BY the time Sheldon Pelletier turned 25, he thought he had only a few weeks left to live. A heroin addict for the past six years, living on the streets of Vancouver, he had lost count of the number of times he’d tried to kick the habit and failed. “Usually, I’d make it to day four,” he recalls. “On the fourth day, you get through most of the physical pain and then your brain clears up. That’s the worst, because you have to deal with your life.”
Then he heard about a mysterious drug that could help people like him. Called ibogaine, it wasn’t available from doctors, but an underground clinic in Vancouver was offering it to those in need. Pelletier eventually took three doses of the capsules. The second time, they triggered a bout of intense hallucinations. He saw scene after scene from his past experiences – both pleasant and unpleasant ones. When he came round, Pelletier had lost all desire for a fix of heroin. That was last September, and he’s been off heroin ever since.
Ibogaine, the substance that has made such a difference in Pelletier’s life, is an unlikely panacea. Its advocates claim it is a folk remedy unsurpassed for kicking heroin. A few even suggest it is a universal cure for drug addiction. But the evidence is scarce. There have been no controlled clinical trials, and there have been troubling side effects, including heart problems and even a few deaths. Partly for this reason, the few scientists working on ibogaine are trying to make safer derivatives. Two such products are nearing human tests, and their developers hope to find out in the next year or two if their long struggles will finally bear fruit.
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Ibogaine is an alkaloid compound that comes from the root of a shrub, Tabernanthe iboga, which grows in Gabon, West Africa. Here followers of the Bwiti religion use it in ceremonies for its vision-giving properties.
In the early 1960s, a young New York student named Howard Lotsof heard of ibogaine while he and his friends – several of them heroin addicts – were experimenting with a wide range of drugs. After trying it, five of the seven addicts found to their surprise they had lost their heroin cravings and stopped taking heroin for up to six months.
Ibogaine’s potency was so striking that Lotsof eventually decided to make championing the compound his life’s work. As the years passed, more and more people found that even a single dose of ibogaine could eliminate the horrors of heroin withdrawal and keep them off drugs for months at a time, even permanently. It seemed equally effective in helping people kick cocaine, and a few addicts found they could also quit smoking or drinking. “I realised the most important thing I could do was bring ibogaine to the medical community,” says Lotsof, who now heads the Dora Weiner Foundation, a non-profit drug users’ advocacy group in New York City.
We certainly need something new to help heroin addicts. The standard options are psychotherapy and regular prescriptions of an alternative opioid – usually methadone – that staves off withdrawal symptoms but gives no high. The theory is that addicts are stabilised on methadone before gradually cutting their dose, but many end up hooked on methadone instead, sometimes taking heroin too. A new option in some countries is a drug called buprenorphine, but again, this merely replaces heroin with another, more manageable opioid. Cocaine addicts have an even bleaker outlook than heroin users, with psychotherapy their main recourse. Part of ibogaine’s appeal is the possibility that addicts will be drug-free after only one or a few doses, or at worst may need only periodic doses, perhaps once a month.
But you couldn’t call Lotsof’s campaign a success. In the US ibogaine is a Schedule I drug just like heroin, which means that its use is illegal except for approved research. Belgium and Switzerland impose similar restrictions. Most other countries, including Britain, don’t ban ibogaine outright, but neither do they sanction its medical use, so it remains an underground treatment almost everywhere.
Ibogaine researchers say it deserves better. “There’s an old adage in medicine: listen to your patients,” says Stanley Glick, a neuro-pharmacologist at Albany Medical Center, New York. “If you hear the same anecdote from enough people, you’ve got to believe there’s something worth investigating.”
Glick has led some of the most persuasive studies of ibogaine’s effects in animals. He and others have found it binds to a bewildering range of receptors in the brain’s nerve endings, interfering to some degree with many of the brain’s signalling systems. These include the opioid receptors that also bind morphine, the substance to which heroin is converted in the brain and that is responsible for its effects. Ibogaine also binds to receptors for glutamate and acetylcholine, two of the brain’s key signalling molecules.
