• N&PD Moderators: Skorpio | thegreenhand

Non-cardiotoxic Ibogaine psychedelic analogs

One alkaloid I found particularly interesting tho is Tabernanthine (which is a positional isomer of ibogaine: It is 11-methoxyibogamine instead of 12-methoxy ibogamine ie ibogaine):

So this is dumb, but how about 11,12-methylenedioxy-ibogamine?
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Everything's better with a MDxx ring on it, right?

Also, so if ibogaine and voacaganine are hERG blockers and 18-MC is (seemingly) not, how about ibogamine? That is, is it the 12'MeO that is an issue or is it something else?

Also also,
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^ excellent idea! it would certainly have very interesting bioactivity spectrum adding a MD twist to Ibogaine. It would be a synthetic new compound tho as I am not sure if Iboga alkaloid containing a methyelenedioxy have not been described (then again, almost everyday new bioactive indole alkaloids are found in nature.. so who knows? but it would certainly be interesting and patentable for sure!!

The 11,12 dimethoxy ibogamine is Ibogaline, an alkaloid almost always found in Ibogaine TA extracts preparations since it is very very hard to separate from Ibogaine..they're both found in T Iboga roots bark and have pretty much same Rf..

Now that you mentioned it, I wonder if it has something to do with the difference of bioactivity spectrum between Ibogaine TA and purified 99% Ibogaine HCl. Some people claims the TA extracts which contains Ibogaline (at least ~5-10% Ibogaine concentration) is better tolerated and easier on the body with less tremors and other body load than IBG-HCl I mean at equivalent concentration of Ibogaine..
 

^^ nice jobs summarizing that study out of Austria.. ( I think there are more papers from Pr Koenig group on Ibogaine and hERG.. will post more later time permitting)..
As for microdosing, yeah I think it is the way to go. Microdosing Iboga has tremendous potential especially for heavy depression and anxiety. Maybe even more useful than for OP treatment. Ibogaine is pretty safe at low doses (a NIH/FDA phase 1 clinical trial in 1990s evaluating 300mg dose in healthy volunteers showed it is well tolerated with no obvious side-effects including cardiovascular at this dose. But that was right before NIH helped scheduled Ibogaine and 'killed" all future clinical studies of Ibogaine in the US.


so the NIH had a hand in scheduling Ibogaine? that and they obviously had a time machine in 1990 which enabled them to travel back to 1968 and added it to schedule 1 of the list of prohibited substances. and perhaps on the way drop some off in 1972 for big Ed Muskie
http://willrabbe.com/microblog/2011...g-addiction-according-to-hunter-thompson.html
 
..so the NIH had a hand in scheduling Ibogaine..
yeah in a sense: the NIH doesnt actually schedule a drug substance but certainly, NIH-NIDA (National Institute of Drug Abuse) had a hand in keeping Ibogaine in Schedule I classification . Ibogaine (along with a bunch of "hallucinogens") was Scheduled I in ~ 1968 even tho there were ample evidence for its medical usefulness in opiates detox at that time .

The way it works is like this: Schedule I is for substances that have no medical uses whatsoever as determined by NIH. But if the NIH decides a drug substance classified in Schedule I has a possible medical use following its own funded studies, then the substance has to be removed from Class I and reclassified Schedule II or III or else declassified altogether so further medical research can be done legally. Schedule I essentially "killed" and put an end to any formal further studies of the drug in the US.

So in early 1990s, the NIH-NIDA funded Phase I and II clinical trials of Ibogaine hydrochloride to assess safety in healthy volunteers and efficacy for cocaine/stimulants/opiates detox... These NIH-NIDA funded studies (Phase 1) found 150 mg and 300 mg purified Ibogaine hydrochloride were well tolerated in healthy humans with no reported side-effects (ref: ).. FURTHER STUDIES OF IBOGAINE WERE STOPPED at this point when the NIH decided not to fund anymore its IBOGAINE PROJECT.

. here is short history of the NIH-NIDA IBOGAINE PROJECT (extracted from here):
In 1991, NIDA Medication Development Division began its IBOGAINE PROJECT. This initiative was based on case reports and preclinical evidence suggesting possible efficacy. The major objectives of the IBOGAINE PROJECT were preclinical toxicological evaluation and development of a human protocol.

In August 1993, FDA Advisory Panel meeting formally considered Investigational New Drug Application filed by Dr Deborah Mash, Professor of Neurology at the University of Miami. Approval for human trials was given with 1, 2, and 5 mg/kg of ibogaine dosage levels. The Phase I dose escalation study began in December 1993, but activity was eventually suspended.

From October 1993 to December 1994, phase I/II protocols were discussed by the NIDA and fixed doses of ibogaine of 150 and 300 mg versus placebo for the indication of cocaine dependence were proposed. The next year, a NIDA IBOGAINE REVIEW meeting decided to end the IBOGAINE PROJECT but to continue to support some preclinical research on iboga alkaloids... more here
So by deciding not to further fund its own IBOGAINE PROJECT and prove the medical usefulness of Ibogaine, the NIH essentially helped maintained Ibogaine in Schedule I and killed any and all medical research of Ibogaine in the US to this day ..
too bad.. hundreds perhaps thousands deaths might have been avoided by this wonderful substance thanks to the Gods-spirits (called it what you want) of this amazing rain forest tree Tabernanthe Iboga.. too bad
 
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.. so if ibogaine and voacaganine are hERG blockers and 18-MC is (seemingly) not, how about ibogamine? That is, is it the 12'MeO that is an issue or is it something else?
Actually MC-18 is hERG blocker only less than Ibogaine or noribogaine but still its hERG EC50 is still in the range of therapeutic doses..Plain ibogamine hERG activity, I don't know. The added methyl ether of 18-MC (compare to coronaridine) seems to lower hERG while still active so may be extending the methyl ether of 18-MC I mean from methyl -> ethyl -> propyl, isopropyl ..etc will eliminate hERG problems.
coronaridine.gif

Whether it retains Iboagaine-like activity is another matter.. I don't think it would affect much .. but who knows?

edit: I like that methylenedioxyIbogaine ie Ibogaine-MD..should be straightforward to prepare from Tabersonine but that naprobogaine..hmmm 12-16-steps synthesis!!
 
yeah in a sense: the NIH doesnt actually schedule a drug substance but certainly, NIH-NIDA (National Institute of Drug Abuse) had a hand in keeping Ibogaine in Schedule I classification . Ibogaine (along with a bunch of "hallucinogens") was Scheduled I in ~ 1968 even tho there were ample evidence for its medical usefulness in opiates detox at that time .

The way it works is like this: Schedule I is for substances that have no medical uses whatsoever as determined by NIH. But if the NIH decides a drug substance classified in Schedule I has a possible medical use following its own funded studies, then the substance has to be removed from Class I and reclassified Schedule II or III or else declassified altogether so further medical research can be done legally. Schedule I essentially "killed" and put an end to any formal further studies of the drug in the US.

So in early 1990s, the NIH-NIDA funded Phase I and II clinical trials of Ibogaine hydrochloride to assess safety in healthy volunteers and efficacy for cocaine/stimulants/opiates detox... These NIH-NIDA funded studies (Phase 1) found 150 mg and 300 mg purified Ibogaine hydrochloride were well tolerated in healthy humans with no reported side-effects (ref: ).. FURTHER STUDIES OF IBOGAINE WERE STOPPED at this point when the NIH decided not to fund anymore its IBOGAINE PROJECT.

. here is short history of the NIH-NIDA IBOGAINE PROJECT (extracted from here):

So by deciding not to further fund its own IBOGAINE PROJECT and prove the medical usefulness of Ibogaine, the NIH essentially helped maintained Ibogaine in Schedule I and killed any and all medical research of Ibogaine in the US to this day ..
too bad.. hundreds perhaps thousands deaths might have been avoided by this wonderful substance thanks to the Gods-spirits (called it what you want) of this amazing rain forest tree Tabernanthe Iboga.. too bad

I know what CSA sch 1 means, MDMA was schedule 1 when MAPS ran their PTSD study. It still is and apart from tha admin fuck up in 1988 it has been sch1 for a long time, it disn't stop the trial and MDMA was not reclassified to allow the trial. Whilst there are more obstacles to Sch1 clinical trials they are not insurmountable and a successful trial would have to lead eventually to rescheduling at the point the drug was licenced. Psilocybin sch1 has been in clinical trials for depression and is now progressing through PII it will be sch2 if the trials work out. There are plenty of drugs without NIH NIDA funding, NIH and NIDA are charitees for academics to milk.
I don't agree with the concept of schedule 1 no medical use because that assumes that the DEA have some kind of omnipotent and omniscient abilities in knowing whether something will have some use, and they clearly don't. After all THC is still sch1.
But the classification itself it is not the reason why ibogaine hasn't made it, there have been other obstacles and some of those obstacles are actually from addiction researchers and others who didn't like the idea of an antiaddictive drug as well as entrenched resistance from certain people in the NIDA who I won't name who think it would interfere with their own game of twisting new flavours of buprenophine and methadone type replacement therapy.

There is a standing FDA approved IND protocol for ibogaine trials, Deborah Mash had the agreement of the FDA in 1993 but depending on who you believe couldn't get the funding for work in the US and went off to St Kitts or perhaps the intellectual property squabble was the reason. Since then DemerRx spun out of that, and has been working on desmethyl ibogaine (noribogaine) and prodrugs of noribogaine, but in April this year they went into chapter 11 so probably will go no further.
Ibogaine has no legs because it cannot be patented, the use patent is also unavailable and the companies working on addiction therapeutics have already gone down the blind alley of substitution therapy, companies like Indivior are literally making a killing, and to ensure they continue making a killing they have bought off all the regulators.
this is just the tip of the iceberg. http://thefederalist.com/2018/01/29/big-pharma-fox-anti-addiction-hen-house/

So it wasn't just the NIDA/NIH it is a whole raft of people with ulterior motives as Sinclair put it ?It is difficult to get a man to understand something, when his salary depends on his not understanding it.?
 
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Ibogaine has no legs because it cannot be patented, the use patent is also unavailable and the companies working on addiction therapeutics have already gone down the blind alley of substitution therapy, companies like Indivior are literally making a killing, and to ensure they continue making a killing they have bought off all the regulators.
this is just the tip of the iceberg. http://thefederalist.com/2018/01/29/big-pharma-fox-anti-addiction-hen-house/

So it wasn't just the NIDA/NIH it is a whole raft of people with ulterior motives as Sinclair put it ?It is difficult to get a man to understand something, when his salary depends on his not understanding it.?
Very informative .. but I think it is not necessarily the issues of patentability of Ibogaine that doomed the drug. "methods of use" patents while not ideal are still very profitable for the industry. The use patents were and are still available not for Ibogaine in addiction treatment specifically which was patented earlier by Lotsof but for a lots of other Iboga-type alkaloids having similar (or even superior) bioactivity as Ibogaine. Mash and DemeRx successfully patented Ibogaine metabolites Noribogaine. Of course, "composition of matter" patents are better but also riskier since with "methods of use" you already know a great deal about your drug safety tolerability..etc so there is less risk of Phase 2/3surprises killing your drug after having spent millions $ earlier.

