The purpose of this document is to provide information. Treatment providers and patients are solely responsible for their actions.
Manual for Ibogaine Therapy
Screening, Safety, Monitoring & Aftercare
Howard S. Lotsof & Boaz Wachtel
Marc Emery, Geerte Frenken, Sara Glatt
Brian Mariano, Karl Naeher
Martin Polanko, Marko Resinovic
Nick Sandberg, Eric Taub
Samuel Waizmann, Hattie Wells
Table of Contents
Introduction to the Second Edition
Intake and Safety Issues
Dose and Effect
Opioid withdrawal tables
Post Ibogaine Treatment Therapy
Treatment Regimen and Dose
Post Ibogaine Therapy
Invitation to Contributing Authors
Selections NIDA Draft Ibogaine Protocol
Related Protocol Bibliography
Additional Document links
Introduction to the Second Revision
The Second Revision of the Ibogaine Manual follows a year and a half after the publication of the First Revision providing new information to the field.
This revision of the manual offers additional information on ibogaine therapy as well as, differing philosophies of ibogaine providers and their approaches to therapy. There is consensus as to the benefits of post ibogaine therapy but, no agreement that any one therapy offers benefits over others to a majority of subjects. Many authors feel the exclusion criteria indicated in the draft protocol of the National Institute on Drug Abuse (NIDA) are not realistic to allow treatment of today’s chemically dependent drug users who may be depressed or display other psychiatric disorders nor does it allow for the prevalence of HCV and/or HIV to allow those individuals to be treated with ibogaine. The authors review broader ibogaine dose regimens and their advantage than were presented in the First Revision of this manual. The new material is principally found in the Discussion Section that may be referenced from the links of the Table of Contents above though some changes and corrections have been made throughout the text as a whole. Opinions of authors remain diverse.
Links to a medical encyclopedia as well as, both the home edition and Centennial/Professional edition of the Merck Manual are included in the Additional Documents section. "The Merck Manual, the textbook of medicine most widely used by health care professionals provides vital information about diseases, diagnosis, prevention, and treatment." The Ibogaine Manual now also contains a link to a redacted version of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) to allow better understanding of mental disorders that may be concurrently seen in persons who are chemically dependent.
Though the Internet allows rapid publication it also has a component of rapid disintegration with web pages linked to the manual being withdrawn from the web by original authors. Therefore the authors of this manual have included where possible multiple links to any particular subject in the appendices so as to maintain information access for the reader.
All links that will take the reader outside of the Ibogaine Manual will highlight on mouseover with most but, not all browsers. These links are found only in the Additional Document section. Links that will take the reader outside of the Ibogaine Dossier web page will appear in separate windows with the Manual remaining visible in the background.
Ibogaine therapy has emerged in the last twenty years as a viable option for motivated chemically dependent individuals who wish to cease their dependence. The extremely costly regulatory approval process and the reluctance by major pharmaceutical firms to pursue regulatory approval in the West has led to the formation of non-medical ibogaine treatment movements in many countries. This document is intended for medical doctors as well as, for lay-healers who have little or no medical experience, but who are nevertheless concerned with patient safety and the outcome of Ibogaine treatments. The NIDA draft clinical protocol, however, may be useful to researchers in formal drug development.
It is the responsibility of those treatment providers to safely conduct the procedure despite possible limitations of clinical knowledge, patient compliance, money, time etc. The safety of Ibogaine treated patients is the primary objective of this document. Reported Ibogaine-related problems or fatalities might very likely be avoided if simple screening, dosing and monitoring guidelines are adhered to. However, this must be taken in some context as, in 1999 there were 116,000 drug related fatalities in United States hospitals associated with FDA approved medications.
This manual includes selected portions of the National Institute on Drug Abuse (NIDA) Draft Ibogaine Clinical Protocol obtained under a Freedom of Information Act (FOIA) request. Selections are principally directed towards safety issues. Aspects of the therapeutic sessions from the NIDA protocol are included as well as, bibliographical citations relevant to the sections from the protocol. More recent reports providing updated information are included in the Additional Documents section.
Any comments of the author(s) within the selected protocol text are indicated by "[ ]" brackets. The "*" asterisk is used to indicate tests procedures or surveys not included in NIDA’s 1993, draft protocol but, suggested either in discussion with the FDA or by later publication.
In a memorandum dated March 10, 1995, Dr. Curtis Wright, Medical Review Officer, Pilot Drug Evaluation Unit, FDA wrote, "I think that ibogaine research will be propelled forward by its advocates, as it will be very hard to make a case that it is unsafe to take a drug into man when there is such substantial documented human experience. I agree with the speaker [March 1995, NIDA Ibogaine Review Meeting] that it is a risk-benefit analysis, but all such development decisions are finally reduced to this basis. The Development question is if ibogaine can be given safely, and if so, will it provide some benefit."
Ibogaine has been propelled by its advocates since then, and administered in many countries often outside the medical establishment. Unfortunately, safety issues are not frequently addressed or evaluated properly. Our objective is to provide basic guidelines and improve patient safety with information. This information is made available for the benefit of the treatment provider and their patients.
Intake and Safety Issues
Needless to say, it is evident that most persons outside of a research institution would not be able to undertake the testing presented in the NIDA ibogaine protocol. The primary issue the authors are attempting to address is that no medical testing is the norm for many persons receiving ibogaine therapy. This leaves both providers and patients at risk. Risk cannot be eliminated but, as inferred by Dr. Curtis Wright in the introduction to this article, risks must be weighed against benefits. It is apparent from the actions of both ibogaine providers and chemically dependent persons who seek treatment that the benefits are significant. However, with no less than three documented ibogaine-related fatalities, so are the risks. Having safety procedures in effect are not for the benefit of the majority of the patients who will go through ibogaine therapy with no problems but, to assure the survival of a small minority of the patients who may experience some form of adverse medical event that may be life threatening.
One of the recorded fatalities was reported to have taken place in 1989 in France. The patient, a forty year old woman was provided a dose of 8 mg/kg of purified ibogaine for purposes of psychotherapy from which she died approximately four hours after administration of ibogaine. The dose given was the lowest dose associated with an ibogaine related fatality that has been recorded and the autopsy found significant blockage of the main arteries to the heart. It was indicated that the patient had a history of cardiovascular disorders that may not have been investigated. This immediately indicates two areas that should be given priority attention by ibogaine providers: 1) A medical history and 2) an electrocardiogram (EKG).
The most common form of a medical history is usually a questionnaire required of every patient visiting a doctor for the first time and your doctor’s office is an excellent source of such a document. Among the information required on such forms are issues relating to heart disease and these questions if honestly answered will provide an alert to the existence of a cardiac disorder. As, previously stipulated because medical conditions may not be known to the patient an electrocardiogram (EKG) should be included in any basic intake for ibogaine therapy. Information on electrocardiograms can be found in documents #6 and #7. Any history of heart attacks should be a reason not to treat a patient with ibogaine.
Whether in a hospital or outside of a medical environment the patient’s safety can be best provided for by continuously observing the patient. A nursing assistant or other trained person should observe the patient continuously for 48 hours or longer if the patient response to ibogaine requires it. During this period pulse and blood pressure should be monitored at regular intervals and at any time that patients indicate discomfort or the observer has concern. The regular intervals may be as short as 30 minutes for the first four hours or until blood pressure and pulse are stable and then at time points of 1 hour to 4 hours thereafter.
Observers should have training in cardiopulmonary resuscitation and be prepared to call a hospital or emergency medical services should the patient’s pulse drop below 50 beats per minute. If you are not prepared to call for emergency medical help you should not be providing ibogaine therapy. A hospital should be called at any time if a patient loses consciousness. The emergency number to be called should be available to all provider personnel at all times. Observing the patient is more work then one person can realistically accomplish. In a hospital setting nursing staff would normally rotate on 8 to 12 hour shifts.
The evaluation of blood chemistry is a standard means of assessing the health of a patient and is often used in medical evaluations of patients during annual physicals or to determine the health of a patient at any time for any purpose. The SMA-20 (a series of tests to evaluate blood chemistry) along with a CBC (complete blood count) with differential now appear to be the tools of choice to provide a wide range of information relating to blood chemistry that includes a liver profile but, does not include a hepatitis or HIV screen. Excellent resources concerning the SMA-20, CBC and definitions to allow an understanding of the associated terminology can be found in #3, #4, and #5 of the document section.
The second recorded fatality was that of a woman in her mid twenties in the Netherlands who received 29 mg/kg in a split dose of 23 mg/kg and an additional 6 mg/kg approximately 3 hours later. The patient died 16 hours after the administration of ibogaine. The autopsy did not determine the cause of death. The unanswered question of the cause of death brings us to another important safety issue. Ibogaine has been shown to increase the effects of opiates as well as opiate toxicity. Ibogaine may also increase the potency and toxicity of stimulants. Therefore patients should be warned that concurrent drug use during ibogaine therapy may be fatal. It does not mean that concurrent drug use will always be fatal as an early report of an ibogaine experience, Reflections on an Ibogaine Experience found in document #8 of this manual indicates concurrent heroin use that did not result in a fatality. It must be recognized that the response to drugs is individual and that each patient may present a dramatic or not so dramatic distinction in how they respond to ibogaine or other drugs. Ibogaine providers should attempt to minimize danger to the patient by eliminating the use of unauthorized drugs by the patient while under the influence of ibogaine. Good luck on that matter in circumstance where you are treating experienced and dependent drug users. This is why it is very important to let the patient know that drug interaction may be fatal.
The third fatality of record occurred in 2000, in the UK. The patient was a 38 year old male who was administered a total of 5 or 6 grams of a 15% total iboga alkaloid extract over a period of six hours. The patient appeared fully recovered, had eaten breakfast, gone to the toilet and suddenly died approximately 38 hours after the administration of the plant extract. The patient had hepatitis C but, exact data on the state of the disease is not available. The subject had been using heroin for 15 years. The most troubling issue relating to this fatality is that it occurred after the apparent recovery of the subject and quite suddenly. The extract has been widely used and there appears to be no greater fatality-related issues associated to it than to purified ibogaine.
NIDA in its draft protocol and the FDA in the protocol it approved in 1993, excluded patients with hepatitis C. One of the authors believes this was not so much a safety issue but, one that would allow a determination of the transformation of ibogaine into its metabolites by the liver and the associated plasma levels to be validated in pharmacokinetic studies within ranges that would be normal and not to have them skewed by a diseased liver. It is reported that the St. Kitts facility excludes HCV and HIV patients. NDA International, Inc. in its work in The Netherlands and Panama accepted HCV and HIV that were not symptomatic for the diseases. As many chemically dependent drug users test positive for HCV and as there has been no known correlation of fatalities with HCV, it does not seem that this is a reasonable exclusion criteria in the real world of chemical dependence. Non-symptomatic HIV patients have also been treated without apparent medical events. NIDA chose to exclude patients with liver enzyme values exceeding 400% above normal from a later study design. A decision to follow NIDA’s footsteps on this matter may be reasonable until more information is available.
Ibogaine appears to be a very safe drug in terms of psychiatric events. One of the authors is aware of a single event from a report where a patient apparently regressed, acted in a childlike manner and urinated in bed for a period of two days, thereafter recovering. An early patient who had been hospitalized on a number of occasions for glue-sniffing related psychosis became paranoid during his first treatment and exhibited behavior distinct from any other ibogaine patient during a second treatment episode. Ibogaine providers should be aware that chemically dependent or not, many persons are going to come to them with underlying and in some cases significant underlying psychiatric disorders. NIDA’s exclusion criteria for "patients with a history of active neurological or psychiatric disorders, such as cerebellar dysfunction, psychosis, bipolar illness, major depression, organic brain disease or dementia, that require treatment", may be well thought out and these patients should be avoided by persons not having professional skills in psychiatry and psychopharmacology. These matters are further reviewed in the Discussion section of this manual.
Anything that can be learned about the patient prior to treatment is valuable. And, anything learned before treatment will most likely allow a greater interpretation of events after treatment. To this end the Beck Depression Inventory, document #9, linked in the Additional Documents Section may be valuable as may the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) document #10. The tests are generally only available to persons who are professionally involved in psychology or testing who then provide them to patients. Once provided with a diagnoses it is necessary to understand those disorders. To that extent the Diagnostic and Statistical Manual of Mental Disorders, 4th. Edition, better known as the DSM-IV, document #11 is published by the American Psychiatric Association is a standard in the field.
Taking this broad ranging discussion to a brief conclusion, every ibogaine patient should receive an SMA-20 and CBC blood test and an EKG. These discussions are made in the hope of initiating greater associations between non-medical ibogaine providers and medical professionals who can assist them in increasing the safety of ibogaine treated patients. Questions coming out of the London Ibogaine Conference held in December of 2001, concerned the required testing, how to obtain it and how to understand it. The International Coalition for Addict Self-Help (ICASH) in their work in the late 1980s and early 1990s faced the same problems. Their solution was to have the patient walk into an emergency room or community health service with a friend and to have the friend inform the staff that the person with them had a pain in the chest and passed out and when unconscious appeared to go into convulsions. This usually resulted in the patient obtaining a blood chemistry, an EKG and EEG to investigate the possibility of epilepsy and cardiovascular disorders. ICASH would then obtain a written authorization to obtain the medical records from the patient and request the tests results and reports of the results from the hospital where the patient was evaluated indicating that the patient was to be included in a research program. The tests and reports were then usually reviewed by a doctor who had some interest in ibogaine therapy. In any case, with the basic medical testing accomplished there is at least a place to begin in offering safe ibogaine therapy. Patients who could afford to pay for testing and did not want to indicate their chemical dependence would inform a doctor that they were going on a trek in some physically taxing geographical location and that medical testing was required to participate.
Dose and effect
After years of review of reports of hundreds of ibogaine patient treatments, the effective dose for the treatment of chemical dependence, including opioid dependence, has been seen to be between 15 mg/kg and 20 mg/kg of ibogaine. It has been reported by some researchers that lower doses are effective but, this has been disputed. Effects of ibogaine generally will make themselves evident within 45 minutes to as long as, three hours after administration. In most cases opioid withdrawal signs will be reduced within 45 minutes of ibogaine administration. Ibogaine is usually administered in place of what would be the next scheduled dose of narcotics. This would provide for an ibogaine administration schedule 8 hours after the last dose of heroin, morphine or demerol and 24 hours after the last dose of methadone. It is expected that the patient would be exhibiting minor withdrawal signs at the time of ibogaine administration. There is no experience with ibogaine in the treatment of LAAM dependence.
Another issue pursuant to dose is that of dose increases, should anticipated effects including the diminishment of opioid withdrawal not be seen. Modification upwards of ibogaine doses have been used occasionally within medical environments and commonly by some lay providers as well as, within the African religious context. The issues remain of ability to respond to medical emergencies and of the experience of the provider to determine the safety at any time of the patient. It may be prudent to allow the primary dose of ibogaine to run its course and then provide a second dose a week later if required. That is, if the patient is still chemically dependent or exhibiting drug craving?
Once ibogaine has been administered, effects follow. The patient will usually want to lay prone and should be encouraged to remain still as nausea and vomiting as well as, being systemic have been seen to be motion related. The skin tends to become numb. Patients will report an initial buzzing or oscillating sound. A period of dream-like visualization lasting for 3 to 4 hours in most but, not all patients is considered to be the first prominent stage of ibogaine effects. This stage ends abruptly should it occur at all. Another aspect of ibogaine effect that is common are random flashes of light that appear everywhere with eyes open. This may last for hours or days. Visualization on the other hand is most common with eyes closed.
The second stage that follows visualization has been described as one in which the subject principally experiences cognitive evaluation or a review of issues that are important to the subject. These may cover every possible scenario from early childhood experiences to current health issues. This period may last for as few as 8 hours or for 20 hours or longer.
The third or final stage of ibogaine effects is that of residual stimulation. This stage, because it tends to leave the subject/patient exhausted is somewhat uncomfortable. Subjects may remain awake for two or more days. Most patients will sleep within 48 hours of ibogaine administration. Some within 24 hours of administration. Usually, there is a long term long term diminishment of the need for sleep over weeks or months. Some patients may require or request sedation. Sedatives that have been used include benzodiazepines, barbiturates and melatonin.
