Anti-addictive Effects Research Articles

Evaluation of (S)-T1 and (S)-T2 ligands targeting α3β4 nAChR as potential nicotine addiction pharmacotherapy.

Substance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR). The effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice. The results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10mg/kg) and (S)-T2 (10mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC). These findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction.

Exploring the Pharmacological Potential of Lobelia trigona and its Bioactive Compounds

Aim:: The aim of this in-depth review is to provide an overview of the pharmacologi-cal effects of Lobelia trigona and its bioactive components, highlighting its potential as a source of medicinal agents for various diseases Methods:: This review involved a comprehensive analysis of existing literature and research studies on the pharmacological effects of Lobelia trigona and its bioactive compounds. A bib-liography survey was carried out using various electronic databases like Google Scholar, Sci-enceDirect, Springer, Scopus, PubMed, Wiley, etc., and other offline as well as online aca-demic libraries were also used for the bibliography survey and compilation of data. Results:: Lobelia trigona was found to exhibit diverse pharmacological effects, primarily me-diated by bioactive alkaloids, such as lobeline, lobelanidine, and lobelanine. It demonstrated bronchodilator effects with potential applications in respiratory conditions, analgesic and anti-inflammatory properties for treating painful and inflammatory conditions, and cardiovascular effects, including vasodilation and hypotensive effects. The alkaloid lobeline was reported to have promising anti-addictive effects, particularly in smoking cessation. Nanocarrier-based formulations have the potential to address limitations, improve dosing schedules, and enhance the pharmacological effects of Lobelia trigona. Conclusion:: Lobelia trigona demonstrates diverse pharmacological effects, primarily attribut-ed to its bioactive alkaloids. It holds promise as a source of medicinal agents for a range of diseases. The potential synergy between the pharmacological effects of Lobelia trigona and nanocarrier technology highlights the significance of nanotechnology in improving Lobelia trigona-based therapeutics. However, further research is warranted to determine the clinical effectiveness, safety, biocompatibility, and long-term effects of nanocarrier-based Lobelia trigona formulations in different disease models.

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.

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.

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

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. 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. 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. 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. IBO displays complex effects through multiple targets. The information detailed here should guide future research on both mechanistic and therapeutic studies.

Interplay between the renin angiotensin system and oxidative stress contributes to alcohol addiction by stimulating dopamine accumulation in the mesolimbic pathway

The brain renin–angiotensin system (RAS) has recently been implicated in the development of substance abuse and addiction. However, the integrative roles of the two counter-regulating RAS arms, including the ACE1/Ang II/AT1R axis and the ACE2/Ang(1–7)/MasR axis, in alcohol addiction remain unclear. Using the 20% ethanol intermittent-access two-bottle-choice (IA2BC) paradigm, we observed significant alcohol preference and addictive behaviors in rats. Additionally, we observed significant disruption in the RAS and redox homeostasis in the ventral tegmental area (VTA), as indicated by upregulation of ACE1 activities, Ang II levels, AT1R expression, and glutathione disulfide contents, as well as downregulation of ACE2 activities, Ang(1–7) levels, MasR expression and glutathione content. Moreover, dopamine accumulated in the VTA and nucleus accumbens of IA2BC rats. Intra-VTA infusion of the antioxidant tempol substantially attenuated RAS imbalance and addictive behaviors. Intra-VTA infusion of the ACE1 inhibitor captopril significantly reduced oxidative stress, alcohol preference, addictive behaviors, and dopamine accumulation, whereas intra-VTA infusion of the ACE2 inhibitor MLN4760 had the opposite effects. The anti-addictive effects of the ACE2/Ang(1–7)/MasR axis were further observed using intra-VTA infusion of Ang(1–7) and a MasR-specific antagonist A779. Therefore, our findings suggest that excessive alcohol intake causes RAS imbalance via oxidative stress, and that a dysregulated RAS in the VTA contributes to alcohol addiction by stimulating oxidative stress and dopaminergic neurotransmission. Breaking the vicious cycle of RAS imbalance and oxidative stress using brain-permeable antioxidants, ACE1 inhibitors, ACE2 activators, or Ang(1–7) mimetics thus represents a promising strategy for combating alcohol addiction.