Imho the reason the Industry pursued the development of opioid replacement route rather than addiction "cure" route is because chronic conditions and therefore chronic treatments makes more financial sense. It is more profitable to have a customer for life than one off, isn't it? So the entire Industry focus has been and still is on chronic rather than acute conditions and treatments. This is what killed Ibogaine, its own success in curing addiction often after a SINGLE DOSE. That makes it (and potential patentable derivatives) unattractive for the industry. Compared to chronic replacement therapy like methadone/bupe which is essentially for the rest of the life of the patient, Ibogaine treatment is for at most a week or so .. DemeRx, Savants and similar biotech companies pursuing acute rather than chronic indications do not make darling of investors altho they might be threat to those pursuing chronic treatment in the case of addiction.. This may be one of the reason DemeRx went under.. but who knows?
 
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Imho the reason the Industry pursued the development of opioid replacement route rather than addiction "cure" route is because chronic conditions and therefore chronic treatments makes more financial sense. It is more profitable to have a customer for life than one off, isn't it? So the entire Industry focus has been and still is on chronic rather than acute conditions and treatments. This is what killed Ibogaine, its own success in curing addiction often after a SINGLE DOSE. That makes it (and potential patentable derivatives) unattractive for the industry. Compared to chronic replacement therapy like methadone/bupe which is essentially for the rest of the life of the patient, Ibogaine treatment is for at most a week or so .. DemeRx, Savants and similar biotech companies pursuing acute rather than chronic indications do not make darling of investors altho they might be threat to those pursuing chronic treatment in the case of addiction.. This may be one of the reason DemeRx went under.. but who knows?

The idea that pharmaceutical companies pursue treatments but not cures for financial reasons doesn't hold up under scrutiny. Just look at the recent financial success Gilead has had with the hepatitis-C cures Sovaldi and Harvoni. Insurers are willing to pay huge sums of money for cures because of the long-term cost savings. The reason that addiction treatments are on the market while addiction cures are not is because addiction involves immensely complicated biology and psychology that we have a very shallow understanding of and that, like in other drug development subfields, it is scientifically easier to find treatments than to find cures. The idea that profit-driven companies didn't pursue ibogaine because it was too good at curing addiction after a single dose is absurd. Any company that came out with a drug that could actually "cure addiction" even semi-reliably would make a tremendous fortune in a short period of time.
 
..Any company that came out with a drug that could actually "cure addiction" even semi-reliably would make a tremendous fortune in a short period of time.
You're right..if anybody can come up with such magic bullet, they'll make a killing like it said in OP, they can charge whatever they want.

However, I don't believe it is that hard to get a drug that "could actually cure addiction"..As as long there is money to be made doing so, there will be one.. I so happen to strongly believe that Ibogaine is as close as "curing" addiction a drug can gets. At least with opiates (If by "curing addiction" one means treating acute withdrawals and more important eliminating the cravings and need to take the drug for extended period.. Here is a most remarkable story of Ibogaine I came across, a Clinically Documented Case Study of Ibogaine OP detox at Vancouver General Hospital..
a 37 year old caucasian woman with a 19-year history of heroin use.. In entire 19 years, she's been off heroin for only 2 months (while on methadone) only to relapse.. Following 4-day Ibogaine course, not only she didnt suffer protracted withdrawals but more important she's since been and stayed sober for the following 1.5 year following flood dose (as far as the study follow-up time).. Amazingly the woman credit the psychological insights of her Ibogaine trip as the key for her staying sober.. true! this is only one case that may or may not apply to everybody! Ibogaine may or may not work for each and every single person.. but among those who benefit, it is truly magical.. but, as in anything in life, if you believe it wont work, it wont work; if you believe it'll work for you, it'll work .. The Buddha discovered that Universal Law of how the human mind works 2500 years ago: " you are what you think you are"..

Remission of Severe Opioid Use Disorder with Ibogaine: A Case Report Laurie Cloutier-Gill , M.D., Evan Wood , M.D., Ph.D., A.B.I.M., F.R.C.P.C., Trevor Millar, Caroline Ferris , M.D., C.C.F.P., F.C.F.P. & M. Eugenia Socias , M.D., M.Sc.

Journal of Psychoactive Drugs Volume 48, 2016 - Issue 3


Background
: Opioid use disorders (OUD) translate into major health, social, and economic consequences. Opioid agonist medications, which generally require long-term administration, are the mainstay pharmacological treatment of OUD. However, a large proportion of individuals with OUD either refuse or fail to respond to these therapies. Ibogaine, a naturally occurring substance found in the Tabernanthe iboga plant, has shown potential to bring about transformative or spiritual experiences that have reportedly been associated with long-term abstinece. Although research on ibogaine is limited, an ibogaine subculture persists, offering unregulated ibogaine preparations for the treatment of addiction.
Case presentation: We describe the case of a 37-year-old female with a 19-year history of severe OUD achieving an ongoing 18-month period of abstinence following a four-day ibogaine treatment. Her previous longest period of continuous abstinence from opioids was two months while on methadone. No safety issues associated with ibogaine were observed.
Conclusions: A four-day treatment with ibogaine was succesful in achieving long-term remission of a previously treatment-refractory patient with severe OUD
. While rigorous trials are required to establish safety and efficacy, future studies should seek to delineate the potential role of ibogaine or other molecules that may produce transformative experiences for individuals with substance use disorder.
nb: that article is $$paying$$ ie $pay-per-view unless you have institutional free access
 
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^ Here is the full report:

Remission of severe opioid use disorder with ibogaine: a case report

Laurie Cloutier-Gill, Evan Wood, Trevor Millar, Caroline Ferris, M. Eugenia Socias

Background

Opioid Use Disorders (OUD) translate into major health, social, and economic consequences. Opioid agonist medications, which generally require long-term administration, are the mainstay pharmacological treatment of OUD. However, a large proportion of individuals with OUD either refuse or fail to respond to these therapies. Ibogaine, a naturally occurring substance found in the Tabernanthe iboga plant, has shown potential to bring about transformative or spiritual experiences that have reportedly been associated with long-term abstinence. Although research on ibogaine is limited, an ibogaine subculture persists in offering unregulated ibogaine preparations for the treatment of addiction.

Case presentation

We describe the case of a 37-year-old female with a 19-year history of severe OUD achieving an ongoing 18-month period of abstinence following a four-day ibogaine treatment. Her previous longest period of continuous abstinence from opioids was 2 months while on methadone. No safety issues associated with ibogaine were observed.

Conclusions

A four-day treatment with ibogaine was successful in achieving long-term remission of a previously treatment-refractory patient with severe OUD. While rigorous trials are required to establish safety and efficacy, future studies should seek to delineate the potential role of ibogaine or other molecules that may produce transformative experiences for individuals with substance use disorder.

---

In North America, an estimated 1 million individuals are affected by Opioid Use Disorders (OUD). Although this prevalence is relatively low, these figures translate into major health and societal costs. Overdose, suicide, end-stage liver disease, psychiatric illnesses, as well as increased risk of Hepatitis C (HCV) and HIV infection are frequent health consequences of untreated OUD. The economic burden of OUD is also large, including health care costs, loss in productivity and criminal justice expenditures.

At present, Opioid Agonist Treatment (OAT, e.g. methadone, buprenorphine) is considered the gold standard treatment for OUD. Methadone Maintenance Therapy (MMT) has been shown to effectively reduce heroin use, as well as improve the physical and mental health status of those who are retained in treatment. However, many patients are unwilling to take daily OAT or do not respond to these treatments. For instance, some studies report that up to 40% of individuals with OUD have an unfavorable response to MMT. Furthermore, previous studies show that MMT programs fail to meet self-perceived needs and preferences of many opioid users, which might contribute to the high attrition rate observed in these programs. The limited efficacy of OAT could be in part related to the need for long-term adherence to therapy. Thus, further research and development of new treatment programs for OUD is warranted to better meet the needs of individuals with OUD for whom available treatment options have failed or are unsuitable.

Ibogaine is an alkaloid found in the Tabernanthe iboga root bark, traditionally used in initiatory rituals in West Central Africa. Since the 1960s, anecdotal evidence has suggested its potential to treat addictions without the need for ongoing administration. This initial evidence of ibogaines anti-addictive properties has been subsequently supported by pre-clinical and observational studies. However, ibogaines toxicity profile, including fatalities temporally-associated with its ingestion, have likely hampered subsequent clinical research on ibogaines anti-addictive properties.

Although ibogaine is a Schedule I substance in the United States, it is unregulated in most countries, including Canada. Dozens of clinics worldwide are hence offering ibogaine for the treatment of addictions in both non-medical and medical settings. For instance, as of February 2006, it was estimated that 3414 individuals had taken ibogaine. Of those, 68 percent had used it for the treatment of a substance use disorder and most commonly for opioid detoxification (53 percent).

We present a case of a woman with long standing severe OUD and a history of multiple previous unsuccessful treatments. Eighteen months after a short treatment course with ibogaine, she remains abstinent from opioids.

CASE REPORT

A 37-year-old Caucasian woman was referred to the Addiction Outpatient Clinic at St-Pauls hospital in Vancouver for follow-up of her OUD remission subsequent to a 4-day treatment with ibogaine 18 months prior. She had been addicted to heroin since she was 18 years old. Apart from her substance use disorder, other medical comorbidities included stable angina, dyslipidemia, obesity, chronic HCV, peripheral vascular disease, and attention-deficit hyperactivity disorder. Before undergoing her ibogaine treatment, the patient repeatedly tried and exhausted most available addiction treatment options, including 12-step programs, detoxification centers, support groups, sponsors, recovery houses and MMT, all without sustained success. Her prior longest period of continuous abstinence was 2 months while on MMT.

As previously stated, 18 months prior to this consultation the patient was admitted to a residential ibogaine program in Vancouver to receive ibogaine therapy for her OUD. She had last used opioids (16 mg of hydromorphone) approximately 12 hours prior to admission to the centre. The centers protocol involved a series of ibogaine HCl test doses (up to 2.5 mg/kg) on the first day, followed by a series of larger doses (up to 20 mg/kg) on the second day, and booster doses on the last 2 days (5 mg/kg/day). Over the course of the four-day admission, she received a total of 2300 mg (32 mg/kg) of ibogaine HCl. The clinics protocol also allowed for the use of oral hydromorphone to manage acute withdrawal. The patient required 32 mg of hydromorphone on the first day and 45 mg on the second day to manage her withdrawal symptoms which were already present on admission.

During the ibogaine treatment, the center provided food and a quiet place to rest, but there was no formal psychotherapy performed. In addition to continuous nursing monitoring with hourly heart rate and blood pressure, the clinic safety protocol included liver and cardiovascular screening prior to the initiation of the ibogaine treatment. The patients baseline ECG was within normal parameters, including a normal QTc.

