Low Dose Naltrexone and Cancer

Questions from the Clinic:

What is naltrexone? Does low-dose naltrexone have anti-cancer properties? If so, in which cancers is it most effective? How does it compare with existing standards of care?

Figure 1: Naltrexone (C20H23NO4) has many purported uses beyond the treatment of alcohol and opioid use disorders at low doses, but its value in cancer is currently contested.

I. Introduction

Naltrexone is a semi-synthetic opioid antagonist approved by the U.S. Food and Drug Administration (FDA) in 1984 for the treatment of patients with alcoholism or opioid use disorders. Since receiving initial regulatory approval, naltrexone has gained traction in off-label settings at doses ten times less than those administered in patients with substance abuse disorders.(1) Clinical evidence, ranging from case reports to randomized controlled trials, indicates that low-dose naltrexone (LDN) has therapeutic value in Crohn’s disease, fibromyalgia, and other disease states featuring chronic inflammation or immune dysregulation.(2,3) That said, considerable controversy still surrounds the quality of evidence supporting the use of LDN among patients with cancer.(4) Clarifying the utility of LDN in cancer is paramount, as a well-tolerated, affordable, and relatively easy to administer drug would be a welcome addition to evolving oncology treatment arsenal. Many chemotherapies, while effective, have severe treatment-related adverse events that can prompt treatment discontinuation; others can lose efficacy over time and leave patients seeking viable alternatives.(5,6)

II. Mechanism of Action

Naltrexone’s properties appear dependent upon the concentration present inside the body.(4) At the standard dose of 50 mg, naltrexone functions as expected as a competitive antagonist of µ-opioid receptors expressed by cells in the central nervous system. Certain substances, like alcohol, promote the endogenous release of opioid peptides, which upon binding µ-opioid receptors activates the brain’s reward circuitry. Blockading these receptors disrupts this signaling pathway and weakens the euphoria that typically accompanies the consumption of alcohol.(7) Reducing the pleasure associated with alcohol intake and opioid use, in turn, helps individuals with substance use disorders suppress cravings and break their addiction.(8) Standard dosing of naltrexone, while useful in these contexts, simultaneously enhances cellular growth and proliferation by inhibiting opioid growth-factor cellular regulatory mechanisms.(4,9) This property renders naltrexone undesirable in patients with tumors (Figure 2):

Figure 2: Certain substances, like naltrexone, have different effects depending upon their concentration. A low-dose response that is opposite in effect to that seen at high doses is a phenomenon known as hormesis. Image courtesy Li et al. (2018)

LDN, in contrast to standard dose naltrexone, produces a temporary receptor blockade of µ-opioid receptors. Although the mechanism of LDN is not yet fully elucidated, available evidence indicates that it functions as a modulator of neuroglia–support cells in the central nervous system. Specifically, LDN disrupts another signaling cascade linked to Toll-like receptor 4 and reduces the synthesis of inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interferon-beta. Beyond reducing inflammation, LDN also promotes upregulation of the endogenous opioid system and circulation of met-enkephalin, otherwise known as the opioid growth factor. Endorphins produced in response to LDN stimulate natural killer cells and helper T cells and bind cancer cells, triggering apoptosis.(10)

III. Case Reports and Clinical Trial Data

Over the years, several case reports have emerged with evidence suggesting that LDN benefits patients with a variety of cancers. In a 50-year-old male with TTF-1 positive adenocarcinoma, clinicians prescribed LDN 4.5 mg HS (at bedtime) after the patient could not tolerate the second round of chemotherapy treatment. After initiating this complementary therapy, imaging technicians found no signs of recurrence in a PET scan performed 3 years later; findings were similarly negative in a computed tomography scan performed 4 years later. Although the patient remains on several medications (e.g., rivaroxaban, atorvastatin, metoprolol, LDN), clinicians caring for the patient believe that LDN warrants further consideration and research from the medical community.12 A separate group experimenting with LDN and a nutritional supplement (α-lipoic acid) uncovered similarly encouraging findings in a small cohort of patients with confirmed, advanced pancreatic cancer. Of the 4 patients treated with LDN, 2 individuals were free of disease progression after starting LDN, with the third achieving substantial clinical benefits. This third patient died after stopping the protocol after 14 months of diagnosis.(11) In the fourth patient, improvement after LDN therapy allowed for pancreatic cancer surgery. Ultimately, this fourth patient died from postoperative septicemia.(12)

