Ibogaine Induces Cardiotoxic Necrosis in Rats-The Role of Redox Processes.

Ibogaine is an organic indole alkaloid that is used in alternative medicine to combat addiction. Numerous cases of life-threatening complications and sudden deaths associated with ibogaine use have been reported, and it has been hypothesized that the adverse effects are related to ibogaine's tendency to induce cardiac arrhythmias. Considering that the bioavailability of ibogaine and its primary metabolite noribogaine is two to three times higher in female rats than in male rats, we here investigated the effect of a single oral dose (1 or 20 mg/kg) of ibogaine on cardiac histopathology and oxidative/antioxidant balance. Our results show that ibogaine induced dose-dependent cardiotoxic necrosis 6 and 24 h after treatment and that this necrosis was not a consequence of inflammation. In addition, no consistent dose- and time-dependent changes in antioxidant defense or indicators of oxidative damage were observed. The results of this study may contribute to a better understanding of ibogaine-induced cardiotoxicity, which is one of the main side effects of ibogaine use in humans and is often fatal. Nevertheless, based on this experiment, it is not possible to draw a definitive conclusion regarding the role of redox processes or oxidative stress in the occurrence of cardiotoxic necrosis after ibogaine administration.

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters.

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3ß2ß3 or α6/α3ß4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Ibogaine.

BACKGROUND: Ibogaine is a plant-derived alkaloid that has been used for thousands of years in rites of passage and spiritual ceremonies in West-Central Africa. In the West, it has primarily been used and studied for its anti-addictive properties and more recently for other neuropsychiatric indications, including post-traumatic stress disorder, depression, anxiety, and traumatic brain injury. AREAS OF UNCERTAINTY: Ibogaine requires careful patient screening and monitoring because of significant safety issues. There is potential for cardiotoxicity (prolonged QT interval); without rigorous screening, fatal arrhythmias may occur. However, preliminary research suggests that co-administration of ibogaine with magnesium may mitigate cardiotoxicity. Additionally, ibogaine may have dangerous interactions with opiates, so patients who receive ibogaine treatment for opioid use disorder must withdraw from long-acting opioids. Other potential concerning effects of ibogaine include rare incidences of mania or psychosis. Anticipated transient effects during ibogaine treatment can include ataxia, tremors, and gastrointestinal symptoms. THERAPEUTIC ADVANCES: Robust effects after a single treatment with ibogaine have been reported. In open-label and randomized controlled trials (RCTs), ibogaine reduces heroin and opioid cravings by upwards of 50%, up to 24 weeks after the treatment. An observational study of 30 Special Operations Forces veterans with mild traumatic brain injury reported that 86% were in remission from post-traumatic stress disorder, 83% from depression, and 83% from anxiety, one month after a single-dose ibogaine treatment. LIMITATIONS: Although there are several observational and open-label studies, there is only a single double-blind, placebo-controlled RCT on ibogaine. More RCTs with large sample sizes must be conducted to support ibogaine's safety and efficacy. CONCLUSIONS: Given the promising preliminary findings, ibogaine could potentially fill a much-needed gap in treatments for challenging conditions, including opioid dependence. Ibogaine's remarkable effects in traditionally treatment-resistant, combat-exposed individuals hints at its potential in broader populations with physical and psychological trauma.

The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients.

OBJECTIVE: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. METHODS: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. RESULTS: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. CONCLUSIONS: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.

Noribogaine acute administration in rats promotes wakefulness and suppresses REM sleep.

Ibogaine is a potent atypical psychedelic that has gained considerable attention due to its antiaddictive and antidepressant properties in preclinical and clinical studies. Previous research from our group showed that ibogaine suppresses sleep and produces an altered wakefulness state, which resembles natural REM sleep. However, after systemic administration, ibogaine is rapidly metabolized to noribogaine, which also shows antiaddictive effects but with a distinct pharmacological profile, making this drug a promising therapeutic candidate. Therefore, we still ignore whether the sleep/wake alterations depend on ibogaine or its principal metabolite noribogaine. To answer this question, we conducted polysomnographic recordings in rats following the administration of pure noribogaine. Our results show that noribogaine promotes wakefulness while reducing slow-wave sleep and blocking REM sleep, similar to our previous results reported for ibogaine administration. Thus, we shed new evidence on the mechanisms by which iboga alkaloids work in the brain.

Prospective associations of psychedelic treatment for co-occurring alcohol misuse and posttraumatic stress symptoms among United States Special Operations Forces Veterans.

