Non-cardiotoxic Ibogaine psychedelic analogs

[mr peabody]

hERG Blockade by Iboga Alkaloids


Synthesis of new series of iboga analogues*

Sibasish Paul, Sankha Pattanayak, Surajit Sinha

The iboga-alkaloids are naturally occurring indole alkaloids, which are found in a variety of African shrubs of the Tabernanthe genus. Members of this family of alkaloids combine the structural features of indole and isoquinuclidinyl ring fused by a seven-membered indoloazepine ring. Anti-addictive properties of ibogaine have been known for decades. Apart from their anti-addictive properties, iboga-alkaloids and their congeners show a wide variety of pharamacological effects, auch as antifungal or antilipase, anti-HIV-1, anti-cholinesterasic and leishmanicide activities (against Leishmania amazonensis). However, the clinical application of ibogaine is limited because the natural ibogaine is tremorigenic, and neurotoxic, particularly due to the degeneration of brain cells (purkinje cells) if the dose is high. Chemical modifications of iboga-alkaloids have been reported in order to have more potent analogues or congeners. So far a limited number of its analogues 6a–d and congeners 6e–g have been accessible.

In the continuation of our research towards the synthesis of iboga-alkaloids, we describe herein the synthesis and characterization of iboga-analogues and replacing the indole ring with a benzofuran moiety. The benzofuran moiety was chosen because it is a bioisostere of indole, the pharmacological properties might be unchanged and the synthesis of this compound could be easier than the natural ibogaine as benzofuran does not require anyprotection like indole. Moreover these compounds are expected to be more stable than the natural ibogaine which is heat and light sensitive and spontaneously oxidize in solution.

In summary, we have reported the synthesis of benzofuran-analogues of iboga alkaloids. Our synthetic approach is non-biochemical, extremely short, flexible and also anticipated that minor modifications of the starting materials (phenol and alkyne) should provide access to several other analogues of this alkaloid family for biological screening. Also functional group transformation of C 19 ester can provide us the true SAR to optimize the potency and efficacy of the analogues. Conversion of endo-6-substituted dehydroisoquinuclidine into its exo-isomer, a key component of iboga-alkaloids has been achieved.

*From the article here: https://kundoc.com/pdf-synthesis-of-new-series-of-iboga-analogues-.html

 

[DotChem]

^^ The issues of cardiovascular side-effects(hERG blockade) is a more serious issue than the so called “hallucinations”. But even that is actually overblown. Those side-effect happens only at high “flood”doses to people with pre-existing heart problems. Actually, lots of pharmaceuticals now on the market have hERG liabilities, some like OTC loperamide much worse than high dose Ibogaine. And so is methadone which also is a hERG substrate with higher risks of cardiac QT interval prolongation than Ibogaine..

But nevertheless, it would be interesting to have Ibogaine derivatives without hERG liabilities. As I mentioned in the OP before, I heard a Canadian company has come up with Iboga type isoquinuclidines compounds (structure undisclosed afaik) that do not haveI bogaine hERG cardiovascular issues but have same spectrum of psychoactivity otherwise. Can't wait to see that hit the market. I know the Chinese are working on synthetic Iboga analogs especially total synthesis so maybe we'll see safer and cheaper Ibogaine derivatives from China on the market very soon.

^^ This method is adaptation of the rather old Barry Trost synthesis of Iboga-type isoquinuclidines. So far I have yet to see any meaningful improvement over that route. Probably the only one with potential to be commercially viable..:

Trost BM, Godleski SA, Genet JP. J. Am. Chem. Soc. 1978;100:3930

This one above is of the unnatural enantiomer of Ibogamine. But you can see that starting with the other enantiomer of the diene, it will give you Ibogamine. Likewise, starting with commercial 5-methoxyTryptamine instead of Tryptamine will stereoselectively give you all stereoisomers of Ibogaine..Or like this paper above did, starting with benzofuranylethylamine (benzofuran congener of tryptamine) to get benzofuran congeners of ibogaine. But then again, it is so cheaper to just extract Iboga alkaloid from plants. Advantage of synthetic methods is one can play around and synthesize lots of analogs, like with different substituted tryptamines, benzofurans, benzothiophen, naphthyl.. etc etc
​

 

[mr peabody]

DemeRx (Dr. Deborah Mash et. al.) recently filed for Chapter 11 protection in South Florida Bankruptcy Court from claims amounting to $2m.

