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Naltrexone itself is a novel and innovative drug. When taken orally in high dose which provides a complete opioid receptor blockade, there can be increased cell proliferation. There have been many studies published using high doses for this effect in autism, fertility issues, brain diseases and compulsive addictive behavior disorders at doses of >50mg.

Other methods of delivery of Naltrexone are recently being studied in ophthalmology for treatment of ocular surface diseases such as impaired corneal wound healing and severe dry eye with ocular films (1) and eye drops (2). A Phase I clinical trial to test the tolerability of eye drops has also been published (3). For those living with complications in wound healing, topical Naltrexone cream in high concentration has also been studied because it encourages cell proliferation on the surface of the skin. This has been shown to enhance closure of epithelial, surgical, or full thickness cutaneous wounds in normal or diabetic individuals (4) (5).

In 1979 the effects of taking Naltrexone in low doses (LDN) was discovered. Two years of experimentation to clarify its mechanism were required to study the effects of LDN and were published in 1983 (6). LDN has been prescribed in doses <5mg in the clinical setting since the late 1980s (7).

There are a lot of questions surrounding what dose people should take with more and more people wanting to use this non toxic biotherapy approach to medicine for various illnesses. Here we will talk about how LDN modifies a biological system through the rebound effect. 

In order to benefit from taking LDN to manage autoimmune/central nervous system disorders and cancer, understanding it’s mechanism (8) is important to make an informed decision about your dosing protocol.

What happens when you antagonize the receptors?

When used in low doses (<4.5mg) LDN antagonizes a sufficient percentage of the receptors for a short period of time on average for about 4 hours.

During this time, it tricks your body into believing it is not producing endorphins and enkephalins, specifically met-5-enkephalin known as Opioid Growth Factor, (OGF). As a result, the body compensates by stimulating an enhanced production of these opioids along with their receptors (9). OGF is a tonically active, inhibitory endogenous peptide which is made in the adrenal gland, by all proliferating cells, and the brain. LDN also upregulates the opioid receptors and the all too important nuclear-associated OGF receptor (OGFr) during the receptor blockade time.

What happens during the rebound effect?

Antagonizing the receptors for around 4 hours allows the upregulated levels of the body’s OGF and receptor to then interact and work long enough during the rebound effect in a non toxic manner to produce a positive outcome of suppressing the unwanted proliferation of cells (in autoimmune conditions and cancer).

Of importance, is the understanding that if there is not an adequate amount of receptors for OGF and endorphins to bind to and interact, the body is not able to utilize the endorphins and OGF efficiently. Only when LDN is no longer antagonizing or blocking the receptors, can the upregulated levels of endorphins and OGF interact with its receptor. It is this cell interaction during the rebound effect that is critical to one’s health with controlling errant cell proliferation, inhibiting inflammation, slowing down disease progression and promoting homeostasis/healing

As LDN does not need to be in your system in order for you to reap the benefits, an important question that needs to be asked, is how long will the rebound effect last after taking LDN? For some, the rebound effect can last longer than 24 hours in which case every other day dosing or three times a week (Mon, Wed, Fri) dosing is beneficial.

Pre-clinical studies with Head & Neck cancer have shown that the upregulated levels of OGF remain elevated for one week (10). The six-month clinical trial with MS done by Dr Gironi in Italy has shown that beta endorphins remain elevated one month after patients stopped LDN (11). This reiterates that it’s not just the upregulated levels of OGF and endorphins that are important, but the length of time they interact with the receptors which can only happen when LDN is no longer blocking or antagonizing them.

What dose is the correct dose?

It is worth noting that if you want to benefit from the rebound effect, taking too high of a dose of LDN or taking it too frequently will cancel out this effect.

Some Doctors prescribe more frequent dosing ie three times a day at higher doses for chronic pain relief. We cannot find any peer reviewed articles/studies to support this protocol. This is a different approach when using LDN to control errant cell proliferation and to slow down disease progression.

Dr Patricia J McLaughlin states “The clinical use of LDN for treatment of autoimmune disorders outpaced rigorous scientific research. Even today, many internet-originated rumors exist that warrant clarification. For example, ‘‘more is not better’’. The fallacy in this statement is obvious; LDN patients should not be encouraged to increase their dosage or take more than one tablet daily. At present, the timing of administration of LDN is a patient preference, and there are no basic science studies that conclude morning or evening consumption is either harmful or better.” (12).

Dr Jarred Younger states “Successful treatment of chronic pain with naltrexone may require low dosages. Theoretically, a complete blockade of endogenous opioid systems would not be a desirable outcome with a chronic pain patient. Basic science evidence supports that concept by showing that low- and high-dose opioid antagonists have quite different impacts on the physiologic system.” (13)

With responses to LDN being so varied it is proving challenging for both Doctors and patients to get the best effect with dosing. Some Doctors recommend starting at a low dose (1mg) increasing by 0.5mg-1mg every two weeks with a view to alleviating any potential side effects. In the six-month clinical trial with MS, participants started out at 2mg and worked their way up to 4mg throughout the first month. Participants in the trial were allowed to remain at a lower their dose if they felt that this dose was most suitable (14). Typically, the dose people take varies between 2mg-4.5mg, either once daily, every other day or three times a week. Again, the maximum daily dose for LDN effects if 4.5mg once a day.

