Benzofuran Iboga-Analogs Modulate Nociception and Inflammation in an Acute Mouse Pain Model.

Pain management following acute injury or post-operative procedures is highly necessary for proper recovery and quality of life. Opioids and non-steroidal anti-inflammatory drugs (NSAIDS) have been used for this purpose, but opioids cause addiction and withdrawal symptoms whereas NSAIDS have several systemic toxicities. Derivatives of the naturally occurring iboga alkaloids have previously shown promising behavior in anti-addiction of morphine by virtue of their interaction with opioid receptors. On this frontier, four benzofuran analogs of the iboga family have been synthesized and their analgesic effects have been studied in formalin induced acute pain model in male Swiss albino mice at 30 mg/kg of body weight dose administered intraperitoneally. The antioxidant, anti-inflammatory and neuro-modulatory effects of the analogs were analyzed. Reversal of tail flick latency, restricted locomotion and anxiogenic behavior were observed in iboga alcohol, primary amide and secondary amide. Local neuroinflammatory mediators' substance P, calcitonin gene related peptide, cyclooxygenase-2 and p65 were significantly decreased whereas the depletion of brain derived neurotrophic factor and glia derived neurotrophic factor was overturned on iboga analog treatment. Behavioral patterns after oral administration of the best analog were also analyzed. Taken together, these results show that the iboga family of alkaloid has huge potential in pain management.

Streamlined screening platforms lead to the discovery of pachysiphine synthase from Tabernanthe iboga.

Plant-specialized metabolism is largely driven by the oxidative tailoring of key chemical scaffolds catalyzed by cytochrome P450 (CYP450s) enzymes. Monoterpene indole alkaloids (MIAs) tabersonine and pseudo-tabersonine, found in the medicinal plant Tabernanthe iboga (commonly known as iboga), are tailored with oxidations, and the enzymes involved remain unknown. Here, we developed a streamlined screening strategy to test the activity of T. iboga CYP450s in Nicotiana benthamiana. Using multigene constructs encoding the biosynthesis of tabersonine and pseudo-tabersonine scaffolds, we aimed to uncover the CYP450s responsible for oxidative transformations in these scaffolds. Our approach identified two T. iboga cytochrome P450 enzymes: pachysiphine synthase (PS) and 16-hydroxy-tabersonine synthase (T16H). These enzymes catalyze an epoxidation and site-specific hydroxylation of tabersonine to produce pachysiphine and 16-OH-tabersonine, respectively. This work provides new insights into the biosynthetic pathways of MIAs and underscores the utility of N. benthamiana and Catharanthus roseus as platforms for the functional characterization of plant enzymes.

Total Synthesis of Ervaoffine J and K.

Herein, we describe the total synthesis of ervaoffine J & K from a central intermediate. Ervaoffine J was synthesized in eight steps in 14 % yield. Our strategy features an aerobic Winterfeldt oxidation to introduce the 4-quinolone moiety. Ervaoffine K was produced in ten steps and 10 % yield. The synthesis leveraged (bromodifluoromethyl)-trimethylsilane to induce a regioselective von Braun-type C-N bond fragmentation. This C-N bond cleavage unveiled the tetrasubstituted all-syn cyclohexane core of ervaoffine K and enabled the completion of its synthesis.

New Approach Methodologies (NAMs) for ad hoc human health risk assessment of food and non-food products - Proceedings of a workshop.

RIVM convened a workshop on the use of New Approach Methodologies (NAMs) for the ad hoc human health risk assessment of food and non-food products. Central to the workshop were two case studies of marketed products with a potential health concern: the botanical Tabernanthe iboga which is used to facilitate mental or spiritual insight or to (illegally) treat drug addiction and is associated with cardiotoxicity, and dermal creams containing female sex hormones, intended for use by perimenopausal women to reduce menopause symptoms without medical supervision. The workshop participants recognized that data from NAM approaches added valuable information for the ad hoc risk assessment of these products, although the available approaches were inadequate to derive health-based guidance values. Recommendations were provided on how to further enhance and implement NAM approaches in regulatory risk assessment, specifying both scientific and technical aspects as well as stakeholder engagement aspects.

Natural Products for the Treatment of Drug Addiction: Narrative Review.

Drug addiction is considered a chronic disorder affecting the individual's life, his/her family and society. Up till now the treatment of drug addiction is considered a problematic issue. Synthetic drugs available for the treatment of drug addiction are few, of limited efficacy and associated with serious side effects. Therefore, there is a continuous search for better therapeutic agents for drug addiction. Natural products represent a promising source for drug addiction treatment. This review summaries drug addiction definition, its mechanism of action, its types, its diagnosis, factors affecting its development and different available approaches for its treatment especially the use of natural products. Six plants were discussed thoroughly in this review, including, Tabernanthe iboga Baill., Mitragyna speciosa Korth., Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep, Hypericum perforatum L., Panax ginseng C.A. Mey., and Withania somnifera (L.) Dunal.

