Clival chordoma research
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LDN, vitamin D, immunity

Research agent report, 4 September 2026. Sources: PubMed (NCBI E-utilities queries run today; hit counts recorded), ClinicalTrials.gov API v2 (queried today), the UK naltrexone Summary of Product Characteristics (Adepend, medicines.org.uk), NHS and British Dietetic Association vitamin D pages, and published trials. No prognosis or survival figures. Where a statement is inference or clinical judgement rather than citation it is labelled. No em dashes. The web-search budget for this session was exhausted before this thread started, so some UK pages (NICE CKS, Royal Osteoporosis Society guideline, LDN Research Trust opioid pages, Dickson Chemist price list) could not be fetched live; where I rely on my knowledge of those documents I say so and mark it "verify".

Patient context: 34-year-old woman, 51 kg after 12 to 15 percent unintentional weight loss, 3.8 cm invasive clival mass with partial basilar artery encasement and right third and fourth nerve palsies, working diagnosis chordoma (chondrosarcoma the lookalike), biopsy pending, expected plan endoscopic surgery then proton beam therapy. On diclofenac suppositories, omeprazole and paracetamol; has needed as-needed morphine on the ward; travelling to Southampton tonight with uncontrolled trigeminal-distribution pain and very likely to need opioid analgesia again; a nerve-pain drug and possibly dexamethasone are likely. Her partner heard a podcast promoting low-dose naltrexone (LDN), very high vitamin D3 levels and "getting the innate immune system functioning better".

0. The short version

  1. LDN is the wrong drug for the patient this month, whatever one thinks of the cancer claims, because it is an opioid blocker. Naltrexone at any dose occupies the receptor that morphine, oxycodone, codeine and tramadol need. Taken alongside them it blunts or abolishes pain relief; taken by someone who has been on regular opioids it can precipitate withdrawal; taken in the days before surgery it makes anaesthetic and post-operative pain control harder and riskier. The licensed product information says opioid analgesics are a contraindication and warns that overriding the block with bigger opioid doses "might result in acute and possibly fatal opioid intoxication". Nothing about LDN's cancer evidence comes close to justifying that trade while she is in uncontrolled trigeminal pain and heading for skull base surgery.

  2. The human anticancer evidence for LDN is, put plainly, case reports, one small uncontrolled prostate series by the patent holders, two tiny 1990s and 2002 studies that used full-dose (100 mg) naltrexone, and one properly randomised trial (110 glioma patients, 2022) that was negative for its endpoints. No randomised trial has ever shown LDN changes any tumour outcome. The "half the chemotherapy dose" claim traces to a 2016 dish experiment in colorectal cancer cells by a group that holds patents on the idea, and a 2025 study in oral cancer cells found the opposite (antagonism) across the full dose range. Chordoma and chondrosarcoma: PubMed has zero papers on naltrexone or opioid growth factor with either.

  3. Vitamin D: test her, replace to the normal range, keep her there. Do not megadose. The best randomised evidence (VITAL, 25,871 people; the Kuznia 2023 individual-patient meta-analysis of 14 trials, 104,727 people) shows that ordinary daily doses may modestly reduce cancer death in the general population, that cancer incidence is unchanged, and that large infrequent bolus dosing does not help and in D-Health (21,315 people) trended the wrong way. No trial in cancer patients has shown high-dose beats standard-dose (SUNSHINE 2019 suggestive, SOLARIS 2026 phase 3 null). "A hundred" is a good target if it means 100 nmol/L; it is above the toxicity threshold of every UK and international guideline if it means 100 ng/mL (250 nmol/L). For a 51 kg woman on an NSAID and probably about to start dexamethasone, the kidney and calcium risks of megadosing are real and the cancer benefit is nil.

  4. "Boosting the innate immune system" is not a coherent treatment goal for chordoma and no supplement sold for it has evidence in this disease. The things that genuinely support immune function are sleep, pain control, adequate protein and calories, gentle activity and up-to-date vaccination. The one mushroom product with real randomised evidence (PSK, a Japanese prescription extract) was tested only in gastric and colorectal cancer alongside chemotherapy, is not the same as the turkey tail capsules sold online, and has no chordoma data. Antioxidant supplements at high dose during radiotherapy were associated with more recurrence in a 540-patient head and neck trial, which is the closest evidence to her situation and argues for caution with anything "immune" during protons.

  5. Timing rule for the family: nothing that antagonises opioids while she needs pain control or in the 3 days before surgery; a vitamin D blood test now and normal-range repletion is cheap and reasonable; immune supplements are not, and some interfere with treatment. Every supplement, including vitamin D dose, should be on the medication list the Southampton team sees.

1. Low-dose naltrexone (LDN)

1a. What it is and the proposed mechanisms

Naltrexone is a pure opioid receptor antagonist licensed at 50 mg daily to help people stay off heroin or alcohol. "Low-dose naltrexone" means roughly 1 to 4.5 mg at night, about a tenth of the licensed dose, used off-label. Naltrexone's half-life is about 4 hours and its active metabolite 6-beta-naltrexol about 13 hours (Toljan and Vrooman 2018, Med Sci, PMID 30248938, PMC6313374).

History. Ian Zagon and Patricia McLaughlin (Penn State) reported in Science in 1983 that in mice inoculated with neuroblastoma, a small daily dose of naltrexone (0.1 mg/kg, which blocked opioid receptors for 4 to 6 hours a day) reduced tumour incidence and delayed tumour appearance, while a large dose (10 mg/kg, blocking receptors all day) did the reverse and accelerated the tumours (Zagon and McLaughlin 1983, Science 221:671, PMID 6867737). That single observation is the origin of the whole "low dose, intermittent blockade" idea. Bernard Bihari, a New York physician, began giving 3 mg naltrexone at night to people with HIV in the mid-1980s and later to people with cancer; his published record is a 1995 conference-style paper on HIV (Bihari 1995, AIDS Patient Care, PMID 11361353) and a 2013 interview (Altern Ther Health Med, PMID 23594453). None of Bihari's cancer claims were published as controlled studies.

Proposed mechanisms. Four are usually cited; all are plausible biology, none is proven to matter in a human tumour. - Opioid growth factor (OGF) and its receptor (OGFr). Zagon's group identified [Met5]-enkephalin as a growth-inhibiting peptide acting through a nuclear receptor, OGFr, that tonically slows cell replication. Brief receptor blockade by LDN is proposed to cause a compensatory rise in OGF and OGFr, so that when the blocker wears off the cells are hit with more growth inhibition (McLaughlin and Zagon 2015, Biochem Pharmacol, PMID 26119823, "Duration of opioid receptor blockade determines biotherapeutic response"). Continuous blockade (full-dose naltrexone) removes the inhibition and, in their model, promotes growth. This is why the dose and timing are said to matter. - Transient blockade and endorphin rebound. A few hours of blockade is said to raise endogenous endorphin and enkephalin production, which then act on immune cells once the receptors are free again (LDN Research Trust, "How LDN works"; Toljan 2018). - Toll-like receptor 4 (TLR4) antagonism. Hutchinson and colleagues showed that both mirror-image forms of naltrexone and naloxone reverse neuropathic pain in rodents through TLR4 on glial cells, independently of opioid receptors (Hutchinson 2008, Eur J Neurosci, PMID 18662331). This underpins the "glial modulator" and "anti-inflammatory" story (Younger, Parkitny and McLain 2014, Clin Rheumatol, PMID 24526250). In human blood cells, however, Cant, Dalgleish and Allen found naltrexone reduced IL-6 and TNF-alpha after stimulation of the intracellular TLR7, TLR8 and TLR9, but had no effect via TLR4 (Cant 2017, Front Immunol, PMID 28744288). - Immune modulation. Shifts in T-cell subsets, natural killer cell activity and cytokines have been reported in small studies and in vitro (Lissoni 2002, below; Kazemi 2023 Iran J Immunol, PMID 37151015, in stem cells).

The Liu 2016 paper and the "priming" claim. Liu, Scott, Dennis, Kaminska, Levett and Dalgleish (St George's, London) treated cancer cell lines with naltrexone at low and at standard concentrations and profiled gene expression (Liu 2016, Int J Oncol 49:793, PMID 27279602; published online June 2016, print August 2016; the family may have heard it cited as 2017). Findings, verbatim from the abstract: LDN "had a selective impact on genes involved with cell cycle regulation and immune modulation"; pro-apoptotic genes BAD and BIK1 rose only after LDN; "continuous treatment with LDN had little effect on growth in different cell lines", but a schedule of LDN followed by a drug-free phase "resulted in enhanced cell killing"; and cells pre-treated with LDN were more sensitive to chemotherapy. The headline number: priming HCT116 cells (a human colorectal cancer line) with LDN before oxaliplatin raised cell killing to 49 percent versus 14 percent without priming, and priming with standard-dose naltrexone gave 32 percent. The same group later showed in cell lines and in mice that LDN followed by cannabidiol, then chemotherapy (gemcitabine), reduced cell numbers more than either agent alone (Liu 2022, Oncol Rep, PMID 35179218), and wrote the review that argues for trials (Liu and Dalgleish 2022, Expert Rev Anticancer Ther, PMID 35107043). Declared conflict of interest: Dalgleish and Liu are named inventors on two US patents, "Treatment of cancer with naltrexone" (US 9,895,438) and "Priming of cancer cells with low dose naltrexone" (US 11,065,245) (stated in Dalgleish and Liu 2022, Oncol Lett, PMID 35761946).