 

[DotChem]

DemeRx patent for their clinical candidate compound Noribogaine is rather weak.. pretty hard to enforce. Noribogaine is the O-desmethyl metabolite of Ibogaine with no real clinical advantage over the parent drug. It has similar (actually more) cardiovascular problems than Ibogaine iirc. So "just use Ibogaine"! If at least, it has better cardiovascular safety profile than the parent drug Ibogaine, then may be they convince the FDA for approval of clinical trials. Demerx compound has to compete with plain generic Ibogaine-HCl for which clinical trials are underway in Brazil (where it is legal). hard to convince investors to pour money for more clinical studies..

​

Ibogaine in the Treatment of Alcoholism: a Randomized, Double-blind, Placebo-controlled, Escalating-dose, Phase 2 Trial https://clinicaltrials.gov/ct2/show/NCT03380728?term=Ibogaine&rank=1

Brief Summary:


Approximately 5% of the world's adult population has some alcohol-related disorder, which in addition is associated with 3% of all deaths in the world. In Brazil, harmful use and dependence on alcohol reach about 10% of the population, with alcohol being one of the main factors of disease and mortality. Although the medications currently used have some efficacy, the adverse effects and relatively long time of treatment are factors that may reduce patients' motivation to continue taking the medication correctly. Therefore, it is necessary to conduct research with new drugs for the treatment of alcoholism.

Ibogaine is an alkaloid present in the bush Tabernanthe iboga (iboga), a plant from Central Africa traditionally used in countries such as Gabon and Cameroon. Animal studies and case series suggest that one or a few doses of ibogaine significantly reduce withdrawal symptoms and the intensity of use of various drugs, including opioids, psychostimulants, and alcohol. However, there are no controlled clinical studies that have explored these effects. The aim of the present study is to evaluate the safety, tolerability and efficacy of increasing doses of ibogaine in 12 alcoholic patients. Each patient will be hospitalized for 20 days and receive 3 increasing doses of ibogaine. The first 3 patients will receive oral doses of 20 to 400 mg of ibogaine in an open-label design. If the 3 higher doses (240, 320 and 400 mg) are well tolerated, the next 9 volunteers will receive these doses or placebo randomly. The volunteers will also be evaluated 7, 14 and 21 days and 1, 3, 6 and 12 months after leaving the hospital to monitor the consumption of alcohol and other drugs.

​

 

[mr peabody]

How toxic is ibogaine?

Litjens RP, Brunt TM

Ibogaine and noribogaine interact with multiple neurotransmitter systems, and show micromolar affinity for N-methyl-D-aspartate (NMDA), K- and u-opioid receptors and sigma-2 receptor sites. Furthermore, ibogaine interacts with the acetylcholine, serotonin and dopamine systems, and it alters the expression of several proteins including substance P, brain-derived neurotrophic factor (BDNF), c-fos and egr-1.

NEUROTOXICITY:

Neurodegeneration was shown in rats, probably mediated by stimulation of the inferior olive, which has excitotoxic effects on Purkinje cells in the cerebellum. Neurotoxic effects of ibogaine may not be directly relevant to its anti-addictive properties, as no signs of neurotoxicity were found following doses lower than 25mg/kg intra-peritoneal in rats. Noribogaine might be less neurotoxic than ibogaine.

CARDIOTOXICITY:

Ether-a-go-go-related gene (hERG) potassium channels in the heart might play a crucial role in ibogaine's cardiotoxicity, as hERG channels are vital in the repolarization phase of cardiac action potentials and blockade by ibogaine delays this repolarization, resulting in QT interval prolongation and, subsequently, in arrhythmias and sudden cardiac arrest. 27 fatalities have been reported following the ingestion of ibogaine, and pre-existing cardiovascular conditions have been implicated in the death of individuals for which post-mortem data were available.

TOXICITY FROM DRUG-DRUG INTERACTION:

Polymorphism in the CYP2D6 enzyme can influence blood concentrations of both ibogaine and its primary metabolite, which may have implications when a patient is taking other medication that is subject to significant CYP2D6 metabolism.

CONCLUSIONS:

The case reports presented here suggest that ibogaine caused ventricular tachyarrhythmias and prolongation of the QT interval in individuals, without any pre-existing cardiovascular condition or family history. Noribogaine appears at least as harmful to cardiac functioning as ibogaine.

