Tolerability and Efficacy of Ibogaine in the Treatment of Alcoholism: the First Randomized, Double-blind, Placebo-controlled, Escalating-dose, Phase 2 Trial

Approximately 5% of the world's adult population has some alcohol-related disorder, which in addition is associated with 3% of all deaths in the world. In Brazil, harmful use and dependence on alcohol reach about 10% of the population, with alcohol being one of the main factors of disease and mortality. Although the medications currently used have some efficacy, the adverse effects and relatively long time of treatment are factors that may reduce patients' motivation to continue taking the medication correctly. Therefore, it is necessary to conduct research with new drugs for the treatment of alcoholism. Ibogaine is an alkaloid present in the bush Tabernanthe iboga (iboga), a plant from Central Africa traditionally used in countries such as Gabon and Cameroon. Animal studies and case series suggest that one or a few doses of ibogaine significantly reduce withdrawal symptoms and the intensity of use of various drugs, including opioids, psychostimulants, and alcohol. However, there are no controlled clinical studies that have explored these effects. The aim of the present study is to evaluate the safety, tolerability and efficacy of increasing doses of ibogaine in 12 alcoholic patients. Each patient will be hospitalized for 20 days and receive 3 increasing doses of ibogaine. The first 3 patients will receive oral doses of 20 to 400 mg of ibogaine in an open-label design. If the 3 higher doses (240, 320 and 400 mg) are well tolerated, the next 9 volunteers will receive these doses or placebo randomly. The volunteers will also be evaluated 7, 14 and 21 days and 1, 3, 6 and 12 months after leaving the hospital to monitor the consumption of alcohol and other drugs.

开始日期2022-10-30

申办/合作机构

University of Sao Paulo

[+2]

NCT04313712 / Active, not recruitingN/AIIT

A Pre-post Study Evaluating the Safety and Efficacy of Ibogaine-Magnesium Therapy in Veterans With Sequelae of Repeated Blast Exposure

A Pre-post Study Evaluating the Safety and Efficacy of Ibogaine-Magnesium Therapy in Veterans with Sequelae of Repeated Blast Exposure.

开始日期2021-11-15

申办/合作机构

Stanford University

EUCTR2014-000354-11-NL / Not yet recruiting临床2期IIT

The Efficacy of Ibogaine in the Treatment of Addiction; an open label, single fixed dose pilot-study of the efficacy of ibogaine in opioid-dependent subjects - Ibogaine in opioid-dependence

开始日期2021-04-30

申办/合作机构-

100 项与 Opioid receptors x DAT 相关的临床结果

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100 项与 Opioid receptors x DAT 相关的转化医学

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0 项与 Opioid receptors x DAT 相关的专利（医药）

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项与 Opioid receptors x DAT 相关的文献（医药）

2023-11-01·Obesity reviews : an official journal of the International Association for the Study of Obesity

Effects of bariatric surgery and dietary interventions for obesity on brain neurotransmitter systems and metabolism: A systematic review of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies.

Review

作者: Miras, Alexander D ; Al-Alsheikh, Alhanouf S ; Alabdulkader, Shahd ; Goldstone, Anthony P

This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single-photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low-calorie diet, three very low-calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for ¹¹ C-raclopride, ¹⁸ F-fallypride, ¹²³ I-IBZM; one for dopamine transporter, ¹²³ I-FP-CIT; one used tracer for serotonin 5-HT_2A receptor, ¹⁸ F-altanserin; two used tracers for serotonin transporter, ¹¹ C-DASB or ¹²³ I-FP-CIT; two used tracer for μ-opioid receptor, ¹¹ C-carfentanil; one used tracer for noradrenaline transporter, ¹¹ C-MRB); seven studies assessed glucose uptake using ¹⁸ F-fluorodeoxyglucose; four studies assessed regional cerebral blood flow using ¹⁵ O-H₂ O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using ¹⁸ F-FTHA and one using ¹¹ C-palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies.

