US 20150258114A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0258114A1 Friedhoff (43) Pub. Date: Sep. 17, 2015

(54) METHODS FOR ACUTE AND LONG-TERM Publication Classification TREATMENT OF SUBSTANCE ABUSEUSING BOGANE (51) Int. Cl. A613 L/55 (2006.01) (71) Applicant: DemeRX, Inc., Fort Lauderdale, FL (52) U.S. Cl. (US) CPC ...... A6 IK3I/55 (2013.01) (72) Inventor: Lawrence Friedhoff, Fort Lauderdale, FL (US) (57) ABSTRACT (73) Assignee: DemeRX, Inc., Fort Lauderdale, FL (US) This invention is directed to a method of treating substance Appl. No.: 14/635,934 addiction, including acute and post-acute withdrawal Symp (21) toms, comprising treating an addicted patient with ibogaine, (22) Filed: Mar. 2, 2015 ibogaine derivative, or a pharmaceutically acceptable salt and/or Solvate thereof at a dosage that provides an average Related U.S. Application Data serum concentration of about 50 ng/mL to about 850 ng/mL (60) Provisional application No. 61/952,718, filed on Mar. underconditions where the QT interval prolongation does not 13, 2014. exceed about 50 milliseconds. US 2015/02581. 14 A1 Sep. 17, 2015

METHODS FOR ACUTE AND LONG-TERM SUMMARY TREATMENT OF SUBSTANCE ABUSEUSING 0007 While ibogaine has been disclosed for treatment of BOGANE Substance addiction, its use in humans is complicated by the fact that the ranges generally used to treat addiction (e.g., 15 CROSS-REFERENCE TO RELATED mg/kg to 20 mg/kg) cause hallucinations and may be fatal. APPLICATIONS Lotsof and Wachtel, Manual for Ibogaine Therapy: Screen ing, Safety, Monitoring & Aftercare (2d revision, 2003), 0001. This application claims benefit from U.S. Provi accessed at www.ibogaine.desk.nl/manual.html; Hoelen, et sional Application No. 61/952,718, filed Mar. 13, 2014, al. New Engl. J. Med. 360(3), 308 (2009), which is incorpo which is hereby incorporated by reference in its entirety. rated herein by reference in its entirety for all of its methods, compositions and teachings. FIELD OF THE INVENTION 0008. A prolonged QT interval is a marker of potential Ventricular tachyarrhythmia which, and can result in death. 0002 This invention is directed to a method of treating Serious complications, including Ventricular tachyarrhyth addiction to an illicit or otherwise addictive substance, mia and death, can result from prolongation of the treated including acute and post-acute withdrawal symptoms, com patient’s QT interval by ibogaine, rendering high doses of prising treating an addicted patient with ibogaine, ibogaine ibogaine unacceptable. Heretofore, it was unclear whether a derivative, orpharmaceutically acceptable salt and/or Solvate therapeutic dose of ibogaine could be found that resulted in thereof at a therapeutic dosage that provides both an average QT interval prolongation within an acceptable range. It is serum concentration of about 50 ng/mL to about 850 ng/mL expected that other compounds that share ibogaine's core and a maximum QT interval prolongation of no more than structure will have a similar prolongation effect on QT inter about 50 milliseconds. val. See, U.S. Provisional Patent Application No. 61/945,746 filed Feb. 27, 2014 entitled METHOD FOR ACUTE AND STATE OF THE ART LONG-TERM TREATMENT OF DRUG ADDICTION, which application is incorporated by reference in its entirety. 0003 Substance addiction is a serious public health prob 0009. The current invention is predicated on the surprising lem throughout the world. As many as 23.5 million people in discovery that treatment of addiction with ibogaine, ibogaine the US (almost 10%) have a drug or alcohol abuse problem, derivative, or pharmaceutically acceptable salt and/or Solvate although only a small fraction of those receive treatment. thereof and derivatives thereof can be achieved with an 0004 Complicating the treatment of drug addiction, drug acceptable QT interval prolongation when such compounds addicted patients generally experience significant withdrawal are administered within a narrow dosage range. Specifically, symptoms while attempting to quit using the drug. Acute dosing an addicted patient with from greater than about 1 withdrawal from drug dependence is characterized by dra mg/kg body weight to about 4 mg/kg body weight, ibogaine, matic and traumatic symptoms, including Sweating, racing ibogaine derivative, or pharmaceutically acceptable salt and/ heart, palpitations, muscle tension, tightness in the chest, or solvate thereof will provide a therapeutic reduction in difficulty breathing, tremor, nausea, vomiting, diarrhea, withdrawal symptoms and/or an increase in time to resump grand mal seizures, heart attacks, strokes, hallucinations and tion of Substance use in addicted patients without unaccept delirium tremens (DTs). Withdrawal can also include severe able prolongation of the patient’s QT interval. cravings for the drug, fatigue, lack of pleasure, anxiety, irri 0010 Preferably, the dose range that provides both thera tability, sleepiness, Suicidal thoughts, and sometimes agita peutic results and an acceptable QT interval prolongation of tion or extreme Suspicion or paranoia. Once acute withdrawal less than 50 milliseconds in Substance-addicted humans is symptoms have Subsided, post-acute withdrawal syndrome between about 1.3 mg per kg body weight and no more than can last for months or years. Post-acute withdrawal Symp about 4 mg per kg body weight and, more preferably between toms include fatigue, depression, lack of motivation, and about 1.3 mg per kg body weight and no more than about 3 mg increased pain sensitivity. Acute and post-acute withdrawal per kg body weight, or any Subrange or Subvalue within the symptoms are the primary reason drug-addicted patients aforementioned ranges. return to using the drug after treatment, even when the patient 0011. In a preferred embodiment, the narrow therapeutic has been drug-free for a significant amount of time. doses of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof unexpectedly do not 0005. Although treatments have been developed in prolong the QT interval to unacceptable levels in human attempts to ameliorate acute and post-acute withdrawal addicted patients. It is expected that drug addicted patients symptoms. Such treatments do not work for all types of drugs. will be administered therapeutic doses of ibogaine, ibogaine In addition, treatment of withdrawal may require use of other derivative, or pharmaceutically acceptable salt and/or Solvate addictive substances (e.g., morphine or methadone) and that thereof in a clinical setting with cardiac monitoring. In some the addictattend a clinic daily for an extended amount of time. embodiments, the patient will be pre-screened to evaluate Due to the severity and duration of withdrawal symptoms, tolerance for prolongation of QT interval, e.g., to determine addicted patients have a high rate of relapse. There is a sig whether the patient has any pre-existing cardiac conditions nificant need for effective, non-addictive treatment for acute which would disqualify them from treatment with ibogaine, and post-acute withdrawal symptoms. ibogaine derivative, or pharmaceutically acceptable salt and/ 0006 Prior to the embodiments described herein, the or solvate thereof therapeutic dosing of ibogaine and its derivatives for treating 0012 Some aspects of the current invention are further Substance addiction in humans at an acceptable QT interval predicated on the discovery that even lower doses of ibogaine, prolongation has not previously been addressed, especially as ibogaine derivative, or pharmaceutically acceptable salt and/ it relates to dosing protocols that are effective, as well as safe. or solvate thereof, for example approximately 80% or less of US 2015/02581. 14 A1 Sep. 17, 2015 the therapeutic dose, may be effective for prevention of salt and/or solvate thereof provides prolongation of the QT relapse of drug use in an addicted patient treated to ameliorate interval of less than 80 ms. In a preferred embodiment, the their drug use. That is, a lower dose of the compound can maintenance dose of ibogaine, ibogaine derivative, or phar prevent a patient who is no longer physically addicted to a maceutically acceptable salt and/or solvate thereof provides substance from relapsing to use of that substance. Without prolongation of the QT interval of less than 50 ms. In some being bound by theory, it is believed that a patient who is no embodiments, the maintenance dose or therapeutic dose of longer physically addicted to the drug requires less com ibogaine, ibogaine derivative, orpharmaceutically acceptable pound to prevent relapse because the drug does not compete salt and/or solvate thereof provides prolongation of the QT with the compound for receptor binding, and/or because interval of less than 30 ms. In a preferred embodiment, the desensitization of one or more receptors in the brain by the maintenance dose of ibogaine, ibogaine derivative, or phar drug is reversed when the patient ceases to take the drug. This maceutically acceptable salt and/or solvate thereof provides lower, maintenance dose results in a QT interval prolongation prolongation of the QT interval of less than 20 ms. In one that does not require clinical cardiac monitoring. embodiment, the QT prolongation is equivalent to or less than 0013. In some embodiments, the therapeutic dose of that observed in patients receiving methadone treatment. In a ibogaine, ibogaine derivative, orpharmaceutically acceptable preferred embodiment, the patient is tested to determine QT salt and/or solvate thereof administered to the patient is suf interval before treatment with the compound, and if clinician ficient to provide an average serum concentration of the com determines that the QT prolongation would be unacceptable pound of about 50 ng/mL to about 850 ng/mL, or any sub risk, therapy will be contraindicated. range or subvalue there between. In a preferred embodiment, the dose of ibogaine, ibogaine derivative, orpharmaceutically Compounds Administered acceptable salt and/or solvate thereof administered to the 0017. In the various method, formulation and kit aspects patient provides an average serum concentration of about 50 and embodiments, in one embodiment a compound utilized ng/mL to about 400 ng/mL. herein is represented by, oribogaine as used herein is replaced 0014. In some embodiments, the patient is administered a high (therapeutic) dose of ibogaine, ibogaine derivative, or by, a compound Formula I: pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to drug use. In some embodiments, the patient is administered a therapeutic dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/ or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or Solvate thereof over time until the maintenance dose is reached. In some or a pharmaceutically acceptable salt and/or Solvate thereof, embodiments, a high initial therapeutic dose is administered, wherein followed by administration of a lower therapeutic dose. In 0.018 R is H, halo, C-C alkyl, substituted C-C alkyl, Some embodiments, the dose of the compound is tapered over OR, NH, NHR10 NR'R''NHC(O)R', or NRC time from the high therapeutic dose to a lower therapeutic (O)R'': dose. 0019 R' is H. C-C alkyl, substituted C-C alkyl, 0015. In some embodiments, the dose of ibogaine, C-C alkoxy, CH2 X-CH3, or (CH2).R. ibogaine derivative, or pharmaceutically acceptable salt and/ or Solvate thereof that provides an average serum concentra tion of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/ or Solvate thereof that provides an average serum concentra tion of about 50 ng/mL to about 850 ng/mL is administered as 0021 R is C-C alkyl, benzyl, substituted C-C alkyl, multiple doses. In some embodiments, the aggregate dose of ibogaine, ibogaine derivative, orpharmaceutically acceptable YH, YR, YC(O)R, C(O)YRC(O)NH, C(O)NHR, salt and/or Solvate thereof is from greater than about 1 mg/kg C(O)NR'R'', NH, NHR, NRR, NHC(O)R, O(CH.) to about 8 mg/kg. In a preferred embodiment, the aggregate O(CH)O(CH), CH, or NRC(O)R’. dose of i ibogaine, ibogaine derivative, or pharmaceutically 0022 R is C-C alkyl or (CHCHO),CH: acceptable salt and/or solvate thereof is from greater than 0023 R,R,R,R,R,R', and R'' are independently about 1 mg/kg to about 4 mg/kg. In another preferred embodi alkyl or substituted alkyl: ment, the aggregate dose of ibogaine, ibogaine derivative, or 0024) R' is H, alkyl, or substituted alkyl: pharmaceutically acceptable salt and/or Solvate thereof is 0025) R' is H, OR', alkyl, or substituted alkyl: from greater than about 1 mg/kg to 3 mg/kg. 0026 X is O or NH; 0016. In some embodiments, the serum concentration is sufficient to inhibit or ameliorate said abuse while maintain 0027 Y is O or S; ing a QT interval of less than 500 milliseconds (ms) during 0028 m is an integer selected from 0-8; said treatment. In some embodiments, the therapeutic dose of 0029 each of n, p and q is 1, 2 or 3; and ibogaine, ibogaine derivative, orpharmaceutically acceptable 0030 r is 0, 1 or 2. US 2015/02581. 14 A1 Sep. 17, 2015

0031. In the various method, formulation and kit aspects and embodiments, in one embodiment a compound utilized II herein is represented by, oribogaine as used herein is replaced by, a compound Formula Ii:

Ii

or a pharmaceutically acceptable salt and/or Solvate thereof, 0052 wherein 0.053 R is hydrogen or C-C alkoxy, 0054) R' is hydrogen, C-C alkyl, C-C alkoxy, (CH) OC(O)alkyl, (CH), OH, (CH), Oalkyl, (CH)O (CH)O(CH.) O(CH), CH, or CH, Y CH, where or a pharmaceutically acceptable salt and/or Solvate thereof, each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2.Y is O or 0032 wherein NH, and 0033 R is H, halo, C-C alkyl, substituted C-C alkyl, R is H. (CH),OH, COOH, or COOR, where R is C-C, OR, NH, NHR'9, NR'R'', NHC(O)R, or NRC alkyl or (CH2CH2O), CH, where n is 1, 2, or 3. (O)R'': 0055. In one embodiment a compound utilized herein is I0034) R' is H, C-C alkyl, substituted C-C alkyl, represented by, or ibogaine as used herein is replaced by, a C-C alkoxy, CH, X-CH, or (CH), R: compound Formula II:

II

10036 R is C-C alkyl, benzyl, substituted C-C alkyl, YH, YR,YC(O)R, C(O)YR, C(O)NH, C(O)NHR, C(O)NR'R'', NH, NHR, NRR, NHC(O)R, O(CH2) O(CH)O(CH.), CH, or NRC(O)R’. 0037 R is C-C alkyl or (CHCHO),CH: or a pharmaceutically acceptable salt and/or Solvate thereof, 0038 R,R,R,R,R,R', and R'' are independently 0056 wherein alkyl or substituted alkyl: 0057 R is OCH, 0039) R' is H, alkyl, or substituted alkyl: (0.058 R' is CHCH, 0040) R' is H, OR', alkyl, or substituted alkyl: 0059 R is COOR, where R is (CHCHO), CH, where 0041 X is O or NH; n is 1. 0.042 Y is O or S; 0060. In another embodiment, ibogaine or a pharmaceuti 0043 m is an integer selected from 0-8; cally acceptable salt and/or solvate thereof is utilized. In 0044 each of n, p and q is 1, 2 or 3; and another embodiment, ibogaine or a pharmaceutically accept 0045 r is 0, 1 or 2. able salt and/or solvate thereof is utilized. In another embodi 0046. In one embodiment, the compound is of Formula ment, the ibogaine, ibogaine derivative, is chosen from the IA: group consisting of ibogaine, coronaridine, ibogamine, Voa cangine, 18-methoxycoronaridine, 2-methoxyethyl-18 methoxycoronaridinate, 18-methylaminocoronaridine or a