Iboga Inspired N-Indolylethyl-Substituted Isoquinuclidines as a Bioactive Scaffold: Chemoenzymatic Synthesis and Characterization as GDNF Releasers and Antitrypanosoma Agents.

The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N-indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels-Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC50 1-8 µM) and two of them (compounds 6 and 14) showed a good selectivity index.

Cytochrome P450 and O-methyltransferase catalyze the final steps in the biosynthesis of the anti-addictive alkaloid ibogaine from Tabernanthe iboga.

Monoterpenoid indole alkaloids are a large (∼3000 members) and structurally diverse class of metabolites restricted to a limited number of plant families in the order Gentianales. Tabernanthe iboga or iboga (Apocynaceae) is native to western equatorial Africa and has been used in traditional medicine for centuries. Howard Lotsof is credited with bringing iboga to the attention of Western medicine through his accidental discovery that iboga can alleviate opioid withdrawal symptoms. Since this observation, iboga has been investigated for its use in the general management of addiction. We were interested in elucidating ibogaine biosynthesis to understand the unique reaction steps en route to ibogaine. Furthermore, because ibogaine is currently sourced from plant material, these studies may help improve the ibogaine supply chain through synthetic biology approaches. Here, we used next-generation sequencing to generate the first iboga transcriptome and leveraged homology-guided gene discovery to identify the penultimate hydroxylase and final O-methyltransferase steps in ibogaine biosynthesis, herein named ibogamine 10-hydroxylase (I10H) and noribogaine-10-O-methyltransferase (N10OMT). Heterologous expression in Saccharomyces cerevisiae (I10H) or Escherichia coli (N10OMT) and incubation with putative precursors, along with HPLC-MS analysis, confirmed the predicted activities of both enzymes. Moreover, high expression levels of their transcripts were detected in ibogaine-accumulating plant tissues. These discoveries coupled with our publicly available iboga transcriptome will contribute to additional gene discovery efforts and could lead to the stabilization of the global ibogaine supply chain and to the development of ibogaine as a treatment for addiction.

Metabolite Profiling of Anti-Addictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae).

Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family. In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga. PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively. The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.

Ibogaine Consumption With Seizure-Like Episodes, QTc-Prolongation, and Captured Cardiac Dysrhythmias.

BACKGROUND: Ibogaine is a psychoactive indole alkaloid that has been investigated for use as a treatment for opioid addiction. While not commercially available in the United States, it is available via Internet suppliers. Ibogaine use has been associated with significant cardiac and neurologic effects, such as QT-segment prolongation, cardiac dysrhythmias, hallucinations, seizures, and central nervous system depression. We present a case of verified ibogaine exposure with associated QTc prolongation and torsade de pointes with qualitative analysis of the ingested substance, and examine the history, social context, availability, and perceptions of ibogaine's effects and safety. CASE REPORT: A 34-year-old white woman with medical history significant for heroin and cocaine use disorder presented with reported seizures 1 day after ingestion of 2 g ibogaine powder purchased from an Internet supplier. Shortly after ingestion, she experienced hallucinations and was reported by family to have four to five seizure-like episodes, at one point becoming apneic. In the emergency department, she was noted to have QTc prolongation and several episodes of torsade de pointes. Qualitative analysis confirmed the presence of ibogaine in the empty foil packages containing the ingested substance. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As increasing numbers of opioid-dependent patients attempt to curtail their substance use disorders, we anticipate a rise in ibogaine exposures, necessitating awareness by front-line clinicians in recognizing and treating a drug exposure that can rapidly become life-threatening.

Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties.

Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by -CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the µ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and κ-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain.

Insecticidal bisindole alkaloids from leaves of Tabernaemontana divaricata 'Dwaft'.

Six undescribed bisindole alkaloids, namely taberdisines A-F (1-6), were isolated from the leaves of Tabernaemontana divaricata 'Dwaft'. Among them, alkaloids 1 and 2 were the first examples of strychnos-iboga type alkaloid with both C-C linkage patterns. Alkaloid 3, a new type of aspidosperma-iboga with a furan-ring, as well as other three undescribed ones was disclosed. Their structures were elucidated by comprehensive spectroscopic analyses. Alkaloids 1 and 5 showed insecticide activity on Sf9 cell and eggs of Spodoptera frugiperda in vivo, which might explain the potential of the plants for insect resistance.

Underground ibogaine use for the treatment of substance use disorders: A qualitative analysis of subjective experiences.