The patient maintained an overall stable blood pressure during the 4-day treatment, but developed mild bradycardia (average measured heart rate on day 1, 2, 3, 4 was 67 beats per minute [bpm], 57 bpm, 51 bpm, and 57 bpm respectively). In addition, she experienced mild and transitory side effects such as weakness, dizziness, and diaphoresis. Minor concentration deficits were reported during the first few weeks following therapy, but the patient did not suffer from any other overt persistent side effects. At the time of this consultation, the patient denied any opioid use since she left the ibogaine clinic 18 months ago. She attributed her sustained recovery more to a spiritual awakening induced by the ibogaine experience than to a painless withdrawal, as she had been able to go trough physical withdrawals successfully on various occasions in the past without subsequent sustained abstinence. The patient described that the ibogaine experience allowed her to revisit various recent events of her life, including the loss of her partner to an opioid overdose, as well as other moments where the patient herself suffered nearly fatal overdoses. This new insight into her OUD, became an eye-opening opportunity, giving her emotional strength to attempt and sustain abstinence.

DISCUSSION

We described the case of a 37-year old woman who as of the time of writing of this report denied any opioid use over an 18-month period subsequent to a 4-day treatment with ibogaine without any significant adverse events. This is noteworthy in the setting of a 19 year history of severe OUD and multiple failed attempts at abstinence following various widely accepted treatment modalities. A number of evidence-based pharmacotherapies for the treatment of OUD exist, including methadone and buprenorphine. However, OAT requires long-term adherence, which can be challenging for many individuals. As such, novel therapies are needed for patients who fail to respond to OAT or are reluctant to engage in long-term OAT programs.

Ibogaine shows potential as an alternative treatment for OUD, particularly among cases refractory to OAT for a number of reasons. First, studies have suggested that ibogaine is effective in easing opioid withdrawal, as well as in reducing cravings. Although the pharmacological bases of ibogaines anti-addictive properties are not fully understood, ibogaine and noribogaine (ibogaines main metabolite) simultaneous action on a diversity of neurotransmitter transporters and receptors provides a biological plausibility for its anti-addictive effects. Second, ibogaine is usually administered in a single session, not requiring ongoing administration, which can be a substantial advantage for many individuals with OUD. Without the time and logistical constraints commonly associated with daily-withnessed ingestion of methadone, individuals could have an easier transition back to employment and other factors associated with recovery, which in turn could reduce direct and indirect societal costs. Third, it has been suggested that the mystical experiences associated with ibogaine and other traditional psychedelic drugs might result in the resetting of psychological processes or neuroadaptations underlying substance use disorders, which could contribute to long-term abstinence. Our patient volunteered that it was such transformative phenomenon that was the key to her success this time. Fourth, ibogaine has a low abuse potential, as indicated by animal models where ibogaine did not lead to either desire for the substance or aversion to it.

Despite these promising characteristics of ibogaine, clinical research on its potential for the treatment of subtance use disorders has been hindered due in part to safety concerns. However, this research gap has resulted in a lack of evidence-base clinical and pharmaceutical standards of how to safely administer ibogaine, further exacerbating its potential risks. Twenty-two deaths temporally related to ibogaine use have been reported between 1991 and 2014, most of which were associated with pre-existing medical comorbidities (particularly cardiovascular disease), concurrent use of other substances, and electrolyte imbalances (i.e. hypokalemia). Clinical reports and studies in animal models suggest that cardiac arrhythmias, induced by ibogaines propensity to prolong the QT interval, might have been responsible for many of these deaths. As such, ibogaines safe administration would theoretically dictate, amongst other safety measures, the need for an electrolytes and ECG screening prior to treatment, abstinence from any other potentially QTc prolonging substances, as well as exclusion of patients with cardiovascular disease.

In summary, the case presented here illustrates the challenges associated with the treatment of refractory OUD, and underscores the urgent need for expanding options to treat these cases, as well as for other substances (e.g., cocaine) for which pharmacotherapies are currently unavailable. Although ibogaine is a promising compound, its use on individual patients must be based on a risk-benefit analysis (e.g., potential cardiotoxicity versus untreated substance use disorder), as well as on a careful selection of eligible candidates and ibogaines administration in adequately safe settings. With the growing number of ibogaine users in uncontrolled settings, further clinical research is warranted to clarify the potential role of ibogaine and related congeners (e.g., 18-MC), as well as other molecules that may produce transformative experiences in the treatment of substance use disorders, and to help inform guidelines for their safer administration.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993099/
 
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^ Nice you posted the full article.. here is very recent Ibogaine study from Johns Hopskins and Yale ..
A Mixed-Method Analysis of Persisting Effects Associated with Positive Outcomes Following Ibogaine Detoxification
Davis AK, Renn E, Windham-Herman AM, Polanco M, Barsuglia JP. J Psychoactive Drugs. 2018 Jul 18:1-11


Abstract: We examined persisting effects, self-perceived challenges, and potential benefits associated with positive outcomes following ibogaine detoxification using data collected as part of a larger online retrospective study of 73 patients who received treatment for chronic opioid use in Mexico between 2012 and 2015. A mixed-methods design was used comparing treatment responders versus non-responders, as well as content coding of themes from open-ended questions.

Most participants reported positive persisting effects of ibogaine detoxification (e.g., enhanced personal sense of gratitude and authenticity, and meaning and appreciation for life). Compared to non-responders, treatment responders endorsed greater persisting changes in their ability to tolerate difficult/painful feelings, capacity for coping with stress, and reduced unhealthy anger. Treatment responders reported greater change in subjective levels of inner peace, joy, feelings of love/open heartedness, and experiences of sacredness in life.

Qualitative analyses revealed that treatment responders reported a heightened sense of spiritual awareness and greater connection to their intra-/interpersonal relationships after ibogaine detoxification. Notable challenges of ibogaine detoxification included psychological and health-related difficulties during treatment and challenges with post-treatment integration. Findings highlight the persisting effects associated with positive response to ibogaine detoxification and possible post-treatment needs (i.e., more integration/aftercare resources). Future research using rigorous experimental designs is needed.
 
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Meet the scientists who may have found the cure for drug addiction


Keegan Hamilton, BuzzFeed
October 9, 2014

After nearly two decades of research, Dr. Stanley Glick developed a drug with the potential to revolutionize substance abuse treatment. It is called 18-MC (short for 18-methoxycoronaridine) and it is, in essence, a drug to get people off of drugs. Glick meticulously tested it on animals, observing as rats hopelessly strung out on cocaine suddenly lose their desire to get high after a few doses of 18-MC. It has a similar effect on animals addicted to methamphetamine, morphine, alcohol, and nicotine. It even seems to work with sugar, indicating potential as an obesity treatment. But it's not rats that Glick is trying to help, and that's where this gets tricky.

“We hope it’s a paradigm shift in the way substance abuse is treated,” says Steve Hurst, CEO of Savant HWP, the Bay Area biotech startup developing 18-MC. “But we’re still trying to figure out if it’s OK to give to people in doses that are safe enough to replicate what we see in animal models.”

Naturally, there is cause for skepticism. Although early indications suggest 18-MC is safe, it is related to a naturally occurring substance known to cause severe nausea, intense hallucinations, and other serious side effects. Initial tests on humans haven’t revealed those problems, however, and experts are cautiously hopeful that 18-MC may ultimately allow doctors to prescribe medication that blocks cravings and helps people stay clean.

While a handful of treatments are available to help opiate addicts kick their habits, there are currently no options other than cold turkey for coke, meth, and other addictive stimulants. Glick’s 18-MC is one of several promising new substances to emerge from the rapidly advancing field of anti-addiction science. Glick and Hurst’s competitors include a researcher at Weill Cornell Medical College who has created a vaccine that creates antibodies that he says act “like little Pac-Men floating around in the blood” gobbling up cocaine in the bloodstream before it ever reaches the brain. Another treatment being developed by a Swiss pharmaceutical company and a researcher in New Zealand regulates dopamine, the pleasure-inducing neurotransmitter associated with cocaine, to reduce cravings and prevent relapse.

Despite desperate demand by millions of suffering addicts and their families, it may still take years to determine if these drugs are safe and effective enough to be sold in the United States. Prohibitive costs and red tape have long hindered the development of all types of medication, but public health officials, legislators, academic researchers, and drug developers interviewed for this story say current Food and Drug Administration policies make it especially difficult for companies to bring anti-addiction drugs to market. The FDA requires drugs like 18-MC to produce absolute abstinence in cocaine users in clinical trials, a standard that many believe is impossibly stringent.

Though still staring down a long path of bureaucratic hurdles, Glick and his peers are closer than they’ve ever been before to developing the first medications that combat cocaine and other stimulants. And, after years of shunning anti-addiction science, pharmaceutical companies have begun to realize the potential profits involved and are showing interest in the emerging field.

"Here’s a compound that is effective for models of opioid addiction, stimulant addiction, alcohol addiction, nicotine addiction, and for obesity," says Dr. John Rotrosen, director of the addiction research program at New York University’s Langone Medical Center. Of 18-MC, he says, "It all seems too good to be true."

Though he officially retired in June, Stanley Glick still teaches at the graduate school, and his vitality belies his senior citizen status. His roots as a native New Yorker show through as he talks a mile a minute while recounting the path he traveled to develop 18-MC.

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It began one day around 1989 when he received a phone call from a former heroin addict touting a miracle cure for drug addiction. The ex-junkie was named Howard Lotsof, and his purported cure was a substance called ibogaine, a bitter white powder derived from the roots of a plant indigenous to the rainforests of western Central Africa. Ibogaine is something like the African equivalent of peyote or ayahuasca, a potent hallucinogen used to induce spiritual visions during tribal ceremonies.

Glick wasn’t buying it. As both a Ph.D. and medical doctor specializing in substance abuse treatment, he had been studying the effects of addictive drugs on the brain long before Lotsof came calling.

“I’ve gotten a number of calls over the years from people who want me to study something,” Glick says. “Most of them are just crackpots. But he kept calling back. The more I looked into it, the more my curiosity was piqued.”

Ibogaine is illegal and considered a Schedule I drug in the United States (meaning it officially has a high potential for abuse and no medicinal value), but Lotsof, who died in 2010, was adamant that it eliminated the intense cravings and unpleasant withdrawal symptoms associated with heroin and other opiates. He had obtained a patent for the use of ibogaine in treating addiction, and reportedly had positive results administering it at a clinic in the Netherlands, one of many countries where the drug is legal and still available today.

“Lotsof originally thought if he told the world about this, they would embrace him as a savior and he would rid the world of this terrible scourge of addiction,” Glick says. “Then he realized there was such a thing as science, the FDA, and controlled trials. He had to get scientists to study it. He called every drug abuse scientist in the country, and, for better or worse, I was the first one who was fool enough to get interested in it.”

Glick figured a few preliminary tests on rats would debunk Lotsof’s wild claims, but he became intrigued when animals trained to self-administer morphine stopped taking the drug for days and even weeks after being dosed. He set out to find the precise “mechanism of action” in the brain that caused the phenomenon. A few years later, Glick ended up with 18-MC.

The ibogaine research hit a dead end in 1995 when the National Institute on Drug Abuse, the federal agency that funds scientific research on drug abuse, voted to halt the study of ibogaine over concerns the drug causes fatal cardiac issues and possibly brain damage at high doses.

