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The Discovery of Low Dose Naltrexone

Dr. Ian S. Zagon
November 01, 2009
Interview with Dr. Ian S. Zagon, Distinguished University Professor, Department of Neural and Behavioral Sciences, the Pennsylvania State University
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What first led you into your work on Low Dose Naltrexone (LDN)?

Around 1975, I was interested in the effects of exogenous opioids (opiates from external sources, such as heroin, methadone or morphine) on children who were born to mothers that were addicted. The scientific literature revealed that these babies and children had neurological difficulties and were lower in body weight. We (myself and Dr. Patricia McLaughlin) developed a model to look at this in animals. At the same time, I was also conducting another research project into neuroblastoma, a childhood tumor. When I found that these exogenous opioids altered the growth of developing animals, I decided to see if they could also depress the growth of cancer. And, lo and behold, experiments conducted around 1977-1978 in tissue culture revealed that they did! We then investigated whether exogenous opioids would repress growth of the real cancers in mice. And, once again, they did!

That must have been a very exciting time. How did you continue your research?

We wanted to see if these exogenous opioids exerted their action through an opioid receptor (like a 'key' fitting a 'lock'). We used a chemical which binds preferentially with the opioid receptor, known as an opioid antagonist, along with the exogenous opioid. We knew that if we could neutralize the effects of the exogenous opioid by preventing it from binding to the receptor, its effects must be caused when it does bind to the receptor.

How did you decide which opioid antagonist to use?

We chose to use naloxone, a pure opioid antagonist discovered (with Naltrexone) around 1960 by Blumberg and Dayton. We injected mice with neuroblastoma cells and then divided them into three groups. To the first group, we administered just the exogenous opioid (in this case, heroin), to the second group, we administered the exogenous opioid and naloxone, and to the third, we administered naloxone alone, to ensure that the naloxone itself had no effect on the cancers. We expected that if the heroin was repressing growth through an opioid receptor, the mice receiving heroin and naloxone would grow cancer at the same rate as the controls (the naloxone would block the effect of heroin because it preferentially displaces this at the opioid receptor), and also that naloxone on its own would have no effect. Yes, the heroin made the tumors grow smaller, and yes the heroin/naloxone combination yielded animals with tumors that grew the same as controls - suggesting that heroin worked on tumorigenesis by way of an opioid receptor. However, a complete surprise was that the naloxone animals also had delays in expressing the cancers, and the antitumor effects even surpassed the effects of heroin. This was shocking to us, yet exciting.

You must have been desperate to share these findings!?

I remember going to a major scientific meeting in Anaheim, California in 1979 or so in order to present these exciting findings. I went to the assigned room to present my paper and my wife accompanied me. When I got up to speak, the person speaking before me left and I presented the 15-minute paper to my wife, the chairman of the session, and the projectionist! There lie the illustrious beginnings of 'LDN'! The amusing part is that three years later we received over a million dollars in funding from NIH for our projects, and published two papers in Science heralding the discoveries.

But LDN is Low Dose Naltrexone. Why did you switch from naloxone to Naltrexone?

Naloxone is an opioid antagonist that is short-lived - lasting only 2 hours or so in the body. I decided that if naloxone was so great as an antitumor agent, Naltrexone, which is far more long-lasting and powerful, would be sensational. My excitement was driven by the thought that we had come upon a great new cancer fighting agent.

How did your research with Naltrexone proceed?

In 1980, we began an experiment in which we injected three different dosages of Naltrexone (0.1, 1, and 10 mg/kg) on a daily basis into mice that had been inoculated with cancer cells. We had no funding at this stage, so this was all done on our own time and at our own expense. We expected that the mice receiving the higher dose of Naltrexone would develop fewer tumors than those on the lower doses. After all, Naltrexone is an opioid antagonist that is far more potent and long-lasting than naloxone - and we already had great success with naloxone as an anticancer agent. However, much to our surprise, we discovered that the animals getting the 10 mg/kg each day were coming down with tumors far earlier than the controls. Yet there were no tumors in the group of mice receiving 0.1 mg/kg! One month after tumor injection all of the mice in the 10 mg/kg group and control group had tumors, but none of the mice in the 0.1 mg/kg group. By two and a half months, still only one-third of the mice in the 0.1 mg/kg group had a tumor. Mice receiving 10 mg/kg survived for a significantly shorter time than control animals. Among mice in the 0.1 mg/kg group that developed a tumor, these animals had a survival time of almost 50% longer than controls.

How did you begin to resolve these confusing observations?

