Patent Publication Number: US-2017368074-A1

Title: Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of and claims priority to U.S. patent application Ser. No. 14/624,376 filed Feb. 17, 2015, entitled “Low Dose Noribogaine for Treating Nicotine Addiction and Preventing Relapse of Nicotine Use” which claims benefit of U.S. Provisional Application No. 61/941,390 filed Feb. 18, 2014, and U.S. Provisional Application No. 62/035,335 filed Aug. 8, 2014, which are hereby incorporated by reference in their entirety. 
    
    
     FIELD OF THE INVENTION 
     This invention relates generally to methods and compositions for the treatment of nicotine addiction by administering noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt thereof. This invention further relates generally to methods and compositions for the treatment or prevention of relapse of nicotine use by administering noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt thereof. 
     STATE OF THE ART 
     Noribogaine is sometimes referred to as 12-hydroxyibogaine. U.S. Pat. No. 2,813,873 claims noribogaine albeit as “12—O-demethylibogaine” while providing an incorrect structural formula for ibogaine. The structure of noribogaine has now been thoroughly evaluated and is found to combine the features of tryptamine, tetrahydrohavaine and indolazepines. Noribogaine can be depicted by the following formula: 
     
       
         
         
             
             
         
       
     
     Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S. Pat. No. 6,348,456) and as a potent analgesic (U.S. Pat. No. 7,220,737). Such treatment generally requires administration of high doses of noribogaine, typically 0.1 mg to 100 mg per kg body weight. 
     Noribogaine is a metabolite of ibogaine found in human, dog, rat and monkey. While the prior art suggests that ibogaine at higher doses is useful as a treatment for addiction, use of ibogaine is associated with hallucinations and other negative side effects. In the United States, ibogaine is classified as a Schedule I controlled substance. Noribogaine has been suggested to have a greater and longer lasting activity in humans than ibogaine for reducing craving for addictive substances and treating chemical dependency. U.S. Pat. No. 6,348,456, incorporated by reference herein in its entirety, discloses highly purified noribogaine and teaches that it should be provided at dosages from about 0.01 to about 100 mg per kg body weight per day to treat addiction, although no human data was provided showing an effective dose to treat drug addiction. 
     The therapeutic dosing of noribogaine for long-term treatment in humans has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe. Indeed, prior to the instant invention, it was uncertain as to whether noribogaine could be administered at a dose which was therapeutic while at the same time safe for patients. 
     Nicotine addiction relates generally to smoking, although other forms of nicotine addiction are common (e.g., chewing tobacco). Smoking and other forms of nicotine use pose a serious threat to global health. In the United States alone, annual mortality from smoking (including environmental exposure, i.e. “second-hand smoke”) is greater than 440,000. Costs associated with smoking-related illness in the United States total $96 billion in medical costs and $97 billion in lost productivity each year. Furthermore, smoking significantly increases the risk of a number of diseases, including coronary artery disease, stroke, lung cancer and other cancers, and chronic obstructive pulmonary disease. An estimated 46 million people in the United States are smokers, 20.6 percent of the US population. 
     More than 40 percent of existing smokers attempt to quit smoking annually. Various approved therapies (varenicline, bupropion, nicotine patch/gum, nicotine nasal spray/inhaler, hypnotherapy, biofeedback) have long been in clinical use to treat nicotine dependence. Current therapies directed toward smoking cessation tend to focus on counseling, behavioral treatment such as hypnosis, and/or pharmaceutical therapies. Quitting smoking is difficult and may require multiple attempts, with success rates of 4% to 25% depending on the technique used. Users often relapse because of stress, weight gain, and withdrawal symptoms. Furthermore, nicotine replacement therapies (e.g., nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler) do not directly treat nicotine addiction, as the patient remains addicted to nicotine throughout treatment. 
     A nicotine addict in remission may exhibit psychological symptoms of nicotine addiction long after the physical symptoms of nicotine addiction are gone. Many ex-smokers relapse due to a trigger, such as stress or environmental cues. For example, approximately 50% of relapses occur when the ex-smoker has been drinking alcohol. 
     Given the immense harm of smoking and other forms of nicotine use to the human body, the high degree of cost to the health care system, the addictive nature of nicotine use, and the difficulty in quitting even when using conventional therapy, there remains an acute need for effective strategies for treating nicotine addiction. There also remains an acute need for effective strategies for preventing relapse of nicotine addiction in nicotine addicts who are in remission. 
     SUMMARY OF THE INVENTION 
     This invention is based, in part, on the discovery that at very low doses, direct blood stream delivery of noribogaine reduces the desire to smoke. Such dosing is well below that previously described. Direct blood stream delivery of noribogaine enhances the amount of noribogaine delivered to the brain, because noribogaine so administered does not initially pass through the liver before reaching the brain as it does when ingested. Direct blood stream delivery of noribogaine includes sublingual, pulmonary and intranasal delivery where the noribogaine is absorbed directly into the blood stream and then into the brain. The rapid delivery of noribogaine into the brain causes a significant reduction in the craving to smoke on a rapid basis, typically less than 5 minutes after administration. 
     Noribogaine is believed to bind to several receptors in the brain, including nicotinic acetylcholine receptors (nAChRs) and opiod receptors (e.g., μ-opiod receptors). Without being bound by theory, it is believed that the nAChR has a greater binding affinity for noribogaine than other receptors in the brain. This allows treatment of nicotine addiction and/or nicotine cravings using much lower doses of noribogaine than are currently used for the treatment of other conditions, such as opiod withdrawal. Furthermore, a nicotine addict in remission may not exhibit physical symptoms of addiction, but rather may have psychological cravings for cigarettes or other forms of nicotine, or may anticipate such cravings in certain situations. As such, and without being bound by theory, it is expected that lower amounts of noribogaine are required to treat or prevent nicotine cravings in such situations than would be required in a patient who is currently addicted to nicotine. 
     In one aspect, this invention relates to methods of treating nicotine addiction or preventing relapse of nicotine use, comprising administration of a therapeutic amount of noribogaine. As used herein, unless specified otherwise, noribogaine includes to noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. 
     In one aspect, this invention relates to treating nicotine addiction in a patient in need thereof comprising administering to the patient by direct blood stream delivery a therapeutically effective amount of noribogaine. In one aspect, a therapeutically effective amount of noribogaine or derivative is from about 50 ng to less than 10 μg per kg of body weight. In some embodiments, the therapeutically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day. 
     In another aspect, this invention provides a method for treating nicotine addiction in a patient in need thereof comprising administering to the patient a therapeutic amount of noribogaine or a noribogaine derivative or pharmaceutically acceptable salt thereof, wherein the noribogaine or derivative or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery. 
     In one aspect, this invention relates to methods of preventing relapse of nicotine use, comprising administration of a prophylactic amount of noribogaine to inhibit a behavioral craving for nicotine. As used herein, unless specified otherwise, noribogaine includes to noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. 
     In one aspect, this invention relates to preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient by direct blood stream delivery a prophylactically effective amount of noribogaine. In one aspect, a prophylactically effective amount of noribogaine is from about 50 ng to less than 10 μg per kg of body weight. In some embodiments, the prophylactically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day. In some embodiments, the prophylactically effective amount is administered when the patient feels a craving, or anticipates feeling a craving, for nicotine. 
     In another aspect, this invention provides a method for preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein the noribogaine, derivative, or salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  represents mean noribogaine concentration-time profiles in healthy patients after single oral dosing with 3, 10, 30 or 60 mg doses. Inset: Individual concentration-time profiles from 0-12 h after a 10 mg dose. 
         FIG. 2  represents mean plasma noribogaine glucuronide concentration-time profiles in healthy patients after single oral 30 or 60 mg doses. 
         FIG. 3  illustrates the mean noribogaine concentration-time profile in opioid-addicted patients after a single oral 60 mg (diamonds), 120 mg (squares), or 180 mg (triangles) dose of noribogaine. 
         FIG. 4  illustrates hours to resumption of opioid substitution treatment (OST) for each patient given placebo (circles), or a single oral dose of noribogaine (60 mg, squares; 120 mg, triangles; 180 mg, inverted triangles). Center horizontal line represents mean. Error bars represent standard deviation. 
         FIG. 5  illustrates results of noribogaine treatment on final COWS scores before resumption of OST. Boxes include values representing 25%-75% quartiles. Diamonds represent the median, crossbars represent mean. Whiskers represent values within one standard deviation of mid-quartiles. No outliers were present. 
         FIG. 6A  illustrates of the mean change in total COWS scores over the first 6 hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles). Data is given relative to baseline COWS score. 
         FIG. 6B  illustrates the mean area under the curve (AUC) over the initial 6 hour period after administration of noribogaine or placebo, based on the COWS score data given in  FIG. 6A . A negative change in score indicates that withdrawal symptoms subsided over the period. 
         FIG. 7A  illustrates of the mean change in total OOWS scores over the first 6 hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles). Data is given relative to baseline OOWS score. 
         FIG. 7B  illustrates the mean area under the curve (AUC) over the initial 6 hour period after administration of noribogaine or placebo, based on the OOWS score data given in  FIG. 7A . A negative change in score indicates that withdrawal symptoms subsided over the period. 
         FIG. 8A  illustrates of the mean change in total SOWS scores over the first 6 hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles). Data is given relative to baseline SOWS score. 
         FIG. 8B  illustrates the mean area under the curve (AUC) over the initial 6 hour period after administration of noribogaine or placebo, based on the SOWS score data given in  FIG. 8A . A negative change in score indicates that withdrawal symptoms subsided over the period. 
         FIG. 9A  illustrates the average change in QT interval (AQTc1) for each cohort (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles) over the first 24 hours post administration. 
         FIG. 9B  illustrates the correlation between serum noribogaine concentration and ΔQTcl for each patient over time. The equation of the line is given. 
         FIG. 10A  represents the effects of noribogaine and varenicline in nicotine dependent rats. Data represent mean+standard error of the mean (SEM). *P&lt;0.10; ***P&lt;0.001 compared to vehicle or saline treatment. 
         FIG. 10B  represents the effects of noribogaine and varenicline on percentage of inactive lever press during nicotine self-administration. Data represent mean+SEM. 
         FIG. 11  represents the effects of noribogaine on general motor activity of zebrafish during nicotine withdrawal. Behavioral endpoints examined include, latency to upper half of tank (panel A), transitions to upper half of tank(panel B), transitions to upper half of tank per minute (panel C), time in upper half of tank (panel D), time in upper half of tank per minute (panel E), average entry duration (panel F), and average entry duration per minute (panel G). 
         FIG. 12  represents effects of noribogaine on general motor activity of zebrafish during nicotine withdrawal. Behavioral endpoints examined include, distance moved (panel A), velocity (panel B), rotation angle (panel C), number of rotation events (panel D), change in direction of body/heading (panel E), change in direction of movement per distance moved/meander total (panels F and G). 
         FIG. 13  depicts effects of noribogaine on freezing bouts frequency (panel A) and duration of freezing bouts (panels B and C). 
         FIG. 14  depicts effects of noribogaine treatment on movement mobility. Immobile (dark squares) was used to express the frequency of episodes with degree of movement independent of spatial displacement (duration of immobility). Mobile (medium gray squares) reflects overall locomotor activity. Hi-mobile (light gray squares) reflects bouts of accelerated swimming (&gt;60% of individual average). 
         FIG. 15  shows representative traces of control, chronic nicotine, repeated nicotine withdrawal (WD), and WD+1 mg/L noribogaine treatment (from top to bottom), recorded in the 5 minute novel tank test (NTT) by Ethovision XT8.5 software. 
     
    
    
