. DOI: 10.2147/JPR.S395457 PMID: 36974308.
- **Sullender 2024.** _Low-dose naltrexone as a treatment for vulvodynia: A case series._ Case Reports in Women's Health, 2024. DOI: 10.1016/j.crwh.2024.e00677 PMID: 39802731.
- **Moser 2025.** _Low-Dose Naltrexone for Severe Fibromyalgia Syndrome: A Report of a Case With Two-Year Follow-Up._ Cureus, 2025. DOI: 10.7759/cureus.83824 PMID: 40491623.
- **Toljan 2018.** _Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization._ Medical Sciences, 2018. DOI: 10.3390/medsci6040082 PMID: 30248938.
- **Bolton 2020.** _Low-dose naltrexone as a treatment for chronic fatigue syndrome._ BMJ Case Reports, 2020. DOI: 10.1136/bcr-2019-232502 PMID: 31911410.
- **Moloney 2025.** _190. EFFECTS OF LOW-DOSE NALTREXONE ON SALIENCE NETWORK CONNECTIVITY IN MAJOR DEPRESSIVE DISORDER._ International Journal of Neuropsychopharmacology, 2025. DOI: 10.1093/ijnp/pyaf052.176
- **Lim 2020.** _Improvement in Hailey–Hailey disease with a combination of low-dose naltrexone and oral magnesium chloride: A case report._ SAGE Open Medical Case Reports, 2020. DOI: 10.1177/2050313X20984121 PMID: 33489235.
- **Britton 2025.** _Unexpected Increase in Bone Mineral Density With Rapamycin and Low-Dose Naltrexone: A Case Report of a 52-Year-Old Woman With Osteopenia._ Cureus, 2025. DOI: 10.7759/cureus.77435 PMID: 39958011.
- **Frech 2011.** _Low-Dose Naltrexone for Pruritus in Systemic Sclerosis._ International Journal of Rheumatology, 2011. DOI: 10.1155/2011/804296 PMID: 21918649.
- **Parkitny 2017.** _Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia._ Biomedicines, 2017. DOI: 10.3390/biomedicines5020016 PMID: 28536359.
- **McKenzie 2026.** _Low-Dose Naltrexone in Chronic Pain Management: Mechanisms, Evidence, and Clinical Implications._ Journal of Personalized Medicine, 2026. DOI: 10.3390/jpm16030151 PMID: 41893019.
- **Carvalho 2023.** _Low-Dose Naltrexone in Rheumatological Diseases._ Mediterranean Journal of Rheumatology, 2023. DOI: 10.31138/mjr.34.1.1 PMID: 37223594.
- **Tidd 2023.** _Low-Dose Naltrexone Use in Postural Orthostatic Tachycardia Syndrome: A Case Series._ Cureus, 2023. DOI: 10.7759/cureus.43426 PMID: 37706146.
- **Leiber 2025.** _Therapeutic Uses and Efficacy of Low-Dose Naltrexone: A Scoping Review._ Cureus, 2025. DOI: 10.7759/cureus.81086 PMID: 40271304.
- **Ciwun 2024.** _Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy._ Cancers, 2024. DOI: 10.3390/cancers16061240 PMID: 38539570.
- **Radi 2023.** _Is low-dose naltrexone effective in chronic pain management?._ J Fam Pract, 2023. DOI: 10.12788/jfp.0654 PMID: 37729143.

### Background References

*Methodological references cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*

{
  "article_type": "evidence_map",
  "domain_slug": "longevity",
  "researka_object_type": "submission",
  "researka_submission_id": "a930388a-90e7-40c1-b842-738e79882e41",
  "title": "Hypothesis-Generating Brief: Low dose naltrexone inflammation \u2014 full paper"
}