IA pharmaceutically acceptable salt and/or Solvate thereof. 0061. In another embodiment, the compound utilized herein is chosen from the group consisting of ibogaine, coro naridine, ibogamine, voacangine, 18-methoxycoronaridine, 2-methoxyethyl-18-methoxycoronaridinate, 18-methylami nocoronaridine and a pharmaceutically acceptable salt and/or Solvate. 0062. In another embodiment, the compound utilized 0047 wherein herein is selected from the group consisting of 16-hydroxym 0048 R is hydrogen or C-C-alkoxy, ethyl-18-hydroxyibogaline, 16-hydroxymethyl-18-meth I0049) R' is hydrogen, C-C-alkyl, C-C alkoxy, or oxyibogaline, 16-ethoxycarbonyl-18-hydroxyibogaline lau CH Y CH where Y is O or NH, and rate, and 16-ethoxycarbonyl-18-hydroxyibogaline 10050 X is H, COOH, or COOR, where R is C-C, methoxyethoxymethyl ether and a pharmaceutically accept alkyl or (CH2CH2O), CH, where n=1 to 3. able salt and/or solvate thereof. 0051. In one embodiment a compound utilized herein is 0063. When replacing ibogaine, the compounds of for represented by, or ibogaine as used herein is replaced by, a mula I, II, and subformulas thereofas utilized herein exclude compound Formula II: ibogaine. US 2015/02581. 14 A1 Sep. 17, 2015

0.064 In a preferred embodiment, the compound utilized self-administration by the patient, and/or to indirect admin herein is: istration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-adminis ter a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient. 0072 “Periodic administration” or “periodically adminis tering refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of ibogaine, ibogaine derivative, or N pharmaceutically acceptable salt and/or Solvate thereof one, two, three, or more times per day. Administration may be via a pharmaceutically acceptable salt thereof, or a Solvate of transdermal patch, gum, lozenge, Sublingual tablet, intrana each thereof. sal, intrapulmonary, oral administration, or other administra tion. DETAILED DESCRIPTION 0073 “Comprising or “comprises” is intended to mean that the compositions and methods include the recited ele 0065. It is to be understood that this invention is not lim ments, but not excluding others. “Consisting essentially of ited to particular embodiments described, as such may, of when used to define compositions and methods, shall mean course, vary. It is also to be understood that the terminology excluding other elements of any essential significance to the used herein is for the purpose of describing particular combination for the stated purpose. Thus, a composition con embodiments only, and is not intended to be limiting, since sisting essentially of the elements as defined herein would not the scope of this invention will be limited only by the exclude other materials or steps that do not materially affect appended claims. the basic and novel characteristic(s) of the claimed invention. 0066. The detailed description of the invention is divided “Consisting of shall mean excluding more than trace ele into various sections only for the reader's convenience and ments of other ingredients and Substantial method steps. disclosure found in any section may be combined with that in Embodiments defined by each of these transition terms are another section. Unless defined otherwise, all technical and within the scope of this invention. Scientific terms used herein have the same meaning as com 0074 As used herein, N is a single bondora double bond. monly understood by one of ordinary skill in the art to which 0075. A "pharmaceutically acceptable solvate” or this invention belongs. “hydrate' of a compound of the invention means a solvate or 0067. It must be noted that as used herein and in the hydrate complex that is pharmaceutically acceptable and that appended claims, the singular forms “a”, “an', and “the possesses the desired pharmacological activity of the parent include plural referents unless the context clearly dictates compound, and includes, but is not limited to, complexes of a otherwise. Thus, for example, reference to “a compound compound of the invention with one or more solvent or water includes a plurality of compounds. molecules, or 1 to about 100, or 1 to about 10, or one to about I. Definitions 2, 3 or 4, solvent or water molecules. 0076. As used herein the term “solvate” is taken to mean 0068. Unless defined otherwise, all technical and scien that a solid-form of a compound that crystallizes with one or tific terms used herein have the same meaning as commonly more molecules of solvent trapped inside. A few examples of understood by one of ordinary skill in the art to which this Solvents that can be used to create Solvates, such as pharma invention belongs. As used herein the following terms have ceutically acceptable Solvates, include, but are certainly not the following meanings. limited to, water, methanol, ethanol, isopropanol, butanol, 0069. The term “about when used before a numerical C1-C6 alcohols in general (and optionally substituted), tet designation, e.g., temperature, time, amount, concentration, rahydrofuran, acetone, ethylene glycol, propylene glycol, and Such other, including a range, indicates approximations acetic acid, formic acid, water, and solvent mixtures thereof which may vary by (+) or (-) 10%, 5% or 1%, or any subrange Other such biocompatible solvents which may aid in making or subvalue there between. a pharmaceutically acceptable solvate are well known in the 0070 Administration” refers to introducing ibogaine, art and applicable to the present invention. Additionally, vari ibogaine derivative, or pharmaceutically acceptable salt and/ ous organic and inorganic acids and bases can be added or or solvate thereof into a patient. Typically, an effective even used alone as the solvent to create a desired solvate. Such amount is administered, which amount can be determined by acids and bases are known in the art. When the solvent is the treating physician or the like. Any route of administration, water, the solvate can be referred to as a hydrate. Further, by Such as oral, topical, Subcutaneous, peritoneal, intra-arterial, being left in the atmosphere or recrystallized, the compounds inhalation, vaginal, rectal, nasal, introduction into the cere of the present invention may absorb moisture, may include broSpinal fluid, or instillation into body compartments can be one or more molecules of water in the formed crystal, and thus used. The ibogaine, ibogaine derivative, or pharmaceutically become a hydrate. Even when such hydrates are formed, they acceptable salt and/or solvate thereof may be administered by are included in the term "solvate”. Solvate also is meant to direct blood stream delivery, e.g. Sublingual, intranasal, or include such compositions where another compound or com intrapulmonary administration. plex co-crystallizes with the compound of interest. 0071. The related terms and phrases “administering and 0077. As used herein, the term “alkyl refers to monova “administration of, when used in connection with a com lent saturated aliphatic hydrocarbyl groups having from 1 to pound or pharmaceutical composition (and grammatical 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 equivalents) refer both to direct administration, which may be carbon atoms, and more preferably 1 to 3 carbon atoms. This administration to a patient by a medical professional or by term includes, by way of example, linear and branched hydro US 2015/02581. 14 A1 Sep. 17, 2015 carbyl groups such as methyl (CH ), ethyl (CHCH ), form a heterocycle; and each R is independently selected n-propyl (CHCHCH ), isopropyl ((CH)-CH-), n-bu from the group consisting of alkyl, cycloalkyl, aryl, het tyl (CHCHCHCH ), isobutyl ((CH3)2CHCH ), sec eroaryl, and heterocycle. butyl ((CH)(CH-CH2)CH ), t-butyl ((CH)C ), n-pentyl I0082 “Cyano” refers to the group –CN. (CHCHCHCHCH ), and neopentyl ((CH),CCH ). I0083) “Cycloalkyl refers to cyclic alkyl groups of from 3 The term “C, alkyl refers to an alkyl group having X carbon to 10 or 3 to 8 carbon atoms having single or multiple cyclic atoms, wherein X is an integer, for example, C refers to an rings including fused, bridged, and spiro ring systems. One or alkyl group having 3 carbon atoms. more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non 0078 “Substituted alkyl refers to an alkyl group having aromatic, non-heterocyclic ring carbocyclic ring. Examples from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 of Suitable cycloalkyl groups include, for instance, adaman Substituents selected from the group consisting of alkoxy, tyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. R° C(O) , NRC(O)R2, R° C(O)O , Other examples of cycloalkyl groups include bicycle 2.2.2. NR20R2, C(O)NR20R2, C(S)NR20R20, NR20C octanyl, norbornyl, and Spirobicyclo groups such as spiro4. (O)NR2R39, NRC(S)NR20 R29, O C(O)NR2R, 5dec-8-yl. S(O)NR'R'', O S(O)NR'R'', NR S(O) I0084) “Substituted cycloalkyl refers to a cycloalkyl NR'R'', C(=NRNR'R'', aryl, aryloxy, arylthio, group having from 1 to 5 or preferably 1 to 3 substituents azido, carboxyl, -C(O)C R', NR' C(O)C) R', selected from the group consisting of oxo, thione, alkyl, Sub —O C(O)O R', cyano, cycloalkyl, cycloalkyloxy, stituted alkyl, alkoxy, C(O) R, NRC(O)R, R cycloalkylthio, NR'C(=NR)N(R'), halo, hydroxy, C(O)O NROR2, C(O)NR'R'', C(O)NR'R'', hydroxyamino, alkoxyamino, NRNR'R'', heteroaryl, NRC(S)NR2R39, O C(O)NR20R2, S(O) heteroaryloxy, heteroarylthio, heterocyclic, heterocyclyloxy, NR'R'', O S(O)NR'R'', NR S(O)NR'R'', heterocyclylthio, nitro, spirocycloalkyl, SOH, -OS(O) - C(=NR)NR'R'', aryl, aryloxy, arylthio, azido, car R", S(O) R', —C(S) R', thiocyanate, thiol, and boxyl, C(O)C R', NR C(O)C R', O C(O) alkylthio; each R" is independently selected from the group O R', cyano, cycloalkyl, cycloalkyloxy, cycloalkylthio. consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, - NRC(=NR)N(R), halo, hydroxy, hydroxyamino, and heterocycle, or two R' groups attached to a common alkoxyamino, NRNR'R'', heteroaryl, heteroaryloxy, atom are optionally joined together with the atom bound heteroarylthio, heterocyclic, heterocyclyloxy, heterocy thereto to form a heterocycle; and each R is independently clylthio, nitro, spirocycloalkyl, SOH, - OS(O) R', selected from the group consisting of alkyl, cycloalkyl, aryl, —S(O) R', —C(S) R', thiocyanate, thiol, and alky heteroaryl, and heterocycle. lthio; each R" is independently selected from the group con sisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and 0079. “Alkoxy” refers to the group – O-alkyl wherein heterocycle, or two R' groups attached to a common atom alkyl is defined herein. Alkoxy includes, by way of example, are optionally joined together with the atom bound thereto to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, form a heterocycle; and each R' is independently selected sec-butoxy, and n-pentoxy. from the group consisting of alkyl, cycloalkyl, aryl, het 0080 Aryl or 'Ar' refers to a monovalent aromatic car eroaryl, and heterocycle. bocyclic group of from 6 to 14 carbon atoms having a single I0085. “Halo' or “halogen” refers to fluoro, chloro, bromo ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl and iodo and preferably is fluoro or chloro. or anthryl) which condensed rings may or may not be aro I0086) “Haloalkyl refers to alkyl groups substituted with 1 matic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)- to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are one-7-yl, and the like) provided that the point of attachment is as defined herein. at an aromatic carbon atom. Preferred aryl groups include I0087. “Heteroaryl” refers to an aromatic group of from 5 phenyl and naphthyl. to 14 ring atoms, including from 1 to 10 carbon atoms and 1 0081. “Substituted aryl” refers to aryl groups which are to 4 heteroatoms selected from the group consisting of oxy substituted with 1 to 5, preferably 1 to 3, or more preferably gen, nitrogen and Sulfur. In some embodiments, heteroaryl 1 to 2 substituents selected from the group consisting of alkyl, comprises 5, 6, or 7 ring atoms, including 1 to 4 heteroatoms. substituted alkyl, alkoxy, C(O) R', NRC(O)R', Such heteroaryl groups can have a single ring (e.g., pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., indoliz inyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided NROR2, NR20 S(O)NR20R2, C(-NRNROR2, that the point of attachment is through an atom of the aromatic aryl, aryloxy, arylthio, azido, carboxyl, -C(O)C) R', heteroaryl group. In one embodiment, the nitrogen and/or the NR20 C(O)O R', O C(O)O R', cyano, Sulfur ring atom(s) of the heteroaryl group are optionally cycloalkyl, cycloalkyloxy, cycloalkylthio, NRC oxidized to provide for the N-oxide (N->O), sulfinyl, and/or (—NR)N(R') halo, hydroxy, hydroxyamino, sulfonyl moieties. Preferred heteroaryls include pyridinyl, alkoxyamino, NRNR'R'', heteroaryl, heteroaryloxy, pyrrolyl, indolyl, thiophenyl, and furanyl. heteroarylthio, heterocyclic, heterocyclyloxy, heterocy I0088 “Substituted heteroaryl refers to heteroaryl groups clylthio, nitro, spirocycloalkyl, SOH, - OS(O) R', that are substituted with from 1 to 5, preferably 1 to 3, or more —S(O) R', —C(S) R', thiocyanate, thiol, and alky preferably 1 to 2 substituents selected from the group con lthio; each R' is independently selected from the group con sisting of the same group of Substituents defined for Substi sisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and tuted aryl. heterocycle, or two R' groups attached to a common atom I0089) “Heterocycle” or “heterocyclic” or "heterocy are optionally joined together with the atom bound thereto to cloalkyl or "heterocyclyl refers to a saturated or partially US 2015/02581. 14 A1 Sep. 17, 2015 saturated, but not aromatic, group having from 3 to 14 ring I0098 R is C-C alkyl, benzyl, substituted C-C alkyl, atoms, including from 1 to 10 ring carbonatoms and from 1 to YH, YR, YC(O)R, C(O)YR, C(O)NHC(O)NHR, 4 ring heteroatoms selected from the group consisting of C(O)NR'R'', NH, NHR, NRR, NHC(O)R, O(CH.) nitrogen, Sulfur, or oxygen. In some embodiments, heteroaryl O(CH.) O(CH.), CH, or NRC(O)R’; comprises 3, 4, 5, 6 or 7 ring atoms, including 1 to 4 heteroa 0099 R is C-C alkyl or (CHCHO),CH: toms. Heterocycle encompasses single ring or multiple con 0100 R,R,R,R,R,R', and R'' are independently densed rings, including fused bridged and spiro ring systems. alkyl or substituted alkyl: Infused ring systems, one or more the rings can be cycloalkyl, 0101) R' is H, alkyl, or substituted alkyl: aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring. In one embodi 0102) R' is H, OR', alkyl, or substituted alkyl: ment, the nitrogen and/or Sulfur atom(s) of the heterocyclic (0103 X is O or NH; group are optionally oxidized to provide for the N-oxide, 01.04 Y is O or S; Sulfinyl, and/or Sulfonyl moieties. 0105 m is an integer selected from 0-8; 0090 “Substituted heterocyclic” or “substituted heterocy 010.6 each of n, p and q is 1, 2 or 3; and cloalkyl or “substituted heterocyclyl refers to heterocyclyl 01.07 r is 0, 1 or 2. groups that are substituted with from 1 to 5 or preferably 1 to 0108. In some embodiments, the ibogaine is represented 3 of the same substituents as defined for substituted by Formula II: cycloalkyl. 0091) “Ibogaine' as a specific compound refers to the