     DETAILED DESCRIPTION 
     It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of this invention will be limited only by the appended claims. 
     The detailed description of the invention is divided into various sections only for the reader&#39;s convenience and disclosure found in any section may be combined with that in another section. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. 
     It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of compounds. 
     I. Definitions 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings. 
     The term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by (+) or (−) 20%, 10%, 5%,1%, or any subrange or subvalue there between. Preferably, the term “about” when used with regard to a dose amount means that the dose may vary by +/−20%. For example, “about 2 mg/kg noribogaine” indicates that a patient may be administered a dose of noribogaine between 1.6 mg/kg and 2.4 mg/kg. In another example, about 120 mg per unit dose of noribogaine indicates that the unit dose may range from 96 mg to 144 mg. 
     “Administration” refers to introducing an agent, such as noribogaine, into a patient. Typically, an effective amount is administered, which amount can be determined by the treating physician or the like. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used. Preferably, the agent, such as noribogaine, is administered by direct blood stream delivery, e.g. sublingual, intranasal, or intrapulmonary administration. 
     The related terms and phrases “administering” and “administration of”, when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient. 
     “Periodic administration” or “periodically administering” refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of an agent, such as noribogaine, noribogaine derivative, or salt or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration. 
     “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention. 
     As used herein, the term “alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 —), ethyl (CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl ((CH 3 ) 2 CH—), n-butyl (CH 3 CH 2 CH 2 CH 2 —), isobutyl ((CH 3 ) 2 CHCH 2 —), sec-butyl ((CH 3 )(CH 3 CH 2 )CH—), t-butyl ((CH 3 ) 3 C—), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 —), and neopentyl ((CH 3 ) 3 CCH 2 —). The term “C x  alkyl” refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C 3  refers to an alkyl group having 3 carbon atoms. 
     “Alkenyl” refers to straight or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (&gt;C═C&lt;) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-1-yl. Included within this term are the cis and trans isomers or mixtures of these isomers. 
     “Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic unsaturation. Examples of such alkynyl groups include acetylenyl (—CCH), and propargyl (—CH 2 ≡CCH). 
     “Substituted alkyl” refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 sub stituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein. 
     “Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 sub stituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom. 
     “Substituted alkynyl” refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 sub stituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom. 
     “Alkoxy” refers to the group —O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy. 
     “Substituted alkoxy” refers to the group —O-(substituted alkyl) wherein substituted alkyl is defined herein. 
     “Acyl” refers to the groups H—C(O)—, alkyl—C(O)—, substituted alkyl—C(O)—, alkenyl—C(O)—, substituted alkenyl—C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, cycloalkyl—C(O)—, substituted cycloalkyl—C(O)—, cycloalkenyl—C(O)—, substituted cycloalkenyl—C(O)—, aryl—C(O)—, substituted aryl—C(O)—, heteroaryl—C(O)—, substituted heteroaryl—C(O)—, heterocyclic—C(O)—, and substituted heterocyclic—C(O)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the “acetyl” group CH 3 C(O)—. 
     “Acylamino” refers to the groups —NR 38 C(O)alkyl, —NR 38 C(O)substituted alkyl, —NR 38 C(O)cycloalkyl, —NR 38 C(O)substituted cycloalkyl, —NR 38 C(O)cycloalkenyl, —NR 38 C(O)substituted cycloalkenyl, —NR 38 C(O)alkenyl, —NR 38 C(O)substituted alkenyl, —NR 38 C(O)alkynyl, —NR 38 C(O)substituted alkynyl, —NR 38 C(O)aryl, —NR 38 C(O)substituted aryl, —NR 38 C(O)heteroaryl, —NR 38 C(O)substituted heteroaryl, —NR 38 C(O)heterocyclic, and —NR 38 C(O)substituted heterocyclic wherein R 38  is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Acyloxy” refers to the groups alkyl—C(O)O—, substituted alkyl—C(O)O—, alkenyl—C(O)O—, substituted alkenyl—C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl—C(O)O—, substituted aryl—C(O)O—, cycloalkyl—C(O)O—, substituted cycloalkyl—C(O)O—, cycloalkenyl—C(O)O—, substituted cycloalkenyl—C(O)O—, heteroaryl—C(O)O—, substituted heteroaryl—C(O)O—, heterocyclic—C(O)O—, and substituted heterocyclic—C(O)O—wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Amino” refers to the group —NH 2 . 
     “Substituted amino” refers to the group —NR 39 R 40  where R 39  and R 40  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cylcoalkyl, —SO 2 -cycloalkenyl, —SO 2 -substituted cylcoalkenyl,—SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic and wherein R 39  and R 40  are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 39  and R 40  are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R 39  is hydrogen and R 40  is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R 39  and R 40  are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R 39  or R 40  is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R 39  nor R 40  are hydrogen. 
     “Aminocarbonyl” refers to the group —C(O)NR 41 R 42  where R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aminothiocarbonyl” refers to the group —C(S)NR 41 R 42  where R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aminocarbonylamino” refers to the group —NR 38 C(O)NR 41 R 42  where R 38  is hydrogen or alkyl and R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aminothiocarbonylamino” refers to the group —NR 38 C(S)NR 41 R 42  where R 38  is hydrogen or alkyl and R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aminocarbonyloxy” refers to the group —O—C(O)NR 41 R 42  where R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aminosulfonyl” refers to the group —SO 2 NR 41 R 42  where R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aminosulfonyloxy” refers to the group —O—SO 2 NR 41 R 42  where R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aminosulfonylamino” refers to the group —NR 38 —SO 2 NR 41 R 42  where R 38  is hydrogen or alkyl and R 41  and R 42  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Amidino” refers to the group —C(═NR 43 )NR 41 R 42  where R 41 , R 42 , and R 43  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 41  and R 42  are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl. 
     “Substituted aryl” refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein. 
     “Aryloxy” refers to the group —O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy. 
     “Substituted aryloxy” refers to the group —O-(substituted aryl) where substituted aryl is as defined herein. 
     “Arylthio” refers to the group —S-aryl, where aryl is as defined herein. 
     “Substituted arylthio” refers to the group —S-(substituted aryl), where substituted aryl is as defined herein. 
     “Carbonyl” refers to the divalent group —C(O)— which is equivalent to —C(═O)—. 
     “Carboxy” or “carboxyl” refers to —COOH or salts thereof. 
     “Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O-substituted cycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted cycloalkenyl, —C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “(Carboxyl ester)amino” refers to the group —NR 38 —C(O)O-alkyl, —NR 38 —C(O)O-substituted alkyl, —NR 38 —C(O)O-alkenyl, —NR 38 —C(O)O-substituted alkenyl, —NR 38 —C(O)O-alkynyl, —NR 38 —C(O)O-substituted alkynyl, —NR 38 —C(O)O-aryl, —NR 38 —C(O)O-substituted aryl, —NR 38 —C(O)O-cycloalkyl, —NR 38 —C(O)O-substituted cycloalkyl, —NR 38 —C(O)O-cycloalkenyl, —NR 38 —C(O)O-substituted cycloalkenyl, —NR 38 —C(O)O-heteroaryl, —NR 38 —C(O)O-substituted heteroaryl, —NR 38 —C(O)O-heterocyclic, and —NR 38 —C(O)O-substituted heterocyclic wherein R 38  is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “(Carboxyl ester)oxy” refers to the group —O—C(O)O—alkyl, substituted —O—C(O)O—alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substituted alkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl, —O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl, —O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Cyano” refers to the group —CN. 
     “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicycle[2,2,2,]octanyl, norbornyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl. 
     “Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one &gt;C═C&lt; ring unsaturation and preferably from 1 to 2 sites of &gt;C═C&lt; ring unsaturation. 
     “Substituted cycloalkyl” and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein. 
     “Cycloalkyloxy” refers to —O-cycloalkyl. 
     “Substituted cycloalkyloxy” refers to —O-(substituted cycloalkyl). 
     “Cycloalkylthio” refers to —S-cycloalkyl. 
     “Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl). 
     “Cycloalkenyloxy” refers to —O-cycloalkenyl. 
     “Substituted cycloalkenyloxy” refers to —O-(substituted cycloalkenyl). 
     “Cycloalkenylthio” refers to —S-cycloalkenyl. 
     “Substituted cycloalkenylthio” refers to —S-(substituted cycloalkenyl). 
     “Guanidino” refers to the group —NHC(═NH)NH 2 . 
     “Substituted guanidino” refers to —NR 44 C(═NR 44 )N(R 44 ) 2  where each R 44  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R 44  groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R 44  is not hydrogen, and wherein said substituents are as defined herein. 
     “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro. 
     “Haloalkyl” refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein. 
     “Haloalkoxy” refers to alkoxy groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkoxy and halo are as defined herein. 
     “Haloalkylthio” refers to alkylthio groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein. 
     “Hydroxy” or “hydroxyl” refers to the group —OH. 
     “Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, and/or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. 
     “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of sub stituents defined for substituted aryl. 
     “Heteroaryloxy” refers to —O-heteroaryl. 
     “Substituted heteroaryloxy” refers to the group —O-(substituted heteroaryl). 
     “Heteroarylthio” refers to the group —S-heteroaryl. 
     “Substituted heteroarylthio” refers to the group —S-(substituted heteroaryl). 
     “Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, and/or sulfonyl moieties. 
     “Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl. 
     “Heterocyclyloxy” refers to the group —O-heterocycyl. 
     “Substituted heterocyclyloxy” refers to the group —O-(substituted heterocycyl). 
     “Heterocyclylthio” refers to the group —S-heterocycyl. 
     “Substituted heterocyclylthio” refers to the group —S-(substituted heterocycyl). 
     Examples of heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl. 
     “Nitro” refers to the group —NO 2 . 
     “Oxo” refers to the atom (═O) or (—O). 
     “Spiro ring systems” refers to bicyclic ring systems that have a single ring carbon atom common to both rings. 
     “Sulfonyl” refers to the divalent group —S(O) 2 —. 
     “Substituted sulfonyl” refers to the group —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cylcoalkyl, —SO 2 -cycloalkenyl, —SO 2 -substituted cylcoalkenyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-SO 2 —, phenyl-SO 2 —, and 4-methylphenyl-SO 2 —. The term “alkylsulfonyl” refers to —SO 2 -alkyl. The term “haloalkylsulfonyl” refers to —SO 2 -haloalkyl where haloalkyl is defined herein. The term “(substituted sulfonyl)amino” refers to —NH(substituted sulfonyl), and the term “(substituted sulfonyl)aminocarbonyl” refers to —C(O)NH(substituted sulfonyl), wherein substituted sulfonyl is as defined herein. 
     “Sulfonyloxy” refers to the group —OSO 2 -alkyl, —OSO 2 -substituted alkyl, —OSO 2 -alkenyl, —OSO 2 -substituted alkenyl, —OSO 2 -cycloalkyl, —OSO 2 -substituted cylcoalkyl, —OSO 2 -cycloalkenyl, —OSO 2 -substituted cylcoalkenyl,—OSO 2 -aryl, —OSO 2 -substituted aryl, —OSO 2 -heteroaryl, —OSO 2 -substituted heteroaryl, —OSO 2 -heterocyclic, —OSO 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substituted alkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—, substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substituted cycloalkyl-C(S)—, cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—, aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substituted heteroaryl-C(S)—, heterocyclic-C(S)—, and substituted heterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
     “Thiol” refers to the group —SH. 
     “Thiocarbonyl” refers to the divalent group —C(S)— which is equivalent to —C(═S)—. 
     “Thione” refers to the atom (═S). 
     “Alkylthio” refers to the group —S-alkyl wherein alkyl is as defined herein. 
     “Substituted alkylthio” refers to the group —S-(substituted alkyl) wherein substituted alkyl is as defined herein. 
     “Compound” or “compounds” as used herein is meant to include the stereoiosmers and tautomers of the indicated formulas. 
     “Stereoisomer” or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. 
     “Tautomer” refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring —NH— moiety and a ring ═N— moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. 
     As used herein, the term “phosphate ester” refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine. 
     As used herein, the term “phosphate ester” refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine. 
     As used herein, the term “monophosphate” refers to the group —P(O)(OH) 2 . 
     As used herein, the term “diphosphate” refers to the group —P(O)(OH)—OP(O)(OH) 2 . 
     As used herein, the term “triphosphate” refers to the group —P(O)(OH)— (OP(O)(OH)) 2 OH. 
     As used herein, the term “ester” as it refers to esters of the mono-, di- or triphosphate group means esters of the monophosphate can be represented by the formula —P(O)(OR 45 ) 2 , where each R 45  is independently hydrogen, C 1 -C 12  alkyl, C 3 -C 10  cycloalkyl, C 6 -C 14  aryl, heteroaryl of 1 to 10 carbon atoms and 1 to 4 optionally oxidized heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and the like, provided that at least one R 45  is not hydrogen. Likewise, exemplary esters of the di- or triphosphate can be represented by the formulas —P(O)(OR 45 )—OP(O)(OR 45 ) 2  and —P(O)(OR 45 )—(OP(O)(OR 45 )) 2 OR 45 , where R 45  is as defined above. 
     As used herein, the term “hydrolyzable group” refers to a group that can be hydrolyzed to release the free hydroxy group under hydrolysis conditions. Examples of hydrolysable group include, but are not limited to those defined for R above. Preferred hydrolysable groups include carboxyl esters, phosphates and phosphate esters. The hydrolysis may be done by chemical reactions conditions such as base hydrolysis or acid hydrolysis or may be done in vivo by biological processes, such as those catalyzed by a phosphate hydrolysis enzyme. Nonlimiting examples of hydrolysable group include groups linked with an ester-based linker (—C(O)O— or —OC(O)—), an amide-based linker (—C(O)NR 46 — or —NR 46 C(O)—), or a phosphate-linker (—P(O)(OR 46 )—O—, —O—P(S)(OR 46 )—O—, —O—P(S)(SR 46 )—O—, —S—P(O)(OR 46 )—O—, —O—P(O)(OR 46 )—S—, —S—P(O)(OR 46 )—S—, —O—P(S)(OR 46 )—S—, —S—P(S)(OR 46 )—O—, —O—P(O)(R 46 )—O—, —O—P(S)(R 46 )—O—, —S—P(O)(R 46 )—O—, —S—P(S)(R 46 )—O—, —S—P(O)(R 46 )—S—, or —O—P(S)(R 46 )—S—) where R 46  can be hydrogen or alkyl. 
     Substituted groups of this invention, as set forth above, do not include polymers obtained by an infinite chain of substituted groups. At most, any substituted group can be substituted up to five times. 
     “Noribogaine” refers to the compound: 
     
       
         
         
             
             
         
       
     
     as well as noribogaine derivatives, pharmaceutically acceptable salts thereof, or solvates of each thereof. Noribogaine binds to the mu receptor that is associated with pain relief and euphoria. With respect to noribogaine&#39;s interaction with the mu receptors, it appears that noribogaine acts as a full opioid agonist. In addition, noribogaine elevates brain serotonin levels by blocking synaptic reuptake. 
     Noribogaine can be prepared by demethylation of naturally occurring ibogaine: 
     
       
         
         
             
             
         