The effects herein described are those of single administration high dose ibogaine regimens. Ibogaine has also been given in regimens of small daily doses of 25 mg to 300 mgs/day and in small daily doses where the dose is increased on a daily basis until the desired interruption of drug dependence is accomplished. These low dose modalities have not been validated for efficacy to the same extent as have the full therapeutic doses of ibogaine. However, these low dose regimens can be traced back some decades to the work of Leo Zeff who in the case of a single patient provided ibogaine on an "as needed" basis via nasal administration to a cocaine dependent patient to substitute for his cocaine use. Lines of ibogaine were somewhat equivalent to lines of cocaine and the patient ceased cocaine use after a week of this daily self-regulated ibogaine regimen. Additionally, reports from Canadian sources indicate multi-week low dose ibogaine therapy 20 mg/day following a therapeutic dose of ibogaine in the treatment of cocaine dependence. Further, reports throughout the ibogaine provider community indicate the use of multiple dosing of varying strength doses over varying time periods in the treatment of opioid dependence. As with all determinations in medicine, decisions must be made on observations of the patient and knowledge of the disorder(s) and the medication(s) used.
An issue that all ibogaine providers treating opioid dependent patients will have to address is discomfort due to opioid withdrawal signs, real or imagined by the patient. To this end it may be helpful during a patient intake interview to ask what withdrawal signs the patient has had in previous withdrawal experiences. During ibogaine therapy this information will be more useful if the provider has had experience observing opiate withdrawal signs as well as, observing patients given ibogaine who were not opiate or chemically dependent. The reason being that certain effects of ibogaine may mimic opiate withdrawal. These signs may include inability to sleep, nausea, a feeling of being cold or vomiting. It is the skill of the provider that will enable the provider to determine whether withdrawal signs are real or imagined and to assist the patient in understanding the difference. It must be recognized that elimination of withdrawal signs are not necessarily isolated ends in themselves to heroin or other opioid dependent patients. Being sick is a rational justification for relief and the simple presentation by the patient that they are exhibiting opiate withdrawal to a significant other or peer or other person in their environment has probably been used by the patient to obtain opiates or the money to do so. The conditioned response of obtaining gratification and/or attention by exhibiting opioid withdrawal signs or claiming to exhibit opiate withdrawal signs has been a successful behavioral mechanism for some patients and should be expected. Generally, if the complaint of withdrawal is made it can be expected between the 14th and 24th hour of treatment and may continue through recovery from ibogaine effects.
Two useful surveys that should be included in ibogaine therapy are the Objective Opiate Withdrawal Scale (SOWS) and the Subjective Opiate Withdrawal Scale (SOWS). Examples of these diagnostic tools follow.
Objective Opiate Withdrawal Scale (OOWS)
Instructions: Rate the patient on the basis of what you observe during a timed 10-minute period.
Date:_________________ Time: _________________
Subjective Opiate Withdrawal Scale (SOWS)
Instructions: Answer the following statements as accurately as you can.
Circle the answer that best fits the way you feel now
To assist in an understanding of the comparative effects of ibogaine and opioid withdrawal effects, the reader should review Alper et al., #12 of the Additional Document section as well as, the findings from Ibogaine in the Treatment of Narcotic Withdrawal (document #13) by Lotsof, Della Sera and Kaplan presented during the 37th International Congress on Alcohol and Drug Dependence, University of California, San Diego, (1995). The relevant table from that paper is found below.
Objective Opiate Withdrawal Signs and Ibogaine Signs:
Post Ibogaine Treatment Therapy
The principal effects of ibogaine treatment that are reviewed in Lotsof’s Clinical Perspectives (document #14), Frenken’s An Ibogaine Treatment Protocol (document #15) and Sandberg’s Introduction to Ibogaine (document #16) will usually run their course within two days. There are exceptions with some patients recovering in as little as 24 hours while others may require an additional day or even have to be coaxed out of bed four days after treatment. Thereafter, the patients are left with the rest of their lives to accomplish and with the majority of individuals needing some form of assistance to figure out how to go about moving forward. Some patients will have a fear of going into withdrawal. This is not a realistic expectation on their part. More realistic is the fear of relapse to drug use and except in rare instances this should be anticipated particularly after only the first treatment with ibogaine.
Addiction has been viewed as a chronic relapsing condition. Ibogaine’s value is not only the interruption of withdrawal but, by mechanisms not fully understood to assist the patient in changing learned behavior and becoming more aware of their behavior in order to change it. After ibogaine therapy many patients become more agreeable to change. Thus, ibogaine provides a unique opportunity. The question to the ibogaine treatment community is how to best make use of that opportunity?
A fundamental question remains. Is any form of adjunct therapy to the administration of ibogaine more advantageous than any other form of post ibogaine treatment therapy? The question becomes more diverse where in the absence, in many cases of the possibility of additional treatment with ibogaine, opiate dependent patients who have relapsed have made good use of methadone maintenance as an effective intermittent therapy so that methadone must also be included in the mix of therapies that have been effectively used by ibogaine treated patients to eventually free themselves from addiction. Thus, we see patients making use of psychoanalysis, psychotherapy both individual and group of varieties as distinct as the persons who provide such therapies, methadone maintenance, and associations such as Narcotics Anonymous and Alcoholics Anonymous. What does appear evident is that contact with non-addicted persons is generally beneficial for patients and that continued contact with users of drugs that cause dependence is detrimental to a goal of abstinence if that is the endpoint desired. This is not distinct from the findings observed in non-ibogaine environments.
Many ibogaine patients themselves indicate that they have a need for and want some form of therapy or support. The issues become more complex in patients whose long term addiction has left them without the skills or education to function outside of a drug user context. Providing ibogaine is a relatively easy short term goal. The time needed to heal patients of trauma they have experienced and to address deficits in the patient’s life is more time consuming and a more long term goal. In many cases the patient’s lack of financial ability to obtain assistance for therapy, education or occupational training will require societal assets or private donations to be made available.
Only recently have agencies such as the Center for Substance Abuse Treatment and the National Institute on Drug Abuse in the United States recognized that the prejudice shown towards drug users is harmful in itself and detrimental to patients seeking treatment. A growing number ofindividuals question whether prohibition is the greatest harm of all while a greater number of persons are calling for a harm reduction philosophy wherein the minimalization of the level of harm to drug users and society is viewed as a priority over any immediate requirement of abstinence.
The Second Revision of the Manual for Ibogaine Therapy continues to focus on safety issues while expanding the discussion of dose regimen and forms of ibogaine that include purified forms of the chemical as well as, total alkaloid extracts of varying strengths. These matter are important as ibogaine treatments are taking place in a growing number of countries and under diverse circumstances. Some ibogaine providers in research facilities provide testing as complex as that indicated in the National Institute on Drug Abuse (NIDA) ibogaine protocol. Others in non-medical environments, apartments, hotels or chapels may not include any medical testing at all. This Discussion Section contains viewpoints of all of the authors.
One author in addressing the safety issues of ibogaine states, "The drug is dangerous and shouldn’t be compared to other tryptamines. People definitely have died and there may be more fatalities unrecorded. You need to check liver and heart and be able to assess the results. You need to know resuscitation procedures and be prepared to call emergency medical assistance if necessary." These statements bring us to central issues: key tests and the ability to understand them. While the authors recognize that virtually every drug product may have associated fatal reactions, the issue with ibogaine is, as it is with all drugs, that the responsibility is not only that of the patient/subject but, that of the provider. That alone should be reason for providers to screen for indicated health disorders.
Safety evaluations may be viewed in terms of an optimal screening/testing protocol and a non-optimal screening/testing protocol. The optimal being as complete and far reaching as possible including medical history, laboratory tests, evaluations by physicians as to general, neurological and psychological health including a broad range of questionnaires to allow such determinations. An excellent questionnaire to begin a structured case history on patients can be found in the the Guidelines for Psychiatric Evaluations of Adults, document #17. Instruments to assist in assessments can be found in The Catalogue of Diagnostic Questionnaires, document #18 and the Brief Psychiatric Rating Scale, document #19. Non-optimal testing would include the bare necessities to investigate areas of medical concern that have been raised in ibogaine literature. These include cardiovascular, metabolic and absorption concerns. Additionally, reports from ibogaine treatment observations also indicate respiratory depression may be an issue as one patient was reported to have stopped breathing before then being revived.
It should be noted that female subjects might be more sensitive to ibogaine due to higher blood levels of ibogaine and/or its principal metabolite (noribogaine) than are seen in male subjects. One, of an excellent series of articles published in The Scientist, The Inequality of Drug Metabolism, concerns itself with this matter, document #20. While absorption and metabolism factors are not distinct to ibogaine and are common to many drugs, individual patient responses to dose and particularly sensitivity of females to ibogaine must be recognized. Obviously, further research is required and the authors request the participation of ibogaine providers to supply relevant reports and data for future revisions of this manual. The FDA in their approval of ibogaine clinical studies in 1993, excluded women. This was in conflict with Institute or Medicine (IOM/United States) guidelines that indicate women should be included in the earliest research testing of drugs. The pharmaceutical industry, principally for issues of liability and cost, tests new drugs only on men in the majority of early clinical studies.
While the drug metabolism for ibogaine and for many pharmaceutical products may be better understood for distinctions between men and women, there is still no fundamental agreement on the responses of men and women to ibogaine. Wells in her very well thought out article, Notes for Treatment Providers, document #21, finds that women appear less responsive and more problematic as patients while Lotsof in his work finds women to be more responsive and less problematic as ibogaine patients. Hopefully, as more people are treated we will see a greater statistical understanding of the patient population.
One author suggests that medical testing should not be included when ibogaine is used as a religious sacrament and that under those conditions a religious exemption to medical testing should be considered valid. The author indicates that persons undergoing religious initiation are questioned at length to their health and not only are they questioned but, those who will accompany them during the initiation are also questioned and advised as to the possibility of death. The author indicates that once the possibility of fatalities are mentioned that usually more significant information is provided as to the health of the initiate. The author also indicates that women initiates are informed they may be at greater risk and are asked should they find the door that allows them to leave this life that they must not take that door as it would be destructive for everyone involved. These descriptions appear to be in keeping with the protocol or rites used within the African Bwiti initiations.
The primary question the authors must address is who may be administered ibogaine?
To that end we must present inclusion criteria for ibogaine therapy or initiation. The terms "therapy" and "initiation" are used, as ibogaine is available in paradigms that include religious initiation, treatment for chemical dependence and administration for psychotherapeutic or "exploratory" purposes.
"Testing for sexually transmitted diseases is always important in the chemically dependent population," states an author, "so I would also include VDRL to test for syphilis."
1. Subject participation must be voluntary and not coerced.
2. Subject must sign an Informed Consent that indicates and understanding of the risks and benefits of ibogaine administration.
3. Subject must undergo a general medical evaluation by a doctor who will provide a report.
4. Subject must supply a copy of their medical history questionnaire (generally required upon the intake visit to a physician).
5. Subject must respond to a Beck Depression Inventory questionnaire.
6. Subject must obtain an EKG (electrocardiogram) and report.
7. Blood tests including:
* albumin: 3.9 to 5.0 mg/dl
* alkaline phosphatase: 44 to 147 IU/L
* ALT (SGPT): 6 to 59 IU/L
* AST (SGOT): 10 to 34 IU/L
* BUN: 7 to 20 mg/dl
* calcium – serum: 8.5 to 10.9 mg/dl
* serum chloride: 101 to 111 mmol/L
* CO2: 20 to 29 mmol/L
* creatinine: 0.8 to 1.4 mg/dl
* direct bilirubin: 0.0 to 0.3 mg/dl
* gamma-GT: 0 to 51 IU/L
* glucose test: 64 to 128 mg/dl
* phosphorus – serum: 2.4 to 4.1 mg/dl
* potassium test: 3.7 to 5.2 mEq/L
* serum sodium: 136 to 144 mEq/L
* total bilirubin: 0.2 to 1.9 mg/dl
* total protein: 6.3 to 7.9 g/dl
* uric acid: 4.1 to 8.8 mg/dl
* RBC (varies with altitude): (male: 4.7 to 6.1 million cells/mcl) (female: 4.2 to 5.4 million cells/mcl)
* WBC 4,500 to 10,000 cells/mcl
* hematocrit (varies with altitude): (male: 40.7 to 50.3 %) (female: 36.1 to 44.3 %)
* hemoglobin (varies with altitude): (male: 13.8 to 17.2 gm/dl) (female: 12.1 to 15.1 gm/dl)
8. Upon subject meeting all other inclusion criteria and not being excluded by exclusion criteria, subject will be administered a 100 mg (total) test dose of ibogaine. Should the subject not have an adverse or atypical response, a full therapeutic dose of ibogaine may be considered. See exclusion criteria #4.
9. Ibogaine providers following a medical model may require evaluation of cytochrome P450 enzymes activity. Particularly, P450 2D6 (CYP4502D6) plays a significant role in the metabolism of ibogaine to noribogaine, its active metabolite. Testing allows a determination of whether the patient will be a "poor metabolizer" (PM), "intermediate metabolizer (IM), extensive metabolizer (EM) or "ultra rapid" metabolizer (UM). This testing is now available through commercial laboratories.
In order to begin to address the safety of persons being treated with ibogaine, the following indications should exclude treatment with ibogaine. A discussion of these matters by various authors follow the list below.
1. Patients with a history of active neurological or psychiatric disorders, such as cerebellar dysfunction, psychosis, bipolar illness, major depression, organic brain disease or dementia, that require treatment.
2. Patients who have a Beck Depression Inventory score greater than or equal to twenty-four.
3. Patients requiring concomitant medications that may cause adverse ibogaine/other drug interactions (e.g., anti-epileptic drugs, antidepressants, neuroleptics, etc.)
4. Patients with a history of sensitivity or adverse reactions to the treatment medication.
5. Patients with a history of significant heart disease or a history of myocardial infarction.
6. Patients with blood pressure above 170 mm Hg systolic/105 mm Hg diastolic or below 80 mm Hg systolic/60 mm Hg diastolic or a pulse greater than 120 beats per minute or less than 50 beats per minute.
7. Patients who have a history of hypertension uncontrolled by conventional medical therapy.
8. Patients who have received any drug known to have a well-defined potential for toxicity to a major organ system within the month prior to entering the study.
9. Patients who have clinically significant laboratory values outside the limits thus specified by normal laboratory parameters.
10. Patients who have any disease of the gastrointestinal system, liver or kidneys, or abnormal condition which compromises a function of these systems and could result in a possibility of altered metabolism or excretion of ibogaine will be excluded. As it is not possible to enumerate the many conditions that might impair absorption, metabolism or excretion, the provider should be guided by evidence such as:
A. History of major gastrointestinal tract surgery (e.g., gastrectomy, gastrostomy, bowel resections., etc.) or a history or diagnosis of an active peptic ulcer or chronic disease of the gastrointestinal tract, (e.g. ulcerative colitis, regional enteritis, Crohn’s disease or gastrointestinal bleeding).
B. Indication of impaired liver function.
C. Indication of impaired renal function.
11. Patients with active tuberculosis.
* * * * * * * * * * * * * * * * * * * * * * * *
"Regarding the manual I would disagree with some of the exclusion criteria," says one author. "By excluding patients that are depressed or bipolar you exclude a sizable portion of the addict population. Because ibogaine’s metabolites have been shown to have an antidepressant effect it would probably help these patients. Proper treatment for psychiatric conditions can be administered afterward. You will find below some of the experience we have had with patients taking antidepressants prior to ibogaine and since many patients have psychiatric conditions, we don’t consider it prudent or necessary to suspend psychotropics for longer than 24 hours before treatment. Below are presented three examples of such patients. All of these patients suspended their medications 24 hours prior to treatment and apparently had no different responses to ibogaine or any unexpected side effects."
1) 22 year old male on Prozac (fluoxetine) 20 mg for 14 months.
2) 38 year old male on Zoloft (sertraline) 100 mg for 2 years.