The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence.

Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10-50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether "low-dose" CBD products confer any therapeutic benefits. This is an important question to answer, as low-dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ9 -tetrahydrocannabinol content greater than 2.0%. Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300-400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti-addiction effects in drug-dependent individuals. More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., <300 mg/day) oral doses of CBD.

Neutral CB1 Receptor Antagonists as Pharmacotherapies for Substance Use Disorders: Rationale, Evidence, and Challenge.

Cannabinoid receptor 1 (CB1R) has been one of the major targets in medication development for treating substance use disorders (SUDs). Early studies indicated that rimonabant, a selective CB1R antagonist with an inverse agonist profile, was highly promising as a therapeutic for SUDs. However, its adverse side effects, such as depression and suicidality, led to its withdrawal from clinical trials worldwide in 2008. Consequently, much research interest shifted to developing neutral CB1R antagonists based on the recognition that rimonabant’s side effects may be related to its inverse agonist profile. In this article, we first review rimonabant’s research background as a potential pharmacotherapy for SUDs. Then, we discuss the possible mechanisms underlying its therapeutic anti-addictive effects versus its adverse effects. Lastly, we discuss the rationale for developing neutral CB1R antagonists as potential treatments for SUDs, the supporting evidence in recent research, and the challenges of this strategy. We conclude that developing neutral CB1R antagonists without inverse agonist profile may represent attractive strategies for the treatment of SUDs.

Historical Pathways for Opioid Addiction, Withdrawal with Traditional and Alternative Treatment Options with Ketamine, Cannabinoids, and Noribogaine: A Narrative Review.

Even as prescription opioid dispensing rates have begun to decrease, the use of illicit opioids such as heroin and fentanyl has increased. Thus, the end of the opioid epidemic is not in sight, and treating patients that are addicted to opioids remains of utmost importance. Currently, the primary pharmacotherapies used to treat opioid addiction over the long term are the opioid antagonist naltrexone, the partial-agonist buprenorphine, and the full agonist methadone. Naloxone is an antagonist used to rapidly reverse opioid overdose. While these treatments are well-established and used regularly, the gravity of the opioid epidemic necessitates that all possible avenues of treatment be explored. Therefore, in this narrative review, we analyze current literature regarding use of the alternative medications ketamine, noribogaine, and cannabinoids in treating patients suffering from opioid use disorder. Beyond its use as an anesthetic, ketamine has been shown to have many applications in several medical specialties. Of particular interest to the subject at hand, ketamine is promising in treating individuals addicted to opioids, alcohol, and cocaine. Therapeutically administered cannabinoids have been proposed for the treatment of multiple illnesses. These include, but are not limited to epilepsy, Parkinson's disease, multiple sclerosis, chronic pain conditions, anxiety disorders, and addiction. The cannabinoid dronabinol has been seen to have varying effects. High doses appear to reduce withdrawal symptoms but this comes at the expense of increased adverse side effects such as sedation and tachycardia. Noribogaine is a weak MOR antagonist and relatively potent KOR agonist, which may explain the clinical anti-addictive effects. More research should be done to assess the viability of these medications for the treatment of OUD and withdrawal.