This study evaluated prospective associations of ibogaine and 5-MeO-DMT treatment for risky alcohol use and post-traumatic stress disorder (PTSD) symptoms among United States (US) Special Operations Forces Veterans (SOFV). Data were collected during standard clinical operations at pre-treatment and 1-month (1 m), 3-months (3 m), and 6-months (6 m) post-treatment in an ibogaine and 5-MeO-DMT treatment program in Mexico. Of the 86 SOFV that completed treatment, 45 met criteria for risky alcohol use at pre-treatment (mean age = 44; male = 100%; White = 91%). There was a significant reduction in alcohol use from pre-treatment (M = 7.2, SD = 2.3) to 1 m (M = 3.6; SD = 3.5) post-treatment, which remained reduced through 6 m (M = 4.0; SD = 2.9; p < .001, partial eta squared = .617). At 1 m, 24% were abstinent, 33% were non-risky drinking, and 42% were risky drinkers. At 6 m, 16% were abstinent, 31% were non-risky drinking, and 53% were risky drinkers. There were no differences between responders (abstinent/non-risky drinkers) and non-responders (risky drinkers) in demographics/clinical characteristics. However, there were significant and very large differences between responders and non-responders in PTSD symptom (p < .01, d = -3.26) and cognitive functioning change (p < .01, d = -0.99). Given these findings, future clinical trials should determine whether psychedelic-assisted therapy holds promise for individuals with complex trauma and alcohol misuse who have not been successfully treated with traditional interventions.

Magnesium-ibogaine therapy in veterans with traumatic brain injuries.

Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (Pcorrected < 0.001, Cohen's d = 0.74) and 1 month (Pcorrected < 0.001, d = 2.20) after treatment and in PTSD (Pcorrected < 0.001, d = 2.54), depression (Pcorrected < 0.001, d = 2.80) and anxiety (Pcorrected < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 .

A transcriptomic analysis in mice following a single dose of ibogaine identifies new potential therapeutic targets.

Ibogaine (IBO) is an atypical psychedelic with a complex mechanism of action. To date, the mechanisms that may underlie its anti-addictive effects are still not defined. This study aims to identify changes in gene expression induced by a single oral dose of IBO in the cortex of mice by means of a transcriptomic analysis for the first time. Our results showed significant alterations in gene expression in mouse frontal cortex samples 4 h after a single oral dose of IBO. Specifically, genes involved in hormonal pathways and synaptogenesis exhibited upregulation, while genes associated with apoptotic processes and endosomal transports showed downregulation. The findings were further corroborated through quantitative polymerase chain reaction (qPCR) analysis. However, the validation of gene expression related to hormonal pathways did not entirely align with the transcriptomic analysis results, possibly due to the brain region from which tissue was collected. Sex differences were observed, with female mice displaying more pronounced alterations in gene expression after IBO treatment. High variability was observed across individual animals. However, this study represents a significant advancement in comprehending IBO's molecular actions. The findings highlight the influence of IBO on gene expression, particularly on hormonal pathways, synaptogenesis, apoptotic processes, and endosomal transports. The identification of sex differences underscores the importance of considering sex as a potential factor influencing IBO's effects. Further research to assess different time points after IBO exposure is warranted.

5-HT2A Receptor Knockout Mice Show Sex-Dependent Differences following Acute Noribogaine Administration.

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT2A receptor (5-HT2AR) in mice. In that regard, we used male and female, 5-HT2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT2AR blunted noribo-mediated responses to NMDA synaptic transmission.

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.

Open-label study of consecutive ibogaine and 5-MeO-DMT assisted-therapy for trauma-exposed male Special Operations Forces Veterans: prospective data from a clinical program in Mexico.

Background: Research in psychedelic medicine has focused primarily on civilian populations. Further study is needed to understand whether these treatments are effective for Veteran populations.Objectives: Here, we examine the effectiveness of psychedelic-assisted therapy among trauma-exposed Special Operations Forces Veterans (SOFV) seeking treatment for cognitive and mental health problems in Mexico.Methods: Data were collected from an ibogaine and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) clinical treatment program for SOFV with a history of trauma exposure. This clinical program collects prospective clinical program evaluation data, such as background characteristics, symptom severity, functioning (e.g., satisfaction with life, posttraumatic stress disorder symptoms, depression symptoms, anxiety symptoms, sleep disturbance, psychological flexibility, disability in functioning, cognitive functioning, neurobehavioral symptoms, anger, suicidal ideation), and substance persisting/enduring effects through online surveys at four timepoints (baseline/pre-treatment, one-, three-, and six-months after treatment).Results: The majority of the sample (n = 86; Mean Age = 42.88, SD = 7.88) were Caucasian (87.2%), non-Hispanic (89.5%), and males (100%). There were significant and large improvements in self-reported PTSD symptoms (p < .001, d = .414), depression (p < .001, d = .275), anxiety (p < .001, d = .276), insomnia severity (p < .001, d = .351), and post-concussive symptoms (p < .001, d = .389) as well as self-reported satisfaction with life (p < .001, d = .371), psychological flexibility (p < .001, d = .313) and cognitive functioning (p < .001, d = .265) from baseline to one-month follow-up.Conclusions: Data suggest combined ibogaine and 5-MeO-DMT assisted therapy has potential to provide rapid and robust changes in mental health functioning with a signal of durable therapeutic effects up to 6-months. Future research in controlled settings is warranted.