2023-07-01·Addiction

Repurposing ketamine to treat cocaine use disorder: integration of artificial intelligence‐based prediction, expert evaluation, clinical corroboration and mechanism of action analyses

Article

作者: Xu, Rong ; Davis, Pamela B. ; Gorenflo, Maria ; Gao, Zhenxiang ; Winhusen, T. John ; Ghitza, Udi E. ; Kaelber, David C.

AbstractBackground and aimsCocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost‐effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA‐approved drugs for CUD treatment.DesignOur drug repurposing strategy combines artificial intelligence (AI)‐based drug prediction, expert panel review, clinical corroboration and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI‐based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non‐ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine’s potential mechanisms of action in the context of CUD.SettingThe study utilized TriNetX to access EHRs from more than 90 million patients world‐wide. Genetic‐ and functional‐level analyses used DisGeNet, Search Tool for Interactions of Chemicals and Kyoto Encyclopedia of Genes and Genomes databases.ParticipantsA total of 7742 CUD patients who received anesthesia (3871 ketamine‐exposed and 3871 anesthetic‐controlled) and 7910 CUD patients with depression (3955 ketamine‐exposed and 3955 antidepressant‐controlled) were identified after propensity score‐matching.MeasurementsEHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription.FindingsPatients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics [hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.42–2.78]. Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR = 4.39, 95% CI = 2.89–6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD‐associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand‐receptor interaction, cAMP signaling and cocaine abuse/dependence.ConclusionsKetamine appears to be a potential repurposed drug for treatment of cocaine use disorder.

2023-06-19·Molecules (Basel, Switzerland)

The Kappa Opioid Receptor Agonist 16-Bromo Salvinorin A Has Anti-Cocaine Effects without Significant Effects on Locomotion, Food Reward, Learning and Memory, or Anxiety and Depressive-like Behaviors.

Article

作者: Butelman, Eduardo R ; Prisinzano, Thomas E ; Ewald, Amy ; Williamson, Samuel E ; Welsh, Susan ; McElroy, Bryan D ; van de Wetering, Ross ; Kivell, Bronwyn M ; Kornberger, Lindsay

Kappa opioid receptor (KOR) agonists have preclinical antipsychostimulant effects; however, adverse side effects have limited their therapeutic development. In this preclinical study, conducted in Sprague Dawley rats, B6-SJL mice, and non-human primates (NHPs), we evaluated the G-protein-biased analogue of salvinorin A (SalA), 16-bromo salvinorin A (16-BrSalA), for its anticocaine effects, side effects, and activation of cellular signaling pathways. 16-BrSalA dose-dependently decreased the cocaine-primed reinstatement of drug-seeking behavior in a KOR-dependent manner. It also decreased cocaine-induced hyperactivity, but had no effect on responding for cocaine on a progressive ratio schedule. Compared to SalA, 16-BrSalA had an improved side effect profile, with no significant effects in the elevated plus maze, light-dark test, forced swim test, sucrose self-administration, or novel object recognition; however, it did exhibit conditioned aversive effects. 16-BrSalA increased dopamine transporter (DAT) activity in HEK-293 cells coexpressing DAT and KOR, as well as in rat nucleus accumbens and dorsal striatal tissue. 16-BrSalA also increased the early phase activation of extracellular-signal-regulated kinases 1 and 2, as well as p38 in a KOR-dependent manner. In NHPs, 16-BrSalA caused dose-dependent increases in the neuroendocrine biomarker prolactin, similar to other KOR agonists, at doses without robust sedative effects. These findings highlight that G-protein-biased structural analogues of SalA can have improved pharmacokinetic profiles and fewer side effects while maintaining their anticocaine effects.