Chemical composition of Ayahuasca seized in Poland

Ayahuasca is a traditional psychoactive brew of Amazonian indigenous, used for medicinal and spiritual purposes. Over the years, the consumption of ayahuasca all over the world has increased not only in shamanic and religious rituals, but also for recreational purposes. Wide variation in the concentration of alkaloids, i.e. N,N-dimethyltryptamine (DMT), harmaline, harmine, tetrahydroharmine (THH) and harmalol in Ayahuasca has been reported worldwide. Being a plant preparation, traditional Ayahuasca is variable in appearance, taste, and effects. Several studies suggest that it has anxiolytic, antidepressant, and antiaddictive effects. The aim of our study was to determine alkaloids concentration in Ayahuasca preparation seized in two cases of Ayahuasca rituals in Poland. In these cases we also analyzed plant material, i.e. the bark and stem of Banisteriopsis caapi, leaves of Psychotria viridis, seeds of Peganum Harmala and brown powder substances. The research material consisted of 32 samples of Ayahuasca brew seized in two Ayahuasca rituals cases in Poland and sent for examination to the Institute of Forensic Research in Krakow. Samples were prepared by dilution in ethanol or ethanol:water (1:1 v/v) mixture. The qualitative analyses of the samples were carried out by gas chromatography coupled with mass spectrometry (GC-MS). Gas chromatograph HP 6890N GC System coupled with the 5973 Network Mass Selective Detector with a quadrupole mass analyzer from Agilent Technologies (USA), were used in the study. Chromatographic separation of the tested compounds in the programmed temperature increase was carried out on the HP-5MS capillary column (30 m × 0.25 mm; 0.25 μm). The sample was dosed automatically in the splitless mode. The mass spectrometer operated in positive electron ionisation mode (EJ), and the energy beam was 70 eV. The acquisition was conducted in the scanning mode of the full mass range of m/z from 29 to 600 amu. The concentrations of DMT, harmaline and harmine were determined by liquid chromatography combined with mass spectrometry, a hybrid combination of quadrupole and time of flight analyzer (LC-MS/QTOF). The 1200 series liquid chromatograph and the 6520 Accurate-Mass QTOFMS mass spectrometer from Agilent Technologies (Santa Clara, CA, USA) were used. The separation was carried out on the Ascentis express C18 column (7.5 cm × 2.1 mm; 2.7 μm) from Supelco, thermostated at 35 °C. A mixture of 0.1% formic acid in water (A, v/v) and acetonitrile (B, v/v) was used as a mobile phase. Our research showed large variations in alkaloid profiles of Ayahuasca samples from one source. The concentration ranges of alkaloids was within: for DMT: 0.09–1.60 mg/mL, harmaline: 0.02–5.39 mg/mL and for harmine: 0.11–1.49 mg/mL. Concentration of DMT, HRL and HRM in Ayahuasca preparation was analyzed. Our research showed large variations in alkaloid profiles of Ayahuasca samples from one source. Variability of the brew composition and individual variability of effects together make it difficult for users to assess the quality of the brew that they drink during the ceremony. Our research results may be surely used as warning for participants of illicit Ayahuasca ceremonials, by increasing awareness about the quality of herbal preparations used.

Protein Tyrosine Phosphatase Receptor Type D Regulates Neuropathic Pain After Nerve Injury via the STING-IFN-I Pathway.

Neuropathic pain is usually caused by injury or dysfunction of the somatosensory system, and medicine is a common way of treatment. Currently, there are still no satisfactory drugs, like opioids and lidocaine, which carry a high risk of addiction. Protein tyrosine phosphatase receptor type D (PTPRD) is a known therapeutic target in addiction pathways and small molecule inhibitors targeting it, such as 7-butoxy illudalic acid analog (7-BIA), have recently been developed to tackle addition. PTPRD is also upregulated in the dorsal root ganglion (DRG) in a rat model of neuropathic pain, but is not yet clear whether PTPRD contributes to the development of neuropathic pain. Here, we established a chronic constriction injury (CCI) and evaluated PTPRD expression and its association with neuropathic pain. PTPRD expression was found to gradually increase after CCI in DRGs, and its expression was concomitant with the progressive development of hypersensitivity as assessed by both mechanical and thermal stimuli. Both PTPRD knockdown and administration of PTPRD inhibitor 7-BIA alleviated CCI-induced neuropathic pain while upregulating STING and IFN-α in the DRG. Treatment with H-151, a STING inhibitor, abolished the analgesic effects of PTPRD knockdown. Taken together, our study suggests that increased levels of PTPRD in the DRG following CCI are involved in the development of neuropathic pain via the STING-IFN-I pathway. 7-BIA, a small molecule inhibitor of PTPRD with anti-addiction effects, may represent a novel and safe therapeutic strategy for the clinical management of neuropathic pain without the risk of addiction.