3) 36 year old female on Paxil (paroxetine) 40 mg for 1 year.
"Since most patients are depressed, a fast acting antidepressant can help in the days after ibogaine. We have found S-adenosyl-L-methionine (SAMe) to be useful. If necessary we also prescribe SSRI’s. These take about two weeks to start working. Another simple but effective therapy is DHA (omega-3 fatty acids). These reduce depression and stabilize mood."
Commenting on the exclusion criteria, another author states, "I don’t think depression should be taken as a contraindication. I’ve treated a lady with an extreme depression hoping it would help. It didn’t. The condition remained unchanged. Of course, one case – no case. People on Oxycontin often claim depression. No wonder – that’s what the interruption of oxycontin use usually leads to. Ibogaine is needed to eliminate the addiction. I suggest antidepressants be started immediately after ibogaine therapy under the supervision of a physician."
Further, an author indicates "that Crohn’s disease should not be an exclusion criteria as one patient diagnosed with Crohn’s disease had the disease placed in remission after ibogaine therapy." While other authors have not had such experience it should be noted that an early report from Dutch Addict Self-Help concerning Hepatitis C being placed in remission resulted in most providers, including then, NDA International, Inc. agreeing to treat patients with HCV whose liver enzymes were not greater than 400% above normal. It must be remembered that we are discussing an experimental medical procedure should that definition be accepted and that medicine itself is diverse in its effects, expectations or adverse events.
A number of authors indicate nonfatal adverse medical events in patients with stomach ulcers. Ibogaine may cause pain and/or bleeding in these patients. Whether this is a matter of irritation to the stomach lining or a more systemic effect is unknown at this time thus, it is unknown whether rectal administration rather than oral administration would ovecome this problem.
TREATMENT REGIMEN AND DOSE
Anticipating that the subject and provider have reached this point in discussion and or treatment, the subject will have met all inclusion criteria and no exclusion criteria. This brings us to actual treatment requirements and dose.
1. The patient should be well rested.
2. All drugs that are not medically required and/or contraindicated should be stopped early enough to be cleared by the subject undergoing ibogaine administration.
3. In the treatment of opioid dependence, short acting opioid drugs should be stopped no less than eight hours before ibogaine administration. Methadone should be stopped no less than 24 hours prior to ibogaine administration.
4. The issue of sedation of the subject particularly in the treatment of opioid dependence is not uncommon. The question of whether sedation, post 30 hours should it be requested or required by the patient, would be beneficial or not to ibogaine therapy has not been answered. Some if not all providers feel that ibogaine effects would be best concluded without sedation. However, patient comfort is an issue and sedation may become a requirement in the treatment of any particular patient.
Ibogaine has been administered safely with various forms of sedation including benzodiazepines, barbiturates, melatonin, valerian and chamomile.
On an adjunct issue, one author comments, "benzodiazepines are useful before, during and/or after the ibogaine dose if there is anxiety. If there is considerable anxiety some days after detoxification buspirone is better because of its low liability for addiction."
5. A number of authors comment on the issue of hydration or in the inverse dehydration. "Post ibogaine the drinking of water is very important. Initiates are requested to drink at least 3 liters of water a day. This is not only for the purpose of avoiding dehydration but, as it is the feeling of this author that ibogaine loosens toxins in the body and, they are excreted during the initiation and afterwards. The only vehicle to accomplish this is pure water."
On an issue of safety , states an author, "I would also include avoiding dehydration. Many subjects don’t feel like drinking for some time after ibogaine and if not reminded they would not drink a drop of water for more than 24 hours. This can lead to dehydration even without vomiting. With vomiting I would view the loss of liquids as threatening."
Continuing, another author states, "I have received patient reports that IV hydration is commonly used at the St. Kitts facility. This is not out of keeping with standardized procedures of hydrating patients undergoing surgery or chemotherapy."
6. Emesis or vomiting is a patient condition known to all ibogaine providers. Whether a provider believes there is benefit to vomiting as part of ibogaine therapy or ritual is moot if enough of the drug cannot be absorbed to allow the therapeutic experience. To that end various providers have indicated the use of subtances as diverse as ginger tea, gravol/dramamine (dimenhydrinate), motillium (domperidone) and reglan (metaclopramide). This author participated in research involving all except ginger tea and upon reflection am uncertain if dimenhydrinate or domperidone had any effect above that of keeping the patient motionless. Metaclopramide 20 mg IV was the only medication that immediately stopped vomiting in ibogaine patients. No determination was made of whether oral metaclopramide administered prior to ibogaine would have as significant an effect as the IV administration of the drug. I anticipate this should be determined.
7. "As to dose," one author comments, "given the modest dose range given in the manual (and I agree a publicly presented manual should lend itself to caution), the 15 – 20 mg/kg of body weight will tend to leave 5 – 10% of the opiate withdrawal symptoms. I suggest a test dose of 2 mg/kg of weight be given with an antinauseant an hour before a dose of 13 – 16 mg/kg. The effect of the 2 mg/kg "test dose" will usually produce slight euphoria which lends to a person being more amiable to receive the next and largest dose. Whereas, years ago, during the first series of sessions, after giving the full amount of 18 – 22 mg/kg that followed the 1 mg/kg "test dose", we found that giving a smaller amount of 13 to 16 mg/kg allows for more comfort for a person who is obviously less traumatized by the intensity of the first stage and more open to receiving a booster of 6 – 8 mg/kg 5 to 8 hours later. On occasion, only when necessary, we administer an additional booster of 3 – 4 mg/kg with 24 hours of the beginning of the session, usually during the early morning hours before sunrise. I have written only a synopsis here as there are reasons, exclusions, etc., every step of the way according to the psycho-physical reactions of the individual as the session progresses."
8. The use of a multi-dose regimen of ibogaine, over time, particularly for methadone, is in keeping with literature in the field (Kosten and Kleber, Am J Drug Alcohol Abuse 1984;10(2):249-66) indicating physical withdrawal signs to methadone may be precipitatated as long as 14 days after the administration of methadone by a narcotic antagonist drug such as naltrexone.
Included herewith, is a report of a dose regimen used to treat a patient who had been receiving 300 mg of methadone per day, the highest dose of methadone dependence yet treated with ibogaine says one provider.
We have recently used the following regimen to clear a methadone dependent person who was taking 300 mg of methadone per day.
At 52 hours after the patient’s last 300 mg. methadone dose, we gave him 5,200 mg Indra extract.
Over the next 72 hours, the patient has no physical withdrawl as per usual (in other words, no diarrhea, vomiting, sweating, running nose, pounding headache) but felt miserable.
72 hours after the first dose of Indra extract, we gave him 100 mg Ibogaine Hydrochloride.
96 hours after the first dose of Indra extract, we gave him 100 mg. Ibogaine hydrochloride.
120 hours after the first dose of Indra extract, we gave him 3,800 mg. Indra extract.
168 hours after the first dose of Indra extract, we gave him 100 mg. Ibo HCI.
192 hours after the first dose of Indra extract, we gave him 100 mg. Ibo HCI.
By his 11th day here (12 days from his last 300 mg. methadone dose), he was bright, sharp, lucid, no slurring, no signs of any methadone, no withdrawal or craving or discomfort of any kind. Patient said "I like the way I’m thinking now."
Patient ate little in the 12 days. Lost 25 pounds. Looks robust, healthy skin. "On methadone, I gained 110 pounds" he commented". The ibogaine is returning him to his regular body weight I feel.
"Something should be said about dose and product," states another author. "First, some new guides, new to the use of ibogaine, may be confused in dose distinctions between HCl and extract. It would be a very unpleasant death, I suppose, with 4 or more grams of ibogaine HCl on board. Second, in my opinion 29 mg/kg of HCl is too much. I experimented with dosages in the range of 13 to 22 mg/kg and came to the following conclusion – 15 mg/kg is for the first time the optimal dose. It is effective for withdrawal and craving and for the vast majority of patients is neither too weak or too strong. Then, from the second treatment on (which I prefer to administer not earlier than 3 or 4 weeks afterwards) the subject can easily cope with 20 mg/kg and does not feel it as stronger than the first treatment."
The proposal of discussion of ibogaine product identity particularly for the benefit of new providers and patients is certainly legitimate as three principal forms of ibogaine of diverse purities are in use in ibogaine therapy. These substances may be, a highly purified form of ibogaine, an extract of T. iboga, that may be as low as 90% or as high as 99% in purity. Most examples of these products are 95% pure ibogaine. These products are available from commercial chemical manufacturers or by custom manufacturing by qualified chemists in university laboratories. Purified ibogaine may also be obtained by direct conversion from voacangine. This product when available had been assessed at 99.4% purity. The second principal form of ibogaine currently available is a crude total alkaloid extract and contains a reported 15% to 20% total alkaloids of which half is ibogaine. As the other iboga alkaloids contained in the total alkaloid products are active, this material should be viewed as having a potency of 15% to 20% ibogaine equivalency depending on source and batch. These total alkaloid extracts have been supplied by sources in Denmark and Canada. The third form of ibogaine material is the crude plant root bark. Depending on potency, this product may contain from 1% to 6% ibogaine. Most root bark will be in the 2% – 4% range. Any person taking ibogaine or providing ibogaine to another person should be certain of the identity of the substance as confusion of purified ibogaine and a less potent total alkaloid extract might cause a fatal reaction or not be sufficient as a dose to interrupt chemical dependence.
While the initial discovery and early research with ibogaine principally used single doses in the 15 mg/kg – 25 mg/kg range of ibogaine, the expanding base of data being presented by ibogaine providers throughout the world propose multiple dosing regimens. These dose regimens make use of purified ibogaine HCl, total extracts and root bark though principally, ibogaine HCl and total extracts except in the African religious model. Doses considered by a variety of providers to be full therapeutic doses may vary from 15 mg/kg – 25 mg/kg for ibogaine HCl and from 3 gram to 5 grams for total alkaloid extracts for the treatment of chemical dependence. For the purpose of this discussion a full therapeutic dose of ibogaine is one that will precipitate all three stages of ibogaine activity in most but, not all patients: 1) The waking dreamlike state, 2) the cognitive evaluation period and 3) residual stimulation eventually leading to sleep. Depending on circumstance and patient need, full therapeutic doses may be administered in a multidose paradigm a week to months apart.
Adjunct dose levels of ibogaine may be mediate or low. A mediate dose would be 300 mgs to 400 mgs of ibogaine HCl or possibly 1.5 to 2 grams of total extract while low doses may be in the range of 25mg to 50mg total dose range for ibogaine HCl and 100 mgs to 300 mgs of total alkaloid extracts. Mediate doses are generally used to boost a therapeutic dose should opiate withdrawal signs become evident or in the cases of some providers for a broader set of issues. Low dose regimens have been implemented for periods of ten to twenty days after recovery from a full therapeutic dose for antidepressant, antianxiety or antiwithdrawal applications. These regimens have been used in the treatment of both opiate and stimulant disorders in furtherance of the full therapeutic dose of ibogaine. It must be recognized that providing ibogaine is an art and a science and that ibogaine providers will use a multitude of doses individually determined on a patient by patient basis in accordance with the experience of the provider.
For additional information, comparative dose and strength tables from the chapter by James and Renate Fernandez found in Vol. 56 of The Alkaloids series published by Academic Press (2001) are shown below.
Alper et al.
Ibogaine dose to facilitate personal growth and change:
Ibogaine single dose in self-help network for addiction interruption:
Animal studies for neurotoxicity:
Alternate daily dose ibogaine over 60 days [no toxicity]:
Ibogaine dose associated with no evidence of toxicity [but decrease in drug self administration:
Ibogaine dose associated with cerebellar damage:
(personal communication in preparation for ibogaine conference)
Ibogaine dose causing modest psychoactivity with euphoria, altered perception of time:
Amount of ibogaine ingested by adept that would allow remaining centered enough to assist in initiation ritual:
200 to 300 mg
Ratio of fresh root scraping to dry root bark:
Proportion of iboga alkaloids in dry root bark (50% ibogaine):
2 to 3%
Rounded teaspoon of root bark:
3 to 4 g
Amount iboga alkaloids in rounded teaspoon per above calculations:
60 to 120 mg
Pick-up dose , iboga alkaloid content of 1 rounded teaspoon of dry root bark:
60 to 120 mg
Large dose for initiation into Bwiti, gradual intake of fresh root scrapings, maximal dose observed:
1000 g [one kilo]
Dose recalculated as dry scraping [1000/15]:
Content of iboga alkaloids of the above quantity of root scraping, assuming an average 2.5% iboga alkaloid content:
Total maximal Bwiti iboga alkaloid dose calculated per kilo of body weighty in small initiate weighing 50 kilos [hence a high estimate]:
POST IBOGAINE THERAPY
There is no clarity that any form of adjunct therapy administered during the post ibogaine period following acute ibogaine effects is more efficacious than any other form of adjunct therapy in prolonging periods of abstinence and freedom from drug craving. This is also in keeping with the findings in chemical dependence treatment of non-ibogaine patients. It is the hope of the authors that findings of significance concerning efficacy or advantages of one form of therapeutic modality over another may be addressed in future revisions of the manual. Provider contributions are encouraged.
One author indicates, as for post-ibogaine therapy we have found that it is essential for addicts to quit smoking tobacco. Nicotine has proven to act on receptors that cocaine and other drugs also effect. Statistics show that 90% of addicts smoke and nicotine can cause craving for other drugs. Many patients find that cigarettes taste different after ibogaine and we encourage them to quit by using nicotine patches and Wellbutrin (bupropion HCl).
A second author adds, "With regard to the question of suitable post-ibogaine therapy, my opinion, from personal experience and reading Bwiti literature, is that bio-energetics or other body-based psychotherapies are most useful. The Bwiti dance constantly on iboga in the regular group sessions at the temple (not during the high dose "initiatory" session, you can’t move as I’m sure you’re aware!) and I’m sure this is for a reason."
"My personal opinion, based on my experience of doing ibogaine, doing quite a bit of therapy afterward, and observing others who’ve done ibogaine with or without therapy afterward, is that there is sometimes a real problem with integrating the ibogaine experience properly and not simply at an ego-level. The tendency towards developing a ‘need’ for alternative belief systems to avoid bodily integration of the experience is, in my opinion, particularly marked in ibogaine users. (ie the individual NEEDS to believe something is true as opposed to being able to simply take or leave an idea)"
"Therefore body-based and emotional release therapies like primal, bio-energetics and encounter are probably highly synergistic with the ibogaine experience, in my opinion. My personal recommendation would be Humaniversity therapy, available at the Humaniversity up on the Dutch coast, and available to addicts as the Residential Addiction Foundation Program (RAF Program) lasting 3-6 months or longer."
Another author adds, "I constantly emphasize that to take full advantage of a session it is imperative to follow through with therapy. If the 12 step programs appeal to a person then, by all means incorporate the meetings into the post session program. A couple of ingredients apply specifically to people compelled to consume drugs. One, is they do not want to experience any level of pain, i.e. physical, emotional pain is to be avoided at any cost. The second insight is that a percentage somewhere in the 90’s have experienced a deep level of physical and/or emotional abandonment from the same sex parent. Individual therapy, which necessitates finding a same sex therapist to establish the therapeutic relationship which includes transference of initial role model issues within the framework of the relationship is most healing so that by the time the metabolite washes out of the receptors from the session, the deep issues which created the addiction to begin with from the role model relationship in question has solidly begun to be actively addressed. This crucial type of therapy is, to say the least a challenge to create because of the threat it imposes to the very core ego structure. And so in the name of therapy most people will find a counselor who they are comfortable with and not at all intimidated by. This type of talk therapy will not be sufficient."
A fifth author comments, "It’s frequent that addicted clients think that if they still feel some withdrawal effects or craving after more than 20 hours after ibogaine intake, then it didn’t work out for them and they tend to search for a dose of their drug of choice. The treatment provider must be aware that ibogaine often needs some days to stabilize its effects and therefore should heighten his immunity toward the addict’s heartbreaking performances."