I decided to investigate how long the Naltrexone acted on the opioid receptors. To do this, we use a small machine (like a hot plate) that measures how long it takes for an animal to detect heat. Exogenous opioids are known to suppress pain. The idea is to inject an exogenous opioid (morphine) which diminishes pain in the animals. If the morphine works, there is a delay before the animal experiences pain (and in some cases it does not feel pain at all). If an opioid antagonist like naloxone or Naltrexone is injected, then the animal feels pain because the morphine is displaced from the opioid receptors in the animal and becomes ineffective. Of course, we do not let the animals stay on the hotplate so they burn themselves, and we stop at 45 seconds (well before tissue damage occurs). We found out that at a dosage of 0.1 mg/kg, animals felt pain for the first 4-6 hours; in other words Naltrexone blocked the receptors for this period of time. After this time, we found that animals began to feel no pain when the morphine was injected. This means that after 4-6 hours, the Naltrexone was removed (metabolized), allowing the morphine once again to bind to the receptors. When we injected 10 mg/kg, the animals felt pain during the entire 24-hour duration of the experiment. This meant that at a dose of 10 mg/kg, Naltrexone was permanently bound to the receptors ('continuous opioid receptor blockade'), preventing morphine from binding at any stage. The 1 mg/kg had pain for around 12 hours and then no pain for the next 12 hours.

I know some of this is a little confusing, so let me just recapitulate. Animals with the highest dosage of Naltrexone (10 mg/kg) had increased tumor formation (tumorigenesis) and the drug lasted in its ability to block the opioid receptors for the entire day (continuous/full opioid receptor blockade). The animals with the lowest dosage (0.1 mg/kg) had decreased - or no - tumors and tumor growth, and the drug only lasted 4-6 hr/day (we called this intermittent opioid receptor blockade). The animals that received 1 mg/kg Naltrexone had cancer characteristics that resembled controls, and they had drug lasting around 12 hours per day.

How do you manage to explain these counter-intuitive findings?

Well, I was extremely perplexed! I gave real thought to these experiments, then one morning, shortly after the final data came in, it all dawned on me. We had observed that if Naltrexone blocked the opioid receptors for the entire 24 hours, endogenous opioids (those formed in the body, the 'endorphins') were blocked from the receptors and cancers were grew rapidly. If the blockade was for only 4-6 hours, the cancers either did not appear or were markedly delayed. This indicated to me that 1) endogenous opioids were really regulating the growth of these cancers and were antitumor agents, 2) endogenous opioids are tonically active - they work all the time and if you block them from receptors all the time then cancer growth is less controlled, 3) opioid antagonists can be used to modulate this process, 4) if you block opioid receptors part of the day, you get an exaggerated action of the opioids after the blockade, and 5) the intermediate dosage of drug produced animals that had tumor growth acceleration for 12 hours (when blockade was in effect) and tumor growth inhibition for the next 12 hours (when blockade was no longer in place) - giving you the net effect of tumor growth that looked like normal.

We also knew from previous scientific literature on the action of Naltrexone that opioid receptor blockade by such an opioid antagonist causes cells to have a compensatory increase in endogenous opioids and opioid receptors because they sense they are deprived of these elements. After the opioid antagonist (Naltrexone) is no longer present (having been metabolized by the liver), there is a period of super-sensitivity of the elevated levels of receptors to the increased levels of the endogenous opioids and one sees a more pronounced functional effect. If, the endogenous opioids were really inhibitory to growth (increase in cell number), then more opioids interacting with more opioid receptors would lead to a greater decrease in cell proliferation - hence, tumor cells would be depressed in replication. So, in the 4-6 hr period each day, we elicited what we call an upregulation in endogenous opioids and opioid receptors, and cell division was increased. But in the remaining 18-20 hr when the Naltrexone was no longer present, cell proliferation was greatly diminished by the high levels of opioids interfacing with the increased number of receptors. And, why did tumor growth in the 1 mg/kg Naltrexone group resemble control levels. Because for 12 hr each day there was an acceleration (Naltrexone blocked the "good" opioids from interacting with receptors and cell number increased), and for the next 12 hours when the Naltrexone was no longer present the increased opioids reacted with the increased opioid receptors and cell proliferation was reduced. Overall, therefore, this equaled out to a "normal" looking tumor growth.

How did you interpret these observations?

The interpretation of these experiments was that the duration of opioid receptor blockade by the opioid antagonist determined tumorigenic response, rather than drug dosage per se. To prove this point, we designed an experiment in which a dosage of drug (0.4 mg/kg) was given once a day to mice receiving transplanted neuroblastoma. This produced a reaction that we had seen earlier with 0.1 mg/kg - animals either not displaying tumors, or cancers that grew slowly. We then divided this dosage of 0.4 mg/kg into four individual dosages of 0.1 mg/kg (remember, this dosage proved very potent in arresting tumor expression in our first experiments). But, we now gave the 0.1 mg/kg not once a day, but every 6 hours; in essence, the animals were receiving 0.1 mg/kg Naltrexone for the entire 24-hour period. If it was drug dosage that was key, then we would predict that four times 0.1 mg/kg should yield the same results as 0.4 mg/kg given once daily. However, if it was duration rather than dosage that was important, then the 4 times/day of 0.1 mg/kg Naltrexone would accelerate tumorigenesis (you would be blocking endogenous opioids from opioid receptors continuously each day). The results showed that 4 times daily of 0.1 mg/kg accelerated tumor growth in the same way as a dosage of 10 mg/kg! This provided an important principle of opioid antagonist action how long the blockade of opioids from opioid receptors lasted was a determinant of the outcome.