       
     
     which is isolated from  Tabernanth iboga,  a shrub of West Africa. Demethylation may be accomplished by conventional techniques such as by reaction with boron tribromide/methylene chloride at room temperature followed by conventional purification. See, for example, Huffman, et al., J. Org. Chem. 50:1460 (1985), which incorporated herein by reference in its entirety. Noribogaine can be synthesized as described, for example in U.S. Patent Pub. Nos. 2013/0165647, 2013/0303756, and 2012/0253037, PCT Patent Publication No. WO 2013/040471 (includes description of making noribogaine polymorphs), and U.S. patent application Ser. No. 13/593,454, each of which is incorporated herein by reference in its entirety. 
     “Noribogaine derivatives” refer to, without limitation, esters or O-carbamates of noribogaine, or solvates of each thereof, or pharmaceutically acceptable salts and/or solvants of each thereof. Also encompassed within this invention are derivatives of noribogaine that act as prodrug forms of noribogaine. A prodrug is a pharmacological substance administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into an active metabolite. Noribogaine derivatives include, without limitation, those compounds set forth in U.S. Pat. Nos. 6,348,456 and 8,362,007; as well as in U.S. patent application Ser. No. 13/165,626; and U.S. Patent Application Publication Nos. US2013/0131046; US2013/0165647; US2013/0165425; and US2013/0165414; all of which are incorporated herein by reference. Non-limiting examples of noribogaine derivatives encompassed by this invention are given in more detail in the “Compositions” section below. 
     In some embodiments, the methods of the present disclosure entail the administration of a prodrug of noribogaine that provides the desired maximum serum concentrations and efficacious average noribogaine serum levels. A prodrug of noribogaine refers to a compound that metabolizes, in vivo, to noribogaine. In some embodiments, the prodrug is selected to be readily cleavable either by a cleavable linking arm or by cleavage of the prodrug entity that binds to noribogaine such that noribogaine is generated in vivo. In one preferred embodiment, the prodrug moiety is selected to facilitate binding to the μ and/or κ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the μ and/or κ receptors. Examples of prodrugs of noribogaine are provided in U.S. patent application Ser. No. 13/165,626, the entire content of which is incorporated herein by reference. 
     This invention is not limited to any particular chemical form of noribogaine or noribogaine derivative, and the drug may be given to patients either as a free base, solvate, or as a pharmaceutically acceptable acid addition salt. In the latter case, 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 described below as “pharmaceutically acceptable salts” and the like. As discussed above, noribogaine itself may be formed from the O-demethylation of ibogaine which, in turn, may be synthesized by methods known in the art (see e.g., Huffman, et al., J. Org. Chem. 50:1460 (1985)). 
     A “pharmaceutically acceptable solvate” or “hydrate” of a compound of the invention means a solvate or hydrate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, and includes, but is not limited to, complexes of a compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules. 
     As used herein the term “solvate” is taken to mean that a solid-form of a compound that crystallizes with one or more molecules of solvent trapped inside. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but are certainly not limited to, water, methanol, ethanol, isopropanol, butanol, C 1 -C 6  alcohols in general (and optionally substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention. Additionally, various organic and inorganic acids and bases can be added or even used alone as the solvent to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate. Further, by being left in the atmosphere or recrystallized, the compounds of the present invention may absorb moisture, may include one or more molecules of water in the formed crystal, and thus become a hydrate. Even when such hydrates are formed, they are included in the term “solvate”. Solvate also is meant to include such compositions where another compound or complex co-crystallizes with the compound of interest. The term “solvate” as used herein refers to complexes with solvents in which noribogaine is reacted or from which noribogaine is precipitated or crystallized. For example, a complex with water is known as a “hydrate”. Solvates of noribogaine are within the scope of the invention. It will be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary based on the solvate used. Thus, all crystalline forms of noribogaine or the pharmaceutically acceptable solvates thereof are within the scope of the present invention. 
     “Pharmaceutically acceptable composition” refers to a composition that is suitable for administration to a mammal, particularly, a human. Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan. 
     “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. 
     “Therapeutically effective amount” or “therapeutic amount” refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate, or derivative of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of an agent, such as noribogaine, in the context of treating nicotine dependency, refers to an amount of the agent that attenuates the dependency and/or statistically presents little or no risk of relapse to nicotine use. 
     The therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood administration (e.g., sublingual, pulmonary and intranasal delivery) is used, a lower dose of the compound may be administered. In one aspect, a therapeutically effective amount of noribogaine or derivative is from about 50 ng to less than 100 μg per kg of body weight. Where other routes of administration are used, a higher dose of the compound may be administered. In one embodiment, the therapeutically effective amount of the compound is from greater than about 1 mg to about 8 mg per kg of body weight per day. 
     A “therapeutic level” of a drug is an amount of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that is sufficient to treat nicotine addiction or a disease or disorder or symptoms of a disease or disorder or to treat, prevent, or attenuate cravings for nicotine,a disease or disorder or symptoms of a disease or disorder but not high enough to pose any significant risk to the patient. Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient. This concentration is referred to as the “serum concentration.” Where the serum concentration of noribogaine is mentioned, it is to be understood that the term “noribogaine” encompasses any form of noribogaine, including derivatives thereof. 
     A “sub-therapeutic level” of noribogaine or pharmaceutical salt and/or solvate thereof that is less than the therapeutic level described above. For example, the sub-therapeutic level of noribogaine may be e.g., 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount (e.g., 120 mg) of noribogaine, or any subvalue or subrange there between. Sub-therapeutic levels of noribogaine may coincide with “maintenance amounts” of noribogaine which are amounts, less than the therapeutically effective amount, that provide some attenuation and/or prevention of nicotine cravings. 
     As defined herein, a “prophylactically effective amount” of a drug is an amount, typically less than the therapeutically effective amount, that provides attenuation and/or prevention of nicotine cravings in a patient. The prophylactically effective amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer physically addicted to nicotine. For example, a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount. However, a prophylactically effective amount may be the same as the therapeutically effective amount, for example when a patient who is physically addicted to nicotine is administered noribogaine to attenuate cravings for a period of time when nicotine use is not feasible. 
     As defined herein, a “maintenance amount” of a drug or an agent is an amount, typically less than the therapeutically effective amount that provides attenuation and/or prevention of syndrome disease or disorder or symptoms of a disease or disorder in a patient. The maintenance amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer physically manifests a disease or disorder or symptoms of a disease or disorder. For example, a maintenance amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount, or any subvalue or subrange there between. 
     “Treatment”, “treating”, and “treat” are defined as acting upon a disease, disorder, or condition with an agent, such as noribogaine, to reduce or ameliorate harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. “Treatment,” as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the condition but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition. “Treating” or “treatment of” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to: treating nicotine addiction; treating, preventing, and/or attenuating cravings for nicotine; and preventing relapse of nicotine use. This includes reducing or eliminating smoking in the patient, and/or reducing or eliminating symptoms of withdrawal, cravings, and the like. 
     As used herein, the term “nicotine addict in remission” refers to any patient who has quit using nicotine for a period of time. As used herein, a nicotine addict in remission includes any person who was previously addicted to nicotine in any form, including but not limited to cigarettes, electronic cigarettes or vaporizers (“vaping”), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. The period of time since the nicotine addict in remission quit using nicotine may be short, for example one day to a few weeks, or longer-term, for example months or years. Preferably, the patient has quit using nicotine long enough to no longer exhibit physical symptoms of nicotine addiction. The patient may exhibit psychological symptoms of nicotine addiction. In some embodiments, the patient does not exhibit psychological symptoms of nicotine addiction. 
     As used herein, the term “patient” refers to mammals and includes humans and non-human mammals. 
     As used herein, the term “QT interval” refers to the measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. Prolongation of the QT interval refers to an increase in the QT interval. 
     As used herein, the terms “addiction,” “abuse” and “dependence” are used interchangeably to refer to the patient&#39;s inability to stop using the opioid or opioid-like drug, nicotine, alcohol, substance, or the like, even when it would be in his/her best interest to stop. The DSMIV-TR criteria for dependency include:
         Dependence or significant impairment or distress, as manifested by 3 or more of the following during a 12 month period:   1. Tolerance or markedly increased amounts of the substance to achieve intoxication or desired effect or markedly diminished effect with continued use of the same amount of substance;   2. Withdrawal symptoms or the use of certain substances to avoid withdrawal symptoms;   3. Use of a substance in larger amounts or over a longer period than was intended;   4. Persistent desire or unsuccessful efforts to cut down or control substance use;   5. Involvement in chronic behavior to obtain the substance, use the substance, or recover from its effects;   6. Reduction or abandonment of social, occupational or recreational activities because of substance use;   7. Use of substances even though there is a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.       

     As used herein, the term “nicotine addict in remission” refers to any patient who has quit using nicotine for a period of time. As used herein, a nicotine addict in remission includes any person who was previously addicted to nicotine in any form, including but not limited to cigarettes, electronic cigarettes or vaporizers (“vaping”), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. The period of time since the nicotine addict in remission quit using nicotine may be short, for example one day to a few weeks, or longer-term, for example months or years. Preferably, the patient has quit using nicotine long enough to no longer exhibit physical symptoms of nicotine addiction. The patient may exhibit psychological symptoms of nicotine addiction. In some embodiments, the patient does not exhibit psychological symptoms of nicotine addiction. 
     The term “dose” refers to a range of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that provides a therapeutic serum level of noribogaine when given to a patient in need thereof. The dose is recited in a range, for example from about 20 mg to about 120 mg, and can be expressed either as milligrams or as mg/kg body weight. The attending clinician will select an appropriate dose from the range based on the patient&#39;s weight, age, degree of addiction, health, and other relevant factors, all of which are well within the skill of the art. 
     The term “unit dose” refers to a dose of drug that is given to the patient to provide therapeutic results, independent of the weight of the patient. In such an instance, the unit dose is sold in a standard form (e.g., 20 mg tablet). The unit dose may be administered as a single dose or a series of subdoses. In some embodiments, the unit dose provides a standardized level of drug to the patient, independent of weight of patient. Many medications are sold based on a dose that is therapeutic to all patients based on a therapeutic window. In such cases, it is not necessary to titrate the dosage amount based on the weight of the patient. 
     II. Compositions 
     As will be apparent to the skilled artisan upon reading this disclosure, this invention provides compositions for treating nicotine addiction in a subject, comprising noribogaine, noribogaine derivatives, prodrugs of noribogaine, or pharmaceutically acceptable salts of each thereof. This invention further provides compositions for treating, attenuating, or preventing nicotine cravings in a subject, comprising noribogaine, noribogaine derivatives, prodrugs of noribogaine, or pharmaceutically acceptable salts of each thereof. 
     In one aspect, the invention provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of noribogaine and a pharmaceutically acceptable excipient, wherein the therapeutically or prophylactically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to less than 10 μg per kg body weight per day. In some aspects, the therapeutically or prophylactically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 5 μg per kg body weight per day. In some aspects, the therapeutically or prophylactically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 1 μg per kg body weight per day. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day. 
     In some embodiments, the composition is formulated for sublingual, intranasal, or intrapulmonary delivery. These routes of administration are discussed in further detail below in the subsection titled “Dosage and Routes of Administration.” 
     In one embodiment, the therapeutically effective amount of the compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg per kg body weight per day. 
     Compounds Utilized 
     In one embodiment, the noribogaine derivative is represented by Formula I: 
     
       
         
         
             
             
         
       
         
         or a pharmaceutically acceptable salt and/or solvate thereof, 
         wherein R is hydrogen or a hydrolyzable group such as hydrolyzable esters of from about 1 to 12 carbons. 
       
    
     Generally, in the above formula, R is hydrogen or a group of the formula: 
     
       
         
         
             
             
         
       
         
         wherein X is a C 1 -C 12  group, which is unsubstituted or substituted. For example, X may be a linear alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n -decyl, n-undecyl or n-dodecyl, or a branched alkyl group, such as i-propyl or sec-butyl. Also, X may be a phenyl group or benzyl group, either of which may be substituted with lower alkyl groups or lower alkoxy groups. Generally, the lower alkyl and/or alkoxy groups have from 1 to about 6 carbons. For example, the group R may be acetyl, propionyl or benzoyl. However, these groups are only exemplary. 
       
    
     Generally, for all groups X, they may either be unsubstituted or substituted with lower alkyl or lower alkoxy groups. For example, substituted X may be o-, m- or p-methyl or methoxy benzyl groups. 
     C 1 -C 12  groups include C 1 -C 12  alkyl, C 3 -C 12  cycloalkyl, C 6 -C 12  aryl, C 7 -C 12  arylalkyl, wherein C x  indicates that the group contains x carbon atoms. Lower alkyl refers to C 1 -C 4  alkyl and lower alkoxy refers to C 1 -C 4  alkoxy. 
     In one embodiment, the noribogaine derivative is represented by Formula II: 
     
       
         
         
             
             
         
       
         
         or a pharmaceutically acceptable salt and/or solvate thereof, 
         wherein
          is a single or double bond;   R 1  is halo, OR 2 , or C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 );   R 2  is hydrogen or a hydrolysable group selected from the group consisting of —C(O)R x , —C(O)OR x  and —C(O)N(R y ) 2  where each R x  is selected from the group consisting of C 1 -C 6  alkyl optionally substituted with 1 to 5 R 10 , and each R y  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl optionally substituted with 1 to 5 R 10  , C 6 -C 14  aryl optionally substituted with 1 to 5 R 10 , C 3 -C 10  cycloalkyl optionally substituted with 1 to 5 R 10 , C 1 -C 10  heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , C 1 -C 10  heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , and where each R y , together with the nitrogen atom bound thereto form a C 1 -C 6  heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10  or a C 1 -C 6  heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 ,   R 3  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 , aryl optionally substituted with 1 to 5 R 10 , —C(O)R 6 , —C(O)NR 6 R 6  and —C(O)OR 6 ;   R 4  is selected from the group consisting of hydrogen, —(CH 2 ) m OR 8 , —CR 7 (OH)R 8 , —(CH 2 ) m CN, —(CH 2 ) m COR 8 , —(CH 2 ) m CO 2 R 8 , —(CH 2 ) m C(O)NR 7 R 8 , —(CH 2 ) m C(O)NR 7 NR 8 R 8 , —(CH 2 ) m C(O)NR 7 NR 8 C(O)R 9 , and —(CH 2 ) m NR 7 R 8 ;   m is 0, 1, or 2;   L is a bond or C 1 -C 12  alkylene;   R 5  is selected from the group consisting of hydrogen, C 1 -C 12  alkyl substituted with 1 to 5 R 10 , C 1 -C 12  alkenyl substituted with 1 to 5 R 10 , —X 1 —R 7 , —(X 1 —Y) n —X 1 —R 7 , —SO 2 NR 7 R 8 , —O—C(O)R 9 , —C(O)OR 8 , —C(O)NR 7 R 8 , —NR 7 R 8 , —NHC(O)R 9 , and —NR 7 C(O)R 9 ;   each R 6  is independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, C 6 -C 10  aryl, C 1 -C 6  heteroaryl having 1 to 4 heteroatoms, and C 1 -C 6  heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 10 ;   X 1  is selected from the group consisting of O and S;   Y is C 1 -C 4  alkylene or C 6 -C 10  arylene, or a combination thereof;   n is 1, 2, or 3;   R 7  and R 8  are each independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 , C 1 -C 6  heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , C 3 -C 10  cycloalkyl optionally substituted with 1 to 5 R 10 , C 6 -C 10  aryl optionally substituted with 1 to 5 R 10  and C 1 -C 6  heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 ;   R 9  is selected from the group consisting of C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 , C 1 -C 6  heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 , C 3 -C 10  cycloalkyl optionally substituted with 1 to 5 R 10 °, C 6 -C 10  aryl optionally substituted with 1 to 5 R 10  and C 1 -C 6  heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 ;   R 10  is selected from the group consisting of C 1 -C 4  alkyl, phenyl, halo, —OR 11 , —CN, —COR 11 , —CO 2 R 11 , —C(O)NHR 11 , —NR 11 R 11 , —C(O)NR 11 R 11 , —C(O)NHNHR 11 , —C(O)NR 11 NHR 11 , —C(O)NR 11 NR 11 R 11 , —C(O)NHNR 11 C(O)R 11 , —C(O)NHNHC(O)R 11 , —SO 2 NR 11 R 11 , —C(O)NR 11 NR 11 C(O)R 11 , and —C(O)NR 11 NHC(O)R 11 ; and   R 11  is independently hydrogen or C 1 -C 12  alkyl; provided that:   when L is a bond, then R 5  is not hydrogen;   when   is a double bond, R 1  is an ester hydrolyzable group, R 3  and R 4  are both hydrogen, then -L-R 5  is not ethyl;   when   is a double bond, R 1  is —OH, halo or C 1 -C 12  alkyl optionally substituted with 1 to 5 R 10 °, then R 4  is hydrogen; and   when   is a double bond, R 1  is OR 2 , R 4  is hydrogen, -L-R 5  is ethyl, then R 2  is not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.   
     