"It is important to understand the differences between treating addiction as only a physiological medical condition and treating addiction with its related psychological and social issues. In spite of the fact that ibogaine is not far from being a miraculous treatment tool, the way it is generally used is highly ineffective and wastes ibogaine’s potential. I am talking about overnight treatments that do not include an integrated treatment program. Ibogaine simply needs to be incorporated into already existing addiction treatment networks and then it will show its real potential. "
And, a sixth author: "Private therapy is somewhat hit and miss. There are brilliant practitioners out there but not many with any ibogaine experience (if any)." "… bodywork is extremely important." "So for people that are disillusioned by therapists and group counsellors various forms of bodywork can be extremely effective – acupuncture, rolfing, breathwork (rebirthing or Grofs), dance and movement therapy. Anything that reconnects you with the trauma lodged deep in your body. If you have been addicted for years the ibogaine may bring the reasons for the distress to the surface but that won’t necessarily release them – especially if they are lodged deep – which is why the previously mentioned practices help."
"I would also suggest that a support group is extremely beneficial. Unfortunately no matter how much I tried I couldn’t get the people that I had seen to form an ibogaine support group and I think this would really help. I have seen it help on the ibogaine list. People able to talk to each other about their experiences on line. Perhaps this is the only way to do it but it would be good for example to have a group… that met once a month to talk about things."
"To conclude, no three day recovery program in itself can correct years of substance abuse. It is therefore essential to arrange follow up care. The ibogaine experience itself leaves you open and enthusiastic about creating changes in your life. Post treatment bodywork/counselling is essential, as it will help maintain this positive transformation and facilitate a deeper understanding and release of years of abuse."
While still another reflects, "I think it is important we not only reach for the most significant endpoint in offering ibogaine therapy but, view what we are doing from a harm reduction perspective and a pro-patient perspective in that anything that benefits the patients, short or long-term, should be viewed as a valuable outcome. I think it is universally accepted that multiple ibogaine treatments over time provide better results in most cases than a single administration. This is not to say that a single administration is not dramatic in its ability to interrupt an out of control addiction syndrome. I think it would be fortunate if ibogaine were a legally available medication through both social and private medical insurance programs. Availability coupled with normalization of addiction into mainstream medical treatment will offer the best outcome in our society which is medically directed. Under other circumstance, a religion would do just as well, and that is not to exclude the self-help group or association concept. From what I see of the suggestions of many of the authors, a belief system and the ability to take some action, to allow a sense of power and accomplishment are important."
Invitation to Contribute
Many questions for which we seek answers remain: How do ibogaine providers best care for ibogaine patients? The primary authors continue to seek a consensus from ibogaine providers and patients as well as, others working in addiction medicine. Is a consensus possible? That remains to be seen but, with each revision of the manual we may come closer.
Submissions should be made to Howard Lotsof. Accepted work will be incorporated into the next revision of this manual and the authors indicated as contributing authors to this manual or not, at their discretion. Revisions shall be made periodically.
NIDA DRAFT PROTOCOL
Rising Dose Tolerance Study using Single Administration to Assess Safety and Preliminary Efficacy of Ibogaine for the Treatment of Cocaine and/or Heroin Dependency
Introduction Safety and Exclusion Criteria
Opioid Withdrawal Assessments
General Physical Condition
Assessments During Treatment
Safety and Exclusion Criteria
[ introductory statements ]
To date, there is no published data from a controlled clinical trial that has assessed the safety of ibogaine in the treatment of drug addictions. Information from the anecdotal reports indicates there is a mild transient increase in blood pressure and a minimal effect on pulse and respiration.
To date, there is no published data from a controlled clinical trial that was conducted to assess the preliminary efficacy of ibogaine in the treatment of drug addictions. The initial observations of effects of ibogaine was a narrative account (L.A.C., 1991) of the results of taking ibogaine in the mid 1960s by seven heroin addicts, five of whom several days later reported no signs of withdrawal, abstinence, and no desire to take heroin.
Of the 7 clients in the mid-sixties, 6 received one treatment of ibogaine and the effects were that 2 resumed heroin use 24 hours later, one resumed heron use 5.5 months later and the remaining 3 were drug-free 6 months after receiving ibogaine. One subject reported receiving ibogaine 5 times and reported abstinence from: heroin use for 3 years, cocaine use for 18 months and amphetamine use for 6 months.
Of the 18 clients in a contemporary group, 17 received one treatment of ibogaine and one received 2 treatments. After ibogaine, two clients continued to take heroin and one resumed heroin use 5 days later. Six subjects were drug-free from 2 weeks to 18 months, but contact was lost with them. Two subjects were heroin-free for six months and were awaiting retreatment with ibogaine. One subject was cocaine-free for 3.5 years. The remaining 5 subjects were drug-free for 2-10 months.
Preclinical Studies on Ibogaine
The most salient safety issue is contained in the findings of (O’Hearn et al., 1993) that when rats were administered high doses of ibogaine (100 mg/kg i.p.) glial cells in the cerebellum were activated, thereby suggestive of neuronal damage which the authors hypothesized were most likely the purkinje cells. [see additional documents #1 and #2]
Other safety issues about the effects of ibogaine are contained in the reports of: increased blood pressure and heart rate in conscious dogs and decreased blood pressure and pulse rate in anaesthetized dogs (Gershon and Lang, 1962), decreased blood glucose (ibogaine 20 mg/kg or 40 mg/kg) and increased blood glucose with higher doses in rats (Dhahir, 1971).
Safety Measures – Cerebellar Functioning
Prior preclinical studies indicated that the major safety issue with the administration of ibogaine is the remote possibility of lasting damage to the cerebellum, especially the purkinje cells. The repeated neurological assessments of cerebellar functioning in our subjects will consist of an extensive neurological examination that assesses most of the readily measurable dimensions of cerebellar functioning. The neurological examination was adapted from the application of comprehensive preclinical work on the cerebellum that was summarized in a book by (Ito, 1984) to contemporary texts on neurological examinations (Kaufman, 1990; Scheinberg, 1981). The major neurological signs that indicate cerebellar damage are: dysmetria (inaccurate targeting of goal-directed behavior), delayed movement initiation and delayed reaction time, dysdiadochkinesia (inability to perform rapidly alternating repetitive tasks), hypotonia (reduced muscle tone), disturbances in gait and station, and intention tremor. The check-list for the Neurological Assessment Battery will consist of 12 behaviors that will be evaluated by the following discrete categories of impairment: none, mild, moderate and severe. In addition, while on inpatient status, PET scans will be conducted during the inpatient phase 3 days before and 3 days after the Ibogaine session and during the one-year follow-up assessment battery.
1. Patients with a history of active neurological or psychiatric disorders, such as cerebellar dysfunction, psychosis, bipolar illness, major depression, organic brain disease or dementia, that require treatment or that would make study compliance difficult.
2. Patients who have a Beck Depression Inventory score greater than or equal to twenty-four.
3. Patients requiring concomitant medications that may interfere with a clinical trial or evaluation (e.g., anti-epileptic drugs, sedatives, hypnotics, antidepressants, neuroleptics, methadone, meperidine, etc.) [A significant number of patients treated in the last decade outside of this proposed research study have been dependent on methadone, meperidine or sedatives].
4. Patients with a history of sensitivity or adverse reactions to the treatment medication.
5. Patients with a history of significant heart disease or a history of myocardial infarction.
6. Patients with blood pressure above 170 mm Hg systolic/105 mm Hg diastolic or below 80 mm Hg systolic/60 mm Hg diastolic or a pulse greater than 120 beats per minute or less than 50 beats per minute.
7. Patients who have a history of hypertension uncontrolled by conventional medical therapy.
8. Patients who have received any investigational drug within 6 months prior to entering the study. [The authors received a report of concurrent use of ibogaine and 5 methoxy di isopropyl tryptamine (5meo dipt) that precipitated a medical event of near fatal proportions requiring over a week of hospitalization. Additionally the patient was diabetic and did not monitor blood glucose levels.]
9. Patients who have received any drug known to have a well-defined potential for toxicity to a major organ system within the month prior to entering the study.
10. Patients who have clinically significant laboratory values outside the limits thus specified by the investigators laboratories.
11. Patients who have any disease of the gastrointestinal system liver or kidneys, or abnormal condition which compromises a function of these systems and could result in a possibility of altered metabolism or excretion of the study medication will be excluded. As it is not possible to enumerate the many conditions that might impair absorption, metabolism or excretion, the investigator should be guided by evidence such as:
A. History of major gastrointestinal tract surgery (e.g., gastrectomy, gastrostomy, bowel resections., etc.) or a history or diagnosis of an active peptic ulcer or chronic disease of the gastrointestinal tract, (e.g. ulcerative colitis, regional enteritis, Crohn’s disease* or gastrointestinal bleeding).
B. Indication of impaired liver function.
C. Indication of impaired renal function.
12. Patients who test positive for HIV virus.
13. Patients with active tuberculosis.
A. Addiction Severity Index (ASI)
B. Diagnostic Interview Scale (DIS)
A. Visual Analogue Scale cocaine craving (VAS)
B. Beck Depression Inventory (BDI)
C. Minnesota Multiphasic Personality Inventory-2 (MMPI-2)*
1. Electroencephalography (EEG)
2. Neurological Assessment Battery
B. Coordination/tremor, Repeated rapid alteration tests
a. Palm/back hand slap knee
b. Prone/supine forearm
C. Coordination /ataxia
a. Heel-to-toe walking
b. Romberg test (feet together, eyes open/eyes closed)
D. Muscle tone/hypertonia
a. Resistance to stretch
a. Acoustical startle
b. Pupilary light reflex
c. Vestibulo-occular reflex
Opioid Withdrawal Assessments*
1. Objective Opiate Withdrawal Scale (OOWS)*
2. Subjective Opiate Withdrawal Scale (SOWS)*
General Physical Condition
1. History and Physical
2. Electrocardiogram (EKG)
a. CBC DIFF
b. AST ALT
c. Hepatitis screen
d. Thyroid panel
e. SMA-18 profile
a. Routine urine analysis
b. Toxicology screen (positive for target drugs)
2. morphine (heroin)
Dermal Tuberculin (if positive or previously immunized, then chest x-ray)
Vital signs with weight
HIV test and counseling
Support staff and design of environment
Generally, the session room should be pleasant and the social interactions with staff members supportive. Pastel-colored walls, comfortable hospital bed, soothing murals, paintings or pictures, a comfortable chair for the staff member or therapist to constantly observe the subject during the ibogaine experience. Dim lighting and quite setting. Dialogue should be initiated by the patient. Reduce the need for walking by having a patient lavatory nearby.
Within this context, allow the patient to sleep and rest peacefully ad lib. Otherwise, when the patient is in the talkative phase, the staff member should attentively and unobtrusively attend to but not initiate conversation.
Assessments [during treatment]
Cardiovascular – Apply ambulatory pulse and blood pressure apparatus that is programmed to obtain and record digital quantities q 30 min for a 24 h period. Apply device just before dosing.
Neurological – Observe for the onset (that is time from the administration of ibogaine) for drug-related changes in neurological functioning (e.g., the onset of changes in speech patterns, nausea and vomiting)
Psychological – Observe and record what patients spontaneously say, Record the onset and duration of the somnolent phase.
Related Protocol Bibliography
Dhahir. A comparative study of the toxicology of ibogaine and serotonin. Doctoral Thesis. 1971. return to chapter
Gershon S., Lang W.J., A psycho-pharmacological study of some indole alkaloids. Arc. Int. Phamacodyn. 85, 31-62, 1962. return to chapter
Ito, M. The cerebellum and neural control. New York: Raven Press, 1984, Pp. 353-465. return to chapter
Kaufman, D.M. Clinical neurology for psychiatrists (3rd Ed.). Philadelphia: W.B. Sanders Co., Pp 18-20, 1990. return to chapter
L.A.C. Can a psychedelic drug cure drug addiction? The ibogaine story. Drugs, Toxic Chemicals and Health 6, 1-2, 1991. return to chapter
O’Hearn E., Long D.B., Molliver M.E. Ibogaine induces glial activation in parasagittal zones of the cerebellum. Neruroreport. 4, 299-302, 1993. return to chapter
Scheinberg P. Modern practical neurology; An introduction to diagnosis and management in common neurologic disorders (2nd Ed). New York: Raven Press 1981. return to chapter
***End NIDA Protocol Selections***
5. A CBC or complete blood count along with a differential that indicates the breakdown in the types of white blood cells offers a comprehensive view of blood chemistry in conjunction with the SMA-20. Return to chapter
6. A general review of cardiovascular disorders can be found at The Open Directory Project and at The Medical Center Online. The topic is also well covered in Section 16 of the Merck Manual Return to chapter
8. This early report, Reflections on an Ibogaine Experience, provides an excellent treatment overview that includes concurrent ibogaine/heroin use by the patient. The survival of this patient should not be taken to indicate the survival of other patients under similar circumstance. Return to chapter
9. A copy of the Beck Depression Inventory is available as an FDA document. This page automatically downloads the pdf file of the beck depression inventory to your computer. PDF files require adobe reader programs that are available at no cost from Adobe return to chapter
12. Treatment of Acute Opioid Withdrawal with Ibogaine. Alper et al.’s review article of ibogaine effects on opioid withdrawal signs of subjects from the United States, The Netherlands and Panama over a period of three decades is now available as a downloadable PDF file. In order to read a PDF file you will require an adobe reader program from Adobe. Return to chapter
13. The early paper (1995) Ibogaine in the Treatment of Narcotic Withdrawal by Lotsof, Della Sera and Kaplan provides useful information on the comparative effects of ibogaine and narcotic withdrawal. Return to chapter
23. "Merck & Co., Inc., is proud to introduce The Merck Manual of Medical Information–Home Edition.. This all-new publication is based on The Merck Manual of Diagnosis and Therapy, Centennial Edition , commonly referred to as The Merck Manual, the textbook of medicine most widely used by health care professionals in the U.S. and worldwide. The Home Edition transforms the language of the professionals’ version into commonly used English while retaining the vital information about diseases, diagnosis, prevention, and treatment." The reader should review both volumes to determine which best meets your needs. "The Merck Manual of Medical Information–Home Edition, like all the Merck manuals and The Merck Index, is published by Merck & Co., Inc., on a not-for-profit basis. Copyright © 1995-2001 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved." return to chapter
24. How to Safely Use Ibogaine, a public document of the Iboga Foundation, a not-for-profit group in Slovenia approaching ibogaine use from a religious perspective.
Review articles describing the NMDA-receptor
1. The psychopharmacology of hallucinogens. Abraham, H.D., Aldridge, A.M. and Gogia, P. Neuropsychopharmacology 14:285-298, 1996.
Abstract: The strychnine-insensitive glycine site on the N-methyl-D- aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2- one), a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T- maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA-966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7-chlorkynurenic acid, did not substitute for (+)- HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1,2- cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did not substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizocilpine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site. Furthermore, the lack of substitution of compounds with phencyclidine- like effects (dizocilpine, ibogaine and NPC 17742) or sedative properties (NPC 17742 and (-)-HA-966) suggests that these side-effects may not be part of the subjective effect profile of glycine partial agonists
2. Ibogaine block of the NMDA receptor – in vitro and in vivo studies. Chen, K., Kokate, T.G., Donevan, S.D., Carroll, F.I. and Rogawski, M.A. Neuropharmacology 35:423-431, 1996.
Abstract: 1. Ibogaine, a proposed anti-addictive agent, has been found to interfere with the acquisition of a weak morphine-induced place preference. The present series of experiments determined if ibogaine would interfere with the expression of a previously established morphine (5 mg/kg) place preference. 2. A single injection of 40 mg/kg of ibogaine 24 h, 12 h or 4 h prior to the preference test (Experiment 1) or 80 mg/kg of ibogaine 24 hr prior to the preference test (Experiment 3) did not interfere with the expression of a morphine conditioned place preference. 3. Furthermore two injections of 40 mg/kg of ibogaine 48 h and 24 h or 24 h and 4 h prior to testing (Experiment 2) did not interfere with the expression of a morphine place preference. 4. Ibogaine appears to be incapable of attenuating the expression of a previously established one-trial morphine place preference. [References: 27]
3. [New therapeutic possibilities with low-affinity NMDA receptor antagonists]. [Review] [German]. Kornhuber, J. and Weller, M. Nervenarzt. 67:77-82, 1996.