Yet another test that distinguished an opioid-receptor mediated action from a non-opioid receptor effect of opioid antagonists on proliferating cells was to examine the stereospecificity of these compounds. A fast chemistry lesson...Nature has given our universe biological substances that exist as two mirror image forms of one another. Thus, 19 of the 20 naturally-occurring amino acids that make up proteins are "chiral", meaning that each can be arranged in two orientations around a carbon atom. The result is a mixture of "mirror-image compounds" called L- and D-amino acids. A great mystery of life has been the almost exclusive finding of the L-forms in proteins, the building blocks of life. Now, it turns out that the L-form of opioid antagonists like naloxone is three to four orders of magnitude more active than the D-form in its ability to antagonize the physiological actions of opioids. Therefore, opioid interactions at the receptor level are stereospecific, with isomeric forms showing markedly different affinities for opioid receptors. So, we designed an experiment in which tumor inoculated animals were given daily doses of either the L-form (-) or D-form (+) of naloxone. Remember, our very first studies with neuroblastoma taught us that naloxone was an antitumor agent. We found that tumorigenic events (the incidence of tumors, time to tumor appearance, and survival time) for mice receiving the L-form of naloxone indicated that this form acted like our earlier anticancer effects. However, animals given the D-form on a daily basis had characteristics of tumorigenesis comparable to control subjects that received injections of the vehicle without the drug. We went ahead and did the same experiments investigating the development of body and organ growth in rats using stereoisomers, and once again discovered that the L-form but not the D-form was the active ingredient. All of this pointed to an opioid receptor effect with respect to cancer or animal growth rather than a non-opioid receptor action.

Once this epiphany came to pass, we immediately asked if such a system only applied to cancer or to other phenomena as well, such as development. So we did similar experiments in rats. We found that baby rats receiving Naltrexone grow far more rapidly than those getting sterile saline if the dosage of Naltrexone blocks the opioid receptors for the entire day. Those developing animals who received a low dose of Naltrexone grew more slowly than controls. We repeated all the experiments described earlier (with the hotplate, for example), and found the same results we had observed with mice and cancer.

Likewise, the experiments that divided one dosage into four separate dosages given each day revealed again that duration of opioid receptor blockade was a major factor in determining growth effects. In 1981-1982 when we filed for patents on the use of opioid antagonists such as Naltrexone (and naloxone) as growth regulators (e.g., cancer, development) I had to provide the patent office with the dosages and regimens of Naltrexone and naloxone that humans could take. Using a weight basis of rats and mice, and knowing the pharmacokinetics/metabolism of Naltrexone in humans, we proposed that 3-10 mg/day of Naltrexone would yield a 'Low Dose Naltrexone' effect (growth retardation). A dosage of 30-50 mg/day or higher would block opioid receptors all day and enhance growth - this we knew from previous reports.

How did you share your findings with other researchers?

Our initial paper on the antitumor effects of naloxone was published in the Journal of Brain Research Bulletin in 1981. The first Naltrexone paper on the cancer research (both high and low doses) was submitted to Science on March 21, 1983, and was published August 12, 1983 (Science. 221:671-673, 1983). We also wrote another paper on Naltrexone and the growth of animals and this was published in Science on September 16, 1983 (SCIENCE 221:1179-1180, 1983). These were important papers (even historic, in retrospect) because they provided the first evidence that the endogenous opioids (not exogenous opioids like morphine) were growth regulators, and acted in non-nervous system cells/tissues (the opioids and opioid receptors were originally thought to be confined to the nervous system and to regulate neurotransmission of impulses).

How did these experimental findings begin to have an impact in the lives of real patients?

I had been receiving many inquiries about our experiments from doctors thinking of using this for therapy. Because I believe discoveries should be shared with others, I freely gave out information about dosages and how to use this therapy in humans. Around December, 1983 I received a telephone call from a Dr. Bernard Bihari who was very enthusiastic about our findings. At the time he was at Brooklyn's Downstate Medical Center, I believe. He asked me what dosages to use in his patients, and what Naltrexone would be good for in terms of diseases. The very next day he called me back and told me he took about 4 mg of Naltrexone in the evening and woke up feeling great (as I told him he would). I really never heard from him again, until many years later when someone mentioned that a Dr. Bihari in New York City was prescribing Naltrexone for all types of conditions.

Were your ideas quickly taken up by other scientists?

Many, many studies had to be performed to understand and verify our conclusions. I must tell you that my fellow scientists in general needed considerable convincing. We were suggesting that Naltrexone was really interfering or enhancing the body's own machinery to stimulate or repress cancer appearance/growth or body/organ growth. But... what questions needed to be asked to shore up our hypothesis that opioids were growth regulators? What was this machinery that was in our body perturbed by opioid antagonists such as naloxone or Naltrexone? There were a great many questions to be answered, and a great deal more research to be done.

Over the years, many of these answers have been found, and considerable evidence for the benefits of Naltrexone therapy in low doses, and high doses, has been provided. However, even now, more than 30 years after the original research began, important questions still remain, and the research continues...

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