Low-dose Naltrexone

• Improved survival at 1 year among people with high-grade malignant gliomas treated with radiotherapy plus naltrexone (100 mg every other day), compared with radiotherapy alone in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects¹Lissoni P, Meregalli S et al. Radioendocrine therapy of brain tumors with the long acting opioid antagonist naltrexone in association with radiotherapy. Tumori. 1993 Jun 33;79: 198-201. Note: The dose in this study is a standard dose, much higher than a typical low dose for most off-label uses of naltrexone (0.5-5mg per day). This dose is applicable here because glial cells are derived from macrophages and are stimulated by opioid peptides, which are blocked by naltrexone.  

• No evidence of an effectoverall, one or more studies did not demonstrate that a treatment or intervention led to an expected outcome; this does not always mean that there is no effect in clinical practice, but that the studies may have been underpowered (too few participants) or poorly designed. Larger, well-designed studies provide more confidence in making assessments. on progression among 8 people with estrogen receptor-positive breast cancer treated with naltrexone in a small uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design²Vijayakumar J, Haddad T et al. An open label phase II study of safety and clinical activity of naltrexone for treatment of hormone refractory metastatic breast cancer. Investigational New Drugs. 2023 Feb;41(1):70-75.

Naltrexone and alpha-lipoic acid: weak evidenceone or more case studies, supported by animal evidence OR small treatment effects of limited clinical significance OR studies with no controls OR weak trends of effects (this is the CancerChoices definition; other researchers and studies may define this differently)

• Improvement in symptoms of  follicular lymphoma at 1 year in 1 person treated with LDN and initially with alpha-lipoic acid in a case report³Berkson BM, Rubin DM, Berkson AJ. Reversal of signs and symptoms of a B-cell lymphoma in a patient using only low-dose naltrexone. Integrative Cancer Therapies. 2007 Sep;6(3):293-6.
• Extended survival compared to expectations and 2 complete remissions among people with metastatic pancreatic cancer treated with a protocol of alpha-lipoic acid and low-dose naltrexone in case studiesa descriptive and exploratory analysis of a person, group, or event regarding changes observed over time; because changes due to treatment are not compared to similar changes over time without treatment, a case study is considered a weak study design⁴Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integrative Cancer Therapies. 2009 Dec;8(4):416-22; Berkson BM, Rubin DM, Berkson AJ. The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integrative Cancer Therapies. 2006 Mar;5(1):83-9.

Intravenous alpha-lipoic acid and vitamin C, low-dose naltrexone, hydroxycitrate, and a healthy lifestyle program: weak evidence

• Recovery from metastatic renal cell carcinoma (RCC) to stable disease with disappearance of the signs and symptoms of stage IV RCC and a return to work, continuing 9 years past first treatment in 1 person treated with intravenous alpha-lipoic acid and vitamin C, low-dose naltrexone, hydroxycitrate, and a healthy lifestyle program in a case study⁵Berkson BM, Calvo Riera F. The long-term survival of a patient with stage iv renal cell carcinoma following an integrative treatment approach including the intravenous α-lipoic acid/low-dose naltrexone protocol. Integrative Cancer Therapies. 2018 Sep;17(3):986-993.

Lipoic acid, hydroxycitrate, and low-dose naltrexone: weak evidence

• Tumor response during chemotherapy (1 person), or stable disease or very slow progression among 5 of 10 people with chemoresistant advanced metastatic cancers treated with a combination of intravenous lipoic acid at 600 mg (Thioctacid), hydroxycitrate at 500 mg t.i.d. (Solgar), and low-dose naltrexone at 5 mg (Revia) at bedtime in case studies. However, the remaining 4 patients had disease progression or needed to begin chemotherapy.⁶Schwartz L, Buhler L, Icard P, Lincet H, Steyaert JM. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Research. 2014 Feb;34(2):973-80.

• Fewer pro-inflammatory cytokines and symptoms among women with fibromyalgia treated with LDN compared to baseline in an uncontrolled triala study in which a therapy is used, but without a comparison group against which to judge outcomes; an uncontrolled trial is considered a weak study design⁷Parkitny L, Younger J. Reduced pro-inflammatory cytokines after eight weeks of low-dose naltrexone for fibromyalgia. Biomedicines. 2017 Apr 18;5(2):16.
• Clinical improvement among 74.5% and remission in 25.5% of people with inflammatory bowel disease not in remission and not responding to conventional therapy treated with LDN compared to baseline in a small uncontrolled trial⁸Lie MRKL, van der Giessen J et al. Low dose naltrexone for induction of remission in inflammatory bowel disease patients. Journal of Translational Medicine. 2018 Mar 9;16(1):55.

• Higher lymphocyte numbers during treatment with subcutaneous low-dose interleukin-2a biological response modifier used as immunotherapy to boost the immune system in cancer therapy; also called IL-2 among people with untreatable metastatic solid tumors receiving 20 mg oral melatonin per day in the evening with the addition of 100 mg naltrexone in the morning compared to interleukin-2 and melatonin alone in a small RCTrandomized controlled trial, a study design in which people are randomly assigned to either an experimental group or a control group to compare the outcomes from different treatments; an RCT is considered a strong design for determining a therapy’s effects; the researchers intentionally used a high dose of naltrexone, and during the light hours of the day instead of at night as is typical for LDN, to block a pathway that inhibits anticancer immunity and therefore to increase anticancer white blood cells during the treatment cycle⁹Lissoni P, Malugani F et al. Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous low-dose interleukin-2, melatonin and naltrexone: modulation of interleukin-2-induced antitumor immunity by blocking the opioid system. Neuro Endocrinology Letters. 2002 Aug;23(4):341-4.