It is still a mystery which and how many of these actions account for ibogaine’s effects. But it clearly works. Glick showed that if rats addicted to cocaine or morphine were dosed with ibogaine, their appetite for the drug dropped off sharply and remained low for several days to weeks. The animals also showed few signs of withdrawal.
Still, as every researcher knows, what works in rats may fail in humans. Deborah Mash, a neuropharmacologist at the University of Miami Medical Center has done more research than anyone else with human subjects. In 1993, the US Food and Drug Administration gave Mash permission to start human studies. But unable to get funding for the trials, she headed offshore to the Caribbean island of St Kitts in 1996. There she could raise money by charging patients, which is not usually allowed for experimental drug treatment in the US.
Her clinic has now given ibogaine to more than 280 patients, most of them heroin addicts. “It’s very effective – well above standard treatment,” says Mash. But she refuses to give figures, saying that they would be meaningless based on so few patients. Ibogaine also seems to cut drug cravings in her patients who are cocaine addicts, she says.
Critics point out that Mash’s patients are hardly typical addicts. “Right away, you’re starting with a biased sample – people who can afford that kind of intervention, or come from families that can,” says Herbert Kleber, director of Columbia University’s division on substance abuse in New York City.
Still, Mash is convinced by what she sees. “I’ve got people who haven’t been able to put together 30 days [of abstinence], and then they get ibogaine and they can string together six months,” she says. “Is that a treatment success? You bet it is.” Some are still drug-free more than six years later.
Mash stresses, however, that ibogaine alone isn’t the answer; addicts still need psychotherapy. “You get people suffering from years of substance abuse,” she says. “They don’t have jobs, they’ve lost their friends – you’ve got to rebuild this person, and a single dose of ibogaine is not going to do that.”
Aside from Mash’s research, the literature on ibogaine’s use in humans comprises a motley collection of case studies. When Lotsof surveyed this research in 1995 he found that in 10 of 52 treatments patients stayed off drugs for a year or more, although in 15 they resumed their habit within two months. The anecdotal evidence is ambiguous, says Frank Vocci, director of the treatment research and development division at the US National Institute on Drug Abuse (NIDA) in Bethesda, Maryland. “There are some interesting, striking stories of people actually stopping drugs,” he says. “However, there are other stories of people who did not stop, and there are stories of people who got serious injuries and died while taking ibogaine.”
Because those deaths occurred in informal treatment settings rather than in carefully monitored medical trials, no one knows for sure whether ibogaine or some underlying medical condition was the cause. But ibogaine is known to have several worrying side effects, such as slowing the heart rate and possibly causing nerve damage at high doses. To complicate matters further, people metabolise ibogaine at remarkably different rates so it’s hard to predict the effect of any given dose.
“Ibogaine itself is probably never going to be used,” says Kleber. “It’s too toxic.” He is not the only one who thinks this. In 1995, the NIDA convened a panel of experts, many from the drug industry, to consider further investigating ibogaine. After hearing the evidence, the panel voted 9 to 4 against going on. Vocci says: “They figured it wasn’t worth it. It was going to be a problematic drug.”
That means the real action in scientific circles has shifted away from ibogaine itself towards two close molecular cousins. The hope is that these will offer the same benefits as ibogaine but with fewer side effects. And the patents on these drugs have much longer to run – a big plus for drug companies unwilling to risk much on ibogaine itself, as the first of Lotsof’s patents is due to expire this year.
Troubled by ibogaine’s side effects, Glick joined forces with medicinal chemist Martin Kuehne at the University of Vermont to find a less toxic alternative. After testing about 15 substances, they came across 18-methoxycoronaridine (18-MC), a synthetic relative of ibogaine that differs at just three points in the complex, multi-ringed molecule. When given to rats addicted to cocaine or morphine, this compound was as effective as ibogaine at reducing the amount of drugs they self-administered and it appeared to have fewer side effects. It also eliminated morphine withdrawal symptoms. Interestingly, 18-MC was even more effective at reducing rats’ craving for nicotine, Glick found.
