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Thirty Five Years of LDN Research at Penn State University

Drs. Ian Zagon and Patricia McLaughlin
February 01, 2015
Interview with Drs. Zagon and McLaughlin at Penn State University
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Drs. Zagon and McLaughlin, more than 35 years after discovering the effects of Low Dose Naltrexone, how does it feel to have positively impacted hundreds of thousands of patients globally?

We are thrilled and amazed at how this simple observation that we made many years ago has blossomed into a therapy that has positively impacted many lives. We are humbled by the number of phone calls and emails from patients, family members, and even parents of children taking LDN, expressing their gratitude for how LDN has allowed them to lead normal lives. The steady acceptance of LDN by clinicians is also gratifying.

How has your understanding of LDN changed over time?

In short, our understanding of LDN is the same basic principle that we hypothesized in the early 1980s. The duration of blockade of the opioid receptor by low doses of Naltrexone, in this case the Opioid Growth Factor Receptor (OGFr), determines the biological response. Our studies published in the early 1980s in Science and Brain Research were accurate and have been proven over and over again in the last 3 decades. What we understand now is that LDN works by biofeedback mechanism to upregulate synthesis/secretion of endogenous peptides, particularly OGF. We know that LDN works independently of the immune system or other systemic factors, as we can alter cell replication in a tissue culture model where there is no immune system present. However, LDN does impact the immune system by inhibiting proliferation of activated T and B cells.

What are your current findings (summarized) regarding disorders for which you have been researching LDN: ovarian cancer, MS, etc.?

Focusing on just the last 10 years, we have been actively researching LDN in a variety of diseases including cancer, MS, and even diabetes.

1) With regard to cancer, we have recently investigated LDN for treatment of ovarian cancer, as well as breast cancer.

LDN was fully explored in tissue culture studies of human ovarian cancer cell lines SKOV-3 and OVCAR-3 by Dr. Renee Donahue as part of her doctoral thesis research; all of her studies have been published and are available on PubMed. A model system was established using short term Naltrexone treatment to investigate the mechanism of LDN in cancer. These studies demonstrated the efficacy of LDN is independent of the immune system and other systemic factors, as there is no immune system in a culture dish of ovarian cancer cells. A single application of Naltrexone for 6 hours inhibited growth approximately 25% over a period of 4 days. Culture media, and cancer cells, were assayed for levels of peptide and receptor; OGF levels were increased 37% in culture and receptor levels were increased as much as 133%. OGF and OGFr were neutralized by antibodies or molecularly reduced by siRNA technology and cell replication was shown to be unresponsive if the OGF-OGFr pathway was not intact.

In vivo studies of nude mice with human ovarian inoculated intraperitoneally revealed that LDN treatment reduced the tumor mass by more than 45%.

Molecular regulation of tumor cell progression was studied by stably overexpressing OGFr or under-expressing OGFr in ovarian cancer cells. With these genetically manipulated cell lines, in vitro and in vivo studies demonstrated that the OGF receptor was required for regulation of cancer cell growth by either OGF or LDN.

Evaluation of toxicity of LDN revealed that LDN given for at least 2 months to mice had no toxic effects corroborating our studies that LDN, and OGF, do not alter apoptotic or necrotic pathways.

With regard to breast cancer, studies on a human triple negative breast cancer cell line that lacks the normal hormone receptors that are responsive to therapy, revealed that LDN, and OGF, inhibited growth of this human cell line, suggesting that there may be new, non-toxic alternatives for patients with triple negative breast cancer.

2) With regard to autoimmune diseases, we have made substantial progress in the preclinical field of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). Depending on the strain of mouse and antigen, EAE can be induced to present as a chronic form or as a relapse-remitting form. We have studied both animal models and have used LDN, and OGF, to treat mice at the time of disease induction, as well as when the mice have established disease and there are signs of behavioral deficits in the mice. Tracking muscle tonicity and walking, mice are charted for their behavior, and remissions and relapses are recorded. Again, all of this research has been published, or will soon be published, and can be accessed through PubMed. We are delighted to reveal that OGF, and LDN, are effective at reversing the progression of chronic progressive EAE, and reducing relapses in RR-EAE.