       
    
     In one embodiment, the noribogaine derivative is represented by Formula III: 
     
       
         
         
             
             
         
       
         
         or a pharmaceutically acceptable salt and/or solvate thereof, 
         wherein
          is a single or double bond;   R 12  is halo, —OH, —SH, —NH 2 , —S(O) 2 N(R 17 ) 2 , —R z -L 1 -R 18 , —R z -L 1 -R 19 , —R z -L 1 -R 20  or —R z -L 1 - CHR 18 R 19 , where R z  is O, S or NR 17 ;   L 1  is alkylene, arylene, —C(O)-alkylene, —C(O)-arylene, —C(O)O-arylene, —C(O)O-alkylene, —C(O)NR 20 -alkylene, —C(O)NR 20 -arylene, —C( NR 20 )NR 20 -alkylene or —C(NR 20 )NR 20 -arylene, wherein L 1  is configured such that —O-L 1 R 18 is —OC(O)-alkylene—R 18 , —OC(O)O-arylene-R 18 , —OC(O)O-alkylene-R 18 , —OC(O)-arylene-R 18 , —OC(O)NR 20 -alkylene-R 18 , —OC(O)NR 20 -arylene-R 18 , —OC(NR 20 )NR 20 -alkylene-R 18  or —OC(NR 20 )NR 20 -arylene-R 18 , and wherein the alkylene and arylene are optionally substituted with 1 to 2 R 16 ;   R 13  is hydrogen, —S(O) 2 OR 20 , —S(O) 2 R 20 , —C(O)R 15 , —C(O)NR 15 R 15 , —C(O)OR 15 , C 1 -C 12  alkyl optionally substituted with 1 to 5 R 16 , C 1 -C 12  alkenyl optionally substituted with 1 to 5 R 16 , or aryl optionally substituted with 1 to 5 R 16 ;   R 14  is hydrogen, halo, —OR 17 , —CN, C 1 -C 12  alkyl, C 1 -C 12  alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R 16 ;   each R 15  is independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, aryl, heteroaryl, and heterocycle, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 16 ;   R 16  is selected from the group consisting of phenyl, halo, —OR 17 , —CN, —COR 17 , —CO 2 R 17 , —NR 17 R 17 , —NR 17 C(O)R 17 , —NR 17 SO 2 R 17 , —C(O)NR 17 R 17 , —C(O)NR 17 R 17 , —SO 2 NR 17 R 17  and —C(O)NR 17 NR 17 C(O)R 17 ;   each R 17  is independently hydrogen or C 1 -C 12  alkyl optionally substituted with from 1 to 3 halo;   R 18  is hydrogen, —C(O)R 20 , —C(O)OR 20 , —C(O)N(R 20 ) 2  or —N(R 20 )C(O)R 20 ;   R 19  is hydrogen, —N(R 20 ) 2 , —C(O)N(R 20 ) 2 , —C(NR 20 )N(R 20 ) 2 , —C(NSO 2 R 20 )N(R 20 ) 2 , —NR 20 C(O)N(R 20 ) 2 , —NR 20 C(S)N(R 20 ) 2 , —NR 20 C(NR 20 )N(R 20 ) 2 , —NR 20 C(NSO 2 R 20 )N(R 20 ) 2  or tetrazole; and   each R 20  is independently selected from the group consisting of hydrogen, C 1 -C 12  alkyl and aryl;   provided that:   when   is a double bond and R 13  and R 14  are hydrogen, then R 12  is not hydroxy;   when   is a double bond, R 14  is hydrogen, R 12  is —O-L 1 -R 18 , —O-L 1 -R 19 , —O-L 1 -R 20 , and L 1  is alkylene, then —O-L 1 -R 18 , —O-L 1 -R 19 , —O-L 1 -R 20  are not methoxy;   when   is a double bond, R 14  is hydrogen, R z  is O, L 1  is —C(O)-alkylene, —C(O)-arylene, —C(O)O-arylene, —C(O)O-alkylene, —C(O)NR 20 -alkylene, or —C(O)NR 20 -arylene, then none of R 18 , R 19  or R 20  are hydrogen.   
     
       
    
     In one embodiment, the noribogaine derivative is represented by Formula IV: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt and/or solvate thereof, 
     wherein 
     R 21  is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of —C(O)R 23 , —C(O)NR 24 R 25  and —C(O)OR 26 , where R 23  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R 24  and R 25  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R 26  is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that R 21  is not a saccharide or an oligosaccharide; 
     L 2  is selected from the group consisting of a covalent bond and a cleavable linker group; 
     R 22  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that R is not a saccharide or an oligosaccharide; 
     provided that when L 2  is a covalent bond and R 22  is hydrogen, then R 21  is selected from the group consisting of —C(O)NR 24 R 25  and —C(O)OR 26 ; and 
     further provided that when R 21  is hydrogen or —C(O)R 23  and L 2  is a covalent bond, then R 22  is not hydrogen. 
     In one embodiment, the noribogaine derivative is represented by Formula V: 
     
       
         
         
             
             
         
       
         
         or a pharmaceutically acceptable salt and/or solvate thereof, 
         wherein:
          refers to a single or a double bond provided that when   is a single bond, Formula V refers to the corresponding dihydro compound;   R 27  is hydrogen or SO 2 OR 29 ;   R 28  is hydrogen or SO 2 OR 29 ;   R 29  is hydrogen or C 1 -C 6  alkyl;   provided that at least one of R 27  and R 28  is not hydrogen.   
     
       
    
     In one embodiment, the noribogaine derivative is represented by Formula VI: 
     
       
         
         
             
             
         
       
         
         or a pharmaceutically acceptable salt and/or solvate thereof, 
         wherein:
          refers to a single or a double bond provided that when   is a single bond, Formula VI refers to the corresponding vicinal dihydro compound;   R 30  is hydrogen, a monophosphate, a diphosphate or a triphosphate; and   R 31  is hydrogen, a monophosphate, a diphosphate or a triphosphate;   provided that both R 30  and R 31  are not hydrogen;   
     
         wherein one or more of the monophosphate, diphosphate and triphosphate groups of R 30  and R 31  are optionally esterified with one or more C 1 -C 6  alkyl esters. 
       