compound: II

N -O

N H or a pharmaceutically acceptable salt and/or Solvate thereof, 0109 wherein 0092. It should be understood that where “ibogaine' is mentioned herein, one more polymorphs of ibogaine can be 0110 R is hydrogen or C-C alkoxy, utilized and are contemplated. Ibogaine is isolated from Tab 0111) R' is hydrogen, C-C alkyl, C-C alkoxy, (CH) ernanth iboga, a shrub of West Africa. Ibogaine can also be OC(O)alkyl, (CH), OH, (CH), Oalkyl, (CH)O synthesized using known methods. See, e.g., Biichi, et al. (CH)O(CH.) O(CH), CH, or CH, Y CH, where (1966), J. Am. Chem Society, 88(13), 3099-3109. Unless each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2.Y is O or specified otherwise, “ibogaine' as used herein refers to NH, and ibogaine, ibogaine derivative, or a pharmaceutically accept 0112 R is H, (CH),OH,COOH, or COOR, where R' able salt and/or solvate thereof. is C-C alkyl or (CH2CH2O), CH, where n is 1, 2, or 3. 0093. In some embodiments, the ibogaine is represented 0113. In one embodiment, R is methoxy. In one embodi by Formula Ii: ment, R is ethyl. In one embodiment, R' is methoxy. In one embodiment, R' is CH Y CH, where Y is O. In one embodiment, R is CH Y CH, where Y is NH. In one Ii embodiment, R is hydrogen. In one embodiment. In one embodiment, R is COOR and R is methyl. In one embodi ment, n=1. In a preferred embodiment, R. RandR are all not hydrogen. In one embodiment, when R is methoxy and R' is hydrogen, then R is COOH or COOR. In another embodi ment, when R is methoxy and R' is hydrogen, then X is COOR where R is (CHCHO)CH, I0114. In one embodiment, R' is hydrogen. I0115) In one embodiment, R' is H. In one embodiment, R' or a pharmaceutically acceptable salt and/or Solvate thereof, is C-C alkyl, such as ethyl. In one embodiment, R' is 0094 wherein CHCH-OH. In one embodiment, R is CHCHOCH. In 0.095 R is H, halo, C-C alkyl, substituted C-C alkyl, one embodiment, R' is CHCHOCH.Ph. In one embodi OR, NH, NHR'9, NR'R'', NHC(O)R, or NRC ment, R' is CHCHOC(O)alkyl. In one embodiment, R' is (O)R'': CHCHO(CH)O(CH)O(CH2)CHs. I0096) R' is H, C-C alkyl, substituted C-C alkyl, 0116. In one embodiment, R is CH-OH and CH(OH)R. C-C alkoxy, CH, X-CH, or (CH), R: In one embodiment, R is CHOR. In one embodiment, R is (0097 R is H, COOH, COOR, (CH),OH, CH(OH) COR. In one embodiment, R is C(O)NH2, C(O)NHR, or R.CHOR, C(O)NHC(O)NHR,C(O)NR'R',C(O) C(O)NR'R''. In one embodiment, R is C(O)NHNH, C(O) NHNH, C(O)NHNHR, C(O)NHNRR, C(O) NHNHR, C(O)NRNHC(O)NHNRR, C(O)NHNHR, NRNH, C(O)NR'NHR, C(O)NRNRR", C(O) or C(O)NRNR'R''. In one embodiment, R is C(O)NHNH NHNH(C(O)R), C(O)NHNR(C(O)R), C(O)NR'NH (C(O)R), C(O)NHNR(C(O)R), C(O)NRNHC(O)R), or (C(O)R), C(O)NRNR(C(O)R7), CN, or C(O)R; C(O)NRNR(C(O)R7). In one embodiment, R is C(O)R. US 2015/02581. 14 A1 Sep. 17, 2015

0117. In the various method, formulation and kit aspects I0129. In one embodiment, the ibogaine derivative is and embodiments, in one embodiment a compound utilized selected from the group consisting of coronaridine, iboga herein is represented by, oribogaine as used herein is replaced mine, voacangine, 18-methoxycoronaridine, 2-Methoxy by, a compound Formula I: ethyl-18-methoxycoronaridinate, and 18-Methylaminocoro naridine. 0.130. In one embodiment, the ibogaine derivative is selected from the group consisting of 16-hydroxymethyl-18 hydroxyibogaline, 16-hydroxymethyl-18-methoxyiboga line, 16-ethoxycarbonyl-18-hydroxyibogaline laurate, and 16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxym ethyl ether. I0131. In one embodiment, the compound is of Formula IA: wherein

0118 R is hydrogen or C-C-alkoxy, IA I0119) R' is hydrogen, C-C-alkyl, C-C alkoxy, or CH Y CH where Y is O or NH, and I0120 X is H, COOH, or COOR, where R is C-C, alkyl or (CH2CH2O), CH, where n=1 to 3. 0121. In another embodiment, ibogaine or a pharmaceuti cally acceptable salt and/or solvate thereof is utilized. In another embodiment, ibogaine or a pharmaceutically accept able salt and/or solvate thereof is utilized. In another embodi wherein ment, the ibogaine, ibogaine derivative, is chosen from the group consisting of ibogaine, coronaridine, ibogamine, Voa (0132 R is hydrogen or C-C-alkoxy, cangine, 18-methoxycoronaridine, 2-methoxyethyl-18 I0133) R' is hydrogen, C-C-alkyl, C-C alkoxy, or methoxycoronaridinate, 18-methylaminocoronaridine or a CH Y CH where Y is O or NH, and pharmaceutically acceptable salt and/or solvate thereof. I0134) X is H, COOH, or COOR, where R is C-C, 0122. In another embodiment, the compound utilized alkyl or (CHCHO), CH, where n=1 to 3. herein is chosen from the group consisting of ibogaine, coro I0135) In another embodiment, the ibogaine derivative is naridine, ibogamine, voacangine, 18-methoxycoronaridine, represented by Formula II: 2-methoxyethyl-18-methoxycoronaridinate, 18-methylami nocoronaridine and a pharmaceutically acceptable salt and/or Solvate. II 0123. In another embodiment, the compound utilized herein is selected from the group consisting of 16-hydroxym ethyl-18-hydroxyibogaline, 16-hydroxymethyl-18-meth oxyibogaline, 16-ethoxycarbonyl-18-hydroxyibogaline lau rate, and 16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxymethyl ether and a pharmaceutically accept able salt and/or solvate thereof. 0.124. In one embodiment, the ibogaine derivative is rep or a pharmaceutically acceptable salt and/or Solvate thereof, resented by Formula II: 0.136 wherein 0.137 R is OCH: 0.138) R' is CHCH; and II R’ is COOR, where R is (CHCHO), CH, where n is 1. 0.139. When replacing ibogaine, the compounds of for mula I, II, and subformulas thereofas utilized herein exclude ibogaine. 0140 In a preferred embodiment, the compound utilized herein is: or a pharmaceutically acceptable salt and/or Solvate thereof, 0.125 wherein 0.126 R is hydrogen or C-C alkoxy; I0127) R' is hydrogen, C-C alkyl, C-C alkoxy, (CH) OC(O)alkyl, (CH), OH, (CH), Oalkyl, (CH)O (CH)O(CH.) O(CH), CH, or CH, Y CH, where N each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2.Y is O or NH; and 0128 R is H, (CH),OH,COOH, or COOR, where R' a pharmaceutically acceptable salt thereof, or a Solvate of is C-C alkyl or (CH2CH2O), CH, where n is 1, 2, or 3. each thereof. US 2015/02581. 14 A1 Sep. 17, 2015

0141. In some embodiments, the ibogaine or ibogaine derivative is selected from:

Name Structure coronaridine N

N H COCH

18-hydroxycoronaridine N OH

N H COCH

18-methoxycoronaridine N OCH

N H COCH3

18-benzyloxycoronaridine

N O

N H COCH

18-hydroxycoronaridine laurate N (CH2)10CH3 O

N COCH 18-hydroxycoronaridine / methoxyethoxymethyl ether N o/O

N COCH

18-hydroxycoronaridine acetate N sk

N COCH3 US 2015/02581. 14 A1 Sep. 17, 2015

-continued

Name Structure voacangine N

O 1. N

N H COCH 18-hydroxy voacangine N OH O 1. N

N H COCH 18-methoxy voacangine N OCH O 1. N

N H COCH3 18-benzyloxy voacangine

N O O 1. N

N H COCH3

18-hydroxy voacangine laurate N O (CH2)10CH3

O 1. N O

N H COCH3 18-hydroxy voacangine acetate

1. O N sk

N H COCH 18-hydroxy voacangine / methoxyethoxymethyl ether o/O N O-N/ O 1. N

N H COCH3 conopharyngine N

O 1. N

No N COCH3 US 2015/02581. 14 A1 Sep. 17, 2015 10

-continued

Name Structure

18-hydroxyconopharyngine N OH O 1. N N N O H COCH

18-methoxyconopharyngine N OCH O 1. N N N O H COCH3

18-benzyloxyconopharyngine

N O O 1. N N N O H COCH

18-hydroxyconopharyngine N O (CH2)10CH3CH) CH laurate O 1. N O N N O H COCH

18-hydroxyconopharyngine acetate

N O H COCH

18-hydroxyconopharyngine methoxyethoxymethyl ether N O-N/O -/ O 19 N No N H COCH3 ibogamine

N US 2015/02581. 14 A1 Sep. 17, 2015 11

-continued

Name Structure 16-ethoxycarbonyl-18 hydroxyibogamine N OH

N CO2CH2CH 16-hydroxymethyl-18 hydroxyibogamine N OH

N CH2OH 16-ethoxycarbonyl-18 methoxyibogamine N OCH

N COCH2CH3 16-hydroxymethyl-18 methoxyibogamine N OCH

N H CH2OH 16-ethoxycarbonyl-18 benzyloxyibogamine

N O

N H COCH2CH3 16-ethoxycarbonyl-18- (CH2)10CH3 hydroxyibogamine laurate N O

N COCH2CH3 16-ethoxycarbonyl-18 hydroxyibogamine acetate N sk

N H COCH2CH3 16-ethoxycarbonyl-18- / hydroxyibogamine O methoxyethoxymethyl ether N ON/

N COCH2CH3 US 2015/02581. 14 A1 Sep. 17, 2015

-continued

Name Structure ibogaine N O 1. N

N H 16-ethoxycarbonyl-18 hydroxyibogaine N OH O 1. N

N H CO2CH2CH 16-hydroxymethyl-18 hydroxyibogaine N OH O 1. N

N H CH2OH 16-ethoxycarbonyl-18 methoxyibogaine N O-N- O 1. N

N H COCH2CH3 16-hydroxymethyl-18 methoxyibogaine N OCH O 1. N

N H CH2OH 16-ethoxycarbonyl-18 benzyloxyibogaine

N O O 1. N

N H COCH2CH3

16-ethoxycarbonyl-18 N O (CH2)10CH3CH) CH hydroxyibogaine laurate O 1. N O

N H COCH2CH3 16-ethoxycarbonyl-18 hydroxyibogaine acetate 19 N sk

N CO2CH2CH US 2015/02581. 14 A1 Sep. 17, 2015

-continued

Name Structure 16-ethoxycarbonyl-18 hydroxyibogaine methoxyethoxymethyl ether N O-N/ o/O O 1. N

N H CO2CH2CH ibogaline N O 1. N No N 16-ethoxycarbonyl-18 hydroxyibogaline N OH O 1. N No N H CO2CH2CH 16-hydroxymethyl-18 hydroxyibogaline N OH O 1. N No N H CHOH 16-ethoxycarbonyl-18 methoxyibogaline N OCH O 1. N No N H COCH2CH3 16-hydroxymethyl-18 methoxyibogaline N OCH O 1. N No N H CH2OH 16-ethoxycarbonyl-18 benzyloxyibogaline

N O O 1. N No N H CO2CH2CH

16-ethoxycarbonyl-18 (CH2)(CH3 hydroxyibogaline laurate N O O 1. N O

No N COCH2CH3 US 2015/02581. 14 A1 Sep. 17, 2015

-continued

Name Structure

16-ethoxycarbonyl-18 hydroxyibogaline acetate N O sk 1. N O No N H COCH2CH3 16-ethoxycarbonyl-18 hydroxyibogaline methoxyethoxymethyl ether N o/O O N/ O 1. N No N H CO2CH2CH and pharmaceutically acceptable salts and/or Solvates -continued thereof. N O N, O 0142. In one embodiment, the ibogaine derivative is:

N H N O O N- O N (2-Methoxyethyl-18-methoxycoronaridinate, ME-18-MC) N H H O

(coronaridine) N N H or

N H (18-Methylaminocoronaridine, 18-MAC) (ibogamine)

N 0143. This invention is not limited to any particular chemi O s cal form of the compounds, and the drug may be given to 1. N patients either as a free base, Solvate, or as a pharmaceutically N acceptable acid addition salt. In the latter case, the hydrochlo H ride salt is generally preferred, but other salts derived from O O organic or inorganic acids may also be used. Examples of such acids include, without limitation, those described below (voacangine) as “pharmaceutically acceptable salts' and the like.

N 0144. This invention is not limited to any particular chemi cal form of ibogaine, ibogaine derivative, orpharmaceutically acceptable salt and/or Solvate thereof, and the drug may be given to patients either as a free base, Solvate, or as a phar N maceutically acceptable acid addition salt. In the latter case, O the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of Such acids include, without limitation, those (18-methoxycoronaridine, 18-MC) described below as “pharmaceutically acceptable salts' and the like. US 2015/02581. 14 A1 Sep. 17, 2015

