Low Dose Naltrexone (LDN) in Oncology

Contents Jump Menu

• 1. Overview and the opportunity

• 2. Essential distinctions: LDN, OGF and other opioid antagonists

• 3. Mechanisms explained: growth control, immunity and inflammation

• 4. Evidence map by cancer type

• 5. Anticancer Combinations and Sequencing

• 6. Research Doses, Schedules and Formulation

• 7. Absorption, Metabolism, CYP Enzymes and Interactions

• 8. Tolerability, Pain Planning and Practical Monitoring

• 9. Access and trial leads

• 10. Making the Research Useful: Tracking and Selection.

• Sources and further reading

1. Overview and the opportunity

LDN is a repurposing approach: it uses small amounts of an established opioid-antagonist medicine that differ from its usual 50 mg clinical role. In experimental systems, a brief interruption of opioid-related signalling can produce a compensatory response after the blockade recedes. That idea is that this response restores growth restraint, changes the tumour environment, or makes cancer cells more responsive to another treatment.

The most developed cancer-specific explanation involves opioid growth factor (OGF) and its receptor, OGFr. This is a naturally occurring growth-regulation system. In several experimental cancer models, activation of this system slows the transition into DNA replication. LDN is being studied as a way to increase the activity of that existing brake after a temporary receptor blockade.

A second research strand examines immune and inflammatory biology, including natural killer cells, macrophages and Toll-like receptor signalling.

A third investigates treatment sequence: naltrexone exposure followed by a drug-free interval or another anticancer agent can behave differently from simultaneous exposure. Together, these strands make LDN an interesting potential adjunct rather than a single-mechanism anticancer drug.

The evidence picture is uneven but informative. There are ovarian, colorectal, cervical, breast and other laboratory or animal findings; unusual clinical courses reported in pancreatic cancer and lymphoma; a randomised glioma symptom-support study; and a recent cancer-pain series. A melanoma trial brings naltrexone together with propranolol and checkpoint immunotherapy. The biological rationale is substantial enough to examine carefully, while a general tumour-control or survival benefit from LDN has not yet been established in human trials.

At a glance

2. Essential distinctions: LDN, OGF and other opioid antagonists

Several different interventions appear together in the literature. Keeping them separate makes the positive findings more useful, because it identifies the actual treatment and biological question behind each result.

3. Mechanisms explained: growth control, immunity and inflammation

3A. The temporary-blockade and rebound model

The proposed sequence is: a short period of antagonism → compensatory increases in OGF and/or OGFr → falling antagonist exposure → greater opportunity for OGF to act through its receptor → slower cell-cycle progression. The recovery period is part of the proposed mechanism, not a gap in treatment.

Donahue, McLaughlin and Zagon used human ovarian cancer cells to examine this directly. Short-term and continuous naltrexone exposure produced different proliferative responses. The inhibitory action of short-term exposure depended on OGF–OGFr and required p16 and/or p21, proteins that inhibit cyclin-dependent kinases. In their model increased OGF and OGFr occurred at the protein level without equivalent transcriptional up-regulation.

3B. Cell-cycle control: p16, p21 and the G1/S checkpoint

Cells move through an organised sequence before dividing. G1 is a preparation stage; S is the stage in which DNA is copied. Cyclin-dependent kinases help a cell pass from one stage to the next. The proteins p16 and p21 can restrain those kinases. In OGF-responsive models, increased checkpoint restraint reduces the number of cells entering DNA synthesis.

This is primarily a cytostatic explanation: slowing proliferation. Other naltrexone experiments report apoptosis, or programmed cell death, and still others show G2/M arrest. These results can coexist because dose, exposure duration, cell type and partner drug differ. They should not be compressed into a claim that every LDN exposure kills cancer through the same pathway.

3C. Immune cells and the tumour environment

Cancer grows within a surrounding ecosystem that includes immune cells, blood vessels, connective tissue and signalling molecules. Some LDN models show changes in this ecosystem as well as direct effects on cancer cells.

Colorectal work reports increased M1-type macrophage markers and activation of apoptosis-related proteins. Cervical work reports reduced epithelial–mesenchymal transition and changes in tumour-associated macrophages and IL-10. The breast propranolol–naltrexone model reports enhanced NK-cell activity and altered inflammatory cytokines.