项与 Opioid receptors x DAT 相关的新闻（医药）

2023-08-08

·BioSpace

Sparian Biosciences Awarded $19 Million Five-Year NIH/ NIDA Grant to Fund Development of SBS-518 for Stimulant Use Disorder Through Phase 1 Clinical Development

SBS-518 is a dual sigma receptor antagonist/dopamine active transporter inhibitor in development for the treatment of stimulant use disorder (e.g., cocaine and methamphetamine) Grant awarded by National Institutes of Health / National Institute of Drug Abuse (NIH/NIDA) under the Help End Addiction Long-Term (HEAL) initiative NEW YORK, Aug. 08, 2023 (GLOBE NEWSWIRE) -- Sparian Biosciences, Inc. (“Sparian”), a clinical-stage CNS-focused biopharmaceutical company, today announced that it has been awarded a $19 million, five-year grant to fund development of SBS-518 from IND submission through Phase 1 clinical development. SBS-518 is a first-in-class dual sigma receptor (SR) antagonist/dopamine transporter (DAT) inhibitor in development for the treatment of stimulant use disorder (StUD). StUD is a subset of substance use disorders that includes cocaine and methamphetamine use disorders. The grant was awarded by NIH/NIDA under the Help End Addiction Long-Term (HEAL) initiative. SBS-518 is a novel first-in-class compound that targets within the brain both the sigma receptor (S1 and S2) and the dopamine active transporter (DAT). In pre-clinical efficacy assays, SBS-518 blocks the stimulant induced rise in extra-cellular dopamine and blocks cocaine and methamphetamine self-administration without itself producing self-rewarding behavior. DAT, the site of action for stimulants, including illicit stimulants, has proven to be an elusive target for therapeutics. The combination of sigma and DAT inhibition appears to block the action of methamphetamine and cocaine without interfering with the physiologic transport of dopamine. “Sparian was founded to develop innovative therapeutics to treat CNS disorders, particularly pain and substance use disorders,” said Jeff Reich, M.D., Chief Executive Officer and Co-founder. “StUD presents a major unmet medical and public health need for which there are currently no approved therapies. If we can successfully advance SBS-518 into the clinic, it could represent a significant step forward in the treatment of substance use disorders.” The $19 million dollars in funding represents the third NIH/NIDA grant Sparian has received. Since its founding, Sparian has been awarded a total of $41 million in government grants to support three programs. The lead program SBS1000, a non-opioid analgesic, is now in phase 1 clinical trials. SBS-226, a dual mu opioid receptor (MOR) agonist/delta opioid receptor (DOR) antagonist, is being developed for opioid use disorder (OUD). “We are extremely proud of the ongoing support we have received from NIDA,” said Dr. Reich. “NIDA, through the HEAL initiative, has sparked a new wave of innovation and entrepreneurship dedicated to the treatment of substance use disorders. Sparian, along with our academic partners, is honored to be a trusted collaborator.” SBS-518 is being developed in collaboration with the National Institute of Drug Abuse (NIDA), University of Florida College of Pharmacy, and the Harvard Medical School-McLean Hospital. About Stimulant Use Disorder (StUD) StUD represents a serious public health crisis in the U.S. with a growing prevalence of 4.1 million and approximately 57,000 annual deaths reported in 2021. There are no U.S. Food and Drug Administration-approved drugs to treat StUD. The current treatment approach includes off-label use of prescription therapies, such as antidepressants, and/or behavioral-psychosocial modalities. Only modest benefits have been demonstrated. It is estimated that only 13% of eligible patients are undergoing treatment of any kind reflecting the lack of effective medication. About Sparian Biosciences Sparian Biosciences is a clinical-stage CNS-focused biopharmaceutical company committed to developing transformational therapies to address significant medical needs. The company was co-founded by Jeff Reich, M.D., and Gavril Pasternak, M.D., Ph.D., and was spun out of Memorial Sloan Kettering Cancer Center (MSK). Sparian has five programs that address acute and chronic pain, opioid use disorder (OUD), acute opioid overdose, and stimulant use disorder (StUD). Sparian is the recipient of two NIDA UG3/UH3 grants and an SBIR grant totaling nearly $41M in NIH support. For more information, visit . Research reported in this press release was supported by the National Institute on Drug Abuse of the National Institutes of Health under award number 1UG3DA058553-01.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health Contact: Annie Pasternak Chief Operating Officer annie@sparianbiosciences.com

临床1期