4. The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine. Sershen, H., Hashim, A. and Lajtha, A. Brain Res Bull 40:63-67, 1996.
Abstract: The indole alkaloid ibogaine has been suggested to have potential for inhibiting dependency on stimulant drugs. Radioligand binding studies have suggested possible multisite actions of ibogaine: affinity at the kappa-opioid, NMDA, and sigma receptors, with effects on dopamine (DA) release. To further investigate the multiplicity of sites of action of ibogaine and the presynaptic regulation of the DA release, the effect of ibogaine on NMDA- and sigma-receptor-mediated efflux of [H-3]DA was measured in striatal tissue from C57BL/6By mice. Striatal tissue was incubated in vitro with [H-3]DA and the effect on DA release was measured. Both NMDA (25 mu M) and the sigma receptor agonist (+/-)-pentazocine (20 mu M) alone increased the efflux of DA. (+/-)-Pentazocine (100 nM) did not inhibit the NMDA-evoked release. MK-801 (5 mu M) completely inhibited the NMDA-evoked release and inhibited the (+/-)- pentazocine-evoked release by 49%. Ibogaine (10 mu M) itself increased the efflux of DA; at 1 mu M it was without effect. Ibogaine (1 mu M) inhibited the NMDA-evoked release of DA by 31% and inhibited the (+/-)-pentazocine-evoked release by 48%. In addition, the level of basal release of DA obtained after the NMDA- or (+/-)-pentazocine-evoked-release remained higher in the tissue exposed to ibogaine throughout. The results suggest that sigma receptors can regulate the release of DA, along with an action at the NMDA receptor. We previously reported action of ibogaine at the kappa-opioid site. The elevated basal release of DA in the presence of ibogaine after NMDA-or (+/-)-pentazocine- evoked release may reflect the ibogaine-induced removal of the tonically active kappa-opioid system that acts presynaptically to reduce dopamine release. The kappa-opioid system also appears to be inhibitory on both the NMDA and sigma receptors
5. The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine. Sershen, H., Hashim, A. and Lajtha, A. J Neurochem 66:S59, 1996.
6. Antagonists of the NMDA receptor-channel complex and motor coordination. [Review]. Carter, A.J. Life Sci 57:917-929, 1995.
Abstract: Glutamate receptor antagonists with selective action at the N- methyl-D-aspartate (NMDA) receptor are promising agents for the neuroprotective and symptomatic pharmacotherapy of various neuropsychiatric disorders. Although NMDA receptor antagonists of the phencyclidine (PCP) type are precluded from clinical use because of their psychotomimetic properties, amantadine and memantine have been administered to human patients with idiopathic Parkinson’s disease and spasticity for many years without serious adverse effects. The mechanisms underlying these differences in psychotogenicity of different NMDA receptor antagonist are currently being discussed. Different affinity to the PCP binding site of the NMDA receptor, region-specific pharmacology, as well as different binding profiles to neurotransmitter receptors other than the NMDA type glutamate receptor, most likely play a role in determining whether an NMDA receptor antagonist drug will be tolerated clinically or not. [References: 22]
7. The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. [Review]. Ellison, G. Brain Res Brain Res Rev 20:250-267, 1995.
8. Properties of Ibogaine and Its Principal Metabolite (12 Hydroxyibogamine) at the mK 801 Binding Site of the NMDA Receptor Complex. Mash, D.C., Staley, J.K., Pablo, J.P., Holohean, A.M., Hackman, J.C. and Davidoff, R.A. Neurosci Lett 192:53-56, 1995.
Abstract: The putative anti-addiction alkaloid ibogaine and its principal metabolite 12-hydroxyibogamine appear to act at the (+)-5 methyl- 10,11-dihydro-5H-dibenzo[a,d]cycloheten-5-10 maleate (MK-801) binding site in the N-methyl-D-aspartate (NMDA)- receptor cation channel. This conclusion is based on findings that both compounds competitively displaced specific [H-3]MK-801 binding to membranes from postmortem human caudate and cerebellum and from frog spinal cord. Ibogaine was 4-6-fold more potent than its metabolite and both compounds were less potent (50-1000-fold) than MK-801 binding to the NMDA receptor. In addition, ibogaine (100 mu M) and 12-hydroxyibogamine (1 mM) blocked (85-90% of control) the ability of NMDA (100 mu M, 5 s) to depolarize frog motoneurons in the isolated frog spinal cord. The prevention of NMDA- depolarizations in frog motoneurons showed use-dependency and was very similar to the block produced by MK-801. In view of the abilities of MK-801 to affect the responses to addictive substances in pre-clinical investigations, our results are compatible with the idea that the ability of ibogaine and 12- hydroxyibogamine to interrupt drug-seeking behavior may, in part, result from their actions at the MK-801 binding site
9. Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer’s dementia. [Review]. Muller, W.E., Mutschler, E. and Riederer, P. Pharmacopsychiatry 28:113-124, 1995.
Abstract: Our current knowledge of the structure and function of NMDA receptors is expanding at a rapid pace; however, advances regarding regulation of the supply of glutamate and its co- agonist, glycine, have been slower. While the anatomical sources and metabolic compartmentation of glutamate have been studied, limited efforts have been dedicated to defining the dynamics and compartmentation of the co-agonist, glycine. In fact, most investigators have made the assumption that glycine is freely available, via diffusion, for synaptic transmission at NMDA-type synaptic clefts. This assumption ignores the intricate inactivation mechanisms potentially involved in regulating synaptic levels of this amino acid and the recent descriptions of high levels of endogenous D-serine, another potential agonist of the NMDA-associated glycine receptor, in the brain. In this review, the relevance of these data and pharmacological experiments pertinent to the question of whether the NMDA- associated glycine receptor is saturated in vivo or not, is presented. [References: 62]
10. Neuroprotective properties of the uncompetitive NMDA receptor antagonist remacemide hydrochloride. [Review]. Palmer, G.C., Cregan, E.F., Borrelli, A.R. and Willett, F. Ann NY Acad Sci 765:236-247, 1995.
Abstract: There is a growing body of evidence that disturbances of glutamatergic neurotransmission may underlie the pathomechanism and cognitive deficits of Alzheimer’s disease. This review describes the potential use of low affinity, noncompetitive NMDA receptor antagonists in the treatment of this disease using memantine as an example. Evidence is presented indicating that this class of compound is neuroprotective in preclinical models of subchronic glutamate toxicity without producing side effects characteristic for other classes of NMDA receptor antagonist. This is attributed to their fast blocking kinetics and strong voltage dependency. Memantine also produces symptomatological improvement of cognition in animal models. The mechanism of action of this effect is still unclear but might be related to an enhancement of AMPA receptor mediated neurotransmission. In patients with dementia syndrome of various aetiologies, memantine produces a rapid onset, clinical improvement in various symptomatological deficits. [References: 90]
11. NMDA Antagonist Properties of the Putative Antiaddictive Drug, Ibogaine. Popik, P., Layer, R.T., Fossom, L.H., et al. J Pharmacol Exp Ther 275:753-760, 1995.
Abstract: Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D- aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (K-i, 2.3 mu M at -60 mV). Consistent with this observation, ibogaine competitively inhibits [H-3]1-[1-(2- thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (K-i, 1.5 mu M) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 mu M). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED(50), 64.9 mg/kg) in mice trained to discriminate the prototypic voltage- dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone- precipitated jumping in morphine-dependent mice (ED(50), 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone- precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative ”antiaddictive” property of this alkaloid, its ability to reduce the expression of morphine dependence
12. Excitotoxicity and the NMDA receptor–still lethal after eight years. [Review]. Rothman, S.M. and Olney, J.W. Trends Neurosci 18:57-58, 1995.
13. NMDA and D1 receptors mediate induction of c-fos and junB genes in striatum following morphine administration: implications for studies of memory. [Review]. Sharp, F.R., Liu, J., Nickolenko, J. and Bontempi, B. Behav Brain Res 66:225-230, 1995.
Abstract: Although it has been known for several decades that the administration of amphetamines to experimental animals produces damage to monoaminergic neurons, the mechanism(s) underlying this neuropathology is unknown. In recent years, it has been demonstrated that various N-methyl-D-aspartate (NMDA) receptor antagonists can prevent the damage produced by the amphetamines. The purpose of this communication is to review the evidence which demonstrates the role of NMDA receptors in the neuropathology of neostriatal dopaminergic neurons produced by the amphetamines and to discuss how the action of the amphetamines may potentially affect NMDA receptor function. [References: 27]
14. The role of N-methyl-D-aspartate receptors in dopaminergic neuropathology produced by the amphetamines. [Review]. Sonsalla, P.K. Drug Alcohol Depend 37:101-105, 1995.
Abstract: Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion- channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it’s projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDA antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer’s patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependent. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbic structures may clarify these alterations in this simplified Papez- like circuit. [References: 140]
15. Discriminative Stimulus Effects of R (+) 3 Amino 1 Hydroxypyrrolid 2 One, ((+) Ha 966), a Partial Agonist of the Strychnine Insensitive Modulatory Site of the N Methyl D Aspartate Receptor. Witkin, J.M., Brave, S., French, D. and Geterdouglass, B. J Pharmacol Exp Ther 275:1267-1273, 1995.
Abstract: The strychnine-insensitive glycine site on the N-methyl-D- aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-5-amino-1-hydroxypyrrolid- 2-one], a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T-maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA- 966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7- chlorkynurenic acid, did not substitute for (+)-HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1,2- cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did riot substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizocilpine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site. Furthermore, the lack of substitution of compounds with phencyclidine-like effects (dizocilpine, ibogaine and NPC 17742) or sedative properties (NPC 17742 and (-)-HA-966) suggests that these side-effects may not be part of the subjective effect profile of glycine partial agonists
16. The co-agonist concept: is the NMDA-associated glycine receptor saturated in vivo?. [Review]. Wood, P.L. Life Sci 57:301-310, 1995.
Abstract: Many structurally different, centrally active antagonists of the NMDA receptor-channel complex induce phencyclidine-like side effects in mammals which include head weaving, body rolling, sniffing and disturbances of motor coordination. The ability of these compounds to cause disturbances of motor coordination correlates directly with their ability to antagonize the NMDA receptor-channel complex in vivo. Although noncompetitive antagonists increase motility in rodents, whereas competitive antagonists do not, both classes of compounds appear to induce schizophrenia-like psychosis in human beings, and cause similar changes in a variety of different biogenic amine neurotransmitter systems in the limbic and motoric areas of the brain. The complex spectrum of behavioural effects observed after the administration of antagonists of the NMDA receptor-channel complex probably reflects the intricate nature of the interaction with positive and negative feedback loops of the motor circuit. Recent research indicates that the site of integration of this interaction could be the striatal medium spiny GABAergic neuron. [References: 160]
17. Regulation by neuroprotective factors of NMDA receptor mediated nitric oxide synthesis in the brain and retina. [Review]. Akaike, A., Tamura, Y., Terada, K. and Nakata, N. Prog.Brain Res 103:391-403, 1994.
Abstract: The glutamate transmitter system provides several benevolent/malevolent paradoxes. Glutamate itself serves vitally important functions in the CNS but has enormous neurodestructive potential. NMDA glutamate receptor antagonists protect many neurons against glutamate neurotoxicity, while injuring or destroying certain other neurons and inducing psychotic symptoms and memory impairment. Therefore, the challenge in developing protective therapies against glutamate’s neurodestructive potential is to find benevolent agents that are not malevolent as well. There are two possible approaches. One is to develop neuroprotective agents that are free from neuropsychopathological side effects; the other is to use NMDA antagonists even though they have neuropsychopathological side effects, but to use them in combination with other agents that block the side effects without producing side effects of their own. [References: 79]
18. Assessing structural changes in the brain to evaluate neurotoxicological effects of NMDA receptor antagonists. [Review]. Auer, R.N. Psychopharmacol.Bull 30:585-591, 1994.
Abstract: This article serves as an introduction to the following two articles which describe the effects of drugs that interact with N- methyl-D-aspartate (NMDA) receptors on a number of behavioral baselines. The discussion in the subsequent articles focuses on detailed examination of performance on complex learning tasks, although effects of drugs affecting NMDA receptors on simple learned and unlearned behaviors are also mentioned. This article will provide a framework for interpretation of the results reported. To that end, a short primer on the principles of behavior is provided, followed by a description of a number of behavioral tests and discussion of issues important for the interpretation of results from such tests. The behavioral baselines discussed are, for the most part, the specific tasks from which data are presented in the following reports. A few additional descriptions have been included to illustrate specific points regarding data interpretation. The examples discussed are not necessarily representative of behavioral endpoints used routinely in the assessment of the behavioral effects of drugs. A number of reviews are available to the interested reader (Cabe & Eckerman 1982; Heise 1984; Rice 1990; Thompson & Shuster 1968; World Health Organization 1986). [References: 23]
19. [Neuronal protection in neurologic diseases?]. [Review] [German]. Bahr, M., Eschweiler, G.W. and Dichgans, J. Nervenarzt. 65:355-360, 1994.
20. Effects of NMDA receptor antagonists on the developing brain. [Review]. Constantine-Paton, M. Psychopharmacol.Bull 30:561-565, 1994.
Abstract: Electrophysiologic responses to the glutamate agonist analogue N- methyl-D-aspartate (NMDA) are enhanced in the developing nervous system compared to responses in the adult. Neurotoxicity mediated by comparable amounts of NMDA and its endogenous analogue quinolinate is more than 50 times greater in the 7-day-old rat brain than in the adult. NMDA antagonist drugs reduce this neurotoxicity with the same spectrum of activity with which they prevent injury from hypoxic-ischemic damage. The greater vulnerability of the immature brain to NMDA mediated injury is probably related to the enhanced role that NMDA mechanisms play in long-term potentiation and activity-dependent plasticity during development. [References: 54]
21. The impact of NMDA receptor antagonists on learning and memory functions. [Review]. Cory-Slechta, D.A. Psychopharmacol.Bull 30:601-612, 1994.
Abstract: The c-fos and junB immediate early genes (IEGs) were induced in neurons of the medial and ventral striatum following administration of morphine. The striatal induction of c-fos and junB mRNA and Fos protein was blocked by naloxone, the D1 dopamine (DA) receptor antagonists, SCH23390 and SCH39166, and the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, MK801. SCH23390 and MK801 did not block morphine induction of c- fos and junB in septum. Since the pattern of the morphine induction of c-fos and junB in striatum and nucleus accumbens was similar to that observed with cocaine and amphetamine [2,18,45, 51], these data support current concepts that limbic striatum and nucleus accumbens are among the brain regions that mediate drug abuse [9,10,23,27,49]. If it is true that D1 receptors activate the CRE (cyclase response element) and NMDA receptors activate the SRE (serum response element) in the c-fos promoter , then this data suggests that serial activation of mu opiate, NMDA and D1 receptors on different neurons is required to induce Fos in striatal neurons with D1 Moreover, concurrent activation of NMDA and D1 receptors is required for Fos induction in striatal neurons. The Fos induced by this simultaneous activation of NMDA and D1 receptors should lead to long-term changes of gene expression that might also be involved in changes of brain circuits that could form the basis for ‘memories’ relating to prior exposure to addictive drugs. [References: 51]
22. Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology. [Review]. Hargreaves, R.J., Hill, R.G. and Iversen, L.L. Acta Neurochir.Suppl.(Wien). 60:15-19, 1994.
23. [The phencyclidine-N-methyl-D-aspartate theory of schizophrenia: clinical applications]. [Review] [Hebrew]. Heresco-Levy, U., Elman, I. and Javitt, D. Harefuah. 126:598-601, 1994.