INTRODUCTION: Ibogaine is one of the alkaloids naturally found in plants such as Tabernanthe iboga, which has been traditionally used by members of the Bwiti culture. Since the discovery of its anti-addictive properties by Howard S. Lotsof in 1962, ibogaine has been used experimentally to treat substance use disorders (SUD), especially those involving opioids. We aim to provide a detailed understanding of the underlying psychological aspects of underground ibogaine use for the treatment of SUD. METHODS: Semi-structured interviews were carried out with 13 participants with SUD, which motivated their self-treatment with ibogaine. The data were analysed using the grounded theory approach and considered the context of the treatment, and the nature of the occurring hallucinogenic and cognitive phenomena during the treatment experience. RESULTS: We identified several psychological effects that the study respondents experienced, which seem to play a substantial role in the therapeutic process concerning SUD. The evoking of interpersonal and transpersonal experiences, autobiographical memories, and preparation, integration and motivation for a lifestyle change are important components that participants reported during and after ibogaine intake. DISCUSSION AND CONCLUSION: Ibogaine is increasingly being used for the treatment of SUD, due in part to the limited treatment options currently available. Its beneficial effects seem to be related not only to its complex pharmacology but also to the subjective experience that ibogaine induces. The main aspects of this experience are related to autobiographical memories and valuable personal insights, which together appear to help individuals cope with their SUD.

Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview.

BACKGROUND: There is a growing interest in studying ibogaine (IBO) as a potential treatment for substance use disorders (SUDs). However, its clinical use has been hindered for mainly two reasons: First, the lack of randomized, controlled studies informing about its safety and efficacy. And second, IBO's mechanisms of action remain obscure. It has been challenging to elucidate a predominant mechanism of action responsible for its anti-addictive effects. OBJECTIVE: To describe the main targets of IBO and its main metabolite, noribogaine (NOR), in relation to their putative anti-addictive effects, reviewing the updated literature available. METHODS: A comprehensive search involving MEDLINE and Google Scholar was undertaken, selecting papers published until July 2022. The inclusion criteria were both theoretical and experimental studies about the pharmacology of IBO. Additional publications were identified in the references of the initial papers. RESULTS: IBO and its main metabolite, NOR, can modulate several targets associated with SUDs. Instead of identifying key targets, the action of IBO should be understood as a complex modulation of multiple receptor systems, leading to potential synergies. The elucidation of IBO's pharmacology could be enhanced through the application of methodologies rooted in the polypharmacology paradigm. Such approaches possess the capability to describe multifaceted patterns within multi-target drugs. CONCLUSION: IBO displays complex effects through multiple targets. The information detailed here should guide future research on both mechanistic and therapeutic studies.

Polyneurines A-H, iboga alkaloids from Tabernaemontana polyneura.

Eight undescribed iboga alkaloids, polyneurines A-H, were isolated from the bark of Tabernaemontana polyneura. The structures of these alkaloids were established by interpretation of the MS and NMR data, while the configurations were determined using GIAO NMR calculations and DP4+ probability analysis, TDDFT-ECD method, or X-ray diffraction analysis. Polyneurine A possesses a γ-lactone unit embedded within the iboga skeleton, while polyneurines D and E incorporate a formylmethyl moiety at C-3 of the iboga skeleton. Biosynthetic pathways towards the formation of polyneurines A, C, D, and E were proposed.

New iboga-type alkaloids from Ervatamia officinalis and their anti-inflammatory activity.

Four new iboga-type alkaloids, ervaoffines H-K (1-4), along with five known compounds were obtained from the aerial parts of Ervatamia officinalis. The absolute configurations of 1-4 were confirmed by X-ray diffraction and electronic circular dichroism (ECD) analyses. The isolates were tested for their anti-inflammatory activity. Compounds 1, 5, 6, and 9 showed potential inhibitory effect of NO production in LPS-stimulated BV2 and RAW264.7 cells.

Drug Transporters ABCB1 (P-gp) and OATP, but not Drug-Metabolizing Enzyme CYP3A4, Affect the Pharmacokinetics of the Psychoactive Alkaloid Ibogaine and its Metabolites.

