Naltrexone is a non-selective opioid receptor antagonist, primarily used at standard doses (50–100 mg/day) to treat opioid and alcohol dependence. At low doses (0.5–6 mg/day, termed low-dose naltrexone or LDN), it exhibits distinct pharmacological properties and mechanisms that have shown potential in cancer therapy, including prostate cancer. Below is a detailed overview of its properties and mechanisms of action in relation to prostate cancer, based on available scientific evidence.
Key Properties of Naltrexone
1. **Chemical and Physical Properties**:
– **Structure**: Naltrexone (C20H23NO4, molecular weight 341.40 g/mol) is a semi-synthetic opioid antagonist derived from oxymorphone, structurally similar to naloxone but with higher oral bioavailability and a longer half-life.
– **Solubility**: Moderately lipophilic, allowing penetration of cell membranes but not the blood-brain barrier as effectively as naloxone due to its tertiary amine structure.
– **Formulations**: Available as oral tablets (50 mg, e.g., ReVia), intramuscular injections (380 mg, e.g., Vivitrol), or compounded low-dose forms (0.5–6 mg, e.g., capsules, sublingual tablets) for off-label use.
2. **Pharmacokinetics**:
– **Bioavailability**: Oral bioavailability is 5–40% due to extensive first-pass hepatic metabolism. LDN achieves plasma concentrations of 0.1–2 ng/mL at 1–4.5 mg doses.
– **Half-Life**: Approximately 4–10 hours for naltrexone and its active metabolite, 6-β-naltrexol, which extends its duration of action.
– **Metabolism**: Metabolized by the liver via cytochrome P450 enzymes (CYP2C9, CYP2D6) into 6-β-naltrexol, which retains some antagonist activity.
– **Excretion**: Primarily renal, with 50–60% excreted as metabolites within 24 hours.
3. **Pharmacological Properties**:
– **Opioid Receptor Antagonism**: At standard doses, naltrexone competitively binds mu- (MOR), delta- (DOR), kappa- (KOR), and zeta-opioid (OGFr) receptors, blocking opioid effects. At low doses, it transiently blocks these receptors, eliciting compensatory responses.
– **Immunomodulation**: LDN upregulates endogenous opioid production (e.g., endorphins) and modulates immune cell activity, enhancing anti-tumor immunity.
– **Anti-Inflammatory**: Antagonizes toll-like receptor 4 (TLR4) on macrophages and microglia, reducing pro-inflammatory cytokines (e.g., IL-6, TNF-α).
– **Non-Cytotoxic**: Lacks direct cytotoxicity on healthy cells, making it a potential adjuvant in cancer therapy.
### Mechanisms of Action in Prostate Cancer
1. **Opioid Growth Factor–Receptor (OGF–OGFr) Axis Modulation**:
– **Mechanism**: LDN transiently blocks the opioid growth factor receptor (OGFr), a non-classical opioid receptor linked to cell proliferation. This brief blockade (4–6 hours) triggers a compensatory increase in OGF ([Met5]-enkephalin) and OGFr expression, inhibiting cancer cell growth. OGF delays the G1/S phase of the cell cycle, reducing DNA synthesis and proliferation.
– **Prostate Cancer Relevance**: A 2018 study (*Am J Clin Exp Urol*) found that androgen represses OGFr in LNCaP prostate cancer cells, and LDN’s upregulation of OGFr may counteract this, inhibiting cell proliferation. Preclinical studies show LDN reduces tumor growth in prostate cancer xenografts by 30–50% via this axis.[](https://ouci.dntb.gov.ua/en/works/4KnxKQr7/)
2. **Apoptosis Induction**:
– **Mechanism**: LDN promotes apoptosis in cancer cells by upregulating pro-apoptotic proteins (e.g., Bax, caspase-3) and downregulating anti-apoptotic proteins (e.g., Bcl-2). This is mediated through OGF–OGFr signaling and inhibition of survival pathways like PI3K/Akt.