What those experiments did not show: any effect in a chordoma or chondrosarcoma line; any effect on a tumour in a person; or that a halved chemotherapy dose with LDN equals a full dose without. And a 2025 replication attempt in oral squamous cancer cells found that LDN alone did nothing consistent, that some short pre-treatment schedules helped cisplatin or docetaxel at selected doses, but that "the full dose response demonstrated antagonism between NTX and chemotherapy, independent of the dosing schedule", which the authors note "contrast[s] with previous findings in other cancers" (Kazmi 2025, Int J Mol Sci, PMID 41226687). Dish results in this field are not reproducible across cell types.

1b. Human evidence in cancer

Everything found on PubMed and ClinicalTrials.gov, in order of evidential weight.

Randomised trials. - Peters 2022, Duke University: 110 patients with high-grade glioma randomised to LDN 4.5 mg at night or placebo from day 1 of radiotherapy plus temozolomide for 16 weeks; endpoints quality of life and fatigue. Result: "LDN has no effect on QOL and fatigue in HGG patients during concurrent chemotherapy and radiation therapy"; adverse events similar to placebo (Support Care Cancer 30:3463, PMID 35001215; NCT01303835, results posted 2015). Not designed to test tumour control, and did not report a tumour signal. This is the only completed placebo-controlled randomised trial of LDN in cancer patients. - Lissoni 1993, Milan: 21 patients with high-grade glioma randomised to radiotherapy alone or radiotherapy plus naltrexone 100 mg every other day, i.e. full dose, not LDN. Tumour regression rate not significantly different; a survival difference was reported at one year in a trial of 21 people (Tumori 79:198, PMID 8236504). Too small to mean anything, and it is not the low-dose regimen. - Lissoni 2002: 14 patients with untreatable metastatic solid tumours in a cross-over study of interleukin-2 plus melatonin with or without naltrexone 100 mg on alternate days; outcome was lymphocyte counts, not tumour response (Neuro Endocrinol Lett 23:341, PMID 12195238; and PMID 12080288). Again full dose, and a blood-count endpoint.

Registered trials (ClinicalTrials.gov, queried 4 September 2026). - NCT01650350, LDN for metastatic melanoma, prostate and renal cancer, phase 2: terminated after 7 patients. - NCT00379197, naltrexone in hormone-refractory breast cancer, phase 2: terminated after 13 patients. - NCT02137252, naltrexone for radiotherapy fatigue in breast cancer: terminated after 3. - NCT05968690, naltrexone plus propranolol with checkpoint immunotherapy in advanced melanoma, phase 1, 12 patients, recruiting (Yale). A safety study of a combination, no efficacy data yet. - NCT07224009, LDN for fatigue in prostate cancer on androgen deprivation, phase 2, not yet recruiting (start August 2026). A symptom trial. - Nothing registered in chordoma, chondrosarcoma, sarcoma or skull base tumours.

Case reports and series. - Burton Berkson (New Mexico) with intravenous alpha-lipoic acid plus LDN: one pancreatic cancer with liver metastases (2006, Integr Cancer Ther, PMID 16484716), one B-cell lymphoma on LDN alone (2007, PMID 17761642), three further pancreatic cases (2009, PMID 20042414), one renal cell carcinoma (2018, PMID 29258346). These are single patients, no controls, several also had conventional treatment, and the same author reports all of them. - Dalgleish and Liu 2022: six prostate cancer patients given a heat-killed mycobacterium (IMM-101), "correction of vitamin D3 levels", bromelain and LDN; PSA falls and stable scans described (Oncol Lett, PMID 35761946). Uncontrolled, six patients, patent holders. - Malik 2025, MD Anderson: 20 cancer patients given LDN for refractory cancer pain (not for the tumour); 16 of 20 reported improvement at first follow-up; minor side effects (insomnia, GI upset); 3 stopped. Chart review, no controls (J Pain Symptom Manage, PMID 40849024). Relevant to the patient only as a pain adjunct, and only for someone not on opioids. - A veterinary case series (2026, PMID 41819128) and a Cureus dermatology report make up the 2026 literature; there is no new human anticancer trial in 2024 to 2026.

The OGF peptide itself (not naltrexone) has been given intravenously in trials: a phase 1 in pancreatic cancer (Smith 2004, Anticancer Drugs, PMID 15014352), a phase 2 compared to historical controls (Smith 2010, Open Access J Clin Trials, PMID 20890374; historical-control design, so not proof of benefit) and a 2025 phase 1 in liver cancer showing tolerability only (Kimchi 2025, Cancer Invest, PMID 40196893). This is Zagon's own line of work and it has not progressed to a randomised trial in 20 years.

What the human anticancer evidence amounts to. No randomised trial has shown LDN affects tumour growth, response, recurrence or survival in any cancer. The one adequately sized placebo-controlled trial (glioma) was negative for the endpoints it measured. The positive material is case reports and a six-patient series by people with a financial stake. A 2026 narrative review across all indications concluded that "early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials" and that "current evidence does not support routine clinical use" (Gouda 2026, Adv Ther, PMID 42060160). That is the fair summary for cancer too.

1c. Human evidence in other conditions, and what it says about the anti-inflammatory claim

On the "potent anti-inflammatory" claim specifically. The human data are: an 8-woman single-blind fibromyalgia study in which multiple plasma cytokines fell over 8 weeks of LDN (Parkitny and Younger 2017, Biomedicines, PMID 28536359), and in-vitro cytokine suppression via TLR7 to 9 in blood cells (Cant 2017). No randomised trial has shown LDN lowers C-reactive protein or any inflammatory marker against placebo. "Potent" is not a word the evidence supports; "possibly mildly immunomodulatory, with small and inconsistent clinical effects" is.

1d. Chordoma and chondrosarcoma: PubMed, 4 September 2026

There is no laboratory, animal or human data on LDN or OGF in chordoma or chondrosarcoma. Anyone who says LDN works in chordoma is extrapolating from colorectal cancer cells.

1e. The critical safety issue for the patient: naltrexone blocks opioids

This is the part that matters tonight.

What naltrexone does. It sits on mu-opioid receptors and stops morphine, oxycodone, codeine, dihydrocodeine, tramadol, fentanyl and buprenorphine from acting. At 50 mg the block lasts 24 to 72 hours. At 4.5 mg it is shorter, but with a 13-hour active metabolite the receptor is not clear for most of the night and the next morning (pharmacokinetics from Toljan 2018; the duration at low dose is inference from those half-lives, and the LDN literature itself says the block lasts several hours).

What the licensed product information says (Adepend 50 mg naltrexone SmPC, medicines.org.uk, product 3559; the 50 mg licence, since there is no licensed low-dose product): - Contraindicated in "patients taking opioid analgesics", patients on methadone, and anyone with a positive urine opioid test. Must not be given to opioid-dependent patients because withdrawal will be precipitated. - Before starting, the patient must be opioid-free for "about 5 to 7 days for heroin and at least 10 days for methadone", confirmed if necessary with a naloxone challenge. - If opioid analgesia is needed in an emergency, "the dose needed may be higher than normal" and respiratory depression will be "more profound and longer lasting"; trying to override the block "might result in acute and possibly fatal opioid intoxication". - Liver: liver function tests before and during treatment. - Common adverse effects at 50 mg: headache, restlessness, abdominal pain, nausea, vomiting, anxiety, insomnia, joint and muscle pain.

