A Clinical Review of Evidence and Practice

Yoon Hang Kim, MD, MPH, FAAMA

Introduction

In integrative oncology, clinicians are constantly seeking evidence-based adjunctive therapies that may support patients facing advanced or treatment-resistant cancers. One protocol that has generated considerable interest in the integrative medicine community is Berkson's ALA/LDN protocol, which combines intravenous alpha-lipoic acid with oral low-dose naltrexone. While the published evidence remains limited to case reports and small series, the clinical observations warrant honest discussion about both the potential and the limitations of this approach.

This review examines the available evidence for the Berkson protocol, discusses proposed mechanisms, outlines practical dosing parameters, and provides an honest assessment of where this therapy may fit within a comprehensive integrative oncology program.

Historical Background and Clinical Evidence

Dr. Burton Berkson developed this investigational protocol based on his extensive experience with alpha-lipoic acid, particularly in liver disease. The protocol gained attention following publication of several remarkable case reports, though it is essential to recognize that all human data consists of case reports and small, uncontrolled series rather than randomized controlled trials (Berkson et al., 2006; Berkson et al., 2009).

The initial case report described a patient with metastatic pancreatic adenocarcinoma who received IV ALA 300-600 mg twice weekly combined with oral LDN 4.5 mg nightly, alongside dietary modifications and supplements. This patient remained alive and well many years beyond predicted survival without significant toxicity (Berkson et al., 2006). A subsequent series reported on three additional pancreatic cancer patients, including both metastatic and non-metastatic cases, with some patients demonstrating prolonged survival and complete metabolic responses on PET imaging (Berkson et al., 2009).

Perhaps most striking was a detailed case report of a 71-year-old woman with hepatitis C-related hepatocellular carcinoma who received the comprehensive protocol. After approximately 27 months of treatment, PET/CT imaging demonstrated complete disappearance of her liver lesions (Clinics in Oncology, 2020).

Proposed Mechanisms of Action

Alpha-Lipoic Acid

Alpha-lipoic acid functions as a redox-active cofactor in mitochondrial dehydrogenase complexes and can regenerate other antioxidants while supporting glutathione synthesis and hepatic protection. In laboratory studies, ALA has demonstrated selective pro-apoptotic and growth-inhibitory effects in various tumor cell lines with minimal effects on normal cells, suggesting a potential therapeutic window (CCNM, 2024).

The proposed anticancer mechanisms include modulation of pyruvate dehydrogenase and pyruvate dehydrogenase kinase, potentially affecting the Warburg effect that characterizes cancer cell metabolism. Additional epigenetic effects related to histone deacetylase activity have also been proposed (CCNM, 2024).

Low-Dose Naltrexone

Low-dose naltrexone works through a mechanism quite different from standard-dose naltrexone. At low doses (3-4.5 mg), naltrexone transiently blocks opioid growth factor (OGF, also known as met-enkephalin) receptors for several hours, leading to a rebound increase in endogenous opioids and upregulation of OGF-OGF receptor signaling (Zotarelli Filho Scientific Works, 2023).

This pathway can exert antiproliferative and immunomodulatory effects in preclinical cancer models. The combined rationale suggests that metabolic and redox modulation by ALA plus immune and growth-regulatory effects of LDN may synergize to slow tumor growth, induce tumor dormancy, or occasionally produce radiographic remission (Cancer Therapy Advisor, 2024).

Typical Protocol Parameters

The following table summarizes the typical components as described in Berkson's published reports:

The protocol has been deployed mainly in patients with advanced or refractory cancer or severe liver disease, often after patients have declined or failed conventional therapy. It is frequently combined with dietary modification, lifestyle interventions, and additional nutraceuticals in comprehensive integrative protocols (Berkson et al., 2006).

Safety Profile and Clinical Considerations

Reported adverse effects of IV ALA in oncology settings are generally mild, including transient nausea, dizziness, and phlebitis when properly diluted and infused. Serious toxicity is rare in the published case literature (Cancer Therapy Advisor, 2024).

LDN is usually well tolerated, with possible effects including vivid dreams, insomnia, mild gastrointestinal upset, or skin reactions. These are often mitigated by dose adjustment. In my clinical experience, starting at lower doses and titrating slowly can minimize these effects, particularly in patients with depleted endorphin reserves.

Important cautions include: ALA can affect glucose metabolism, requiring monitoring in diabetic patients; potential interactions with certain chemotherapies or thyroid medications exist; and attention to thiamine and other B-vitamin status is warranted due to ALA's metabolic effects (CCNM, 2024).

