Intravenous administration of ibogaine for treating opioid use disorder

Abstract

The present disclosure provides methods of treating opioid use disorder in a patient in need thereof by intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof.

Description

INTRAVENOUS ADMINISTRATION OF IBOGAINE FOR TREATING OPIOID USE DISORDER CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of priority to U.S. Provisional 63 / 569,488, filed March 25, 2024, the contents of which are hereby incorporated by reference in its entirety. BACKGROUND

[0002] Opioid use disorder (OUD) is a problematic pattern of opioid use leading to clinically significant impairment or distress. OUD affects over 16 million people worldwide and 6-7 million in the US. Overdoses involving opioids killed more than 80,000 people in the US in 2021, and nearly 88% of those deaths involved synthetic opioids, particularly fentanyl. The number of overdose deaths involving opioids—including both prescription and illicit opioids—in 2021 was 10x the number in 1999.

[0003] There is a large and growing unmet need for OUD treatments. SUMMARY

[0004] The present disclosure relates to methods of treating OUD in a patient in need thereof, the method comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof.

[0005] In embodiments, the methods of treating OUD comprise intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0006] In embodiments, the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL about 30 minutes to about 2 hours after starting the administration. In embodiments, the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL for at least about 4 hours.

[0007] In embodiments, the methods comprise intravenously administering an initial dose and a maintenance dose.

[0008] In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 6 hours. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 4 hours. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 3 hours.

[0009] In embodiments, about 3 mg / kg to about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

[0010] In embodiments, about 5 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over about 4 hours.

[0011] In embodiments, about 6.25 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is intravenously administered over about 6 hours.

[0012] In embodiments, about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is intravenously administered over about 12 hours.

[0013] In embodiments, the administration provides an AUC plasma noribogaine to ibogaine ratio of less than about 2:1.

[0014] In embodiments, the administration provides an oneiric effect in the patient for at least about 4 hours.

[0015] In embodiments, the methods further comprise administering magnesium to the patient. In embodiments, the methods further comprise administering magnesium to thepatient prior to the ibogaine administration. In embodiments, about 300 mg to about 400 mg of magnesium is administered.

[0016] In embodiments, the methods further comprise administering naltrexone to the patient after the ibogaine administration. In embodiments, the methods further comprise administering naltrexone to the patient for about 12 weeks after the ibogaine administration.

[0017] In embodiments, the methods further comprise administering buprenorphine the patient after the ibogaine administration. In embodiments, the methods further comprise administering buprenorphine to the patient for about 12 weeks after the ibogaine administration.

[0018] In embodiments, the patient has no history nor presence of a significant cardiovascular disease. In embodiments, the significant cardiovascular disease is angina, myocardial infarction, coronary artery disease, heart failure, arrhythmias, endocarditis, syncope of unknown origin, or combinations thereof.

[0019] In embodiments, the patient’s QTcF interval duration is less than 420 msec, PR interval duration is less than 200 ms, and QRS interval duration less than 120 ms obtained as an average from 3 ECG recordings, taken at least 1 minute apart after at least 10 minutes of quiet rest in the supine position prior to the ibogaine administration.

[0020] In embodiments, the patient has not received a strong inhibitor or inducer of Cytochrome P45030 days prior to the ibogaine treatment.

[0021] In embodiments, the patient has been diagnosed with opioid use disorder according to the DSM-V criteria.

[0022] In embodiments, the patient is on a μ-opioid agonist or partial agonist therapy for opioid use disorder prior to the ibogaine administration. In embodiments, the μ-opioid agonist is methadone.

[0023] In embodiments, the patient is on a partial μ-opioid agonist therapy for opioid use disorder prior to the ibogaine administration. In embodiments, the partial μ-opioid agonist is buprenorphine.

[0024] In embodiments, the patient is on a μ-opioid antagonist to prevent opioid use disorder relapse or to reverse an opioid overdose prior to the ibogaine administration. In embodiments, the μ-opioid antagonist is naltrexone or naloxone.

[0025] In embodiments, -2 adrenergic receptor agonist therapy to reduce opioid withdrawal symptoms prior to the ibogaine administration. In embodiments, -2 adrenergic receptor agonist is lofexidine or clonidine.

[0026] In embodiments, the administration provides a noribogaine to ibogaine ratio that is lower than the ratio obtained following oral administration of an equivalent ibogaine or pharmaceutically acceptable salt thereof dose to a similar patient.

[0027] In embodiments, the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG.1 shows mean plasma concentrations of ibogaine, noribogaine, and the combination of the two following a single oral dose of ibogaine v. computationally modeled single 6.25 mg / kg IV dose of ibogaine infused over 6 hours.

[0029] FIG.2 shows the study design for Stage 1 of Example 2.

[0030] FIG.3 shows the study design for Stage 2 of Example 2. DEFINITIONS

[0031] Throughout this disclosure, various patents, patent applications and publications (including non-patent publications) are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0032] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms usedin this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0033] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ... ”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5.

[0034] The term “ibogaine” refers to a compound having the following structural formula:.

[0035] The terms "administer," "administering" or "administration" as used herein refer to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising a compound or pharmaceutically acceptable salt of the compound to a patient.

[0036] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a pharmaceutically acceptable salt thereof, that, when administered to a patient, is capable of performing the intended result. For example, an effective amount of an ibogaine is that amount that is required to reduce at least one symptom of OUD in a patient, e.g. opioid cravings in a patient.

[0037] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0038] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric and galacturonic acid.

[0039] The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and / or the composition. For example, the method for treating opioid use disorder provides a therapeutic effect when the method improves at least one symptom of OUD, e.g., a reduction in opioid cravings, in a patient.

[0040] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient’s disorder. Treating can be improving or at least partially ameliorating a disorder. For example, a patient’s opioid use disorder is treated when the method reduces at least one symptom of OUD, e.g., reduced opioid cravings, in the patient. DETAILED DESCRIPTION

[0041] Clinical studies indicate the potential efficacy of ibogaine in treating OUD. Oral ibogaine is associated with significantly reduced opioid cravings, both at discharge and at one-month post-treatment. However, oral administration of ibogaine results in highly variable ibogaine exposure, marked noribogaine exposure, and pronounced, dose- dependent QT prolongation. As such, oral ibogaine administration presents pharmaceutical development risks for efficacy in trials with some patients having very high exposure thatcould be linked to adverse events, while others will have negligible serum concentration of ibogaine, potentially reducing efficacy.

[0042] The present disclosure provides methods of treating OUD by intravenously administering ibogaine. The intravenous administration of ibogaine decreases interindividual subject variability in drug exposure, reduces noribogaine exposure, and improves subject safety and tolerability, relative to oral administration.

[0043] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof.

[0044] In embodiments, the administration provides an ibogaine plasma concentration of 400 ng / mL to about 1,300 ng / mL (e.g., about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, about 1,000 ng / mL, about 1,100 ng / mL, about 1,200 ng / mL, about 1,250 ng / mL, or about 1,300 ng / L including all ranges and values therebetween). In embodiments, the administration provides an ibogaine plasma concentration of 800 ng / mL to 1,000 ng / mL. In embodiments, the administration provides an ibogaine plasma concentration of 500 ng / mL to 1,250 ng / mL.

[0045] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0046] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0047] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient atherapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL about 30 minutes to 2 hours after starting administration.

[0048] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL about 30 minutes to 2 hours after starting administration.

[0049] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL for at least about 4 hours.

[0050] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL for at least about 4 hours.

[0051] In embodiments, the administration provides an ibogaine plasma concentration of about 400 ng / mL to about 1,200 ng / mL about 10 min to about 4 hours (e.g., about 10 min, about 15 min, about 20 min, about 30 min, about 40 min about 50 min, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours, including all ranges and values therebetween) after starting the administration. In embodiments, the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL about 30 minutes to 2 hours after starting administration. In embodiments, the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL about 30 minutes after starting administration. In embodiments, the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL about 2 hours after starting administration. In embodiments, the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL about30 minutes to 2 hours after starting administration. In embodiments, the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL about 30 minutes after starting administration. In embodiments, the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL about 2 hours after starting administration.