What that means for the patient, step by step. 1. Now, with uncontrolled trigeminal pain and as-needed morphine. If she took LDN at night, her morphine would work less or not at all for the following hours. She would be in more pain, and a well-meaning nurse or doctor giving repeated doses to "get on top of it" would be loading her with opioid that starts to act all at once when the block wears off. That is the "possibly fatal opioid intoxication" scenario in the licence. LDN and as-needed morphine cannot coexist. 2. If she is put on a regular background opioid (modified-release morphine or oxycodone, which thread 8 argues is the kindest option for her thinking). After even a week or two of regular dosing there is physical dependence; an antagonist then precipitates withdrawal (sweating, cramps, vomiting, agitation, a surge in pain). The licence's opioid-free interval before starting naltrexone is 5 to 10 days. The LDN community's own guidance is the same in spirit: taper off opioids and wait, typically a week or more, before the first LDN dose (LDN Research Trust patient guidance; I could not fetch the page live today, verify). 3. Surgery and anaesthesia. Skull base surgery uses opioids during and after the operation. Anaesthetic guidance for patients on oral naltrexone is to stop it 72 hours before elective surgery so that opioids will work, and to plan multimodal non-opioid analgesia if that cannot be done (Harrison, Kornfeld and Aggarwal, Anesthesiol Clin 2018, PMID 30092933, and 2025 update, PMID 41233100). For low-dose the common advice from prescribers is to stop at least 24 to 72 hours before surgery and to tell the anaesthetist (inference from the half-lives and the perioperative literature; the LDN organisations' pages could not be fetched today). A patient who forgets, or whose team does not know, has unpredictable pain control after a craniotomy or endoscopic skull base operation. Also note the reverse problem: the licence warns that once the block wears off, opioids given to overcome it act fully, so post-operative respiratory depression is harder to predict. 4. Codeine and tramadol count. Co-codamol, codeine linctus, dihydrocodeine and tramadol are all blocked. So is the anti-diarrhoeal loperamide, which works on gut opioid receptors (inference from pharmacology; a practical point if opioids cause constipation then loperamide is not the issue, but it matters if she gets diarrhoea from antibiotics). 5. Dexamethasone. No pharmacokinetic interaction. Both cause insomnia; LDN at night is known for sleep disturbance and vivid dreams in the first weeks (trial reports summarised in Toljan 2018: vivid dreams and insomnia at initiation, improved by morning dosing or lower dose; in an MS cohort 6 percent insomnia and 5 percent nightmares). Stacking it on dexamethasone would make sleep, which is already her scarcest resource, worse. 6. Gabapentinoids, duloxetine, nortriptyline, oxcarbazepine. No known pharmacokinetic interactions with naltrexone. One small case series in post-traumatic trigeminal neuropathic pain found LDN plus an SNRI gave lower pain scores than LDN plus other drugs, in 12 people, retrospective (Ananthan 2025, Quintessence Int, PMID 40590142). That is the only trigeminal-pain LDN literature and it is in people not taking opioids. 7. Liver. The 50 mg licence carries a liver warning; at 4.5 mg the exposure is a tenth and the 2019 meta-analysis of 89 placebo-controlled trials at all doses found no excess of serious adverse events (Bolton 2019, BMC Med, PMID 30642329). But that review explicitly excluded studies in opioid users "owing to possible opioid/opioid antagonist interactions", which is exactly her category. LDN's good safety record is a record in people not taking opioids. 8. Timing summary. LDN is not compatible with her care until she has been opioid-free for at least a week, is not within 3 days of any operation or procedure that may need opioid analgesia, and her surgical, oncology and pain teams all know. Realistically that is after surgery and recovery, and possibly not until after proton therapy, since dexamethasone and analgesic needs during radiotherapy are unpredictable. Judgement, not citation: the earliest sensible moment to even discuss it is when she is off opioids and stable, and the honest reason to discuss it then would be pain, not the tumour.

1f. UK access and cost

LDN has no UK licence at any dose. It is prescribed privately as an unlicensed "special" (compounded capsules or liquid, or the 50 mg tablet dissolved in water) by doctors willing to take responsibility for off-label use. The main routes: Dickson Chemist in Glasgow (private LDN prescription department, LDN Research Trust-certified, consultation booking and repeat prescription service; 0141 404 6545, fetched today; prices not shown on the page); Clinic 158 (an online platform connecting patients to private prescribers; new consultation from £50, repeat prescription from £40, fetched today; LDN pricing not shown); the LDN Research Trust's prescriber and pharmacist directories (ldnresearchtrust.org, fetched today). Typical cost from my knowledge of these services, verify: roughly £20 to £40 a month for the drug plus the consultation fees. Some NHS pain clinics will prescribe it for fibromyalgia-type pain, rarely.

1g. Verdict on LDN

Cheap, generally safe in people who do not take opioids, mildly interesting biology, no human evidence that it affects any cancer, zero data in chordoma, one negative randomised cancer trial, and a direct pharmacological conflict with the pain relief and anaesthesia the patient needs over the coming weeks. Not now. If the family want to revisit it, the right moment is after surgery and radiotherapy, off opioids, with the pain team, and for pain rather than for the tumour.

2. Vitamin D3

2a. Observational association versus trial evidence

The association. Dozens of cohort studies find that people with low 25-hydroxyvitamin D at diagnosis do worse across many cancers. This is real but confounded: illness, weight loss, being indoors, inflammation and poor nutrition all lower vitamin D, so low vitamin D is partly a marker of being ill rather than a cause. The advocacy literature (for example Wimalawansa 2025, Nutrients, PMID 40732958, which argues for keeping levels above 100 nmol/L) rests mainly on these observational data and dismisses the null trials as badly designed; that is a minority position.

The trials. - VITAL (Manson 2019, N Engl J Med 380:33, PMID 30415629): 25,871 US adults over 50, vitamin D3 2000 IU daily versus placebo, 5.3 years. Invasive cancer incidence unchanged (HR 0.96, 95 percent CI 0.88 to 1.06). Death from cancer HR 0.83 (0.67 to 1.02), not statistically significant. No excess hypercalcaemia. Secondary analysis: metastatic or fatal cancer reduced (HR 0.83, 0.69 to 0.99), with the effect confined to people of normal weight (HR 0.62) (Chandler 2020, JAMA Netw Open, PMID 33206192). The patient is 51 kg, so if anything she is in the subgroup where the daily-dose signal looked strongest; note that this is a subgroup of a secondary endpoint. - D-Health (Neale 2022, Lancet Diabetes Endocrinol 10:120, PMID 35026158): 21,315 Australians aged 60 to 85, 60,000 IU once a month versus placebo, 5 years; mean 25(OH)D reached 115 nmol/L versus 77. All-cause mortality HR 1.04; cancer mortality HR 1.15 (0.96 to 1.39), and 1.24 (1.01 to 1.54) when the first two years were excluded. The authors: "Point estimates and exploratory analyses ... were consistent with an increased risk of death from cancer" and "this dosing regimen might not be appropriate in people who are vitamin D-replete". Cancer incidence: no difference (Neale 2025, J Steroid Biochem Mol Biol, PMID 40096917). - Meta-analyses. Keum 2019 (Ann Oncol, PMID 30796437): 10 trials, incidence unchanged; 5 trials, cancer mortality RR 0.87 (0.79 to 0.96), "largely attributable to interventions with daily dosing"; no extra benefit above 100 nmol/L attained. Keum 2022 (Br J Cancer, PMID 35676320): daily dosing RR 0.87 for mortality, bolus dosing no benefit; the incidence benefit of daily dosing limited to normal-weight people. Kuznia 2023 (Ageing Res Rev, PMID 37004841), the individual-patient-data meta-analysis of 14 trials and 104,727 people: overall RR 0.94 (0.86 to 1.02), not significant; daily regimens RR 0.88 (0.78 to 0.98); bolus regimens RR 1.07 (0.91 to 1.24). Petrelli 2024 umbrella review (Clin Nutr ESPEN, PMID 39178988) reaches the same picture. - Trials in people who already have cancer. AMATERASU (Urashima 2019, JAMA, PMID 30964526): 417 patients after surgery for digestive-tract cancers, 2000 IU daily; relapse-free survival HR 0.76 (0.50 to 1.14), not significant; possible benefit in the subgroup with baseline levels 20 to 40 ng/mL. SUNSHINE (Ng 2019, JAMA, PMID 30964527): 139 patients with metastatic colorectal cancer, high-dose (8000 then 4000 IU daily) versus 400 IU; progression-free survival favoured high dose on a one-sided test, overall survival identical. SOLARIS, the phase 3 that followed (Ng 2026, JAMA 336:746, PMID 42545685): 455 patients, high-dose versus standard-dose vitamin D3 with chemotherapy; no difference in progression-free survival (P = 0.25). Post-diagnosis supplement use meta-analysis (Chen 2022, Nutrients, PMID 36014928): overall survival SRR 0.87, but the association came from cohort studies, not trials, and progression-free and cancer-specific survival were not improved. - Bone sarcoma and chordoma. PubMed (vitamin D) AND (chordoma): 0 results. Bone sarcomas: in-vitro only. Active vitamin D reduced viability of one osteosarcoma line by 23 percent and a chondrosarcoma line (SW-1353) by 10 percent, with no effect in two other lines and, oddly, fewer apoptotic osteosarcoma cells (Hein 2026, J Bone Oncol, PMID 42598195); VDR is expressed in osteosarcoma (Baly 2026, Sci Rep, PMID 41872253). No chordoma line was tested and there are no patient data.

Reading of the trial evidence (judgement, stated as such): modest daily doses that bring people into the normal range may lower the chance of dying from cancer in the general population by roughly a tenth, mostly in people of normal weight; they do not prevent cancer; large infrequent doses do not help and may harm; in people who already have cancer, high-dose has not beaten standard-dose in the one phase 3 that tested it. Nothing supports "through the roof".

2b. What "getting levels through the roof" means: units, ranges, protocols, toxicity

Units. 25-hydroxyvitamin D is reported in nmol/L in the UK and ng/mL in the US. 1 ng/mL = 2.5 nmol/L. So: - 25 nmol/L = 10 ng/mL: deficient. - 50 nmol/L = 20 ng/mL: sufficient for bone health in the UK and most guidelines. - 75 nmol/L = 30 ng/mL: the US Endocrine Society's older "optimal". - 100 nmol/L = 40 ng/mL: the target the vitamin D advocacy literature promotes; within normal, not dangerous. - 100 ng/mL = 250 nmol/L: the level at which UK laboratories flag possible toxicity and at which guidelines advise stopping supplements. - 150 ng/mL = 375 nmol/L: "the hallmark of vitamin D toxicity due to overdosing" (Marcinowska-Suchowierska 2018, Front Endocrinol, PMID 30294301). The podcast's "a hundred" is either sensible or dangerous depending on the unit, and that must be pinned down before anyone acts on it.