0145 “Pharmaceutically acceptable composition” refers physically addicted to the drug. For example, a maintenance to a composition that is suitable for administration to a mam amount is preferably 80%, 70%, 60%, 50%, 40%, 30%, 20%, mal, particularly, a human. Such compositions include Vari or 10% less than a therapeutically effective amount, or any ous excipients, diluents, carriers, and Such other inactive subvalue or subrange there between. agents well known to the skilled artisan. 0150. As defined herein, a “prophylactically effective 0146 “Pharmaceutically acceptable salt” refers to phar amount of a drug is an amount, typically less than the thera maceutically acceptable salts, including pharmaceutically peutically effective amount, that provides attenuation and/or acceptable partial salts, of a compound, which salts are prevention of a disease or disorder or symptoms of a disease derived from a variety of organic and inorganic counter ions or disorder in a patient. For example, the prophylactically well known in the art and include, by way of example only, effective amount of the compound is expected to be less than hydrochloric acid, hydrobromic acid, phosphoric acid, Sulfu the therapeutically effective amount because the level of inhi ric acid, methane Sulfonic acid, phosphorous acid, nitric acid, bition does not need to be as high in a patient who is no longer perchloric acid, acetic acid, tartaric acid, lactic acid, Succinic physically addicted to nicotine. For example, a prophylacti acid, citric acid, malic acid, maleic acid, aconitic acid, sali cally effective amount is preferably 90%, 80%, 70%, 60%, cylic acid, thalic acid, embonic acid, enanthic acid, oxalic 50%, 40%, 30%, 20%, or 10% less than a therapeutically acid and the like, and when the molecule contains an acidic effective amount. However, a prophylactically effective functionality, include, by way of example only, Sodium, amount may be the same as the therapeutically effective potassium, calcium, magnesium, ammonium, tetraalkylam amount, for example when a patient who is physically monium, and the like. addicted to nicotine is administered ibogaine, ibogaine 0147 “Therapeutically effective amount’ or “therapeutic derivative, or pharmaceutically acceptable salt and/or Solvate amount refers to an amount of a drug or an agent that, when thereof to attenuate cravings for a period of time when nico administered to a patient Suffering from a condition, will have tine use is not feasible. The prophylactically effective amount the intended therapeutic effect, e.g., alleviation, amelioration, may vary for different a diseases or disorders or symptoms of palliation or elimination of one or more manifestations of the different diseases or disorders. condition in the patient. The therapeutically effective amount 0151. “Treatment,” “treating,” and “treat” are defined as will vary depending upon the patient and the condition being acting upon a disease, disorder, or condition with an agent to treated, the weight and age of the subject, the severity of the reduce or ameliorate harmful or any other undesired effects of condition, the salt, Solvate, or derivative of the active drug the disease, disorder, or condition and/or its symptoms. portion chosen, the particular composition or excipient cho “Treatment, as used herein, covers the treatment of a human sen, the dosing regimen to be followed, timing of administra patient, and includes: (a) reducing the risk of occurrence of tion, the manner of administration and the like, all of which the condition in a patient determined to be predisposed to the can be determined readily by one of ordinary skill in the art. condition but not yet diagnosed as having the condition, (b) The full therapeutic effect does not necessarily occur by impeding the development of the condition, and/or (c) reliev administration of one dose, and may occur only after admin ing the condition, i.e., causing regression of the condition istration of a series of doses. Thus, a therapeutically effective and/or relieving one or more symptoms of the condition. amount may be administered in one or more administrations. “Treating or “treatment of a condition or patient refers to For example, and without limitation, a therapeutically effec taking steps to obtain beneficial or desired results, including tive amount of ibogaine, ibogaine derivative, or pharmaceu clinical results such as the reduction of symptoms. For pur tically acceptable salt and/or solvate thereof in the context of poses of this invention, beneficial or desired clinical results treating drug dependency, refers to an amount of compound include, but are not limited to: treating Substance addiction; that attenuates the dependency and/or symptoms of acute treating, preventing, and/or attenuating acute withdrawal withdrawal for at least 2 hours beyond control (placebo), at symptoms; treating, preventing, and/or attenuating long-term least 5 hours beyond control, and preferably at least 10 hours (post-acute) withdrawal symptoms; and preventing relapse of beyond control. Substance use/abuse. 0148. A “therapeutic level of a drug is an amount of 0152. As used herein, the term “patient” refers to a mam ibogaine, ibogaine derivative, orpharmaceutically acceptable mal and includes humans and non-human mammals. salt and/or solvate thereofthat is sufficient to treat drug addic 0153. As used herein, the terms “addictive substance'. tion or to treat, prevent, or attenuate acute withdrawal Symp “drug”, “addictive drug and the like refer to drugs and other toms, but not high enough to pose any significant risk to the Substances whose use results in addiction in at least a Subset patient. Therapeutic levels of drugs can be determined by of individuals who use them. Addictive substances include, tests that measure the actual concentration of the compound without limitation, benzodiazepines (including chlordiazep in the blood of the patient. This concentration is referred to as oxide, cloraZepate, diazepam, flurazepam, halazepam, the "serum concentration.” Where the serum concentration of prazepam, lorazepam, lormetazepam, oxazepam, ibogaine is mentioned, it is to be understood that the term temazepam, clonazepam, flunitrazepam, nimetazepam, “ibogaine' encompasses any form of ibogaine, including nitrazepam, adinazolam, alprazolam, estazolam, triazolam, ibogaine derivative, or pharmaceutically acceptable salt and/ climaZolam, loprazolam, and midazolam), cannabinoids and or solvate thereof synthetic cannabinoids, stimulants (including amphetamine, 0149. As defined herein, a “maintenance amount of a methylphenidate, dexmethylphenidate, dextroamphetamine, drug is an amount, typically less than the therapeutically mixed amphetamine salts, dextromethamphetamine, lisdex effective amount that provides attenuation and/or prevention amfetamine, modafinil, adrafinil, armodafinil, caffeine, ephe of post-acute withdrawal syndrome in a patient. The mainte drine, methylenedioxymethamphetamine, methylenedioxy nance amount of the compound is expected to be less than the pyrovalerone, mephedrone, phenylpropanolamine, therapeutically effective amount because the level of inhibi propylhexadrine, pseudoephedrine, and khat), barbiturates tion does not need to be as high in a patient who is no longer (including allobarbital, amobarbital, aprobarbital, alphenal, US 2015/02581. 14 A1 Sep. 17, 2015 barbital, brallobarbital, pentobarbital, phenobarbital, and treating nicotine addiction in a Subject, comprising ibogaine, secobarbital), gamma-hydroxybutyrate (GHB), ketamine, ibogaine derivatives, or pharmaceutically acceptable salts PCP. dextromethorphan (DXM), lysergic acid diethylamide and/or Solvates of each thereof. In another aspect, this inven (LSD), mescaline, anabolic steroids, and derivatives of each tion further provides compositions for treating, attenuating, thereof. Addictive Substances may be illicit drugs, prescrip or preventing nicotine cravings in a subject, comprising tion drugs prone to abuse, or other legal drugs prone to abuse. ibogaine, ibogaine derivative, orpharmaceutically acceptable 0154 As used herein, the term “QT interval” refers to the salt and/or solvate thereof. measure of the time between the start of the Q wave and the 0167. This invention is not limited to any particular chemi end of the T wave in the electrical cycle of the heart. Prolon cal form of the compounds, and the drug may be given to gation of the QT interval refers to an increase in the QT patients either as a free base, Solvate, or as a pharmaceutically interval. acceptable acid addition salt. In the latter case, the hydrochlo O155 As used herein, the terms “addiction”, “abuse', and ride salt is generally preferred, but other salts derived from “dependence' are used interchangeably to refer to the organic or inorganic acids may also be used. Examples of patients inability to stop using the addictive Substance, even such acids include, without limitation, those described below when it would be in his/her best interest to stop. A patient may as “pharmaceutically acceptable salts' and the like. Dosing be physically and/or behaviorally addicted to a substance. schemes are discussed in further detail below in the subsec The DSM IV-TR criteria for dependency include: tion titled “Dosing and Routes of Administration.” 0156 Dependence or significant impairment or dis 0.168. In one aspect, the invention provides a pharmaceu tress, as manifested by 3 or more of the following during tical composition comprising a therapeutically or prophylac a 12 month period: tically effective amount of ibogaine, ibogaine derivative, or 0157 1. Tolerance or markedly increased amounts of pharmaceutically acceptable salt and/or Solvate thereof and a the substance to achieve intoxication or desired effector pharmaceutically acceptable excipient, wherein the therapeu markedly diminished effect with continued use of the tically or prophylactically effective amount of ibogaine, same amount of Substance ibogaine derivative, or pharmaceutically acceptable salt and/ 0158 2. Withdrawal symptoms or the use of certain or Solvate thereof is an amount that delivers an aggregate Substances to avoid withdrawal symptoms amount of ibogaine, ibogaine derivative, orpharmaceutically 0159) 3. Use of a substance in larger amounts or over a acceptable salt and/or solvate thereof of about 50 ng to less longer period than was intended than 10 ug per kg body weight per day. In some aspects, the (0160 4. Persistent desire or unsuccessful efforts to cut therapeutically or prophylactically effective amount of down or control Substance use ibogaine, ibogaine derivative, orpharmaceutically acceptable 0.161 5. Involvement in chronic behavior to obtain the salt and/or Solvate thereof is an amount that delivers an aggre Substance, use the Substance, or recover from its effects gate amount of ibogaine, ibogaine derivative, or pharmaceu 0162 6. Reduction or abandonment of social, occupa tically acceptable salt and/or solvate thereof of about 50 ng to tional or recreational activities because of Substance use about 10 ug per kg body weight per day. In some aspects, the 0163 7. Use of substances even though there is a per therapeutically or prophylactically effective amount of sistent or recurrent physical or psychological problem ibogaine, ibogaine derivative, orpharmaceutically acceptable that is likely to have been caused or exacerbated by the salt and/or Solvate thereof is an amount that delivers an aggre Substance. gate amount of ibogaine, ibogaine derivative, or pharmaceu 0164. The term “dose” refers to a range of ibogaine, tically acceptable salt and/or solvate thereof of about 50 ng to ibogaine derivative, or pharmaceutical salt or Solvate thereof about 10 ug per kg body weight per day. In some aspects, the that provides a therapeutic serum level of ibogaine, ibogaine composition is formulated for administration once per day. In derivative, orpharmaceutically acceptable salt and/or Solvate Some aspects, the composition is formulated for administra thereof when given to a patient in need thereof. The dose is tion two or more times per day. recited in a range, for example from about 20 mg to about 120 0169. In some embodiments, the composition is formu mg, and can be expressed either as milligrams or as mg/kg lated for Sublingual, intranasal, or intrapulmonary delivery. body weight. The attending clinician will select an appropri These routes of administration are discussed in further detail ate dose from the range based on the patients weight, age, below in the subsection titled “Dosing and Routes of Admin degree of addiction, health, and other relevant factors, all of istration.” which are well within the skill of the art. 0170 In one aspect, the invention provides a pharmaceu 0.165. The term “unit dose” refers to a dose of drug that is tical composition comprising a pharmaceutically effective given to the patient to provide therapeutic results, indepen amount of ibogaine, derivative, or salt and/or Solvate thereof dent of the weight of the patient. In Such an instance, the unit and a pharmaceutically acceptable excipient, wherein the dose is sold in a standard form (e.g., 20 mg tablet). The unit therapeutically effective amount of ibogaine, ibogaine dose may be administered as a single dose or a series of derivative, or pharmaceutically acceptable salt and/or Solvate Subdoses. In some embodiments, the unit dose provides a thereof is an amount that delivers an aggregate amount of standardized level of drug to the patient, independent of ibogaine, ibogaine derivative, orpharmaceutically acceptable weight of patient. Many medications are sold based on a dose salt and/or solvate thereof of about 50 ng to less than 100 g that is therapeutic to all patients based on a therapeutic win per kg body weight per day. In some aspects, the therapeuti dow. In Such cases, it is not necessary to titrate the dosage cally effective amount of ibogaine, ibogaine derivative, or amount based on the weight of the patient. pharmaceutically acceptable salt and/or Solvate thereof is an amount that delivers an aggregate amount of ibogaine, II. Compositions ibogaine derivative, or pharmaceutically acceptable salt and/ 0166 As will be apparent to the skilled artisan upon read or solvate thereof of about 50 ng to about 50 ug per kg body ing this disclosure, this invention provides compositions for weight per day. In some aspects, the therapeutically effective US 2015/02581. 14 A1 Sep. 17, 2015 amount of ibogaine, ibogaine derivative, or pharmaceutically 0173. In another aspect, provided herein is a pharmaceu acceptable salt and/or solvate thereof is an amount that deliv tical composition comprising a therapeutically effective ers an aggregate amount of ibogaine, ibogaine derivative, or amount of ibogaine, ibogaine derivative, orpharmaceutically pharmaceutically acceptable salt and/or solvate thereof of acceptable salt and/or Solvate thereof and a pharmaceutically about 50 ng to about 10 ug per kg body weight per day. In acceptable excipient, wherein the therapeutically effective Some aspects, the therapeutically effective amount of amount of ibogaine, ibogaine derivative, orpharmaceutically ibogaine, ibogaine derivative, orpharmaceutically acceptable acceptable salt and/or solvate thereof is an amount that deliv salt and/or Solvate thereof is an amount that delivers an aggre ers an aggregate amount of ibogaine of about 50 ng to less gate amount of ibogaine, ibogaine derivative, or pharmaceu than 10 ug per kg body weight per day. tically acceptable salt and/or solvate thereof of about 50 ng to 0.174. In one embodiment, the therapeutically effective about 1 lug per kg body weight per day. In some aspects, the amount of ibogaine, ibogaine derivative, orpharmaceutically composition is formulated for administration once per day. In acceptable salt thereof is an amount that delivers an aggregate Some aspects, the composition is formulated for administra amount of ibogaine of about 50 ng to about 1 Jug per kg body tion two or more times per day. The ranges include both weight per day. extremes as well as any Subranges there between. 0.175. In one embodiment, the therapeutically effective 0171 In some embodiments, the composition is formu amount of the compound is from about 1 mg to about 4 mg per lated for oral, transdermal, internal, pulmonary, rectal, nasal, kg body weight per day. In another embodiment, the thera vaginal, lingual, intravenous, intraarterial, intramuscular, peutically effective amount of the compound is from about 1 intraperitoneal, intracutaneous or Subcutaneous delivery. In mg to about 3 mg per kg body weight per day. In another one embodiment, the therapeutically effective amount of the embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 8 mg per kg body compound is from about 1 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to effective amount of the compound is from about 1.3 mg to about 7 mg per kg body weight per day. In another embodi about 3 mg per kg body weight per day. In another embodi ment, the therapeutically effective amount of the compound is ment, the therapeutically effective amount of the compound is from about 1.3 mg to about 6 mg per kg body weight per day. from about 1.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 5 mg per kg of the compound is from about 1.7 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeuti body weight per day. In another embodiment, the therapeuti cally effective amount of the compound is from about 1.3 mg cally effective amount of the compound is from about 1.3 mg to about 4 mg per kg body weight per day. In another embodi to about 4 mg per kg body weight per day. In another embodi ment, the therapeutically effective amount of the compound is ment, the therapeutically effective amount of the compound is from about 1.3 mg to about 3 mg per kg body weight per day. from about 1.5 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 2 mg per kg of the compound is about about 2 mg per kg body weight per body weight per day. In another embodiment, the therapeuti cally effective amount of the compound is from about 1.5 mg day. The ranges include both extremes as well as any Sub to about 3 mg per kg body weight per day. In another embodi range or subvalue there between. ment, the therapeutically effective amount of the compound is 0176). In one embodiment, the therapeutically effective from about 1.7 mg to about 3 mg per kg body weight per day. amount of the compound is about 4 mg/kg body weight per In another embodiment, the therapeutically effective amount day. In one embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 4 mg per kg of the compound is about 3 mg/kg body weight per day. In body weight per day. In another embodiment, the therapeuti another embodiment, the therapeutically effective amount of cally effective amount of the compound is from about 2 mg to the compound is about 2 mg per kg body weight per day. In about 3 mg per kg body weight per day. In another embodi another embodiment, the therapeutically effective amount of ment, the therapeutically effective amount of the compound is the compound is about 1.7 mg per kg body weight per day. In about 2 mg per kg body weight per day. The ranges include another embodiment, the therapeutically effective amount of both extremes as well as any Subranges there between. the compound is about 1.5 mg per kg body weight per day. In 0172. In one embodiment, the therapeutically effective another embodiment, the therapeutically effective amount of amount of the compound is about 8 mg/kg body weight per the compound is about 1.2 mg per kg body weight per day. In day. In one embodiment, the therapeutically effective amount another embodiment, the therapeutically effective amount of of the compound is about 7 mg/kg body weight per day. In one the compound is about 1 mg per kg body weight per day. embodiment, the therapeutically effective amount of the 0177. In another aspect, provided herein is a pharmaceu compound is about 6 mg/kg body weight per day. In one tically acceptable formulation comprising a unit dose of embodiment, the therapeutically effective amount of the ibogaine, wherein the amount of ibogaine is Sufficient to compound is about 5 mg/kg body weight per day. In one provide a serum concentration of about 50 ng/mL to about embodiment, the therapeutically effective amount of the 500 ng/mL when administered to a patient. compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the III. Methods of the Invention compound is about 3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the 0.178 As will be apparent to the skilled artisan upon read compound is about 2 mg/kg body weight per day. In one ing this disclosure, the present invention provides a method embodiment, the therapeutically effective amount of the for treating Substance abuse or addiction, including acute and compound is about 1 mg/kg body weight per day. post-acute withdrawal symptoms, in an addicted patient, US 2015/02581. 14 A1 Sep. 17, 2015 comprising administering to the patient a dosage of ibogaine, 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about ibogaine derivative, or pharmaceutically acceptable salt and/ 600 ng/mL. In a preferred embodiment, the average serum or solvate thereof concentration of the compound is from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In Therapeutic Administration one embodiment, the average serum concentration of the 0179. In one aspect, this invention relates to treatment of compound is from about 50 ng/mL to about 400 ng/mL, or acute withdrawal from an addictive Substance in an addicted about 60 ng/mL to about 400 ng/mL. In one embodiment, the patient comprising administration of a therapeutically effec average serum concentration of the compound is from about tive amount of ibogaine, ibogaine derivative, or pharmaceu 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about tically acceptable salt and/or solvate thereof. 300 ng/mL. In one embodiment, the average serum concen 0180. In one aspect, this invention relates to a method for tration of the compound is from about 50 ng/mL to about 200 treating Substance abuse in an addicted patient, comprising ng/mL, or about 60 ng/mL to about 200 ng/mL. In one administering to the patient a dosage of ibogaine, ibogaine embodiment, the average serum concentration of the com derivative, orpharmaceutically acceptable salt and/or Solvate pound is from about 50 ng/mL to about 100 ng/mL, or about thereofthat provides an average serum concentration of about 60 ng/mL to about 100 ng/mL. The ranges include both 50 ng/mL to about 850 ng/mL, said concentration being suf extremes as well as any Subranges between. ficient to inhibitor ameliorate said abuse while maintaining a 0.184 In one embodiment, the dosage or aggregate dosage QT interval of less than about 500 ms during said treatment. of ibogaine, ibogaine derivative, or pharmaceutically accept 0181. In one aspect, this invention relates to a method for able salt and/or solvate thereof is from greater than about 1 attenuating withdrawal symptoms in a human patient Suscep mg/kg to about 8 mg/kg body weight per day. The aggregate tible to Such symptoms due to Substance addiction, compris dosage is the combined dosage, for example the total amount ing administering to the patient a dosage of ibogaine, of ibogaine, ibogaine derivative, or pharmaceutically accept ibogaine derivative, or pharmaceutically acceptable salt and/ able salt and/or solvate thereof administered over a 24-hour or Solvate thereof that provides an average serum concentra period where Smaller amounts are administered more than tion of about 50 ng/mL to about 400 ng/mL, said concentra once per day. In one embodiment, the dosage or aggregate tion being Sufficient to attenuate said symptoms while dosage of ibogaine, ibogaine derivative, or pharmaceutically maintaining a QT interval of less than about 500 ms during acceptable salt and/or solvate thereof is from about 1.3 mg/kg said treatment. In some embodiments, the concentration is to about 7 mg/kg body weight. In one embodiment, the dos sufficient to attenuate said symptoms while maintaining a QT age or aggregate dosage of ibogaine, ibogaine derivative, or interval of less than about 470 ms during treatment. Prefer pharmaceutically acceptable salt and/or Solvate thereof is ably, the concentration is sufficient to attenuate said symp from about 1.3 mg/kg to about 6 mg/kg body weight. In one toms while maintaining a QT interval of less than about 450 embodiment, the dosage or aggregate dosage of ibogaine, ms during treatment. In one embodiment, the concentration is ibogaine derivative, or pharmaceutically acceptable salt and/ Sufficient to attenuate said symptoms while maintaining a QT or Solvate thereof is from about 1.3 mg/kg to about 5 mg/kg interval of less than about 420 ms during treatment. In one body weight. In a preferred embodiment, the dosage or aggre embodiment, the withdrawal symptoms are symptoms of gate dosage of ibogaine, ibogaine derivative, or pharmaceu acute withdrawal. tically acceptable salt and/or solvate thereof is from about 1.3 0182. In one aspect, this invention relates to a method for mg/kg to about 4 mg/kg body weight. In one embodiment, the attenuating withdrawal symptoms in a human patient Suscep dosage or aggregate dosage of ibogaine, ibogaine derivative, tible to Such symptoms due to Substance addiction, compris or pharmaceutically acceptable salt and/or Solvate thereof is ing administering to the patient a dosage of ibogaine, from about 1.3 mg/kg to about 3 mg/kg body weight. In one ibogaine derivative, or pharmaceutically acceptable salt and/ embodiment, the dosage or aggregate dosage of ibogaine, or Solvate thereof that provides an average serum concentra ibogaine derivative, or pharmaceutically acceptable salt and/ tion of about 50 ng/mL to about 400 ng/mL, said concentra or Solvate thereof is from about 1.3 mg/kg to about 2 mg/kg tion being Sufficient to attenuate said symptoms while body weight. In one embodiment, the dosage or aggregate maintaining a QT interval of less than about 500 ms during dosage of ibogaine, ibogaine derivative, or pharmaceutically said treatment. In some embodiments, the concentration is acceptable salt and/or solvate thereof is from about 1.5 mg/kg Sufficient to attenuate said symptoms while maintaining a QT to about 3 mg/kg body weight. In one embodiment, the dos interval of less than about 470 ms during treatment. Prefer age or aggregate dosage of ibogaine, ibogaine derivative, or ably, the concentration is sufficient to attenuate said symp pharmaceutically acceptable salt and/or Solvate thereof is toms while maintaining a QT interval of less than about 450 from about 1.7 mg/kg to about 3 mg/kg body weight. In one ms during treatment. In one embodiment, the concentration is embodiment, the dosage or aggregate dosage of ibogaine, Sufficient to attenuate said symptoms while maintaining a QT ibogaine derivative, or pharmaceutically acceptable salt and/ interval of less than about 420 ms during treatment. In one or Solvate thereof is from about 2 mg/kg to about 4 mg/kg embodiment, the withdrawal symptoms are symptoms of body weight. In one embodiment, the dosage or aggregate acute withdrawal. dosage of ibogaine, ibogaine derivative, or pharmaceutically 0183 In one embodiment, the average serum concentra acceptable salt and/or Solvate thereof is from about 2 mg/kg to tion of ibogaine, ibogaine derivative, or pharmaceutically about 3 mg/kg body weight. In one embodiment, the dosage acceptable salt and/or solvate thereof is from about 50 ng/mL or aggregate dosage of ibogaine, ibogaine derivative, or phar to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. maceutically acceptable salt and/or solvate thereof is about 2 In one embodiment, the average serum concentration of the mg/kg body weight. The ranges include both extremes as well compound is from about 50 ng/mL to about 700 ng/mL or as any Subranges there between. about 60 ng/mL to about 700 ng/mL. In one embodiment, the 0185. In one embodiment, the dosage or aggregate dosage average serum concentration of the compound is from about of ibogaine, ibogaine derivative, or pharmaceutically accept US 2015/02581. 14 A1 Sep. 17, 2015 able salt and/or solvate thereof is about 8 mg/kg body weight for example once every two days, once every three days, once per day. In one embodiment, the dosage or aggregate dosage every four days, once a week, etc. of ibogaine, ibogaine derivative, or pharmaceutically accept 0187. In one embodiment, the dosage or aggregate dosage able salt and/or solvate thereof is about 7 mg/kg body weight of compound is from about 1 mg to about 4 mg per kg body per day. In one embodiment, the dosage or aggregate dosage weight per day. The aggregate dosage is the combined dos of ibogaine, ibogaine derivative, or pharmaceutically accept age, for example the total amount of ibogaine, ibogaine able salt and/or solvate thereof is about 6 mg/kg body weight derivative, or pharmaceutically acceptable salt and/or Solvate per day. In one embodiment, the dosage or aggregate dosage thereof administered over a 24-hour period where smaller of ibogaine, ibogaine derivative, or pharmaceutically accept amounts are administered more than once per day. able salt and/or solvate thereof is about 5 mg/kg body weight 0188 In one embodiment, the dosage or aggregate dosage per day. In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative, or pharmaceutically accept of ibogaine, ibogaine derivative, or pharmaceutically accept able salt and/or solvate thereof is between about 70 mg and able salt and/or solvate thereof is about 4 mg/kg body weight about 150 mg. In one embodiment, the dosage or aggregate per day. In one embodiment, the dosage or aggregate dosage dosage of ibogaine, ibogaine derivative, or pharmaceutically of ibogaine, ibogaine derivative, or pharmaceutically accept acceptable salt and/or solvate thereof is between about 75 mg able salt and/or solvate thereof is about 3 mg/kg body weight and about 150 mg. In one embodiment, the dosage or aggre per day. In one embodiment, the dosage or aggregate dosage gate dosage of ibogaine, ibogaine derivative, or pharmaceu of ibogaine, ibogaine derivative, or pharmaceutically accept tically acceptable salt and/or solvate thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage or able salt and/or solvate thereof is about 2 mg/kg body weight aggregate dosage of ibogaine, ibogaine derivative, or phar per day. In one embodiment, the dosage or aggregate dosage maceutically acceptable salt and/or solvate thereof is between of ibogaine, ibogaine derivative, or pharmaceutically accept about 90 mg and about 140 mg. In one embodiment, the able salt and/or solvate thereof is about 1.7 mg/kg body dosage or aggregate dosage of ibogaine, ibogaine derivative, weight per day. In one embodiment, the dosage or aggregate or pharmaceutically acceptable salt and/or Solvate thereof is dosage of ibogaine, ibogaine derivative, or pharmaceutically between about 90 mg and about 130 mg. In one embodiment, acceptable salt and/or solvate thereof is about 1.5 mg/kg body the dosage or aggregate dosage of ibogaine, ibogaine deriva weight per day. In one embodiment, the dosage or aggregate tive, or pharmaceutically acceptable Salt and/or Solvate dosage of ibogaine, ibogaine derivative, or pharmaceutically thereof is between about 100 mg and about 130 mg. In one acceptable salt and/or solvate thereof is about 1.3 mg/kg body embodiment, the dosage or aggregate dosage of ibogaine, weight per day. In one embodiment, the dosage or aggregate ibogaine derivative, or pharmaceutically acceptable salt and/ dosage of ibogaine, ibogaine derivative, or pharmaceutically or solvate thereof is between about 110 mg and about 130 mg. acceptable salt and/or Solvate thereof is about 1 mg/kg body The ranges include both extremes as well as any Subrange or weight per day. subvalue there between. 0186. In one aspect, the invention provides administering 0189 In one embodiment, the average serum concentra a pharmaceutical composition comprising a pharmaceuti tion of ibogaine, ibogaine derivative, or pharmaceutically cally effective amount of ibogaine, ibogaine derivative, or acceptable salt and/or solvate thereof is from about 50 ng/mL pharmaceutically acceptable salt and/or Solvate thereof and a to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. pharmaceutically acceptable excipient, wherein the therapeu In one embodiment, the average serum concentration of tically effective amount of ibogaine, ibogaine derivative, or ibogaine, ibogaine derivative, orpharmaceutically acceptable pharmaceutically acceptable salt and/or Solvate thereof is an salt and/or solvate thereof is from about 50 ng/mL to about amount that delivers an aggregate amount of ibogaine, 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one ibogaine derivative, or pharmaceutically acceptable salt and/ embodiment, the average serum concentration of ibogaine, or solvate thereof of about 50 ng to about 100 ug per kg body ibogaine derivative, or pharmaceutically acceptable salt and/ weight per day. In some aspects, the therapeutically effective or solvate thereof is from about 50 ng/mL to about 600 amount of ibogaine, ibogaine derivative, or pharmaceutically ng/mL, or about 60 ng/mL to about 600 ng/mL. In a preferred acceptable salt and/or solvate thereof is an amount that deliv embodiment, the average serum concentration of ibogaine, ers an aggregate amount of ibogaine, ibogaine derivative, or ibogaine derivative, or pharmaceutically acceptable salt and/ pharmaceutically acceptable salt and/or solvate thereof of or solvate thereof is from about 50 ng/mL to about 500 about 50 ng to about 50 g per kg body weight per day. In ng/mL, or about 60 ng/mL to about 500 ng/mL. In one Some aspects, the therapeutically effective amount of embodiment, the average serum concentration of ibogaine, ibogaine, ibogaine derivative, orpharmaceutically acceptable ibogaine derivative, or pharmaceutically acceptable salt and/ salt and/or Solvate thereof is an amount that delivers an aggre or solvate thereof is from about 50 ng/mL to about 400 gate amount of ibogaine, ibogaine derivative, or pharmaceu ng/mL, or about 60 ng/mL to about 400 ng/mL. In one tically acceptable salt and/or solvate thereof of about 50 ng to embodiment, the average serum concentration of ibogaine, about 10 ug per kg body weight per day. In some aspects, the ibogaine derivative, or pharmaceutically acceptable salt and/ therapeutically effective amount of ibogaine, ibogaine or solvate thereof is from about 50 ng/mL to about 300 derivative, orpharmaceutically acceptable salt and/or Solvate ng/mL, or about 60 ng/mL to about 300 ng/mL. In one thereof is an amount that delivers an aggregate amount of embodiment, the average serum concentration of ibogaine, ibogaine, ibogaine derivative, orpharmaceutically acceptable ibogaine derivative, or pharmaceutically acceptable salt and/ salt and/or Solvate thereof of about 50 ng to about 1 g per kg or solvate thereof is from about 50 ng/mL to about 200 body weight per day. In some aspects, the composition is ng/mL, or about 60 ng/mL to about 200 ng/mL. In one administered once per day. In some aspects, the composition embodiment, the average serum concentration of ibogaine, is administered two or more times per day. In some embodi ibogaine derivative, or pharmaceutically acceptable salt and/ ments, the composition is administered less than once a day, or solvate thereof is from about 50 ng/mL to about 100 US 2015/02581. 14 A1 Sep. 17, 2015 20 ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges “unit dose” means a dose sufficient to provide therapeutic include both extremes as well as any Subranges between. results whether given all at once or serially over a period of 0190. In one embodiment, the average serum concentra time. tion of ibogaine, ibogaine derivative, or pharmaceutically 0194 In some embodiments, the patient is administered acceptable salt and/or solvate thereof is from about 50 ng/mL an initial dose of ibogaine, ibogaine derivative, or pharma to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. ceutically acceptable salt and/or solvate thereof followed by In one embodiment, the average serum concentration of one or more additional doses. ibogaine, ibogaine derivative, orpharmaceutically acceptable 0.195. In some embodiments, the initial dose of ibogaine, salt and/or solvate thereof is from about 50 ng/mL to about ibogaine derivative, or pharmaceutically acceptable salt and/ 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one or solvate thereof is from about 75 mg to about 120 mg. In one embodiment, the average serum concentration of ibogaine, embodiment, the initial dose is about 75 mg. In one embodi ibogaine derivative, or pharmaceutically acceptable salt and/ ment, the initial dose is about 80 mg. In one embodiment, the or solvate thereof is from about 50 ng/mL to about 100 initial dose is about 85 mg. In one embodiment, the initial ng/mL, or about 60 ng/mL to about 100 ng/mL. In one dose is about 90 mg. In one embodiment, the initial dose is embodiment, the average serum concentration of ibogaine, about 95 mg. In one embodiment, the initial dose is about 100 ibogaine derivative, or pharmaceutically acceptable salt and/ mg. In one embodiment, the initial dose is about 105 mg. In or solvate thereof is from about 80 ng/mL to about 150 one embodiment, the initial dose is about 110 mg. In one ng/mL. In one embodiment, the average serum concentration embodiment, the initial dose is about 115 mg. In one embodi of ibogaine, ibogaine derivative, or pharmaceutically accept ment, the initial dose is about 120 mg. able salt and/or solvate thereof is from about 80 ng/mL to 0196. In some embodiments, the one or more additional about 100 ng/mL. In one embodiment. Such a dosing regimen doses are lower than the initial dose. In one embodiment, the provides an average serum concentration of ibogaine, one or more additional doses are from about 5 mg to about 50 ibogaine derivative, or pharmaceutically acceptable salt and/ mg. In one embodiment, the one or more additional doses or solvate thereof of about 50 ng/mL to about 180 ng/mL. In may or may not comprise the same amount of ibogaine, one embodiment, the one or more additional doses maintain ibogaine derivative, or pharmaceutically acceptable salt and/ an average serum concentration of about 50 ng/mL to about or solvate thereofIn one embodiment, at least one additional 180 ng/mL over a period of time. The ranges include both dose is about 5 mg. In one embodiment, at least one additional extremes as well as any Subrange or subvalue there between. dose is about 10 mg. In one embodiment, at least one addi 0191 In one embodiment, the dosage of ibogaine, tional dose is about 15 mg. In one embodiment, at least one ibogaine derivative, or pharmaceutically acceptable salt and/ additional dose is about 20 mg. In one embodiment, at least or solvate thereof provides a serum concentration of between one additional dose is about 25 mg. In one embodiment, at about 1000 nghr/mL and about 6000 nghr/mL. In one least one additional dose is about 30 mg. In one embodiment, embodiment, the dosage of ibogaine, ibogaine derivative, or at least one additional dose is about 35 mg. In one embodi pharmaceutically acceptable salt and/or Solvate thereof pro ment, at least one additional dose is about 40 mg. In one vides a serum concentration of between about 1200 nghr? embodiment, at least one additional dose is about 45 mg. In mL and about 5800 nghr/mL. In one embodiment, the dos one embodiment, at least one additional dose is about 50 mg. age of ibogaine, ibogaine derivative, or pharmaceutically 0.197 In one embodiment, the one or more additional acceptable salt and/or Solvate thereof provides a serum con doses are administered periodically. In one embodiment, the centration of between about 1200 nghr/mL and about 5500 one or more additional doses are administered approximately nghr/mL. The ranges include both extremes as well as any every 4 hours. In one embodiment, the one or more additional subrange or subvalue there between. doses are administered every 6 hours. In one embodiment, the 0.192 In one embodiment, the dosage of ibogaine, one or more additional doses are administered approximately ibogaine derivative, or pharmaceutically acceptable salt and/ every 8 hours. In one embodiment, the one or more additional or Solvate thereof provides a maximum serum concentration doses are administered approximately every 10 hours. In one (Cmax) of less than about 250 ng/mL. In one embodiment, the embodiment, the one or more additional doses are adminis dosage of ibogaine, ibogaine derivative, or pharmaceutically tered approximately every 12 hours. In one embodiment, the acceptable salt and/or solvate thereof provides a Cmax one or more additional doses are administered approximately between about 40 ng/mL and about 250 ng/mL. In a preferred every 18 hours. In one embodiment, the one or more addi embodiment, the dosage of ibogaine, ibogaine derivative, or tional doses are administered approximately every 24 hours. pharmaceutically acceptable salt and/or Solvate thereof pro In one embodiment, the one or more additional doses are vides a Cmax between about 60 ng/mL and about 200 ng/mL. administered approximately every 36 hours. In one embodi In one embodiment, the dosage of ibogaine, ibogaine deriva ment, the one or more additional doses are administered tive, or pharmaceutically acceptable Salt and/or Solvate approximately every 48 hours. thereofprovides a Cmax between about 100 ng/mL and about 0.198. In some embodiments, the patient is administered a 180 ng/mL. The ranges include both extremes as well as any high (therapeutic) dose of ibogaine for a period of time to subrange or subvalue there between. ameliorate the most significant symptoms of a disease or 0193 In another embodiment, there is provided a unit dose disorder, and then is administered a lower (maintenance) dose of ibogaine, ibogaine derivative, or pharmaceutically accept to prevent relapse. In some embodiments, the patient is able salt and/or solvate thereof which is about 50 mg to about administered a therapeutic dose of ibogaine, ibogaine deriva 200 mg perdose. In one embodiment, the unit dose is about 50 tive, or pharmaceutically acceptable Salt and/or Solvate to about 120 mg per dose. In one embodiment, the unit dose thereof for a period of time to ameliorate the most significant is about 120 mg per dose. It being understood that the term symptoms, and then is administered a decreasing (tapered) US 2015/02581. 14 A1 Sep. 17, 2015 amount of ibogaine, ibogaine derivative, or pharmaceutically salt and/or Solvate thereof is a tapered dosing over a period of acceptable salt and/or solvate thereof over time until the time, during which the patient is detoxified, for example, maintenance dose is reached. without Suffering significant acute withdrawal symptoms. Without being bound by theory, it is believed that tapering Maintenance Dose will allow the full therapeutic effect of the compound with 0199. In some embodiments, the maintenance dose of less prolongation of the QT interval. Tapering involves ibogaine, ibogaine derivative, orpharmaceutically acceptable administration of one or more Subsequently lower doses of salt and/or solvate thereof is about 10% to about 80% of the the compound over time. For example, in some embodiments, therapeutic dose. In some embodiments, the maintenance the first tapered dose is about 50% to about 95% of the first or dose of ibogaine, ibogaine derivative, or pharmaceutically original dose. In some embodiments, the second tapered dose acceptable salt and/or solvate thereof is about 70% of the is about 40% to about 90% of the first or original dose. In therapeutic dose. In some embodiments, the maintenance some embodiments, the third tapered dose is about 30% to dose is about 60% of the therapeutic dose. In some embodi about 85% of the first or original dose. In some embodiments, ments, the maintenance dose is about 50% of the therapeutic the fourth tapered dose is about 20% to about 80% of the first dose. In some embodiments, the maintenance dose is about or original dose. In some embodiments, the fifth tapered dose 40% of the therapeutic dose. In some embodiments, the main is about 10% to about 75% of the first or original dose. tenance dose is about 30% of the therapeutic dose. In some 0202 In some embodiments, the first tapered dose is given embodiments, the maintenance dose is about 20% of the after the first dose of ibogaine, ibogaine derivative, or phar therapeutic dose. In some embodiments, the maintenance maceutically acceptable salt and/or Solvate thereof In some dose is about 10% of the therapeutic dose. embodiments, the first tapered dose is given after the second, 0200. In some embodiments, the maintenance average third, or a Subsequent dose of compound. The first tapered serum level of ibogaine, ibogaine derivative, or pharmaceu dose may be administered at any time after the previous dose tically acceptable salt and/or solvate thereof is about 10% to of compound. The first tapered dose can be given once, for about 80% of the therapeutic average serum level of ibogaine, example, followed by subsequent further tapered doses, or it ibogaine derivative, or pharmaceutically acceptable salt and/ can be given multiple times with or without Subsequent, fur or Solvate thereof. In some embodiments, the maintenance ther tapered doses (e.g., second, third, fourth, etc. tapered average serum level of ibogaine, ibogaine derivative, or phar doses), which likewise can be given once or over multiple maceutically acceptable salt and/or solvate thereof is about administrations, for example. In some embodiments, the first 70% of the therapeutic average serum level of ibogaine, tapered dose is administered one hour, 6 hours, 12 hours, 18 ibogaine derivative, or pharmaceutically acceptable salt and/ hours, 24 hours, 36 hours, 48 hours, or more after the previous or Solvate thereof In some embodiments, the maintenance dose of compound. Similarly, second, third, fourth, etc. average serum level of ibogaine, ibogaine derivative, or phar tapered doses, if given, can be given one hour, 6 hours, 12 maceutically acceptable salt and/or solvate thereof is about hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after 60% of the therapeutic average serum level of ibogaine, the previous dose of compound. ibogaine derivative, or pharmaceutically acceptable salt and/ 0203. In some embodiments, one tapered dose is given to or Solvate thereof In some embodiments, the maintenance achieve the desired lower therapeutic dose. In some embodi average serum level of ibogaine, ibogaine derivative, or phar ments, two tapered doses are given to achieve the desired maceutically acceptable salt and/or solvate thereof is about lower therapeutic dose. In some embodiments, three tapered 50% of the therapeutic average serum level of ibogaine, doses are given to achieve the desired lower therapeutic dose. ibogaine derivative, or pharmaceutically acceptable salt and/ In some embodiments, four or more tapered doses are given to or Solvate thereof In some embodiments, the maintenance achieve the desired lower therapeutic dose. Determination of average serum level of ibogaine, ibogaine derivative, or phar the tapered doses, number of tapered doses, and the like can maceutically acceptable salt and/or solvate thereof is about be readily made a qualified clinician. 40% of the therapeutic average serum level of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/ 0204. In one embodiment, the QT interval is not prolonged or Solvate thereof In some embodiments, the maintenance more than about 50 ms. In one embodiment, the QT interval average serum level of ibogaine, ibogaine derivative, or phar is not prolonged more than about 40 ms. In one embodiment, maceutically acceptable salt and/or solvate thereof is about the QT interval is not prolonged more than about 30 ms. In 30% of the therapeutic average serum level of ibogaine, one embodiment, the QT interval is not prolonged more than ibogaine derivative, or pharmaceutically acceptable salt and/ about 20 ms. In one embodiment, prolongation of the QT or Solvate thereof In some embodiments, the maintenance interval is equivalent to or less than the prolongation observed average serum level of ibogaine, ibogaine derivative, or phar for methadone-treated patients. maceutically acceptable salt and/or solvate thereof is about 0205 The patient may suffer from addiction to any addic 20% of the therapeutic average serum level of ibogaine, tive substance or drug. In a preferred embodiment, the addic ibogaine derivative, or pharmaceutically acceptable salt and/ tive substance is selected from the group consisting of ben or Solvate thereof In some embodiments, the maintenance Zodiazepines, cannabinoids and synthetic cannabinoids, average serum level of ibogaine, ibogaine derivative, or phar stimulants, barbiturates, gamma-hydroxybutyrate (GHB), maceutically acceptable salt and/or solvate thereof is about ketamine, PCP. dextromethorphan (DXM), lysergic acid 10% of the therapeutic average serum level of ibogaine, diethylamide (LSD), mescaline, anabolic steroids, and ibogaine derivative, or pharmaceutically acceptable salt and/ derivatives of each thereof or solvate thereof 0206. In one embodiment, ibogaine is administered at an amount by weight that is twice that administered for nori Tapered Dosing bogaine for treating a same or similar condition. For example, 0201 In some embodiments, the therapeutic dose of and without limitation, an administration of a dose 80 mg ibogaine, ibogaine derivative, orpharmaceutically acceptable ibogaine approximates a dose of 40 mg noribogaine. US 2015/02581. 14 A1 Sep. 17, 2015 22