Psychedelics: A new era of treatment?

IntroductionPsychedelics - including LSD (lysergic acid diethylamide), psilocybin, DMT (N, N-dimethyltryptamine), ayahuasca and mescaline - have an ancient history across various civilizations. In 1950, after LSD’s discovery by Hofmann, psychedelics enjoyed a short-lived relationship with psychiatry, before prohibitive legislature emerging in response to the recreational use in the mid-1960s. However, the last decade has witnessed a renewed scientific interest in psychedelics - a phenomenon referred to as the ‘Psychedelic Renaissance’.ObjectivesReview the pharmacology of psychedelic drugs and the latest evidence of its therapeutic potentials in anxiety, mood and addictive disorders.MethodsLiterature review performed on PubMed and Google Scholar databases, using the keywords “psychedelics”, “hallucinogens”, “d-lysergic acid diethylamide (LSD)”, “psilocybin”, “ayahuasca”, “mescaline”, “DMT (N,N-dimethyltryptamine)”.ResultsThe psychedelics or “classic hallucinogens” can be subdivided into three sub-classes: the plant-derived tryptamines (psilocybin and ibogaine) and phenethylamines (mescaline), and the semisynthetic ergolines (LSD). The therapeutic potentials are mediated by an agonist action on 5-HT2A receptors expressed in frontal and paralimbic structures involved in mood and emotion regulation, introspection, interoception and self-consciousness. Stimulation of 5-HT2ARincreases the glutamatergic tone and neuroplasticity and is accompanied by reduced amygdala activity, reducing anxiety. Experimental, open-label, and RCTs showed anxiolytic, antidepressive, and antiaddictive effects with psychedelics. As examples, psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression in treatment-resistant depression.ConclusionsDespite the promising effects of psychedelics on anxiety, depression and addiction, the evidence is still preliminary, waiting for long-term studies with bigger samples.Conflict of interestNo significant relationships.

The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges.

Psychedelics or serotonergic hallucinogens are a group of substances that share the agonism of serotonergic 5-HT2A receptors as their main mechanism of action. Its main effects include changes in perception, cognitive process, and mood. Despite being used for centuries by different cultures in ritual contexts, these substances have currently aroused the interest of science and industry for their promising antidepressant, anxiolytic, and anti-addictive effects. Considering this evidence, this article aims to explore some of the possible health policy challenges to integrate these therapeutic tools into broad and heterogeneous health systems. As a main benefit, these substances produce rapid and enduring effects with the administration of single or few doses, which could lead to new treatment possibilities for patients with severe mental disorders resistant to the usual medications. The main challenge is associated with the fact that these substances remain scheduled in most countries and are associated with social stigma related to their recreational use (especially LSD and psilocybin). This situation makes it exceedingly difficult to conduct clinical trials, although international conventions allow such research. Ethically, this could be interpreted as a violation of human rights since thousands of people are prevented from having access to possible benefits. Interestingly, ritual ayahuasca use is more acceptable to the public than the use of psilocybin-containing mushrooms or LSD. The controlled, clinical use of LSD and psilocybin seems to be less criticized and is being explored by the industry. Rigorous scientific evidence coupled with industrial interests (LSD and psilocybin), together with respect for traditional uses (ayahuasca) and international conventions, seems to be the best way for these drugs to be integrated into health systems in the next years. Which highlights the need for an urgent dialogue between science, health system, society, and politics.

Sintocalmy, a Passiflora incarnata Based Herbal, Attenuates Morphine Withdrawal in Mice.