Alternative therapists and drug users are still using iboga extract, root scrapings, and ibogaine HCl to treat drug addiction with limited medical supervision. These are risky experiments and more ibogaine-related deaths are likely to occur, particularly in those with pre-existing cardiac conditions and those taking concurrent medications.

https://www.ncbi.nlm.nih.gov/pubmed/26807959

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Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

M.L. De Bruin, M. Pettersson, R.H.B. Meyboom, A.W. Hoes, H.G.M. Leufkens

Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice.

All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, Torsade de Pointes, ventricular fibrillation, and ventricular tachycardia, and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 between the anti-HERG activity of drugs, measured as log10, and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database.

Conclusion: Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.

Introduction

Drug-induced prolongation of the QTc-interval usually results from concentration-dependent blocking of cardiac HERG potassium channels.1,2 An excessively prolonged QTc-interval can, under the right circumstances, lead to a polymorphic ventricular arrhythmia known as Torsade de Pointes (TDP). When TDP is sustained, symptoms arising from impaired cerebral circulation, such as dizziness, syncope, and/or seizures, may become manifest. TDP can subsequently degenerate into ventricular fibrillation and, not uncommonly, cardiac arrest or sudden death may occur. It is not clear what percentage of TDP arrhythmias are non-sustained and what percentage degenerate into ventricular fibrillation. Over the last decade, this adverse reaction has attracted considerable clinical and regulatory interest and has been the most common cause of withdrawal, or restriction of the use, of drugs on the market.

Consider’ document which made recommendations for non-clinical and clinical approaches to assess the risk of QTc-interval prolongation and TDP for non-cardiovascular drugs. The strategies described are now being harmonized by the International Conference of Harmonization (ICH), and a draft version of the ‘Note for Guidance’ document is currently available. Based on these regulatory recommendations, most new drugs are tested nowadays for their ability to block HERG potassium channels and rapid potassium currents (IKr). However, there is still much debate going on within the pharmaceutical industry, as well as regulatory authorities, on the predictive value of HERG channel binding and the risk of cardiac arrhythmias. For example, collaborating researchers from several pharmaceutical industries recently published an extensive overview of 100 QTc-prolonging drugs and their ability to bind to HERG-channels in relation to free-plasma concentrations.

These authors related this anti-HERG activity to the tor-sadogenic propensities of the drugs. Drugs were assigned to one of the following five categories of decreasing tor-sadogenicity: (i) anti-arrhythmic drugs, (ii) drugs withdrawn or suspended due to TDP risk, (iii) drugs with measurable TDP risk in humans or many TDP case reports in published literature, (iv) isolated TDP case reports, and (v) no published reports of TDP in humans, but with a certain degree of suspicion because of, for example, therapeutic class, drug interactions, etc. The clinical relevance of this type of categorization, however, remains to be confirmed.

Previously, several studies have shown that female gender is a rather strong predictor for drug-induced TDP, since 70% of the published case reports concerned women. In the present study, we found that (of the ADR reports with known gender of the patient) 56% of the case patients were female, compared with 58% of the patients experiencing other ADRs. We used, however, a composite endpoint which included, apart from TDP: cardiac arrest, sudden death, ventricular fibrillation, and ventricular tachycardia. When we focused solely on the ADR-reports of TDP, we found that more than 68% of these reports concerned females.

General limitations of the dataset should be discussed. First, the study was restricted to drugs for which HERG binding properties as well as therapeutic free plasma concentrations have been studied, and published. The number of drugs being tested for HERG-activities is still increasing and these analyses should be repeated when more data are available. Secondly, the ETCPunbound/1C50 ratios were based on therapeutic plasma levels at recommended doses. The case reports in the WHO-UMC database, however, do not disclose in sufficient detail the doses used by these patients. Plasma Levels may increase when pharmacokinetic drug–drug interactions occur or alternative routes of administration are used. Specific anti-HERG activities were onLy known for terfenadine plus CYP3A4 inhibitors, and iv erythromycin. Uncertainty of actual plasma levels may have influenced our results.