Ibogaína: un psicodélico atípico con potencial antiadictivo / Ibogaine: an atypical psychedelic with anti-addictive potential

El trastorno por uso de sustancias es una enfermedad crónica de graves consecuencias. Actualmente, los tratamientos farmacológicos no apuntan a corregir los cambios neurobiológicos generados en el cerebro por el uso crónico de sustancias de abuso, sino que se enfocan principalmente en la atenuación de algunos de los síntomas que padece el consumidor. La ibogaína es un psicodélico atípico que, tanto en estudios observacionales como en ensayos clínicos abiertos, ha mostrado una propiedad antiadictiva que perdura en el tiempo. Sin embargo, su delicado perfil de toxicidad cardíaca, así como su uso en entornos sin adecuadas medidas de seguridad, han limitado su progresión en las investigaciones clínicas. Los efectos antiadictivos de ibogaína han disparado diversas líneas de investigación básica, preclínica y clínica, que buscan confirmar su efectividad, entender sus mecanismos de acción y delimitar su perfil de seguridad. Dada la poca información disponible para los profesionales de salud sobre esta sustancia, esta revisión busca aportar información acerca de su potencial terapéutico, posibles mecanismos de acción y riesgos asociados a su administración.

Substance use disorder is a chronic disease with severe consequences. Currently, pharmacological treatments do not aim to correct the neurobiological changes generated in the brain by the chronic use of substances of abuse, but rather focus mainly on attenuating some of the user's symptoms. Ibogaine is an atypical psychedelic that has shown long-lasting and interesting antiaddictive properties in both observational studies and open-label clinical trials. However, its delicate profile of cardiac toxicity, as well as its use in settings without adequate safety measures, have limited its progression in clinical research. The anti-addictive effects of ibogaine have triggered diverse scientific research in basic, preclinical, and clinical areas, which seek efficacy confirmation and to fully understand ibogaine´s underlying mechanisms of action and its safety profile. Given that there is little information available to health professionals about ibogaine and its antiaddictive properties, this review aims to provide published data about its therapeutic potential in drug addiction, its mechanisms of action, and risks associated with its administration.

Reactivity of the Iboga Skeleton: Oxidation Study of Ibogaine and Voacangine.

The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio- and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C16-carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C3-oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C7 in the 7-hydroxyindolenine of voacangine was revised to be S, which corrects previous reports proposing an R configuration.

Structure-based discovery of conformationally selective inhibitors of the serotonin transporter.

The serotonin transporter (SERT) removes synaptic serotonin and is the target of anti-depressant drugs. SERT adopts three conformations: outward-open, occluded, and inward-open. All known inhibitors target the outward-open state except ibogaine, which has unusual anti-depressant and substance-withdrawal effects, and stabilizes the inward-open conformation. Unfortunately, ibogaine's promiscuity and cardiotoxicity limit the understanding of inward-open state ligands. We docked over 200 million small molecules against the inward-open state of the SERT. Thirty-six top-ranking compounds were synthesized, and thirteen inhibited; further structure-based optimization led to the selection of two potent (low nanomolar) inhibitors. These stabilized an outward-closed state of the SERT with little activity against common off-targets. A cryo-EM structure of one of these bound to the SERT confirmed the predicted geometry. In mouse behavioral assays, both compounds had anxiolytic- and anti-depressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.

IUPHAR - invited review - Ibogaine - A legacy within the current renaissance of psychedelic therapy.

Ibogaine is a powerful psychoactive substance that not only alters perception, mood and affect, but also stops addictive behaviors. Ibogaine has a very long history of ethnobotanical use in low doses to combat fatigue, hunger and thirst and, in high doses as a sacrament in African ritual contexts. In the 1960's, American and European self-help groups provided public testimonials that a single dose of ibogaine alleviated drug craving, opioid withdrawal symptoms, and prevented relapse for weeks, months and sometimes years. Ibogaine is rapidly demethylated by first-pass metabolism to a long-acting metabolite noribogaine. Ibogaine and its metabolite interact with two or more CNS targets simultaneously and both drugs have demonstrated predictive validity in animal models of addiction. Online forums endorse the benefits of ibogaine as an "addiction interrupter" and present-day estimates suggest that more than ten thousand people have sought treatment in countries where the drug is unregulated. Open label pilot studies of ibogaine-assisted drug detoxification have shown positive benefit in treating addiction. Ibogaine, granted regulatory approval for human testing in a Phase 1/2a clinical trial, joins the current landscape of psychedelic medicines in clinical development.

