03/17/20

The Unique Scientific Value of Ibogaine Part 2

credit: The Drug classroom

Howard Lotsof said in 1962 while he was having breakfast with a chemist friend of his, the friend began rooting through a freezer, which was full of different psychoactive drugs. “He pulled out a small vial and said, ‘I think you’ll be interested in this.’” Howard asked what it was and the friend said it was an African hallucinogen that lasted 36 hours, so of course he took it. At home he laid down, and it continued to work and work, leaving him exhausted. After 33 hours he thought he would never take ibogaine again, until he realized he was not in narcotic withdrawal. You see, Howard was a 19-year-old heroin addict.

Afterwards, I was walking and I looked at this tree, and as I looked at it, I realized I no longer had any fear of death. Also, that I was no longer addicted to narcotics.

He administered it to a few of his addicted friends, who had similar results. Without withdrawal symptoms, ibogaine appeared to interrupt addiction and provide the user insight into why they used drugs often through ‘visions.’ This began a life-long pursuit of ibogaine as both an “addiction interrupter” and aid to psychotherapy. Despite the interest and research into ibogaine, it remains a Schedule I drug. This means it is illegal to use and difficult to research, within the US.

Psychedelic Times said Dr. Deborah Mash, who has been researching ibogaine for over two decades, thinks moving it from Schedule 1 into Schedule 2 is important for future research with ibogaine. She thought a consortium of credentialed people from academia, and the public and private sector could help stimulate the movement out of Schedule 1. She wants its consumption to be ethical and used for the right purpose. “We have an epidemic of heroin addiction in the US and we need this now more than ever before.”

One of the big barriers for studying ibogaine is that it is in Schedule 1. Ibogaine has no abuse potential. People don’t even like it! Animals don’t self-administer it. We have a way to scientifically look at drugs that might have abuse liability, and ibogaine does not have it. Moving it out of Schedule 1 and into Schedule 2 would open the door for many more people to be able to research it.

Dr. Mash obtained FDA approval to clinically test ibogaine on humans in 1993, but found every grant that she would write for ibogaine was rejected by the NIDA. Scientists at the institute recruited to review the application were concerned about ibogaine’s safety. Frustrated with this catch 22, she found some investors and opened a clinic on St. Kitts, for clinical trials and treatment, the Healing Visions Institute for Addiction Recovery. By 2004, Mash had collected the data she needed to once again approach the FDA, and she closed Healing Visions, which always struggled with money. She said: “This was never run for profit… It was always for research and development.”

Dr.  Alberto Solà who was one of the clinicians trained by Dr. Mash at Healing Visions, now owns and operates Clear Sky Recovery, which acknowledges Dr. Mash as a cofounder. The website for Clear Sky Recovery claims, “We are the world’s foremost experts in medically-based ibogaine treatment.” They assert Clear Sky Recovery is the only ibogaine treatment center in the world whose founders are regularly published in peer-reviewed medical journals on the topic “of dosing human, drug dependent individuals with ibogaine.” Watch “Heroin Cure?”, a segment for America Tonight Investigation on the Clear Sky Recovery website, which is linked above, for more information on ibogaine and Clear Sky Recovery.

In “Heroin Cure?” Dr.  Mash said at first, she didn’t believe the claims about ibogaine: “How could one molecule have an effect on alcohol, nicotine, cocaine, opiates. It didn’t make sense.”  She wanted to see the results firsthand, so she travelled to the Netherlands, where ibogaine trials were going on and watched a detox in action. “I saw people who were at the end of the rope, completely detoxed; looked like new human beings; no signs of withdrawal; and ready to change their life.” She wanted to know what that taught us about the brain, so she organized a clinical trial of ibogaine and received approval from the FDA. It was eventually suspended as the result of no ongoing grant support for the research.

Despite the glowing testimonials on the Clear Sky Recovery website, there are several individuals who are opposed to ibogaine treatment. Dr. Phil Skolnick, a drug development expert at NIDA, the National Institute on Drug Abuse, said he would not recommend it. “Might ibogaine work for some people? It’s absolutely possible. Has its safety and efficacy been established in a rigorous way, absolutely not.” He added there was data in the literature indicating animals administered ibogaine could get brain lesions.

Dr. Mash countered, saying that was exactly why further research was needed and worth doing. She added: “One dose of ibogaine is not going to have toxicity to the brain.” But funding for the necessary research isn’t being offered. Dr. Skolnick, who worked in pharmaceutical companies for several years admitted that addiction medications are rarely embraced. “Pharma has generally been indifferent to addictions; to developing medications to treat addictions.”