UK guidance (NICE CKS "Vitamin D deficiency in adults" and the Royal Osteoporosis Society 2018 guideline; both blocked to my fetch today, so this is from my knowledge of those documents, verify): deficiency below 25 nmol/L; 25 to 50 possibly inadequate; above 50 sufficient. Treatment of deficiency: a loading course of about 300,000 IU over 6 to 10 weeks (for example 50,000 IU weekly for 6 weeks), then maintenance 800 to 2000 IU daily; check serum calcium about a month after loading; no need to re-test 25(OH)D routinely; sustained levels above about 220 to 250 nmol/L carry risk of toxicity. NHS public advice (nhs.uk, fetched today): 10 micrograms (400 IU) daily for adults, and "do not take more than 100 micrograms (4,000 IU) of vitamin D a day as it could be harmful"; too much over time causes hypercalcaemia, which "can weaken the bones and damage the kidneys and the heart". SACN 2016 (gov.uk, fetched today): reference nutrient intake 10 micrograms a day for everyone over 4. British Dietetic Association (fetched today): 10 micrograms meets most needs; "much larger amounts are unnecessary and can be harmful"; consult a clinician before supplementing if you have high calcium or take steroids or cancer medicines. The US Endocrine Society's 2024 guideline (Demay 2024, J Clin Endocrinol Metab, PMID 38828931) moved away from routine testing and high-dose supplementation in healthy adults.

The Coimbra protocol and other megadose regimens. Cicero Coimbra (Brazil) treats autoimmune disease with very high daily vitamin D3, titrated to suppress parathyroid hormone, with a strict low-calcium diet and at least 2.5 litres of fluid a day. The only sizeable safety report is from a German private clinic: 319 autoimmune patients, mean dose 35,291 IU a day for up to 3.5 years, mean calcium, creatinine and urinary calcium within normal, under close supervision (Amon 2022, Nutrients, PMID 35458137; co-authored by Holick, a prominent vitamin D advocate). There is no efficacy trial of the Coimbra protocol in any disease and none in cancer. The "hypothesis" paper behind it (Lemke 2021, Front Immunol, PMID 33897704) is about autoimmune disease. The regimen depends on restricting dietary calcium, which is the last thing a 51 kg woman losing weight and probably heading for steroids and radiotherapy should be doing.

Toxicity picture. Hypercalcaemia (thirst, polyuria, nausea, constipation, confusion, muscle weakness, arrhythmia), hypercalciuria and kidney stones, acute kidney injury, and vascular and soft-tissue calcification with prolonged excess. Susceptibility varies with CYP24A1 genotype, so some people become hypercalcaemic at doses others tolerate (Aberger 2024, Int J Mol Sci, PMID 39337491, which reports a case needing steroids to bring calcium down). Case reports of acute kidney injury from over-the-counter megadosing continue to appear (Mason 2024, Mil Med, PMID 37402617). Hypercalcaemia from vitamin D toxicity is now an "emerging" cause of hypercalcaemia in tertiary referrals (Sheikh 2026, Cureus, PMID 42245902). Dexamethasone is in fact one of the treatments for vitamin D toxicity because it lowers calcium absorption and speeds vitamin D breakdown (Aberger 2024), which illustrates the point in 2c below.

Testing. Serum 25(OH)D (the storage form; the right test), adjusted calcium, phosphate, renal function, and PTH if calcium is high or the picture is odd. All routine NHS tests; the 25(OH)D assay is cheap and can be added to bloods she is already having.

2c. Relevance to the patient

Reasons she may well be low: 12 to 15 percent weight loss and poor intake; months indoors and in hospital; chronic pain and inflammation. Reasons megadosing is specifically a bad idea for her: - Kidneys. She is on regular diclofenac, which reduces renal blood flow; adding hypercalcaemia and hypercalciuria from vitamin D excess on top of an NSAID in a 51 kg woman is a recipe for acute kidney injury and stones (inference from the pharmacology of each; there is no trial of the combination, which is itself the point). - Dexamethasone. Glucocorticoids reduce intestinal calcium absorption, increase urinary calcium loss, and accelerate bone loss within weeks; every guideline on glucocorticoid use recommends normal-range calcium and vitamin D for anyone on more than a few weeks of steroid (2022 ACR guideline, Humphrey 2023, Arthritis Rheumatol, PMID 37845798; Belgian Bone Club, Laurent 2022, PMID 35757436; Rizzoli 2015, Nat Rev Rheumatol, PMID 25385412). That is an argument for making sure she is replete, not for exceeding the range; steroids also blunt vitamin D's calcaemic effect, so a level that was "safe" on steroids can become toxic when the steroid stops. - Radiotherapy. No evidence that vitamin D changes proton therapy outcomes either way; the proton centre will want the supplement list. - Bone. She has a tumour in the clivus, may be on steroids, is underweight and premenopausal; bone health matters for the years after treatment. The evidence-based approach is exactly the standard one: test, correct, maintain.

The sensible plan: ask for 25(OH)D, adjusted calcium and renal function now (Southampton admission bloods). If below 50 nmol/L, a standard loading course then 800 to 2000 IU daily; if 50 to 75, 1000 to 2000 IU daily; if above 75, 400 to 1000 IU daily through winter is enough. Calcium check a month after any loading. Nobody should aim above 100 to 125 nmol/L, and nothing above 4000 IU a day should be taken without a doctor watching calcium. Daily dosing, not monthly boluses, is what the trial evidence supports.

2d. Verdict on vitamin D

Test and replete to normal: yes, cheap, reasonable, and it is what the steroid guidelines would require anyway. Aim for 100 nmol/L (40 ng/mL): acceptable if that is what "a hundred" meant. Aim for 100 ng/mL, the Coimbra protocol, or any "through the roof" target: no; no evidence of benefit in any cancer, none in chordoma, a phase 3 in cancer patients showing high-dose is no better than standard, and a real risk to her kidneys and calcium on diclofenac and dexamethasone.

3. "Innate immune system" and immune-support claims

3a. What innate immunity is and what actually modulates it

Innate immunity is the fast, non-specific arm: physical barriers, neutrophils, macrophages, natural killer cells, dendritic cells, complement and the inflammatory cytokine response. It is not a dial that supplements turn up. What is documented to change it in humans: - Sleep. Sleep loss reduces natural killer cell activity and vaccine responses and, when chronic, produces low-grade systemic inflammation; sleep restores inflammatory homeostasis (Besedovsky, Lange and Haack 2019, Physiol Rev 99:1325, PMID 30920354). For the patient this means pain control and night-time protection from observations are immune interventions. - Physical activity. Moderate regular exercise improves immune surveillance and lowers inflammation; very heavy exertion transiently suppresses it (Nieman and Wentz 2019, J Sport Health Sci, PMID 31193280). Walking, not training, during treatment. - Nutrition. Protein-energy malnutrition is the most common cause of secondary immunodeficiency worldwide; for a 51 kg woman losing weight, the dietitian is the immune specialist (judgement, and the standard teaching; thread 12 already recommends dietitian input). - Vaccination. Flu and COVID vaccines before radiotherapy and any chemotherapy; the immunology is adaptive but the infections they prevent are what actually derails treatment. - Avoiding unnecessary steroids. Dexamethasone suppresses both innate and adaptive responses; it is sometimes necessary for oedema and there is no supplement that offsets it. Thread 12 covers Boswellia as a possible steroid-sparing agent during radiotherapy, which is the evidence-based version of this wish. - Stress and psychology. Mind-body interventions have Cochrane-level evidence for sleep, fatigue and anxiety (thread 12) and small effects on immune markers; worth doing for wellbeing regardless.

Versus the products marketed as "immune boosters": - Beta-glucans. Modest evidence of changes in immune markers in athletes and small trials; no cancer outcome trial (Bobovcak 2010, PMID 21164546, is representative). - Turkey tail (Trametes versicolor), PSK and other mushrooms. PSK ("Krestin") is a purified protein-bound polysaccharide extract given as a prescription medicine in Japan at about 3 g a day with chemotherapy. Meta-analysis of 8 randomised trials, 8,009 patients with resected gastric cancer: hazard ratio for death 0.88 (0.79 to 0.98) with PSK added to chemotherapy (Oba 2007, Cancer Immunol Immunother, PMID 17106715); a 23-trial network meta-analysis across gastric, colorectal and oesophageal cancer found similar benefit and no added toxicity (Ma 2017, Oncotarget, PMID 29179503). These are genuine data, in gastrointestinal cancers, with chemotherapy, using a standardised pharmaceutical product. The turkey tail capsules sold online are crude mushroom powder of unknown PSK content; the only Western trial is a 9-woman phase 1 in breast cancer showing tolerability of up to 9 g a day (Torkelson 2012, ISRN Oncol, PMID 22701186). Cancer Research UK's summary (fetched today): "there is currently not enough evidence to say that any type of mushroom can prevent or cure cancer", and most extracts have not been tested for drug interactions. No mushroom product has any chordoma data. - Zinc. Corrects deficiency if present; no cancer benefit above that; excess causes copper deficiency and nausea (standard nutrition; no chordoma data). - High-dose intravenous vitamin C. Systematic review of 34 studies including 5 randomised trials: "no high-quality evidence to suggest that ascorbate supplementation in cancer patients either enhances the antitumor effects of chemotherapy or reduces its toxicity" (Jacobs 2015, Oncologist, PMID 25601965). Oral doses above 1000 mg a day cause stomach pain, diarrhoea and flatulence (nhs.uk, fetched today). Private IV vitamin C clinics charge hundreds of pounds a session for this. - Echinacea. Cochrane: 24 trials, 4,631 people, possibly a small reduction in colds, no evidence for anything else (Karsch-Völk 2014, CD000530, PMID 24554461). - Elderberry. Small trials in influenza symptoms; nothing in cancer. - Probiotics. Useful for antibiotic-associated diarrhoea; live organisms are a concern in the neutropenic or immunosuppressed and in anyone with a CSF leak risk after skull base surgery (judgement; ask the surgeons). - Thymus extracts. Cochrane: 26 trials, 2,736 patients; thymostimulin and thymosin fraction 5 gave no benefit in survival, disease-free survival or response; fewer severe infections during chemotherapy; thymosin alpha-1 a non-significant trend (Wolf 2011, CD003993, PMID 21328265). Not available in the UK. - Mistletoe is covered in thread 11 (best trial negative for survival; no chordoma data).