“They just washed their hands of the whole thing,” Glick says. “It became pretty clear to me there was no way, shape, or form that ibogaine would ever be something that would even be pursued as a legitimate medication in this country.”

A few years prior to the NIDA vote, Glick began collaborating with a chemist at the University of Vermont named Martin Kuehne. Kuehne had experience synthesizing medications for cancer and other diseases, and together they had the idea of tweaking the basic chemical structure of ibogaine to eliminate the side effects while keeping the potent anti-addiction properties. After testing about 60 different compounds — all close chemical cousins of ibogaine — Glick settled on 18-MC.

In simple terms — which Glick often has trouble using — 18-MC blocks the pleasurable effects of cocaine by “dampening the response” to dopamine. Glick pulls up several graphs that show the cocaine intake of addicted rats dropping precipitously after they receive 18-MC.

“What the rat is telling you here is, ‘The drug is getting in, I feel it, but it’s not giving me the kick that it used to,’” Glick says. “That’s really the essence of how we think 18-MC works. ... No matter what dose of the addictive drug you take, it’s just not giving you the buzz it used to.”

Virtually every addictive drug known to man, from booze to heroin to cocaine, stimulates an area of the brain commonly known as the reward pathway. When a person snorts a line or downs a shot of liquor, it triggers a surge of dopamine in this pathway. Many others have tried unsuccessfully to create drugs that work directly inside the reward pathway by blocking the release of dopamine or preventing it from binding with neurons. Glick’s drug takes a different tact.

According to Glick, 18-MC works on a specific type of nicotinic receptor, an area strongly associated with tobacco addiction and cravings. Most crucially, it also works in an “alternate reward pathway” that indirectly impacts the way neurons in the brain release and absorb dopamine.

“It turned out that in the early ‘80s there was a flurry of studies on this,” Glick says. “But by the late ‘80s everyone was studying dopamine. We had discovered how rewarding events occur in the brain and everyone had forgotten about this alternate reward pathway. I felt like what happened is we rediscovered the importance of this pathway.”

After Glick made his first discoveries about 18-MC, he set about finding a partner willing to invest in the additional research and development necessary to gain FDA approval for testing in humans. He ended up writing letters to 38 different pharmaceutical companies. Nobody was interested.

“I’d done everything conceivable I could do to try to get some pharmaceutical interest,” Glick says. “I was on the verge of giving up.”

As Glick soon learned, he was hardly the first addiction researcher to be spurned by big pharma. For a variety of reasons, industry titans have long been reluctant to develop treatments for drug addiction. The main problem, according to several scientists interviewed for this story, is one of perception: Corporations simply don’t want their brands associated with dope fiends, cokeheads, and tweakers.

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Dr. Jed Rose, director of the Duke Center for Smoking Cessation and a professor in the Department of Psychiatry and Behavioral Sciences at Duke University Medical Center, says the stigma of drug addiction is so strong that companies have even been reluctant to invest in something as seemingly mainstream as anti-nicotine research. Rose says he has experienced instances where drugs for schizophrenia and Alzheimer's also showed potential as smoking treatments, but no further testing was permitted.

“Over the years I’ve pleaded with companies to allow us to test their agents on smoking,” Rose says. “Time and time again I was refused. The companies didn’t want to have their image tainted with addiction, even smoking addiction.”

Another issue is a perceived lack of profitability. According to the National Survey on Drug Use and Health, in 2013 an estimated 1.5 million Americans used cocaine, but only a fraction of those could be expected to receive treatment in any given year. Many hardcore users also abuse alcohol, opiates, and other drugs, making pharmacological treatments a dicey proposition in terms of safety and efficacy.

“Pharma thinks drug addiction is not a good enough market,” says Nurulain Zaveri, president and CSO of Astraea Therapeutics, a San Francisco Bay Area startup developing an addiction drug that targets the same set of nicotinic receptors as 18-MC. “It’s fraught with risk. You’re dealing with high-risk people who have addictions. It’s a disease of the mind. When you’re dealing with drugs that work on the brain, it’s risky business.”

In recent years, however, pharmaceutical companies have gradually come to realize that major money can be made treating addiction. The catalyst for this shift is the drug buprenorphine (commonly sold as the compound Suboxone), an anti-opiate medication that generated $1.5 billion in sales in 2012 — outselling both Viagra and Adderall.

Buprenorphine was introduced in Belgium in 1983, but did not become widely available in the U.S. until 2003. The drug allows addicts to gradually taper down their opiate intake, mimicking heroin in the brain but with more muted effects on the body. The FDA granted the drug "orphan" status, which is intended for products that treat rare diseases. From a business perspective, the appeal of orphan drugs is that they qualify for significant tax credits, and the FDA cannot rescind status after it is granted. Suboxone sales have skyrocketed in conjunction with the recent rise of heroin and painkiller addiction.

NYU's Rotrosen believes pharmaceutical companies have recently become much more receptive to anti-addiction drugs after the stunning success of Suboxone. “Nobody saw addiction as a profitable area,” he says. “The fact that buprenorphine has been successful and the fact that addiction is in many ways becoming an everyman’s disease, rather than one for down-and-out junkies, has changed that.”

Perception was initially part of Glick’s problem too. Potentially hallucinogenic miracle cures are a tough sell, no matter how promising the data. The unusual experiments with rats and Miles Davis haven’t always gone over well either. A related experiment landed him on a list of “Most Ridiculous Research on Animals” compiled by In Defense of Animals, a California-based animal rights group.

“I had reporters breathing down my neck,” Glick grumbles. “It was because they looked at the one paper and didn’t realize it was a series leading up to what we wanted to do with it.”

Two twists of fate helped Glick reverse his fortunes. In 2010, he gave a talk at the prestigious American College of Neuropsychopharmacology Annual Meeting, an event where elite biochemists and neuroscientists convene to discuss the state of their field. He recalls arriving late on a delayed flight the night before his presentation — “I thought I was half asleep” — but later received unprecedented interest in his project, particularly from NIDA.

“Within a week I started getting a whole bunch of calls from people who were interested,” Glick says. “All of a sudden they wanted to help me.”

Also in 2010, Glick was approached by Steve Hurst, the founder and CEO of Savant HWP. An attorney with a background in patent law, Hurst has years of experience in the pharmaceutical industry, working previously with groups that developed an inhalable form of insulin and other novel medications, including a clot-busting stroke medicine derived from snake venom. Glick says Hurst “knows more science than any lawyer I’ve ever met.”

The pair agreed to a partnership, and Hurst added to the equation business savvy and connections that Glick sorely lacks. Personality-wise, the two are polar opposites. While Glick is staid and erudite, Hurst sips a glass of bourbon neat during an interview at the posh Tribeca Grand Hotel in Manhattan and casually riffs on the science of addiction and the failure of the war on drugs.

“We know that addiction is a disease and that ‘Just Say No’ is a delusion,” Hurst says. “If your brain tells you to go drink, or do cocaine, or shoot heroin — that’s not willpower. This whole notion is a reason I think addiction medicine is such an emerging field. We understand a lot about the disease we didn’t understand 10 years ago.”

With Hurst’s help, in September 2012, Glick secured a $6.5 million grant from NIDA to prepare 18-MC for clinical trials in humans. After more than a year of exhaustive toxicology analysis and other procedures to prove the drug is unlikely to cause serious harm in people, the first limited trial was tentatively scheduled to begin earlier this year on seven healthy volunteers at a facility in Kansas.

“As you can imagine, it’s very, very difficult for addicts to achieve drug abstinence,” says Dr. Ivan Montoya, a deputy director at NIDA. “We are in a dialogue with [the FDA] and trying to see if it’s possible to have a significant drug-use reduction as an outcome measure.”

When a company submits an Investigational New Drug (IND) application to the FDA, the agency has 30 days “to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.” Exactly 30 days after filing the paperwork, Hurst says he received a call from the FDA informing him that the project was on hold indefinitely pending further review.

“They said basically, ‘We have no info for you as to why, and you'll get a letter within 30 days,'Hurst says. “It was one of the oddest FDA calls I've ever been on.”

FDA spokeswoman Sandy Walsh declined to comment on the status of 18-MC. “For pending applications, under the law FDA staff are prohibited from discussing the existence of, or status of, any drug application,” Walsh said via email. “That is confidential information.”

Meanwhile, Glick and Hurst constantly receive email from people pleading for a chance to be among the first crop of 18-MC human guinea pigs. The messages are gut-wrenching. One shared by Glick is from a mother seeking help for her “horribly addicted” 28-year-old disabled daughter.

“Our family has done everything we can think of,” the mother wrote. “She’s been through inpatient rehab, outpatient treatment, Suboxone and methadone clinics. She wants out of addiction or out of this life.”

Glick says he responds personally to every message, but his replies are a cold comfort at best. He urges them to try a conventional treatment and explains that he and Hurst are working diligently to bring 18-MC to market.

“It just breaks my heart,” Glick says. “I can’t do much to help them. The really sad part is that they are usually ridiculously grateful because usually they can’t get anybody to even talk to them.”

From 2003 to 2005, 115 addicts at a methadone clinic in West Haven, Connecticut, volunteered for an experimental new treatment. Heroin was their main problem, but 9 out of 10 “considered smoked cocaine their second drug of choice after opioids.” Over the course of 12 weeks, 58 people were injected with a cholera vaccine in addition to receiving their regular dose of methadone.

This was no ordinary vaccine. Researchers from Baylor University had modified the common medicine to fight cocaine. If it worked the way it was intended, the vaccine would make it nearly impossible for people to feel the effects of snorting, smoking, or injecting cocaine. The hope was that the test subjects would lose their taste for the drug when they found out it no longer delivered the high they craved.

Testing showed that 21 people “significantly reduced” their cocaine use, but the rest struggled to abstain from use or fell back into their old ways. A four-week follow-up period revealed little in the way of overall improvement in the group. The vaccine was considered a failure. “We need improved vaccines and boosters,” the researchers concluded in a paper published in 2009.

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Fast-forward five years, and a new and improved cocaine vaccine is on the eve of undergoing a similar trial. Dr. Ronald Crystal of Weill Cornell Medical College is at roughly the same point in the drug development process as Glick and Hurst. Crystal has created a cocaine vaccine that is linked to adenovirus, a cause of the common cold. The idea is that the human body produces much stronger natural response to colds than it does for cholera, meaning the cocaine-fighting component of this new vaccine should be more powerful than before.

“Let’s say you go on the subway and someone sneezes with a common cold,” Crystal explains. “You may get the cold, but your body will respond to the adenovirus and produce antibodies. The adenovirus is very immunogenic. It evokes very high levels of antibodies against itself. That’s what we’re taking advantage of.”

Crystal has tested his vaccine extensively in mice, rats, and primates, all with promising results. He is in the final stages of safety analysis, and aims to have the vaccine tested in humans by the end of the year. He is skeptical of 18-MC, noting that similar drugs that have attempted to regulate dopamine production inside the brain have caused harmful side effects or been proven ineffective. “This is a different approach,” Crystal says. "We’re working outside the brain and developing a shield to prevent the cocaine from reaching the brain.”