Macrophages are often described as M1-like or M2-like. These labels are useful shorthand for tendencies toward inflammatory/tumour-opposing or tissue-remodelling/tumour-supporting functions, but real tumours contain mixed and changing states. The informative claim is that a particular model shifted its macrophage markers and tumour behaviour—not that all macrophages must be pushed in one direction.

Natural killer cells can recognise and kill stressed or abnormal cells without the same antigen-specific recognition required by conventional T cells. Increased NK activity in animal work gives one rationale for combination studies. It is a functional immune observation in that model, rather than a clinical promise that LDN will raise every person's NK-cell count or activity.

3D. Toll-like receptors, microglia and inflammatory signalling

TLR4 is an innate immune sensor involved in inflammatory signalling. Naltrexone-related TLR4 effects have been explored particularly in microglia, the immune-support cells of the central nervous system. Signalling through adaptors such as MyD88 and TRIF can influence NF-kappaB, cytokines and inflammatory pain processing. This is part of the rationale for LDN research in central sensitisation and neuropathic symptoms.

The literature also discusses other Toll-like receptors, including TLR7–9, and IL-6-related effects. These are different experimental observations not one fully mapped clinical mechanism. The relative contribution of TLR signalling, endogenous opioid peptides and OGFr to an individual patient's response remains a research question.

3E. Angiogenesis, apoptosis and invasion-related pathways

In ovarian xenografts, LDN reduced DNA synthesis and angiogenesis. Colorectal experiments implicate Bax/Bcl-2, caspase-3 and PARP-related apoptosis. Cervical studies describe PI3K/AKT/mTOR-associated changes and reduced invasion-related behaviour.

For example, the 2024 review describes cervical work in which PI3K, PDK1 and mTOR protein changes but AKT changes were not so clear.

3F. Why dose and duration both matter

Some models show inhibition after short blockade and accelerated proliferation during sustained blockade. This is the experimental basis for interest in intermittent exposure. It does not establish that conventional-dose naltrexone causes cancer progression in people, nor does it identify a universal number of blockade-free hours for every tumour.

4. Evidence map by cancer type

Detailed Research Findings by Cancer Type

Ovarian Cancer: The Clearest Growth-Control Programme

The 2011 Experimental Biology and Medicine study examined naltrexone alone and with paclitaxel or cisplatin in ovarian cancer cells and mouse tumours. In tissue culture, six hours of exposure every two days reduced DNA synthesis and replication, whereas continuous exposure did not reproduce the same inhibitory pattern. Brief naltrexone exposure with either chemotherapy produced greater anticancer activity in the cell experiments.

In mice with established ovarian tumours, low-dose naltrexone repressed progression, with reduced DNA synthesis and angiogenesis rather than altered cell survival as the central mechanism. LDN plus cisplatin produced an additive inhibitory effect; the corresponding paclitaxel pairing did not show the same additional tumour-control effect in vivo. LDN also alleviated cisplatin-associated weight loss in the reported experiment.

The study found increased OGF and OGFr expression, connecting the animal findings to the proposed feedback mechanism. The separate 2011 mechanistic paper strengthened this connection by testing receptor/pathway dependence and p16/p21 involvement. A related Gynecologic Oncology paper also examined OGF and LDN in ovarian tumour progression.

Colorectal Cancer: Apoptosis, Macrophages and Chemotherapy Priming

Two strands should be separated. The colorectal macrophage/apoptosis work, summarised in the 2024 review, used SW480 and HCT116 cells and xenografts. Reported changes included increased pro-apoptotic Bax and caspase activity, reduced Bcl-2 and survivin, lower proliferative markers and increased M1-type macrophage features. The review reports some cell exposures as high as 1 mg/mL; sadly those experiments are not equivalent to the blood exposure after a few-milligram oral dose.

The second strand is Liu and colleagues' 2016 gene-expression and sequencing paper. Their terminology defined low-dose cell exposures as nanomolar concentrations, with typical comparisons of 1–10 nM versus 1–10 micromolar conventional experimental exposures. LDN changed genes involved in cell-cycle regulation, apoptosis and immune modulation in ways not reproduced by the higher experimental concentrations.