3b. Does "boosting" immunity make sense for chordoma?

Chordoma is usually described as an immunologically cold tumour with a low mutation burden, although the picture is heterogeneous. PD-L1 protein was detected in most chordoma samples on a 78-specimen tissue array, correlated with the presence of tumour-infiltrating lymphocytes, and both were associated with metastasis, not with better outcome (Feng 2015, Oncotarget, PMID 25871477). The 2026 single-cell study of 35 chordomas found tumours ranging "from highly infiltrated to immune-desert", dominated by tumour-associated macrophages, with exhausted CD8 T cells of restricted clonality (Arrieta 2026, Neuro Oncol, PMID 41586579). Checkpoint inhibitor trials in advanced chordoma (thread 12, section A6) produced responses in a minority. So: there is real immunology in chordoma, it is the subject of serious trials, and none of it is reached by swallowing beta-glucan. Stimulating innate immunity non-specifically has never been shown to shrink a chordoma or any solid tumour in a controlled trial, with the single exception of PSK in gastrointestinal cancers alongside chemotherapy. Inference: the macrophage-dominated microenvironment described in 2026 is, if anything, a reason to be cautious about non-specific "immune stimulants", since tumour-associated macrophages are often pro-tumour.

3c. Safety with surgery and radiotherapy

3d. Verdict on immune support

Sleep, pain control, protein and calories, gentle walking, vaccines, and a dietitian: yes, all of it, now. Beta-glucan, turkey tail, IV vitamin C, echinacea, elderberry, zinc above dietary need, thymus extracts, "immune protocols" from private clinics: no evidence in chordoma, no evidence they help any solid tumour outside the specific PSK-with-chemotherapy setting, a randomised signal that antioxidants during radiotherapy can worsen local control, and unknown interactions. Leave them alone, at least until treatment is complete.

4. The podcast claims, checked one by one

"LDN is a potent anti-inflammatory." Origin: the TLR4 glial hypothesis (Hutchinson 2008; Younger 2014) and an 8-woman cytokine study (Parkitny 2017). Evidence: in vitro cytokine reduction via TLR7 to 9 in blood cells, not TLR4 (Cant 2017); no randomised trial showing reduced CRP or any inflammatory marker versus placebo; the best fibromyalgia trials show no meaningful clinical effect (FINAL 2024; INNOVA 2026); more adverse events than placebo in meta-analysis (Hegde 2025). Exaggerated. "Possibly mildly immunomodulatory" is defensible; "potent" is not.

"LDN shuts off the fuel to the cancer." Origin: this is not a mechanism described anywhere in the scientific literature; it is a lay paraphrase, perhaps of the OGF growth-inhibition story or of the cell-cycle genes in Liu 2016. Evidence: chordoma has no known dependence on opioid signalling; PubMed has zero chordoma papers on naltrexone or OGF; the one randomised cancer trial of LDN was negative; the 1983 mouse work showed that getting the dose wrong accelerated tumours. False as stated. There is no "fuel" that LDN switches off in any human cancer.

"Half the chemotherapy dose with the same effect." Origin: Liu 2016's dish experiment in HCT116 colorectal cells (priming with LDN raised oxaliplatin cell-kill from 14 to 49 percent) and the 2022 mouse study with cannabidiol and gemcitabine, both from a group holding patents on the concept. Evidence: no human study has tested chemotherapy dose reduction with LDN; a 2025 study in oral cancer cells found antagonism across the full dose range (Kazmi 2025); and, decisive for the patient, chordoma is not treated with chemotherapy, so the claim has nothing to attach to. Her treatment is surgery and protons. Unsupported in humans, contradicted in some cell types, and irrelevant to chordoma.

"Get D3 levels through the roof." Origin: the observational literature and its advocates (Coimbra; Holick; Wimalawansa 2025). Evidence: daily modest dosing may lower cancer death in the general population (Keum 2019; Kuznia 2023); bolus and high-dose regimens do not help and trended to harm in D-Health; high-dose was no better than standard-dose in cancer patients in SOLARIS 2026; toxicity is well documented above 250 nmol/L, and 100 ng/mL is that number. True that being replete matters; false that higher is better; dangerous for her kidneys and calcium at "through the roof" levels on diclofenac and dexamethasone.

"Make the cancer more receptive to whatever treatment." Origin: a generalisation of the chemosensitisation dish data and of vitamin D and immune claims. Evidence: nothing shows LDN, vitamin D or any immune supplement sensitises a tumour to surgery or to proton radiotherapy, which are her treatments; the one randomised supplement-during-radiotherapy trial in a head and neck population suggested the opposite for antioxidants (Bairati 2005). Unsupported. The things that genuinely make her treatment more likely to succeed are covered in thread 12: tissue banking, joint surgical and proton planning at the national MDT, and getting to the proton centre before surgery.

5. Honest bottom line for the family, and questions for the team

For her partner. The podcast is selling hope in the form of a cheap pill, a vitamin and a story about the immune system. The pill blocks the drugs the patient needs for pain and for surgery, and there is no evidence it touches chordoma. The vitamin is worth testing and correcting to the normal range, and worth nothing beyond that. The immune story is true in the sense that sleep, food, pain relief and rest matter, and false in the sense that nothing in a capsule has been shown to help a tumour like this one.

Timing, plainly. 1. Nothing that antagonises opioids while she needs pain control or in the 3 days before any operation or procedure. That rules out LDN now, during surgery and recovery, and probably through proton therapy. If it ever comes back on the table it is for pain, off opioids, with the pain team. 2. Vitamin D: test now (25(OH)D, adjusted calcium, renal function), replete to 50 to 100 nmol/L with daily dosing, maintain at 800 to 2000 IU a day, check calcium a month after any loading. Do not take more than 4000 IU a day without a doctor monitoring calcium, and do not aim for 250 nmol/L (100 ng/mL) under any name. 3. Immune supplements: no, during surgery and radiotherapy in particular. Declare anything she is already taking. Put the effort into the dietitian, sleep, walking and vaccines. 4. Everything she swallows goes on the medication list that Southampton, the anaesthetist and the proton centre see.

Questions for the oncology and pain teams. 1. Can 25-hydroxyvitamin D, adjusted calcium and renal function be added to her admission bloods, and will you prescribe the standard replacement if she is low? 2. If dexamethasone is started, what calcium and vitamin D cover do you want, and for how long? 3. What is your policy on supplements during surgery and proton therapy, and specifically on antioxidants and mushroom or "immune" products? 4. Is there any circumstance, after treatment and off opioids, in which you would consider low-dose naltrexone for residual neuropathic pain, and who would prescribe and monitor it? 5. Is she up to date with flu and COVID vaccination, and when should they be given relative to surgery and radiotherapy? 6. Can she see a dietitian this week, given 12 to 15 percent weight loss?

6. Sources

PubMed and registry searches run 4 September 2026 via NCBI E-utilities and ClinicalTrials.gov API v2: (naltrexone) AND (chordoma) 0; (opioid growth factor OR OGF OR met-enkephalin) AND (chordoma) 0; (naltrexone) AND (chondrosarcoma) 0; (opioid growth factor OR OGFr) AND (chondrosarcoma) 2 false positives; (vitamin D) AND (chordoma) 0; low-dose naltrexone AND cancer AND clinical trial 7 (listed above); ClinicalTrials.gov naltrexone with cancer, glioma, sarcoma, chordoma (listed in 1b).