But the vaccine is hardly a sure thing either. One troubling finding from the study in New Haven was that many users tried to “override” the vaccine by taking huge doses of cocaine. A number of test subjects had as much as 10 times the amount of cocaine in their blood than would typically be expected, posing a serious risk of overdose. Rather than putting people on the road to recovery, the vaccine seemed to provoke even more intense addiction.

Part of the problem may have been that the original trial involved people who were on methadone treatment for heroin addiction. Crystal says for the next round of vaccine trials, “We would prefer cocaine-specific individuals, but that doesn’t mean we won’t accept others.”

At NIDA, which has exclusively funded Crystal’s research, Deputy Director Dr. Ivan Montoya says if the cocaine vaccine is ever approved, it “most likely will be for people who are motivated, with ways of controlling for potential overdoses.” That might mean offering the vaccine only to people who have already shown the ability to stay clean for a few months or weeks — not exactly the neediest group.

Crystal remains optimistic that the more potent vaccine, perhaps combined with booster shots, won’t have the same issues as its predecessor. There’s also the potential to combine the vaccine with enzymes — the molecules in the body responsible for metabolism — to more effectively break down cocaine in the bloodstream. Montoya notes that an Israeli company called Teva Pharmaceuticals has “developed an enzyme that is 1,000 times more efficient than the natural enzyme that breaks down cocaine,” but it has not yet been approved by the FDA.

Although the vaccine is technically competing with 18-MC, Glick says he hopes the rival treatment turns out to be safe and effective. His concern, however, is that even if the improved vaccine totally blocks the effects of cocaine, addicts will end up substituting other stimulants, such as meth, to achieve a similar high.

“I have my doubts,” Glick says of Crystal’s vaccine. “If all it does is block the drug from reaching the brain, it doesn’t address the craving or underlying cause of addiction.”

Of course, eliminating cravings is much easier said than done. Scientists know exactly how cocaine and other drugs work once they reach the brain, but relatively little is known about craving and relapse. Glick and others are banking on the idea that indirectly regulating the way brain releases and absorbs dopamine in the reward pathway is the key to solving the riddle.

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At the University of Canterbury in New Zealand, Dr. Juan Canales is collaborating with the Swiss pharmaceutical giant Roche to study how certain types of receptors in the brain can be used to modulate dopamine in the reward pathway. Canales focuses on trace amine receptors, which he says “give us the opportunity to regulate dopamine function in different stages of the addiction cycle.”

Like Glick, Canales devised ways to study relapse in cocaine-addicted rats. By working with trace amine receptors, rats that were once addicted to cocaine stopped self-administering the drug, even after they were given a little taste to remind them of the high. Canales says "The experiment mimics human addicts who fall hard off the wagon after even the slightest exposure to their drug of choice."

“A cigarette for smokers, a drink for alcoholics, or a little bit of cocaine — that little bit of drug acts as a reminder and they relapse,” Canales says. “In that situation we’ve blocked relapse. We are able to indirectly modulate dopamine concentrations within a very narrow margin, which keeps the dopamine system in check, not allowing it to go too high or too low.”

The drawback to interfering with the brain’s dopamine system is that it can often cause serious side effects, including abnormal movements of the face and loss of motor skills. Both Glick and Canales have found nothing in their animal research that suggests their drugs will have similar problems, but there’s only way to find out for sure if they’re wrong: testing on real human beings.

When Glick came up with the idea to play a Miles Davis song to rats on cocaine, he wasn’t really considering how ridiculous it might look to the rest of the world. He simply wanted to test whether 18-MC could effectively block cravings for cocaine. And, although he is a jazz fanatic with pictures of Louis Armstrong decorating his office, he claims the choice of the song “Four” had nothing to do with his — or the rats’ — taste in music.

“The reason I chose that song is it has a very limited range of pitches,” Glick explains. “It’s very recognizable and it’s very repetitive. It doesn’t vary enough so that it arouses the juices. It’s almost monotonous.”

Glick published his findings from the study in 2012, and the results are both impressive and intriguing for what they reveal about 18-MC’s apparent power to make cravings vanish. Glick concluded that 18-MC “blocked cue-induced reinstatement,” which means the addicted rats no longer had any interest in getting high, even when they heard the Miles Davis song. He also speculated that nicotinic receptors — the parts of the brain impacted by his drug — “may be involved in the mechanism of craving, and that 18-MC may help prevent relapse to drug addiction in humans.”

In July, after a lengthy back-and-forth with the FDA, Hurst convinced the agency to lift the “clinical hold” on 18-MC, clearing the way for human trials to eventually begin in the United States. At the same time, a separate round of trials are already underway in Brazil, where 18-MC holds appeal not only as an addiction treatment but also for leishmaniasis, a nasty parasitic disease that is common in tropical climates. By pure coincidence, 18-MC shows promise as a treatment for both maladies.

The upshot of 18-MC’s dual purpose is that leishmaniasis potentially qualifies as an orphan disease under FDA regulations. That means 18-MC might be eligible for the same tax breaks and fast-track status that led to the blockbuster success of heroin treatment Suboxone.

In a Sept. 23 press release, Savant announced the preliminary results of the first “double-blind, placebo-controlled human safety study” of 18-MC. The drug was reportedly “well tolerated by healthy volunteers.” Hurst noted that 18-MC appears to have none of the harmful side effects of ibogaine, and said a peer-reviewed academic article with additional details is forthcoming.

Even if 18-MC ultimately proves ineffective, Hurst says the company can still fall back on the dozens of related compounds created years ago by Glick and Kuehne. From a business perspective, Savant might not have that kind of time. Rival companies are developing similar drugs that work on nicotinic receptors, and a Florida group is in the advanced stages of testing an anti-opiate drug that uses noribogaine — a naturally occurring metabolite of ibogaine — as the key component.

Yet as of right now, no major pharmaceutical companies are interested in developing 18-MC. The problem is apparently not with the safety of the drug. At NIDA, Montoya says “All the preclinical studies that have been done so far seemed to indicate 18-MC is safe to be administered to humans,” and, “if there are problems, they will be tolerable side effects — it will not be lethal side effects.”

The risks, rather, are regulatory and financial. Even if 18-MC helps a significant percentage of patients reduce their cocaine intake dramatically during a clinical trial, it’s still possible that the FDA would refuse to make the drug available in the United States. The agency mandates that anti-addiction drugs result in nothing short of an addict becoming completely abstinent. Companies are naturally reluctant to wager millions of dollars in development costs on the long odds that virtually every addict who uses 18-MC will stay clean.

Walsh, the FDA spokeswoman, responded to questions about the agency’s abstinence standard by sending a commentary on anti-addiction drugs authored by FDA officials and published in 2012 in an academic journal. The gist of the article is that clinical studies on hard-drug addiction should be treated like studies on alcoholism, where six months of no drinking is the gold standard for success.

In March, Sen. Ed Markey, whose home state of Massachusetts has been plagued by heroin and painkiller addiction, issued a joint statement with 37 other members of Congress imploring the FDA to create “a larger, faster and more predictable pipeline for the approval of new and promising drugs.” Markey followed up with a sternly worded letter to FDA Commissioner Margaret Hamburg demanding answers about the abstinence standard and the state of anti-addiction research.

“I am concerned that even a perceived focus by FDA on treatments that only result in full cessation of drug use (abstinence) limits the engagement of developers/industry on a broader portfolio of treatment options,” Markey wrote.

Walsh declined to comment on the correspondence, and said the FDA “will review the letter and respond to Senator Markey directly.” Five months later, the FDA replied to Markey's letter, suggesting that labeling could eventually be used to warn that anti-addiction drugs might not be 100% effective in all cases.

"A better relationship between patterns of drug use, and their clinical benefits, would allow us to identify treatments that are effective in helping patients, even if complete abstinence is not achieved," the FDA wrote. "We need to better understand what patterns of use, if achieved and sustained, translate to clinical benefit, and so serve as a surrogate for the clinical benefit."

While lawmakers and scientists deal with the red tape, cocaine addiction continues to cause significant public health and crime problems. Roughly 34% of federal prisoners locked up on drug charges were sentenced for cocaine or crack, and cocaine is involved in over a third of illicit drug-related emergency room visits.

Experts emphasize that drugs alone probably aren’t going to cure somebody with a serious addiction. The problem runs deeper than just brain chemistry, involving ingrained habits and lifestyle choices.

“In the end, what you want to change is human behavior,” Rotrosen says. “And it is not necessarily as easy to change somebody's behavior around cocaine as it is overeating or lack of exercise.”

Glick and Hurst are quick to acknowledge that, even in a best-case scenario, 18-MC isn’t likely to be a panacea. It would likely have to be administered over the course of weeks or months along with conventional rehab. But before that happens, it has to earn the FDA’s stamp of approval. And, though the outlook is positive, Hurst cautions there’s still a long way to go before 18-MC is deemed safe and effective enough for American addicts.

“I tell people it’s sort of like a journey through the Himalayas,” Hurst says of the drug development process. “You reach the top of the mountain in front of you, and you look out and see another mountain range you have to climb over. We’ve gotten up over the first mountain range. There’s at least another one beyond that.”

https://www.buzzfeed.com/keeganhami...aine-addiction?utm_term=.rwmQ0aBVl#.imO7LONRB
 
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Ibogaine and the heart: A delicate relation*

Xaver Koenig and Karlheinz Hilber
Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, Vienna 1090, Austria

Ibogaine has shown promising anti-addictive properties in humans as the drug alleviates drug craving and impedes relapse of drug use. Though unlicensed as therapeutic drug, and despite safety concerns, ibogaine is currently used as an anti-addiction medication in alternative medicine clinics worldwide. In recent years, alarming reports of life-threatening complications and sudden death cases associated with the administration of ibogaine have been accumulating. These reactions are hypothesized to be associated with ibogaine’s propensity to induce cardiac arrhythmias. The aim of this review is to recapitulate the current knowledge about ibogaine’s effects on the heart and the cardiovascular system, and to assess the cardiac risks associated with the use of this drug in anti-addiction therapy. The actions of 18-methoxycoronaridine (18-MC), a less toxic ibogaine congener, are also considered.

The mechanisms by which ibogaine exerts its psychoactive effects in the brain are only poorly understood, which is attributable to the alkaloid’s complex pharmacology. Effects on multiple neurotransmitter systems via numerous brain targets have been reported. Among those, ibogaine interacts with neurotransmitter transporters, opioid receptors, sigma receptors, glutamate receptors, and nicotinic receptors in low micromolar concentrations. Long-lasting effects after ibogaine intake are attributed to the alkaloid’s long-lived active metabolite, noribogaine.

Although all efforts to clinically approve ibogaine have failed as yet, NIDA has recently committed financial support for preclinical testing and chemical manufacturing, as well as control work intended to enable clinical trials to develop the synthetic ibogaine congener 18-methoxycoronaridine (18-MC) as a pharmacotherapy for addiction. 18-MC also exhibits anti-addictive effects, and is less toxic in animals than ibogaine.