    
     Noribogaine as utilized herein, can be replaced by a noribogaine derivative or a salt of noribogaine or the noribogaine derivative or a solvate of each of the foregoing. 
     In a preferred embodiment, the compound utilized herein is noribogaine or a salt thereof. In a more preferred embodiment, the compound utilized herein is noribogaine. 
     III. Methods of the Invention 
     As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating nicotine addiction in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of noribogaine, a noribogaine derivative, a noribogaine prodrug, or a pharmaceutically acceptable salt of each thereof. This invention further provides a method for treating, attenuating, or preventing nicotine cravings in a subject, comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of noribogaine, a noribogaine derivative, a noribogaine prodrug, or a pharmaceutically acceptable salt of each thereof. 
     a. Treating Nicotine Addiction 
     In some embodiments, the invention provides for a method for treating nicotine addiction in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. 
     The subject or patient may be any patient who uses nicotine in any form, including cigarettes, electronic cigarettes or vaporizers (“vaping”), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. In some embodiments, the patient is addicted to nicotine. In some embodiments, the patient is physically addicted to nicotine. In some embodiments, the patient is psychologically addicted to nicotine. 
     In some embodiments, the therapeutically effective amount of the compound is from about 50 ng to less than 10 μg per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 μg per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 μg per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 μg per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 500 ng to less than 10 μg per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 1 μg to less than 10 μg per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 μg, about 2 μg, about 3 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10 μg per kilogram body weight per day. The therapeutically effective amount of the compound may be any amount within any of these ranges, including endpoints. 
     In some embodiments, the therapeutically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the therapeutically effective amount is administered twice per day. In some embodiments, the therapeutically effective amount is administered more than two times per day. 
     Where the therapeutically effective amount is administered more than one time per day, a portion of the total therapeutically effective amount is administered at each time. For example, an 90 kg patient taking 1 μg noribogaine per kg body weight per day would take 90 μg once a day, 45 μg twice a day, or 30 μg three times a day, etc. 
     In some embodiments, the therapeutically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once when needed, e.g., when the patient has a craving for nicotine or anticipates to have a craving for nicotine as described herein. 
     In some embodiments, the noribogaine or noribogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled “Dosage and Routes of Administration.” 
     b. Preventing Relapse of Nicotine Use 
     In some embodiments, the invention provides for a method for treating, preventing, or attenuating nicotine cravings in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. In some embodiments, the invention provides for a method for preventing recurrence of nicotine addiction in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. 
     In some situations, a patient who has not ceased nicotine use nonetheless is unable to use nicotine for an extended amount of time. For example, most airplane flights no longer allow smoking, and have banned vaporizers and e-cigarettes, as well. Other places and situations where nicotine use is not feasible or is difficult include movie theaters, other entertainment venues (including theater, opera, concerts, and the like), and even workplaces, notably hospitals and schools where smoking may not be allowed anywhere on the property. In some embodiments, a prophylactically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered before and/or during a period of time when the patient expects to be unable to use nicotine, wherein the noribogaine, derivative, or salt prevents, interrupts, or attenuates cravings for nicotine. In some embodiments, nicotine cravings are attenuated, interrupted, or prevented for at least 2, 3, 4, 5, 6, 7, 8, 10, 15, or 24 hours. 
     In some embodiments, the noribogaine is administered on an as-needed basis by the patient. In some embodiments, the noribogaine may be administered before the nicotine craving occurs. For example, the patient may take a dose of noribogaine in anticipation of cravings, such as before drinking alcohol, before a stressful situation occurs, or when facing another trigger for nicotine use. In some embodiments, the patient takes a dose of noribogaine after the nicotine craving occurs, for example during the craving, in order to reduce or eliminate the craving. In some embodiments, the dose of noribogaine is low enough that a patient can take one dose before a craving occurs, and another later the same day if he/she feels or anticipates another craving. 
     In one embodiment, the prophylactically effective amount of the compound is from about 50 ng to less than 10 μg per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 5 μg per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 1 μg per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 500 ng to less than 10 μg per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 1 μg to less than 10 μg per kilogram body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges, including endpoints. 
     In some embodiments, the prophylactically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the prophylactically effective amount is administered twice per day. In some embodiments, the prophylactically effective amount is administered more than two times per day. 
     Where the prophylactically effective amount of noribogaine is administered more than one time per day, a portion of the total prophylactically effective amount is administered at each time. For example, an 90 kg patient taking 1 μg noribogaine per kg body weight per day would take 90 μg once a day, 45 μg twice a day, or 30 μg three times a day, etc. 
     In some embodiments, the noribogaine or noribogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled “Dosage and Routes of Administration.” 
     c. Dosage and Routes of Administration 
     The compositions, provided herein or known, suitable for administration in accordance with the methods provided herein, can be suitable for a variety of delivery modes including, without limitation, oral, transdermal, sublingual, buccal, intrapulmonary or intranasal delivery. Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used. Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington&#39;s Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980). 
     Noribogaine or a noribogaine derivative can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer&#39;s solution, etc. 
     The compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal administration. The compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient may be provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), (for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide or other suitable gases. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine. In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler. 
     The compositions utilized herein may be formulated for sublingual administration, for example as sublingual tablets. Sublingual tablets are designed to dissolve very rapidly. The formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol. 
     It has been discovered that noribogaine has a bitter taste to at least some patients. Accordingly, compositions for oral use (including sublingual, inhaled, and other oral formulations) may be formulated to utilize taste-masking technologies. A number of ways to mask the taste of bitter drugs are known in the art, including addition of sugars, flavors, sweeteners, or coatings; use of lipoproteins, vesicles, and/or liposomes; granulation; microencapsulation; numbing of taste buds; multiple emulsion; modification of viscosity; prodrug or salt formation; inclusion or molecular complexes; ion exchange resins; and solid dispersion. Any method of masking the bitterness of the compound of the invention may be used. 
     Other embodiments are included in the Appendix hereto, which is incorporated herein by reference. 
     Patient Pre-Screening and Monitoring 
     Pre-screening of patients before treatment with noribogaine and/or monitoring of patients during noribogaine, noribogaine derivative, or pharmaceutically acceptable sald and/or solvate thereof treatment may be required to ensure that QT interval is not prolonged beyond a certain value. For example, QT interval greater than about 500 ms can be considered dangerous for individual patients. Pre-screening and/or monitoring may be necessary at high levels of noribogaine treatment. 
     In a preferred embodiment, a patient receiving a therapeutic dose of noribogaine is monitored in a clinical setting. Monitoring may be necessary to ensure the QT interval is not prolonged to an unacceptable degree. A “clinical setting” refers to an inpatient setting (e.g., inpatient clinic, hospital, rehabilitation facility) or an outpatient setting with frequent, regular monitoring (e.g., outpatient clinic that is visited daily to receive dose and monitoring). Monitoring includes monitoring of QT interval. Methods for monitoring of QT interval are well-known in the art, for example by ECG. 
     In one embodiment, a patient receiving a maintenance dose of noribogaine is not monitored in a clinical setting. In one embodiment, a patient receiving a maintenance dose of noribogaine is monitored periodically, for example daily, weekly, monthly, or occasionally. 
     In one aspect, this invention relates to a method for treating, preventing, or attenuating a disease or disorder or symptoms of a disease or disorder described herein who is prescreened to evaluate the patient&#39;s expected tolerance for prolongation of QT interval, administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse or symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 420 ms during treatment. 
     In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 450 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 420 ms. In one embodiment, prescreening comprises determining the patient&#39;s pre-treatment QT interval. 
     As it relates to pre-screening or pre-selection of patients, patients may be selected based on any criteria as determined by the skilled clinician. Such criteria may include, by way of non-limiting example, pre-treatment QT interval, pre-existing cardiac conditions, risk of cardiac conditions, age, sex, general health, and the like. The following are examples of selection criteria for disallowing noribogaine treatment or restricting dose of noribogaine administered to the patient: high QT interval before treatment (e.g., such that there is a risk of the patient&#39;s QT interval exceeding about 500 ms during treatment); congenital long QT syndrome; bradycardia; hypokalemia or hypomagnesemia; recent acute myocardial infarction; uncompensated heart failure; and taking other drugs that increase QT interval. In some embodiments, the methods can include selecting and/or administering/providing noribogaine to a patient that lacks one more of such criteria. 
     In one embodiment, this invention relates to pre-screening a patient to determine if the patient is at risk for prolongation of the QT interval beyond a safe level. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is not administered noribogaine. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is administered noribogaine at a limited dosage. 
     In one embodiment, this invention relates to monitoring a patient who is administered a therapeutic dose of noribogaine. In one embodiment, the dose of noribogaine is reduced if the patient has serious adverse side effects. In one embodiment, the noribogaine treatment is discontinued if the patient has serious adverse side effects. In one embodiment, the adverse side effect is a QT interval that is prolonged beyond a safe level. The determination of a safe level of prolongation is within the skill of a qualified clinician. 
     Kit of Parts 
     One aspect of this invention is directed to a kit of parts for the treatment, prevention, or attenuation of a disease or disorder or symptoms of a disease or disorder described herein, wherein the kit comprises a composition comprising noribogaine, noribogaine derivative, or salt or solvate thereof and a means for administering the composition to a patient in need thereof. The means for administration to a patient can include, for example, any one or combination of noribogaine, or a noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, a transdermal patch, a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, an inhaler comprising the composition, etc. In one embodiment, the kit of parts further comprises instructions for dosing and/or administration of the composition. 
     In some aspects, the invention is directed to a kit of parts for administration of noribogaine, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of noribogaine and further wherein each delivery vehicle is identified by the amount of noribogaine provided therein; and optionally further comprising a dosing treatment schedule in a readable medium. In some embodiments, the dosing treatment schedule includes the amount of noribogaine required to achieve each average serum level is provided. In some embodiments, the kit of parts includes a dosing treatment schedule that provides an attending clinician the ability to select a dosing regimen of noribogaine based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve. In some embodiments, the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight (or mass) and sex of the patient. In an embodiment, the storage medium can include an accompanying pamphlet or similar written information that accompanies the unit dose form in the kit. In an embodiment, the storage medium can include electronic, optical, or other data storage, such as a non-volatile memory, for example, to store a digitally-encoded machine-readable representation of such information. 
     The term “delivery vehicle” as used herein refers to any formulation that can be used for administration of noribogaine to a patient. Non-limiting, exemplary delivery vehicles include caplets, pills, capsules, tablets, powder, liquid, or any other form by which the drug can be administered. Delivery vehicles may be intended for administration by oral, inhaled, injected, or any other means. 
     The term “readable medium” as used herein refers to a representation of data that can be read, for example, by a human or by a machine. Non-limiting examples of human-readable formats include pamphlets, inserts, or other written forms. Non-limiting examples of machine-readable formats include any mechanism that provides (i.e., stores and/or transmits) information in a form readable by a machine (e.g., a computer, tablet, and/or smartphone). For example, a machine-readable medium includes read-only memory (ROM); random access memory (RAM); magnetic disk storage media; optical storage media; and flash memory devices. In one embodiment, the machine-readable medium is a CD-ROM. In one embodiment, the machine-readable medium is a USB drive. In one embodiment, the machine-readable medium is a Quick Response Code (QR Code) or other matrix barcode. 
     In some aspects, the machine-readable medium comprises software that contains information regarding dosing schedules for the unit dose form of noribogaine and optionally other drug information. In some embodiments, the software may be interactive, such that the attending clinician or other medical professional can enter patient information. In a non-limiting example, the medical professional may enter the weight and sex of the patient to be treated, and the software program provides a recommended dosing regimen based on the information entered. The amount and timing of noribogaine recommended to be delivered will be within the dosages that result in the serum concentrations as provided herein. 
     In some embodiments, the kit of parts comprises multiple delivery vehicles in a variety of dosing options. For example, the kit of parts may comprise pills or tablets in multiple dosages, such as 240 mg, 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, 10 mg, and/or 5 mg of noribogaine per pill. Each pill is labeled such that the medical professional and/or patient can easily distinguish different dosages. Labeling may be based on printing or embossing on the pill, shape of the pill, color of pill, the location of the pill in a separate, labeled compartment within the kit, and/or any other distinguishing features of the pill. In some embodiments, all of the delivery vehicles within a kit are intended for one patient. In some embodiments, the delivery vehicles within a kit are intended for multiple patients. 
     One aspect of this invention is directed to a kit of parts for the treatment, prevention, or attenuation of a disease or disorder or symptoms of a disease or disorder described herein, wherein the kit comprises a unit dose form of noribogaine, noribogaine derivative, or salt or solvate thereof. The unit dose form provides a patient with an average serum level of noribogaine of from about 50 ng/mL to about 180 ng/mL or about 60 ng/mL to about 180 ng/mL. 
     In some embodiments, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 20 mg to 120 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 80 mg. In one embodiment, the unit dose is 90 mg. In one embodiment, the unit dose is 100 mg. In one embodiment, the unit dose is 110 mg. In one embodiment, the unit dose is 120 mg. 
     In one aspect, provided herein is a kit of parts comprising two or more doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the two or more doses comprise an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that is sufficient to maintain a serum concentration of 50 ng/mL to 180 ng/mL when administered to a patient. 
     In one embodiment, one dose comprises an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, said initial dose being sufficient to achieve a therapeutic serum concentration when administered to a patient; and at least one additional dose, said additional dose sufficient to maintain a therapeutic serum concentration when administered to a patient, wherein the therapeutic serum concentration is between 50 ng/mL and 180 ng/mL In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. 
     In some embodiments, the unit dose form comprises one or multiple dosages to be administered periodically, such as once, twice, three times, four times or five times daily with noribogaine or its prodrug. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician. 
     These dose ranges may be achieved by transdermal, oral, or parenteral administration of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof in unit dose form. Such unit dose form may conveniently be provided in transdermal patch, tablet, caplet, liquid or capsule form. In certain embodiments, the noribogaine is provided as noribogaine HCl, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HCl is provided in hard gelatin capsules containing only noribogaine HCl with no excipients. In some embodiments, noribogaine is provided in saline for intravenous administration. 
     Formulations 
     This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the amount of noribogaine is sufficient to provide an average serum concentration of about 50 ng/mL to about 180 ng/mL when administered to a patient. In a preferred embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of about 80 ng/mL to about 100 ng/mL when administered to a patient. In one embodiment, the amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 10 μg per kg body weight per day. 
     In some embodiments, the unit dose of noribogaine is administered in one or more dosings. 
     This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the amount of noribogaine is sufficient to provide and/or maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL when administered to a patient. In a preferred embodiment, the amount of noribogaine is sufficient to provide and/or maintain an average serum concentration of 80 ng/mL to 100 ng/mLwhen administered to a patient. 
     In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 80 ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 80 ng/mL to 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 80 ng/mL to about 100 ng/mL.The ranges include both extremes as well as any subranges between. 
     In some embodiments, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg. In one embodiment, the unit dose is about 20 mg. In one embodiment, the unit dose is about 30 mg. In one embodiment, the unit dose is about 40 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 60 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 120 mg. 
     In some embodiments, the at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 5 mg to 75 mg. In one embodiment, the unit dose is 5 mg. In one embodiment, the unit dose is 10 mg. In one embodiment, the unit dose is 15 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 25 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 35 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 45 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 55 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 65 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 75 mg. 
     In some embodiments, the formulation is a controlled release formulation. The term “controlled release formulation” includes sustained release and time-release formulations. Controlled release formulations are well-known in the art. These include excipients that allow for sustained, periodic, pulse, or delayed release of the drug. Controlled release formulations include, without limitation, embedding of the drug into a matrix; enteric coatings; micro-encapsulation; gels and hydrogels; implants; transdermal patches; and any other formulation that allows for controlled release of a drug. 
     In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 80 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between. 
     In some embodiments, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg. In one embodiment, the unit dose is about 20 mg. In one embodiment, the unit dose is about 30 mg. In one embodiment, the unit dose is about 40 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 60 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 120 mg. 
     In some embodiments, the formulation is designed for periodic administration, such as once, twice, three time, four times or five time daily with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician. 
     In some embodiments, the formulation designed for administration in accordance with the methods provide herein can be suitable for a variety of delivery modes including, without limitation, oral,transdermal, sublingual, buccal, intrapulmonary or intranasal delivery. Formulations suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All formulations may be prepared using methods that are standard in the art (see e.g., Remington&#39;s Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980). 
     In a preferred embodiment, the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. In certain embodiments, the noribogaine is provided as noribogaine HCl, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HCl is provided in hard gelatin capsules containing only noribogaine HCl with no excipients. 
     Noribogaine or a noribogaine derivative can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer&#39;s solution, etc. 
     The compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal administration. The compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient may be provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), (for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide or other suitable gases. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine. In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler. 
     The compositions utilized herein may be formulated for sublingual administration, for example as sublingual tablets. Sublingual tablets are designed to dissolve very rapidly. The formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol. 
     It has been discovered that noribogaine has a bitter taste to at least some patients. Accordingly, compositions for oral use (including sublingual, inhaled, and other oral formulations) may be formulated to utilize taste-masking technologies. A number of ways to mask the taste of bitter drugs are known in the art, including addition of sugars, flavors, sweeteners, or coatings; use of lipoproteins, vesicles, and/or liposomes; granulation; microencapsulation; numbing of taste buds; multiple emulsion; modification of viscosity; prodrug or salt formation; inclusion or molecular complexes; ion exchange resins; and solid dispersion. Any method of masking the bitterness of the compound of the invention may be used. 
     EXAMPLES 
     Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. 
     The following Examples are intended to further illustrate certain embodiments of the disclosure and are not intended to limit its scope. 
     Example 1 
     Pharmacokinetics and Pharmacodynamics of Noribogaine in Humans 
     Thirty-six healthy, drug-free male volunteers, aged between 18-55 years, were enrolled in and completed the study. This was an ascending single-dose, placebo-controlled, randomized double blind, parallel group study. Mean (SD) age was 22.0 (3.3) years, mean (SD) height was 1.82 (0.08) m, and mean (SD) weight was 78.0 (9.2) kg. Twenty-six subjects were Caucasian, 3 were Asian, 1 Maori, 1 Pacific Islander, and 5 Other. The protocol for this study was approved by the Lower South Regional Ethics Committee (LRS/12/06/015), and the study was registered with the Australian New Zealand Clinical Trial Registry (ACTRN12612000821897). All subjects provided signed informed consent prior to enrolment, and were assessed as suitable to participate based on review of medical history, physical examination, safety laboratory tests, vital signs and ECG. 
     Within each dose level, 6 participants were randomized to receive noribogaine and 3 to receive placebo, based on a computer-generated random code. Dosing began with the lowest noribogaine dose, and subsequent cohorts received the next highest dose after the safety, tolerability, and blinded pharmacokinetics of the completed cohort were reviewed and dose-escalation approved by an independent Data Safety Monitoring Board. Blinded study drug was administered as a capsule with 240 ml of water after an overnight fast of at least 10 hours. Participants did not receive any food until at least 5 hours post-dose. Participants were confined to the study site from 12 hours prior to drug administration, until 72 hours post-dose, and there were subsequent outpatient assessments until 216 hours post-dose. 
     Blood was obtained for pharmacokinetic assessments pre-dose and then at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 18, 24, 30, 36, 48, 60, 72, 96, 120, 168 and 216 hours post-dose. Samples were centrifuged and plasma stored at −70° C. until analyzed. Block 24 hour urine collections were obtained following study drug administration for the 30 and 60 mg cohorts. Aliquots were frozen at −20° C. until analyzed. 
     Pulse oximetry and capnography data were collected continuously using a GE Carescape B650 monitoring system from 2 hours prior to dosing and until six hours after dosing, and thereafter at 12, 24, 48 and 72 hours post-dosing. Additional oximetry data were collected at 120, 168 and 216 hours. Pupillary miosis was assessed by pupillometry. Dark-adapted pupil diameter was measured in triplicate using a Neuroptics PLR-200 pupillometer under standardized light intensity (&lt;5 lux) pre-dose, and at 2, 4, 6, 12, 24, 48, 72, 96, 120, 168 and 216 hours post-dosing. 
     Plasma noribogaine concentrations were determined in the 3 mg and 10 mg dose groups using a validated, sensitive LCMSMS method. Sample preparation involved double extraction of basified plasma samples with tert-butyl methyl ether, drying the samples under a stream of nitrogen and reconstitution of sample with acetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid. The compounds were separated by a 150×2.0 mm Luna 5 μm C18 column and detected with a triple—quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d 4  was used as the internal standard. The precursor-product ion transition values for noribogaine were m/z 297.6 −&gt;122.3, and for the internal standard noribogaine-d 4  m/z 301.1 −&gt;122.2. Analyst® software was used for data acquisition and processing. The ratio of the peak area of noribogaine to the internal standard noribogaine-d 4  was used for calibration and measurement of the unknown concentration of noribogaine. The lower limit of quantification (LLOQ) was 0.025 ng/ml noribogaine. The calibration curve was between 0.025 and 25.600 ng/ml noribogaine. Mobile phase A was acetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid, and mobile phase B was acetonitrile:B.P. water (95:5, v/v) containing 0.1% (v/v) formic acid. Total run time was 6 minutes. Binary flow: Initial concentration was 8% mobile phase B; hold at 8% mobile phase B for 0.5 minutes and linear rise to 90% mobile phase B over 1.5 minutes; hold at 90% mobile phase B for 1 minute and then drop back to 8% mobile phase B over 0.01 minute. Equilibrate system for 3 minutes. Total run time was 6 minutes. Within- and between-day assay precision was &lt;9%, and within- and between-day assay accuracy was &lt;9%. 
     Plasma noribogaine concentrations were determined in the 30 mg and 60 mg dose groups using a validated, sensitive LCMSMS method. Sample preparation involved deproteinization of plasma samples with acetonitrile and dilution of sample with 0.1% (v/v) formic acid. The compounds were separated by a 150×2.0 mm Luna 5 μm C18 column and detected with a triple—quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d 4  was used as the internal standard. The precursor-product ion transition values for noribogaine were m/z 297.6 −&gt;122.3, and for the internal standard noribogaine-d 4  m/z 301.1 −&gt;122.2. Analyst® software was used for data acquisition and processing. The ratio of the peak area of noribogaine to the internal standard noribogaine-d 4  was used for calibration and measurement of the unknown concentration of noribogaine. The LLOQ was 0.50 ng/ml noribogaine. The calibration curve was between 0.50 and 256.00 ng/ml noribogaine. Mobile phase was the same as method A, and binary flow was also the same as method A. The within- and between-day assay precision was &lt;9%, and the within- and between-day assay accuracy was &lt;9%. 
     Plasma noribogaine glucuronide concentrations were determined in the 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method. Sample preparation involved deproteinization of plasma samples with acetonitrile, drying the samples under a stream of nitrogen and reconstitution of sample with acetonitrile: B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid. The compounds were separated by a 150×2.0 mm Luna 5 μm C18 column and detected with a triple—quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d 4  was used as the internal standard. The precursor-product ion transition values for noribogaine glucuronide were m/z 472.8 −&gt;297.3, and for the internal standard noribogaine-d 4  m/z 301.1 −&gt;122.2. Analyst® software was used for data acquisition and processing. The ratio of the peak area of noribogaine glucuronide to the internal standard noribogaine-d 4  was used for calibration and measurement of the unknown concentration of noribogaine glucuronide. The LLOQ was 0.050 ng/ml noribogaine glucuronide. The calibration curve was between 0.050 and 6.400 ng/ml noribogaine glucuronide. Mobile phases was the same as method A. Binary flow: Initial concentration was 6% mobile phase B; hold at 6% mobile phase B for 0.5 minutes and linear rise to 90% mobile phase B over 2 minutes; hold at 90% mobile phase B for 1 minute and then drop back to 6% mobile phase B over 0.01 minute. Equilibrate system for 3.5 minutes. Total run time was 7 minutes. The within- and between-day assay precision was &lt;11%, and the within- and between-day assay accuracy was &lt;10%. 
     Urine noribogaine and noribogaine glucuronide concentrations were determined in the 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method. Sample preparation involved deproteinization of urine samples with acetonitrile and dilution of the sample with 0.1% (v/v) formic acid. The compounds were separated by a 150×2.0 mm Luna 5 μm C18 column and detected with a triple—quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d 4  was used as the internal standard. The precursor-product ion transition values for noribogaine were m/z 297.6 −&gt;122.3, noribogaine glucuronide m/z 472.8 −&gt;297.3, and for the internal standard noribogaine-d 4  m/z 301.1 −&gt;122.2. Analyst® software was used for data acquisition and processing. The ratios of the peak area of noribogaine and noribogaine glucuronide to the internal standard noribogaine-d 4  were used for calibration and measurement of the unknown concentration of noribogaine and its glucuronide. Assay LLOQ was 20.0 ng/ml for noribogaine and 2.0 ng/ml for noribogaine glucuronide. The calibration curve was between 20.0 and 5120.0 ng/ml noribogaine, and 2.0 and 512.0 ng/ml noribogaine glucuronide. Mobile phases were as described in method A, and binary flow as in method C. The within- and between-day assay precision was &lt;13%, and within- and between-day assay accuracy was &lt;12%. 
     Noribogaine and noribogaine glucuronide concentrations above the limit of quantification were used to calculate pharmacokinetic parameters using model-independent methods. The maximum plasma concentration (Cmax) and time to maximum plasma concentration (Tmax) were the observed values. Plasma concentration data in the post-distribution phase of the plasma concentration-time plot were fitted using linear regression to the formula ln C=ln Co−t.Kel, where Co was the zero-time intercept of the extrapolated terminal phase and Kel was the terminal elimination rate constant. The half-life (t 1/2 ) was determined using the formula t 1/2 =0.693/Kel. The area under the concentration-time curve (AUC) from time zero to the last determined concentration-time point (tf) in the post distribution phase was calculated using the trapezoidal rule. The area under the curve from the last concentration-time point in the post distribution phase (Ctf) to time infinity was calculated from AUC t-∞ =Ctf/Kel. The concentration used for Ctf was the last determined value above the LLOQ at the time point. The total AUC 0-∞ was obtained by adding AUC tf  and AUC t-∞ . Noribogaine apparent clearance (CL/F) was determined using the formula CL/F=Dose/AUC 0-∞ ×1000, and apparent volume of distribution (Vd/F) was determined using the formula Vd/F=(CL/F)/Kel. Total urine noribogaine was the sum of both analytes. 
     Summary statistics (means, standard deviations, and coefficients of variation) were determined for each dose group for safety laboratory test data, ECG and pharmacokinetic parameters, and pharmacodynamic variables. Categorical variables were analysed using counts and percentages. Dose-proportionality of AUC and Cmax was assessed using linear regression. The effect of dose on pharmacodynamic parameter values over time was assessed using two-factor analysis of variance (ANOVA). Pairwise comparisons (with Tukey-Kramer adjustment) between each dose group to the placebo were conducted at each time point using the least squares estimates obtained from the ANOVA, using SAS Proc Mixed (SAS ver 6.0). 
     Results 
     Pharmacokinetics: Mean plasma concentration-time plots of noribogaine are shown in  FIG. 1 , and mean pharmacokinetic parameters are shown in Table 1. 