Dr. Mash said her intent was to either show that ibogaine worked, or to debunk it. “Either ibogaine works, or it doesn’t. But we in the scientific community need to test, to study. This is too big of a problem, the drug addiction in our society—it’s too large to leave this stone unturned.” She also cautioned that ibogaine has some serious side effects, like cardiac arrest. She was critical of the protocol followed in a MAPS-funded clinical trial in New Zealand, discussed in Part 1, where one of the patients died. She said in an article for Markets Insider,

This recent death underscores the persistent problem associated with the use of ibogaine in unregulated, nonmedical settings by unqualified persons. Ibogaine has complicated pharmacokinetics that contribute to concerns for careful dosing, potential drug interactions, and issues of cardiovascular safety.

A 2006 article in the journal Medical Hypotheses, “Fatalities after taking ibogaine” hypothesized deaths may be the result of cardiac arrhythmias, “caused by a dysregulation of the autonomic nervous system.” Kenneth Alper and others reviewed all the available autopsy reports for known ibogaine-related deaths outside of West Central Africa between 1990 and 2008. The evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical conditions (mainly cardiovascular, and/or one or more typically abused substances) either explained or contributed to the deaths of 12 of 14 cases. “Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and the uninformed use of ethnopharmacological forms of ibogaine.”

A 12-minute YouTube showed Dr. Alper giving a report at the ICEERS Ibogaine Conference on the above study. He said the risk factor for ibogaine fatalities were the same as for drug overdose. The risk factors with ibogaine fatalities were: significant preexisting medical, particularly cardiac disease; pulmonary embolisms related to things like travel, immobility within a treatment; using opiates or stimulants during a treatment; and using indigenous forms of uncertain origin and composition, like iboga root bark, by the inexperienced or uninformed patients. He said there was one overriding risk factor for providers. In many cases providers were influenced by someone to do a treatment under circumstances they normally would not; “they bent their own rules.” Dr. Alper believed the widespread adoption of exclusion criteria and pretreatment evaluation before ibogaine treatment; and the inclusion of internists and medical physicians in the pretreatment evaluation were the key factors in decreasing the risk of fatalities with ibogaine.

The mechanism behind the effectiveness of ibogaine is still unknown and the risk factor of sudden, unexplained death during ibogaine treatment is real enough for a report of fatalities to be done at an ibogaine conference held by the International Center for Ethnobotanical Education, Research, and Service (ICEERS). Further research is needed, but is hampered by ibogaine’s classification as a Schedule I drug, and the inconsistent protocols of most centers offering ibogaine treatment. Dr. Mash has expressed concern the adverse effects and unexplained deaths resulting from these treatment centers will hold back any serious consideration by the US research community of ibogaine as an addiction treatment. The stakes are high for the potential help of ibogaine treatment as well as risks for patients. Dr Skolnick said that addicts should not have to face risks with ibogaine in their addiction treatment when they risked so much when actively using. But out of desperation, many addicts are willing to take the risks associated with current ibogaine treatment.

The danger of medical complications with ibogaine for some individuals seems to limit the willingness of the FDA to fund research into ibogaine, despite its promise for treating addiction to multiple substances. The inability of pharmaceutical companies to develop ibogaine into a blockbuster, billion-dollar new molecular entity (NME) because it is an extract of the West African Tabernanthe iboga plant is another reason the research funds are not there. This lack of funding has stymied the scientific, medical investigation of ibogaine. Despite these roadblocks to ibogaine research, it has become a kind of patent medicine touted as a cure all for various addictions. At this time, ibogaine treatment centers necessarily exist outside the US, since ibogaine is a Schedule I substance. There are two registered clinical trials with ibogaine in Brazil, one looking at the safety and tolerability of ibogaine in alcoholic patients; and the other investigating the safety and efficacy of ibogaine for methadone detoxification.

The fact that ibogaine is a hallucinogen, whose effects are likened to waking dreams, is another factor in its failure to attract research funding. Yet many of its advocates view the waking dreams as a crucial part of the ibogaine healing process. Even Dr. Mash, who describes herself as agnostic to the supposed importance of subjective effects of the waking dreams, acknowledged how the therapists she works with believe the hallucinations are part of the healing process with ibogaine. At this point we approach the limits of hard scientific knowledge and the investigation of the neurochemical effects of ibogaine and turn toward its subjective effects, and that of other hallucinogens like psilocybin. Are these molecules a panacea for whatever ails us; or are they more of a placebo effect that will eventually result in a more modest assessment of their potential? We will reflect on this in Part 3.

03/10/20

The Unique Scientific Value of Ibogaine, Part 1

credit: Wikimedia Commons

Investigating the potential of psychedelic drugs to treat addiction has been around since the 1950s, when a British psychiatrist named Humphry Osmond first wondered in 1953 if a controlled LSD-produced delirium would help alcoholics stay sober. He would treat over 700 patients in the following ten years and Bill W., a co-founder of A.A., was one of them. Currently, there are a variety of psychedelics being investigated as treatments for conditions ranging from addictions with various drugs to PTSD. One of those is ibogaine, a psychoactive compound extracted from the West African Tabernanthe iboga plant.