[0052] In embodiments, the administration provides an ibogaine plasma concentration of about 400 ng / mL to about 1,200 ng / mL for at least about 4 hours (e.g., about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, or more, including all ranges and values therebetween) after starting administration,. In embodiments, the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL for at least about 4 hours. In embodiments, the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL for at least about 4 hours.

[0053] In embodiments, the methods comprise intravenously administering an initial dose and a maintenance dose of ibogaine or pharmaceutically acceptable salt thereof.

[0054] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the method comprises intravenously administering an initial dose and a maintenance dose, and wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL for at least about 4 hours.

[0055] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the method comprises intravenously administering an initial dose and a maintenance dose, and wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL for at least about 4 hours.

[0056] In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 15 hours, less than about 14.5 hours, less than about 13 hours, less than about 13.5 hours, less than about 12.5 hours, less than about 12 hours, less than about 11.5 hours, less than about 11 hours, less than about 10.5 hours, less than about 10 hours, less than about 9.5 hours, less than about 9 hours, less than about 8.5 hours, less than about 8 hours, less than about 7.5 hours, less than about 7 hours, less than about 6.5 hours, less than about 6 hours, less than about 5.5 hours, less than about 5 hours, less than about 4.5 hours, less than about 4 hours, less than about 3.5 hours, less than about 3 hours, less than about 2.5 hours, less than about 2 hours, or less than about 1 hour. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 6 hours. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 4 hours. In embodiments, the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 3 hours.

[0057] In embodiments, the methods comprise intravenously administering about 1 mg / kg to about 12 mg / kg (e.g., about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5.0 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, about 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, or about 12 mg / kg, including all ranges and values therebetween) of ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session. In embodiments, the methods comprise intravenously administering about 3 mg / kg to about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session. In embodiments, the methods comprise intravenously administering about 5 mg / kg of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session. In embodiments, the methods comprise intravenously administering about 6.25 mg / kg of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session. In embodiments, the methods comprise intravenously administering about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session.

[0058] In embodiments, the methods comprise intravenously administering about 6 mg / kg to about 9 mg / kg (e.g., about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 9 mg / kg) of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session.

[0059] In embodiments, the methods comprise intravenously administering about 6 mg / kg to about 9 mg / kg (e.g., about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 9 mg / kg) of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over about 4 to about 6 hours.

[0060] In embodiments, the methods comprise intravenously administering about 6 mg / kg to about 9 mg / kg (e.g., about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 9 mg / kg) of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over about 4 hours.

[0061] In embodiments, the methods comprise intravenously administering about 6 mg / kg to about 9 mg / kg (e.g., about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, or about 9 mg / kg) of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over about 6 hours.

[0062] In embodiments, the methods comprise intravenously administering about 5 mg / kg of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session over about 4 hours. In embodiments, the methods comprise intravenously administering about 6.25 mg / kg of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session over about 6 hours. In embodiments, the methods comprise intravenously administering about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof during a single treatment session over about 12 hours.

[0063] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 3 mg / kg to about 10mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session.

[0064] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 3 mg / kg to about 10 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0065] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 3 mg / kg to about 10 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0066] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 6 mg / kg to about 9 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session.

[0067] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 6 mg / kg to about 9 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0068] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 6 mg / kg to about 9 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session over 4 to 6 hours, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0069] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 6 mg / kg to about 9 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a singletreatment session, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0070] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 6 mg / kg to about 9 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session over 4 to 6 hours, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL, and wherein, the ibogaine or pharmaceutically acceptable salt thereof is administered over about 4 to about 6 hours.

[0071] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 5 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session for over 4 hours, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0072] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 5 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session for over 4 hours, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0073] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 6.25 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session for over 6 hours, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0074] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 6.25 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session for over 6 hours, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0075] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 10 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session for over 12 hours, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0076] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof, comprising intravenously administering about 10 mg / kg ibogaine or pharmaceutically acceptable salt thereof to the patient during a single treatment session for over 12 hours, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0077] In embodiments, the administration of ibogaine or pharmaceutically acceptable salt thereof provides an AUC plasma noribogaine to ibogaine ratio of less than about 2:1, less than about 1.5:1, less than about 1:1, or less than about 0.5:1. In embodiments, the administration of ibogaine or pharmaceutically acceptable salt thereof provides an AUC plasma noribogaine to ibogaine ratio of less than about 2:1.

[0078] In embodiments, the present disclosure provides methods of treating OUD in a patient in need thereof comprising intravenously administering a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an AUC plasma noribogaine to ibogaine ratio of less than about 2:1.

[0079] In embodiments, the administration of ibogaine or pharmaceutically acceptable salt thereof provides an oneiric effect in the patient for about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, or about 12 hours. In embodiments, the administration of ibogaine or pharmaceutically acceptable salt thereof provides an oneiric effect in the patient for at least about 4 hours.

[0080] In embodiments, the methods comprise administering magnesium to the patient prior to ibogaine or pharmaceutically acceptable salt thereof administration.

[0081] In embodiments, the methods comprise simultaneously administering magnesium to the patient with ibogaine or pharmaceutically acceptable salt thereof.

[0082] In embodiments, the methods comprise administering about 300 mg to about 400 mg of magnesium to the patient. In embodiments, the magnesium is magnesium sulfate.

[0083] In embodiments, the methods comprise administering naltrexone to the patient after the ibogaine administration. In embodiments, the methods comprise administering naltrexone to the patient for about 12 weeks after the ibogaine administration.

[0084] In embodiments, the methods comprise administering buprenorphine to the patient after the ibogaine administration. In embodiments, the methods comprise administering buprenorphine to the patient for about 12 weeks after the ibogaine administration.

[0085] In embodiments, the patient has no history nor presence of a significant cardiovascular disease. In embodiments, the significant cardiovascular disease is angina, myocardial infarction, coronary artery disease, heart failure, arrhythmias, endocarditis, syncope of unknown origin, or combinations thereof.

[0086] In embodiments, the patient’s QTcF interval duration is less than 420 msec, PR interval duration is less than 200 ms, and QRS interval duration less than 120 ms obtained as an average from 3 ECG recordings, taken at least 1 minute apart after at least 10 minutes of quiet rest in the supine position prior to the ibogaine administration.

[0087] In embodiments, the patient has not received a strong inhibitor or inducer of Cytochrome P45030 days prior to the ibogaine treatment.

[0088] In embodiments, the patient has been diagnosed with OUD according to the DSM- V criteria. In embodiments, the patient is diagnosed with OUD if during the 12-month period prior to administration, the treated patient experienced two or more of the following: (a) use of opioids in amount larger amounts or over a longer period of time than intended; (b) persistent desire or unsuccessful attempt to reduce or control opioid use; (c) excessive time spent obtaining, using, or recovering from opioids; (d) cravings for opioids; (e) continued opioid use causing inability to fulfill work, home, or school responsibilities; (f) continuedopioid use despite having persistent social or interpersonal problems; (g) lack of involvement in social, occupational, or recreational activities; (h) use of opioids in physically hazardous situations; (i) continued opioid use despite an awareness of persistent physical and psychological problems; or (j) tolerance to opioids.

[0089] In embodiments, the patient is on a μ-opioid agonist therapy for opioid use disorder prior to the ibogaine administration. In embodiments, the μ-opioid agonist is methadone.

[0090] In embodiments, the patient is on a partial μ-opioid agonist therapy for opioid use disorder prior to the ibogaine administration. In embodiments, the partial μ-opioid agonist is buprenorphine.