Continuous LDN exposure had little growth effect in several lines, whereas exposure followed by drug-free culture increased cell killing. Cells primed with LDN were more sensitive to subsequent chemotherapy. In a reported HCT116 oxaliplatin comparison, cell killing was 49 ± 7.0% with LDN priming versus 14 ± 2.4% without priming. These are cell-culture killing percentages, not patient response rates.

One schedule used 48 hours of naltrexone exposure before replacement with chemotherapy-containing medium. Oxaliplatin, gemcitabine and cyclophosphamide were among the experimental partners. The key finding was that low-concentration LDN priming increased the activity of all three chemotherapy partners—oxaliplatin, gemcitabine and cyclophosphamide—in both colorectal and lung cancer cells. The lower naltrexone concentration generally primed more effectively than the higher one. These laboratory findings highlight a potentially useful treatment principle: first change the cancer cell’s state to make it more vulnerable, then introduce chemotherapy.

Cervical Cancer: Invasion-Related Behaviour and the Immune Environment

The 2020 and 2021 cervical papers describe effects on epithelial–mesenchymal transition, migration and the PI3K/AKT/mTOR-associated network. The studies include HeLa and SiHa-related work, increased OGFr expression in selected lines and reduced migratory behaviour. In xenograft work, tumour-associated macrophage changes and lower IL-10 were part of the proposed link between direct cancer-cell changes and the surrounding immune environment. The slower cell division, reduced invasion-related behaviour and altered macrophage signalling represent distinct effects on tumour progression. The cervical cancer findings place LDN within this broader context and link it to changes in cancer-cell growth and migration plus changes in the surrounding immune environment.

Breast Cancer and the Direct Connection with Propranolol

Murugan, Rousseau and Sarkar's paper was published in 2021, not 2023 as some secondary summaries imply. It tested propranolol and naltrexone in MDA-MB-231, MDA-MB-468 and T47D breast cancer cells, followed by MDA-MB-231 xenografts in T-cell-deficient nude rats. The rationale was complementary adrenergic and opioid-related signalling, including evidence of receptor interaction in the cell models.

The combination reduced cell viability, colony formation, migration and invasion, with formal combination-index analysis supporting synergy in the tested cell assays. Cell-cycle findings included G2/M accumulation, with apoptosis-related changes involving Bcl-2-family proteins, cytochrome c and caspase-3. Much of the detailed laboratory work used 100 micromolar concentrations, far above the blood levels expected with the under-5 mg daily oral regimen discussed here. These findings show what the combination did at high laboratory concentrations; they do not establish that the same effects occur at low oral doses.

In rats, treatment began after tumours were established. Naltrexone 10 mg/kg and propranolol 10 mg/kg were injected subcutaneously daily, individually or together. The combination reduced tumour growth and imaging signal and changed NK-cell activity and inflammatory features. The paper reports approximate survival times of 28 days for controls, 45 for naltrexone, 40 for propranolol and 50 for the combination.

A separate 2013 triple-negative breast cancer paper investigated the OGF–OGFr axis. That study supports the relevance of the biological pathway in breast cancer, but OGF pathway activity, injected naltrexone/propranolol synergy and clinical low-dose oral naltrexone are still three distinct evidence categories.

LDN and Cannabidiol: Sequence Matters

Liu and colleagues' 2022 study tested LDN and cannabidiol (CBD) in cancer cells and mouse models. Simultaneous exposure had little effect on cell number, whereas sequential treatment was more active. LDN followed by CBD produced a reported 35% reduction in cell numbers compared with 22% when the order was reversed in the cited comparison.

Pretreatment also sensitised cells to chemotherapy. In mice, the paired pretreatment enhanced gemcitabine's activity, and animals receiving the pretreatment gained more weight in the reported comparison. The important idea is priming: the first intervention changes the cell state before the next arrives.

Pancreatic Cancer: The Alpha-Lipoic Acid/LDN Reports

Berkson, Rubin and Berkson published an initial pancreatic cancer case in 2006 and three additional cases in 2009 using an approach that combined intravenous alpha-lipoic acid (ALA) with oral LDN. The reports attracted interest because they described unusually long survival and striking scan changes in some individuals with advanced disease.

