zolunicant (MM-110) / Mindmed - LARVOL DELTA

Effects of psychedelics on opioid use disorder: a scoping review of preclinical studies. (PubMed, Cell Mol Life Sci) - "Most studies showed that 18-methoxycoronaridine (18-MC), ibogaine, noribogaine, and ketamine could reduce opioid self-administration, alleviate withdrawal symptoms, and change conditioned place preference. This review strengthens support for translational studies testing psychedelics as potential innovative targets for OUD. It also suggests clinical studies need to include a broader range of agents beyond iboga derivatives but can also explore several ongoing questions in the field, such as the mechanism of action behind the potential therapeutic effect, safety profiles, doses, and frequency of administrations needed."

Journal • Preclinical • Review • Addiction (Opioid and Alcohol) • Cardiovascular • Pain • Substance Abuse

Coronaridine congeners induce anticonvulsant activity in rodents by hippocampal mechanisms involving mainly potentiation of GABAA receptors. (PubMed, Eur J Pharmacol) - "The coronaridine congeners catharanthine and 18-methoxycoronaridine (18-MC) display sedative, anxiolytic, and antidepressant properties by acting on mechanisms involving GABAergic and/or monoaminergic transmissions. Here, we expanded their pharmacological properties by studying their anticonvulsant activity in male and female mice using the pentylenetetrazole (PTZ)-induced seizure test...However, a comparatively higher susceptibility was observed in male mice after repeated treatment. The underlying hippocampal mechanisms mainly involve GABAAR potentiation, whereas monoamines play a minor role in the anticonvulsive action."

Journal • Preclinical • CNS Disorders • Epilepsy

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters. (PubMed, ACS Chem Neurosci) - "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...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."

Journal • Addiction (Opioid and Alcohol) • Anesthesia • CNS Disorders • Nicotine Addiction • Psychiatry • Substance Abuse

Ibogaine: a promising treatment for substance dependence? (ECNP 2023) - "The main metabolite of ibogaine, noribogaine, as well as its synthetic congener, 18-methoxycoronaridine (18MC), have shown efficacy in the treatment of addictions, but have a better safety profile... Ibogaine has a growing interest in the treatment of substance dependence, in part due to the limitation of available options. Its beneficial effects are related not only to its complex psychopharmacology but also to the subjective experience induced. Thus, the need for reliable phase I and II studies to evaluate its benefit in clinical practice, such as tolerance, safety, dose-effect relationship, and interactions, becomes evident."

Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Psychiatry • Substance Abuse

Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABA receptor affinity for GABA. (PubMed, Eur J Pharmacol) - "The sedative and anxiolytic-like activity of two coronaridine congeners, (+)-catharanthine and (-)-18-methoxycoronaridine (18-MC), was studied in male and female mice...Coronaridine congeners did not block pentylenetetrazole-induced anxiogenic-like activity in mice...Functional and radioligand binding results showed that coronaridine congeners interact with a site different from that for benzodiazepines, increasing GABA receptor affinity for GABA. Our study showed that coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice in a sex-independent fashion, likely by a benzodiazepine-independent allosteric mechanism that increases GABA receptor affinity for GABA."

Journal • Preclinical

(+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission. (PubMed, Eur J Pharmacol) - "Our study shows that coronaridine congeners induce antidepressant-like activity in a dose- and time-dependent, and sex-independent, manner. The antidepressant-like property of both compounds involves serotonin transporter inhibition, without directly activating/inhibiting serotonin receptors 3, while (+)-catharanthine also mobilizes norepinephrinergic neurotransmission."

Journal • Preclinical

A Study to Assess 18-Methoxycoronaridine (18-MC HCl) in Healthy Volunteers (clinicaltrials.gov) - P1; N=108; Completed; Sponsor: Mind Medicine, Inc.; Recruiting ➔ Completed

Clinical • Trial completion • CNS Disorders • Psychiatry

A Study to Assess 18-Methoxycoronaridine (clinicaltrials.gov) - P1; N=112; Recruiting; Sponsor: Mind Medicine, Inc.; Trial completion date: Aug 2021 ➔ Dec 2021; Trial primary completion date: Aug 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry

A Study to Assess 18-Methoxycoronaridine (clinicaltrials.gov) - P1; N=112; Recruiting; Sponsor: Mind Medicine, Inc.; Trial completion date: Apr 2021 ➔ Aug 2021; Trial primary completion date: Mar 2021 ➔ Aug 2021

Clinical • Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry

A Study to Assess 18-Methoxycoronaridine (clinicaltrials.gov) - P1; N=112; Recruiting; Sponsor: Mind Medicine, Inc.; N=77 ➔ 112

Clinical • Enrollment change • CNS Disorders • Psychiatry

A Study to Assess 18-Methoxycoronaridine (clinicaltrials.gov) - P1; N=77; Recruiting; Sponsor: Mind Medicine, Inc.; N=56 ➔ 77; Trial completion date: Oct 2020 ➔ Apr 2021; Trial primary completion date: Sep 2020 ➔ Mar 2021

Clinical • Enrollment change • Trial completion date • Trial primary completion date • CNS Disorders • Psychiatry

A Study to Assess 18-Methoxycoronaridine (clinicaltrials.gov) - P1; N=56; Recruiting; Sponsor: Mind Medicine, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • CNS Disorders • F2

Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and Ca2.2 channels. (PubMed, Neuropharmacology) - "The primary aim of this study was to determine the anti-neuropathic activity of (±)-18-methoxycoronaridine [(±)-18-MC] and (+)-catharanthine in mice by using the oxaliplatin-induced neuropathic pain paradigm and cold plate test. The results showed that (±)-18-MC and (+)-catharanthine competitively inhibit α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly block Ca2.2 channels without activating GABARs. Considering the potency of the coronaridine congeners at Cav2.2 channels and α9α10 nAChRs, and the calculated brain concentration of (+)-catharanthine, it is plausible that the observed anti-neuropathic pain effects are mediated by peripheral and central mechanisms involving the inhibition of α9α10 nAChRs and/or Ca2.2 channels."

Journal • Preclinical • Neuralgia • Pain

Coronaridine congeners potentiate GABA receptors and induce sedative activity in mice in a benzodiazepine-insensitive manner. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "The results showed that (+)-catharanthine induces sedative-like activity in the 63-72 mg/Kg dose range in a flumazenil-insensitive manner, but neither this effect nor anxiolytic/anxiogenic-like activity was observed at lower doses. To determine the underlying molecular mechanism of the sedative-like activity, electrophysiological and radioligand binding experiments were performed with (+)-catharanthine and (±)-18-methoxycoronaridine [(±)-18-MC] on GABA (GABARs) and glycine receptors (GlyRs)...This is supported by the observed activity at hα1β2 (lacking the BDZ site) and similar effects between α1- and α2-containing GABARs. Our study shows, for the first time, that (+)-catharanthine induced sedative-like effects in mice, and coronaridine congeners potentiated human α1β2γ2, α1β2, and hα2β2γ2, but not ρ1, GABARs, both in a benzodiazepine-insensitive fashion, whereas only (+)-catharanthine slightly potentiated GlyRs."

Journal • Preclinical

Phase 2 Trial to Evaluate 18-Methoxycoronaridine Efficacy, Safety and Tolerability in Cutaneous Leishmaniasis Patients (clinicaltrials.gov) - P2; N=52; Not yet recruiting; Sponsor: Infan Industria Quimica Farmaceutica Nacional; Trial completion date: Nov 2019 ➔ Jul 2024; Trial primary completion date: Mar 2019 ➔ Dec 2023

Clinical • Trial completion date • Trial primary completion date