Maintenance Administration 0213. In one embodiment, the therapeutic dose is tapered 0207. In one aspect, this invention relates to treatment or over time until the desired maintenance dose is reached. For attenuation of post-acute withdrawal from an addictive sub example, in some embodiments, the first tapered dose is about stance in an addicted patient with a maintenance amount of 50% to about 95% of the therapeutic dose. In some embodi ibogaine, ibogaine derivative, orpharmaceutically acceptable ments, the second tapered dose is about 40% to about 90% of salt and/or solvate thereof the therapeutic dose. In some embodiments, the third tapered 0208. In some aspects, this invention relates to a method to dose is about 30% to about 85% of the therapeutic dose. In prevent relapse of Substance abuse in an addicted patient some embodiments, the fourth tapered dose is about 20% to treated to ameliorate said abuse, said method comprising about 80% of the therapeutic dose. periodically administering to said patient a maintenance dos 0214. In some embodiments, the fifth tapered dose is about age of ibogaine, ibogaine derivative, or pharmaceutically 10% to about 75% of the therapeutic dose. In some embodi acceptable salt and/or solvate thereof ments, one tapered dose is given to achieve the maintenance 0209. In some embodiments, the patient undergoes long dose. In some embodiments, two tapered doses are given to term (e.g., one year or longer) treatment with maintenance achieve the maintenance dose. In some embodiments, three doses of ibogaine, ibogaine derivative, or pharmaceutically tapered doses are given to achieve the maintenance dose. In acceptable salt and/or solvate thereof In some embodiments, Some embodiments, four or more tapered doses are given to the patient is treated for acute withdrawal with therapeutic achieve the maintenance dose. Determination of the tapered doses of ibogaine, ibogaine derivative, or pharmaceutically doses, number of tapered doses, and the like can be readily acceptable salt and/or solvate thereofas described above, and made a qualified clinician. then the amount of compound is reduced to maintenance 0215. In one embodiment, the QT interval is not prolonged levels after acute withdrawal symptoms would be expected to more than 30 ms. In a preferred embodiment, the QT interval have subsided. Acute withdrawal symptoms generally are the is not prolonged more than 20 ms. most pronounced in the first 48 to 72 hours after cessation of 0216. In some embodiments, the patient is administered the drug of addiction, although acute withdrawal may last as periodically, Such as once, twice, three time, four times or five long as a week or more. time daily with ibogaine, ibogaine derivative, or pharmaceu 0210. In some embodiments, the patient is administered a tically acceptable salt and/or solvate thereofIn some embodi high (therapeutic) dose of ibogaine, ibogaine derivative, or ments, the administration is once daily, or once every second pharmaceutically acceptable salt and/or solvate thereof for a day, once every third day, three times a week, twice a week, or period of time to ameliorate the most significant withdraw once a week. The dosage and frequency of the administration symptoms, and then is administered a lower (maintenance) depends on the route of administration, content of composi dose to prevent relapse to Substance abuse. In some embodi tion, age and body weight of the patient, condition of the ments, the patient is administered a therapeutic dose of patient, without limitation. Determination of dosage and fre ibogaine, ibogaine derivative, orpharmaceutically acceptable quency Suitable for the present technology can be readily salt and/or solvate thereof for a period of time to ameliorate made a qualified clinician. the most significant withdraw symptoms, and then is admin 0217 Ibogaine, ibogaine derivative, or pharmaceutically istered a decreasing (tapered) amount of the compound or acceptable salt and/or solvate thereofsuitable for administra pharmaceutically acceptable salt and/or solvate thereof over tion in accordance with the methods provide herein, can be time until the maintenance dose is reached. suitable for a variety of delivery modes including, without 0211. In some embodiments, the maintenance dose of limitation, oral and transdermal delivery. Compositions Suit ibogaine, ibogaine derivative, orpharmaceutically acceptable able for internal, pulmonary, rectal, nasal, Vaginal, lingual, salt and/or solvate thereof is 70% of the therapeutic dose. In intravenous, intra-arterial, intramuscular, intraperitoneal, some embodiments, the maintenance dose is 60% of the intracutaneous and Subcutaneous routes may also be used. therapeutic dose. In some embodiments, the maintenance Possible dosage forms include tablets, capsules, pills, pow dose is 50% of the therapeutic dose. In some embodiments, ders, aerosols, Suppositories, parenterals, and oral liquids, the maintenance dose is 40% of the therapeutic dose. In some including Suspensions, Solutions and emulsions. Sustained embodiments, the maintenance dose is 30% of the therapeutic release dosage forms may also be used. All dosage forms may dose. In some embodiments, the maintenance dose is 20% of be prepared using methods that are standard in the art (see the therapeutic dose. In some embodiments, the maintenance e.g., Remington’s Pharmaceutical Sciences, 16th ed., A. Oslo dose is 10% of the therapeutic dose. editor, Easton Pa. 1980). 0212. In some embodiments, the maintenance average 0218. In a preferred embodiment, ibogaine is adminis serum level of compound is 70% of the therapeutic average tered orally, which may conveniently be provided in tablet, serum level. In some embodiments, the maintenance average caplet, Sublingual, liquid or capsule form. In certain embodi serum level of compound is 60% of the therapeutic average ments, the compound is provided as a pharmaceutically serum level. In some embodiments, the maintenance average acceptable salt, for example ibogaine HCl, with dosages serum level of compound is 50% of the therapeutic average reported as the amount of free base compound. In some serum level. In some embodiments, the maintenance average embodiments, the pharmaceutically acceptable salt and/or serum level of compound is 40% of the therapeutic average Solvate is provided in hard gelatin capsules containing only serum level. In some embodiments, the maintenance average the salt with no excipients. serum level of compound is 30% of the therapeutic average 0219. This invention further relates to pharmaceutically serum level. In some embodiments, the maintenance average acceptable formulations comprising a unit dose of ibogaine, serum level of compound is 20% of the therapeutic average ibogaine derivative, or pharmaceutically acceptable salt and/ serum level. In some embodiments, the maintenance average or solvate thereof In some embodiments, the amount of serum level of compound is 10% of the therapeutic average ibogaine, ibogaine derivative, orpharmaceutically acceptable serum level. salt and/or Solvate thereof is sufficient to provide an average US 2015/02581. 14 A1 Sep. 17, 2015