In the 2009 report, the original patient was described as alive and well 78 months after presentation. Among the three additional cases, one was reported alive and well at 39 months after presentation with pancreatic adenocarcinoma and liver metastases. Another had a PET scan described as showing no evidence of disease after five months of the protocol. A third, with a complex history including other cancers, had no PET evidence of cancer after four months according to the authors.

Lymphoma, Lung and Other Individual Observations

A 2007 report, Reversal of Signs and Symptoms of a B-Cell Lymphoma in a Patient Using Only Low-Dose Naltrexone, is frequently cited in the LDN literature. Later reviews describe complete radiological remission in a follicular lymphoma case. The title and reference are included here as a clinical observation; the full original treatment history was not independently reconstructed in this review, and inconsistent secondary dose descriptions were not used to create a dosing claim.

High-grade Glioma: The Randomised Supportive-Care Study

Peters and colleagues randomised 110 patients with high-grade glioma to LDN 4.5 mg nightly (54 patients) or placebo (56), starting on day 1 of radiation plus temozolomide and continuing for 16 weeks. Most participants had WHO grade IV disease under the classification used at the time. Primary outcomes focused on quality of life and fatigue.

Changes in quality of life and fatigue did not differ significantly between groups. The adverse-event profiles were similar and largely attributed to concurrent temozolomide. The earlier conference report also described no significant overall survival difference and greater sleepiness in the LDN group at 16 weeks. The conference abstract and 2022 full publication describe the same trial, not two independent studies.

This study gives useful human information about concurrent administration in a monitored chemoradiotherapy setting. Its principal result is that this schedule did not improve the supportive-care outcomes tested. It should neither be promoted as a positive anticancer trial nor used as a blanket answer to every different LDN combination or tumour type.

Cancer-related Pain: The 2025 MD Anderson Series

Malik, Ye and Chung reviewed 20 cancer patients prescribed LDN in a specialist pain service during 2022–2023. Nine had breast cancer. Ten had pain related to cancer burden and ten had treatment-related pain. A responder was someone whose record attributed improvement in the main pain complaint to LDN; this was not a tumour-response measure.

At the first follow-up, 16/20 patients (80%) were recorded as responders. At the second, 10/13 assessed patients (76.9%) were responders. Mean follow-up times were approximately 66 and 105 days. The denominator changed because only 13 were assessed at the second visit; 76.9% should not be presented as a result in all 20 patients.

The most common maximum titration dose was 3 mg/day, in nine patients; the overall maximum-dose range was 1.5–4.5 mg/day. Seven patients had therapy-related neuropathy and 71% of that subgroup reported a positive response at the first follow-up. Insomnia and gastrointestinal upset were reported early in two patients. By the second follow-up, three of 20 had discontinued: two for inadequate relief and one for diarrhoea.

5. Anticancer Combinations and Sequencing

Combination research is most useful when the partner, model, endpoint and exposure schedule are carried together. "Synergy" is a specific pharmacological interaction, not just a synonym for a hopeful combination.

Why There Is No Universal "Take It Before Chemotherapy" Rule

The laboratory sequence may involve removing naltrexone-containing medium completely before adding another agent. A person continues to metabolise and eliminate both parent drug and active metabolite, so swallowing a capsule a set number of hours before an infusion is not the same intervention. Human sequencing research needs pharmacokinetics and tumour-response measurements, not just calendar imitation.

6. Research Doses, Schedules and Formulation

LDN is a dose strategy rather than a separate registered drug. Common human reports use 3–4.5 mg once daily; definitions range more widely. The table records exposures that appear in the reviewed material, not a universal cancer dose.

Starting Low and Adjusting: What This Means

Clinical LDN literature often describes gradual titration to improve tolerability, rather than beginning at the eventual maintenance dose. Starting dose, increment size and interval vary between practices and indications. A single 1.5 → 3 → 4.5 mg ladder is therefore a familiar prescribing convention, not an oncology trial-validated sequence.