 
     Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing. Fluctuations in individual distribution-phase concentration-time profiles may suggest the possibility of enterohepatic recirculation (see highlighted individual 4-8 hour profiles in  FIG. 1 , insert). Both Cmax and AUC increased linearly with dose (Table 1, upper panel). Mean half-life estimates of 28-50 hours were observed across dose groups for noribogaine. Volume of distribution was extensive (1417-3086 L across dose groups). 
     Mean plasma noribogaine glucuronide concentration-time plots for the 30 mg and 60 mg dose group are shown in  FIG. 2 , and mean pharmacokinetic parameters are shown in Table 1, lower panel. Noribogaine glucuronide was detected in all subjects by 0.75 hours, with peak concentrations occurring 3-4 hours after noribogaine dosing. Mean half-life of 21-23 hours was estimated for plasma noribogaine glucuronide. The proportion of noribogaine glucuronide Cmax and AUC relative to noribogaine was 3-4% for both dose groups. Total urine noribogaine elimination was 1.16 mg and 0.82 mg for the 30 mg and 60 mg dose groups respectively, representing 3.9% and 1.4% of the doses administered. 
     The subject mean serum levels over time of noribogaine free base from a single dose of 3 mg noribogaine free base under fasting conditions were plotted. The mean C max  of 5.2 ng/ml was observed 1.9 hours after administration, while the mean AUC/24 hr of 3.1 ng/ml was obtained. 
     The subject mean serum levels over time of noribogaine free base from a single dose of 10 mg noribogaine free base under fasting conditions were plotted. The mean C max  of 14.5 ng/ml was observed 2.9 hours after administration, while the mean AUC/24 hr of 10.6 ng/ml was obtained. 
     The subject mean serum levels over time of noribogaine free base from a single dose of 30 mg noribogaine free base under fasting conditions were plotted. The mean C max  of 55.9 ng/ml was observed between 1.75 hours after administration, while the mean AUC/24 of 29.2 ng/ml was obtained. 
     The subject mean serum levels over time of noribogaine free base from a single dose of 60 mg noribogaine free base under fasting conditions were plotted. The mean C max  of 116 ng/ml was observed between 1.75 hours after administration, while the mean AUC/24 ng/ml of 61 was obtained. 
     The subject mean serum levels over time of noribogaine free base for all 4 cohorts were plotted. The extrapolated dosage of noribogaine free base required to provide a C max  ranging from about 5.2 ng/ml to about 1980 ng/ml and an AUC/24 hr of about 3.1 ng/ml to about 1100 ng/ml was determined. 
     Pharmacodynamics: There was no evidence of pupillary constriction in subjects dosed with noribogaine. No between-dose group differences in pupil diameter were detected over time. After adjusting for baseline differences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p&gt;0.9). 
     Noribogaine treatment showed no analgesic effect in the cold pressor test. Analgesic effect was assessed based on duration of hand immersion in ice water and on visual analog scale (VAS) pain scores upon hand removal from the water bath. For duration of hand immersion, after adjusting for baseline differences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p&gt;0.9). Similarly, for VAS pain scores, after adjusting for baseline differences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p=0.17). 
     Example 2 
     Safety and Tolerability of Noribogaine in Healthy Humans 
     Safety and tolerability of noribogaine were tested in the group of volunteers from Example 1. Cold pressor testing was conducted in 1° C. water according to the method of Mitchell et al. ( J. Pain  5:233-237, 2004) pre-dose, 6, 24, 48, 72 and 216 hours post-dosing. Safety evaluations included clinical monitoring, recording of adverse events (AEs), safety laboratory tests, vital signs, ECG telemetry from −2 h to 6 h after dosing, and 12-lead electrocardiograms (ECGs) up to 216 hours post-dosing. 
     Results 
     A total of thirteen adverse events were reported by seven participants (Table 2). Six adverse events were reported by three participants in the placebo group, five adverse events were reported by two subjects in the 3 mg dose group, and one adverse event was reported by single subjects in the 10 mg and 30 mg dose groups, respectively. The most common adverse events were headache (four reports) and epistaxis (two reports). All adverse events were of mild-moderate intensity, and all resolved prior to study completion. There were no changes in vital signs or safety laboratory tests of note. In particular, there were no changes in oximetry or capnography, or changes in respiratory rate. There were no QTcF values &gt;500 msec at any time. One subject dosed with 10 mg noribogaine had a single increase in QTcF of &gt;60 msec at 24 hours post-dosing. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Dose 
                   
                   
                   
               
               
                 (mg) 
                 Mild 
                 Moderate 
                 Severe 
               
               
                   
               
             
            
               
                 Placebo 
                 Blepharitis 
                 Epistaxis 
                 — 
               
               
                   
                 Bruising 
                   
                   
               
               
                   
                 Dry Skin 
                   
                   
               
               
                   
                 Eye pain, nonspecific 
                   
                   
               
               
                   
                 Infection at cannula site 
                   
                   
               
               
                 3 
                 Back pain 
                 Headache 
                 — 
               
               
                   
                 Dizziness 
                   
                   
               
               
                   
                 Epistaxis 
                   
                   
               
               
                   
                 Headache 
                   
                   
               
               
                 10 
                 Headache 
                 — 
                 — 
               
               
                 30 
                 Headache 
                 — 
                 — 
               
               
                 60 
                 — 
                 — 
                 — 
               
               
                   
               
            
           
         
       
     
     Example 3 
     Safety, Tolerability, and Efficacy of Noribogaine in Opioid-Addicted Humans 
     This example is to illustrate that noribogaine can be administered at a therapeutic dosing while maintaining an acceptable QT interval. While the therapy employed is directed to opioid-dependent participants in a randomized, placebo-controlled, double-blind trial, the results show that a therapeutic window can be established for noribogaine. 
     The efficacy of noribogaine in humans was evaluated in opioid-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients had been receiving methadone treatment as the opioid substitution therapy, but were transferred to morphine treatment prior to noribogaine administration. This was done to avoid negative noribogaine-methadone interactions that are not observed between noribogaine and morphine. See U.S. application Ser. No. 14/214,157, filed Mar. 14, 2014 and Ser. No. 14/346,655, filed Mar. 21, 2014, which are incorporated herein by reference in their entireties. 
     Three cohorts of nine (9) subjects (6 administered noribogaine and 3 administered placebo in each cohort) were evaluated for tolerability, pharmacokinetics, and efficacy. Cohort 1 received a single dose of 60 mg noribogaine or placebo. Cohort 2 received a single dose of 120 mg noribogaine or placebo. Cohort 3 received a single dose of 180 mg noribogaine or placebo. Treatment was administered 2 hours after last morphine dose and the time to resumption of morphine (opioid substitution treatment, OST) was determined. Few adverse effects of noribogaine were observed in any of the participants, including no hallucinatory effects. Table 3 shows the reported adverse events for each treatment that were not attributable to withdrawal from opioids. Headaches were frequent in the placebo and 60 mg noribogaine treatment groups, but were attenuated in the 120 mg and 180 mg dose groups. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Treatment Emergent Adverse Events Summary 
               
            
           
           
               
               
               
               
               
            
               
                 System Organ Class 
                 Placebo 
                 60 mg 
                 120 mg 
                 180 mg 
               
               
                 Preferred Term 
                 (N = 9) 
                 (N = 6) 
                 (N = 6) 
                 (N = 6) 
               
               
                   
               
               
                 Number of Subjects Reporting any AEs 
                 19:7 (77.8%)  
                 15:5 (83.3%)  
                 28:6 (100.0%) 
                 17:4 (66.7%)  
               
               
                 Ear and Labyrinth Disorders 
                 0 
                 0 
                 2:2 (33.3%) 
                 0 
               
               
                 Tinnitus 
                 0 
                 0 
                 2:2 (33.3%) 
                 0 
               
               
                 Eye Disorders 
                 2:2 (22.2%) 
                 3:3 (50.0%) 
                 5:5 (83.3%) 
                 5:4 (66.7%) 
               
               
                 Visual Impairment 
                 2:2 (22.2%) 
                 2:2 (33.3%) 
                 5:5 (83.3%) 
                 5:4 (66.7%) 
               
               
                 Dry Eye 
                 0 
                 1:1 (16.7%) 
                 0 
                 0 
               