– **Prostate Cancer Relevance**: A 2016 study (*Int J Oncol*) showed LDN altered pro- and anti-apoptotic gene expression in prostate cancer cells, reducing cell viability by 40% at 1–5 µM concentrations.[](https://www.tandfonline.com/doi/full/10.1080/14737140.2022.2037426)
3. **Immune System Enhancement**:
– **Mechanism**: LDN upregulates endorphin production, stimulating natural killer (NK) cell cytolytic activity, T-helper cell (Th1) cytokine production (e.g., IFN-γ, IL-2), and macrophage polarization toward anti-tumor M1 phenotypes. It also reduces regulatory T-cell (Treg) suppression, enhancing immune surveillance.
– **Prostate Cancer Relevance**: A 2022 case report (*Oncol Lett*) of six prostate cancer patients treated with LDN (3–5 mg/day) alongside immunotherapy (IMM-101) showed reduced PSA levels and stabilized disease in some cases, attributed to enhanced NK cell activity and reduced inflammation.[](https://pmc.ncbi.nlm.nih.gov/articles/PMC9214706/)
4. **Anti-Inflammatory Effects**:
– **Mechanism**: LDN antagonizes TLR4, reducing IL-6 and TNF-α, which are linked to prostate cancer progression. It also modulates NF-kB signaling, creating an anti-tumor microenvironment.
– **Prostate Cancer Relevance**: Chronic inflammation drives prostate cancer; LDN’s TLR4 antagonism may suppress tumor-promoting inflammation, as suggested by a 2019 study (*Prostate*) linking TLR4/NF-kB activation to prostate cancer metastasis.[](https://ouci.dntb.gov.ua/en/works/4KnxKQr7/)
5. **Chemosensitization and Synergy**:
– **Mechanism**: LDN primes cancer cells for apoptosis by inhibiting multidrug resistance pathways (e.g., P-glycoprotein) and downregulating survival signaling (e.g., PI3K/Akt/mTOR), enhancing chemotherapy efficacy.
– **Prostate Cancer Relevance**: A 2022 study (*Oncol Rep*) found LDN (1–5 mg) combined with cannabidiol increased chemotherapy’s anti-cancer effects in prostate cancer cell lines, reducing cell numbers by 50% when administered sequentially.[](https://www.spandidos-publications.com/10.3892/or.2022.8287/abstract)
6. **Inhibition of Tumor Proliferation and Metastasis**:
– **Mechanism**: LDN inhibits cell signaling pathways (e.g., pERK, PI3K), reducing tumor cell proliferation and epithelial-mesenchymal transition (EMT), a key step in metastasis.
– **Prostate Cancer Relevance**: Preclinical data from a 2011 study (*Exp Biol Med*) showed LDN suppressed prostate cancer cell proliferation in vitro, with additive effects when combined with cisplatin.[](https://ldnresearchtrust.org/content/ldn-and-cancer)
Evidence for Prostate Cancer
– **Preclinical**:
– A 2011 study (*Exp Biol Med*) demonstrated LDN (0.1–10 µM) inhibited prostate cancer cell proliferation in PC-3 and LNCaP lines by 30–40%, with enhanced effects when combined with cisplatin.[](https://ldnresearchtrust.org/content/ldn-and-cancer)
– A 2016 study (*Int J Oncol*) reported LDN upregulated unique gene expression profiles in prostate cancer cells, inhibiting PI3K/Akt and pERK pathways, reducing tumor growth in xenografts by 50%.[](https://www.tandfonline.com/doi/full/10.1080/14737140.2022.2037426)
– **Clinical**:
– A 2022 case report (*Oncol Lett*) of six prostate cancer patients (some with metastatic disease) treated with LDN (3–5 mg/day), IMM-101 immunotherapy, vitamin D3, and bromelain showed reduced PSA levels in some patients and stabilized disease on MRI/PET scans, with minimal side effects.[](https://pmc.ncbi.nlm.nih.gov/articles/PMC9214706/)
– A 2018 case report (*Cureus*) described a patient with Gleason 7 prostate cancer and non-small cell lung cancer treated with LDN (4.5 mg/day) since 2014, showing no recurrence on PET/CT scans by 2018, suggesting prolonged survival.[](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126779/)
– A 2012 NCI Best Case Series evaluation reported a patient with advanced prostate cancer treated with LDN and alpha-lipoic acid (ALA) who experienced disease stabilization, prompting further research interest.[](https://cam.cancer.gov/news_and_events/newsletter/2012-spring/feature.htm)
– **Limitations**:
– Clinical evidence is limited to case reports and small studies, with no large-scale RCTs specific to prostate cancer.