The useful questions are what the intended role is, which exposure the supporting study actually used, and what symptoms or outcomes would justify staying at a dose. A person tolerating 4.5 mg does not establish that more would improve cancer control. Conversely, the pain series shows that some clinical use occurs below 4.5 mg; that number is not a compulsory threshold for every goal.

Night-time Dosing, Morning Dosing and Drug-Free Days

Night-time administration is common and was used in the glioma trial. The reviewed oncology evidence does not establish that a particular clock time maximises anticancer activity. Sleep disruption or vivid dreams can make timing a practical discussion point. Whether to use daily dosing, alternate days or scheduled breaks is a separate question; no universal cycling calendar follows from the available studies.

Compounded Capsules, Liquids and Release Characteristics

Small strengths commonly require a compounding pharmacy. Immediate-release pills and capsules and appropriately prepared oral liquids can allow low-dose prescribing and smaller adjustments. Modified-release or depot preparations are not interchangeable with an immediate-release LDN because duration of exposure is key.

7. Absorption, Metabolism, CYP Enzymes and Interactions

8A. Established oral naltrexone pharmacology

These values largely come from conventional-dose oral pharmacology. They are useful background, but the label's dose proportionality data cover 50–200 mg, not a validated relationship across every low-dose oncology schedule. Human intratumoural naltrexone/6-beta-naltrexol exposure and OGFr engagement remain valuable research targets.

Is naltrexone a CYP-metabolised drug?

Naltrexone is not primarily cleared through the cytochrome P450 system. Reduction to 6-beta-naltrexol involves non-CYP cytosolic enzymes, including aldo-keto reductase pathways discussed in the literature; additional conjugation and extrahepatic metabolism occur. It should not be treated as if it has propranolol's CYP2D6/1A2/2C19 clearance profile.

The practical distinction is between metabolism of naltrexone itself, enzyme inhibition under experimental conditions, and a demonstrated change in the concentration of a co-administered cancer drug. Sharing a pathway name in a review is not enough to infer that LDN raises or lowers every medicine handled by that pathway.

Interaction map

8. Tolerability, Pain Planning and Practical Monitoring

LDN is generally well tolerated in the reviewed clinical literature. Commonly reported effects include vivid dreams, insomnia, nausea, gastrointestinal upset, headache or dizziness; they are often mild or transient. The glioma trial found similar overall adverse-event profiles between LDN and placebo. In the cancer-pain series, early adverse effects were uncommon, and three of 20 patients had discontinued by the second follow-up.

The essential issue: preserve good pain control

Naltrexone blocks opioid effects. Even a low dose can be relevant when a person is physically dependent on an opioid or needs reliable opioid analgesia. This includes tramadol, codeine, methadone and buprenorphine, not just morphine or fentanyl. Milligram-dose LDN should not be confused with ultra-low-dose experiments that deliberately combine extremely small antagonist amounts with opioids.

Conventional oral labelling recommends at least 7–10 opioid-free days after short-acting opioid dependence, with vulnerability potentially lasting up to two weeks after methadone or buprenorphine. These are label-based transition considerations, not a self-managed countdown for someone with cancer pain. The pain/prescribing team needs to decide whether a transition is appropriate and how analgesia will be maintained.

For planned procedures, agree beforehand whether naltrexone should be withheld, for how long and when it can be restarted after any opioid use. A universal LDN-specific perioperative interval has not been validated in oncology. In an emergency, tell the treating team immediately; do not try to overcome blockade with extra opioid doses.

A compact monitoring plan

• Before starting: record the purpose, complete medicine list, opioid exposure, existing liver and kidney results, formulation and baseline symptom measures.

• After initiation or a dose change: review sleep, dreams, nausea, bowel symptoms, dizziness, pain control and day-to-day functioning.

• If tumour control is the intended role: retain the usual cancer-specific imaging and assessment schedule; symptom improvement alone is not a tumour response.

• If symptom support is the goal: agree what meaningful improvement would look like—pain intensity, sleep continuity, walking, daily activities or reduced interference.

• For laboratory tests: coordinate with existing oncology monitoring rather than adding a rigid schedule for everyone; liver or renal disease and concurrent medicines may justify closer review.