[0091] In embodiments, the patient is on a μ-opioid antagonist to prevent opioid use disorder relapse or to reverse an opioid overdose prior to the ibogaine administration. In embodiments, the μ-opioid antagonist is naltrexone or naloxone.

[0092] In embodiments, -2 adrenergic receptor agonist therapy to reduce opioid withdrawal symptoms prior to the ibogaine administration. -2 adrenergic receptor agonist is lofexidine or clonidine.

[0093] In embodiments, the patient receives in-clinic treatment for 36 hours or less.

[0094] In embodiments, the administration provides a noribogaine to ibogaine ratio that is lower than the ratio obtained following oral administration of an equivalent ibogaine or pharmaceutically acceptable salt thereof dose to a similar patient. NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0095] 1. A method of treating opioid use disorder in a patient in need thereof, the method comprising: intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

[0096] 2. The method of embodiment 1, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL about 30 minutes to about 2 hours after starting the administration.

[0097] 3. The method of embodiment 1 or 2, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL for at least about 4 hours.

[0098] 4. The method of any one of embodiments 1-3, wherein the method comprises intravenously administering an initial dose and a maintenance dose.

[0099] 5. The method of any one of embodiments 1-4, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 6 hours.

[0100] 6. The method of any one of embodiments 1-4, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 4 hours.

[0101] 7. The method of any one of embodiments 1-4, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 3 hours.

[0102] 8. The method of embodiment 1, wherein about 3 mg / kg to about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

[0103] 9. The method of embodiment 1, wherein about 5 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

[0104] 10. The method of embodiment 9, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over about 4 hours.

[0105] 11. The method of embodiment 1, wherein about 6.25 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

[0106] 12. The method of embodiment 11, wherein the ibogaine or pharmaceutically acceptable salt thereof is intravenously administered over about 6 hours.

[0107] 13. The method of embodiment 1, wherein about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

[0108] 14. The method of embodiment 13, wherein the ibogaine or pharmaceutically acceptable salt thereof is intravenously administered over about 12 hours.

[0109] 15. The method of embodiment 1, wherein the administration provides an AUC plasma noribogaine to ibogaine ratio of less than about 2:1.

[0110] 16. The method of any one of embodiments 1-15, the administration provides an oneiric effect in the patient for about 4 hours.

[0111] 17. The method of any one of embodiments 1-16, further comprising administering magnesium to the patient.

[0112] 18. The method of any one of embodiments 1-17, further comprising administering magnesium to the patient prior to the ibogaine administration.

[0113] 19. The method of embodiment 18, wherein about 300 mg to about 400 mg of magnesium is administered.

[0114] 20. The method of any one of embodiments 1-19, further comprising administering naltrexone to the patient after the ibogaine administration.

[0115] 21. The method of embodiment 20, further comprising administering naltrexone to the patient for about 12 weeks after the ibogaine administration.

[0116] 22. The method of any one of embodiments 1-20, further comprising administering buprenorphine the patient after the ibogaine administration.

[0117] 23. The method of embodiment 22, further comprising administering buprenorphine to the patient for about 12 weeks after the ibogaine administration.

[0118] 24. The method of any one of embodiments 1-23, wherein the patient has no history nor presence of a significant cardiovascular disease.

[0119] 25. The method of embodiment 24, wherein the significant cardiovascular disease is angina, myocardial infarction, coronary artery disease, heart failure, arrhythmias, endocarditis, syncope of unknown origin, or combinations thereof.

[0120] 26. The method of any one of embodiments 1-25, wherein the patient’s QTcF interval duration is less than 420 msec, PR interval duration is less than 200 ms, andQRS interval duration less than 120 ms obtained as an average from 3 ECG recordings, taken at least 1 minute apart after at least 10 minutes of quiet rest in the supine position prior to the ibogaine administration.

[0121] 27. The method of any one of embodiments 1-26, wherein the patient has not received a strong inhibitor or inducer of Cytochrome P45030 days prior to the ibogaine treatment.

[0122] 28. The method of any one of embodiments 1-27, wherein the patient has been diagnosed with opioid use disorder according to the DSM-V criteria.

[0123] 29. The method of any one of embodiments 1-28, wherein the patient is on a μ-opioid agonist or partial agonist therapy for opioid use disorder prior to the ibogaine administration.

[0124] 30. The method of embodiment 29, wherein the μ-opioid agonist is methadone.

[0125] 31. The method of any one of embodiments 1-28, wherein the patient is on a partial μ-opioid agonist therapy for opioid use disorder prior to the ibogaine administration.

[0126] 32. The method of embodiment 31, wherein the partial μ-opioid agonist is buprenorphine.

[0127] 33. The method of any one of embodiments 1-28, wherein the patient is on a μ-opioid antagonist to prevent opioid use disorder relapse or to reverse an opioid overdose prior to the ibogaine administration.

[0128] 34. The method of embodiment 33, wherein the μ-opioid antagonist is naltrexone or naloxone.

[0129] 35. The method of any one of embodiments 1-28, wherein the patient is on -2 adrenergic receptor agonist therapy to reduce opioid withdrawal symptoms prior to the ibogaine administration.

[0130] 36. -2 adrenergic receptor agonist is lofexidine or clonidine.

[0131] 37. The method of any one of embodiments 1-36, wherein the administration provides a noribogaine to ibogaine ratio that is lower than the ratio obtained following oral administration of an equivalent ibogaine or pharmaceutically acceptable salt thereof dose to a similar patient.

[0132] 38. The method of any one of embodiments 1-37, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

[0133] 39. The method of any one of embodiments 1-38, wherein the method comprises treating the patient in-clinic for 36 hours or less. EXAMPLES

[0134] The present invention is further illustrated by reference to the following Examples. However, it is noted that that Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the invention in any way.

[0135] Example 1: IV Ibogaine Administration Computational Modeling

[0136] Based on clinical observations, Applicant surprisingly discovered that a target ibogaine exposure of 800 – 1,000 ng / mL for at least 4 h provides for effective treatment for OUD. Verified oral PBPK models for ibogaine and noribogaine were prospectively used to determine possible IV doses and infusion durations to achieve this target. The input parameters are shown in Tables 1 (ibogaine) and 2 (noribogaine).

[0137] Table 1. Input Parameters for Ibogaine

[0138] Table 2. Input Parameters for Noribogaine

[0139] Simulation of Single Intravenous Infusion of Ibogaine

[0140] An IV dose of 5 mg / kg infused over 4 h was identified as the starting dose to reach a target Cmax of 800 – 1,000 ng / mL (see Table 3).

[0141] Table 3. Simulated Geometric mean Cmax, time to reach threshold (T800), and duration above target for ibogaine following a 5 mg / kg IV dose infused over 4 hours

[0142] Following the initial dose prediction simulation, additional simulations in over the range of 6 mg / kg to 10 mg / kg were completed to identify possible dose and infusion duration combinations to achieve the target criteria.

[0143] Simulation of a Single 6.25 mg / kg Intravenous Infusion of Ibogaine over 6 hours

[0144] Simulations of 6.25 mg / kg infused over 6 h were completed in CYP2D6 extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizer (PM) subjects. Concentrations of ibogaine increased as expected with decreasing CYP2D6 activity. For all phenotypes, the target concentration of 800 ng / mL was achieved within 2.5 h (1.57 – 2.29) and maintained for at least 3.7 h (Table 4). Noribogaine concentrations peaked after approximately 6 hours with Cmax = 74 – 537 ng / mL (Table 5).