Ibogaine’s complex pharmacology has a considerable potential to generate adverse effects. Besides neurotoxic actions, ibogaine also affects the cardiovascular system, and, in recent years, alarming reports of life-threatening complications and sudden death cases, temporally associated with the administration of the alkaloid, have been accumulating. It was hypothesised that the above-mentioned sudden deaths cases in humans were related to cardiac arrhythmias. These are most probably associated with ibogaine’s propensity to induce a QT interval prolongation in the electrocardiogram (ECG), which is known to enhance the risk for life-threatening Torsade de pointes (TdP) arrhythmia generation.

Effects on the cardiovascular system

Several indole alkaloids exert effects on the cardiovascular system, and have been or are still used as therapeutic drugs. Among those reserpine has a history as antihypertensive drug, and ajmaline is still approved as an antiarrhythmic medicine. Cardiovascular effects of iboga alkaloids have been known for many years. For example, Tabernanthine, contained in Tabernanthe iboga root bark extracts, induced bradycardia and hypotension in rats and dogs. Low doses of ibogaine didn't change the resting heart rate or blood pressure, but at higher doses ibogaine decreased the heart rate without affecting blood pressure.

In contrast, a significant decrease in heart rate was found in rats already at low ibogaine doses. 18-MC, even at high doses, did not show any apparent effects on either heart rate or blood pressure. Besides these findings on animals, anecdotal evidence suggests that ibogaine can also slow the heart rate in humans. Mash et al. performed intensive cardiac monitoring in 39 human subjects who received single doses of ibogaine for the treatment of cocain/heroin addiction. With dosages in the range of 500–1000 mg, six out of 39 subjects showed a significant bradycardia, and one subject a significant hypotension.

Ibogaine's effects on heart rate

A drug modulating several neurotransmitter systems, such as ibogaine, may generate effects on the cardiovascular system related to its central nervous activity. Further, ibogaine was shown to inhibit voltage-gated calcium channels in rat sympathetic and parasympathetic neurons via sigma receptor activation. This may influence cell-to-cell signalling in autonomic ganglia, and thus the regulation of heart rate by the peripheral nervous system. Interestingly, compared to ibogaine, 18-MC shows significantly less affinity to sigma receptors. If the heart rate is indeed affected by sigma receptor activation, 18-MC will be less effective in this regard.

Ibogaine’s bradycardic action is often related to stimulatory effects of the drug on the cholinergic system. Here, two possible mechanisms were proposed: (1) inhibition of acetylcholinesterase by the drug; and (2) an agonistic action on muscarinic acetylcholine receptors. 18-MC’s affinity for muscarinic receptors is at least two-fold less than that of ibogaine.

A further postulated mechanism by which ibogaine could induce bradycardia is a blockade of voltage-gated sodium channels. Indeed, ibogaine has low micromolar affinity for sodium channels in the brain, and cardiac sodium channel blockers can exert a bradycardic effect. We recently tested ibogaine’s effects on human cardiac sodium channels heterologously expressed in TSA -201 cells. To our surprise we found that low micromolar ibogaine (18-MC) concentrations did not affect Nav1.5 channel currents at all. Consequently, it is unlikely that cardiac sodium channel inhibition by ibogaine significantly contributes to bradycardia generation. However, in this context, the modulation of ion channels, representing major physiological determinants of the heart rate, deserves special consideration.

Ibogaine's effects on cardiac ion channels

Cases of ibogaine-induced QT interval prolongation and associated life-threatening TdP arrhythmias have been accumulating in recent years. The most common reasons for QT prolongation and arrhythmia induction by drugs are modulatory effects on cardiac ion channels. It is therefore noteworthy to look at ibogaine’s effects on ion channels with major importance for electrical impulse conduction in the heart. In this context, we have recently studied the effects of ibogaine and its congener 18-MC on cardiac sodium, L-type calcium, and "human ether-a-go-go-related gene" (hERG), and we found that cardiac sodium and calcium currents are not significantly modulated by ibogaine and its congener 18-MC in a regime of doses normally used to treat human addicts.

The described effects of ibogaine and noribogaine: prolongation and flattening of the human cardiac AP, and relative selective hERG channel inhibition as triggers of QT interval prolongation must be considered proarrhythmic. Moreover, ibogaine’s effects on in vitro cardiac electrophysiology within the drug’s therapeutic plasma concentration range, closely resemble the cardiac actions of formerly approved drugs like cisapride or astemizole, which have been withdrawn from the market because of their propensity to induce TdP arrhythmias.

Here we want to emphasize that not only QT prolongation itself, but also and especially a flattening of the repolarization phase in the AP is considered a proarrhythmic characteristic. Moreover, ibogaine’s effects on in vitro cardiac electrophysiology within the drug’s therapeutic plasma concentration range closely resemble the cardiac actions of formerly approved drugs like cisapride or astemizole, which are known to be unsafe, and have been withdrawn from the market because of their pronounced propensity to induce TdP arrhythmias. Thus, ibogaine, at the doses currently used in humans, must be classified an unsafe drug! Because of its considerably longer half-life in human plasma, ibogaine’s metabolite noribogaine might represent the major proarrhythmic factor. This clearly challenges the idea of noribogaine being considered a potentially safer alternative to ibogaine for anti-addiction medication development.

Risk factors

Based on the findings of the above described experimental studies and case reports on ibogaine’s cardiovascular actions, this section deals with risk factors and their practical impacts for the future application of ibogaine and 18-MC as anti-addiction drugs. First, application of ibogaine, should be done under strict medical observation and continuous electrocardiographic monitoring for an extended time period, which carefully takes noribogaine’s longevity in human plasma into account.

Secondly, prior to ibogaine application one must carefully consider additional risk factors for drug-induced TdP arrhythmias in a patient including female gender, prolonged baseline QT interval, bradycardia, abnormal electrolyte levels, pre-existing cardiovascular disease, ion channel mutations, drug-drug interactions, and genetic variants influencing drug metabolism.

For anti-addiction treatment with ibogaine, two risk factors deserve special attention: bradycardia and hypokalemia. Ibogaine itself induces bradycardia, and hypokalemia is frequent in drug users. Compared with the large number of people who have received ibogaine treatments over many years worldwide, comparably few fatality cases have occurred or have been reported. In addition, drug safety studies on human addicts performed under well-controlled conditions revealed no significant adverse effects.

Baseline screening should include a medical evaluation, physical examination, ECG recording, blood chemistries, haematological workup, and psychiatric and chemical dependency evaluations.
In some cases more extensive evaluations should be performed to rule out cardiac risk factors and to exclude subjects for study entry.

Drug-drug interactions

Addicts often have a long history of substance abuse. Alcohol, heroin, cocaine, benzodiazepines, and methadone are among the abused substances, frequently also combinations thereof. Methadone is also prescribed for opioid substitution therapy. When ibogaine is administered to addicts, the presence of other substances in the patient’s blood plasma is not uncommon. This paves the way for adverse drug interactions.

Concerning the heart, alcohol, cocaine and methadone have been associated with QT interval prolongation. If relevant concentrations of such substances are still residing in the plasma when ibogaine is applied, the drug’s QT prolonging effect, and thus the risk of TdP arrhythmias will be raised. Here, methadone deserves special attention because it additionally has an exceptionally long plasma half-life.

Given that noribogaine has a long half-life in human plasma (1–2 days), the inhibition of its metabolism by other drugs will have strong impacts. Thus, cardiotoxic effects may persist for weeks after intake of a single dose of ibogaine. Therefore, we strongly encourage researchers to determine the pathways involved in the metabolic conversion of noribogaine.

Is 18-MC less cardiotoxic than ibogaine?

Even high doses of 18-MC did not show any apparent effects on either heart rate or blood pressure in animal experiments. We have previously shown that the affinity of 18-MC to human cardiac voltage-gated ion channels is lower than that of ibogaine. In principle, these findings imply a reduced risk for cardiac adverse effects for 18-MC in comparison with ibogaine application. A recent study from Alper’s group also suggested that 18-MC shows lower affinity for hERG channels than ibogaine. Together these studies suggest that compared with ibogaine, 18-MC is less cardiotoxic, and has a lower propensity to induce TdP arrhythmias when applied in similar concentrations.

Conclusions

Due to the longevity of noribogaine—ibogaine’s active metabolite—in human plasma, cardiac adverse events may also occur several days, in some cases weeks after intake of a single dose of ibogaine. Noribogaine, on the other hand, may also convey long-lasting anti-addictive efficacy after ibogaine application.

Future administration of ibogaine to treat addiction may be justified by the urgent medical need for an effective anti-addiction drug. Thus, the use of a drug known to prolong the QT interval must be based on risk-benefit analysis in individual patients. Where benefit outweighs risk, QT prolongation should not limit necessary therapy. Recommendations on prevention and guidelines for the management of drug-induced QT prolongation and TdP in hospital settings can be found in. Two things need to be carefully considered:

(1) Ibogaine application should only take place under strict medical observation and continuous electrocardiographic monitoring over a sufficiently long period of time.

(2) Additional risk factors for drug-induced TdP arrhythmias must be clarified prior to ibogaine application. Eventually, informed consent should be received from drug addicts, in which the risk of ibogaine-induced sudden cardiac death is appropriately highlighted. Based on the rapidly accumulating knowledge about the potentially harmful cardiotoxicity of ibogaine, the responsible medical authorities are now requested to define respective standards and exclusion criteria to allow for a safer ibogaine anti-addiction therapy in the future.

18-MC is likely associated with a reduced risk of TdP arrhythmia induction, and we encourage researchers to develop ibogaine-like drugs with preserved anti-addictive properties, but negligible hERG affinity, and thus absent TdP arrhythmia risk.

*From the study here: https://www.ncbi.nlm.nih.gov/pmc/art...emss-62840.pdf
 
Ibogaine has no legs because it cannot be patented, the use patent is also unavailable and the companies working on addiction therapeutics have already gone down the blind alley of substitution therapy, companies like Indivior are literally making a killing, and to ensure they continue making a killing they have bought off all the regulators. This is just the tip of the iceberg.

Indivior shares fall 30% after abrupt shift in US market conditions

Addiction treatment specialist scraps revenue guidance for financial year

Katie Martin and Sarah Neville July 10, 2018

Shares in addiction treatment specialist Indivior fell by 32% in early trading on Wednesday after the company warned shareholders that its guidance for this financial year was “no longer valid” after an abrupt shift in US market conditions.

The UK pharmaceuticals company said it was now “seeing the impact” of a generic rival to its opioid addiction treatment Suboxone Film, sold in the US by Indian group Dr Reddy’s Laboratories, which it is seeking to halt through the courts. The impact on revenue could be $25m for the 2018 financial year, Indivior said. The UK company also expects a minimum $50m revenue hit from discounting in generic tablets.

It said that it could not “reliably provide updated full-year 2018 net revenue and adjusted net income guidance until the impact of Dr Reddy’s launch is better understood”.

The company said it expected that this would be no later than its third-quarter results announcement scheduled for November 1. Indivior added that it also “continues to await a ruling from the US District Court for the District of New Jersey on Indivior’s motion for a preliminary injunction against Dr Reddy’s”.