Erowid said the first report of Tabernanthe iboga use as a stimulant and aphrodisiac in Gabon and the Congo was in 1864 by Griffon du Bellay, a doctor in the French Navy. A syncretic Christian church called “Bwiti,” who used Tabernanthe iboga in their initiation rites, was founded among the Fang people of Gabon in the late 19th century. In 1903 was the first report of iboga being used as a visionary plant in the Congo. By 1939 an extract of the Tabernanthe iboga plant was sold in tablet form under the name Lambarene for treating fatigue and depression. “It was popular among athletes who used it as a stimulant and to accelerate red blood cell production.”

In 1962 Howard Lotsof inadvertently discovered the anti-addictive properties of ibogaine when he realized after a several-hour trip on ibogaine, he had no withdrawal symptoms even though he had not used any heroin. He administered the drug to several of his addicted friends with similar results. He would later acquire patents for ibogaine as a treatment for acute addiction in 1985 and 1992. In 2009 he founded The Global Ibogaine Therapy Alliance (GITA), a non-profit corporation dedicated to supporting the sacramental and therapeutic uses of iboga. He has authored or coauthored several scientific papers on ibogaine and produced a web portal for scientific studies and lay information on ibogaine, the “Ibogaine Dossier.”

Ibogaine was completely synthesized in 1966, classified as a hallucinogen and made an illegal substance in the USA in 1967. It was classified then as a Schedule I substance, meaning it was considered to have a high potential for abuse and no acceptable medical use. Because of this action, most of the research into ibogaine’s use in addiction treatment has occurred outside of conventional clinical and medical settings and outside of the US.

The Ibogaine Dossier said there were two general types of ibogaine treatment. The first type is sometimes referred to as “initiatory,” and involves a dosage around 8 to 12 mg/kg; it’s used to orient users towards psychotherapeutic or spiritual insight. The other type of ibogaine treatment, which is used for addiction, involves a dosage of 15 to 25 mg/kg, twice as much as an initiatory dose. Lotsof’s early “research” reported that he gave up to 19 mg/kg to a total of 20 individuals.

A subset (n= 7) of Lotsof’s individuals were heroin addicts who reported the alleviation of physical dependence and cravings. Five of the seven individuals reportedly remained free of heroin for 6 months or more following their treatment with ibogaine. “The activity of the group eventually ceased in 1963 when FDA and law-enforcement agencies eliminated the ability of S&L Laboratories, as Lotsof put it, ‘to procure drugs and administer them to interested persons.’” The pharmaceutical industry was not interested at the time in developing ibogaine, viewing addiction as an economically unattractive area for medication development.

But Lotsof and others persisted in their efforts to do research and provide treatment with ibogaine. Lotsof organized a company, NDA International, which provided research funding to Dr. Stanley Glick at Albany Medical College, who demonstrated ibogaine decreased the intake of morphine in rats. See here and here for Glick’s 1991 articles on his research. Glick would continue his research on “iboga” for the next ten years and generate a body of work with over 60 peer-reviewed articles on ibogaine and related compounds. His work has been supported by the National Institutes of Health (NIH).

NDA International recruited and treated patients in the Netherlands because ibogaine treatment could not be legally provided in the US. A total of 40 to 45 individuals were treated between 1989 and 1993 in the Netherlands. “The data from these treatments, together with the 20 subjects treated in the United States by Lotsof between 1962 and 1963, provide the principal source of the case study evidence that has been presented to the National Institute on Drug Abuse (NIDA) and the FDA.” But the death of a female patient in the Netherlands in June of 1993 ended the treatments there by NDA International. Although the official Dutch inquiry into the woman’s death was not conclusive, it nevertheless decreased the enthusiasm to do further investigations with ibogaine.

Kenneth Alper said in “Ibogaine: A review” that while the death of the 24-year-old woman during a heroin detoxification treatment was a significant factor in the NIDA decision not to fund a clinical trial in 1995, “Forensic pathological examination revealed no definitive conclusion regarding the probable cause of death.” There was some evidence that suggested the possibility she had secretively used opioids, presenting another element of uncertainty for her death. He then added: “There is evidence suggesting that the interaction of opioids and ibogaine potentiates opioid toxicity.”

However, in 1991 there was some interest in ibogaine research sparked with Deborah Mash, a faculty member in the Department of Neurology of the University of Miami. In a 1996 radio interview, she said she became interested in ibogaine after hearing a presentation by Dr. Glick on his research with ibogaine and rats. Dr. Mash organized a clinical trial of ibogaine and received approval of an Investigational New Drug Application from the FDA. The study began in December of 1993, but was eventually suspended as result of the unavailability of grant support. She said the ibogaine molecule was unique, doing something to human consciousness, “something to the brain, something to craving and withdrawal signs that’s very different than anything we know about right now.”