serum concentration of about 50 ng/mL to about 850 ng/mL tives, glycols, etc. Coloring and flavoring agents may also be when administered to a patient. In other embodiments, the added to preparations, particularly to those for oral adminis amount of ibogaine, ibogaine derivative, or pharmaceutically tration. Solutions can be prepared using water or physiologi acceptable salt and/or solvate thereof is sufficient to provide cally compatible organic solvents such as ethanol, 1,2-propy an average serum concentration of about 50 ng/mL to about lene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, 400 ng/mL when administered to a patient. triglycerides, partial esters of glycerine and the like. 0220. In some embodiments, the unit dose of ibogaine, Parenteral compositions containing ibogaine, ibogaine ibogaine derivative, or pharmaceutically acceptable salt and/ derivative, or pharmaceutically acceptable salt and/or Solvate or Solvate thereof is administered in one or more dosings. thereof may be prepared using conventional techniques that 0221. In one embodiment, the amount of ibogaine, may include Sterile isotonic Saline, water, 1,3-butanediol. ibogaine derivative, or pharmaceutically acceptable salt and/ ethanol. 1,2-propylene glycol, polyglycols mixed with water, or Solvate thereof is sufficient to provide an average serum Ringer's solution, etc. concentration of ibogaine, ibogaine derivative, or pharma ceutically acceptable salt and/or solvate thereof from about 0223) The compositions utilized herein may be formu 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 lated for aerosol administration, particularly to the respira ng/mL. In one embodiment, the amount of ibogaine, ibogaine tory tract and including intrapulmonary or intranasal admin derivative, orpharmaceutically acceptable salt and/or Solvate istration. The compound will generally have a small particle thereof is Sufficient to provide an average serum concentra size, for example of the order of 5 microns or less. Such a tion of ibogaine, ibogaine derivative, or pharmaceutically particle size may be obtained by means known in the art, for acceptable salt and/or solvate thereoffrom about 50 ng/mL to example by micronization. The active ingredient may be pro about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In vided in a pressurized pack with a suitable propellant Such as one embodiment, the amount of ibogaine, ibogaine deriva a chlorofluorocarbon (CFC), (for example, dichlorodifluo tive, or pharmaceutically acceptable Salt and/or Solvate romethane, trichlorofluoromethane, or dichlorotetrafluoroet thereof is Sufficient to provide an average serum concentra hane), carbon dioxide or other suitable gases. The aerosol tion of ibogaine, ibogaine derivative, or pharmaceutically may conveniently also contain a surfactant such as lecithin. acceptable salt and/or solvate thereoffrom about 50 ng/mL to The dose of drug may be controlled by a metered valve. about 600 ng/mL, or about 60 ng/mL to about 600 ng/mL. In Alternatively, the active ingredients may be provided in the a preferred embodiment, the amount of ibogaine, ibogaine form of a dry powder, for example a powder mix of the derivative, orpharmaceutically acceptable salt and/or solvate compound in a suitable powder base such as lactose, starch, thereof is Sufficient to provide an average serum concentra starch derivatives such as hydroxypropylmethylcellulose and tion of ibogaine, ibogaine derivative, or pharmaceutically polyvinylpyrrolidine. In some embodiments, the powder car acceptable salt and/or solvate thereoffrom about 50 ng/mL to rier will form a gel in the nasal cavity. The powder composi about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In tion may be presented in unit dose form, for example in one embodiment, the amount of ibogaine, ibogaine deriva capsules or cartridges, gelatin or blisterpacks, from which the tive, or pharmaceutically acceptable Salt and/or Solvate powder may be administered by means of an inhaler. thereof is Sufficient to provide an average serum concentra 0224. The compositions utilized herein may be formu tion of ibogaine, ibogaine derivative, or pharmaceutically lated for Sublingual administration, for example as Sublingual acceptable salt and/or solvate thereoffrom about 50 ng/mL to tablets. Sublingual tablets are designed to dissolve very rap about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In idly. The formulations of these tablets contain, in addition to one embodiment, the amount of ibogaine, ibogaine deriva the drug, a limited number of soluble excipients, usually tive, or pharmaceutically acceptable Salt and/or Solvate lactose and powdered Sucrose, but sometimes dextrose and thereof is Sufficient to provide an average serum concentra mannitol. tion of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or solvate thereoffrom about 50 ng/mL to 0225. It has been discovered that ibogaine, ibogaine about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In derivative, or pharmaceutically acceptable salt and/or Solvate one embodiment, the amount of ibogaine, ibogaine deriva thereofhas a bitter taste to at least some patients. Accordingly, tive, or pharmaceutically acceptable Salt and/or Solvate compositions for oral use (including Sublingual, inhaled, and thereof is Sufficient to provide an average serum concentra other oral formulations) may be formulated to utilize taste tion of ibogaine, ibogaine derivative, or pharmaceutically masking technologies. A number of ways to mask the taste of acceptable salt and/or solvate thereoffrom about 50 ng/mL to bitter drugs are known in the art, including addition of Sugars, about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In flavors, Sweeteners, or coatings; use of lipoproteins, Vesicles, one embodiment, the amount of ibogaine, ibogaine deriva and/or liposomes; granulation; microencapsulation; numbing tive, or pharmaceutically acceptable Salt and/or Solvate of taste buds; multiple emulsion; modification of viscosity; or thereof is Sufficient to provide an average serum concentra salt formation; inclusion or molecular complexes; ion tion of ibogaine, ibogaine derivative, or pharmaceutically exchange resins; and Solid dispersion. Any method of mask acceptable salt and/or solvate thereoffrom about 50 ng/mL to ing the bitterness of the compound of the invention may be about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The used. ranges include both extremes as well as any Subranges 0226. The patient may suffer from addiction to any addic between. tive Substance. In a preferred embodiment, the drug is 0222. The compositions provided herein can also be used selected from the group consisting of benzodiazepines, can in conjunction with any of the vehicles and excipients com nabinoids and synthetic cannabinoids, stimulants, barbitu monly employed in pharmaceutical preparations, e.g., talc, rates, gamma-hydroxybutyrate (GHB), ketamine, PCP. dex gum Arabic, lactose, starch, magnesium Stearate, cocoa but tromethorphan (DXM), lysergic acid diethylamide (LSD), ter, aqueous or non-aqueous solvents, oils, paraffin deriva mescaline, anabolic steroids, and derivatives of each thereof US 2015/02581. 14 A1 Sep. 17, 2015 24