LDN - Zagon IS, McLaughlin PJ. Naltrexone modulates tumor response in mice with neuroblastoma. Science 1983;221:671. PMID 6867737. - McLaughlin PJ, Zagon IS. Duration of opioid receptor blockade determines biotherapeutic response. Biochem Pharmacol 2015. PMID 26119823. - Bihari B. Efficacy of low dose naltrexone as an immune stabilizing agent for the treatment of HIV/AIDS. AIDS Patient Care 1995. PMID 11361353. Interview, Altern Ther Health Med 2013, PMID 23594453. - Hutchinson MR et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of TLR4. Eur J Neurosci 2008. PMID 18662331. - Younger J, Parkitny L, McLain D. The use of low-dose naltrexone as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol 2014. PMID 24526250. - Cant R, Dalgleish AG, Allen RL. Naltrexone inhibits IL-6 and TNF-alpha production in human immune cell subsets following stimulation with ligands for intracellular toll-like receptors. Front Immunol 2017. PMID 28744288. - 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. Int J Oncol 2016;49:793. PMID 27279602. https://doi.org/10.3892/ijo.2016.3567 - Liu WM et al. Combination of cannabidiol with low-dose naltrexone increases the anticancer action of chemotherapy in vitro and in vivo. Oncol Rep 2022. PMID 35179218. - Liu WM, Dalgleish AG. Naltrexone at low doses (LDN) and its relevance to cancer therapy. Expert Rev Anticancer Ther 2022. PMID 35107043. - Dalgleish AG, Liu WM. The role of immune modulation and anti-inflammatory agents in the management of prostate cancer: a case report of six patients. Oncol Lett 2022. PMID 35761946 (patent disclosures). - Kazmi S et al. Naltrexone has variable and schedule-dependent effects on oral squamous cell carcinoma cells. Int J Mol Sci 2025. PMID 41226687. - Peters KB et al. Effects of low-dose naltrexone on quality of life in high-grade glioma patients: a placebo-controlled, double-blind randomized trial. Support Care Cancer 2022;30:3463. PMID 35001215. NCT01303835. - Lissoni P et al. Radioendocrine therapy of brain tumors with naltrexone in association with radiotherapy. Tumori 1993. PMID 8236504. Lissoni P et al. Neuro Endocrinol Lett 2002. PMID 12195238, PMID 12080288. - Berkson BM et al. Integr Cancer Ther 2006 (PMID 16484716), 2007 (PMID 17761642), 2009 (PMID 20042414), 2018 (PMID 29258346). - Smith JP et al. Anticancer Drugs 2004 (PMID 15014352); Open Access J Clin Trials 2010 (PMID 20890374). Kimchi ET et al. Cancer Invest 2025 (PMID 40196893). - Malik A, Ye A, Chung M. Low dose naltrexone for refractory cancer pain: case series. J Pain Symptom Manage 2025. PMID 40849024. - Ananthan S et al. Low-dose naltrexone in posttraumatic trigeminal neuropathic pain: retrospective case series. Quintessence Int 2025. PMID 40590142. - Due Bruun K et al. Naltrexone 6 mg once daily versus placebo in women with fibromyalgia (FINAL). Lancet Rheumatol 2024;6:e31. PMID 38258677. Editorial PMID 38258679. Re-analysis Korean J Pain 2026, PMID 41469218. - Rodríguez-Freire C et al. INNOVA study. Eur J Pain 2026. PMID 42385209. - Hegde NC et al. LDN in chronic pain: meta-analysis of RCTs. Curr Pain Headache Rep 2025. PMID 40540205. - Parker CE et al. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane 2018, CD010410. PMID 29607497. - Cree BA et al. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol 2010. PMID 20695007. - Byambasuren O et al. Effect of low-dose naltrexone for long COVID: systematic review and meta-analysis. BMJ Open 2026. PMID 42463201. - Parkitny L, Younger J. Reduced pro-inflammatory cytokines after eight weeks of LDN for fibromyalgia. Biomedicines 2017. PMID 28536359. - Rupp A et al. LDN for non-cancer centralized pain: scoping review. Pain Med 2023. PMID 37302106. - Gouda AHK et al. Low-dose naltrexone: what is the evidence? Adv Ther 2026. PMID 42060160. - Toljan K, Vrooman B. Low-dose naltrexone: review of therapeutic utilization. Med Sci 2018. PMID 30248938. https://pmc.ncbi.nlm.nih.gov/articles/PMC6313374/ - Bolton M et al. Serious adverse events in placebo RCTs of oral naltrexone. BMC Med 2019. PMID 30642329. - Harrison TK, Kornfeld H, Aggarwal AK. Perioperative considerations for buprenorphine, methadone or naltrexone. Anesthesiol Clin 2018 (PMID 30092933) and 2025 (PMID 41233100). - Adepend 50 mg naltrexone Summary of Product Characteristics. https://www.medicines.org.uk/emc/product/3559/smpc (fetched 4 September 2026). - LDN Research Trust. https://ldnresearchtrust.org/ (home, "What is LDN", "How LDN works", safety pages fetched; opioid guidance page not reachable today). - Dickson Chemist LDN private prescription department. https://shop.dicksonchemist.co.uk/the-ldn-private-prescription-dept/ (fetched). Clinic 158. https://www.clinic158.com/ (fetched).

Vitamin D - Manson JE et al. Vitamin D supplements and prevention of cancer and cardiovascular disease (VITAL). N Engl J Med 2019;380:33. PMID 30415629. NCT01169259. - Chandler PD et al. Effect of vitamin D3 supplements on development of advanced cancer: secondary analysis of VITAL. JAMA Netw Open 2020. PMID 33206192. - Neale RE et al. The D-Health Trial: effect of vitamin D on mortality. Lancet Diabetes Endocrinol 2022;10:120. PMID 35026158. ACTRN12613000743763. Cancer incidence: J Steroid Biochem Mol Biol 2025, PMID 40096917. - Keum N et al. Ann Oncol 2019;30:733. PMID 30796437. Keum N et al. Br J Cancer 2022;127:872. PMID 35676320. - Kuznia S et al. Efficacy of vitamin D3 supplementation on cancer mortality: IPD meta-analysis of RCTs. Ageing Res Rev 2023. PMID 37004841. - Petrelli F et al. Umbrella review. Clin Nutr ESPEN 2024. PMID 39178988. - Urashima M et al. AMATERASU. JAMA 2019;321:1361. PMID 30964526. Ng K et al. SUNSHINE. JAMA 2019;321:1370. PMID 30964527. Ng K et al. SOLARIS (Alliance A021703). JAMA 2026;336:746. PMID 42545685. - Chen QY et al. Post-diagnosis vitamin D supplement use and survival: meta-analysis. Nutrients 2022. PMID 36014928. - Hein M et al. Vitamin D decreases tumor cell growth in primary malignant bone tumors in vitro. J Bone Oncol 2026. PMID 42598195. Baly I et al. Sci Rep 2026. PMID 41872253. - Wimalawansa SJ. Vitamin D's impact on cancer incidence and mortality: systematic review. Nutrients 2025. PMID 40732958 (advocacy position). - Demay MB et al. Vitamin D for the prevention of disease: Endocrine Society guideline. J Clin Endocrinol Metab 2024. PMID 38828931. - Marcinowska-Suchowierska E et al. Vitamin D toxicity: a clinical perspective. Front Endocrinol 2018. PMID 30294301. - Aberger S et al. Targeting calcitriol metabolism in acute vitamin D toxicity. Int J Mol Sci 2024. PMID 39337491. - Mason N et al. Vitamin D abuse resulting in acute kidney injury. Mil Med 2024. PMID 37402617. Sheikh JA et al. Cureus 2026. PMID 42245902. - Amon U et al. Safety data during treatment with high doses of vitamin D3 according to the Coimbra protocol. Nutrients 2022. PMID 35458137. Lemke D et al. Front Immunol 2021. PMID 33897704. - Humphrey MB et al. 2022 ACR guideline for glucocorticoid-induced osteoporosis. Arthritis Rheumatol 2023. PMID 37845798. Laurent MR et al. Belgian Bone Club. Front Endocrinol 2022. PMID 35757436. Rizzoli R, Biver E. Nat Rev Rheumatol 2015. PMID 25385412. - NHS, Vitamin D. https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-d/ (fetched). SACN Vitamin D and Health 2016. https://www.gov.uk/government/publications/sacn-vitamin-d-and-health-report (fetched). British Dietetic Association, Vitamin D food fact sheet. https://www.bda.uk.com/resource/vitamin-d.html (fetched). NICE CKS Vitamin D deficiency in adults. https://cks.nice.org.uk/topics/vitamin-d-deficiency-in-adults/ (not reachable today; thresholds and regimen quoted from knowledge, verify). Royal Osteoporosis Society, Vitamin D and bone health in adults, 2018 (not reachable today, verify).

Immune support - Besedovsky L, Lange T, Haack M. The sleep-immune crosstalk in health and disease. Physiol Rev 2019;99:1325. PMID 30920354. - Nieman DC, Wentz LM. The compelling link between physical activity and the body's defense system. J Sport Health Sci 2019. PMID 31193280. - Oba K et al. Efficacy of adjuvant immunochemotherapy with PSK after curative resection of gastric cancer: meta-analysis. Cancer Immunol Immunother 2007. PMID 17106715. Ma Y et al. Oncotarget 2017. PMID 29179503. - Torkelson CJ et al. Phase 1 trial of Trametes versicolor in women with breast cancer. ISRN Oncol 2012. PMID 22701186. - Cancer Research UK, Mushrooms in cancer treatment. https://www.cancerresearchuk.org/about-cancer/treatment/complementary-alternative-therapies/individual-therapies/mushrooms-in-cancer-treatment (fetched). - Jacobs C et al. Is there a role for oral or intravenous ascorbate in treating patients with cancer? Oncologist 2015. PMID 25601965. NHS, Vitamin C. https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-c/ (fetched). - Karsch-Völk M et al. Echinacea for preventing and treating the common cold. Cochrane 2014, CD000530. PMID 24554461. - Wolf E et al. Thymic peptides for treatment of cancer patients. Cochrane 2011, CD003993. PMID 21328265. - Bairati I et al. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer. J Clin Oncol 2005;23:5805. PMID 16027437. Meyer F et al. Int J Cancer 2008. PMID 18059031. - Feng Y et al. Expression of PD-L1 and prevalence of tumor-infiltrating lymphocytes in chordoma. Oncotarget 2015. PMID 25871477. - Arrieta VA et al. Integrated immune profiling of chordomas reveals spatially organized niches and functional heterogeneity. Neuro Oncol 2026;28:440. PMID 41586579. - Bobovcak M et al. Pleuran beta-glucan and cellular immune response after exercise. Appl Physiol Nutr Metab 2010. PMID 21164546.

