The Biology of . . . Addiction

A controversial new drug seems to stop addiction cold.

By Michael Abrams|Thursday, May 01, 2003
The rats in Stanley Glick's lab are junkies. They spend their days and nights lounging around in steel cages, twiddling their claws, waiting for the next hit. Each rat has a small plastic tube protruding from the base of its skull. Once a day, for an hour, each tube is connected to an infusion pump that controls a syringe containing a common addictive substance: morphine, cocaine, nicotine, or methamphetamine. The rats are trained to pull levers for water, but for one hour each day they can use the same system to mainline as much of the drugs as they want. And they want. "Just about any drug that humans abuse, animals will self-administer," Glick says.

Glick gets the rats addicted only to get them back on the wagon later with a substance called 18-methoxycoronaridine (18-MC, for short). The new drug may be the miracle pill that addicts have always needed: A single dose of it can remarkably diminish both withdrawal symptoms and craving. By revealing its mechanism, Glick, director of the Center for Neuropharmacology and Neuroscience at Albany Medical College in New York, offers a new understanding of the brain's pleasure zones.

Eighteen-MC is a synthesized derivative of ibogaine, an extract of the bark of the root of the African iboga shrub. For centuries the Bwiti tribe of West Africa has used the root for initiation ceremonies and, in smaller amounts, to stay awake during long hunts. The drug's story as an anti-addictive began in 1962, when college dropout and heroin addict Howard Lotsof obtained a dose from a chemist friend. "What happened is indelibly ingrained in my mind," Lotsof says. "I was living with my parents. I felt my feet hit the ground, and I realized I had no desire to use opiates."

In 1986 Lotsof created a company called NDA International and began to supply ibogaine to a clinic for addicts in Holland. The clinic found that ibogaine works in three stages. First the addict has about four hours of waking dreams in which he seems to confront inner demons. This is followed by an eight- to 10-hour "cognitive evaluation period," during which the user analyzes the waking dream. Then comes a sleepless day or two, which Lotsof calls the "residual stimulation phase."

The clinic treated about 30 addicts and reported impressive results: After a single dose, a majority stayed off drugs for several months or more. But Lotsof was unable to find funding for follow-up studies—and they were needed: One of the patients died of unknown causes, and a study at Johns Hopkins University showed that high doses of ibogaine cause brain damage in rats. Lotsof's lack of scientific degrees, as well as his history of drug use, also raised questions.

"The personalities involved are, for lack of a better word, peculiar," says Glick. He is lanky, has a closely trimmed beard, and wears a white lab coat over black pants as if to match his Holstein-style rats. The closest he has ever gotten to drug culture is playing trumpet in a jazz band called SwingDocs. "Certainly in the beginning everybody thought that Lotsof was an absolute lunatic, and I was included. But when you hear the same things enough times from enough people who have taken ibogaine, you've got to believe that there is at least something there that is worth investigating."

In 1991 Glick and his colleagues began to look for a synthetic derivative of ibogaine without the drug's side effects. The search eventually led to Martin Kuehne, a chemist at the University of Vermont who is an expert on the anticancer drug vincristine. Vincristine is structurally similar to ibogaine, and Kuehne knew how to tinker with the compound to produce derivatives. Glick tested 15 or so of the derivatives on rats before zeroing in on 18-MC.

"Withdrawal is related to the rapidity with which the drug disappears from the nervous system," Glick says. "It really reflects the change from the drug state to the nondrug state." To test 18-MC's effect on withdrawal, Glick gave the rats a continuous supply of morphine. He then administered an opiate antagonist that removes morphine from the neurons in the brain and causes immediate withdrawal symptoms. The rats given 18-MC suffered few if any withdrawal symptoms. Unlike people who take ibogaine, who may tremble as well as hallucinate, the animals seemed normal.

Hallucinogens like ibogaine raise serotonin levels in the brain; 18-MC doesn't. At the same time, 18-MC counteracts the increase in dopamine levels that opiates create. When Glick's addicted rats received 18-MC, their dopamine levels plummeted. The next time the rats were offered their daily hour of fun, they just said no. "Here's a drug that supposedly decreases craving, that supposedly decreases self-administration, and it also appears to block a key neurochemical correlate," Glick says. "But the real question is how exactly it is doing this. And this question plagued us for several years."

Activities in the brain occur at synapses, where neurons and receptors almost touch. Neurons fire off chemicals known as neurotransmitters (of which serotonin and dopamine are two), and neurotransmitters find their way to particular receptors. By using a technique that isolates receptors, called patch-clamp electrophysiology, Glick's colleague Mark Fleck discovered that 18-MC blocks only one kind of receptor effectively (ibogaine blocks several, which accounts for its many side effects). Receptors of this kind are clustered in two very specific parts of the brain, which are connected by a channel called the habenulo-interpeduncular pathway.

Since the 1960s, scientists have known that the brain's primary reward circuit is the mesolimbic dopamine pathway. When rats are rigged with electrodes that allow them to stimulate this pathway by pressing a lever, they develop an instant and insatiable craving. "It's an amazing phenomenon," Glick says. "The rats wake up and as soon as they find the lever, they just go nuts pressing it. They'll do it to the exclusion of food and water." When Glick went back and examined similar studies done in the 1980s, he discovered that rats would behave the same way if they were allowed to stimulate another area of the brain—the medial habenula. As it happens, the medial habenula is also part of the habenulo-interpeduncular pathway. "What we believe is that we've found an alternate reward system that has been ignored for 15 years," Glick says.

The two pathways are tightly connected, and the secondary reward system seems able to modulate the activity of the primary pathway. When 18-MC binds to a receptor in the alternate circuit, it sends a signal to the main circuit that dampens its responsiveness. When the rats in a later study had 18-MC injected directly into this secondary pathway, they all but stopped administering morphine to themselves—at least for a day, and sometimes for a few weeks.

Despite the mounting evidence that 18-MC is a simple and clean way to end addiction, Glick, like Lotsof, has had trouble raising funds to test the drug on humans. The problem, he says, is guilt by association. In 1995 the National Institute on Drug Abuse hired a panel of nine academics and nine members of the pharmaceutical industry to review all the existing ibogaine research. After hearing presentations from Lotsof and others, 16 of the panel members reportedly voted to end trials of ibogaine in humans. Unfortunately, Glick says, 18-MC was tarred by the same brush. "I keep fighting the same battles over and over again," he says. "People lump 18-MC with ibogaine, and I'm constantly making the same point—that we've got something that is a hell of a lot better."

In the meantime, Glick gets about three calls a month from addicts and their families. "They're desperate for anything that will help," he says. "They've tried everything. They always want to know when can I give them 18-MC, and it's really hopeless. I'm just not in the position to do that yet."
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