               
                 Gastrointestinal Disorders 
                 3:2 (22.2%) 
                 2:2 (33.3%) 
                 7:2 (33.3%) 
                 4:2 (33.3%) 
               
               
                 Nausea 
                 1:1 (11.1%) 
                 0 
                 3:2 (33.3%) 
                 2:2 (33.3%) 
               
               
                 Dry Mouth 
                 0 
                 0 
                 1:1 (16.7%) 
                 1:1 (16.7%) 
               
               
                 Vomiting 
                 0 
                 0 
                 2:1 (16.7%) 
                 1:1 (16.7%) 
               
               
                 Diarrhoea 
                 1:1 (11.1%) 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                 Dyspepsia 
                 1:1 (11.1%) 
                 2:2 (33.3%) 
                 0 
                 0 
               
               
                 General Disorders and Administration Site Conditions 
                 4:3 (33.3%) 
                 0 
                 2:2 (33.3%) 
                 1:1 (16.7%) 
               
               
                 Catheter Site Related Reaction 
                 0 
                 0 
                 0 
                 1:1 (16.7%) 
               
               
                 Catheter Site Pain 
                 3:2 (22.2%) 
                 0 
                 2:2 (33.3%) 
                 0 
               
               
                 Malaise 
                 1:1 (11.1%) 
                 0 
                 0 
                 0 
               
               
                 Infections and Infestations 
                 1:1 (11.1%) 
                 0 
                 1:1 (16.7%) 
                 2:2 (33.3%) 
               
               
                 Cellulitis 
                 0 
                 0 
                 1:1 (16.7%) 
                 1:1 (16.7%) 
               
               
                 Urinary Tract Infection 
                 0 
                 0 
                 0 
                 1:1 (16.7%) 
               
               
                 Catheter Site Infection 
                 1:1 (11.1%) 
                 0 
                 0 
                 0 
               
               
                 Musculoskeletal and Connective Tissue Disorders 
                 1:1 (11.1%) 
                 2:1 (16.7%) 
                 0 
                 2:2 (33.3%) 
               
               
                 Back Pain 
                 1:1 (11.1%) 
                 2:1 (16.7%) 
                 0 
                 1:1 (16.7%) 
               
               
                 Limb Discomfort 
                 0 
                 0 
                 0 
                 1:1 (16.7%) 
               
               
                 Nervous System Disorders 
                 7:5 (55.6%) 
                 7:4 (66.7%) 
                 5:4 (66.7%) 
                 3:2 (33.3%) 
               
               
                 Headache 
                 6:5 (55.6%) 
                 7:4 (66.7%) 
                 2:2 (33.3%) 
                 3:2 (33.3%) 
               
               
                 Hyperaesthesia 
                 0 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                 Pseudoparalysis 
                 0 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                 Tremor 
                 0 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                 Somnoience 
                 1:1 (11.1%) 
                 0 
                 0 
                 0 
               
               
                 Psychiatric Disorders 
                 1:1 (11.1%) 
                 1:1 (16.7%) 
                 0 
                 0 
               
               
                 Depressed Mood 
                 0 
                 1:1 (16.7%) 
                 0 
                 0 
               
               
                 Euphoric Mood 
                 1:1 (11.1%) 
                 0 
                 0 
                 0 
               
               
                 Respiratory, Thoracic and Mediastinal Disorders 
                 0 
                 0 
                 4:2 (33.3%) 
                 0 
               
               
                 Epistaxis 
                 0 
                 0 
                 2:1 (16.7%) 
                 0 
               
               
                 Oropharyngeal Pain 
                 0 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                 Rhinorrhoea 
                 0 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                 Skin and Subcutaneous Tissue Disorders 
                 0 
                 0 
                 2:1 (16.7%) 
                 0 
               
               
                 Skin Discomfort 
                 0 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                 Skin Irritation 
                 0 
                 0 
                 1:1 (16.7%) 
                 0 
               
               
                   
               
               
                 Note: 
               
               
                 Within each system organ class, Preferred Terms are presented by descending incidence of descending dosages groups and then the placebo group. 
               
               
                 Note: 
               
               
                 N = number of subjects in the safety population. 
               
            
           
         
       
     
       FIG. 3  indicates the average serum noribogaine concentration over time after administration of noribogaine for each cohort (60 mg, diamonds; 120 mg, squares; or 180 mg, triangles). Further results are detailed in U.S. Provisional Patent Application No. 62/023,100 , filed Jul. 10, 2014, and titled “METHODS FOR ACUTE AND LONG-TERM TREATMENT OF DRUG ADDICTION,” which is incorporated herein by reference in its entirety. 
     Results 
     Pharmacokinetic results for each cohort are given in Table 4. Maximum serum concentration of noribogaine (Cmax) increased in a dose-dependent manner. Time to Cmax (Tmax) was similar in all three cohorts. Mean half-life of serum noribogaine was similar to that observed in healthy patients. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Pharmacokinetic results from the Patients in Phase IB Study 
               
            
           
           
               
               
               
               
            
               
                 PK  
                 Cohort 1 (60 mg) 
                 Cohort 2 (120 mg) 
                 Cohort 3 (180 mg) 
               
               
                 param- 
                 Data (mean ± SD) 
                 Data (mean ± SD) 
                 Data (mean ± SD) 
               
               
                 eter 
                 [range] 
                 [range] 
                 [range] 
               
               
                   
               
               
                 Cmax 
                 81.64 ± 23.77 
                 172.79 ± 30.73  
                 267.88 ± 46.92  
               
               
                 (ng/ml) 
                  [41.29-113.21] 
                 [138.84-229.55] 
                 [204.85-338.21] 
               
               
                 Tmax 
                 3.59 ± 0.92 
                 2.99 ± 1.23 
                 4.41 ± 1.80 
               
               
                 hours 
                 [2.50-5.00] 
                 [0.98-4.02] 
                 [3.00-8.00] 
               
               
                 AUC (0-T)   
                 2018.01 ± 613.91  
                 3226.38 ± 1544.26 
                 6523.28 ± 2909.80 
               
               
                 (ng · hr/ 
                 [1094.46-2533.44] 
                 [1559.37-5638.98] 
                  [3716.69-10353.12] 
               
               
                 ml) 
                   
                   
                   
               
               
                 AUC (0-¥)   
                 2060.31 ± 609.39  
                 3280.50 ± 1581.43 
                 6887.67 ± 3488.91 
               
               
                 (ng · hr/ 
                 [1122.29-2551.63] 
                 [1595.84-5768.52] 
                  [3734.21-12280.91] 
               
               
                 ml) 
                   
                   
                   
               
               
                 Half-life  
                 29.32 ± 7.28  
                 30.45 ± 9.14  
                 23.94 ± 5.54  
               
               
                 (hrs) 
                 [18.26-37.33] 
                 [21.85-48.33] 
                 [19.32-34.90] 
               
               
                   
                 1440.7 ± 854.0  
                 2106.43 ± 1644.54 
                 1032.19 ± 365.30  
               
               
                 Vd/F 
                  [619.5-2772.5] 
                  [824.24-5243.78] 
                  [581.18-1608.98] 
               
               
                   
                 32.14 ± 12.38 
                 44.68 ± 21.40 
                 31.47 ± 13.12 
               
               
                 Cl/F 
                 [23.51-53.46] 
                 [20.80-75.20] 
                 [14.66-48.20] 
               
               
                   
               
            
           
         
       
     