• For new jaundice, dark urine, significant abdominal pain, severe vomiting/withdrawal symptoms or an allergic reaction: obtain prompt assessment rather than assuming a harmless adjustment effect.

Naltrexone itself is not an opioid agonist and is not associated with opioid-type dependence. A taper is not generally required to prevent naltrexone withdrawal. Stopping or restarting still needs coordination if it changes opioid sensitivity, pain treatment or a clinical-trial regimen. Pregnancy, breastfeeding, paediatric use and significant organ impairment require population-specific decisions; adult research schedules should not be transferred automatically.

9. Access and trial leads

Naltrexone products and prescribing rules differ between countries. Oral LDN generally involves off-label prescribing and low-strength compounding where available. Long-acting injections, naltrexone/bupropion combination products and research-grade chemicals are not equivalent substitutes for a prescribed low-dose oral preparation. Cross-border supply requires checking the local rules for both origin and destination.

Clinical-trial leads

10. Making the Research Useful: Tracking and Selection.

Define the Intended Role

The starting question is whether the proposed role is tumour growth restraint, sensitisation to a particular treatment, neuropathic pain support, or another symptom. These goals call for different outcomes. Someone can have better pain control without tumour shrinkage, or stable scans without a noticeable change in symptoms. Neither should be substituted for the other.

For a study-support library, the strongest structure is to record each claim as a short chain: actual agent → dose/exposure → tumour/model → partner and sequence → measured outcome. This protects useful discoveries from being diluted by broad claims and helps clinicians see which part of a study is relevant to a particular situation.

A Simple Discussion and Tracking Sheet

Can Biomarkers Identify Likely Responders?

OGFr expression, OGF levels, classical opioid receptors, inflammatory profiles and immune-cell features are plausible research markers. No validated routine test identified in this review selects cancer patients for LDN or defines an anticancer dose. A pathway being present is a starting point, not a complete predictor: exposure, downstream cell-cycle machinery, tumour heterogeneity and the treatment partner also matter.

Likewise, a gene mutation in PI3K/AKT signalling does not automatically predict LDN sensitivity. Pathway-modulation findings can generate a hypothesis for a trial, but do not make LDN interchangeable with a drug designed to inhibit a specific mutated target.

A Grounded Reason for Interest

LDN brings together a credible growth-regulation pathway, several converging experimental observations, unusual clinical reports and an accessible repurposing concept. Its most interesting possibilities are mechanism- and partner-specific: restoring a growth brake, changing the surrounding immune environment, or priming cells for another treatment. A useful hopeful account keeps those possibilities visible and specific, while allowing each study to speak at its actual evidence level.

Sources and further reading

Section-to-source guide

1. Ciwun M, Tankiewicz-Kwedlo A, Pawlak D. Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy. Cancers. 2024;16(6):1240. DOI: 10.3390/cancers16061240.

https://www.mdpi.com/2072-6694/16/6/1240

Source role: Cancer-focused review used for the overall evidence map, cervical/colorectal and additional combination studies. Some mechanistic and pharmacology statements require qualification; not a substitute for every original paper.

2. Liu WM, Dalgleish AG. Naltrexone at low doses (LDN) and its relevance to cancer therapy. Expert Review of Anticancer Therapy. 2022;22(3):269–274. DOI: 10.1080/14737140.2022.2037426.

https://pubmed.ncbi.nlm.nih.gov/35107043/

Source role: Mechanistic review covering Toll-like receptors, immune modulation and signalling/priming hypotheses.

3. Liubchenko K, Kordbacheh K, Khajehdehi N, et al. Naltrexone’s Impact on Cancer Progression and Mortality: A Systematic Review of Studies in Humans, Animal Models, and Cell Cultures. Advances in Therapy. 2021;38:904–924. Published online 18 December 2020. DOI: 10.1007/s12325-020-01591-9.

https://link.springer.com/article/10.1007/s12325-020-01591-9

Source role: Systematic review spanning different evidence levels and doses. Its publication count is not a count of independent human LDN trials.