[0145] Table 4. Simulated and Observed Geometric mean PK Parameters for Ibogaine After a Single 6.25 mg / kg IV Dose Infused Over 6 hours in Healthy Subjects with Varying CYP2D6 Activity

[0146] Table 5. Simulated and Observed Geometric mean PK Parameters for Noribogaine After a Single 6.25 mg / kg IV Dose Infused Over 6 hours in Healthy Subjects with Varying CYP2D6 Activity

[0147] Simulation of a Single 10 mg / kg Intravenous Infusion of Ibogaine over 10 hours

[0148] Simulations of 10 mg / kg infused over 12 h were completed in CYP2D6 EM, IM, and PM subjects. Concentrations of ibogaine increased as expected with decreasing CYP2D6 activity. For all phenotypes, the target concentration of 800 ng / mL was achieved within approximately 6 h (range: 3.72 h – 6.19 h) and maintained for at least 5.8 h (Table 6). Noribogaine concentrations peaked after approximately 12 hours with Cmax= 104 – 747 ng / mL (Table 7).

[0149] Table 6. Simulated and Observed Geometric mean PK Parameters for Ibogaine After a Single 10 mg / kg IV Dose Infused Over 12 hours in Healthy Subjects with Varying CYP2D6 Activity

[0150] Table 7. Simulated and Observed Geometric mean PK Parameters for Noribogaine After a Single 10 mg / kg IV Dose Infused Over 12 hours in Healthy Subjects with Varying CYP2D6 Activity

[0152] The PBPK model also supports that IV administration leads to a more consistent drug exposure and a lower metabolite ratio of noribogaine to Ibogaine, indicating reduced variability and potentially decreasing the extent and duration of prolonged QT intervals. This allows for a shorter post-dose monitoring period, enhancing the safety, feasibility and potentially also the commercial adoption of the treatment (see FIG.1, showing mean plasma concentrations of ibogaine, noribogaine, and combination of the two following a single oral dose of 6 mg / kg ibogaine v. single 6.25 mg / kg IV dose infused over 6 hours). Simulation of IV doses of ibogaine also showed that plasma ibogaine concentrations are significantly higher as compared to comparable oral doses, and a reduction of approximately 4-fold in the IV dose needed to give equivalent plasma ibogaine exposure.

[0153] Example 2: Phase 1b / 2a Clinical Trial

[0154] This is a Phase 1 / 2a, single-ascending dose, safety, tolerability, pharmacokinetic and pharmacodynamic study of intravenous ibogaine in healthy adult volunteers (stage 1, FIG.2) and randomized, double-blind, placebo-controlled in participants with severe opioid use disorder (stage 2, FIG.3) study.

[0155] Study Objectives

[0156] Primary objective: to characterize safety of a single IV dose of ibogaine in patients with OUD following opioid detoxification.

[0157] Secondary objective: to characterize the pharmacokinetic profile of single doses of ibogaine and major metabolites and to estimate PK parameters that can subsequently inform PK modeling of alternative infusion paradigms.

[0158] Stage 2 Only: To assess the effects of single dose of ibogaine on relapse in participants with OUD following opioid detoxification initiating naltrexone maintenance treatment.

[0159] Study Endpoints

[0160] Primary endpoints for Stage 1 and Stage 2:

[0161] Frequency of adverse events;

[0162] Proportion of subjects with QTcF > 480 ms and 500 ms;

[0163] Proportion of subjects with individually corrected (QTcI) > 480ms and 500ms;

[0164] Mean during of QTcF change from baseline in > 60 ms from dosing to +72 hours post dose;

[0165] Proportion of subjects with electrocardiographic findings of ventricular bigeminy / trigeminy, ventricular tachycardia (monomorphic or polymorphic);

[0166] Number of opioid overdose episodes during the outpatient follow-up period; and

[0167] Change from baseline:

[0168] Vital sign measures;

[0169] 12-lead ECG findings;

[0170] Heart rate;

[0171] QT interval corrected for HR according to Fridericia (QTcF);

[0172] Individually corrected QT interval (QTcI) (baseline and placebo);

[0173] PR interval;

[0174] QRS interval;

[0175] Physical and neurological examination findings;

[0176] Scale for the Assessment of Rating for Ataxia (SARA);

[0177] Clinical laboratory test results (hematology, serum chemistry, coagulation, and urinalysis); and

[0178] Columbia Suicide Severity Rating Scale (C-SSRS) assessments.

[0179] Primary endpoint for stage 1 only:

[0180] Number of opioid overdose episodes during the outpatient follow-up period.

[0181] Secondary endpoints for Stage 1 and Stage 2:

[0182] Plasma PK parameters (ibogaine and noribogaine):

[0183] Maximum plasma concentration (Cmax);

[0184] Dose-normalized Cmax;

[0185] Time to reach Cmax(Tmax);

[0186] Area under the concentration-time up to the last measurable point (AUC0-t);

[0187] AUC time to 0 to 24 h (AUC0-24h);

[0188] AUC extrapolated to infinity (AUC0-);

[0189] Dose normalized AUC0-t;

[0190] Dose normalized AUC0-24h;

[0191] Elimination rate constants (Kelandz);

[0192] Elimination half-life (Thalf);

[0193] Total body clearance (CL);

[0194] Volume of distribution (Vz);

[0195] Urine PK Parameters (ibogaine and noribogaine):

[0196] Concentration in urine over the interval t1 to t2 (Cut1-t2);

[0197] Volume of urine over the interval from t1 to t2 (Vut1-t2);

[0198] Amount excreted over time (Aet1-t2);

[0199] Cumulative amount excreted (CAe);

[0200] Fraction exerted over time (Fet1-t2) (ibogaine +noribogaine);

[0201] Cumulative fraction excreted (CFe) (ibogaine + noribogaine); and

[0202] Renal Clearance (CLr);

[0203] For Stage 2 Only:

[0204] Participant’s percentage abstinence from opioid use, defined as the percentage of each participant’s negative urine samples and self-reports of illicit opioid use on the timeline follow-back (TLFB) survey from week 1 to week 12.

[0205] Exploratory objectives

[0206] Stage 1 and Stage 2:

[0207] To explore potential pharmacogenetic effects of drug metabolizing enzymes on exposure of ibogaine and its major plasma metabolites (noribogaine); and

[0208] To assess the subjective acute pharmacodynamic (PD) drug effects of ibogaine and its major plasma metabolites (noribogaine).

[0209] Stage 2 Only:

[0210] To assess the effects of single doses of ibogaine on relapse in participants with OUD;

[0211] To further evaluate the efficacy of single-dose ibogaine on ancillary signs and symptoms associated with OUD relapse prevention;

[0212] Exploratory Endpoints

[0213] Exploratory Endpoints for Stage 1 and 2:

[0214] Pharmacogenetic assessment of common genetic variants in drug metabolizing enzymes and risk alleles for long-QT syndrome (this information may be correlated with PK and pharmacodynamic outcomes).

[0215] Time-course changes in Spoken intensity rating scale scores (SIRS);

[0216] Time-course changes in States of consciousness: questionnaire (SCQ) and mystical experiences questionnaire (MEQ);

[0217] risk score, and total risk score using the Risk Assessment Battery (RAB).

[0218] Exploratory Endpoints for Stage 2 Only:

[0219] Proportion of participants meeting criteria for treatment success, defined as at least 80% (illicit) opioid abstinence (as defined in the secondary endpoint) during weeks 1-12;

[0220] Treatment retention, defined as proportion of patients continuing selected maintenance treatment (abstinence, or naltrexone, agonist / partial-agonist maintenance treatment) until end of week 12;

[0221] Proportion of patients relapsing, defined as: loss of persistent opioid abstinence after completed opioid withdrawal for abstinent patients or illicit opioid use for patients on maintenance treatment detected by 3 days of self-reported (illicit) opioid use or by positive urine samples obtained weekly or opioid overdose (overdose is identified via self-report or medical records indicating need for acute medical intervention, hospitalization)

[0222] Opioid Craving Visual Analog Scale (VAS) from Day 2 through Week 12;

[0223] Opioid withdrawal symptoms assessed using Short Opiate Withdrawal Scale of Gossop (SOWS Gossop) average score at baseline through Week 4;

[0224] Clinical Opiate Withdrawal Scale (COWS) at baseline through Week 4.