Shaun Thaxter, chief executive, said it was continuing to monitor developments in the US market to gauge the impact of Dr Reddy’s launch. It knew that its rival was “skilled in rapid distribution in quantity and, as such, there is a range of uncertainty around the amount of product they were able to ship” before a temporary restraining order [TRO] had been granted by the court in June.

Indivior was “looking at cost saving opportunities, initially targeting at least $25m in cost savings in 2018, to partially offset the financial impact of these developments”, added Mr Thaxter.

https://www.ft.com/content/f916d6f2-84d0-11e8-96dd-fa565ec55929
 
^ Indivior has a restraining order against Dr Reddy preventing sale of the generic, which is complete abuse of the regulatory system.

Their sales last year of buprenorphoine in the USA was north of 1 bn dollars, this bear in mind is not their drug, it is long out of patent and they did fuck all work on developing it. They are raking it in and trying every underhand move they can think of to keep the money flowing.
if the Indivior share price crashed to zero it would still be more than they are worth.

Teva the other generic manufacturer who is launching a generic buprenorphine has agreed with Indivior to hold off launching, which is bullshit anti competitive behaviour. Teva are not exaclty paragons of virtue at the best of times, and there is often a stench of anti competitive behaviour around their operations

People wonder why a common prevailing opinion of Pharma is it is a moneymaking racket with some positive health outcomes as an unfortunate unintended side effect.
 
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Indivior shares drop for second day as hopes for nextblockbuster drug dim
Sept 27 (Reuters) - Shares of Indivior fell for a secondstraight day, as prospects for the British drugmaker’s new potentialblockbuster drug waned, months after revealing that its former market-leadingopioid addiction drug lost market share to a generic rival. T
he company sharply lowered guidance for itsrecently-launched once-monthly injection Sublocade on Wednesday, citing furtherdelays in getting the drug to patients, while also announcing a new set oflower full-year expectations for total revenue and earnings... via reuters ..
 
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hERG Blockade by Iboga Alkaloids


Alper K, Bai R, Liu N, Fowler SJ, Huang XP, Priori SG, Ruan Y

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, Torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine or by extraction from T. iboga; ibogaine's principal metabolite noribogaine; and voacangine. In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 uM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 uM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

https://www.ncbi.nlm.nih.gov/pubmed/25636206
 
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Howard Lotsof


Credit for discovering ibogaine’s medicinal potential is widely attributed to Howard Lotsof. Ten years before the events that gave rise to Fear and Loathing, Lotsof was a junkie living in New York. Having bought some ibogaine for recreational use, Lotsof was astounded to find that when the drug wore off, he no longer craved heroin. Days passed, and he didn’t experience any of the excruciating symptoms associated with kicking a dope habit.

Lotsof, who died in 20101 of liver cancer at age 66, devoted his life to making ibogaine available as an addiction treatment. But he experienced a significant setback in 1967, when the U.S. government banned the drug, along with several other psychedelics. In 1970 officials categorized ibogaine as a Schedule I substance—on par with heroin, marijuana, and other drugs that, by definition, have "a high potential for abuse" and "no currently accepted medical use."

By the late ’80s, doctors and scientists were confirming what Lotsof knew: Ibogaine blocks cravings and withdrawal symptoms for many types of drugs, and opiates in particular.

"Its effects are pretty dramatic," says Dr. Kenneth Alper, an associate professor of psychiatry at New York University who specializes in addiction research. "I’ve observed this firsthand,
and it’s difficult to account for.“



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Dr. Stanley Glick


Dr. Stanley Glick, a pharmacologist and neuroscientist at Albany Medical College, was among the first researchers to test ibogaine on rats. Glick hooked up the rodents to IVs in cages with levers that allowed them to inject themselves with morphine.

"If rats do it, you can be pretty sure that humans will, too, given the opportunity," Glick explains. "It’s really the time-tested model of any human behavior."

Strung-out rats dosed with ibogaine stopped pressing the lever that gave them morphine. Glick and other researchers have subsequently replicated the morphine results with other addictive drugs, including alcohol, nicotine, cocaine, and methamphetamine.

In the early 1990s, Lotsof teamed with Dr. Deborah Mash, a neurologist and pharmacologist at the University of Miami, to study the effect of ibogaine on people. Mash was granted FDA approval to administer ibogaine in 1993 and was able to test the drug on eight people before the experiment came to an abrupt halt.

"I was unable to get it funded," Mash says. "We had the rocket ship on the launch pad, with no fuel."

A few months after the FDA gave Mash the green light, a committee of academics and pharmaceutical-industry professionals assembled by the National Institute on Drug Abuse (NIDA) concluded that the U.S. government should not fund ibogaine research. Earlier that year, a researcher from Johns Hopkins University had found that rats injected with massive doses of ibogaine suffered irreparable damage to the cerebellum, the part of the brain that controls balance and motor skills. According to Dr. Frank Vocci, former director of treatment research and development at NIDA, "The fact that ibogaine increases the risk of seizures for people addicted to alcohol or benzodiazepines such as Valium raised eyebrows as well."

"The question that was posed to them was, 'Do you think that this could be a project that could result in, essentially, a marketable product?' " Vocci recalls. "There was concern about brain damage, seizures, and heart rate. But it wasn’t so much that the safety of the drug was being damned, it was just felt that there were an awful lot of warts on this thing."

Mash and Lotsof soon parted ways, on unfriendly terms. Lotsof sued his former colleague and the University of Miami in federal court in 1996, claiming that her research had infringed on his patent. A judge eventually ruled in favor of Mash and her employer, absolving them of wrongdoing.


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Dr. Deborah Mash


Mash opened a private clinic on the Caribbean island of St. Kitts and administered ibogaine to nearly 300 addicts. "It really works,“ Mash says. "If it didn’t work, I would have told the world
'It doesn’t work.' I would have debunked it, and I would have been the most outspoken leader of the pack. My scientific and professional credibility was on the line.“

Mash had devised two ways to isolate the metabolite noribogaine and administer it: a pill, and a patch similar to the nicotine variety.

"It has all the benefits without the adverse side effects—and no hallucinations," Mash says. "I spent a lot of years really pushing ibogaine as far as I could, both in preclinical and clinical studies. But everything that I’ve learned in the course of 18 years of working on ibogaine has convinced me that the active metabolite is the drug to be developed."

---

Glick, meanwhile, teamed up with a chemist named Martin Kuehne from the University of Vermont to create and research a chemical called 18-MC (18-methoxycoronaridine) that mimics ibogaine’s effect on a specific nicotinic receptor. Just like ibogaine, 18-MC appears to work wonders on drug-addicted rats.

"Cocaine, meth, nicotine, morphine—we did the same studies with 18-MC, and it worked as well or better than ibogaine," Glick says. "We also have data that it will be useful in treating obesity. In animals, it blocks their intake of sweet and fatty foods without affecting their nutrient intake."

Glick and his cohorts have yet to determine whether their synthetic ibogaine has psychedelic properties. The rats, after all, aren’t talking.

"You look at an animal given ibogaine, and you can’t tell if they’re hallucinating. But they look strange," Glick says. "You give them 18-MC and you can’t really tell. But we hope when it gets to people, it won’t produce psychedelic effects."

The first human testing of 18-MC is scheduled to begin later this month in Brazil. But scientists there won’t be studying its effect on addiction. They’ll be investigating the drug’s potential as a cure for the parasitic infection Leishmaniasis, an affliction similar to malaria that is common in tropical climates. Through pure coincidence, 18-MC is chemically similar to other drugs that are used to treat the disease.

The Americans jumped at the chance to test their product in South America. Although 18-MC has shown promise and no observable side effects in animals, not a single pharmaceutical company has shown interest in developing it as an anti-addiction product.

"We are fortunate we have this other disease apart from addiction, where we know it can be tested," says Kuehne, a veteran of big pharma who worked for Ciba (a predecessor of Novartis). "Pharmaceutical companies don’t like cures. Really, they don’t—that’s the sad thing. They like treatment. Something for cholesterol or high blood pressure that you take for years and years, every day. That’s where the profit is."

Further complicating matters is the fact that 18-MC has proven difficult to manufacture. Obiter Research, a company based in Champaign, Illinois, that specializes in synthesizing experimental chemicals, spent nearly two years refining the process before successfully creating about 200 grams of the substance—just enough to send to Brazil to be administered to human subjects.


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Bill Boulanger


"Imagine a Tinkertoy Ferris wheel,"
says Bill Boulanger, Obiter’s CEO and a former chemistry professor at the University of Illinois. "It’s like taking that apart, then trying to use half of the parts to build a fire engine. Ibogaine is a natural product, and sometimes Mother Nature does a better job than the lab."

Boulanger is convinced there’s money to be made from 18-MC. With Obiter, he plans to patent the manufacturing process and secure intellectual-property rights. He and two partners also created a separate company, Savant HWP, in hopes of eventually opening addiction clinics across the United States that administer 18-MC in conjunction with conventional rehab techniques such as 12-step programs.

"One part is resetting the trigger that’s saying, 'Oh, I’ve got to have it,' " Boulanger says. "That’s helping the people fight withdrawal, and that would be part of the whole operation. But it’s just one facet. It’s got to be holistic. Just handing out a pill and sending them on their way is a bad idea."

---

The notion of hallucination-free ibogaine, however, rubs the drug’s die-hard supporters the wrong way. Many believe the "visions" ARE THE CURE...

"With methadone, they just removed euphoria from opiates," says Dimitri "Mobengo“ Mugianis. "This is the same process they’re doing now—removing the psychedelic and visionary experience. Ibogaine works. What are they trying to improve or fix? It’s not broken, and they’re spending a great amount of time and money to fix it."

A former heroin addict, Mugianis is an underground ibogaine-treatment provider. He kicked his habit with the help of ibogaine administered at Lotsof’s clinic in Holland. The experience was so extraordinary that Mugianis was inspired to travel to Gabon to be initiated into the native Bwiti religion and was trained by local shamans. He says he has performed more than 400 ritualistic ceremonies on addicts, most of them in New York City hotel rooms, using ibogaine and iboga root bark.

Despite his strong belief in the power of ibogaine, Mugianis does not see it as a miracle cure for addiction.

"The 12-step approach really helped in combination with ibogaine," he says. "I say it interrupts the physical dependency, because that’s what it does. There’s no cure. It’s not a cure. It allows you a window of opportunity, particularly with opiate users."

Efforts are afoot to legalize—or at least legitimize—ibogaine in the United States. Convincing doctors and elected officials to support a potent, occasionally lethal psychedelic can be a tough sell. That pitch becomes doubly difficult when some of the ibogaine enthusiasts themselves inspire skepticism.

One of ibogaine’s most outspoken advocates is Dana Beal. An eccentric character who helped found the Yippies in the 1960s, Beal sports a bushy white mustache that inspired a New York Times reporter to liken him to "a Civil War-era cavalry colonel." Beal travels the country giving PowerPoint presentations touting the benefits of ibogaine and medical marijuana.