Chronic opioid use changes brain chemistry in areas related to reward processes, memory, decision-making, and addiction. Both neurons and astrocytes are affected, ultimately leading to dependence. Passiflora incarnata L. (Passifloraceae) is the basis of frequently used herbals to manage anxiety and insomnia, with proven central nervous system depressant effects. Anti-addiction properties of P. incarnata have been reported. The aim of this study was to investigate the effect of a commercial extract of Passiflora incarnata (Sintocalmy®, Aché Laboratory) in the naloxone-induced jumping mice model of morphine withdrawal. In addition, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100B) levels were assessed in the frontal cortex and hippocampus, and DNA damage was verified on blood cells. In order to improve solubilization a Sintocalmy methanol extract (SME) was used. SME is mainly composed by flavonoids isovitexin and vitexin. The effects of SME 50, 100 and 200mg/kg (i.p.) were evaluated in the naloxone-induced withdrawal syndrome in mice. SME 50 and SME 100mg/kg decreased naloxone-induced jumping in morphine-dependent mice without reducing locomotor activity. No alterations were found in GFAP levels, however SME 50mg/kg prevented the S100B increase in the frontal cortex and DNA damage. This study shows anti-addiction effects for a commercial standardized extract of P. incarnata and suggests the relevance of proper clinical assessment.

EEG Gamma Band Alterations and REM-like Traits Underpin the Acute Effect of the Atypical Psychedelic Ibogaine in the Rat.

Ibogaine is a psychedelic alkaloid that has attracted large scientific interest because of its antiaddictive properties in observational studies in humans as well as in animal models. Its subjective effect has been described as intense, vivid dream-like experiences occurring while awake; hence, ibogaine is often referred to as an oneirogenic psychedelic. While this unique dream-like profile has been hypothesized to aid the antiaddictive effects, the electrophysiological signatures of this psychedelic state remain unknown. We previously showed in rats that ibogaine promotes a waking state with abnormal motor behavior along with a decrease in NREM and REM sleep. Here, we performed an in-depth analysis of the intracranial electroencephalogram during "ibogaine wakefulness". We found that ibogaine induces gamma oscillations that, despite having larger power than control levels, are less coherent and less complex. Further analysis revealed that this profile of gamma activity compares to that of natural REM sleep. Thus, our results provide novel biological evidence for the association between the psychedelic state and REM sleep, contributing to the understanding of the brain mechanisms associated with the oneirogenic psychedelic effect of ibogaine.

A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats.

Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose- and time-dependence) induced by the acute ibogaine and noribogaine administration in rats using the forced swim test (FST, 20 and 40 mg/kg i.p., single injection for each dose). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine's FST effect was short-lived (30 min) and correlated with high brain concentrations (estimated >8 μM of free drug), while the ibogaine's antidepressant-like effect was significant at 3 h. At this time point, both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own (ibogaine ∼0.5 μM, noribogaine ∼2.5 μM). Our data suggests a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.

GABAB Receptors and Drug Addiction: Psychostimulants and Other Drugs of Abuse.

Metabotropic GABAB receptors (GABABRs) mediate slow inhibition and modulate synaptic plasticity throughout the brain. Dysfunction of GABABRs has been associated with psychiatric illnesses and addiction. Drugs of abuse alter GABAB receptor (GABABR) signaling in multiple brain regions, which partly contributes to the development of drug addiction. Recently, GABABR ligands and positive allosteric modulators (PAMs) have been shown to attenuate the initial rewarding effect of addictive substances, inhibit seeking and taking of these drugs, and in some cases, ameliorate drug withdrawal symptoms. The majority of the anti-addiction effects seen with GABABR modulation can be localized to ventral tegmental area (VTA) dopamine neurons, which receive complex inhibitory and excitatory inputs that are modified by drugs of abuse. Preclinical research suggests that GABABR PAMs are emerging as promising candidates for the treatment of drug addiction. Clinical studies on drug dependence have shown positive results with GABABR ligands but more are needed, and compounds with better pharmacokinetics and fewer side effects are critically needed.

Massive in Silico Study of Noble Gas Binding to the Structural Proteome.

