00:00 to 02.26—Dr. Bihari gives his background and credentials.
Dr. Bihari: My medical training started at Harvard Medical School. I graduated in 1957. Then I trained in Internal Medicine at one of the Harvard teaching hospitals in Boston, Beth Israel, and then in Neurology at Massachusetts General in Boston. Then I went to the National Institutes of Health for two years doing brain physiology—brain research. I did another residency training in Psychiatry in New York, at Columbia Presbyterian Medical Center and then, over the following five or six years, I got very involved in working in Drug Addiction. By 1974, I was the City Addiction Commissioner. I ran all the programs that the city funded for addicts. Then in 1978, the governor and the mayor met, when the governor took over management of the city’s addiction programs, because the city was in a budget crisis. Mayor Koch saved about $8 million and I moved to the city health department as a Deputy Commissioner. I was the only deputy medical commissioner. I basically ran the city health department for about three years. Then I moved to King’s County Hospital, where I ran a cluster of addiction programs for drug addicts and alcoholics. By the early ‘80s, as the AIDS epidemic began, I got very concerned about it. I was seeing large numbers of the heroin addicts I was treating die. I had a couple of friends who died of HIV in the late ‘80s. I got very concerned about what I saw as a major epidemic—a worldwide epidemic—coming over time. That’s sort of a background, taking me up to the point where I started doing this research.
QUESTION: Can you talk about working with methadone?
Dr. Bihari: Yes, my first job with city government was running all of the city health department’s methadone programs. There were forty-one—shortly after the methadone system had been put in place. It was while I was doing that that the mayor, Abe Beame, moved the addiction services agency into the health department, and I took over the management of all the addiction programs: the drug-free and the methadone programs. And I ran both for about four years. I was one of the early proponents of methadone and, because of my job in city government, for a couple of years I was a major spokesperson for methadone—which in subsequent years, I had mixed feelings about. Then I became more broadly involved in drug addiction and alcoholism as a public health problem. Then, later, I shifted my energy to AIDS.
Q: How did your connection with Naltrexone begin?
Dr. Bihari: In 1984, the National Institute on Drug Abuse finished the development of Naltrexone as an adjunct to treating heroin addicts. Its purpose was to block the heroin high with the hope that it would become a very useful treatment for heroin addicts. It works in heroin addicts by blocking the receptors in cells, mostly in the brain in that situation. Heroin uses primarily the pain receptors. They're all called opioid receptors. Those that are involved in pain relief, and relief of fear. It’s a designer drug, really. It was designed in the laboratory to block those receptors and prevent heroin from having access to them. So addicts would take 50 mg a day in the morning and couldn't get high for hours. It would take a very large amount of heroin to overcome the high. The blockade caused by naltrexone. And when the drug came out, I was interested in trying it. I gave it to about two dozen heroin addicts who had recently stopped using heroin. None of them would stay on it. At the doses involved it caused anxiety, depression, irritability. They couldn't sleep, and even minor stresses that they could handle the day before, they couldn't handle on days that they took naltrexone in the morning. So it was out on the market, and has remained so since, but has been relatively little used.
One of the things I did know from its development, which I had followed closely because I was treating addicts, is that naltrexone, when taken in these high doses, would get the body to triple its production of endorphins. Endorphins are the hormones that heroin works by mimicking. They have a number of functions in the body. They relieve pain; they relieve fear. They're the hormones we use when we’re teenagers to cope with social situations and other anxiety-producing situations. It’s really endorphins that relieve the anxiety. They also play a major role during acute stress. For example, an animal who’s attacked in the jungle—his body responds by pouring out large amounts of endorphins, and in parallel, of corisol, which is a cortisone-related hormone. And the endorphins in that situation not only relieve the pain so that when the animal gets injured he’s not distracted. They relieve the fright. They also shift blood from the whole gastrointestinal tract where a lot of the blood flow is to the muscles and brain, which need it during a fight. And, most importantly, in this situation, they boost the immune system so that the immune cells double very quickly and the immune functions all improve with the large amount of endorphins poured out, so that if the animal gets injured, it’s much less likely to get infected, so there will be better wound healing. Because of its role in regulating immune function, I got interested in it in the mid-‘80s. In 1985, as I saw the AIDS epidemic expanding, I decided to shift my research energies from addiction to AIDS, and in particular, to look for something that might boost immune function. I knew that the immune system was regulated almost entirely by endorphins, and that also the endorphin production was markedly increased by naltrexone. My colleagues and I worked to find some way of using that ability of naltrexone to raise endorphins, but without the downside of naltrexone blocking the endorphins, the purpose being to find a way to raise endorphins to boost immune function. Along the way, we tested endorphin levels in ten people with AIDS and found they were extremely low—less than 30% of normal. So the hormones that people with AIDS need the most, to have the immune system fight the virus—those hormones are lacking. So, what we did was to do what's called a “dose ranging trial” to find the best dose of the drug to use to raise endorphins without blocking them at the same time.
What we did was we measured the endorphin rises with different doses of Naltrexone. We got the same rise with 50 mg, 10 mg, 5 mg, and 3 mg. What we were looking for was the smallest dose that could produce a full naltrexone-induced endorphin rise, if taken late at night. The reason the hour is important is that 90% of the endorphins are made in the middle of the night, between 2 and 4 in the morning. If a small dose of naltrexone is taken in the late evening, generally at bedtime, generally endorphin production is boosted as much as threefold, 300%. The naltrexone itself is gone in about 3 hours, but the endorphins remain elevated all the next day. So the naltrexone doesn't significantly block the endorphins but does cause them to rise. If someone with low endorphin levels starts taking low dose naltrexone every night, their endorphin levels will triple and stay tripled as long as they're taking the drug.