4. Gouda AHK, Aitcheson NEC, Steadman KJ. Low-Dose Naltrexone: What is the Evidence? A Narrative Review. Advances in Therapy. 2026;43:2852–2870. DOI: 10.1007/s12325-026-03612-5.

https://pmc.ncbi.nlm.nih.gov/articles/PMC13290944/

Source role: Broad human LDN review, searched through February 2026. Oncology section includes glioma and case literature. A correction is flagged on the article; correction text was not separately audited. Used alongside primary sources, not as a sole basis for consequential claims.

5. Donahue RN, McLaughlin PJ, Zagon IS. Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin. Experimental Biology and Medicine. 2011;236(7):883–895. DOI: 10.1258/ebm.2011.011096.

https://journals.sagepub.com/doi/10.1258/ebm.2011.011096

Source role: Primary abstract: six-hour intermittent tissue-culture exposure; mouse tumour, angiogenesis and cisplatin/paclitaxel findings.

6. Malik A, Ye A, Chung M. Low Dose Naltrexone for Refractory Cancer Pain: Case Series of Initial Safety and Effectiveness. Journal of Pain and Symptom Management. 2025;70(6):e492–e497. DOI: 10.1016/j.jpainsymman.2025.08.015.

https://mdanderson.elsevierpure.com/en/publications/low-dose-naltrexone-for-refractory-cancer-pain-case-series-of-ini/

Source role: Institutional primary abstract: 20 patients, changing follow-up denominators, patient-attributed symptom response and reported adverse effects.

7. Zagon IS, Porterfield NK, McLaughlin PJ. Opioid growth factor–opioid growth factor receptor axis inhibits proliferation of triple negative breast cancer. Experimental Biology and Medicine. 2013;238(6):589–599. DOI: 10.1177/1535370213489492.

https://doi.org/10.1177/1535370213489492

Source role: Pathway paper identified through the systematic review; not an oral LDN clinical trial. Detailed original-paper extraction not completed.

8. Liu WM, Scott KA, Dennis JL, Kaminska E, Levett AJ, Dalgleish AG. Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy. International Journal of Oncology. 2016;49:793–802. DOI: 10.3892/ijo.2016.3567.

https://www.spandidos-publications.com/10.3892/ijo.2016.3567

Source role: Primary study: nanomolar versus micromolar exposures, gene expression and sequential chemotherapy priming. Reported cell killing is not a patient response rate.

9. Murugan S, Rousseau B, Sarkar DK. Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer. Cancers. 2021;13(19):4858. DOI: 10.3390/cancers13194858.

https://pmc.ncbi.nlm.nih.gov/articles/PMC8508249/

Source role: Primary methods/results reviewed. Cell experiments largely used 100 micromolar; rats received 10 mg/kg of each drug subcutaneously. Welfare-limited survival endpoint; not clinical oral LDN.

10. Donahue RN, McLaughlin PJ, Zagon IS. Low-dose naltrexone targets the opioid growth factor–opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model. Experimental Biology and Medicine. 2011;236(9):1036–1050. DOI: 10.1258/ebm.2011.011121.

https://journals.sagepub.com/doi/full/10.1258/ebm.2011.011121

Source role: Primary mechanistic findings verified through indexed abstract/full-text summaries: pathway dependence, p16/p21 and protein-level upregulation.

11. Liu N, Ma M, Qu N, et al. Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo. International Immunopharmacology. 2020;86:106718.

https://doi.org/10.1016/j.intimp.2020.106718

Source role: Primary study identified and summarised through the 2024 cancer review; detailed original methods not independently audited.

12. Liu N, Yan L, Shan F, et al. Low-dose naltrexone plays antineoplastic role in cervical cancer progression through suppressing PI3K/AKT/mTOR pathway. Translational Oncology. 2021;14:101028.

https://doi.org/10.1016/j.tranon.2021.101028

Source role: Primary study identified through the 2024 review. Protein/pathway observations should not be relabelled as selective clinical PI3K inhibition.

13. Liu WM, Hall NK, Liu HSY, Hood FL, Dalgleish AG. Combination of cannabidiol with low-dose naltrexone increases the anticancer action of chemotherapy in vitro and in vivo. Oncology Reports. 2022;47(4):76. DOI: 10.3892/or.2022.8287.

https://openaccess.sgul.ac.uk/id/eprint/114166/

Source role: Institutional primary abstract: sequence dependence, chemotherapy sensitisation and mouse gemcitabine experiment.