Identifying setting factors associated with improved ibogaine safety: a systematic review of clinical studies.

Ibogaine is a psychoactive alkaloid derived from the west-African shrub Tabernanthe iboga. Western cultures are increasing the interest for the substance due to its claimed anti addictive properties, although the evidence supporting this effect is still preliminary. The use of ibogaine often occurs with no medical supervision in uncontrolled settings, and its use has been associated with several reports of severe adverse events. This review aims to evaluate the clinical studies of ibogaine, with a focus on administration settings, to elucidate specific criteria that may promote safer contexts for ibogaine use. A systematic review of the literature was conducted based on PRISMA guidelines. PubMed, Scielo, ClinicalTrials.gov and Core.ac.uk electronic databases were searched, and clinical studies published until November 17, 2022, were retrieved. The final synthesis included 12 sources. Information about general characteristics of the studies, adverse effects, screening of participants and setting characteristics were summarized and discussed. It is concluded that the use of controlled settings, supported by trained professionals and equipment allowing for rigorous medical, psychiatric, and cardiac monitoring, are essential to promote the safety of patients receiving ibogaine.

Psychedelic Treatments for Substance Use Disorder and Substance Misuse: A Mixed Methods Systematic Review.

Renewed interest in psychedelic substances in the 21st century has seen the exploration of psychedelic treatments for various psychiatric disorders including substance use disorder (SUD). This review aimed to assess the effectiveness of psychedelic treatments for people with SUD and those falling below diagnostic thresholds (i.e. substance misuse). We systematically searched 11 databases, trial registries, and psychedelic organization websites for empirical studies examining adults undergoing psychedelic treatment for SUD or substance misuse, published in the English language, between 2000 and 2021. Seven studies investigating treatment using psilocybin, ibogaine, and ayahuasca, alone or adjunct with psychotherapy reported across 10 papers were included. Measures of abstinence, substance use, psychological and psychosocial outcomes, craving, and withdrawal reported positive results, however, this data was scarce among studies examining a wide range of addictions including opioid, nicotine, alcohol, cocaine and unspecified substance. The qualitative synthesis from three studies described subjective experience of psychedelic-assisted treatments enhanced self-awareness, insight, and confidence. At present, there is no sufficient research evidence to suggest effectiveness of any of the psychedelics on any specific substance use disorder or substance misuse. Further research using rigorous effectiveness evaluation methods with larger sample sizes and longer-term follow-up is required.

Chemistry, bioactivity, biosynthesis, and total synthesis of stemmadenine alkaloids.

Covering: up to July 2022Stemmadenine alkaloids are a restrictive sub-group of monoterpene indole alkaloids, represented by two congeners: stemmadenine and vallesamine. Their skeleton is defined by the cleavage of the C-3-C-7 bond of the Strychnos group's pentacyclic scaffold in monoterpene indole alkaloids. The parent alkaloid stemmadenine acts as a key intermediate in the biosynthesis of several major monoterpene indole alkaloid families, including regular Strychnos alkaloids, Aspidosperma alkaloids, and Iboga alkaloids. In this review, a complete coverage of the stemmadenine alkaloids, from the early reports till the present day at 2022, are presented, and their diverse biological activities are briefly described. Moreover, the biosynthetic proposal for stemmadenine and the proposed biogenetic conversion of stemmadenine-type alkaloids into vallesamine-type congeners are discussed in detail. Moreover, the successful synthetic strategies to access the strained stemmadenine scaffolds are fully reviewed.

The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology.

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.

What We Have Gained from Ibogaine: α3ß4 Nicotinic Acetylcholine Receptor Inhibitors as Treatments for Substance Use Disorders.

For decades, ibogaine─the main psychoactive alkaloid found in Tabernanthe iboga─has been investigated as a possible treatment for substance use disorders (SUDs) due to its purported ability to interrupt the addictive properties of multiple drugs of abuse. Of the numerous pharmacological actions of ibogaine and its derivatives, the inhibition of α3ß4 nicotinic acetylcholine receptors (nAChRs), represents a probable mechanism of action for their apparent anti-addictive activity. In this Perspective, we examine several classes of compounds that have been discovered and developed to target α3ß4 nAChRs. Specifically, by focusing on compounds that have proven efficacious in pre-clinical models of drug abuse and have been evaluated clinically, we highlight the promising potential of the α3ß4 nAChRs as viable targets to treat a wide array of SUDs. Additionally, we discuss the challenges faced by the existing classes of α3ß4 nAChR ligands that must be overcome to develop them into therapeutic treatments.