In June 2008, he was arrested by police in Mattoon, Illinois, and charged with money laundering. He was carrying $150,000 in cash in two duffel bags, money he claims was going to finance an ibogaine clinic and research center in Mexico. Beal maintains his innocence and is free on bail as the case heads to trial.

"It’s folks like Beal," says pharmacologist Stanley Glick, "who keep ibogaine and 18-MC from being embraced by the medical mainstream."

"Some of my colleagues, as well as funding agencies, lump us together without really considering the data," Glick says. "There’s a lot of baggage that comes with ibogaine, some of it warranted, some of it unwarranted. It’s really a stigma. Drug abuse itself has a stigma, and unfortunately so does ibogaine. It has really hurt the science."

Beal shrugs off the criticism, arguing that grassroots activism is the only way to ensure that politicians will endorse ibogaine. Besides, he adds, the government stopped funding ibogaine research long before he was arrested.

"The scientists think if they stay away from us activists, NIDA will bless them," says the self-styled rabble-rouser. "NIDA is not blessing them. They’re washed up and on a strange beach.
How will they get FDA-approved clinical trials without activists? Explain to me a way that works, and I will do it."


Beal jokes that the best advertisement for ibogaine might be an episode from the 11th season of Law & Order: Special Victims Unit in which a heroin addict who needs to testify in court is administered ibogaine to make his withdrawal symptoms disappear overnight. "Maybe Congress will watch SVU and say, 'Maybe we should check this out—wow!—it works for methamphetamine, too?' " he says sarcastically.

Ibogaine’s effectiveness against meth has already helped it gain acceptance abroad. Lawmakers in New Zealand, where meth use has skyrocketed in recent years, recently altered the nation’s laws to allow physicians to prescribe ibogaine. Dr. Gavin Cape, an addiction specialist at New Zealand’s Dunedin School of Medicine, says the nation’s doctors are so far reluctant to wield their new anti-meth weapon.

"There are no true controlled studies to give evidence as to its safety and effectiveness," Cape says. "There is a strong advocacy group in New Zealand for ibogaine, and it may turn out to have a place alongside conventional therapies for the addictions, but I’m afraid we are a few years away from that goal."


KennethAlper.jpg

Dr. Kenneth Alper


Last month, dozens of ibogaine researchers, activists, and treatment providers gathered for a conference in Barcelona, where topics included safety and sustainable sourcing of ibogaine from Africa. Dr. Kenneth Alper was among the attendees who gave a presentation on the benefits of ibogaine to the Catalan Ministry of Health. The NYU prof believes ibogaine’s most likely path to prominence in the United States will be as a medication for meth addiction, for the simple reason that doctors and treatment providers have found that small daily—and thus drug-company-friendly—doses seem to work better for meth addiction than the mind-blowing "flood doses" used on opiate addicts.

Alper says no one thought to try non-psychedelic quantities of ibogaine until recently. Ibogaine treatment providers tend to have been former ibogaine users, and most assumed that the introspection brought on by tripping was key to overcoming their addictions. "That’s just how it evolved," he says, noting that the large doses do seem to work best for opiate detox. "You’re talking about a drug that has been used in less than 10,000 people in the world in terms of treatment. It’s not surprising that’s how it evolved."

"The visions have some psychological content that is salient and meaningful," Alper adds. "On the other hand, there is no successful treatment for addiction that’s not interpreted as a spiritual transformation by the people who use it."

*From the article here: https://exilope.wordpress.com/tag/treatment/
 
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The notion of hallucination-free ibogaine, however, rubs the drug’s die-hard supporters the wrong way. Many believe the "visions" ARE THE CURE...

I am one of them: The “hallucinations” ARE the cure. And I think it is actually wrong to call Iboga visions “hallucinations” in the sense of other psychoactives. a historical confusion from the 60-70s I guess. They're more like recollection, memory retrieval of actual people,events and situations that happened in one's life that are relevant to the issue(s) the person is seeking to address with Ibogaine treatment. Those memories may show up in emotionally charged symbolic (and very personal) forms sometimes, as in normal dreaming. Only difference with normal dream state is the subject is in total control. Just open your eyes and they cease. So if one were to call iboga visions “hallucinations” then in that case every person on earth, every single night for at least 2-4 hours experience Iboga-type“hallucinations” in the form of dreams.
The “brain re-setting” of whatever issues the subject seeks to address takes place during this psychological introspection, “dreaming”period.

So I guess Ibogaine will never be approved by the FDA since its therapeutic effects are the “hallucinations” and FDA and the establishment don't want hear anything about drug-induced “hallucinations”. The one Ibogaine analog that they may approve like 18-MC, purportedly reported as non “hallucinogenic”) will probably not work like Ibogaine imho. It may work for withdrawal symptoms but then again it's pretty easy to get a drug to do that: NMDA antagonists like memantine or mecamylamine work fine for acute PAWs or adrenergic ligands like lofexidine. But afaik, they do not promote long term abstinence which Ibogaine does IN ADDITION to eliminating PAWs during acute phase before the psychological introspective phase which can last 24-72 hours or more following ingestion.

So yes, the so-called Iboga “hallucinations” are the cure imho. That's what most people (80%+!?) who benefit from Iboga said helped them resolve whatever issues they may seek to address (addiction, spiritual, depression, ptsd..etc). The psychological introspection experience phase is the key. There is no reasons not to believe them even though the neuroscientific establishment tend to dismiss that since they can't really figure out how a molecule can do that. Unlike other psychedilics like LSD where it is clear cut: you activate central 5-HT2a receptors you get a psychedelic response. Simple as that.

With Iboga-type alkaloids, it is much more complex: for one,it doesnt bind to 5HTR with any meaningful affinity, neither to a whole hosts of receptors targeted by psychoactives like the NMDA, opioid or monoamines neurotransmission system. Imho, a candidate Ibogaine target(s) is to be found among central cholinergics (nicotinic or muscarinic). Not necessarily the a3b4 as there are “tons”of different cholinergic receptors subtypes made up of different combinations of alfa and beta subunits to yield a bunch of different polymeric ion channels (a4b2, a3b4, a7...etc etc) each with very important specific brain functions involved in memory, sleep, dream, cognition, ..etc. To make matter worse, not only some are selectively expressed in very specific brain (and soma!) areas but each may also be upregulated or downregulated depending on prior exposure to substances, mood of the subject at the time or even simply “site and setting”. Imho, somehow Ibogaine hits one or several of as yet unknown cholinergic targets.. Too bad the molecule is illegal in lots of countries so we may not know which one and how it interacts with it in the near future... At the very least, the drug should be classified schedule II by FDA, NIH..Big Brother..etc so research can be done
 
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Ibogaine inhibits hERG channels: A cardiac arrhythmia risk!

Xaver Koenig, Michael Kovar, Stefan Boehm, Walter Sandtner, Karlheinz Hilber

Ibogaine, an alkaloid derived from the African shrub Tabernanthe iboga, has shown promising anti-addictive properties in animals. Anecdotal evidence suggests that ibogaine is also anti-addictive in humans. Although not licensed as therapeutic drug, and despite evidence that ibogaine may disturb the rhythm of the heart, ibogaine is currently used as an anti-addiction drug in alternative medicine. Here we report that therapeutic concentrations of ibogaine reduce currents through human ERG potassium channels. Thereby, we provide a mechanism by which ibogaine may generate life-threatening cardiac arrhythmias.

In preclinical studies on animals, ibogaine, an indole alkaloid derived from the root bark of the African shrub Tabernanthe iboga, has shown promising anti-addictive properties: ibogaine attenuates opioid withdrawal signs and reduces the self-administration of a variety of drugs including opioids, cocaine, nicotine, and alcohol. The inhibition of dopamine release in the nucleus accumbens as essential part of the brain’s reward systems offers an explanation for ibogaine’s anti-addictive actions. The underlying molecular mechanisms may involve interactions with neurotransmitter transporters as well as opioid and glutamate receptors, effects that have been observed at ibogaine concentrations between 0.1 and 30 uM.

Since ibogaine interacts with numerous different cellular and molecular targets, its potential to generate adverse effects is significant. Besides the expected neurotoxic actions, ibogaine also affects the cardiovascular system. In both animals and humans, high doses of ibogaine decrease the heart rate. Alarming are several reported cases of sudden deaths with unclear cause after ibogaine use, which have been hypothesised to be related to cardiac arrhythmias. In accordance with this hypothesis, a severely prolonged QT interval of the electrocardiogram (ECG), associated with ventricular tachyarrhythmias, was observed in a 31-year-old woman after she had taken a single dose of ibogaine.

Here, we provide first experimental evidence on the mechanism by which ibogaine may generate life-threatening cardiac arrhythmias: inhibition of human ERG (hERG) potassium channels in the heart. Conducting the rapid component of the delayed rectifier potassium current IKr, hERG channels are crucial for the re-polarisation phase of cardiac action potentials. hERG current reduction, either due to genetic defects or blockade by drugs, delays cardiac repolarisation resulting in QT interval prolongation and in an increased risk for torsade de pointes arrhythmias and sudden cardiac death. Consequently, hERG channel blockade has become a common reason for drug failure in pre-clinical safety trials.

We show in Fig. 1 below that ibogaine reduces currents through hERG channels, heterologously expressed in TSA-201 cells, in a reversible and concentration-dependent manner. The ibogaine concentration required to inhibit the current by 50 % (IC50) was 4 uM. Drugs with little or no margin between their therapeutic plasma concentrations and their IC50 values for hERG inhibition delay cardiac repolarisation. Ibogaine plasma concentrations in humans are in the low micromolar range after single oral doses of 500-1000 mg, doses that are typically employed to treat drug addicts (10-25 mg/kg of body weight). Hence, our finding of hERG channel blockade by low micromolar ibogaine concentrations explains the previously published case report of QT interval prolongation after ibogaine intake. Moreover, drugs that have their IC50 values for hERG inhibition in the range of their therapeutic plasma concentrations, such as astemizole, cisapride, and terodiline, have been withdrawn from the market because of their high propensity to cause Torsade de Pointes arrhythmias. As the same holds true for ibogaine, the use of this indole alkaloid in humans is highly risky. Ibogaine derivatives with reduced propensity to block hERG channels but preserved anti-addictive properties need to be developed.


emss-59627-f001.jpg


A) Typical whole cell currents through hERG potassium channels heterologously expressed in a TSA-201 cell. Currents elicited by the pulse protocol on top under control conditions, after steady-state block with 10 uM ibogaine, and after wash out are displayed. In addition, typical endogenous currents of an untransfected TSA cell are shown. hERG currents were recorded at
22 +/- 1.5 degrees C using the whole-cell patch clamp technique as in our earlier work. In this study, the hERG channel blocker sotalol was used to validate the expression system employed.

B) Concentration-response curve for the reduction of hERG tail currents by ibogaine. The inset shows the pulse protocol applied at a frequency of 1 Hz. Tail current peaks are plotted against ibogaine concentrations. Values are means +/- SD (n = 4-17). The solid line represents a sigmoidal fit to the data points; Hill coefficient: 0.81 +/- 0.04; IC50 value: 3.9 +/- 0.3 uM.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888945/
 
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