The method of reaction proportion signalling has several drawbacks. ADRs were reported on a voluntary basis, and therefore represented only a fraction of the actual adverse events that occurred. Selective under- and over-reporting of particular ADRs within the overall under-reporting can Lead to misinterpretations when comparing drugs with respect to ADRs. ADRs which are more likely than others to be reported are ADRs of relatively new drugs severe ADRs, and ADRs which are not listed in the summary of product characteristics. All these aspects can be seen in the subgroup analyses we performed. The association was stronger shortly after marketing, and it was Less well pronounced among patients taking anti-arrhythmic drugs, for which the pro-arrhythmic side-effects have been already described. The association weakens when the study event is Less severe (syncope vs. ventricular arrhythmia). Another factor which may have influenced our results is selective reporting as a result of media attention. This factor has been described previously for the association between cardiac arrhythmias and the use of anti-histamine drugs, and similarly in our study the association between exposure and outcome is stronger after 1 January 1998 than before.

We did not, of course, study the effects of individual drugs, but the in vitro anti-HERG activities of drugs, and combinations of drugs. These molecular properties of drugs are unlikely to be known by healthcare providers in daily practice. We therefore think that we have used a more objective exposure measure, which is less susceptible to recognized bias. Moreover, all sub-group analyses point in a similar direction and negative control outcomes which should not be reLated to anti-HERG activity (hepatitis, skin ulcer) are indeed unrelated to the exposure. We therefore believe that our findings represent a true connection.

There were several drugs that appeared not to follow the predicted association. Their observed cases/non-cases ratios were relatively high or Low compared with the ratios fitted by our logistic model. For ibutilide, bepridil, amiodarone, sotalol, and flecainide, the cases/non-cases ratio is higher than expected. These drugs are prescribed to patients with cardiac diseases and therefore ‘confounding by indication’ may have caused this relatively high fraction of ‘case-events’. In addition, only less than 200 case reports were used to estimate the ratio for ibutilide and bepridil. Slightly more than 300 case reports were used to estimate the cases/non-cases ratio for combination of terfenadine and CYP3A4 inhibiting drugs. This relatively high ratio may have been caused by selective reporting of ADRs due to media attention for cardiac arrhythmias associated with the combined use of these drugs.

For ketoconazole, mefloquine, and aprindine the fraction of ‘case-events’ in the WHO-UMC database is much lower than expected, based on anti-HERG activity. These drugs could be regarded as drugs with ‘false positive’ anti-HERG activities. For ketoconazole this effect was described before. However, the low ratio may also be explained by the fact that there were relatively many ADR reports of ‘skin and appendages disorders’ as well as ‘liver and biliary system disorders’, competing with the ADRs of our interest to stand out is proportionately against all other case reports. Both ADRs counted for 23% of all ADRs that were reported for ketoconazole, whereas the percentages among the case reports of all studied drugs together were 12% and 4%, respectively. Similarly the relatively high proportion of case reports of ‘psychiatric disorders’ (31% for mefloquine vs. 13% overall) and ‘central and peripheral nervous system disorders’ (25% for mefloquine vs. 14% overall) could have competed with the ADRs of our interest.

Drugs that bind to HERG potassium channels in concentrations close to or lower than therapeutic plasma concentrations (i.e. have a high Log10 ETCPunbound/1C50 ratio) have a high risk of reports of serious ventricular arrhythmias, and sudden death, in the WHO-UMC database, indicating a higher pro-arrhythmic risk. The higher the 1C50 (toxic drug level) compared with the ETCP unbound value (therapeutic drug level), the higher this risk. These findings support the vaLue of pre-clinical HERG testing for predicting proarrhythmic effects of medicines.

https://pdfs.semanticscholar.org/dc...8.2125483196.1540870256-1162897731.1540369811

 

[mr peabody]

Cardiac arrest after ibogaine intoxication

Christian Steinberg, MD, Marc Deyell, MD, MSc

Abstract

Ibogaine is a psychoactive herbal medication with alleged anti-addiction properties. We report a case of ibogaine intoxication mimicking Long‐QT syndrome resulting in ventricular flutter and nearby cardiac arrest. A 61-year-old man experienced massive QT prolongation and ventricular flutter at a rate of 270 beats per minute requiring defibrillation after ingestion of a large dose of Ibogaine. The ingested dose of 65-70 mg/kg represents the highest survived ibogaine dose reported to date. As a result of the long plasma half-life of ibogaine, it took 7 days for the patient's QT interval to normalize.