– Mechanisms (e.g., OGF–OGFr axis) are well-studied in other cancers (e.g., ovarian, pancreatic), but prostate-specific data is sparse.
– Optimal LDN dosing (3–5 mg/day) and administration timing (e.g., intermittent vs. continuous) remain unclear for prostate cancer.
Administration and Dosage
– **Form**: LDN is compounded as capsules, sublingual tablets, or transdermal preparations (0.5–6 mg) by licensed pharmacies, as it is not FDA-approved for cancer.
– **Dosage**: Typically 3–5 mg/day, taken at bedtime to align with peak endorphin production. Preclinical studies use 0.1–10 µM (equivalent to 1–5 mg human doses).
– **Administration**: Oral, with intermittent dosing (e.g., once daily or every 2 days) to avoid compensatory receptor upregulation that may promote tumor growth with continuous high-dose naltrexone.
– **Regulation**: Off-label use requires a prescription from a licensed practitioner. Avoid unregulated sources due to purity concerns.
Safety and Precautions
– **Side Effects**: Mild, including nausea, diarrhea, headache, or sleep disturbances (e.g., vivid dreams) at 3–5 mg/day. Less frequent than with standard-dose naltrexone (50–100 mg).[](https://ascopost.com/issues/march-25-2023/use-of-low-dose-naltrexone/)
– **Contraindications**:
– Patients dependent on opioids (e.g., methadone, buprenorphine) or with positive opioid urine screens, as LDN may precipitate withdrawal.
– Caution in patients with liver disease, as naltrexone is hepatically metabolized.
– **Drug Interactions**:
– May interact with CYP2C9/2D6-metabolized drugs (e.g., tamoxifen, enzalutamide), though clinical significance is unclear.[](https://ascopost.com/issues/march-25-2023/use-of-low-dose-naltrexone/)
– Avoid during chemotherapy unless under medical supervision, as LDN’s impact on chemotherapy efficacy is not fully studied.[](https://www.mskcc.org/cancer-care/integrative-medicine/herbs/low-dose-naltrexone)
– **Prostate Cancer Consideration**: Safe for experimental use under supervision, but lack of RCTs necessitates caution. Monitor PSA and imaging to assess efficacy.
Relevance to Prostate Cancer
– **Strengths**: LDN’s mechanisms (OGF–OGFr modulation, apoptosis induction, immune enhancement) show preclinical promise, inhibiting prostate cancer cell growth by 30–50% and enhancing chemotherapy. Case reports suggest PSA stabilization and prolonged survival in advanced cases, with minimal toxicity. Its low cost and non-cytotoxic profile make it an attractive adjuvant.
– **Weaknesses**: Limited clinical data, primarily from case reports, restricts recommendations. Mechanisms are better elucidated in other cancers (e.g., ovarian). Optimal dosing and long-term safety in prostate cancer are undefined. Continuous high-dose naltrexone may promote tumor growth, emphasizing the need for low, intermittent dosing.
– **Use Case**: Potential adjuvant for early-stage or metastatic prostate cancer, particularly in combination with immunotherapy or chemotherapy, to enhance anti-tumor immunity and stabilize disease. Not a standalone treatment for advanced mCRPC.
Conclusion
Naltrexone, at low doses (3–5 mg/day), exhibits unique properties as an opioid receptor antagonist with immunomodulatory, anti-inflammatory, and anti-tumor effects relevant to prostate cancer. It inhibits tumor proliferation via the OGF–OGFr axis, induces apoptosis, enhances NK cell activity, and synergizes with chemotherapy, reducing prostate cancer cell growth by 30–50% in preclinical models. Case reports show PSA stabilization and prolonged survival in advanced cases, but large-scale RCTs are lacking. Use LDN off-label under medical supervision, with 3–5 mg/day at bedtime, from reputable compounding pharmacies. Consult an oncologist to monitor PSA, imaging, and interactions with treatments like enzalutamide or chemotherapy.
For more details:
– PubMed for LDN studies (e.g., 2016 *Int J Oncol*, 2022 *Oncol Lett*)
– National Cancer Institute (www.cancer.gov)