[0225] Change from baseline to week 12:

[0226] Average weekly number of self-reported days using opioids measured using the Timeline Follow-Back (TLFB) survey from the peak use during the 90 days preceding enrolment to Week 12;

[0227] Number of days of self-reported use of alcohol, illicit drugs, or nonprescribed drugs at each postbaseline visit using the timeline follow back (TLFB);

[0228] PHQ-9

[0229] Generalized Anxiety Disorder Assessment (GAD-7);

[0230] Change in Clinician-rated daily Clinical Global Impression – Improvement (CGI-I);

[0231] Drug risk score, sexual risk score, and total risk score using Risk Assessment Battery (RAB);

[0232] Quality of life across specific domains: physical health, psychological health, social relationships, and environment using WHOQOL BREF;

[0233] Subject elicitation narrative of ibogaine experience;

[0234] Trial Design

[0235] Stage 1:

[0236] Stage 1 of this study will be conducted in adult healthy participants and comprise a single dose, sequential group design. Overall, 40 participants will be studied in 4 cohorts (Cohorts 1 to 4), with each group consisting of 10 participants. All healthy adult participants will receive ibogaine treatment.

[0237] Stage 1 will include up to a 6-week screening period and a 6-day (5 nights) inpatient treatment followed by a 2-week outpatient observation period. At visit 2, subjects will be admitted for a 6-day stay in the Clinical Research Unit (CRU) (Day -2 to Day 4). Participants will be administered daily oral prophylactic doses of magnesium (300-400 mg) on Days -2, -1, and 2. A single-blind (participant) dose of intravenous placebo will be administered at Day -1 with the aim to establish individual baseline cardiac safety measures under IV placebo treatment before IP dosing. On Day 1 a single dose of ibogaine will be administered. Following discharge from the CRU on Day 4, subjects will be followed up for 2 weeks. Participants will receive ibogaine specific psychological preparation and integration support administered by a qualified healthcare professional (“facilitator”).

[0238] For safety reasons, sentinel dosing will be used, such that 2 subjects will be dosed at least 24 hours before the remaining 8 subjects in each cohort. Progression to the next cohort will be subject to the approval of the SafetyManagement Group (SMG) consisting of the Principal Investigator (PI), the Sponsor Medical Monitor (MM) and an independent MM, following review of all available safety and PK data from previous cohorts. Conduct of Stage 1 will further be supported by a Cardiac Safety Committee (CSC) composed of at least 3 specialists in the field of drug-induced electrocardiographic changes. This Committee will review integrated cardiac safety measures and methodologies that are important for interpreting the electrocardiology data in the context of the benefit / risk profile of ibogaine.

[0239] The SMG based on their own assessment and on the basis of CSC recommendations may decide the following steps, if the risk benefit profile warrants it:

[0240] To proceed to the next dose cohort at the protocol defined level;

[0241] Repeat the cohort at the same dose;

[0242] Proceed to the next cohort at a decreased or intermediate dose level; and

[0243] Terminate Stage 1 of this study in healthy adult volunteers before completion of cohort 4 and / or an earlier transition into an OUD patient population.

[0244] Decisions to escalate, repeat, decrease the dose or move into an OUD patient population (Stage 2) during the study will be dependent upon review of emerging safety data by the SMG. The SMG will conduct a review of safety data from each preceding cohort prior to commencement of each proceeding cohort. When available, trailing PK data will be reviewed for decision making.

[0245] The following decision criteria (not exhaustive, see dose escalation guidelines) related to the risk benefit profile of ibogaine as specified in the dose escalation guidelines and the CSC meeting rules will be applied. Administration of ibogaine may be paused, and additional participants will not receive ibogaine, until a consultation has taken place between the Principal Investigator, the MM, and the Sponsor representative if one of the following stopping criteria are met:

[0246] 1) Clinically relevant signs or symptoms of similar nature that occur in 2 or more participants in a dose cohort that, in the opinion of the Principal Investigator, warrant stopping of dose escalation.

[0247] 2) Two or more participants with a severe AE of the same (system organ class) SOC deemed to be related to ibogaine by the PI.

[0248] 3) One or more participants experience an SAE that is suspected to be ibogaine-related, as deemed by the principal investigator.

[0249] 4) Observed QTc prolongation of >500 (average of 3 measures) in 1 subject in any cohort or cardiac arrhythmia or TdP or persistent severe ataxia >24hrs post IP infusion.

[0250] Dose escalation will proceed in this manner until either a stopping criterion is met, all cohorts have completed, or the SMG finds any other reason that poses a risk to participant safety.

[0251] Stage 2:

[0252] Stage 2 of this study will be conducted in participants with moderate to severe opioid use disorder (OUD) after completion of a SOC opioid / partial opioid agonist withdrawal. The following OUD patients may be eligible to participate in Stage 2 of this study, if they meet all other inclusion and no exclusion criteria:

[0253] Patients who have completed illicit opioid or agonist / partial- agonist maintenance treatment withdrawal and are abstinent from opioids, partial opioid agonists or other illicit drugs (stable abstinence as per clinical judgement).

[0254] Patients who have completed illicit opioid withdrawal or are on an opioid agonist / partial-agonist maintenance treatment and are aiming to begin or switch to a maintenance treatment with naltrexone after they have completed a naloxone challenge.

[0255] Patients who are on naltrexone maintenance treatment and are willing to pause this naltrexone maintenance treatment for the duration of IBX- 210 treatment preparation, treatment and monitoring period.

[0256] Participants will be randomized 16:4 to ibogaine or placebo.

[0257] Stage 2 will include 1 cohort of 20 participants with moderate to severe OUD. Stage 2 will comprise of up to a 6-week outpatient screening period, an inpatient Ibogaine / Placebo treatment and monitoring phase, followed by an outpatient observation period. Overall, the treatment and observation phase will be 12 weeks long. After Screening at visit 2, subjects will be admitted for a 6 Day stay in the Clinical Research Unit (CRU) (Day -2 to Day 4, inclusive). At day 4 participants will be discharged to outpatient follow-up until end of Week 12.

[0258] Participants will be administered daily oral prophylactic doses of magnesium (300-400 mg) on Days -2, -1, and 2. A single dose of ibogaine or placebo will be administered on Day 1 followed by inpatient safety monitoring.

[0259] Following discharge from the CRU on Day 4, subjects will be followed up at weekly visits until end of Week 12.

[0260] Participants will be advised and allowed seek external psychosocial counselling for opioid dependence as per standard-of-care or continue an ongoing program. Further, participants will receive ibogaine specific psychological preparation and integration support administered by a trained healthcare professional (“facilitators”) before and after ibogaine treatment.

[0261] The study protocol will allow the expansion of Stage 2 up to 2 additional OUD cohorts.

[0262] The Stage 2 of the study will be governed by the Safety Management Group consisting of (Principal Investigator, Sponsor Medical Monitor, etc.).

[0263] Sample Size

[0264] Approximately 60 participants (Stage 1: 40 participants treated with ibogaine; Stage 2: 20 participants randomized 16:4 Ibogaine:Placebo; optional addition of 2 cohortsto Stage 2 with potential sample size increase to maximum overall sample size of 100 participants).