14. Berkson BM, Rubin DM, Berkson AJ. The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integrative Cancer Therapies. 2006;5:83–89. DOI: 10.1177/1534735405285901.

https://doi.org/10.1177/1534735405285901

Source role: Initial combination case, identified through the systematic review and subsequent primary report; not an independent controlled comparison.

15. Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integrative Cancer Therapies. 2009;8(4):416–422. DOI: 10.1177/1534735409352082.

https://pubmed.ncbi.nlm.nih.gov/20042414/

Source role: Primary abstract used for individual survival/follow-up and PET descriptions. Combination cases cannot isolate LDN.

16. Reversal of Signs and Symptoms of a B-Cell Lymphoma in a Patient Using Only Low-Dose Naltrexone. Integrative Cancer Therapies. 2007. DOI: 10.1177/1534735407306358.

https://doi.org/10.1177/1534735407306358

Source role: Case-report title and DOI verified through review references. Full original text was not retrievable; inconsistent secondary dose details were omitted.

17. Peters KB, Affronti ML, Woodring S, et al. Effects of low-dose naltrexone on quality of life in high-grade glioma patients: a placebo-controlled, double-blind randomized trial. Supportive Care in Cancer. 2022;30:3463–3471. DOI: 10.1007/s00520-021-06738-0.

https://link.springer.com/article/10.1007/s00520-021-06738-0

Source role: Primary publication: 110 randomised, 54 on LDN and 56 placebo. Earlier conference report from the same trial: https://pmc.ncbi.nlm.nih.gov/articles/PMC4639177/ ; the two reports must not be double-counted.

18. DailyMed / US National Library of Medicine. Naltrexone hydrochloride tablets, film coated; SpecGx LLC. Label updated 4 September 2026.

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=06ff2d5a-e62b-4fa4-bbdb-01938535bc65

Source role: Regulator-hosted oral product label: absorption, bioavailability, half-lives, elimination, opioid antagonism, liver effects and transition considerations. Most pharmacokinetic data are conventional-dose data.

19. DailyMed / US National Library of Medicine. Naltrexone for extended-release injectable suspension: prescribing information.

https://dailymed.awsprod.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6de5637f-d527-4228-af1a-3aae71155cb5

Source role: CYP substrate/inhibition/induction statements from regulator-hosted label. Used for the metabolism discrepancy, not as evidence that depot exposure matches oral LDN.

20. ClinicalTrials.gov. NCT01650350: Low Dose Naltrexone for Metastatic Melanoma, Castrate Resistant Prostate Cancer and Renal Cancer.

https://clinicaltrials.gov/study/NCT01650350

Source role: Protocol: 5 mg/day, 28-day cycles, response and toxicity endpoints. Live status and complete results not verified in retrieved text.

21. ClinicalTrials.gov. NCT05968690: Naltrexone and Propranolol Combined With Immunotherapy.

https://clinicaltrials.gov/study/NCT05968690

Source role: Rutgers phase I melanoma protocol. Retrieved cohorts include 4.5, 9 and 25 mg naltrexone with propranolol and ipilimumab/nivolumab. No efficacy results or current site recruitment confirmed.

22. Therapeutic Goods Administration. Australian Register of Therapeutic Goods: NALTREXONE LUPIN naltrexone hydrochloride 50 mg film coated tablets, ARTG 128710.

https://www.tga.gov.au/resources/artg/128710

Source role: Australian registration record. Does not establish current pharmacy stock or a low-dose oncology indication.

23. Pharmaceutical Benefits Scheme. Naltrexone hydrochloride 50 mg tablets, 30; item 8370M.

https://www.pbs.gov.au/medicine/item/8370m

Source role: Public listing retrieved: Authority Required (Streamlined); ARX-Naltrexone and Naltrexone GH listed. Full restriction wording was not exposed in retrieved text; subsidy eligibility is not inferred.

Template provenance: Propranolol in oncology, consolidated working report Version 2, 30 October 2026, supplied by the user. Used for structure, breadth and the study-support-library format; not treated as an LDN efficacy source.