       FIG. 4  indicates the time to resumption of morphine (OST) for patients treated with placebo (circles), 60 mg noribogaine (squares), 120 mg noribogaine (triangles), and 180 mg noribogaine (inverted triangles). Patients receiving a single 120 mg dose of noribogaine exhibited an average time to resumption of opioids of greater than 20 hours. Patients receiving a single 180 mg dose of noribogaine exhibited an average time to resumption of opioids similar to that of placebo. This demonstrates that increasing the dose of noribogaine to 180 mg results in a shorter time to resumption of OST than observed in patients receiving 120 mg noribogaine. Time to resumption of OST after treatment with 180 mg was still longer than untreated patients (7 hours, not shown) or those administered 60 mg noribogaine. 
     Patients were evaluated based on the Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), and Objective Opiate Withdrawal Scale (OOWS) scoring systems over the period of time between administration of noribogaine (or placebo) until resumption of OST. These scales are outlined in Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence, World Health Organization, Geneva (2009), Annex 10, which is incorporated herein by reference in its entirety. The scales measure the intensity of withdrawal symptoms, based on clinical, subjective, and objective indicia. 
       FIG. 5  shows the COWS scores at time of resumption of OST for each cohort. Box includes values representing 25%-75% quartiles. Diamond=median; crossbar in box=mean; whiskers=values within standard deviation of mid-quartiles. No outliers present. The highly variable COWS scores across and within each cohort indicates that patients were resuming opiates without relation to the intensity of withdrawal. This was also reflected in SOWS and OOWS scores at the time of resumption of OST. 
       FIG. 6A  shows the mean change in total COWS scores over the first six hours following dosing and prior to resumption of OST.  FIG. 6B  shows the mean AUC(0-6 hours) of the COWS total score change from baseline.  FIG. 7A  shows the mean change in total OOWS scores over the first six hours following dosing and prior to resumption of OST.  FIG. 7B  shows the mean AUC(0-6 hours) of the OOWS total score change from baseline.  FIG. 8A  shows the mean change in total SOWS scores over the first six hours following dosing and prior to resumption of OST.  FIG. 8B  shows the mean AUC(0-6 hours) of the SOWS total score change from baseline. These data indicate that withdrawal symptoms get worse over time after cessation of OST, and that patients administered placebo experience generally worse withdrawal symptoms over that period. Patients who received 120 mg noribogaine generally experienced fewer withdrawal symptoms than the other patients, regardless of the scale used. Patients administered placebo generally experienced more withdrawal symptoms than patients who were administered noribogaine. 
     Patients&#39; QT intervals were evaluated at regular time points throughout the study.  FIG. 9A  shows the average change in QT interval (ΔQTcl, i.e., QT interval prolongation) over the first 24 hours post noribogaine (or placebo) administration.  FIG. 9B  shows the estimated correlation between noribogaine concentration and change in QT interval. There is a dose-dependent increase in QT interval prolongation that is correlated with the serum concentration of noribogaine. 
     Based on above data, it is believed that the therapeutic window for a single bolus dose of noribogaine is bound at the lower end by 50 mg and at the upper end by less than 180 mg. In particular, the therapeutic serum concentration in vivo appears to be between about 50 ng/mL and about 180 ng/mL. 
     Example 4 
     Effect of Noribogaine on Nicotine Dependence in Sprague-Dawley Rats Animals 
     Fourteen young adult, male Sprague-Dawley rats (300-325 g) from Harlan were used in this study. The rats underwent catheter surgery and training of nicotine self-administration. 
     Upon arrival, the rats were assigned a unique identification numbers (tail marks). Animals were housed 2-3 per cage in suspended polycarbonate rat cages with filter paper covering mesh shelf and were acclimated for up to 7 days. All rats were examined, handled, and weighed prior to initiation of the study to assure adequate health and suitability. During the course of the study, 12/12 light/dark cycles were maintained. The room temperature was 20-23° C. with a relative humidity maintained 30-70%. Water was provided ad libitum for the duration of the study. Following surgery (in 14 nicotine training rats), all rats were single housed and remained single housed throughout the duration of the study. 
     Test Compounds 
     Noribogaine (12.5, 25 and 50 mg/kg, converted to free base doses with a correction factor 1.12) was dissolved in 35% of the total required volume of 0.5% Tween 80 in 5% Dextrose. Suspension was stirred for at least 30 minutes. 1.5% methylcellulose was added to make up 65% of the total volume and the suspension was stirred again for at least 30 minutes. As a result, 12.5 mg/kg and 25 mg/kg doses were clear solutions and 50 mg/kg was a slightly cloudy suspension. 
     The mix of 0.5% Tween 80 in 5% Dextrose (35% of total volume) and 1.5% methylcellulose solution (65% of total volume) was used as compound vehicle treatment. 
     Vehicle and noribogaine were administered orally 2 hours prior to test at a dose volume of 5 ml/kg. 
     Varenicline (1.7 mg/kg) was dissolved in saline (0.9% NaCl) and administered intraperitoneal 30 minutes prior to test. Dose volume of varenicline was 1 ml/kg. The formulation of varenicline (1.7 mg/kg) was a clear solution. 
     Nicotine Self-Administration Test 
     Apparatus: Intravenous drug self-administration and tests took place in experimental chambers within sound-attenuating cubicles equipped with an exhaust fan (Med Associates, VT). Each chamber contained two response levers situated on one wall of the chamber. A stimulus light was located above each lever and a house light is located at the top of opposite wall. An infusion pump mounted above each chamber delivered drug solution via Tygon tubing connected to a single channel fluid swivel, which was mounted on a balance arm above the operant chamber. The output of the liquid swivel was attached to the external terminus of the intravenous catheter. 
     Food Training and Surgery: Prior to intravenous catheterization, animals were trained to lever press for food. After acquiring the lever-press response rats were prepared with intravenous catheters. One week later, rats were allowed to self-administer nicotine solution (0.03 mg in 0.1 ml over a 0.8 second period under a fix-ratio 3 (FR3)) by pressing the previously food-paired lever in return for delivery of the drug solution. In present study, 4 weeks of operant training was needed to obtain stable nicotine infusion (defined as no less than 6 infusions and less than 20% variation in the mean number of reinforcers earned in 1-hour training over 3 consecutive days). 
     Self-administration Procedures: Animals were first trained to respond for nicotine (0.03 mg/kg/infusion) under a FR3, time-out 20 seconds schedule of reinforcement. After the completion of training and the establishment of stable baselines, the effects of noribogaine were assessed. Noribogaine or the reference compound varenicline (a nicotinic acetylcholine receptor partial agonist) were only administered when the animals exhibited responding at baseline levels (i.e. no less than 6 infusions and less than 20% variation in the mean number of reinforcers earned in 1-hour training over last three consecutive non-drug test days). Compound testing was performed on Wednesdays and Fridays, assuming baseline levels of self-administration behavior on Tuesdays and Thursdays. 
     Study Design and Data Analysis 
     A within-subject design in which each rat received all treatments was applied with a Latin square test schedule. The six treatments which were blind to the experimenter were: 
     1. Saline 
     2. Varenicline 1.7 mg/kg 
     3. Vehicle (35% of 0.5% Tween-80 in 5% Dextrose and 65% of 1.5% methylcellulose) 
     4. Noribogaine 12.5 mg/kg 
     5. Noribogaine 25 mg/kg 
     6. Noribogaine 50 mg/kg 
     The data of nicotine infusions obtained during test sessions were analyzed via repeated measure ANOVA followed by Fisher LSD post hoc comparisons where appropriate. Percentage of inactive lever presses were also analyzed with repeated measure ANOVA for non-specific behavioral effects. An effect is considered significant if P&lt;0.05. Data are represented as the mean and standard error to the mean (s.e.m.). Statistical outliers falling beyond mean +/−(2× standard deviation) are removed from the analysis. With this criterion, 0-2 outliers were eliminated in different measures. 
     Results 
     The effects of noribogaine and varenicline on nicotine infusion are shown in  FIG. 10A . Repeated measure ANOVA found a significant main effect of treatment [F(5,58)=29.708, P&lt;0.001]. Post hoc comparisons indicated that varenicline and noribogaine at both 25 and 50 mg/kg significantly depressed nicotine infusion (Ps&lt;0.001). A trend of depression of nicotine infusions was also found at 12.5 mg/kg dose (P&lt;0.10). Data represent mean+s.e.m. 
     The effects of noribogaine and varenicline on inactive lever press during nicotine self-administration are shown in  FIG. 10B . Repeated measure ANOVA found no significant main effect of treatment. [F(5,54)=0.356, P&gt;0.05]. These results suggest that the effects of the test compounds on lever-pressing for nicotine infusion was not compromised by nonspecific inactive lever pressing. 
     Example 5 
     Effect of Noribogaine on Nicotine Withdrawal in Zebrafish Expressed by Anxiety-Related Endpoints 
     Animals 
     A total of 60 adult wild type short-fin zebrafish (50:50 male:female ratio) were used in this study. Fish were housed in groups of 20-30 fish per 40-L tank. Tanks were filled with filtered water and maintained at 25° C. Illumination (1000-1100 1×) was provided by ceiling-mounted fluorescent lights on a 12-h cycle (on: 6.00 h, off: 18.00 h) according to the standards of zebrafish care. All fish used in this study were experimentally naïve and fed Tetramin Tropical Flakes (Tetra USA, Blacksburg, Va.) twice a day. Following behavioral testing, the animals were euthanized in 500 mg/L Tricaine (Sigma-Aldrich, St. Louis, Mo.) buffered to pH=7.0. Animal experimentation in this study fully adhered to national and institutional guidelines and regulations. 
     Test Compounds 
     A 1 mg/L dose of noribogaine (DMX1) was chosen based on pilot experiments and literature reports on effective doses other similar compounds. A pilot experiment revealed sub-maximal efficacy of noribogaine at 1 mg/L, a dose that did not promote any locomotors effects susceptible to be confounded with efficacy endpoints of interest in other protocols. A standard 20-min pre-treatment time was chosen based on experience with a wide range of other neuroactive compounds and the results of pilot studies. This exposure time was also sufficient for provoking physiological (e.g., cortisol and c-fos) responses of zebrafish to multiple drugs. Drug exposure in this study was performed by submerging individual zebrafish in a 1-L plastic beaker for 20 min prior to the testing. The solution was regularly changed after each exposure, to ensure that each fish is exposed to a consistent concentration of noribogaine. Control fish were exposed to noribogaine-free water for the same treatment time, as described above. 
     Tests and Procedures 
     Apparatus: Behavioral testing was performed between 11:00 and 15:00 h using tanks with water adjusted to the holding room temperature (25° C.). The study used the novel tank test (NTT) protocol. NTT represents one of the most commonly used neurophenotyping tests for adult zebrafish. To avoid the test battery or handling effects, each assay was performed once, on a separate individual naive fish each time. Prior to testing, fish were pre-exposed individually in a 1-L plastic beaker for 20 min to either drug-treated or drug-free water. During testing, zebrafish behavior was recorded by two trained observers blind to the treatments, who manually scored different behavioral endpoints (inter- and intra-rater reliability in all experiments &gt;0.85) with subsequent automated analysis of generated traces by Ethovision XT8.5 software (Noldus IT, Wageningen, Netherlands). The NTT, used to assess zebrafish anxiety and locomotion, was a 1.5-L trapezoidal tank (15 cm height×28 cm top×23 cm bottom×7 cm width; Aquatic Habitats, Apopka, Fla.) maximally filled with water and divided into two equal virtual horizontal portions by a line marking the outside walls. Fish were individually pre-exposed to water (water control), chronic nicotine (1 mg/L), repeated withdrawal from chronic nicotine (WD), and repeated withdrawal plus noribogaine (1 mg/L) for 20 min and tested in the standard 5-min NTT. 
     Behavioral analyses: Zebrafish behavior was recorded by trained observers, scoring the latency to reach the top half of the tank(s), time spent in top(s), number of transitions to top, as well as the number and duration(s) of freezing bouts. Freezing was defined as a total absence of movement, except for the gills and eyes, for &gt;2 s. Trials were also recorded to a computer using a USB webcam (2.0-megapixel, Gigaware, UK) and subsequently analyzed by Ethovision XT8.5, assessing distance traveled (m), velocity (m/s), and meandering endpoints. During manual observation, videos were recorded in MPEG1 format with the maximum sample rate 30 fps for each trial by auto-focusing 2.0 MP USB webcams, placed 25 cm in front of the tanks, and attached to laptop computers. Recorded videos were analyzed with Ethovision XT8.5 software. All environments were calibrated for each arena and the calibration axes were placed to designate the origin (0,0) at the center of each tank. The exported traces were independently evaluated on a consensus basis by two trained observers blinded to the treatments, to illustrate the spatial pattern of zebrafish swimming. 
     Study Design and Data Analysis: The study exposed adult zebrafish individually (15 animals per group) to water control, chronic nicotine, repeated nicotine withdrawal, and nicotine withdrawal +1 mg/L noribogaine acutely (for 20 min) by water immersion, following testing in NTT for 5 min, prior to euthanizing the fish. Raw data from manual and automatic endpoints were analyzed using GraphPad Prism to generate graphics and descriptive statistics, for manual and computer-generated endpoints. D&#39;Agostino &amp; Pearson omnibus normality K2 test was performed on data groups . When control group passed normality test, data groups were analyzed by the Bennett&#39;s test or Boniferroni all paired-wise comparisons test (ANOVA). When data were not following Gaussian distribution or were non-suitable for previously described statistical approach, sub-grouping and/or ranking was performed, data were treated in a differential manner to allow sub-groups and/or categorical comparison. The accepted value for significance was P&lt;0.05 and higher significance was indicated where it applied. For illustration purposes, data analyzed by parametric statistics were represented as mean±SEM, while non-parametric data were represented as scattered points or categorical sub-grouping. 
     Results 
     The effects of noribogaine on zebrafish behavior are shown in  FIG. 11 , panels A-G, and  FIG. 12 , panels A-G. Zebrafish in the chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups showed increased latency to top(s), while zebrafish in the withdrawal +1 mg/L noribogaine (Nic WD-DMX1) group showed a statistically significant decrease.  FIG. 11 , panel A. Zebrafish in the chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups also showed decreased transitions to top, while zebrafish in the withdrawal +1 mg/L noribogaine (Nic WD-DMX1) group showed a statistically significant increase.  FIG. 11 , panel B. In addition, zebrafish in the chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups exhibited normal habituation patterns, while zebrafish in the withdrawal +1 mg/L noribogaine (Nic WD-DMX1) group reached values equivalent to the control group at 5 minutes.  FIG. 11 , panel C. Statistically significant increases in the duration of time spent in the top(s) portion of the tank was exhibited by zebrafish in the withdrawal +1 mg/L noribogaine (Nic WD-DMX1) group as compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups.  FIG. 11 , panel D. Furthermore, zebrafish in the withdrawal +1 mg/L noribogaine (Nic WD-DMX1) group exhibited statistically significant increases in the duration of time spent in and average entry duration in the top(s) portion of the tank as compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups.  FIG. 11 , panels E and F. Fish treated with noribogaine spent an average of more time in each of their travels to the top, suggesting a likely anxiolytic-like effect of noribogaine. Fish treated with noribogaine also exhibited an increased average entry duration as compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups.  FIG. 11 , panel G. 
     Total distance traveled in the tank was measured and zebrafish in the nictotine withdrawal group exhibited an increased anxiety-like response which was corrected by treatment with noribogaine ( FIG. 12 , panel A). Average velocity of zebrafish was also corrected by noribogaine treatment ( FIG. 12 , panel B). There was no difference observed in the absolute change in direction of zebrafish in any of the test group ( FIG. 12 , panel C). In addition, zebrafish receiving noribogaine treatment exhibited a slight increase in turning rotation rate over both chronic nicotine and nicotine withdrawal groups ( FIG. 12 , panel D). On the other hand, no change was seen in the relative change in direction between any of the groups or absolute change in direction of movement per distance moved ( FIG. 12 , panels E and F). Reduced absolute change in direction of movement per distance moved observed in the nicotine withdrawal group was corrected by treatment with noribogaine. ( FIG. 12 , panel G). These results suggest anxiolytic-like anti-withdrawal effects of noribogaine treatment. 
     Anxiety/fear responses were also tested by recording freezing bout frequency and freezing duration.  FIG. 13 . More freezing bouts and longer freezing duration indicate elevated anxiety and/or fear. Noribogaine treatment (Nic WD+Cpd 1 mg/L) re-established the high bouts due to nicotine withdrawal toward control levels (panel A) and duration of freezing (panels B and C). 
     Effect of noribogaine treatment on movement mobility was also detected.  FIG. 14 . The labele “immobile” was used to express the frequency of episodes with dress of movement independent of spatial displacement (duration of immobility). The label “mobile” reflects overall locomotor activity. The label “Hi-mobile” reflects bouts of accelerated swimming (&gt;60% of individual average). A strong decrease in immobile, mobile, and high mobile events was observed in nicotine withdrawal zebrafish, while noribogaine-treated zebrafish exhibited an increase in high-mobility number of events. ( FIG. 14 , panel A). In addition, nicotine withdrawal specifically decreased mobility of fish and increased immobility. Chronic nicotine treated fish showed a moderate increase of mobility and moderate decrease in immobility durations, while noribogaine-treated fish showed control-equivalent values for mobility and immobilitiy endpoints and displayed a slight increase of high-mobile activity. ( FIG. 14 , panel B). 
     Discussion 
     Analyses of manual NTT endpoints indicate statistically significant anxiolytic-like effects of noribogaine at 1 mg/L, as assessed by shorter latency to enter the top from control and longer time spent by noribogaine-treated fish in the more aversive top (vs. more ‘protective’ bottom) compartment of the test ( FIG. 11 , panels A and D). The number of transitions from top to bottom (top entries) also differed at 1 mg/L noribogaine in nicotine withdrawal fish, suggesting general activation of exploration as this dose. ( FIG. 11 , panel B). Freezing bouts&#39; frequency and duration were increased in chronic nicotine and especially nicotine withdrawal fish. Noribogaine at 1 mg/L reversed that effect in nicotine withdrawal fish and re-established levels to that of the control fish group. ( FIG. 13 ) All fish showed normal habituation responses, as assessed by the per-minute distribution of swimming activity in all manual parameters, generally confirming the lack of behavioral anomalies in the applied testing conditions, which were standard and consistent with other published NTT studies. Analyses of computer-generated NTT endpoints reveal a consistent pattern of unaltered motor activity (assessed by distance traveled and velocity measures) at 1 mg/L noribogaine, but reduced activity in WD group. ( FIG. 12 , panels A and B). Heading (movement directionality index) and mean meandering (straightness index) were similar in all groups. ( FIG. 12 , panels E and F). 
     Erratic movements in this study were automatically measured using the frequency of high-mobility episodes. These endpoints are generally characteristic of higher anxiety states, but may be seen when reaching characteristic states of altered perception (e.g., hallucinogenic drugs). In this experiment there was no changes seen for chronic nicotine and nicotine withdrawal treatment. ( FIG. 14 ). An increase of hi-mobility duration and frequency (by a factor of ˜2) was observed in the noribogaine-treated fish in the nicotine withdrawal state. Noriobgaine did not evoke circling behavior (note unaltered turn angle as well), which would have been common for anti-glutaminergic drugs given acutely. Movement mobility (mobility frequency) and mobility duration, whose endpoints were reflecting general locomotor activity and anxiogenic treatments, showed significant effects of chronic nicotine, nicotine withdrawal and noribogaine treatment. ( FIG. 14 ). Hypo-locomotive effects of nicotine withdrawal were observed (as seen in both in duration and frequency of mobility endpoints, as well as in distance moved and velocity endpoints). ( FIG. 14 ). Moderate hyper-locomotive effects of chronic nicotine (as in literature) was observed. ( FIG. 14 ). Noribogaine at 1 mg/L reestablished mobility (mobile and immobile) durations and frequency in nicotine treated fish to control values suggesting noribogaine is able to rescue locomotor effects of nicotine withdrawal state. ( FIG. 14 ). 
     Conclusion 
     Noribogaine treatment can reverse the effects of nicotine withdrawal, particularly both anxiogenia and hypolocomotion induced by nicotine withdrawal. The 1 mg/L dose of acute noribogaine evoked a robust anxiolytic-like behavior without any overt hyperactivity/hypoactivity in comparison to control in the repeated nicotine withdrawal zebrafish model. Chronic nicotine, and especially repeated WD, evoke anxiogenic-like and locomotor effects in zebrafish, consistent with zebrafish and rodent literature. Anxiogenic-like and locomotor effects of repeated nicotine withdrawal were fully reversed by noribogaine at dose 1 mg/L. Based on these results, beneficial activity of noribogaine in other behavioral paradigms is relevant to nicotine abuse, as well as other drugs&#39; abuse-related models, can be expected at a potential dose of 1 mg/L. 
     Example 6 
     Effect of Low Dose of Noribogaine on Smoking Cessation 
     A female habitual smoker intranasally absorbed a nanogram amount of noribogaine hydrochloride. During a period of several hours, any craving to smoke is determined.