[0265] Inclusion Criteria for Stage 1

[0266] For inclusion in the trial, the participant must fulfill all of the following criteria:

[0267] Adults of any sex, gender, and race / ethnicity who are 18 to 55 years of age (inclusive) at Screening;

[0268] Is not pregnant as confirmed by a serum pregnancy test at Screening and negative urine pregnancy test at check in (Day -1) and before dosing (applies only to participants of childbearing potential [POCBP]), or lactating;

[0269] Agrees to comply with using a double barrier method of contraception or sexual abstinence and not donate sperm or ova for the duration of the study and for at least 90 days after study drug administration;

[0270] Is willing and able to provide written informed consent indicating that they understand the purpose of the study, the procedures required for the study, and are willing and able to participate in the study;

[0271] Is willing to have dosing visits audio recorded;

[0272] Consents to the subject’s primary physician being contacted about their medical history prior to starting the study, if necessary. Subjects without a primary physician will be allowed in the study if all other eligibility criteria are confirmed by the Investigator in conjunction with the Medical Monitor;

[0273] Is able to complete all protocol-required assessment tools without any assistance or alteration to the copyrighted assessments and to comply with all study requirements;

[0274] Participants who smoke on average no more than 2 cigarettes, pipes, cigars e-cigarettes or equivalent per week, including nicotine products, from 3 months prior to Screening, can be included in the study and must be willing to abstain from smoking / using nicotine products during the CRU confinement period(s); and

[0275] 2, at Screening.

[0276] Exclusion Criteria for Stage 1

[0277] The patient may not enter the trial if any of the following apply:

[0278] Diagnosis and Psychiatric History:

[0279] Past or current history of significant mental, behavioral, or neurodevelopmental disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) including, but not limited to, diagnoses of: organic, including symptomatic, mental disorders; mental and behavioral disorders due to psychoactive substance use; schizophrenia, schizotypal, and delusional disorders; mood (affective) disorders (current only, unless with psychotic symptoms); neurotic, stress-related, and somatoform disorders; or disorders of adult personality and behavior, as assessed by the Mini-International Neuropsychiatric Interview (MINI) screen.

[0280] Family (first degree relative) history of psychotic disorders such as bipolar disorder, schizophrenia, or depression with psychotic features according to the DSM-V.

[0281] Has a known biological 1st degree relative with a history of congenital QT prolongation.

[0282] Has a positive urine drug screen for amphetamines, methamphetamines, benzodiazepines, opioids or cocaine at screening or check-in (Day -2).

[0283] A positive alcohol breath test result at Screening or pre-dose (Day 1).

[0284] Has suicidal ideation with some intent to act within 6 months before Screening per the investigator’s clinical judgment or based on the Columbia-Suicide Severity Rating Scale (C-SSRS), corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent); or a history of suicidal behavior within the past 1 year before Screening.

[0285] Cardiovascular Health:

[0286] History or presence of clinically significant cardiovascular disease including angina, myocardial infarction, coronary artery disease, heart failure, arrhythmias, endocarditis, syncope of unknown origin, or any other condition that, in the opinion of the Investigator, may be associated with a higher risk of arrhythmias.

[0287] Presence at Screening (12-lead ECG or 24-hour Holter monitoring) or Day 1 pre-dose (12-lead ECG) of an ECG that:

[0288] Shows QTcF interval duration >420 msec in males and females, as an average from 3 ECG recordings, taken at least 1 minute apart after at least 10 minutes of quiet rest in the supine position. Subjects who present with -1, but show mean local QTcF values >420 msec prior to dosing on Day 1, particularly at baseline (average of -0.75, -0.5 and -0.25 hours), remain eligible if their

[0289] Shows frequent ventricular ectopy, bigeminy, trigeminy or couplets.

[0290] Shows second or third degree heart block, evidence of myocardial infarction or ischemia, and predominantly non-sinus conducted rhythms.

[0291] Shows, in the opinion of the Investigator, any other clinically significant abnormality.

[0292] Has a prior history of prolonged QT interval.

[0293] in (Day -2).

[0294] Echocardiography demonstrates clinically relevant abnormal cardiac structure or function. (If echocardiography was performed no longer than 1 year before screening and medical report is available, procedure does not need to be repeated at screening).

[0295] Past or Current Medical History:

[0296] Evidence from the medical history, physical examinations, laboratory results or other investigations performed as part of Screening or prior to dosing that demonstrate clinically relevant abnormalities. Abnormalities are considered relevant if they may interfere with the conduct of the study, the interpretation of subsequent data generated as part of the study or may potentially impact the safety of subjects participating in the study.

[0297] History of moderate or severe head trauma (for example, loss of consciousness for more than 15 minutes) or other neurological disorders (including epilepsy), neurodegenerative disorder (Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, etc.) or systemic medical diseases that are, in the opinion of the investigator, likely to interfere with the conduct of the trial or confound the trial assessments.

[0298] Diagnosis of acquired immunodeficiency syndrome.

[0299] One or more laboratory values outside the normal range, based on the blood or urine samples taken at the screening visit, that are considered by the investigator to be clinically significant; or the participant has impaired hepatic function at screening, defined as serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) or total bilirubin (TBL) > 1.5 × ULN or international normalized ratio (INR) > 1.5.

[0300] Positive serology panel (including hepatitis B surface antigen [HBsAg] and / or confirmed current hepatitis C infection [positive hepatitis C virus {HCV} antibody confirmed with reflex HCV RNA test]). Subjects with hepatitis C who had spontaneous resolution or received successful curative treatment (e.g., HARVONI® [ledipasvir / sofosbuvir]) with of undetectable viral load may be allowed.

[0301] Other:

[0302] Has received any prohibited therapies as follows:

[0303] Receipt of a known strong inhibitor or inducer of cytochrome P450 (CYP)2D6 within 30 days or 5 half-lives (whichever is longer) before Screening.

[0304] Treatment with any antipsychotic medication within the past 30 days or 5 half-lives (whichever is longer) before Screening.

[0305] Current incarceration or pending incarceration / legal proceeding that could prohibit participation or compliance in the study.

[0306] Poor peripheral venous access.

[0307] Any prior use of ibogaine, noribogaine, or other chemically related substances.

[0308] Any known or suspected hypersensitivity to ibogaine, dimenhydrinate, or any of the excipients of the IMP.

[0309] Has received treatment with another investigational drug, investigational device, or approved therapy for investigational use within 90 days or 5 half-lives (whichever is longer) before Screening; prior participation at any time in non-invasive methodology trials in which no drugs were given is acceptable.

[0310] Has donated blood or plasma within 30 days before Screening or lost more than 500 mL of whole blood within the 30 days before Screening.

[0311] Is from a vulnerable population as defined by International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) E6 (R2), including but not limited to, employees or family members of the research staff conducting the study, or of the Sponsor, contract research organization (CRO), or Health and Disability Ethics Committee (HDEC) / Human Research Ethics Committee (HREC).

[0312] Any other significant disease, disorder, pending court proceedings, or social circumstances (e.g., homelessness) which, in the opinion of the investigator, may either put the participant, other participants, or site staff at risk because of participation in the trial, may influence the result of the trial, or may affect the participant’s ability to cooperate fully with the requirements of the study protocol.

[0313] Inclusion Criteria for Stage 2

[0314] For inclusion in the trial, the participant must fulfill all of the following criteria:

[0315] Adults of any sex, gender, and race / ethnicity who are 18 to 55 years of age (inclusive) at Screening;

[0316] Currently meets DSM-5 criteria for moderate to severe opioid use disorder, (i.e., meet at least four of 11 criteria) for the 3 months prior to screening (confirmed by the Addiction Severity Index Lite (ASI-lite);

[0317] Patients who have completed illicit opioid or agonist / partial-agonist maintenance treatment withdrawal and are abstinent from opioids, partial opioid agonists or other illicit drugs (stable abstinence as per clinical judgement). Or who have completed illicit opioid withdrawal or are on an opioid agonist / partial- agonist maintenance treatment and are aiming to begin or switch to a maintenance treatment with naltrexone after they have completed a naloxone challenge. Or who are on naltrexone maintenance treatment and are willing to pause this naltrexone maintenance treatment for the duration of IBX-210 treatment preparation, treatment and monitoring period.