Universal cure
In the brain 18-MC binds to some of the same receptors as ibogaine. The one to which it binds most avidly is the relatively rare alpha-3-beta-4 nicotinic receptor. This receptor is characteristic of a circuit called the alternate reward pathway, which may modulate the brain’s main dopamine reward pathway. Glick thinks that 18-MC may dampen down drug cravings via this route. “We’ve rediscovered the importance of this other pathway, and it serves to regulate the primary reward pathway,” he says. If he’s right, the implications would be huge. Glick would have a drug that could muzzle any addiction: heroin, cocaine, alcohol, nicotine, you name it.
But as sceptics are quick to point out, that notion is a long way from being proved. “I’ve been in this field 40 years and come across a lot of ‘universal cures’, and haven’t found that any of them stand up,” says Kleber. Addiction is a many-faceted disorder, he says, with genetic components and social ones, and there can be no one cure. Not everyone agrees that humans even have an alternate reward pathway.
Because of its association with ibogaine, Glick has struggled to get funding for 18-MC’s development. “Ibogaine has achieved a degree of notoriety,” he says. “Guilt by association has been a constant thorn.” In November, however, a group of investors – whose identity he prefers to keep secret – agreed to raise $5 million in the next two years for 18-MC’s first clinical trial.
Glick faces some competition. Mash is working on her own compound, a natural metabolite of ibogaine called noribogaine, which she thinks is the true source of ibogaine’s anti-addictive power. Within hours of taking ibogaine, the body has converted most of it into noribogaine. Mash has found that, as with ibogaine, giving noribogaine to addicted rodents stops them helping themselves to morphine or cocaine and stops withdrawal symptoms. Noribogaine also binds to many different receptors in the brain. Mash thinks the most important of these is the mu-opioid receptor, the main binding site for morphine. Morphine flits repeatedly on and off this receptor, and that may account for its kick. Mash thinks noribogaine locks firmly onto the receptor and stifles the stimulus.
Mash has not yet given noribogaine to humans, but for several years she has been checking its levels in her St Kitts patients after they take ibogaine. Noribogaine levels peak a few hours after taking ibogaine, just as the hallucinations and heart effects start fading.
And one patient who quickly converted ibogaine to noribogaine had no hallucinations. In contrast, a slow metaboliser had hallucinations for hours. The implication is that using noribogaine may get round some of ibogaine’s side effects.
Within the next six months Mash should be ready to seek FDA approval to test noribogaine in US patients. But she worries that in shedding ibogaine’s hallucinogenic baggage she may also lose one of the keys to its success. Many patients say the hallucinations allow them to review their lives and past decisions, and that they emerge from the experience resolved to do better. “For some, it really is somewhat of a life-transforming experience,” says Mash.
Certainly, that was true for former addict Pelletier, who thinks the visions forced him to deal with the reasons he started taking drugs in the first place, and let him do so without the fear that would usually accompany starting over in life. He recalls: “It really cleansed me out – the hallucinations, the visions are mandatory if you’re trying for something more than physical detox.” But until someone tests noribogaine in humans, no one will know whether it has the same effect as ibogaine without the hallucinations.
If they don’t, Mash thinks ibogaine’s Schedule I status should be revoked so that doctors could provide “compassionate use” of it on an unlicensed basis. She says: “They’re going to take it once or twice in their life. Then let them have noribogaine. That’s going to keep the cravings away, and keep the depression away. And that’s something a pharmaceutical company can make money on.”
For all their tantalising promise, though, ibogaine and its derivatives remain the poor relations in the drug-treatment world. “Ibogaine was an outsider’s invention,” says Lotsof. “It was a drug principally discovered and developed by drug users. If you were a researcher who had spent years developing your career, the last thing you’d want is that someone with no academic credentials has developed the grail that you’ve been seeking.”
Mash agrees one of the main obstacles is ibogaine’s image problem. “It’s got every darn thing going against it,” she says. “But meanwhile it’s helping people, and that’s why it’s never gone off the radar screen.”