The psychedelic alkaloid ibogaine is increasingly used as an oral treatment for substance use disorders, despite being unlicensed in most countries and having reported adverse events. Using wild-type and genetically modified mice, we investigated the impact of mouse (m)Abcb1a/1b and Abcg2 drug efflux transporters, human and mouse OATP drug uptake transporters, and the CYP3A drug-metabolizing complex on the pharmacokinetics of ibogaine and its main metabolites. Following oral ibogaine administration (10 mg/kg) to mice, we observed a rapid and extensive conversion of ibogaine to noribogaine (active metabolite) and noribogaine glucuronide. Mouse Abcb1a/1b, in combination with mAbcg2, modestly restricted the systemic exposure (plasma AUC) and peak plasma concentration (Cmax) of ibogaine. Accordingly, we found a ∼2-fold decrease in the relative recovery of ibogaine in the small intestine with fecal content in the absence of both transporters compared to the wild-type situation. Ibogaine presented good intrinsic brain penetration even in wild-type mice (brain-to-plasma ratio of 3.4). However, this was further increased by 1.5-fold in Abcb1a/1b;Abcg2 -/- mice, but not in Abcg2 -/- mice, revealing a stronger effect of mAbcb1a/1b in restricting ibogaine brain penetration. The studied human OATP transporters showed no major impact on ibogaine plasma and tissue disposition, but the mOatp1a/1b proteins modestly affected the plasma exposure of ibogaine metabolites and the tissue disposition of noribogaine glucuronide. No considerable role of mouse Cyp3a knockout or transgenic human CYP3A4 overexpression was observed in the pharmacokinetics of ibogaine and its metabolites. In summary, ABCB1, in combination with ABCG2, limits the oral availability of ibogaine, possibly by mediating its hepatobiliary and/or direct intestinal excretion. Moreover, ABCB1 restricts ibogaine brain penetration. Variation in ABCB1/ABCG2 activity due to genetic variation and/or pharmacologic inhibition might therefore affect ibogaine exposure in patients, but only to a limited extent. The insignificant impact of human CYP3A4 and OATP1B1/1B3 transporters may be clinically advantageous for ibogaine and noribogaine use, as it decreases the risks of undesirable drug interactions or interindividual variation related to CYP3A4 and/or OATP activity.

New Iboga-Type Indole Alkaloids from Tabernaemontana divaricata.

Two hitherto unknown iboga-type indole alkaloids, namely (3R)-7,19-di-epi-3-methoxytabernoxidine (1) and (3R,19R)-19-hydroxy-3-(2-oxopropyl)voacangine (2), together with eight known alkaloids (3-10), were isolated from the twigs and leaves of Tabernaemontana divaricata. Their structures were established on the basis of spectroscopic data interpretation, single crystal X-ray diffraction analysis and circular dichroism spectrum.

DARK Classics in Chemical Neuroscience: Ibogaine.

The West African iboga plant has been used for centuries by the Bwiti and Mbiri tribes to induce hallucinations during religious ceremonies. Ibogaine, the principal alkaloid responsible for iboga's psychedelic properties, was isolated and sold as an antidepressant in France for decades before its adverse effects precipitated its removal from the market. An ibogaine resurgence in the 1960s was driven by U.S. heroin addicts who claimed that ibogaine cured their opiate addictions. Behavioral pharmacologic studies in animal models provided evidence that ibogaine could blunt self-administration of not only opiates but cocaine, amphetamines, and nicotine. Ibogaine displays moderate-to-weak affinities for a wide spectrum of receptor and transporter proteins; recent work suggests that its actions at nicotinic acetylcholine receptor subtypes may underlie its reputed antiopiate effects. At micromolar levels, ibogaine is neurotoxic and cardiotoxic and has been linked to several deaths by cardiac arrest. Structure-activity studies led to the isolation of the ibogaine analog 18-methoxycoronaridine (18-MC), an α3ß4 nicotinic receptor modulator that retains ibogaine's anticraving properties with few or no adverse effects. Clinical trials of 18-MC treatment of nicotine addiction are pending. Ibogaine analogs may also hold promise for treating anxiety and depression via the "psychedelic-assisted therapy" approach that employs hallucinogens including psilocybin and methylenedioxymethamphetamine ("ecstasy").

Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine.

Opioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants' OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials.

Ibogaine as a treatment for substance misuse: Potential benefits and practical dangers.

Ibogaine is an indole alkaloid found in the root bark of the Iboga shrub native to west Africa possessing hallucinogenic properties. For centuries it has been used in religious ceremonies and to gain spiritual enlightenment. However, since the early 1960s, its apparent ability to reduce craving for psychoactive substances including alcohol, cocaine, methamphetamine, opiates, and nicotine has led to its use in detoxification treatments. In many instances, clients receive treatment in non-medical settings, with little by way of robust scientific clinical trials. This chapter provides an overview of the potential benefits that could arise from such research. This is balanced against the serious adverse effects that can occur due to undiagnosed health conditions and/or concomitant use of other drugs. A detailed update is provided of the 33 deaths known to have occurred, including 5 in the UK. Looking forward, there is a need to develop better opiate detoxification treatment against a background of increasing opioid-related fatalities. A congener of ibogaine, 18-MC, appears to be safer and is to undergo clinical trials. In the meantime, would-be consumers and treatment providers must make more careful, detailed risk-assessments before using ibogaine. Treatment outcomes, including deaths, need to be accurately recorded and published.