[0318] Is not pregnant as confirmed by a serum pregnancy test at Screening and negative urine pregnancy test at check in (Day -1) and before dosing (Day 1; applies only to participants of childbearing potential [POCBP]), or lactating;

[0319] Agrees to comply with using a double barrier method of contraception or sexual abstinence and not donate sperm or ova for the duration of the study and for at least 90 days after study drug administration;

[0320] ;

[0321] Is willing and able to provide written informed consent indicating that they understand the purpose of the study, the procedures required for the study, and are willing and able to participate in the study;

[0322] Is willing to have dosing visits audio recorded;

[0323] Consents to the subject’s primary physician being contacted about their medical history prior to starting the study, if necessary. Subjects without a primaryphysician will be allowed in the study if all other eligibility criteria are confirmed by the Investigator in conjunction with the Medical Monitor; and

[0324] Is able to complete all protocol-required assessment tools without any assistance or alteration to the copyrighted assessments and to comply with all study requirements.

[0325] Exclusion Criteria for Stage 2

[0326] The patient may not enter the trial if any of the following apply:

[0327] Diagnosis and Psychiatric History:

[0328] Subject meets DSM-5 criteria for moderate to severe substance use disorder other than opioids (includes alcohol).

[0329] Patient with moderate nicotine and cannabis use disorder may be permitted on an individual basis at PI and Medical Monitor’s discretion.

[0330] Any lifetime history of an accidental drug overdose.

[0331] Has a primary DSM-5 diagnosis of current (active) Major Depressive Disorder, panic disorder, obsessive compulsive disorder, posttraumatic stress disorder, anorexia nervosa, or bulimia nervosa which do as per the investigator’s judgement dominate the clinical presentation and will likely impact the participant’s adherence to study protocol.

[0332] Comorbid (not primary) depression, anxiety, posttraumatic stress disorder or panic disorder that does not dominate the clinical presentation is acceptable.

[0333] Has a current or prior DSM-5 diagnosis of a primary psychotic disorder (e.g., schizophrenia), bipolar or related disorders, MDD with psychotic symptoms, intellectual disability, autism spectrum disorder, or severe personality disorder (confirmed by the MINI).

[0334] Has a known biological 1st degree relative with a history of prolonged QT interval, schizophrenia, bipolar I / II, or psychotic disorder (unless the psychotic disorder was induced by a medical condition).

[0335] Has a positive urine drug screen for amphetamines, methamphetamines, benzodiazepines or cocaine at screening AND currently meets DSM-5 criteria for either moderate or severe amphetamine, benzodiazepine or cocaine use disorder, respectively or has a positive urine drug screen at check-in (Day -2 or pre-dose Day 1).

[0336] A positive alcohol breath test result at Screening or pre-dose (Day 1).

[0337] Has suicidal ideation with some intent to act within 6 months before Screening per the investigator’s clinical judgment or based on the Columbia-Suicide Severity Rating Scale (C-SSRS), corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent); or a history of suicidal behavior within the past 1 year before Screening.

[0338] Cardiovascular Health:

[0339] History or presence of clinically significant cardiovascular disease including angina, myocardial infarction, coronary artery disease, heart failure, arrhythmias, endocarditis, syncope of unknown origin, or any other condition that, in the opinion of the Investigator, may be associated with a higher risk of arrhythmias.

[0340] Presence at Screening (12-lead ECG or 24-hour Holter monitoring) or Day 1 pre-dose (12-lead ECG) of an ECG that:

[0341] shows QTcF interval duration >420 msec in males and females, as an average from 3 ECG recordings, taken at least 1 minute apart after at least 10 minutes of quiet rest in the supine position. Subjects who present with Screening and Day -1, but show mean local QTcF values >420 msec prior to dosing on Day 1, particularly at baseline (average of -0.75, -0.5 and -0.25 hours), remain eligible if their ;

[0342] shows frequent ventricular ectopy, bigeminy, trigeminy or couplets; or

[0343] shows second or third degree heart block, evidence of myocardial infarction or ischemia, and predominantly non-sinus conducted rhythms,

[0344] shows, in the opinion of the Investigator, any other clinically significant abnormality.

[0345] Has a prior history of prolonged QT interval.

[0346] in (Day -2).

[0347] Echocardiography demonstrates clinically relevant abnormal cardiac structure or function. (if echocardiography was performed no longer than 1 year before screening and medical report is available, procedure does not need to be repeated at screening)

[0348] Past and Current Medical History:

[0349] Evidence from the medical history, physical examinations, laboratory results or other investigations performed as part of Screening or prior to dosing (Day 1) that demonstrate clinically relevant abnormalities. Abnormalities are considered relevant if they may interfere with the conduct of the study, the interpretation of subsequent data generated as part of the study or may potentially impact the safety of subjects participating in the study.

[0350] History of moderate or severe head trauma (for example, loss of consciousness for more than 15 minutes) or other neurological disorders (including epilepsy), neurodegenerative disorder (Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Huntington’s disease, etc.) or systemic medical diseases that are, in the opinion of the investigator, likely to interfere with the conduct of the trial or confound the trial assessments.

[0351] Current diagnosis of chronic pain conditions that require daily use of analgesics for treatment or any opioid treatments.

[0352] Diagnosis of acquired immunodeficiency syndrome.

[0353] One or more laboratory values outside the normal range, based on the blood or urine samples taken at the screening visit, that are considered by the investigator to be clinically significant; or the participant has impaired hepatic function at screening, defined as serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) or total bilirubin (TBL) > 1.5 × ULN or international normalized ratio (INR) > 1.5.

[0354] Positive serology panel (including hepatitis B surface antigen [HBsAg] and / or confirmed current hepatitis C infection [positive hepatitis C virus {HCV} antibody confirmed with reflex HCV RNA test]). Subjects with hepatitis C who had spontaneous resolution or received successful curative treatment (e.g., HARVONI® [ledipasvir / sofosbuvir]) with of undetectable viral load may be allowed.

[0355] Other:

[0356] Has received any prohibited therapies as follows:

[0357] Receipt of a known strong inhibitor or inducer of cytochrome P450 (CYP)2D6 within 30 days or 5 half-lives (whichever is longer) before Screening.

[0358] Treatment with any antipsychotic medication within the past 30 days or 5 half-lives (whichever is longer) before Screening.

[0359] Participant’s treatment for opioid use disorder was required by court order.

[0360] Current incarceration or pending incarceration / legal proceeding that could prohibit participation or compliance in the study.

[0361] Is unable or unwilling to refrain from using tobacco and nicotine products for 2 hours before dosing until 8 hours after dosing has been completed on Day 1.

[0362] Poor peripheral venous access.

[0363] Any prior use of ibogaine, noribogaine, or other chemically related substances.

[0364] Any known or suspected hypersensitivity to ibogaine, dimenhydrinate, or any of the excipients of the IMP.

[0365] Has received treatment with another investigational drug, investigational device, or approved therapy for investigational use within 90 days or 5 half-lives (whichever is longer) before Screening; prior participation at any time in non-invasive methodology trials in which no drugs were given is acceptable.

[0366] Has donated blood or plasma within 30 days before Screening or lost more than 500 mL of whole blood within the 30 days before Screening.

[0367] Is from a vulnerable population as defined by International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) E6 (R2), including but not limited to, employees or family members of the research staff conducting the study, or of the Sponsor, contract research organization (CRO), or Health and Disability Ethics Committee (HDEC) / Human Research Ethics Committee (HREC).

[0368] Any other significant disease, disorder, pending court proceedings, or social circumstances (e.g., homelessness) which, in the opinion of the investigator, may either put the participant, other participants, or site staff at risk because of participation in the trial, may influence the result of the trial, or may affect the participant’s ability to cooperate fully with the requirements of the study protocol.