Noble gases are chemically inert, and it was therefore thought they would have little effect on biology. Paradoxically, it was found that they do exhibit a wide range of biological effects, many of which are target-specific and potentially useful and some of which have been demonstrated in vivo. The underlying mechanisms by which useful pharmacology, such as tissue and neuroprotection, anti-addiction effects, and analgesia, is elicited are relatively unexplored. Experiments to probe the interactions of noble gases with specific proteins are more difficult with gases than those with other chemicals. It is clearly impractical to conduct the large number of gas-protein experiments required to gain a complete picture of noble gas biology. Given the simplicity of atoms as ligands, in silico methods provide an opportunity to gain insight into which noble gas-protein interactions are worthy of further experimental or advanced computational investigation. Our previous validation studies showed that in silico methods can accurately predict experimentally determined noble gas binding sites in X-ray structures of proteins. Here, we summarize the largest reported in silico reverse docking study involving 127 854 protein structures and the five nonradioactive noble gases. We describe how these computational screening methods are implemented, summarize the main types of interactions that occur between noble gases and target proteins, describe how the massive data set that this study generated can be analyzed (freely available at group18.csiro.au), and provide the NDMA receptor as an example of how these data can be used to understand the molecular pharmacology underlying the biology of the noble gases. We encourage chemical biologists to access the data and use them to expand the knowledge base of noble gas pharmacology, and to use this information, together with more efficient delivery systems, to develop "atomic drugs" that can fully exploit their considerable and relatively unexplored potential in medicine.

Cessation and reduction in alcohol consumption and misuse after psychedelic use.

Meta-analysis of randomized studies using lysergic acid diethylamide (LSD) for alcohol use disorder (AUD) showed large, significant effects for LSD efficacy compared to control conditions. Clinical studies suggest potential anti-addiction effects of LSD and mechanistically-related classic psychedelics for alcohol and other substance use disorders. To supplement clinical studies, reports of psychedelic use in naturalistic settings can provide further data regarding potential effects of psychedelics on alcohol use. An anonymous online survey of individuals with prior AUD reporting cessation or reduction in alcohol use following psychedelic use in non-clinical settings. 343 respondents, mostly White (89%), males (78%), in the USA (60%) completed the survey. Participants reported seven years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption, with 72% meeting retrospective criteria for severe AUD. Most reported taking a moderate or high dose of LSD (38%) or psilocybin (36%), followed by significant reduction in alcohol consumption. After the psychedelic experience 83% no longer met AUD criteria. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced alcohol misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with a greater reduction in alcohol consumption, controlling for prior alcohol consumption and related distress. Although results cannot demonstrate causality, they suggest that naturalistic psychedelic use may lead to cessation or reduction in problematic alcohol use, supporting further investigation of psychedelic-assisted treatment for AUD.

Strategies for the in vitro production of antiaddictive ibogan type alkaloids from Apocynaceae species

Monoterpenoid indole alkaloids (MIAs) of the ibogan type, such as ibogaine, have shown promising antiaddictive effects against several drugs of abuse in humans and animal models of addiction. Unfortunately, international ibogaine demand has led to the overexploitation of natural populations of the African species Tabernanthe iboga (Apocynaceae), the main source of this alkaloid. Therefore, it is necessary to identify alternative ibogan type alkaloid-containing plant species, as well as to develop new sustainable production systems for said group of pharmaceutically important compounds. In this review, we focus on strategies for the in vitro production of the antiaddictive ibogan type MIAs coronaridine, ibogamine, voacangine, and ibogaine (collectively named “CIVI-complex”) from Apocynaceae species, with particular emphasis on the Tabernaemontana genus. Since plant tissue culture (PTC)-related information on the CIVI-complex is scarce, we also consider reports on the in vitro production of other ibogan type MIAs and where necessary, of compounds belonging to the aspidospermatan, corynanthean, and plumeran type. This review aims at giving an overview of potential strategies to produce antiaddictive ibogan type alkaloids from in vitro cultures of Apocynaceae species.