Ibogaine has a very unique structure, it’s almost as if that plant has created a magical structure that has a very rigid backbone, that is somewhat seratonin-like. Seratonin is a neurotransmitter that is associated with drugs like Prozac and with depression and changes in the brain that are normal with aging. Ibogaine also has another alkaloydal piece that hangs off the side of this rigid backbone that seems to resemble cocaine. It’s a molecule that seems to have affinity for the opiate side, and has some affinity for the cocaine side and as a pharmacologist that really grabbed my attention. There’s something real fundamental about this molecule that maybe explains its efficacy, and if these anecdotal reports that were out there in the addict self-help movement were true and could be validated, then together with our knowledge of the structural chemistry of the molecule, we might get some fundamental insight into the process of addiction itself.

This was not the end of Dr. Mash’s research and treatment efforts with ibogaine. In 1998 she coauthored a study into the safety, pharmacokinetics and dose effects of ibogaine and its metabolite, noribogaine in cocaine-dependent patients. In 2001 she coauthored a chapter in The Alkaloids: Chemistry and Biology, “Ibogaine in the treatment of heroin withdrawal.” Along with her coauthors, Dr. Mash found ibogaine to be effective in blocking opiate withdrawal. However, it has complex pharmacokinetics and an uncertain mechanism of action with regards to treating opiate dependency. The authors suggested “Identifying noribogaine’s mechanism of action may explain the way ibogaine promotes rapid detoxification from opiates after only a single dose.”

In a 2016 a study of noribogaine, Mash and others investigated the effects it had on substance-related disorders. Their findings suggested the metabolite noribogaine rather than ibogaine mediated the effects of ibogaine blocking withdrawal. “Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence.” Then in 2018 Mash and others published a study whose results “Confirms the original claims made by Howard Lotsof.” It demonstrated that medically assisted ibogaine detoxification was a safe and effective method to discontinue substance dependence or misuse. Dr Mash has published additional studies with ibogaine besides those mentioned here.

MAPS, the Multidisciplinary Association for Psychedelics, has been supportive of research into the use of ibogaine to treat addiction and has an extensive listing of research updates, news and event announcements on a variety psychedelic drugs, including ibogaine. It also funded two observational studies of the long-term effects of ibogaine treatment in Mexico and New Zealand. The Mexican study reported on outcomes up to one year following opioid detoxification with ibogaine of 30 individuals with OUD (opioid use disorder). Participants were followed up at intervals of 1, 3, 6, 9 and 12 months. The results indicated that ibogaine had a substantial treatment effect in opioid detoxification and appeared to reduce drug use at one month, which was sustained up to 12 months in a subgroup of subjects. “No clinically significant cardiovascular or other medical events occurred in this study.”

The New Zealand study was a prospective observational case series of 14 participants seeking ibogaine treatment for opioid dependence and who were committed to regular contact for 12 months post-treatment follow up. “Consistent with preceding studies, evidence showed significant attenuation of withdrawal, sustained reduction in drug craving/use, and cessation of use in some cases.” This sustained reduction occurred in 12 of 14 participants. One patient died during treatment before they were formally enrolled. Two investigations suggested the participant’s death was due to a failed duty of care by the treatment provider. The death was likely “related to ibogaine ingestion and most probably related to a cardiac arrhythmia.”  There will be more discussion of this potential adverse event with ibogaine treatment in part 2 of this article. In conclusion, the author noted that despite the limitations, which included its reliance on a small (n= 14) convenience sample already intending treatment,

This study has demonstrated that for some opioid-dependent individuals, ibogaine treatment can be effective in significantly reducing opioid withdrawal, craving and depressed mood, and reducing or ceasing opioid use. Given the modest success of existing treatments, some of which involve extensive, repeated administration and considerable risk, and the significant increase in opioid dependence globally, it seems prudent to more seriously examine the place of ibogaine in the context of treating this intractable problem.

Despite the apparent promise of the research reported above, the ghost of adverse events, particularly fatalities, haunts serious research into ibogaine for opioid treatment. It was what stopped the clinical trial in the Netherlands in June of 1993, and raised its head again in the New Zealand study described above. Yet, there seems to be a growing body of research interest into its use for opioid treatment. For example, there are two clinical trials registered for ibogaine in the treatment of alcoholism and methadone detoxification. Neither study is recruiting yet and neither study is to be done in the US.

The fact that ibogaine is largely unregulated as a treatment for addiction and used to promote spiritual and healing experiences—sometimes by the same provider—should give someone seeking it for addiction treatment pause. But addicts are often desperate individuals, willing to take the risk. We will look at some of the risks and concerns in Part 2.

For more information on Bill W. and LSD, see “As Harmless as Aspirin?”