Related threads: 08 (pain and cognition), 11 (plant compounds, mistletoe), 12 (cutting edge and traditional, checkpoint inhibitors, Boswellia, diet).

Addendum, 12 September 2026: vitamin D level and cancer mortality, her partner's 9 percent figure

Her partner asked on 12 Sep whether every 20 nmol/L rise in 25(OH)D correlates with a 9 percent mortality reduction in cancer patients. It does, for one cancer.

Observational dose-response meta-analyses, per 20 nmol/L increment in circulating 25(OH)D:

So the headline figure is cancer specific and the pooled mortality effect is an order of magnitude smaller than the prostate number. Nothing exists for chordoma.

The confounding, which is the whole difficulty. These are observational. Sicker patients go outdoors less and systemic inflammation lowers circulating 25(OH)D independently, so a low level plausibly marks advanced disease rather than causing it. Reverse causation is the standing objection to the entire observational literature here.

Randomised evidence, which is the actual test:

Where this lands for the patient. The randomised signal, such as it is, sits in people who were deficient at baseline. Correcting a deficiency is supported; raising an already normal level is not. This is an argument for measuring her 25(OH)D, which has never been done, and not for increasing the 2,000 IU/day she already takes. It converges with the standing position in this thread and in em-dalgleish.md.

Cross-reference the calcium caution: vitamin D raises serum calcium, she had bilateral lip and tongue tingling on 11 Sep consistent with hypocalcaemia or hypomagnesaemia, and no calcium result has ever been seen. Level first, dose second.

Addendum, 14 September 2026: the OGF-OGFr axis, and whether morphine itself feeds a tumour

Written after her partner asked in em-research: "on the front of opioids being used to treat cancer pain... have you come across anything on the OGFr receptor?" Every PMID verified through NCBI E-utilities on 14 September 2026.

This is two questions in one and they have different answers. The first is what the opioid growth factor receptor is and whether anything can be done with it. The second, which is the one underneath it, is whether giving the patient morphine is helping her tumour along.

1. What OGFr actually is, and the distinction that decides most of this

Opioid growth factor (OGF) is [Met5]-enkephalin, an endogenous opioid pentapeptide. OGFr is its receptor, and it is not a classical opioid receptor. It is nuclear and perinuclear rather than a G-protein-coupled membrane receptor, it does not mediate analgesia, and it has no role in reward or respiratory depression. It is opioid-antagonist-sensitive, which is how it was found and why it carries the name.

Its function is to hold proliferation down. The OGF-OGFr axis delays the G1/S interface of the cell cycle by upregulating cyclin-dependent kinase inhibitors, p16INK4a and p21WAF1/CIP1. McLaughlin and Zagon describe it as "a tonically active, inhibitory pathway" regulating homeostasis and re-epithelialisation, with roles in autoimmune disease and cancer (Biochem Pharmacol 2012, PMID 22687282, L5). It is a brake on growth, not a killing mechanism. Expression has been mapped in a range of human cancers including thyroid (PMID 19014324, L5) and gynaecological (PMID 31408839, L5).

The distinction that matters, and the reason the question is easy to get tangled in: morphine does not act here. Morphine is a mu agonist at a classical membrane receptor. OGF-OGFr is a separate axis with a separate ligand, a separate receptor and a separate function. The patient being on morphine neither engages this pathway nor benefits from it. Both have "opioid" in the name and that is the whole of the connection.

2. How you would actually engage it, which brings us back to LDN

Zagon's mechanistic proposal, and the reason this thread already has an LDN section: intermittent blockade of the axis with low-dose naltrexone produces rebound upregulation of both OGF and OGFr, and therefore more growth inhibition than baseline. That is the theoretical basis for LDN in cancer, and it is the same axis being invoked for LDN in Crohn's and multiple sclerosis (PMID 22687282, L5).

The practical obstacle is the one already recorded in this thread and it has got sharper, not softer. Naltrexone is an opioid antagonist. The patient is on morphine MR plus Oramorph. Giving her naltrexone at any dose risks precipitated withdrawal and would strip out her analgesia at a point where she is running 7 to 9 with it. This is not a theoretical conflict; it is a direct one, today.

There is a forward path worth recording honestly, because it connects to something the patient is already doing. She has asked to come off morphine and has begun reducing on her own. If she succeeds, the pharmacological objection to LDN goes away. That is a real observation and her partner is entitled to it. The caveats stay exactly where they were: no chordoma evidence of any kind, no randomised evidence in any cancer, and it must not become a reason to taper faster than her pain allows.

3. The human evidence for OGF itself, appraised honestly

There is one clinical study of consequence. Smith 2010 (Open Access J Clin Trials, PMID 20890374, L2 at best): 24 patients with advanced pancreatic cancer who had failed standard chemotherapy, given OGF 250 µg/kg intravenously each week. Clinical benefit response 53 per cent against historical figures of 23.8 per cent for gemcitabine and 4.8 per cent for 5-FU. Of those surviving beyond eight weeks, 62 per cent showed stable or reduced tumour size. Median survival 65.5 days against 21 days, p < 0.001. No haematological or biochemical toxicity, quality of life improved.

Five things to hold against that, none of which are nitpicking.

  1. Open-label, single-arm, non-randomised. The paper says so.
  2. Historical controls, and the authors concede that measurements other than survival were not available in the comparator.
  3. A 21-day median survival in the comparator is implausibly short for advanced pancreatic cancer, which points to a comparator population recruited at a much later point in the illness. That inflates the ratio. A 65.5-day median is itself about nine weeks.
  4. Zagon, who originated the hypothesis, is an author, in a low-profile journal.
  5. It is 2010, and in the fifteen years since there has been no phase III. For a therapy reported to triple median survival with no toxicity, that absence is the loudest fact in the file.

It should not be dismissed. It should also not be described as evidence that OGF works.

4. The question underneath the question: does morphine feed cancer?

This is the one that actually bears on the patient and it has a better answer than the first.

The mechanistic case for concern is real. Mu-opioid receptor expression correlates with worse outcomes in several cancers, and MOR has been proposed as an anticancer target in its own right (Curr Oncol Rep 2021, PMID 34342720, L5). Janku 2016 (Ann Oncol, PMID 27573565, L3) found methylnaltrexone, a peripherally acting MOR antagonist given for opioid-induced constipation, associated with longer overall survival in advanced cancer. That is an unplanned post hoc analysis of pooled data from two trials designed to study constipation, which is hypothesis-generating and nothing more.

The decisive evidence is randomised and it is negative. Sessler 2019 (Lancet, PMID 31645288, L1, NCT00418457). 2,108 women undergoing potentially curative breast cancer surgery at 13 hospitals across eight countries, randomised to regional anaesthesia and analgesia with paravertebral blocks and propofol, versus sevoflurane with opioid analgesia. The trial's own stated rationale was that opioids are one of three perioperative factors thought to impair host defence against recurrence. Recurrence was 102 of 1,043 (10 per cent) with regional versus 111 of 1,065 (10 per cent) with opioids, hazard ratio 0.97, p = 0.84. Stopped at a preplanned futility boundary. Persistent incisional pain was also identical.

Systematic reviews in breast cancer (PMID 34771662, L2) and colorectal cancer (PMID 30212256, L2) find no consistent signal either.

So: mechanistically plausible, clinically not demonstrated, and the one large randomised test of the proposition was flatly negative.

5. Chordoma

Nothing. Searched 14 September 2026: there is no published work on OGFr in chordoma or chondrosarcoma of any kind.

6. Where this lands for the patient

Addendum to the addendum, 14 September 2026 19:55: her partner's ligand-level objection

Her partner, in em-research: "OK but there is evidence of exogenous opioids downregulating the OGFr receptor pathway by lowering the amount of endogenous opioids being produced. Even though the pain receptor pathways are distinctly separate."

He is right that my statement was too absolute. I wrote that morphine "does not act here", meaning at the receptor. He is proposing a different route: not morphine binding OGFr, but morphine suppressing production of the ligand, [Met5]-enkephalin, by negative feedback, thereby lifting tonic inhibition off the axis. That is a coherent mechanism and the right kind of objection. It needs answering on evidence rather than by restating the receptor point.

Three findings answer it, and two of them are from Zagon's own laboratory.

1. The OGF acting on a tumour cell is made by that tumour cell. Zagon, Smith and McLaughlin 1999 (Int J Oncol, PMID 10024694, L5), the foundational paper in human pancreatic cancer lines: OGF is "constitutively expressed, autocrine produced, and tonically capable of suppressing cell replication". Radioimmunoassay confirmed the cells both produce and secrete it, and immunocytochemistry found OGF and its receptor together in the cytoplasm of the same log-phase cells. This is a local autocrine loop, not a hormone delivered from the brain or adrenal. Central negative feedback on hypothalamic or striatal proenkephalin does not reach it. That is the main answer.

