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Home , Dextromethorphan, Dextrorphan, Ibogaine

USOO6780871B2 (12) Patent (10) Patent No.: US 6,780,871 B2 Glick et al. (45) Date of Patent: Aug. 24, 2004

(54) METHODS AND COMPOSITIONS FOR OTHER PUBLICATIONS TREATING DISORDERS Murray et al., “Interaction of Dextrorotary with (75) Inventors: Stanley D. Glick, Delmar, NY (US); Recognition Sites in Rat Membranes,” Isabelle M. Maisonneuve, Delmar, NY Life Sci., 34:1899–1911 (1984). (US) Nishikawa et al., “Evidence for, and Nature of, the Tonic Inhibitory Influence of Habenulointerpeduncular Pathways (73) