Imagine a heroin addict taking a substance to get high and finding it cured his addiction? That’s what reportedly happened to Howard S. Lotsof in 1962 when he swallowed a bitter-tasting white powder that was derived from a South African shrub called Tabernanthe iboga. In the nearly 40 years since then, Ibogaine, as the drug was called, has had a checkered history in the long and difficult process of coming to market as a legitimate medication. It’s not here yet, not legally, that is, and it may never be – at least not in its present form – and maybe not for the disease originally intended. But that’s getting ahead of the story.
How Ibogaine Got Its Start in the U.S.
Ibogaine isn’t new. Its roots, literally, trace to West Central Africa, where T. iboga was purportedly known by Pygmies of the Congo Basin for 20,000 years. T. iboga is still used today in certain religious tribal ceremonies in Africa.
As to more modern history, T. iboga has been around for more than 100 years, with the first description and the first specimen brought to France from Gabon in 1864. In 1885, a description of its ceremonial use in Gabon appears. Between 1901 and 1905, ibogaine is isolated and crystallized from the T. iboga rootbark. Ibogaine was originally developed as an ethno-medicine. It was marketed as a neuromuscular stimulant in France under the trade name Lambarene and prescribed in low doses for about 30 years (1939-1970) for the treatment of fatigue, depression and recovery from infectious diseases.
Although ibogaine was administered to 8 already detoxified morphine addicts at the U.S. Addiction Research Center in Lexington, Kentucky in 1955, not much else happened with the drug in this country for a while, with the exception of the first description of definitive chemical structure reported in 1957 and first total synthesis published in 1965.
Meanwhile, in 1962, while people were experimenting with LSD and psilocybin, a small amount of ibogaine got into the U.S. in diplomatic pouches. The drug made its way into various circles in California and New York, and Howard Lotsof got his hands on some. He took a dose of Ibogaine and found out 36 hours later that he wasn’t dope-sick, wasn’t going through opiate withdrawal and he hadn’t used any heroin. He repeated that experiment with a few of his friends, some of whom were freebasing cocaine. And they, too, stopped. Lotsof figured out right then and there that there was something to this.
Between 1967 and 1970, the World Health Organization (WHO) classifies ibogaine with hallucinogens and stimulants as substances likely to cause harm to individuals, and the U.S. Food and Drug Administration (FDA) assigns it a Schedule I drug under the Controlled Substances Act. Schedule I drugs have a high potential for abuse, have no current accepted medical use in treatment in the U.S., and there is a lack of accepted safety for use of the drug under medical supervision. In 1969, a psychiatrist in France receives a French patent for low-dose Ibogaine for psychotherapeutic use.
Nevertheless, progress in the development of Ibogaine as a legitimate drug stayed dormant until the 1980s when Lotsof put together a corporation, of sorts, called NDA International. Here, it is necessary to disclose that much of the following information comes from a recent interview conducted by the author with Deborah Mash, Ph.D., professor of neurology and molecular and cellular pharmacology at the University of Miami. Dr. Mash, it will be revealed, has a long history of involvement, along with respected medical colleagues, in trying to bring Ibogaine to the forefront as an Investigational New Drug (IND).
Lotsof’s sole purpose was to get someone behind Ibogaine. They did an underground railroad, of addicts helping addicts in the 1980s up to early 1990s. They were shuttling addicts across to the Netherlands, where there was a doctor working with them. These Ibogaine treatments were conducted outside conventional medical settings and involved NDA International and two other groups: Dutch Addict Self-Help Group (DASH), and the International Coalition of Addict Self Help (ICASH). Lotsof filed for and received patents for ibogaine for opiate (heroin) withdrawal, but also for dependence on psycho stimulants like cocaine, as well as nicotine, alcohol and poly-drug dependence.
How Ibogaine Gains Wider Interest from Respected Medical Community
Dr. Mash had heard about ibogaine three separate times in the 1990s. The third time, Howard Lotsof contacted her at her office at the University of Miami, “because I had just been getting recognition for some work that I was doing on cocaethylene – what is formed in the body when you drink alcohol and use cocaine. We discovered that it was more potent and more lethal – and we were getting national recognition for this.” In the course of the conversation, Dr. Mash asked Lotsof, “What is this, how does it work, what is the mechanism of action, what do we know about it, and is this real?” Lotsof came down to the University of Miami and the two met in person. Dr. Mash told Lotsof that if ibogaine is real, someone should be testing it. It should be tested in an academic medical center. At the time, 1991, there was only methadone and no medication for the treatment of cocaine addiction.
Intrigued, in 1992, Dr. Mash went to see with her own eyes an ibogaine treatment in the Netherlands. Upon her return she wrote the first IND application for ibogaine to the FDA, submitting it from the University of Miami with her colleagues. Dr. Mash started clinical trials and began to raise funds for them. At the same time, Dr. Mash talked to the National Institute on Drug Abuse (NIDA) and tried to enlist their support. So, while she worked closely to get support of her colleagues and peers, she also worked closely with the FDA to go forward.
“The FDA was incredibly cooperative, wonderfully helpful, and understood that we were an investigator-initiated IND,” says Dr. Mash. “We weren’t the big drug companies, we were academics, and they were extremely helpful. And at the same time NIDA was looking into this, and had put some money into doing some animal work, and to do some of the things that are necessary in drug development – for any drug that’s going through the FDA. You have to have certain animal studies, to look at safety, to look at tolerability, toxicity, etc.”
Dr. Mash and her colleagues have their first meeting with the FDA in 1993 and receive permission to go forward at the University of Miami, first in Ibogaine veterans. “These were individuals that had already taken a dose of Ibogaine but could elect to be part of a Phase I study – basically a dose run up where you’re looking at the dose and the effect and you’re just getting an understanding of the levels in blood. We knew nothing about Ibogaine, so we were really starting from scratch.”
Some of the studies were conducted at the University of Miami, and Dr. Mash and her colleagues were trying to work with Lotsof. It was also hard to find Ibogaine veterans, who would have to fly into Miami to be part of the trial. “It was an impossible trial,” recalls Dr. Mash. “In the course of all this, Howard Lotsof has a death. A woman dies in the Netherlands. And she dies because he accidentally overdoses her. She was a healthy young woman and it was an accidental overdose.”
After working up that case and some other cases, Dr. Mash says she told Lotsof: “You cannot proceed like this. You have to proceed in a proper medical facility. I’m in the FDA with an IND for ibogaine and you cannot be having adverse events.”
To remedy what could prove an untenable situation, Dr. Mash got permission and found a doctor in Panama and set Lotsof up with a program in Panama under a proper medical doctor. “Not only that, he was flying the patients here to Miami – which was on the way to Panama. We would do the workups here, then they would go to Panama, take the dose in Panama, then come back here to Miami and we would do the follow up. So with that information, now Howard was in a safe environment.”
In 1995, Dr. Mash got full permission to go forward with ibogaine in the U.S. from the FDA. “They let me go forward with a Phase I for cocaine,” she recalls. “I started with cocaine-dependent volunteers because at that time, there was methadone for heroin and Suboxone was being considered, but there was nothing for cocaine. Basically, I was very excited about this because the FDA gave us the green light to go forward.” Meanwhile, Dr. Mash was working to get funding for the research. She returned to NIDA and asked for a contract. While NIDA had originally considered a contract, they told Dr. Mash she needed to go through a peer review and get a grant. Now, writing a grant application is something the doctor knows how to do. She’s written grants every year since leaving Harvard in 1986. Dr. Mash wrote the grant, and was very proud of it.
“We had fantastic collaborators, people from the uniformed health services, people from UCSF, the best pharmacokineticists in U.S., people from Canada, just a wonderful group of people. There was a lot of interest in this, and even though it was controversial, it would be the first time we were going to be able to study this. And no one was getting paid. The team just put a lot of their effort into putting this together.” And we didn’t get it.”
NIDA had a public hearing where they convened groups of advisors – half industry, half academics. This is where it fell apart, according to Dr. Mash. “The upshot was that some people thought it should go forward and some industry people did not. Drug development at the National Institutes of Health level is very expensive. It is very expensive to take a drug through the FDA, and NIDA certainly couldn’t put all her resources just through this drug. Their mission is much broader than that, including basic biology, basic neuroscience, etc. So they couldn’t put all their money behind ibogaine.” Bottom line, Dr. Mash didn’t get the grant.
But there was another problem: Lotsof held the patent. He would need to sign a cooperative research and development agreement.
Dr. Mash Discovers Noribogaine, an Active Metabolite of Ibogaine
Here’s where the story gets more interesting. Let’s hear Dr. Mash tell it.
“Also, at the same time, I had discovered, working with my colleagues here at the University of Miami, that ibogaine gets converted to an active metabolite, called noribogaine. I had early on hypothesized that there was an active metabolite. This cannot just be visions [one of the side effects of ibogaine]. This cannot be that you have this visionary experience and you’re cured from addictions. That’s simply not how it works. There must be a mechanism here. You’ve got to hit a target that’s resetting the brain in some way. We’ve got to find out. And that’s why I was really interested because I thought in the beginning that ibogaine could be a lead molecule. Even if that molecule wasn’t ultimately the end product for treatment of addiction, maybe it would teach us something about addiction and we could work around it.”
Dr. Mash disclosed her invention (noribogaine) to the University of Miami. She and Lotsof had signed a material transfer agreement wherein he agreed to provide the drug source to Dr. Mash and the University of Miami. Dr. Mash didn’t have the money to make the drug and the FDA required a good manufacturing product. They had one through Howard’s agreement.
In the course of all this, Dr. Mash and her colleagues also described this new metabolite. Lotsof came down with his wife, and the University of Miami people spoke with them. The discussions boiled down to going 50-50. Lotsof would retain 50 percent of the rights and the University of Miami would retain 50 percent and together they would develop it. After a handshake agreement, Lotsof returned to New York. Subsequently, he sent a letter from his lawyer claiming it was all his, and threatening litigation against the University. “Keep in mind that this is the only scientific group ever to step forward to test this,’ Dr. Mash explains. “He had never paid for any of the work, forget the intellectual contribution, he never paid for any of it.”
The University of Miami decided not to litigate, and gave Dr. Mash permission to do whatever she wanted with the intellectual property (IP).
As Dr. Mash relates, “At that point, I said, if he thinks he owns me and my collaborators, well, that’s not going to work, because I’m not going to cooperate. I’m not an indentured servant. He shot an arrow into the heart of the only academics who ever supported him in this quest for cure for addiction.”
Then, the situation got worse. Without the grant and lacking funding, even with FDA approval to go ahead, plus the fact that they didn’t own the patents to Ibogaine, Dr. Mash and her colleagues can’t gain any industry interest. It looks like the project is dead.
Dr. Mash’s solution is to raise the money herself from family and friends and go offshore to St. Kitts. “We went offshore and started the only government-approved facility which was set up for research and development. We didn’t advertise. We didn’t make money. We put every dime we had into development, because we wanted to help people. I did this because I wanted to know. If this could help people, I wanted to know.”
Clinical Testing of Noribogaine
Dr. Mash says she’ll never forget that first round of testing with the initial six clinical trial participants. These included individuals dependent on opiates (3), cocaine (2), and one alcohol. Dr. Frank Ervin, the study’s clinical director, a biological psychiatrist, former faculty member at Harvard University and today, professor emeritus at McGill University in Canada, turned to Dr. Mash, as she recalls, and said, “Well, Deborah, it blocks opiate withdrawals.”
With that auspicious beginning, Dr. Mash and her colleagues began. Staying in touch with five participants from the first round, Dr. Mash says, “I know that for sure the first 2 patients – first male and first female – are still clean and sober from November of 1996. That kept me going.”
Although she never wanted to do clinical trials outside the U.S., Dr. Mash said the prime minister of St. Kitts was terrific. “We had wonderful doctors, doctors who would fly in with their patients, counselors, and, with Dr. Frank Ervin, we collected a lot of data. Basically what we learned was that the metabolite explains the beneficial effects of ibogaine.”
Dr. Mash’s clinical testing of the active metabolite, noribogaine, confirmed several different things:
• The pharmacology of the active metabolite is the reset for addiction. “It is what blocks the opiate withdrawals. It is a very gentle detox from opiates, a great detox for opiates.”
• It doesn’t work for everyone. “It doesn’t change personality. You still have to deal with the whole human being. If you have people that have to deal with the wreckage of addiction, get ready to deal with that. If you’ve got patients that are co-morbid for bipolar disorder or generalized affective disorder, or severe depression, get ready to deal with that. But noribogaine is also an anti-depressant. We got to see, while the metabolite was still in the body, we could see the effects – depression scores would drop. Energy would increase.”
• The bottom line was these people were clean, sober and ready to put together a treatment plan. ‘They were treatment ready. Whenever possible, we tried to encourage our patients to go into treatment. First we did 2 weeks, then 11 days, then 10 days in residence in St. Kitts. Ten days was not enough for many patients. We had some patients, physicians who had gotten addicted to painkillers, whom we could detox and they could be right back in the O.R. For some people who had good family structure and businesses, they could get back to work. But for others, who had maybe 10 years of hard-core use – we had many long-term treatment failures down there – you had to give them something afterward. So, we’d say you’ve got to go to meetings, go to 12-steps, and go into treatment. Get into NA/AA rooms, and get a sponsor.”
• This is not a cure, this is an addiction interrupter. “You’re going to have a window of opportunity. What are the recovery tools that you’ll have in your toolbox? What’s going to be different this time? But, clearly, this took patients from being pre-contemplative to being ready for change.”
The exciting thing was that Dr. Mash and her colleagues accelerated recovery. Did it work for everyone? No, it did not. Were there relapses? Absolutely. But for some, and for a significant percentage, says Dr. Mash, “We helped a lot of people.”
Still, Dr. Mash tried to get interest behind this. “Obviously, this is a Schedule I drug. There’s no money to develop it. Howard Lotsof is now dead (he died in January 2010). His patents are dead. Who’s going to pay for this? That was all a recent problem. That was the same problem 18 years ago when I started.”
Dr. Mash Holds Patents for Metabolite - Noribogaine
Since that first clinical testing in St. Kitts, Dr. Mash has worked to perfect the intellectual property around the metabolite’s IP. She holds the patents around the metabolite – both for the treatment of non-addicting pain as well as for addiction. It has been a long road for Dr. Mash, trying to elicit interest from the pharmaceutical companies. Today, she’s trying to work in the private sector to develop the drug for the treatment of pain - to develop noribogaine as an alternative to morphine for pain. “Many people are addicted to pain pills now. It staggers my imagination. The phone calls I get are heartbreaking, mothers and fathers desperate because their valedictorian is now chewing, smoking or snorting OxyContin.”
In order to raise dollars around a technology you have to have IP. “The metabolite, noribogaine, is free of the visions. There are none of the hallucinations of ibogaine. It’s something that people can take in a pill or a patch. Wouldn’t it be great to have a non-addictive alternative to morphine? How many people – even how wonderful methadone is, when you want to get off methadone, it’s very difficult. We were able with Ibogaine, through the active metabolite, to taper people off of methadone very effectively. For people who want the option to get out of the methadone system, this would be an alternative. For people who are coming out of an acute surgical situation, instead of going on a strong opiate, we would have an alternative. It might be great for the elderly, with all their aches and pains. Pain is the number one reason for seeking medical attention in the U.S. today,” Dr. Mash emphasizes.
Opioid addiction, which includes the use of illegal drugs such as heroin and the non-medical use of such medications as methadone, morphine, oxycodone (OxyContin), and hydrocodone (Vicodin), impacts millions of American families each year. The 2008 National Study of Drug Use and Health (NSDUH) shows that in 2008, 282,000 persons aged 12 or older were dependent on or abused heroin. This compares with 1.7 million classified with dependence on or abuse of pain relievers and 1.4 million who were dependent or abused cocaine. Development of an IND doesn’t necessarily follow in a straight line. “My fantasy when I started was to have patients take the ibogaine in a proper medical setting, with all the safety and credentialed individuals and then to supplement the noribogaine in their blood with a noribogaine patch while they go to treatment. That would keep away the cravings and the desire to use. Because patients would tell me they could feel it washing out over time. They would call me up and tell me “the metabolite is gone” they could feel it wearing off. If they were set in their recovery, they were probably okay. But for some of the others, especially cocaine, which is so addicting and the cravings are the thing that triggers them back into using, wouldn’t it be great if we could have had a noribogaine patch on their arm? So that’s where I’m at. That’s where I’m working.”
How Noribogaine Works
Noribogaine is an active metabolite of ibogaine that is long-lasting. Ibogaine is cleared from the blood in less than 24 hours. Noribogaine, on the other hand, last for weeks.
In Dr. Mash’s clinical testing, she had opiate addicted chronic pain patients who were pain free until the metabolite washed out.
Noribogaine is an atypical opioid with activity at mu, kappa and delta receptors and the serotonin transporter.
Side effects of OxyContin and other opiates are addiction and tolerance. You need more and more. Noribogaine will be a low-abuse alternative.
When asked about ibogaine versus Suboxone, Dr. Mash says, “I was actually amazed at how many people have been maintained on Suboxone, then when they tried to taper, they couldn’t get off. Suboxone maintenance is much like methadone maintenance, and people who were on quite high doses of it, when they tried to get off, they had a problem. I had one young woman whose physician called us, had a legitimate pain syndrome, was on Suboxone and couldn’t get off. And she was motivated. There may be underlying genetic differences which explain their sensitivity when they try to taper down and get off. “ Some people have transitioned from Suboxone to a short-acting opiate and then have used ibogaine. Dr. Mash says, “I’ve recommended that you don’t go straight from Suboxone to ibogaine. It has a long-acting metabolite much like noribogaine. I don’t like to see drug interaction studies going on. If you’re on morphine or methadone and you take ibogaine, that’s a good way to go. It’s very effective for opiates. And the reason is the active metabolite is an atypical opiate.