In collaboration with our colleagues in the Department of Neurology, we are currently looking at levels of biomarkers in patients taking LDN, along or in conjunction with other FDA-approved therapies such as Copaxone. We are planning clinical studies to following LDN patients closely.

3) Basic research on the immune system has shown in tissue culture that LDN inhibits proliferation of activated T cells, as well as B cells. These are early responders to immunity and whether LDN also change the differentiation and distribution of T cells is unknown and currently understudy in our laboratory. We have examined T and B cells in culture, T and B cells from peripheral lymphoid tissue such as lymph glands and spleen, and T and B cells that have migrated to the spinal cord and brain following autoimmune stimulation.

What has most surprised you in the last five to ten years of LDN research?

Our biggest surprise is the broad-based effectiveness of LDN. Originally we studied LDN in cancer models, but it really has positive impact on autoimmune-diseases such as rheumatoid arthritis, fibromyalgia, and multiple sclerosis, as well as HIV/AIDS and cancer.

In which way do you think LDN is most misunderstood?

There are a few misconceptions: (i) LDN will not necessarily work for everyone, just as aspirin does not reduce pain or inflammation for everyone. (ii) Many folks still believe that "more" LDN is better, but it is not. Again, the duration of receptor blockade is critical, not the dosage. More LDN will have opposite effects and possibly even be detrimental. (iii) Although not a misunderstanding, physician knowledge about LDN is behind the curve, and more physicians and patients need to report their findings. This is the purpose of websites like LDNscience, and I encourage physicians to report the outcomes of patients so that more clinicians can rely on these findings and feel more comfortable prescribing LDN.

What is the list of projects you are currently working on to advance our understanding of LDN?

Several students in the laboratory are working on LDN as part of their doctoral thesis research. Specifically, we are continuing studies on (i) LDN therapy of multiple sclerosis, and examining biomarkers in patients on LDN. (ii) The role of LDN to modify T and B immune cell replication and possibly modify the distribution of Th1, Th2, or Th17 T cells is being examined. (iii) A new era of collaboration is beginning to examine whether LDN has a potential to deter abuse, addiction, and or death from opioid pain medications or illicit drug use.

What LDN research topic or direction are you most excited about or think holds the most promise?

Clinical studies demonstrating safety and efficacy for a variety of disorders including MS, fibromyalgia, and cancer. With widespread clinical trials and presumably good results, LDN will gain broader acceptance by clinicians, and possibly become more available. If LDN can be used to reduce addiction to opioids or pain medication, this will broaden the impact of LDN substantially.

In which areas do you think LDN is not getting enough attention?

As we alluded to above, clinicians are unaware of LDN and frequently, patients bring LDN to the attention of physicians, requiring the physician to either contact us or read websites (with possibly incorrect information) and make a decision about prescribing LDN. We would encourage clinicians to publish case studies and short reports in peer-reviewed journals so that other colleagues would be able to read, understand, and appreciate the safety and efficacy of LDN. Again, LDN does not work for everyone or for every disease - but it is safe and should be considered as a treatment, alone or in combination with other standard therapies, for many autoimmune disorders, and even early stages of cancer. Regarding cancer, LDN will be most effective if given when tumor burden is small or following resection of a tumor, in an attempt to curtail proliferation of residual neoplasia and metastases.

How can our LDNscience News subscribers be most helpful in advancing LDN research?

LDNscience News subscribers should continue to share their positive results, share the names of clinicians who will prescribe LDN, and share the names of pharmacies that will compound LDN. Importantly, patients need to encourage their physicians to report positive findings in clinical journals so that other clinicians can read and understand the utility of LDN.