Abstract: Several types of lesions of the mature central nervous system (CNS), such as craniocerebral trauma or spinal cord trauma, may initiate secondary cascades, which may cause damage to primarily uninjured neurons. The exact mechanisms which cause neuronal cell death are still unknown. It has been suggested that retrogradely transported target-derived neurotrophic factors which are necessary for neuronal survival might be lacking after certain types of lesions. On the other hand, neurons might be damaged by calcium-overload resulting from excessive release of excitatory amino acids (EAAs) after trauma. The present review summarizes current concepts of post-traumatic neuronal cell damage with a focus on the putative neuroprotective role of calcium channel blockers and their interaction with glutamate mediated cytotoxicity, neurotrophic factors and free radicals. [References: 50]
24. Pharmacological evidence for a role of long-term potentiation in memory. [Review]. Izquierdo, I. FASEB J 8:1139-1145, 1994.
Abstract: The focus of this article will be on toxic symptoms associated with blockade of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. We have been studying two parallel phenomena: NMDA-antagonist neurotoxicity (NAN) in rats and NMDA-antagonist psychotogenicity (NAP) in humans. These phenomena have a common denominator–NMDA receptor hypofunction, which is putatively a mechanism operative in schizophrenia. We have found that the NAN reaction in rats can be prevented by specific drugs that prevent NAP in humans and by certain antipsychotic agents, including clozapine, that ameliorate symptoms in schizophrenia. By studying mechanisms by which clozapine prevents the NAN reaction in rats, we hope to gain insight into mechanisms by which clozapine or other atypical antipsychotics ameliorate symptoms in schizophrenia. [References: 26]
25. Developmental aspects of NMDA receptor agonists and antagonists in the central nervous system. [Review]. Johnston, M.V. Psychopharmacol.Bull 30:567-575, 1994.
Abstract: Like all pharmacologic agents known, N-methyl-D-aspartate (NMDA) antagonist compounds have side effects. It is expected that neuroactive molecules have effects, including side effects, in the central nervous system (CNS). With NMDA antagonists in rodents, these side effects are remarkably focal in the cingulate and retrosplenial cortex. The salient features of NMDA antagonist neurotoxicity which should be underscored are hypermetabolism, lactate accumulation, neuronal vacuolization in aldehyde fixed material, and neuronal death in older rodents. The scope of this phenomenon must urgently be determined in non-rodent species, specifically primates. This is important from both a regulatory and neurotherapeutic point of view, since effective molecules having potential in human disease states may also have NMDA antagonist properties. [References: 27]
26. Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. [Review]. Kornhuber, J., Weller, M., Schoppmeyer, K. and Riederer, P. J Neural Transm.Suppl. 43:91-104, 1994.
27. The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential. [Review]. Leeson, P.D. and Iversen, L.L. J Med Chem 37:4053-4067, 1994.
Abstract: Age-related changes of N-methyl-D-aspartate (NMDA) receptors have been found in cortical areas and in the hippocampus of many species. On the basis of a variety of experimental observations it has been suggested that the decrease of NMDA receptor density might be one of the causative factors of the cognitive decline with aging. Based on these findings several strategies have been developed to improve cognition by compensating the NMDA receptor deficits in aging. The most promising approaches are the indirect activation of glutamatergic neurotransmission by agonists of the glycine site or the restoration of the age-related deficit of receptor density by several nootropics. [References: 40]
28. Laboratory basis of novel therapeutic strategies to prevent HIV-related neuronal injury. [Review]. Lipton, S.A. Res Publ.Assoc.Res Nerv.Ment.Dis. 72:183-202, 1994.
29. Current concepts of ethanol dependence. [Review]. Littleton, J. and Little, H. Addiction. 89:1397-1412, 1994.
Abstract: NMDA receptor-antagonists were tested in dose ranges that have previously been found to produce anticonvulsant and anticataleptic (antiparkinsonian) effects in rats. Non- competitive NMDA receptor-antagonists had strong psychomotor stimulating effects, the competitive ones were weaker in this respect when given systemically. However, when locally injected into the striatum or into the nucleus accumbens, also the competitive NMDA-antagonists induced psychomotor stimulation. If at all, NMDA receptor-antagonists have rewarding effects, then they seem to be elicited only by the non-competitive NMDA receptor-antagonists. In maze tests, sensitive for hippocampally mediated learning, NMDA receptor-antagonists impaired learning. While non-competitive NMDA-antagonists produced learning deficits over the whole dose range tested, competitive ones were only effective at higher dose levels. [References: 33]
30. Therapeutic potential of NMDA antagonists in neurodegenerative diseases. [Review]. McBurney, R.N. Neurobiol.Aging 15:271-273, 1994.
Abstract: Alcohol dependence is considered to be divisible into two types (although the divisions between these are indistinct). These are psychological dependence, in which the rewarding effects of alcohol play a primary role, and chemical dependence, in which adaptive changes in the brain initiate punishing effects on withdrawal of alcohol, and suppression of these becomes the primary motive for using the drug. The neurochemical basis for the rewarding effects of alcohol may be the potentiation of GABA at GABAA receptors (causing relaxation) and release of dopamine from mesolimbic neurones (causing euphoria). The adaptive changes which cause the alcohol withdrawal syndrome are not known for certain, but alterations in GABAA receptors, NMDA receptors and voltage-operated calcium channels all have a claim. However, it is distinctly doubtful whether these all contribute to the negatively reinforcing effects of alcohol that are important in chemical dependence, although they may be important in other pathological effects of alcohol abuse. Current research badly needs better communication between basic scientists and clinicians to establish research goals and to improve current models. [References: 75]
31. Molecular pharmacology of NMDA receptors: modulatory role of NR2 subunits. [Review]. Molinoff, P.B., Williams, K., Pritchett, D.B. and Zhong, J. Prog.Brain Res 100:39-45, 1994.
Abstract: Memory processes and long-term potentiation (LTP) are blocked at the time of their initiation by antagonists of glutamate NMDA or metabotropic receptors, by drugs that hinder the activity of carbon monoxide or the platelet-activating factor, and by GABA type A receptor agonists. In the next 2 h, memory and LTP are accompanied by an enhancement of the activity of calcium/calmodulin-dependent protein kinase II and of protein kinase C, and are blocked by inhibitors of these enzymes. At the time of expression, memory and LTP are blocked by antagonists of glutamate AMPA receptors. The effects of drugs on memory are seen upon their infusion into areas of the brain known to be responsible for the storage and retrieval of declarative memories (hippocampus, amygdala, medial septum, entorhinal cortex) and are both task- and structure-specific. When put together with other pharmacologic findings, with lesion and recording studies, and with data on transgenic animals showing deficits of both memory and LTP, the data reviewed here lend strong support to the hypothesis that LTP in these brain areas underlies memory processes. [References: 66]
32. Glutamatergic treatment strategies for age-related memory disorders. [Review]. Muller, W.E., Scheuer, K. and Stoll, S. Life Sci 55:2147-2153, 1994.
33. Biochemical analysis of glial fibrillary acidic protein as a quantitative approach to neurotoxicity assessment: advantages, disadvantages and application to the assessment of NMDA receptor antagonist-induced neurotoxicity. [Review]. O’Callaghan, J.P.Psychopharmacol.Bull 30:549-554, 1994.
Abstract: This overview describes two effects of N-methyl-D-aspartate (NMDA) receptor antagonists that are not strictly speaking toxic: There are no signs that cells are dying. Nevertheless, these antagonists, if applied for prolonged periods in young children, could permanently cripple normal brain function. Disturbing the function of the NMDA channel during development can severely disrupt the wiring of defined neural circuits. It also can disrupt the developmental upregulation of the receptor protein itself and possibly many other molecular components of the synapse. [References: 49]
34. Efficacy of clozapine compared with other antipsychotics in preventing NMDA-antagonist neurotoxicity. [Review]. Olney, J.W. and Farber, N.B. J Clin.Psychiatry 55 Suppl B:43-46, 1994.
Abstract: It has been reported that several uncompetitive NMDA receptor ion channel blocking agents (phencyclidine, ketamine, dizocilpine, dextrorphan) cause transient reversible vacuolation in neurons in the posterior cingulate cortex of rats. Similar effects have also been observed with competitive glutamate antagonists such as CPP, CGS 19755 and CGP 37849. This transient morphological change has been noted to be coincident anatomically with brain regions showing hypermetabolism after administration of uncompetitive NMDA receptor ion channel blockers and competitive glutamate antagonists. These results therefore indicate that the functional consequences of NMDA receptor blockade with competitive glutamate and uncompetitive channel antagonists are ultimately the same. These changes do not appear to be a prelude to irreversible damage except after relatively high doses of the receptor ion channel antagonists but they have given rise to concern over the safety in use of NMDA antagonists as neuroprotective agents. In contrast, vacuolation has not yet been demonstrated with agents acting at the glycine (L-687,414) or polyamine (eliprodil) modulatory sites of the NMDA receptor complex suggesting that agents acting at these sites may have a greater potential therapeutic window. [References: 20]
35. Neurotoxicity of NMDA receptor antagonists: an overview. [Review]. Olney, J.W. Psychopharmacol.Bull 30:533-540, 1994.
Abstract: Hypertrophy appears to be a universal response of astrocytes, a central nervous system (CNS) cell type, to all forms of brain injury. The hallmark of this response, often termed "reactive gliosis," is the enhanced expression of the major intermediate filament protein of astrocytes, glial fibrillary acidic protein (GFAP). Reactive gliosis traditionally has been examined qualitatively by immunohistochemistry of GFAP. But, the widespread availability of enzyme-linked immunosorbent assays (ELISAs) now makes it possible to quantify damage-induced expression of GFAP as a potential biomarker of diverse neurotoxic insults. To evaluate this possibility, we administered prototype neurotoxicants to experimental animals and then assessed the effects of these agents on the tissue content of GFAP, as determined by a recently developed sandwich ELISA. We found that assays of GFAP reveal dose-, time-, and region-dependent patterns of neural damage, often at toxicant dosages below those that cause light microscopic evidence of cell loss or damage. No false positives have been seen following exposure to a variety of pharmacological agents at therapeutic dosages. With respect to NMDA receptor antagonists, we find that MK-801 causes a large dose-dependent increase in GFAP that, within the cortex, appears to be restricted to the retrosplenial zone. Among the advantages of the CFAP-based approach re its simplicity, objectivity, cost and the fact that the assay can be automated. Among the disadvantages are the need to perform brain dissections and the requirement for a time-course analysis.(ABSTRACT TRUNCATED AT 250 WORDS) [References: 18]
36. The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex. Popik, P., Layer, R.T. and Skolnick, P. Psychopharmacology 114:672-674, 1994.
Abstract: Ibogaine is a putative anti-addictive drug with potential efficacy for the treatment of opiate, stimulant, and alcohol abuse. We now report ibogaine is a competitive inhibitor (Ki, 1.01 +/- 0.1 microM) of [3H]MK-801 binding to N-methyl-D- aspartate (NMDA) receptor coupled cation channels. Since MK-801 can attenuate the development of tolerance to morphine and alcohol as well as sensitization to stimulants in preclinical studies, the reported ability of ibogaine to modify drug-seeking behavior in man may be attributable to a blockade of NMDA receptor coupled cation channels
37. Introduction to principles and procedures in behavioral testing. [Review]. Rice, D.C. Psychopharmacol.Bull 30:593-599, 1994.
38. Behavioural effects of NMDA-receptor antagonists. [Review]. Schmidt, W.J. J Neural Transm.Suppl. 43:63-69, 1994.
Abstract: The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson’s disease, Huntington’s disease and Alzheimer’s disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor- dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes. [References: 94]
39. Structural requirements for the development of potent N-methyl-D-aspartic acid (NMDA) receptor antagonists. [Review]. Bigge, C.F. Biochem Pharmacol 45:1547-1561, 1993.
40. Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury. [Review]. Gentile, N.T. and McIntosh, T.K. Ann Emerg.Med 22:1028-1034, 1993.
41. Pharmacologic regulation of the NMDA receptor-ionophore complex. [Review]. Johnson, K.M., Snell, L.D., Sacaan, A.I. and Jones, S.M. NIDA Res Monogr 133:13-39, 1993.
Abstract: NMDA and non-NMDA (AMPA/kainate) antagonists have potential in the treatment of a diverse group of neurological disorders associated with excessive activation of excitatory amino acid receptors. Here Michael Rogawski reviews recent progress in the development of therapeutically useful NMDA receptor channel blockers and a new class of selective AMPA/kainate receptor antagonists, the 2,3-benzodiazepines. Research on these novel noncompetitive excitatory amino acid antagonists has opened promising new avenues for the development of drugs to treat epilepsy, ischaemia, neurodegeneration and Parkinson’s disease. [References: 60]
42. Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. [Review]. Lipton, S.A. Trends Neurosci 16:527-532, 1993.
43. Heterocyclic modulators of the NMDA receptor. [Review]. Pellicciari, R., Natalini, B., Costantino, G., et al. Farmaco. 48:151-157, 1993.
Abstract: Ethanol, acutely, is a potent and selective inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in primary cultures of cerebellar granule cells. The effect of ethanol can be reversed by high concentrations of glycine, and nonequilibrium ligand binding studies in brain membrane preparations suggest that ethanol may act by decreasing the frequency of ion channel opening. After chronic consumption of ethanol by animals, the number of NMDA receptors (measured by ligand binding) is increased in many brain areas. Similarly, NMDA receptor function is increased in cerebellar granule cells exposed chronically to ethanol. In the intact animal, this receptor up-regulation may be associated with ethanol withdrawal seizures, which are attenuated by uncompetitive antagonists at the NMDA receptor. In contrast to ethanol, barbiturates have a greater inhibitory effect at the kainate subtype of glutamate receptor than at the NMDA receptor. After chronic barbiturate ingestion, kainate binding is decreased in certain brain areas, while ligand binding to the NMDA receptor is increased. Overall, the pattern of brain area-specific effects of barbiturates on NMDA and kainate receptor function is quite distinct from that of ethanol. [References: 50]
44. Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. [Review]. Rogawski, M.A. Trends Pharmacol Sci 14:325-331, 1993.
Abstract: Several acute and chronic neurological diseases might be mediated, at least in part, via stimulation of excitatory amino acid receptors, such as the N-methyl-D-aspartate (NMDA) receptor. Antagonists of excitatory amino acid receptors ameliorate neurotoxic damage in several animal models of these disorders. This review focuses on the potential for clinically tolerated NMDA receptor antagonists, with emphasis on agents that have been in clinical use for other conditions and that recently have been shown to inhibit NMDA receptor activity by a mechanism of open- channel block or redox modification. [References: 69]
45. Subtypes of NMDA receptors. [Review]. Stone, T.W. Gen.Pharmacol 24:825-832, 1993.
Abstract: Trauma to the central nervous system can lead to primary injuries occurring at the time of impact as well as secondary or delayed injury processes that can result from cellular hypoxia, oligemia/ischemia, edema and swelling, and intracranial hypertension that are manifested over a period of hours to weeks after the initial event. Although the mechanisms underlying delayed tissue injury are poorly understood, they appear to be associated with endogenous neurochemical changes resulting from traumatic nervous system injury. These neurochemical changes may include excessive neurotransmitter release, deregulation of ion homeostasis, and the synthesis, release, or activation of various "autodestructive" neurochemical factors. Experimental studies over the past decade indicate that these alterations mediate important components of the neurochemical cascade leading to central nervous system injury. Furthermore, pharmacologic manipulations of these neurochemical changes have been reported to attenuate secondary central nervous system damage, ameliorate neuronal death, and promote functional recovery after central nervous system injury. This article focuses on the role of excitatory amino acid neurotransmitters, endogenous opioid peptides, and magnesium in the pathophysiology of central nervous system injury and on the therapeutic manipulation of these systems to improve functional outcome after central nervous system injury. [References: 85]
46. Ethanol, sedative hypnotics, and glutamate receptor function in brain and cultured cells. [Review]. Tabakoff, B. and Hoffman, P.L. Behav Genet. 23:231-236, 1993.
47. [NMDA agonists and antagonists]. [Review] [Japanese]. Toki, S. Tanpakushitsu.Kakusan.Koso. 38:1863-1872, 1993.