An Honest Assessment: Limitations and Context

It is essential to be transparent about what we know and what we don't know regarding this protocol. All human data for the Berkson cancer protocol consists of case reports and small, uncontrolled series. There are no large prospective trials confirming efficacy, and the authors themselves note that the protocol appears to induce tumor reduction or dormancy rather than cure. Tumor progression can recur when therapy is stopped in some patients (Townsend Letter, 2023).

This does not mean the protocol lacks value, but it does mean clinicians must present it to patients with appropriate informed consent and realistic expectations. The combination should be considered experimental for oncology applications and should ideally be used with close monitoring and coordination with the oncology team.

Clinical Integration: A Practical Approach

In my practice, I approach integrative oncology by first reviewing and optimizing conventional care before adding integrative treatments. This aligns with Society for Integrative Oncology guidelines endorsed by ASCO. The ALA/LDN protocol may be considered for patients who meet certain criteria: those with advanced or treatment-resistant disease, patients seeking adjunctive options alongside or after conventional therapy, individuals with reasonable functional status who can commit to the treatment schedule, and patients who understand the experimental nature of the approach.

For LDN specifically, I recommend assessing each patient's functional capacity and what I call their "endorphin reserve" before determining dosing strategy. Severely ill patients often require much lower starting doses and slower titration schedules than standard protocols suggest.

Conclusion

Berkson's ALA/LDN protocol represents an intriguing investigational approach in integrative oncology with published case reports suggesting possible benefit in select patients with advanced cancers. The proposed mechanisms involving metabolic modulation, antioxidant support, and immune regulation provide biological plausibility, and the safety profile appears favorable in published reports.

However, honest medicine requires acknowledging that we lack randomized controlled trial data, and the protocol should be considered experimental. Clinicians incorporating this approach should do so within the context of comprehensive care, with appropriate informed consent, close monitoring, and coordination with oncology colleagues.

The key is individualization. There is no one-size-fits-all approach to integrative oncology, and this protocol represents one option among many that may benefit carefully selected patients.

References

Berkson, B. M., Rubin, D. M., & Berkson, A. J. (2006). 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, 5(1), 83-89. https://doi.org/10.1177/1534735405285901

Berkson, B. M., Rubin, D. M., & Berkson, A. J. (2009). 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, 8(4), 416-422. https://doi.org/10.1177/1534735409352082

Canadian College of Naturopathic Medicine. (2024). IV alpha-lipoic acid: Professional resource. https://ccnm.edu/sites/default/files/2024-05/IV-ALA-professional-resource-Jan2024.pdf

Cancer Therapy Advisor. (2024). Alpha-lipoic acid and cancer [Fact sheet]. https://www.cancertherapyadvisor.com/factsheets/alpha-lipoic-acid-and-cancer/

Clinics in Oncology. (2020). A review of the integrative treatment approach using the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Clinics in Oncology. https://www.clinicsinoncology.com/open-access/a-review-of-the-integrative-treatment-approach-usingnbspthe-6760.pdf

Kim, Y. H. (2018). Low dose naltrexone therapy: An evidence-based review and case histories. CreateSpace.

Kim, Y. H., & West, K. (2019). Treating chronic pain with low dose naltrexone and ultralow dose naltrexone: A review paper. Journal of Pain Management and Therapy, 3(1), 1-5.

LDN Research Trust. (2013). Bert Berkson presentation [Conference presentation]. LDN Conference 2013. https://ldnresearchtrust.org/sites/default/files/Bert-Berkson-2013-LDN-CONFERENCE.pdf

Townsend Letter. (2023). A review of the integrative treatment approach using the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Townsend Letter. https://townsendletter.com/a-review-of-the-integrative-treatment-approach-using-the-intravenous-alpha-lipoic-acidlow-dose-naltr/

Zotarelli Filho Scientific Works. (2023). Low-dose naltrexone in oncology: A systematic review. International Journal of Nutrology. https://ijn.zotarellifilhoscientificworks.com/index.php/ijn/article/download/386/356/544

About the Author

Yoon Hang Kim, MD, MPH, FAAMA is a board-certified preventive medicine physician specializing in integrative and functional medicine. A graduate of Dr. Andrew Weil's Integrative Medicine Fellowship at the University of Arizona, Dr. Kim has established integrative oncology programs at Miami Cancer Institute and the University of Kansas Medical Center. He has been prescribing LDN for over two decades and has presented at multiple LDN Research Trust conferences in Glasgow and Portland. Dr. Kim practices telemedicine through Direct Integrative Care (www.directintegrativecare.com), serving patients in Iowa, Illinois, Missouri, Georgia, Florida, and Texas.

Disclaimer: This article is for educational purposes only and does not constitute medical advice. The Berkson ALA/LDN protocol is considered experimental for oncology applications. Always consult with qualified healthcare providers before starting or modifying any treatment regimen.