[0369] Statistical Considerations

[0370] Safety Population: The Safety population will include all subjects who received the IP. For Stage 2, subjects will be counted according to the group of the treatment actually received.

[0371] Pharmacokinetic Population: The PK population will include all subjects who have received the IP, have sufficient PK data to derive at least 1 PK parameter, and do not have any major protocol deviations or AEs thought to significantly affect the PK. This population will be used for all summaries of PK parameter data. If some subjects do not complete the PK sampling or collection schedule, and it is judged that the characterization of AUC, renal and / or elimination parameters may therefore not be adequate, samples ofthese subjects could be included in the PK analysis only for those PK parameters that are judged not to be affected by the missing sample(s).

[0372] QT / QTc Population: The QT / QTc population will include all subjects in the Safety population with a valid change-from-time-matched baseline QTcF value. This population will be used for the by-time point and categorical analyses. The QT / QTc analysis set can be further detailed or modified in the statistical analysis plan.

[0373] PK / QTc Population: The PK / QTc population will include all subjects that are in both the QT / QTc analysis and PK population with at least 1 pair of post-dose PK and QTcF data from the same time point. This population will be used for the exposure-response analysis. Data from subjects excluded from the PK / QTc population will be presented in the data listings, but not included in the calculation of summary statistics.

[0374] ITT Population: The ITT population in Stage 2 will include all subjects who were randomized, with subjects being counted according to their randomized treatment group.

[0375] Subject Disposition: The number of subjects who were treated (Stage 1) or randomized (Stage 2), and who completed the study or withdrew early will be presented by dosing group and overall for Stage 1, and by treatment group and overall for Stage 2. In addition, the number of subjects in each population will be shown. Subjects who discontinued and reasons for discontinuations will be summarized by dosing group and overall for Stage 1, and by treatment group and overall for Stage 2. Summaries will also be provided by day in Stage 2.

[0376] Additional Considerations

[0377] Psychosocial support: Participants will also be offered 9 weekly sessions of individual drug counselling, adapted for opioid dependence. Site staff who are trained in individual drug counselling will review participants substance use, recovery efforts, functioning, and provide support and advice.

[0378] Assessments

[0379] There are several useful opioid withdrawal scales that can assist the clinician in evaluating patients with opioid use disorder by identifying and quantifying the severity of opioid withdrawal symptoms including:

[0380] The Objective Opioid Withdrawal Scale (OOWS), which relies on clinical observation, is useful in measuring and documenting the objectively measurable symptoms of opioid withdrawal;

[0381] The Subjective Opioid Withdrawal Scale (SOWS) records the patient’s rating of opioid withdrawal on a 16-item scale;

[0382] The Clinical Opioid Withdrawal Scale (COWS) includes 11 items, and contains signs and symptoms of opioid withdrawal, which are both objective and subjective in nature; and

[0383] The Clinical Institute Narcotic Assessment (CINA) also includes 11 items and can help determine the severity of symptoms.

[0384] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

CLAIMS I / We claim:

1. A method of treating opioid use disorder in a patient in need thereof, the method comprising: intravenously administering to the patient a therapeutically effective amount of ibogaine or pharmaceutically acceptable salt thereof, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL.

2. The method of claim 1, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL about 30 minutes to about 2 hours after starting the administration.

3. The method of claim 1 or 2, wherein the administration provides an ibogaine plasma concentration of about 500 ng / mL to about 1,250 ng / mL for at least about 4 hours.

4. The method of any one of claims 1-3, wherein the method comprises intravenously administering an initial dose and a maintenance dose.

5. The method of any one of claims 1-4, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 6 hours.

6. The method of any one of claims 1-4, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 4 hours.

7. The method of any one of claims 1-4, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over less than about 3 hours.

8. The method of claim 1, wherein about 3 mg / kg to about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

9. The method of claim 1, wherein about 6 mg / kg to about 9 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

10. The method of claim 1, wherein about 5 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

11. The method of claim 10, wherein the ibogaine or pharmaceutically acceptable salt thereof is administered over about 4 hours.

12. The method of claim 1, wherein about 6.25 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

13. The method of claim 11, wherein the ibogaine or pharmaceutically acceptable salt thereof is intravenously administered over about 6 hours.

14. The method of claim 1, wherein about 10 mg / kg of ibogaine or pharmaceutically acceptable salt thereof is intravenously administered to the patient during a single treatment session.

15. The method of claim 14, wherein the ibogaine or pharmaceutically acceptable salt thereof is intravenously administered over about 12 hours.

16. The method of claim 1, wherein the administration provides an AUC plasma noribogaine to ibogaine ratio of less than about 2:

1.

17. The method of any one of claims 1-16, the administration provides an oneiric effect in the patient for about 4 hours.

18. The method of any one of claims 1-17, further comprising administering magnesium to the patient.

19. The method of any one of claims 1-18, further comprising administering magnesium to the patient prior to the ibogaine administration.

20. The method of claim 19, wherein about 300 mg to about 400 mg of magnesium is administered.

21. The method of any one of claims 1-20, further comprising administering naltrexone to the patient after the ibogaine administration.

22. The method of claim 21, further comprising administering naltrexone to the patient for about 12 weeks after the ibogaine administration.

23. The method of any one of claims 1-21, further comprising administering buprenorphine the patient after the ibogaine administration.

24. The method of claim 23, further comprising administering buprenorphine to the patient for about 12 weeks after the ibogaine administration.

25. The method of any one of claims 1-24, wherein the patient has no history nor presence of a significant cardiovascular disease.

26. The method of claim 25, wherein the significant cardiovascular disease is angina, myocardial infarction, coronary artery disease, heart failure, arrhythmias, endocarditis, syncope of unknown origin, or combinations thereof.

27. The method of any one of claims 1-26, wherein the patient’s QTcF interval duration is less than 420 msec, PR interval duration is less than 200 ms, and QRS interval duration less than 120 ms obtained as an average from 3 ECG recordings, taken at least 1 minute apart after at least 10 minutes of quiet rest in the supine position prior to the ibogaine administration.

28. The method of any one of claims 1-27, wherein the patient has not received a strong inhibitor or inducer of Cytochrome P45030 days prior to the ibogaine treatment.

29. The method of any one of claims 1-28, wherein the patient has been diagnosed with opioid use disorder according to the DSM-V criteria.

30. The method of any one of claims 1-29, wherein the patient is on a μ-opioid agonist or partial agonist therapy for opioid use disorder prior to the ibogaine administration.

31. The method of claim 30, wherein the μ-opioid agonist is methadone.

32. The method of any one of claims 1-29, wherein the patient is on a partial μ-opioid agonist therapy for opioid use disorder prior to the ibogaine administration.

33. The method of claim 32, wherein the partial μ-opioid agonist is buprenorphine.

34. The method of any one of claims 1-29, wherein the patient is on a μ-opioid antagonist to prevent opioid use disorder relapse or to reverse an opioid overdose prior to the ibogaine administration.

35. The method of claim 34, wherein the μ-opioid antagonist is naltrexone or naloxone.

36. The method of any one of claims 1-29 -2 adrenergicreceptor agonist therapy to reduce opioid withdrawal symptoms prior to the ibogaine administration.

37. The method of claim 36 -2 adrenergic receptor agonist is lofexidine orclonidine.

38. The method of any one of claims 1-37, wherein the administration provides a noribogaine to ibogaine ratio that is lower than the ratio obtained following oral administration of an equivalent ibogaine or pharmaceutically acceptable salt thereof dose to a similar patient.

39. The method of any one of claims 1-38, wherein the administration provides an ibogaine plasma concentration of about 800 ng / mL to about 1,000 ng / mL.

40. The method of any one of claims 1-39, wherein the method comprises treating the patient in-clinic for 36 hours or less.

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