INTRODUCTION

Drug‐induced QT prolongation can result in life‐threatening ventricular arrhythmia and is part of the differential diagnosis of unexplained Torsades de Point or ventricular fibrillation. We report an uncommon case of life-threatening ventricular arrhythmia caused by massive QT prolongation after ingestion of ibogaine as anti-addiction therapy.

CASE

A 61-year-old male presented for treatment to overcome a long-standing opioid dependency related to chronic pain. His past medical history was significant for multiple spine operations resulting in a chronic cervico‐lumbar pain syndrome. Additional comorbidities included depression, mild hypertension, and dyslipidemia. He had no history of cardiovascular disease, unexplained syncope, presyncope, or sustained palpitations. His family history was negative for unexplained sudden cardiac death or inherited arrhythmia.

The patient was provided with ibogaine capsules (first-time use) that were administered with the intention to blunt opioid addiction symptoms and achieve a sustained anti-craving effect. The patient ingested an approximate single dose of 5.6 g of ibogaine corresponding to a total body dose of 65-70 mg/kg. It is important to mention that ibogaine was administered without medical prescription and supervision, as this substance is not approved in North America for medical use. At 6‐12 hours post-ingestion, the patient started to develop severe gastrointestinal symptoms including heavy vomiting and diarrhea. Those symptoms were quickly followed by a significant alteration of his level of consciousness, and the patient was urgently transferred to the ER of the nearest hospital.

On arrival at the ER, the patient was pale, diaphoretic, and barely arousable. His radial pulse was not palpable, and no blood pressure could be measured. The initial 12-lead ECG revealed a monomorphic wide QRS complex tachycardia at a rate of 270 beats per minute—representing almost ventricular flutter (Figure 1A). Emergent defibrillation was performed and converted the patient to sinus rhythm. The ECG postdefibrillation demonstrated massive QT prolongation associated with ventricular bigeminy (Figure 1B). The initial serum potassium concentration was 2.4 mmol/L, and the serum concentrations of Mg2+ and Ca2+ were normal. After initial stabilization, the patient was transferred to the intensive care unit for further management. His hypokalemia was aggressively treated and corrected within 12 hours. His hemodynamics quickly improved with supportive treatment. Laboratory screening for cointoxication was negative.

Figure 1

Life‐threatening ventricular arrhythmia upon ibogaine intoxication.
A, The 12‐lead ECG after ingestion of an estimated dose of 65‐70 mg/kg of ibogaine showed monomorphic ventricular tachycardia/ventricular flutter at a rate of 270 beats per minute requiring emergent defibrillation.
B, The ECG post-defibrillation demonstrated massive QT prolongation with prominent U‐waves associated with ventricular bigeminy.

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There was no evidence of any significant heart disease after extensive investigation including coronary CT‐angiogram, cardiac magnetic resonance imaging, and echocardiogram.

Serial ECGs demonstrated a delayed recovery for his corrected QT intervals (QTc on admission = 655 ms, QTc 24 hours later = 714 ms) requiring 7 days for complete normalization (Figure 2).
No further ventricular arrhythmia occurred during his hospitalization. An exercise treadmill test was performed 12 days after his arrhythmic event to screen for underlying hereditary Long‐QT syndrome. The exercise test demonstrated strictly normal QT dynamics during exercise and recovery (Figure S2).

Figure 2

Delayed QTc recovery after ibogaine intoxication. Serial ECGs demonstrating delayed recovery of the corrected QT (QTc) interval due to long plasma half‐life of the active metabolite noribogaine. Complete QTc normalization required 7 d. The absolute QT interval was measured using maximal slope technique. The QTc interval was then calculated using Bazett's formula.

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A final diagnosis of ibogaine-induced QT prolongation (cotriggered by secondary hypokalemia) triggering ventricular tachycardia was retained, and the patient was discharged home. Given his normal cardiac test results and the well‐known cardiotoxicity of ibogaine, no genetic testing was performed.

DISCUSSION

Ibogaine is a psychoactive indole alkaloid from the root bark of Tabernanthe iboga, a West‐Central African rainforest shrub (Figure S1). Traditionally, ibogaine has been used by various indigenous nations from Gabon, Cameron, and the Republic of the Congo for spiritual ceremonies because of its neuro-stimulating and hallucinogen effect.