Abstract: 1. Beginning with electrophysiological evidence for two populations of receptors for N-methyl-D-aspartate (NMDA) which did or did not respond to the agonist quinolinic acid, evidence has grown for such subdivision. 2. Data from binding studies is consistent with differences between three NMDA receptors in the striatum, thalamus and cerebellum with respect to their preferences for agonist or antagonist binding and the modulation of binding by dizocilpine, cations and polyamines. 3. The recent isolation and sequencing of several different molecular species of NMDA receptor supports the view that at least two pharmacologically distinct sites exist, with the cerebellar receptor being unique in the brain. [References: 62]
48. Prevention of post-traumatic excitotoxic brain damage with NMDA antagonist drugs: a new strategy for the nineties. [Review]. Bullock, R., Kuroda, Y., Teasdale, G.M. and McCulloch, J. Acta Neurochir.Suppl.(Wien). 55:49-55, 1992.
Abstract: The design of new heterocyclic derivatives as modulatory agents at EAA receptors is described. In particular, the potent and selective activity at the NMDA receptor of trans-4- hydroxypipecolic acid-4-sulfate, as well as the neuroprotective properties of substituted thiokynurenates, a new class of competitive antagonists at the glycine site of the NMDA receptor complex, are reported. [References: 20]
49. Naturally-occurring excitatory amino acids as neurotoxins and leads in drug design. [Review]. Krogsgaard-Larsen, P. and Hansen, J.J. Toxicol Lett 64-65 Spec No:409-416, 1992.
Abstract: The triad of rigidity, fever, and elevation of serum creatine phosphokinase (CPK) levels, labeled ‘neuroleptic malignant syndrome’ (NMS), is a dangerous complication of neuroleptic drug treatment. Amantadine was introduced for the pharmacological management of NMS because of its beneficial effects in Parkinson’s disease which were attributed to direct or indirect dopaminomimetic properties of amantadine. While the dopaminomimetic effects of amantadine are weak under experimental conditions, recent studies have confirmed that amantadine is an antagonist at the N-methyl-D-aspartate (NMDA) type of glutamate receptor. Two lines of evidence suggest that amantadine or other NMDA receptor antagonists could be effective drugs for the reversal of NMS symptoms. First, glutamate antagonists restore the balance between glutamatergic and dopaminergic systems when dopaminergic transmission has been antagonized by neuroleptic drugs. Second, by virtue of their effects against rigor and spasticity, NMDA antagonists may reduce increased muscle tone and prevent rhabdomyolysis. In conclusion, NMS may be considered an iatrogenic excitatory aminoacid syndrome which is amenable to NMDA receptor antagonist therapy. [References: 53]
50. Does modulation of glutamatergic function represent a viable therapeutic strategy in Alzheimer’s disease?. [Review]. Lawlor, B.A. and Davis, K.L. Biol Psychiatry 31:337-350, 1992.
Abstract: Excitotoxic mechanisms due to overactivity of the amino acid neurotransmitters glutamate and aspartate maybe responsible for brain damage after injury. In this review we examine ischaemia and shear injury, which are relevant to human head injury. The opportunities for treatment using glutamate antagonist drugs are discussed. [References: 36]
51. A rationale for NMDA receptor antagonist therapy of the neuroleptic malignant syndrome. [Review]. Weller, M. and Kornhuber, J. Med Hypotheses. 38:329-333, 1992.
Abstract: Although glutamate dysfunction has been implicated in the pathogenesis of Alzheimer’s disease (AD), it is unclear which direction a glutamatergic strategy should take in this illness. Increasing glutamate function may enhance excitotoxicity and neuronal death, whereas decreasing activity in this excitatory amino acid pathway may impair memory processes. Pharmacological modulation of the different NMDA and nonNMDA receptor sites, together with the concept of an agonist versus antagonist approach, are discussed in this review. It would appear that a glutamatergic approach may represent a new and exciting option to pursue in the experimental pharmacotherapeutics of AD. [References: 75]
52. Excitatory amino acids in epilepsy and novel anti-epileptic drugs. [Review]. Chapman, A. and Meldrum, B. Epilepsy Res Suppl. 3:39-48, 1991.
53. NMDA receptor agonists: relationships between structure and biological activity. [Review]. Ebert, B., Madsen, U., Johansen, T.N. and Krogsgaard-Larsen, P. Adv Exp Med Biol 287:483-487, 1991.
Abstract: Recent data on the aptitude of adamantamines to inhibit or to stimulate glutamatergic (NMDA) neuromediation, to display anti- GABAergic and antiglycinergic components (by blocking the Cl- channel), on the one hand, and on the opposition of the central glutamatergic and dopaminergic systems, on the other, could suggest that the glutamatergic (NMDA) or the anti-NMDA activity, exhibited by some adamantamines, could play an important role in the expression of their pharmacological profile. Anti-NMDA properties, for the adamantamines which exhibited them, could be, by themselves or by developing their anti-GABAergic or antiglycinergic components, the first cause of the hypermotility and dopaminomimetic activity induced by these molecules. Glutamatergic (NMDA) component, which could be displayed by some lipophilic or important steric obstruction on azote exhibiting adamantamines, could amplifie the excitating effects of their anti-GABAergic and antiglycinergic components on the limbic system’s brain structures (hippocampus, amygdala) and could contribute to the exhibition of hypomotility, fright, agressivity and convulsions. According to these data, which must be amplier confirmed and deeped, it would be possible to envisage the improvement of adamantamines against the Parkinson’s disease (when they exhibit anti-NMDA activity) or their use against the Alzheimer’s disease and the late stages of the Parkinson’s disease (when they exhibit NMDA activity). [References: 75]
54. N-methyl-D-aspartate antagonists in the treatment of Parkinson’s disease [see comments]. [Review]. Greenamyre, J.T. and O’Brien, C.F. Arch.Neurol. 48:977-981, 1991.
55. Competitive antagonism of glycine at the N-methyl-D-aspartate (NMDA) receptor. [Review]. Huettner, J.E. Biochem Pharmacol 41:9-16, 1991.
56. Autoradiographic assessment of the effects of N-methyl-D-aspartate (NMDA) receptor antagonists in vivo. [Review]. McCulloch, J. and Iversen, L.L. Neurochem Res 16:951-963, 1991.
57. Phencyclidine, NMDA receptor and schizophrenia. [Review]. Nishikawa, T., Tanii, Y., Umino, A., et al. Yakubutsu.Seishin.Kodo. 11:65-69, 1991.
Abstract: Current long-term treatment of Parkinson’s disease is inadequate, and improved symptomatic and neuroprotective therapies are needed. Recent interest has focused on the use of antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in Parkinson’s disease. Abnormally increased activity of the subthalamic nucleus is postulated to play a central pathophysiological role in the signs of Parkinson’s disease, and NMDA antagonists may provide a means of decreasing this activity selectively. Like dopaminergic agonists, NMDA antagonists can reverse the akinesia and rigidity associated with monoamine depletion or neuroleptic-induced catalepsy. Very low doses of NMDA antagonists markedly potentiate the therapeutic effects of dopaminergic agonists. There is evidence that the beneficial effects of anticholinergic drugs and amantadine may be mediated, in part, by NMDA receptor blockade. Moreover, NMDA antagonists provide profound protection of dopaminergic neurons of the substantia nigra in the MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) and methamphetamine models of Parkinson’s disease. The clinical use of NMDA antagonists may prove useful in Parkinson’s disease to treat symptoms and retard disease progression. [References: 72]
58. Effects of quinolinic and kynurenic acids on central neurons. [Review]. Stone, T.W. and Connick, J.H. Adv Exp Med Biol 294:329-336, 1991.
59. [Action mechanism of adamantamines: do their activity on glutamatergic receptors intervene in the expression of their pharmacological profile?]. [Review] [French]. Vamvakides, A. Ann Pharm.Fr. 49:249-257, 1991.
60. Sites for antagonism on the N-methyl-D-aspartate receptor channel complex. [Review]. Wong, E.H. and Kemp, J.A. Annu.Rev Pharmacol Toxicol 31:401-425, 1991.
61. Measuring and controlling the extracellular glycine concentration at the NMDA receptor level. [Review]. Ascher, P. Adv Exp Med Biol 268:13-16, 1990.
62. Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted?. [Review]. Buchan, A.M. Cerebrovasc.Brain Metab.Rev 2:1-26, 1990.
Abstract: There is considerable interest in the development of NMDA antagonists as potential therapeutic agents in the treatment of convulsant, neurodegenerative and anxiety disorders. Because the clinical use of phencyclidine (PCP) has been precluded by its psychotomimetic effects and abuse potential, there has been concern that other NMDA antagonists including those acting competitively might produce similar untoward effects. However, the studies in animals, reviewed here by Joyce Willetts, Robert Balster and David Leander, suggest that while there are certain similarities in the behavioral effects of PCP-like and competitive antagonists, there are also differences. These differences have implications for the development of NMDA antagonists with less likelihood for producing PCP-like side- effects. [References: 42]
63. Quinoxalinediones as excitatory amino acid antagonists in the vertebrate central nervous system. [Review]. Davies, S.N. and Collingridge, G.L. Int.Rev Neurobiol. 32:281-303, 1990.
64. CGP 37849 and CGP 39551: novel competitive N-methyl-D-aspartate receptor antagonists with potent oral anticonvulsant activity. [Review]. Fagg, G.E., Olpe, H.R., Schmutz, M., et al. Prog.Clin.Biol Res 361:421-427, 1990.
Abstract: Perinatal cerebral asphyxia, which results in significant neurologic and cognitive disabilities in infants and children, remains a major health problem. Potential neurologic sequelae include cerebral palsy, mental retardation, and epilepsy. Over the next few years, neuroprotective agents that prevent asphyxial neuronal injury and death are likely to be developed. These agents may also be effective in prophylaxis and treatment of chronic neurologic disorders, including epilepsy and neurodegenerative disorders, such as Huntington disease. [References: 50]
65. Results of N-methyl-D-aspartate antagonists in perinatal cerebral asphyxia therapy. [Review]. Ford, L.M. Pediatr.Neurol. 6:363-366, 1990.
66. Therapeutic potential of NMDA receptor antagonists as neuroprotective agents. [Review]. Foster, A.C., Gill, R., Iversen, L.L., Kemp, J.A., Wong, E.H. and Woodruff, G.N. Prog.Clin.Biol Res 361:301-329, 1990.
67. The behavioral pharmacology of NMDA receptor antagonists [see comments]. [Review]. Willetts, J., Balster, R.L. and Leander, J.D. Trends Pharmacol Sci 11:423-428, 1990.
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AN ACCLAIMED documentary maker has admitted that he is prepared to die while filming himself taking a powerful hallucinogenic drug that has been hailed as a cure for addiction but linked to a number of deaths around the world.
David Graham Scott, who is based in Glasgow, said that he will take the controversial drug, ibogaine, in a film that will form the final part of his trilogy on Scotland’s drugs culture. In the documentary, provisionally titled The Quick Fix, Scott intends to overcome his own methadone addiction, which he says has plagued him since he stopped using street heroin and prescribed drugs 15 years ago.
Under the supervision of colleagues who are working to set up an ibogaine clinic in London, and a recording team, Scott will be filmed next month undergoing an intense 36-hour hallucinogenic “trip”, from which he hopes to emerge free from his addiction. Although the substance is legal in the UK, where it is classed as an unlicensed, experimental drug, there are wider concerns over its safety. The drug has been banned in the US, Belgium and Switzerland and experts also say that in recent years ibogaine is known to have contributed to at least four deaths in Europe.
Last year, a 35-year-old woman died after taking 500mg of the drug during an informal ibogaine session in Germany. In 2001, an inquest in London into the case of JW, a 40-year-old heroin addict, ruled that the man had died principally from a fatal reaction to the drug.
But with advocates of the substance claiming it is a “magic bullet” for addicts, the Bafta-nominated film-maker says he now plans to put the claims to the test and undergo the treatment as an experiment to get himself clean.
He said: “There is always a chance that there could be some permanent damage or that it could kill you. But I think the positive factors outweigh the negative aspects. I have found methadone impossible to come off. I am doing this because I can’t stand being an addict anymore. This will be my personal story about taking ibogaine.”
The Quick Fix comes after two films in which Scott examined the issue of drugs and his own reasons for becoming embroiled in Britain’s drug culture in the 1980s. In Little Criminals, Scott spent 1999 filming a group of heroin addicts in and around Glasgow. The film, distributed internationally at film festivals by Scottish Screen, also won him a Bafta new talent nomination last year. Beyond The Highlands, screened by STV in 2002, attempted to answer the question of why Scott, originally from Caithness, turned his back on his rural upbringing and embraced Edinburgh’s underground heroin culture.
“This will be a film that shows how the daily routines that an addict has to face demeans them. I also want this to open up the debate about how society treats addicts and to ask questions about alternatives to the methadone programme,” explained Scott.
“There is ample evidence that ibogaine treatment works and that should be explored further. If I make this film and find that it does work there are serious questions that the government is required to answer about its current drug policy. If anything goes wrong, it will be my sole responsibility.”
Scott, now 41, said he first began researching the effects of ibogaine in the mid-1990s. However, with the only legitimate detox programmes available in a limited number of countries, including Panama, Costa Rica and Italy, and costing thousands of pounds, it was not a feasible option. His unofficial ibogaine detox will cost him just under (pounds) 500.
Once under the effects of the drug, extracted from the root bark of a west African plant and used in spiritual rituals in parts of Gabon, Scott hopes to re-evaluate his life experiences. Less than one gram of ibogaine is said to produce stimulant and aphrodisiac effects. Up to three grams produces a mellow euphoric trip during which the user may experience various hallucinations. Up to six grams, the maximum safe dosage, produces powerful near-death experiences.
Those taking the highest doses of ibogaine report that they first enter a dream-like phase that lasts several hours and consists of vivid visions of past memories. The second consists of high levels of analytical mental activity to comprehend the reasons why they drifted into drug-using.
However, Deborah Mash, a professor of neurology at the University of Miami, a world authority on ibogaine, warned of the dangers of taking the drug outwith a strictly regulated environment.
“It should only be taken in the presence of trained medical staff who can administer drugs or revive someone if they get into difficulty.”
Ibogaine: The Book
Following the New York University School of Medicine’s International Ibogaine Conference held in 1999, Drs. Kenneth R. Alper of NYU and Stanley D. Glick of the Albany Medical College edited submissions and additions of the proceedings now published by Academic Press.The Alkaloids, Volume 56 brings together the world’s experts on ibogaine. This book represents the state of the art. View the Table of Contents from where you can link to individual PDF files of each of the book’s 16 chapters and index.
By special permission of Academic Press The Ibogaine Dossier presents A Contemporary History of Ibogaine in the United States and Europe. The chapter by Kenneth R. Alper, Charles D. Kaplan and Dana Beal portrays the amazing and exciting story of ibogaine development. This selection is of Chapter 14, Volume 56, The Alkaloids, Ibogaine: Proceedings of the First International Conference.
Ibogaine lab research
The Ibogaine Dossier continues its historical document collection with the seminal literature review of ibogaine, opioid and stimulant interaction, providing a long unavailable copy of the 1984 Literature Report by Doris H. Clouet, Assistant Director, Testing and Research Laboratory, New York State Drug Abuse Control Commission, Brooklyn, New York. The 1984 Report was supported by a grant of the Dora Weiner Foundation to Dr. Clouet and reviews early literature not readily availale elsewhere. We therefore present The Clouet Report – 1984. The Clouet Report was the first document used to garner scientific support for the use of ibogaine in the treatment of substance use and dependence disorders. Clouet’s review includes thirty peer reviewed papers published between the 1950s and 1980s. The report is in PDF format.
A Chronology of Selected Abstracts, Ibogaine: Rapid Method for the Interruption of the Narcotic Addiction Syndrome. The Chronology is an excellent collection of abstracts relating to the use of ibogaine in the treatment of narcotic dependence as well as, addressing safety issues. The document was originally presented at the 20th conference of the American Association for the Treatment of Opioid Dependence (AATOD) held in Orlando in October 2004. It is also available as a downloadable PDF document file. PDF files require an Adobe Reader. I you don’t have one, a free version may be obtained from Adobe.