Patient Pre-Screening and Monitoring 0232. As it relates to pre-screening or pre-selection of 0227 Pre-screening of patients before treatment with patients, patients may be selected based on any criteria as ibogaine, ibogaine derivative, orpharmaceutically acceptable determined by the skilled clinician. Such criteria may salt and/or Solvate thereof and/or monitoring of patients dur include, by way of non-limiting example, pre-treatment QT ing treatment may be required to ensure that QT interval is not interval, pre-existing cardiac conditions, risk of cardiac con prolonged beyond a certain value. For example, QT interval ditions, age, sex, general health, and the like. The following greater than 500 ms can be considered dangerous for indi are examples of selection criteria for disallowing treatment or vidual patients. Pre-screening and/or monitoring may be nec restricting dose of ibogaine, ibogaine derivative, or pharma essary at high dosage levels. ceutically acceptable salt and/or solvate thereof administered 0228. In a preferred embodiment, a patient receiving a to the patient: high QT interval before treatment (e.g., Such therapeutic dose of ibogaine, ibogaine derivative, or pharma that there is a risk of the patient’s QT interval exceeding 500 ceutically acceptable salt and/or solvate thereof is monitored ms during treatment); congenital long QT syndrome; brady in a clinical setting. Monitoring may be necessary to ensure cardia; hypokalemia or hypomagnesaemia; recent acute myo the QT interval is not prolonged to an unacceptable degree. A cardial infarction; uncompensated heart failure; and taking “clinical setting refers to an inpatient setting (e.g., inpatient other drugs that increase QT interval. In some embodiments, clinic, hospital, rehabilitation facility) or an outpatient setting the methods can include selecting and/or administering/pro with frequent, regular monitoring (e.g., outpatient clinic that viding ibogaine to a patient that lacks one more of Such is visited daily to receive dose and monitoring). Monitoring criteria. includes monitoring of QT interval. Methods for monitoring 0233. In one embodiment, this invention relates to pre of QT interval are well-known in the art, for example by ECG. screening a patient to determine if the patient is at risk for 0229. In one embodiment, a patient receiving a mainte prolongation of the QT interval beyond a safe level. In one nance dose of ibogaine, ibogaine derivative, or pharmaceuti embodiment, a patient at risk for prolongation of the QT cally acceptable salt and/or solvate thereof is not monitored in interval beyond a safe level is not administered ibogaine, a clinical setting. In one embodiment, a patient receiving a ibogaine derivative, or pharmaceutically acceptable salt and/ maintenance dose of ibogaine, ibogaine derivative, or phar or solvate thereof In one embodiment, a patient at risk for maceutically acceptable salt and/or Solvate thereof is moni prolongation of the QT interval beyond a safe level is admin tored periodically, for example daily, weekly, monthly, or istered ibogaine, ibogaine derivative, or pharmaceutically occasionally. acceptable salt and/or Solvate thereof at a limited dosage. 0230. In one aspect, this invention relates to a method for 0234. In one embodiment, this invention relates to moni treating Substance abuse and/or symptoms of withdrawal in toring a patient who is administered a therapeutic dose of an addicted patient, comprising selecting an addicted patient ibogaine, ibogaine derivative, orpharmaceutically acceptable who is prescreened to evaluate the patient’s expected toler salt and/or solvate thereof In one embodiment, the dose is ance for prolongation of QT interval, administering to the reduced if the patient has serious adverse side effects. In one patient a dosage of ibogaine, ibogaine derivative, or pharma embodiment, treatment is discontinued if the patient has seri ceutically acceptable salt and/or solvate thereofthat provides ous adverse side effects. In one embodiment, the adverse side an average serum concentration of about 50 ng/mL to about effect is a QT interval that is prolonged beyond a safe level. 850 ng/mL, said concentration being sufficient to inhibit or The determination of a safe level of prolongation is within the ameliorate said abuse or symptoms while maintaining a QT skill of a qualified clinician. interval of less than 500 ms during said treatment. In some Kit of Parts embodiments, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less 0235. One aspect of this invention is directed to a kit of than about 470 ms during treatment. Preferably, the concen parts for the treatment of substance abuse and/or symptoms of tration is sufficient to attenuate said abuse or symptoms while withdrawal in an addicted patient, wherein the kit comprises maintaining a QT interval of less than about 450 ms during a composition comprising ibogaine, ibogaine derivative, or treatment. In one embodiment, the concentration is sufficient pharmaceutically acceptable salt and/or Solvate thereof and a to attenuate said abuse or symptoms while maintaining a QT means for administering the composition to a patient in need interval of less than about 420 ms during treatment. thereof The means for administration to a patient can include, 0231. In one embodiment, prescreening of the patient for example, any one or combination of ibogaine, ibogaine comprises ascertaining that treatment with ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or Solvate derivative, orpharmaceutically acceptable salt and/or Solvate thereof, a transdermal patch, a syringe, a needle, an IV bag thereof will not result in a QT interval over about 500 ms. In comprising the composition, a vial comprising the composi one embodiment, prescreening of the patient comprises tion, an inhaler comprising the composition, etc. In one ascertaining that treatment with ibogaine, ibogaine deriva embodiment, the kit of parts further comprises instructions tive, or pharmaceutically acceptable Salt and/or Solvate for dosing and/or administration of the composition. thereof will not result in a QT interval over about 470 ms. In 0236. In some aspects, the invention is directed to a kit of one embodiment, prescreening comprises ascertaining that parts for administration of ibogaine, ibogaine derivative, or treatment with ibogaine, ibogaine derivative, or pharmaceu pharmaceutically acceptable Salt and/or Solvate thereof, the tically acceptable salt and/or solvate thereof will not result in kit comprising multiple delivery vehicles, wherein each a QT interval over about 450 ms. In one embodiment, pre delivery vehicle contains a discrete amount of compound and screening comprises ascertaining that treatment with further wherein each delivery vehicle is identified by the ibogaine, ibogaine derivative, orpharmaceutically acceptable amount of compound provided therein; and optionally further salt and/or solvate thereof will not result in a QT interval over comprising a dosing treatment schedule in a readable about 420 ms. In one embodiment, prescreening comprises medium. In some embodiments, the dosing treatment sched determining the patient’s pre-treatment QT interval. ule includes the amount of compound required to achieve US 2015/02581. 14 A1 Sep. 17, 2015