Ibogaine came into the focus of medical research since the 1960s because of its alleged anti-addiction and anticraving properties.1 Because of safety concerns, the substance is currently not approved in many Western countries including the United States and Canada. However, increased use of ibogaine by independent, non-medical addiction clinics has been observed over the last decade. Those clinics often operate in a legal gray zone and typically without any form of cardiac monitoring.

Ibogaine has a complex pharmacology and is metabolized in the liver. The active substance is the metabolite noribogaine, which has a long plasma half‐life of 28-40 hours. Ibogaine and noribogaine exposition can be detected in serum and urine.

Cardiac effects of ibogaine are characterized by sinus bradycardia and marked QT prolongation, which are the result of complex interaction with various cardiac ion channels. The electro-physiological effect of ibogaine mimics the hereditary Long-QT syndrome type 2 that is caused by a genetic loss‐of‐function of the IKr channel (encoded by the KCNH2 gene).

Malignant ventricular arrhythmia and sudden death after ibogaine ingestion have been reported and are thought to be caused by the massive QT prolongation with subsequent torsades de pointes or ventricular fibrillation. Mimicking Long‐QT syndrome type 2, it is thought that ventricular arrhythmia is caused by triggered activity and initiated by late‐coupled ventricular ectopy as demonstrated in the post-arrest ECG of our patient (Figure 1B).

The present case extends our knowledge about the clinical manifestation of ibogaine-related cardiotoxicity. Our patient presented with significant hypokalemia, which served as a pro-arrhythmic co-trigger and was related to the heavy gastrointestinal symptoms. Those symptoms are predominantly caused by activation of central dopaminergic and serotonergic receptors. The onset of symptoms in our case was consistent with the literature. Symptoms of cardiotoxicity can manifest within 1.5-76 hours post-ingestion. The massive QT prolongation up to 714 ms in our patient is among the highest reported so far. The estimated ingested dose of 65-70 mg/kg would represent the highest survived ibogaine dose reported to date. However, this has to be interpreted with caution, as non-standardized preparation of ibogaine capsules makes dose estimations challenging, and we did not perform a direct measure of the serum ibogaine concentration. Depending on the type of preparation, the total content of ibogaine alkaloid may vary from 15% to 50%. It becomes obvious that those uncontrolled and non-standardized preparations result in unpredictable dosing putting potential customers at risk.

The long half‐life of the active metabolite noribogaine is well illustrated by the delayed QT recovery of our patient. As illustrated in Figure 2, it took 7 days for our patient to normalize his corrected QT interval despite normal electrolytes and in the absence of any competing QT‐affecting medication. None of the previous reports on ibogaine intoxication provided a detailed documentation of the QT recovery. Our findings illustrate the potential risk for late recurrence of ventricular arrhythmia and emphasize the need for prolonged cardiac monitoring in those patients.

In conclusion: Ibogaine intoxication is an uncommon, but potentially life‐threatening scenario due to the high cardiotoxicity of this substance and urgent admission to a critical care unit is required. Cardiotoxicity is characterized by massive QT prolongation with risk of ventricular arrhythmia that may develop early or late after ingestion. Delayed QT recovery is related to the long plasma half-life of the active metabolite and prolonged cardiac monitoring until entire QT normalization is recommended.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111465/

 

[DotChem]

^ 5600 mg free base equivalent!?!.now! this is one massive dose! ~7 times average flood dose (800mg hydrochloride) or 20 times psychoactive dose! The highest dose survided I've even seen reported.
On the other hand that tells you that analogs of Ibogaine devoid of cardiovascular side-effects would make quite safe drugs. Since almost any psychoactive compound at this dosage will probably do more damage besides cardiovascular, if one survives it. I am talking about irreversible neuronal damage to some brain areas that could lead to all sort of problems the worse being partial or total brain dead!!. The paper didn't mention any other damage which I am sure they've conducted battery of test to verify before discharging the patient...So I guess the cardiovascular arrythmia is the only serious side-effects of the drug.


Imho there is tremendous need in the market for Ibogaine analogs that are devoid of hERG liabilities. hERG issue is really the biggest obstacle for widespread use of this drug class. Actually, it is not that hard to get such compounds. The problem is money!! how to get Pharma investors interests in the addiction treatment field? iirc there was a thread earlier discussing some of the reasons BigPharma shy away from the field. One being the stigma attached to "psychedelic-hallucinogen" like Ibogaine and the other being that Ibogaine class of drug are one-off drug ie you only need 2-3 days treatment as opposed to chronic lifetime use (like say methadone) … Anyhow, thanks for posting very interesting case

nb: the patient has hypokalemia (low blood potassium levels) which co-trigger QT prolongation by ibogaine since Ibogaine is a hERG cardiac potassium channel blocker.