Future of Noribogaine
As for the future, Dr. Mash is committed to pursuing studies of the active metabolite. Her focus is on two things:
1) Being back in the U.S.
2) Working toward development of the active metabolite for pain
Perhaps this is where the greatest potential exists. If Dr. Mash can get approval and funding for the development of noribogaine for pain, maybe there could be an eventual transition to something else. There is no question that there’s a multi-billion dollar market for pain in this country. It’s also true that no pharmaceutical company wants to have its products be involved with addiction, particularly stigmatizing addiction such as heroin.
Dr. Mash muses, “With all NIDA’s resources, what has been developed? They’re making vaccines now, directing grant money toward the nicotine vaccine and the cocaine vaccine. Meanwhile, we’ve got Chantix for nicotine, and we’ve got Suboxone and methadone for opiates. For all these years, we’ve gotten one more drug, Suboxone. For alcohol, we’ve got naltrexone – doesn’t work well. Acamprosate – I don’t know how good that is. What I wanted to do was combine noribogaine with naltrexone - as a treatment for alcohol. That, I believe, would be a winner.” Where does the future of noribogaine stand today?
“We’re starting with pain,” continues Dr. Mash. “I’ve presented and I’m talking with people. I had a meeting with the FDA to talk about the metabolite. Where we are now is we can go forward if we have the money.” To reiterate, it is very expensive. “Just to get started with a drug program, you’re looking at a $10 million price tag. That’s why academics and academic medical centers don’t develop drugs. We can study them, but we can’t develop them. You really need the pharmaceutical companies or some kind of private capital, venture capital, small biotech company – but, you’re starting a company around a drug development program.” Back to the multi-billion dollar market for pain medications in the U.S., and it becomes clear that the pharmaceutical companies may be more receptive to an IND for noribogaine for pain. What does it take to get to market with a new drug? Good manufacturing practice supplies of the drug would be needed for an FDA filing, which, according to Dr. Mash, would be done under contract. Then, basically, there are three phases of drug testing (Phase I, II and III), which take about 5 to 7 years before the drug can enter the market:
• Phase I – This is the safety trial, tolerance, etc., and can be pretty fast.
• Phase II – Involves the efficacy study, and the FDA may have specific requirements.
• Phase III – This is the big one, involving placebo-controlled, randomized, double-blind testing, and multi-site testing. Again, FDA may have specific requirements. The more money you have behind the program, the quicker this phase may be able to proceed.
Then, FDA works with you on packaging – contraindications, warnings, side effects, etc.
But Dr. Mash isn’t deterred by the prospect of yet another 5 to 7 years. “I’ve been working on this for 18 years. I’m not giving up now.” So, whatever happened to Ibogaine as a potential cure for heroin addiction? For now, it’s taking a backseat to a medication to address much more widespread problem, a low-abuse pain medication, noribogaine, that may benefit millions of Americans.
Warning About Underground Clinics for Ibogaine
When asked about the underground clinics for Ibogaine currently advertised on the Internet, Dr. Mash urges interested parties to exercise extreme caution. “Because of all the publicity that’s gone on, and also because of the patients that know this works, there’s a network, a bunch of underground clinics have sprung up – some better than others. Now I haven’t been to visit all of them. But I’m very afraid for people who take ibogaine in unsafe settings. I say, buyer beware. I know that there are some people – self-styled therapists – who’ve been telling patients that they have doctors present, and they don’t. Who may or may know what they’re doing – and they don’t.”
And, yes, there have been deaths in these underground clinics. Besides the death with Lotsof, clinics in the Western part of Mexico have had deaths. People who were getting ibogaine illegally in the U.S. have had deaths. “Who are these people that think they know what they’re doing, or are they just capitalizing on something to make a fast dollar,” asks Dr. Mash. Referring to other news interviews she’s given, Dr. Mash says, “I’ve called it an abortion-style network.” But she elaborates here. “People deserve better than that. If you’re going to provide treatment, know what you’re doing. One program in Mexico, the doctor came and was in residence with me in St. Kitts. When I closed St. Kitts, I worried about where people were going to go.”
Her advice to people seeking ibogaine treatment for heroin addiction:
• Be certain that you’re taking it with a doctor, with the right skills.
• Ask questions: What is your background? What is your training? Do you have government permission to do this? Where is the ibogaine coming from? How do you know it is ibogaine? Has it been tested for purity? Have you had any adverse events here? How will I be protected? What if something goes wrong?
• Examine the risk/benefit as for any procedure that you undertake. But, unfortunately, when you go off shore, you may not find it. And a lot of these people are not even who they say they are.