each average serum level is provided. In some embodiments, guishing features of the pill. In some embodiments, all of the the kit of parts includes a dosing treatment schedule that delivery vehicles within a kit are intended for one patient. In provides an attending clinician the ability to select a dosing some embodiments, the delivery vehicles within a kit are regimen based on the sex of the patient, mass of the patient, intended for multiple patients. compound, and the serum level that the clinician desires to 0241 One aspect of this invention is directed to a kit of achieve. In some embodiments, the dosing treatment sched parts for the treatment of substance abuse and/or symptoms of ule further provides information corresponding to the Volume withdrawal in an addicted patient, wherein the kit comprises of blood in a patient based upon weight (or mass) and sex of a unit dose form of ibogaine, ibogaine derivative, or pharma the patient. In an embodiment, the storage medium can ceutically acceptable salt and/or solvate thereof The unit dose include an accompanying pamphlet or similar written infor form provides a patient with an average serum level of com mation that accompanies the unit dose form in the kit. In an pound of from about 50 ng/mL to about 800 ng/mL or about embodiment, the storage medium can include electronic, 60 ng/mL to about 800 ng/mL. In one embodiment, the unit optical, or other data storage. Such as a non-volatile memory, dose form provides a patient with an average serum level of for example, to store a digitally-encoded machine-readable ibogaine, ibogaine derivative, orpharmaceutically acceptable representation of Such information. salt and/or solvate thereof of from about 50 ng/mL to about 0237. The term “delivery vehicle' as used herein refers to 400 ng/mL or about 60 ng/mL to about 400 ng/mL. any formulation that can be used for administration of 0242. In some embodiments, the unit dose form comprises ibogaine, ibogaine derivative, orpharmaceutically acceptable one or multiple dosages to be administered periodically, Such salt and/or Solvate thereof to a patient. Non-limiting, exem as once, twice, three time, four times or five time daily with plary delivery vehicles include caplets, pills, capsules, tab ibogaine, ibogaine derivative, orpharmaceutically acceptable lets, powder, liquid, or any other form by which the drug can salt and/or solvate thereof In some embodiments, the admin be administered. Delivery vehicles may be intended for istration is once daily, or once every second day, once every administration by oral, inhaled, injected, or any other means. third day, three times a week, twice a week, or once a week. 0238. The term “readable medium' as used herein refers The dosage and frequency of the administration depends on to a representation of data that can be read, for example, by a criteria including the route of administration, content of com human or by a machine. Non-limiting examples of human position, age and body weight of the patient, condition of the readable formats include pamphlets, inserts, or other written patient, sex of the patient, without limitation, as well as by the forms. Non-limiting examples of machine-readable formats severity of the addiction. Determination of the unit dose form include any mechanism that provides (i.e., stores and/or providing a dosage and frequency suitable for a given patient transmits) information in a form readable by a machine (e.g., can readily be made by a qualified clinician. a computer, tablet, and/or Smartphone). For example, a 0243 These dose ranges may beachieved by transdermal, machine-readable medium includes read-only memory oral, or parenteral administration of ibogaine, ibogaine (ROM); random access memory (RAM); magnetic disk stor derivative, or pharmaceutically acceptable salt and/or Solvate age media; optical storage media; and flash memory devices. thereof in unit dose form. Such unit dose form may conve In one embodiment, the machine-readable medium is a CD niently be provided in transdermal patch, tablet, caplet, liquid ROM. In one embodiment, the machine-readable medium is or capsule form. In certain embodiments, the ibogaine, a USB drive. In one embodiment, the machine-readable ibogaine derivative, or pharmaceutically acceptable salt and/ medium is a Quick Response Code (QR Code) or other matrix or solvate thereof is provided as ibogaine HCl, with dosages barcode. reported as the amount of free base ibogaine, ibogaine deriva 0239. In some aspects, the machine-readable medium tive, or pharmaceutically acceptable Salt and/or Solvate comprises Software that contains information regarding dos thereof In some embodiments, the ibogaine HCl is provided ing schedules for the unit dose form of ibogaine, ibogaine inhard gelatin capsules containing only ibogaine HCl with no derivative, orpharmaceutically acceptable salt and/or Solvate excipients. In some embodiments, ibogaine, ibogaine deriva thereof and optionally other drug information. In some tive, or pharmaceutically acceptable Salt and/or Solvate embodiments, the software may be interactive, such that the thereof is provided in saline for intravenous administration. attending clinician or other medical professional can enter 0244. In another aspect, provided herein is a kit of parts for patient information. In a non-limiting example, the medical administration of ibogaine, ibogaine derivative, or pharma professional may enter the weight and sex of the patient to be ceutically acceptable salt and/or solvate thereof, the kitcom treated, and the software program provides a recommended prising multiple delivery vehicles, wherein each delivery dosing regimen based on the information entered. The vehicle contains a discrete amount of ibogaine and further amount and timing of compound recommended to be deliv wherein each delivery vehicle is identified by the amount of ered will be within the dosages that result in the serum con ibogaine provided therein; and optionally further comprising centrations as provided herein. a dosing treatment schedule in a readable medium. 0240. In some embodiments, the kit of parts comprises 0245. In one embodiment, the amount of ibogaine, multiple delivery vehicles in a variety of dosing options. For ibogaine derivative, or pharmaceutically acceptable salt and/ example, the kit of parts may comprise pills or tablets in or Solvate thereof required to achieve each maximum serum multiple dosages, such as 240 mg, 120 mg, 90 mg, 60 mg, 30 level is provided in the readable medium. In another embodi mg, 20 mg, and/or 10 mg of ibogaine, ibogaine derivative, or ment, the readable medium is a computer-readable medium. pharmaceutically acceptable salt and/or Solvate thereof per In another embodiment, the multiple delivery vehicles con pill. Each pill is labeled such that the medical professional tain different amounts of ibogaine, ibogaine derivative, or and/or patient can easily distinguish different dosages. Label pharmaceutically acceptable salt and/or solvate thereof In ing may be based on printing or embossing on the pill, shape another embodiment, the dosing treatment schedule provides of the pill, color of pill, the location of the pill in a separate, an attending clinician the ability to select a dosing regimen of labeled compartment within the kit, and/or any other distin ibogaine, ibogaine derivative, orpharmaceutically acceptable US 2015/02581. 14 A1 Sep. 17, 2015 26 salt and/or solvate thereof based on the sex of the patient, lations Suitable for internal, pulmonary, rectal, nasal, vaginal, mass of the patient, and the serum level that the clinician lingual, intravenous, intra-arterial, intramuscular, intraperito desires to achieve. In another embodiment, the dosing treat neal, intracutaneous and Subcutaneous routes may also be ment schedule further provides information corresponding to used. Possible formulations include tablets, capsules, pills, the volume of blood in a patient based upon weight and sex of powders, aerosols, Suppositories, parenterals, and oral liq the patient. uids, including Suspensions, solutions and emulsions. Sus tained release dosage forms may also be used. All formula Formulations tions may be prepared using methods that are standard in the 0246 This invention further relates to pharmaceutically art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., acceptable formulations comprising a unit dose of ibogaine, A. Oslo editor, Easton Pa. 1980). ibogaine derivative, or pharmaceutically acceptable salt and/ 0251. In a preferred embodiment, the formulation is or solvate thereof, wherein the amount of compound is suffi designed for oral administration, which may conveniently be cient to provide an average serum concentration of about 50 provided in tablet, caplet, Sublingual, liquid or capsule form. ng/mL to about 850 ng/mL when administered to a patient. In a preferred embodiment, the amount of compound is suffi EXAMPLES cient to provide an average serum concentration of about 50 0252. The following Examples are intended to further ng/mL to about 400 ng/mL when administered to a patient. illustrate certain embodiments of the disclosure and are not 0247. In some embodiments, the unit dose of ibogaine, intended to limit its scope. ibogaine derivative, or pharmaceutically acceptable salt and/ or Solvate thereof is administered in one or more dosings. Example 1 0248. In one embodiment, the amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/ Efficacy of Ibogaine in Humans or Solvate thereof is sufficient to provide an average serum concentration from about 50 ng/mL to about 800 ng/mL or 0253) The efficacy of ibogaine, ibogaine derivative, or a about 60 ng/mL to about 800 ng/mL. In one embodiment, the pharmaceutically acceptable salt and/or Solvate thereof is amount of compound is Sufficient to provide an average evaluated in Substance-dependent participants in a random serum concentration from about 50 ng/mL to about 700 ized, placebo-controlled, double-blind trial. Patients are ng/mL or about 60 ng/mL to about 700 ng/mL. In one administered 60 mg or 120 mg of the compound and QT embodiment, the amount of compound is sufficient to provide interval is measured. an average serum concentration from about 50 ng/mL to 1. A method for treating Substance abuse in a human patient about 600 ng/mL, or about 60 ng/mL to about 600 ng/mL. In addicted thereto, comprising administering to the patient a a preferred embodiment, the amount of compound is suffi dosage of ibogaine, ibogaine derivative, or a pharmaceuti cient to provide an average serum concentration from about cally acceptable salt and/or solvate thereof, wherein the dos 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about age provides an average serum concentration of about 50 500 ng/mL. In one embodiment, the amount of compound is ng/mL to about 500 ng/mL, said concentration being Suffi Sufficient to provide an average serum concentration from cient to inhibit or ameliorate said abuse while maintaining a about 50 ng/mL to about 400 ng/mL, or about 60 ng/mL to QT interval of less than about 500 ms during said treatment. about 400 ng/mL. In one embodiment, the amount of com pound is Sufficient to provide an average serum concentration 2. The method of claim 1, wherein the ibogaine, ibogaine from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL derivative, or a pharmaceutically acceptable salt and/or sol to about 300 ng/mL. In one embodiment, the amount of vate thereof is administered as a single dose or multiple doses. compound is Sufficient to provide an average serum concen 3. The method of claim 1, wherein the aggregate dosage of tration from about 50 ng/mL to about 200 ng/mL, or about 60 ibogaine, ibogaine derivative, or a pharmaceutically accept ng/mL to about 200 ng/mL. In one embodiment, the amount able salt and/or solvate thereof is selected from the group of compound is Sufficient to provide an average serum con consisting of from about 1.3 mg/kg to about 4 mg/kg per day, centration from about 50 ng/mL to about 100 ng/mL, or about from about 1.5 mg/kg to about 3 mg/kg per day, from about 2 60 ng/mL to about 100 ng/mL. The ranges include both mg/kg to about 4 mg/kg per day, from about 2 mg/kg to about extremes as well as any Subranges between. 3 mg/kg per day, and about 2 mg/kg per day. 0249. In some embodiments, the formulation is designed 4. The method of claim 1, wherein the dosage of ibogaine, for periodic administration, such as once, twice, three time, ibogaine derivative, or a pharmaceutically acceptable salt four times or five time daily with ibogaine, ibogaine deriva and/or Solvate thereof provides an average serum concentra tive, or pharmaceutically acceptable Salt and/or Solvate tion of about 50 ng/mL to about 200 ng/mL. thereof In some embodiments, the administration is once 5. The method of claim 1, wherein the QT interval is daily, or once every second day, once every third day, three selected from the group consisting of less than about 470 ms times a week, twice a week, or once a week. The dosage and and less than about 450 ms. frequency of the administration depends on the route of 6. A method for attenuating withdrawal symptoms in a administration, content of composition, age and body weight human patient Susceptible to Such symptoms due to Substance of the patient, condition of the patient, without limitation. addiction, comprising administering to the patient a dosage of Determination of dosage and frequency Suitable for the ibogaine, ibogaine derivative, or a pharmaceutically accept present technology can be readily made a qualified clinician. able salt and/or Solvate thereofthat provides an average serum 0250 In some embodiments, the formulation designed for concentration of about 50 ng/mL to about 400 ng/mL, said administration in accordance with the methods provide concentration being Sufficient to attenuate said symptoms herein can be suitable for a variety of delivery modes includ while maintaining a QT interval of less than about 500 ms ing, without limitation, oral and transdermal delivery. Formu during said treatment. US 2015/02581. 14 A1 Sep. 17, 2015 27

7. The method of claim 6, wherein the withdrawal symp 15. The method of claim 1, wherein the patient is pre toms are due to acute withdrawal. screened to evaluate tolerance for prolongation of QT inter 8. The method of claim 6, wherein the ibogaine, ibogaine val. 16. The method of claim 15, wherein the prescreening step derivative, or a pharmaceutically acceptable salt and/or sol comprises ascertaining that treatment with ibogaine, ibogaine vate thereof is administered as a single dose or multiple doses. derivative, or a pharmaceutically acceptable salt and/or sol 9. The method of claim 6, wherein the aggregate dosage of vate thereof will not result in a QT interval selected from the ibogaine, ibogaine derivative, or a pharmaceutically accept group consisting of greater than about 500 ms, about 470 ms, able salt and/or solvate thereof is selected from the group and about 450 ms. consisting of from about 1.3 mg/kg to about 4 mg/kg per day, 17. The method of claim 15, wherein the ibogaine deriva from about 1.5 mg/kg to about 3 mg/kg per day, from about 2 tive is 18-methoxycoronaridine or a pharmaceutically accept mg/kg to about 4 mg/kg per day, from about 2 mg/kg to about able salt and/or solvate thereof 3 mg/kg per day, and about 2 mg/kg per day. 18. The method of claim 1, wherein the addictive substance 10. The method of claim 6, wherein the QT interval is is selected from the group consisting of benzodiazepines, selected from the group consisting of less than about 470 ms cannabinoids and synthetic cannabinoids, stimulants, barbi and less than about 450 ms. turates, gamma-hydroxybutyrate (GHB), ketamine, PCP. 11. A method to prevent relapse of substance abuse in a dextromethorphan (DXM), lysergic acid diethylamide patient treated to ameliorate said abuse, said method compris (LSD), mescaline, anabolic steroids, and derivatives of each ing periodically administering to said patient a maintenance thereof dosage of ibogaine, ibogaine derivative, or a pharmaceuti 19. The method of claim 1, wherein the ibogaine, ibogaine cally acceptable salt and/or solvate thereof, wherein the derivative, or a pharmaceutically acceptable salt and/or sol patient is no longer abusing the Substance. vate thereof is selected from the group consisting of ibogaine, 12. The method of claim 11, wherein the dosage is less than coronaridine, ibogamine, voacagine, 18-methoxycoronari about 70% of a therapeutic dose of ibogaine, ibogaine deriva dine, 2-methoxyethyl-18-methoxycoronaridinate, and tive, or a pharmaceutically acceptable salt and/or Solvate 18-methylaminocoronaridine. thereof, and further wherein the prolongation of the QT inter 20. The method of claim 1, wherein 18-methoxycoronari Val is selected from the group consisting of no greater than dine or a pharmaceutically acceptable salt and/or Solvate about 30 ms and no greater than about 20 ms. thereof is administered. 13-14. (canceled) k k k k k