An important paper by Stanley Glick and Isabelle Maisonneuve in PDF format Mechanisms of antiaddictive actions of ibogaine
Pharmacology of Ibogaine and Ibogaine-Related Substances. A review by Piotr Popik and Phil Skolnick. Appeared as Chapter 3 in "THE ALKALOIDS", Vol.52, 1998.
Selected abstracts 18-Methoxycoronaridine and some full-text papers. Review data on this synthetic iboga alkaloid congener developed by the Albany Medical College research group.
Ibogaine is one of the psychoactive indole alkaloids isolated from the shrub, Tabernanthe iboga. Preclinical studies demonstrate that ibogaine reduces self-administration of both cocaine and morphine, as well as attenuates the symptoms of morphine withdrawal. Several anecdotal observations in humans seem to support the hypothesis that ibogaine may have antiaddictive properties.
Now available online: a review article by Piotr Popik and Stanley Glick.
Ibogaine a brief history. This easy to read review summarizes the qualities of Ibogaine. It includes research conducted in 1995 and 1996.
An evaluation of ibogaine neurotoxicity, including abstracts of relevant papers.
The Ibogaine bibliography. References to over 130 scientific articles, most with abstract. Now with coverage of NMDA-receptor review articles. The NMDA-receptor complex has been implicated in the ‘psychological dependence’ pathway.
A number of articles have been selected to appear in our special abstracts section because of their thought provoking content.
In continuation of the Ibogaine Dossier’s Historical Document Project we are pleased to present an English translation of the first paper published on the extraction and identification of ibogaine. The authors, in fact, named the alkaloid in their 1901 publication: Concerning Iboga, its excitement-producing properties, its composition, and the new alkaloid it contains, ibogaine by J. Dybowski and Ed. Landrin. Also available in PDF format. This article is presented for historical value and not scientific accuracy as much has been learned about ibogaine and its use since 1901.
Ibogaine clinical research and experience
The Ibogaine Medical Subculture by Kenneth R. Alper, Howard S. Lotsof and Charles D. Kaplan is available in web page format. For your pleasure and information we present The Ibogaine Medical Subculture published in the Journal of Ethnopharmacology. The paper is also available in its original pdf format
The first long-term study of ibogaine effects. Udi Bastiaans’ paper, Life After Ibogaine discusses the medical, psychological, social and legal history of patients treated with ibogaine. This report is in PDF format.
A report by Howard Lotsof on dose and dose regimens for both ibogaine HCl and total alkaloid extracts in PowerPoint slide show format: Ibogaine Therapy: Forms and Dose Regimens
Ibogaine therapy has emerged in the last twenty years as a viable option for the treatment of chemical dependence. The Manual for Ibogaine Therapy – Second Revision by Lotsof and Wachtel is intended for ibogaine providers who are concerned with patient safety and the outcome of Ibogaine treatments. The manual presents medical safety data and clinical discussions with links to additional resources. Now also available as The Ibogaine Manual in PDF format. Just click to download. Includes active links.
Ibogaine, Trauma and Abreaction: The Treatment of Chemical Dependence.H.S. Lotsof, C.A. Smith F., J. Bastiaans; presented at 40th International Conference on the Prevention and Treatment of Dependencies, ICAA, Amsterdam, 1996.
Sometimes the ability to understand a subject comes from being able to understand its beginnings. We are now able to provide a copy of Reaching a State of Wellness: Multistage Explorations in Social Neuroscience This paper by Charles D. Kaplan’s Erasmus University Rotterdam working group provides insight into the early Dutch addict self-help ibogaine scene with a comparison to traditional Tibetan medicine.
Long unavailable, Claudio Naranjo, M.D.’s paper, Psychotherapeutic Possibilities of New Fantasy-Enhancing Drugs is now available thanks to the Canadian Research Knowledge Network. Naranjo’s paper was the first to report outside of Africa of the psychotherapeutic benefits of ibogaine.
A Preliminary Investigation of Ibogaine: Case Reports and Recommendations for Further Study. A peer reviewed Journal of Substance Abuse Treatment article.
Daniel Luciano MD describes observations of treatment with ibogaine
Ibogaine in the treatment of chemical dependence disorders: clinical perspectives (A Preliminary Review) H.S. Lotsof. The primary purpose of this paper is to provide general information to the clinician who will be using ibogaine in the treatment of addiction.
Alexander Shulgin and Ann Shulgin’s description of ibogaine is scientific but engaged. "Here is an example of a most remarkable material that has allowed people to have some rather complex and dramatic experiences." An excerpt from their book Tihkal, the sequel to Pihkal, a Chemical Love Story.
A fascinating account by Sarah Emanon, a psychotherapist who speaks about her own experiences with ibogaine – both as a facilitator and as an experiencer- and her plans to direct an ibogaine clinic in Central America. Interviewer is Primal Therapist Donald A. Allan.
Deborah Mash answers Frequently Asked Questions about ibogaine research.
Ibogaine in Drug Detoxification. From Preclinical Studies to Clinical Trials
Deborah C. Mash, Ph.D.
Phase I trial conducted at the University of Miami. Juan Sanchez-Ramos, Ph.D., M.D. and Deborah Mash, Ph.D.
Ibogaine, een oplossing voor het verslavingsprobleem? A literature review in dutch.
Stephen Snelders. Het gebruik van psychedelische middelen in de jaren zestig.
Netherlands Hallucinogen Research (in dutch)
Netherlands Hallucinogen Research 1950 – 1970
Ibogaine in the treatment of narcotic withdrawal
H. S. Lotsof, E. Della Sera, C.D. Kaplan
The Necessity of Addict Self-Help Involvement in Ibogaine Treatment Procedures.
Seminars, conferences and presentations
A Calendar of ibogaine conferences, forums and meetings is now available. Conference presentations are listed immediately below.
Kenneth R. Alper reviews the Significance of Unofficial Ibogaine Treatment Scenes.. A PowerPoint presentation.
Rick Doblin’s presentation A Non-Profit Approach to Developing Ibogaine into an FDA-Approved Medication. An excellent how-to manual for drug development. A PowerPoint presentation.
Comparative Development of Ibogaine, Methadone and Buprenorphine. H.S. Lotsof’s presentation from the NYC Iboga and Ibogaine Forum. A historical review of why the government backed the development of some medications and not others. A PowerPoint presentation.
What does the future hold? One vision is 18-methoxycoronaridine (18-MC). Jon Friedlander provides his PowerPoint presentation 18-MC: A Review
The Conference on Ibogaine will be held on November 5 and 6, 1999 at the New York University School of Medicine. It is the first meeting to be devoted to the subject of ibogaine to be held at a US academic medical center.
The Lindesmith Center Drug Policy Seminars, Winter 1998. March 2: Ibogaine Treatment. The feasibility and effectiveness of ibogaine in treating chemical dependence.
Innovative approaches for the treatment of substance abuse for the twenty-first century. U.S. Probation Symposium, New York, June 5, 1997.
ICAA 1996 AMSTERDAM. Speakers & abstracts.
The 1996 International Institute on the Prevention and Treatment of Dependencies Conference Ibogaine Sessions. Meet the researchers and listen to their most recent hypotheses.
The Danish Drug Users Union (BrugerForeningen) hosted drug user advocates from around the world to celebrate International Drug Users Day and the Conference on Drug User Activism. Concurrent to these events were the General Assembly of the International Network of People who Use Drugs (INPUD) and the fifteenth anniversay celebration of the Danish Drug Users Union. Among the presentations given during the conference was a unique ibogaine slide show directed towards those who would benefit most from ibogaine. Please see: The Ibogaine Community Worldwide – User to User.
While the majority of the people of Gabon are familiar with the Bwiti religon and its sacrament Iboga, very few are familiar with ibogaine science. Howard Lotsof, the discoverer of ibogaine’s antiaddictive effects now presents that information. The PowerPoint slide show is available both in english and french. Please see: Iboga and Ibogaine: From the Forest to the Laboratory or L’iboga et l’ibogaïne: De la forêt au laboratoire
The Religion of Iboga or the Bwiti of the Fangs by P. Barabe, Chief physician, Professor of Tropical Medicine.
Georgio Samorini’s The Bwiti Religion and the psychoactive plant Tabernanthe iboga (Equatorial Africa). Originally published in Integration, 5: 105-114.
Jurg Schneider’s Patent assigned to Ciba (PDF file) Tabernanthine, Ibogaine Containing Analgesic Compositions
Rapid Method for Interrupting the Narcotic Addiction Syndrome
Rapid method for interrupting or attenuating poly-drug dependency syndromes
Compositions for the treatment of hepatitis C – a patent application (PDF file)
A chronology of psycho-active substance use.
NYU Conference on Ibogaine Nov 5-6, 1999
T. iboga roots
The philosophy of the editors of the Ibogaine Dossier is to offer a very diverse collection of ibogaine experience reports so that patients and providers as well as ibogaine researchers may gain a comprehensive understanding of the variety of ibogaine effects. We also suggest you read the experiences on other web pages in addition to our collection as those very positive reports also represent the ibogaine reality.
Those persons seeking technical medical information should read The Manual for Ibogaine Therapy.
The personal reports on this page have not been verified by The Ibogaine Dossier editors.
Ibogaine Patients’ Bill of Rights What every patient should know.
Daniel Luciano MD describes observations of treatment with ibogaine
Ibogaine Trip Report Prepared For BrugerForeningen (Danish Drug Users Union). The report presents up to date status on international cooperation between patients, doctors and user advocacy grougs.
Ibogaine and an older couple. A discovered love and an exploration of post traumatic stress disorder (PTSD).
Methadone and Ibogaine: A Patient in Transition, Part I. A description of a self-administered ibogaine therapy.
Another Chance, Part II. The story continues.
Ibogaine treatment: Diary of a Pain Patient An important develpment in ibogaine therapy expands the knowledge of the diversity of information exploring the utility of ibogaine in pain management.
Methadone Patient Reports This patient report adds to our understanding of ibogaine effects in the treatment of methadone dependence.
Some considerations about ibogaine treatment from the ibogaine mailing list.
The "Third" Ibogaine Experience examines fundamental issues of patient rights to determine when, under what circumstances and how many ibogaine treatments should be administered.
Who wants to be a junkie?" A magnificanet story of ibogaine treatment and adventure.
A report of two self-administration experiences presented by one of the participants. An interesting description as to the distinct effects on each person and, as to the similarities.
An infinity of graphical representations continue to show me knowledge, much of which I can but begin to grasp, even though my awareness has expanded a million fold.
I took 1.67 grams of pure Ibogaine. I was looked after by someone who had administered about 17 treatments to drug addicts and spiritual seekers. The setting had no spiritual content which made me realize how important it is to provide some kind of spiritual/religious/meditative setting as a base of referral.
I ingested the Ibogaine in the evening of December 1st, 1997. After 45 minutes the first wave hit. I had no nausea with the ibo coming on or through the entire journey. Then the second wave hit. The best way to describe the waves would be a freight train plowing through my energy field.
It is Wednesday now, nearly 72 hours since I last took any Methadone. I feel very weak, but I am not experiencing any withdrawal symptoms
I have never been addicted to any kind of opiates but I most certainly have had my trials with drugs, alcohol, cigarettes and coffee. The way I heard about ibogaine was in my search for a REAL treatment of opiate addiction for my husband.
Reflections on an ibogaine experience. "I heard about ibogaine from a friend in New York and then requested treatment for me and my boyfriend. We were the first people to be treated in Holland. My ibogaine treatment took place on October 25, 1989, in a hotel room in Amsterdam. My boyfriend had been succesfully treated the day before."
I had a window of opportunity and I went through it. I was fortunate enough to be on the receiving end of the "Gift of Freedom" … Ibogaine.
A fascinating account by Sarah Emanon, a psychotherapist who speaks about her own experiences with ibogaine – both as a facilitator and as an experiencer- and her plans to direct an ibogaine clinic in Central America. Interviewer is Primal Therapist Donald A. Allan.
I am an alcoholic. It absolutely did not work. As for addicts, I was treated along with about 10 heroin addicts who also felt that it probably did not work for them.
Synthetic iboga alkaloid congener
The ibogaine research team at Albany Medical College has developed a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC). Animal research shows that 18-MC shares ibogaine’s anti-addictive properties, possibly without ibogaine’s hallucinogenic effects, possibly not. View the molecular structure at bottom of page.
The most recent research indicates that 18-MC may have anti-HIV activity thus providing a very interesting perspective as a medication capable of treating two vector related disorders: Chemical dependence and HIV. We now await the testing of ibogaine and other iboga alkaloids and congeners to determine if they may also have such broad spectrum activity and to what degree.
The following is a list of selected publications.
1. Anti-HIV-1 activity of the Iboga alkaloid congener 18-methoxycoronaridine. Silva EM, Cirne-Santos CC, Frugulhetti IC, Galvao-Castro B, Saraiva EM, Kuehne ME, Bou-Habib DC. Planta Med. 2004 Sep;70(9):808-12. Abstract
2. Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment. Maisonneuve IM, Glick SD. Pharmacol Biochem Behav. 2003 Jun;75(3):607-18. Abstract
3. Metabolism of 18-Methoxycoronaridine, an Ibogaine Analog, to 18-Hydroxycoronaridine by Genetically Variable CYP2C19. Zhang W, Ramamoorthy Y, Tyndale RF, Glick SD, Maisonneuve IM, Kuehne ME, Sellers EM. Drug Metab Dispos 2002 Jun 1;30(6):663-669Abstract
4. Antagonism of alpha3beta4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. Glick SD, Maisonneuve IM, Kitchen BA, Fleck MW. Eur J Pharmacol 2002 Mar 1;438(1-2):99-105 Abstract
5. Drug discrimination studies with ibogaine. Helsley S, Rabin RA, Winter JC. Alkaloids Chem Biol 2001;56:63-77 Abstract
6. 18-MC reduces methamphetamine and nicotine self-administration in rats. Glick SD, Maisonneuve IM, Dickinson HA. Neuroreport 2000 Jun 26;11(9):2013-5 Abstract
7. Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig. Mundey MK, Blaylock NA, Mason R, Glick SD, Maisonneuve IM, Wilson VG. Br J Pharmacol 2000 Apr;129(8):1561-8 Abstract
8. Synthesis of enantiomerically pure (+)- and (-)-18-methoxycoronaridine hydrochloride and their preliminary assessment as anti-addictive agents. King CH, Meckler H, Herr RJ, Trova MP, Glick SD, Maisonneuve IM. Bioorg Med Chem Lett 2000 Mar 6;10(5):473-6Abstract
9. 18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action. Glick SD, Maisonneuve IM, Szumlinski KK. Ann N Y Acad Sci 2000;914:369-86 Abstract
10. Development of novel medications for drug addiction. The legacy of an African shrub. Glick SD, Maisonneuve IM. Ann N Y Acad Sci 2000;909:88-103 Abstract*
11. Acute iboga alkaloid effects on extracellular serotonin (5-HT) levels in nucleus accumbens and striatum in rats. Wei D, Maisonneuve IM, Kuehne ME, Glick SD. Brain Res 1998 Aug 3;800(2):260-8 Abstract
12. Effects of 18-methoxycoronaridine on acute signs of morphine withdrawal in rats. Rho B, Glick SD. Neuroreport 1998 May 11;9(7):1283-5 Abstract
13. Attenuation of alcohol consumption by a novel nontoxic ibogaine analogue (18-methoxycoronaridine) in alcohol-preferring rats. Rezvani AH, Overstreet DH, Yang Y, Maisonneuve IM, Bandarage UK, Kuehne ME, Glick SD. Pharmacol Biochem Behav 1997 Oct;58(2):615-619. Abstract
14. Time-dependent interactions between iboga agents and cocaine. Maisonneuve IM, Visker KE, Mann GL, Bandarage UK, Kuehne ME, Glick SD. Eur J Pharmacol 1997 Oct 8;336(2-3):123-126. Abstract
15. 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administration and on mesolimbic dopamine release in rats. Glick SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH. Brain Res 1996 May 6;719(1-2):29-35. Abstract
Check Medline here to find out about the most recent publications.