2. The interaction her partner proposes has been tested directly, and it was null. Zagon, Verderame and McLaughlin 2003 (Neuropeptides, PMID 14607106, L5) examined the axis in COS-7 cells, chosen because they lack classical opioid receptors, which isolates the OGF axis cleanly. OGF depressed growth by 41.6 per cent; naltrexone increased cell number by 29.8 per cent; antisense to OGFr more than doubled cell number. And then the line that matters here: "Exposure to a wide variety of synthetic and natural opioid peptides, including those selective for mu, delta, and kappa opioid receptors, showed that only OGF had an effect." Mu-selective agonists, the class morphine belongs to, were put on this axis and did nothing.

3. The underlying premise is thinner than the framing suggests. The evidence that exogenous opioids suppress endogenous opioid production is real but narrow. Yukhananov and Handa 1997 (Brain Res Bull, PMID 9227847, L5) gave rats morphine 10 mg/kg and measured the proenkephalin primary transcript: levels fell in nucleus accumbens and olfactory tubercle from 0.5 to 24 hours, but not in dorsal striatum, and steady-state proenkephalin mRNA did not change at all. The authors state the significance is "not clear" for that reason. Bianchi 1988 (Neuroendocrinology, PMID 2963966, L5) gave rats oral morphine for 21 days and found plasma and hypothalamic beta-endorphin and methionine-enkephalin moved with pregnancy "without any specific effect of morphine". So: a transient transcriptional dip in two brain regions, not reaching steady-state message, and no chronic plasma effect.

Where her partner is right, and it is not a small thing

There is good preclinical evidence that morphine promotes tumour progression. It just runs through the classical mu receptor, not OGFr.

Mathew 2011 (Anesth Analg, PMID 21156980, L5 but a strong package), from Singleton and Moss at Chicago:

Declared conflict: Moss is a methylnaltrexone patent holder through the University of Chicago with stock options from Progenics. It is disclosed in the paper and is worth carrying.

So her partner's instinct is well founded and his mechanism is the wrong one. The worry that exogenous opioids are bad for a tumour has genuine support; the route is mu receptors expressed on the tumour itself, which is both simpler and better evidenced than ligand depletion of an autocrine enkephalin loop.

And the reconciliation, which is the point of the whole exchange

That preclinical package is exactly why Sessler 2019 was run. The Lancet trial's stated rationale names opioids as one of three perioperative factors thought to impair host defence against recurrence. Two thousand one hundred and eight women were randomised to find out, and recurrence was 10 per cent either way, hazard ratio 0.97, stopped for futility (PMID 31645288, L1).

Strong mechanism in cells and mice, tested properly in humans, did not translate. That is one of the most common shapes in oncology and it is the honest summary of this whole area.

Net effect on the patient: none. The advice is unchanged, and so is the reason for it. Bring the morphine down because it is not touching the sensory pain and because she does not want it. Do not bring it down faster than her pain allows in order to avoid a tumour effect that the one adequately powered randomised trial could not find.

Addendum, 14 September 2026 20:00: opioid-induced immunosuppression

Her partner, in em-research: "What about opioid induced immunosuppression", then "I've got quite a few reasons to get the patient off these opiates" and "Outside of the fact they're not taking her pain away."

The phenomenon is real and better established than either of the two previous threads. Morphine acting at the mu receptor downregulates natural killer cell activity, T and B cell responses to mitogens, antibody formation, phagocytic and microbicidal activity of neutrophils and macrophages, and cytokine production by macrophages and microglia. Receptor specificity was confirmed pharmacologically and in MOR-deficient mice (Eisenstein 2019, Front Immunol, PMID 31921165, L5 review). It operates both directly on immune cells and indirectly through HPA axis activation.

The human clinical evidence is about infection, not cancer, and it is decent. Wiese 2018 (Ann Intern Med, PMID 29435555, L3, nested case-control): 1,233 cases of invasive pneumococcal disease against 24,399 matched controls in Tennessee Medicaid linked to Active Bacterial Core surveillance, 1995 to 2014. Current opioid use adjusted OR 1.62 (95% CI 1.36 to 1.92). Dose- and formulation-dependent: long-acting 1.87, high potency 1.72, 50 to 90 MME/day 1.71, 90 MME/day or more 1.75. Consistent after applying an IPD risk score and when pneumonia and non-pneumonia cases were analysed separately.

Applied to the patient, this is more reassuring than it sounds, and the reason is the dose. The Wiese risk bands begin at 50 to 90 morphine milligram equivalents a day. Her peak was 90 mg on 10 and 11 September, squarely in the highest band. Today she is at 20 mg. By reducing she has already moved herself out of the range where the signal was strongest. That is a concrete argument that the reduction already under way is worth having, and it does not require her to reach zero to collect most of the benefit.

The differential-opioid story is widely repeated and the underlying data do not agree with each other. This matters because it is the point at which someone will suggest a switch.

Those two directly contradict each other on both buprenorphine and fentanyl. One is rat in vivo with a metastasis endpoint, the other isolated human cells with a cytotoxicity endpoint, and they disagree in opposite directions. So there is no defensible "switch to the immune-sparing opioid" recommendation to be made, and I am not going to make one. Anyone who offers a confident ranking here is reading one paper.

The accumulation, which deserves a straight answer

Her partner now has: it is not touching the sensory pain; she does not want it; her dose tripled between 6 and 11 September without the score moving, which is opioid-induced hyperalgesia; mu receptors on tumours with a strong preclinical package behind them; and now immunosuppression with a real human infection signal.

That is a good case and it should be said plainly rather than qualified into nothing. He is right that she should come off these.

The honest caution is not about whether, it is about rate, and it is one sentence: stacked reasons create momentum, and the only thing in this that can actually injure her is coming down faster than the non-opioid floor is built. The floor is still the same four items and none of them has been obtained: gabapentin titration with a written schedule, dexamethasone, a sphenopalatine ganglion block, and, if a swap is wanted rather than a cut, a conversion done from the true daily total.

Where the immunosuppression argument is actually most useful

Not as a reason to taper faster now. As a question for the surgical team.

She faces endoscopic transnasal skull base surgery, which carries meningitis risk, and she may already have a CSF leak. Perioperative NK suppression and infection risk are exactly where this literature bites, and it is the setting in which the whole field was developed. The useful form of her partner's question is therefore: can the perioperative and postoperative analgesia be planned to be opioid-sparing, using regional and local techniques and non-opioid adjuncts, given the meningitis risk and her low body weight.

Added to the appointment sheet as a question rather than argued here.

Addendum, 14 September 2026 20:15: Franchi 2007 and metastasis, and the finding that turns the argument round

Her partner, in em-research: "Franchi 2007 increased metastasis?"

Yes, in one condition, and the qualifier matters more than the headline. Chasing this one detail turned up the most important paper in the whole evening's exchange, and it cuts against the direction we had been travelling in.

What Franchi actually reported

Franchi 2007 (PMID 17291715, L5). Two separate findings:

  1. In normal, unstressed rats, morphine and fentanyl stimulated the HPA axis, decreased NK activity and augmented tumour metastasis. Buprenorphine did none of these.
  2. In surgically stressed rats, surgery itself raised corticosterone, suppressed NK activity and increased metastasis, and only buprenorphine prevented it.

The model, which needs stating before anyone builds on it

MADB106 is an NK-sensitive mammary adenocarcinoma line syngeneic to Fischer 344 rats. It is injected intravenously and lung retention or colony count is measured over roughly 18 to 24 hours (Page 1994, PMID 7865895; von Hörsten 2000, PMID 10821944, both L5).

It is therefore an in vivo natural killer cell function assay with a tumour endpoint, not spontaneous metastasis from a primary tumour. It measures how many circulating tumour cells survive NK clearance in the lung. That is a real and meaningful readout, and it is the experimental foundation of the entire perioperative-oncology hypothesis. It is not the same claim as "morphine makes tumours spread".

The paper that turns it round

Page, Ben-Eliyahu and Liebeskind 1994 (Brain Behav Immun, PMID 7865895, L5). Same rat strain, same MADB106 line, same lung retention assay.

The authors' own closing sentence: "these results reinforce concern about the pathogenic consequences of unrelieved pain."

The reconciliation, which is the point

Put the two papers side by side and there is no contradiction, only a condition:

Unrelieved pain is immunosuppressive in its own right, through HPA activation and sympathetic outflow. Adrenaline alone cut lung tumour cell numbers by 80 per cent within five minutes in the von Hörsten work, which shows how fast stress hormones move this endpoint.

What this means for the patient, stated plainly

the patient is not an unstressed rat. She is at 7 to 9.

The immunosuppression argument, followed all the way through its own literature rather than stopping at the first paper, does not support removing opioids from someone whose pain is uncontrolled. It supports controlling the pain, by whatever route works.

So the conclusion does not change but its force does. Get her off the opioids by fixing the pain, not by subtracting the drug. That is the same thing the hyperalgesia argument, the dose-response in Wiese, and the patient's own account all point at, and it is the fourth independent route to the same four asks.

One further caveat specific to her disease: chordoma metastasises late and uncommonly. Her problem now is local invasion of the clivus, cavernous sinus and cranial nerves. Even taking the MADB106 work entirely at face value, the endpoint it measures is not the one that is threatening her.

Research thread 13 · source file em-research/13-ldn-vitamin-d-immune.md · last edited 14 September 2026