When using LDN for cancer, it is important to understand that cell proliferation happens during the time the receptors are blocked. It is the upregulated levels of OGF and its receptor that suppresses cancer cell proliferation which happens during the rebound effect. (15). Pre-clinical studies with an aggressive cancer have shown that taking LDN every other day is also effective. LDN can be used on it’s own or as an adjunct therapy to chemotherapy (16)

By using LDN, we are modulating the OGF-OGFr axis which helps balance the immune system and works towards slowing down disease progression. While we are discovering that for some diseases there aren’t enough OGF receptors for the OGF to attach to and other diseases have too many receptors and not enough OGF. Either situation creates an imbalance which needs correcting.

We hope by explaining the above, this will help further your understanding with making an informed decision about dosing. To speed up cell proliferation (fertility, brain diseases etc.) studies show a higher dose of Naltrexone may be beneficial. To slow down cell proliferation (autoimmune diseases/cancer), a low enough dose (LDN <4.5mg) to create a rebound effect is required.

LDN is novel in the sense that you only need a specific amount of the med to get the benefits. The science behind LDN and clinical evidence of the OGF-OGFr axis as a homeostatic regulator of proliferation has shown support that modulation of the OGF-OGFr pathway is an effective therapeutic paradigm for maintaining human health and treatment of disease (17).

References:-

(1)     Novel in situ gelling ocular films for the opioid growth factor-receptor antagonist-naltrexone hydrochloride: Fabrication, mechanical properties, mucoadhesion, tolerability and stability studies. International Journal of Pharmaceutics, 30 Dec 2014

(2)     Topical naltrexone reverses dry eye and restores corneal sensation in diabetes mellitus 2010 March 17. Ian S. Zagon, M.S., Ph.D., Matthew S. Klocek, M.S., Ph.D., Joseph W. Sassani, M.D., M.H.A., and Patricia J. McLaughlin, M.S., D.Ed.

(3)     Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: A Tolerability Study Liang David, Sassani Joseph W., McLaughlin Patricia J., and Zagon Ian S.. Journal of Ocular Pharmacology and Therapeutics. January 2016

(4)     Topical treatment with the opioid antagonist naltrexone facilitates closure of full-thickness wounds in diabetic rats McLaughlin PJ1, Pothering CAImmonen JAZagon IS.

(5)     Topical Naltrexone as Treatment for Type 2 Diabetic Cutaneous Wounds, Jessica A. Immonen, Ian S. Zagon, and Patricia J. McLaughlin Adv Wound Care (New Rochelle). 2014 Jun 1;

(6)     Naltrexone modulates tumor response in mice with neuroblastoma. Zagon IS, McLaughlin PJ

(7)     Low dose naltrexone for normalizing immune system function. Dr Bernard Bihari

(8)     Researchers discover mechanism of low dose naltrexone on cell proliferative-related disorders. Society for Experimental Biology and Medicine. R.N. Donahue, P.J. McLaughlin, I.S. Zagon

(9)     Low Dose Naltrexone: Tricking the body to heal itself. Society for Experimental Biology and Medicine. R.N. Donahue, P.J. McLaughlin, I.S. Zagon

(10)     Modulation of the Opioid Growth Factor ([Met5]-Enkehalin-Opioid Growth Factor Receptor Axis: Novel Therapies for Squamous Cell Carcinoma of the Head and Neck. Wiley Publications; Patricia J. McLaughlin, MS, Ded, Jaimon K Stucki, BS, Ian S Zagon, MS, PhD

(11)     A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis, Mult Scler 2008,M Gironi, F Martinelli-Boneschi, P Sacerdote, C Solaro, M Zaffaroni, R Cavarretta, L Moiola, S Bucello, M Radaelli, V Pilato, ME Rodegher, M Cursi, S Franchi, V Martinelli, R Nemni, G Comi and G Martino

(12)     Duration of opioid receptor blockade determines biotherapeutic response. Biochemical pharmacology. Patricia J McLaughlin, Ian S Zagon.

(13)     The Use of Low Dose Naltrexone as a novel anti inflammatory treatment for chronic pain. Jarred Younger, Luke Parkitny, and David McLain

(14)     A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis, Mult Scler 2008,M Gironi, F Martinelli-Boneschi, P Sacerdote, C Solaro, M Zaffaroni, R Cavarretta, L Moiola, S Bucello, M Radaelli, V Pilato, ME Rodegher, M Cursi, S Franchi, V Martinelli, R Nemni, G Comi and G Martino

(15)     Growth inhibition of thyroid follicular cell-derived cancers by the opioid growth factor (OGF) – opioid growth factor receptor (OGFr) axis. Patricia J McLaughlin, Ian S Zagon, Sunny S Park, Andrea Conway, Renee N Donahue and David Goldenberg

(16)     Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin. Experimental Biology Medicine. Donahue RN, McLaughlin PJ, Zagon IS

(17)     The opioid growth factor-opioid growth factor receptor axis: homeostatic regulator of cell proliferation and its implications for health and disease. Biochemistry pharmacology. McLaughlin PJ, Zagon IS