A final diagnosis of ibogaine-induced QT prolongation (cotriggered by secondary hypokalemia) triggering ventricular tachycardia was retained, and the patient was discharged home.

Actually, lots of people (eating typical western diet) have low blood potassium! That's why it is of paramount importance to check potassium (and Calcium and other minerals) levels before taking Ibogaine. Bananas are a rich source of Potassium..

 

[mr peabody]

^^
Very interesting. You can do it! Just ran across this:

2-Methoxyethyl-18-methoxycoronaridinate (ME-18-MC)

(–)-2-Methoxyethyl-18-methoxycoronaridinate (ME-18-MC) is a second generation synthetic derivative of ibogaine developed by the research team led by the pharmacologist Stanley D. Glick from the Albany Medical College and the chemist Martin Kuehne from the University of Vermont. In animal studies it has shown similar efficacy to the related compound 18-methoxycoronaridine (18-MC) at reducing self-administration of morphine and methamphetamine but with higher potency by weight, showing anti-addictive effects at the equivalent of half the minimum effective dose of 18-MC. Similarly to 18-MC itself, ME-18-MC acts primarily as a selective a3B4 nicotinic acetylcholine antagonist, although it has a slightly stronger effect than 18-MC as an NMDA antagonist, and its effects on opioid receptors are weaker than those of 18-MC at all except the kappa opioid receptor, at which it has slightly higher affinity than 18-MC.

http://abuse.wikia.com/wiki/2-Methoxyethyl-18-methoxycoronaridinate

 

[polymath]

Is it possible that harmine and harmaline could also have a arrhythmogenic effect? Apparently lab specimen can't completely discriminate between the effect of ibogaine and those more typical harmala alkaloids. Not that anyone would use them as an ibogaine replacement though, unless there's some ROA that doesn't produce the nauseating effect.

 

[DotChem]

Is it possible that harmine and harmaline could also have a arrhythmogenic effect? Apparently lab specimen can't completely discriminate between the effect of ibogaine and those more typical harmala alkaloids...

That's possible harmine and harmaline may have hERG modulating activity, I don't know if they have been specifically tested for these but here is a list of natural products with potential cardiac arrythmogenic effect: ​

https://www.ncbi.nlm.nih.gov/pubmed/28497823

I won't be surprised the effect of Ibogaine and that of harmaline alkaloids cannot be differentiated in some lab test. For one, they are both tremorgenic and tend to bind to the same brain areas. Pinoline (tetrabetacarboline) and Tryptoline (5-methoxy-tetrahydrobetacarboline) are closer to Ibogaine than the oxidized carboline and dihydrocarboline congeners plus they have no MAO inhibitory unlike harmine harmaline.
Pinoline is thought to be synthesized in the pineal gland as the endogenous DMT-like ligand but there is huge controversy on this topics since the levels are so minutes some authors claims it is just an artifact. Nevertheless, according to Glick and others, Ibogaine anti-addiction effects may be attributed to antagonism at alfa3beta4 nicotinic acetylcholine receptors in the brain. Coincidentally, a3b4-nACh receptors are very specifically expressed in the brain mostly in the pineal gland and the INP. They are actually isolated from rat pinealocytes to test compounds as a3b4 selective ligands.

..Not that anyone would use them as an ibogaine replacement though, unless there's some ROA that doesn't produce the nauseating effect.

Why not? I came up with pretty potent tetrahydrocarbolines as possible legal alternatives to ibogaine. They are pretty similar to Ibogaine in all aspects but there is no money in this field so didn't pursue it further... The nauseating effect of Ibogaine and Harmane alkaloids is probably due to their activating serotonin 5HT3R (highly emetogenic) so 5HT3 antagonists like Tropisetron (2mg) may help with the nausea and emesis. It is used to treat vomiting and nausea in cancer chemotherapy patients. ​

 

[mr peabody]

To any chemist reading this with a keen interest in the above: do you have any special insight on the development of non-cardiotoxic ibogaine analogs? If so, please PM me right away.