Findings from recent randomized clinical trials have not proven as promising. In a placebo-controlled, double-blind study, investigators assessed the efficacy and tolerability of LDN 4.5 mg orally once nightly against placebo in patients with high-grade glioma. Participants in the trial received treatment over 16 weeks, with researchers measuring a pair of patient-reported outcomes: quality of life and fatigue. After the trial, the trial’s conductors concluded that LDN had no significant effect on the quality of life or fatigue in patients with high-grade glioma patients. Treatment-related adverse events in the LDN and placebo groups were attributable to the concomitant use of temozolomide –chemotherapy used for brain cancer.(13) On ClinicalTrials.gov, there is only one other clinical trial registered on LDN in cancer, entitled “Low Dose Naltrexone for Metastatic Melanoma, Castrate Resistant Prostate Cancer and Renal Cancer.” Sponsored by Brown University, this study intended to assess the efficacy of LDN in three different kinds of cancers in patients who had no previous exposure to chemotherapy. Researchers included this eligibility criterion because the previous weakening of the immune system reduces the potential for response to LDN. Unfortunately, according to the study record detail, investigators prematurely terminated the phase 2 trial because of insufficient enrollment.(14) No other trials are currently pending on LDN in cancer and published clinical guidelines from the National Comprehensive Cancer Network do not outline how it should be used in various cancers. That said, LDN’s distinct lack of toxicity in case reports makes it an intriguing, low-risk, adjunctive therapy worthy of investigation in future clinical trials.(15)

IV. Cost and Availability

Oral naltrexone tablets, typically covered by insurance providers, cost between $25 and $60 for a month’s supply.(16) Injectable naltrexone administered monthly lacks a generic form and ranges between $700 and $1,100.17.(17) The relative affordability of oral LDN, coupled with its favorable safety profile, makes it easy to obtain from various healthcare providers. Nationwide, several integrative cancer centers and compounding pharmacies companies offer LDN, like the Californian-based American Integrative Pharmacy, Nebraska-based Redline Specialty Pharmacy, and Florida-based Pharmacy Specialists.(18,19) LDN requires a prescription, so prospective patients cannot obtain this medication through traditional, retail pharmacies that offer other, over-the-counter medications. The LDN Research Trust, a United Kingdom-based nonprofit founded in 2004, features a pair of directories that individuals can use to locate pharmacists and prescribers close to them; the website also contains further patient educational materials and links to clinical links trials examining LDN in many different medical conditions.(20)

V. Conclusions & Future Directions

While LDN has not yet gained widespread adoption among the medical establishment due to the absence of clinical trial support, compelling evidence from scientific studies suggests that this therapeutic approach warrants closer examination. Further examination is particularly needed in the context of cancer patients, as the majority of investigations on LDN assess its value in pain management and immune-mediated disorders. Further research may also crucially unveil additional mechanisms through which LDN operates at the cellular level. By better understanding how naltrexone functions at lower doses, scientists and healthcare providers can identify candidate cancers in which it may be most useful. Because of its low cost and high tolerability, however, LDN is a worthwhile adjunctive therapy that patients should consider examining and researching with their clinicians. Even if it proves ineffective against cancer, its ability to possibly reduce perceptions of pain makes it an attractive alternative to opioids.

Stay strong and curious,

- Chuck

Charles J. Meakin MD, MHA, MS

Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.

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11 Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (α-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integr Cancer Ther. 2009;8:416-422.

12 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 α-lipoic acid/low-dose naltrexone protocol. Integr Cancer Ther. 2006;5:83-89.

13 Peters KB, Affronti ML, Woodring SW, et al. Effects of low-dose naltrexone on quality of life in high-grade glioma patients: a placebo-controlled, double-blind randomized trial. Supp Care Can. 2022;30:3463-3471.

14 Low dose naltrexone for metastatic melanoma, castrate resistant prostate cancer and renal cancer. https://clinicaltrials.gov/ct2/show/results/NCT01650350/. Updated March 4, 2022. Accessed May 5, 2022.

15 Schwartz L, Buhler L, Icard P, et al. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014;34(2):973-980.

16 Thomas S. Naltrexone: cost, dosage, and side effects. American Addiction Centers. https://recovery.org/treatment-medication/naltrexone/. Published November 29, 2021. Accessed May 5, 2022. .

17 Smith J. How much does naltrexone cost with and without insurance? Addition Resource. https://www.addictionresource.net/mat/naltrexone/cost/. Updated March 17, 2022. Accessed May 1, 2022.

18 Low Dose Naltrexone (LDN) Pharmacy | American Integrative Pharmacy. American Integrative Pharmacy. https://www.americanintegrative.com/low-dose-naltrexone-ldn-pharmacy-american-integrative-pharmacy/. Published May 26, 2017. Accessed May 5, 2022.

19 Low Dose Naltrexone (LDN). Pharmacy Specialists. https://makerx.com/low-dose-naltrexone-ldn/. Accessed May 5, 2022.

20 What is LDN? Low Dose Naltrexone Trust. https://ldnresearchtrust.org/. Accessed May 5, 2022.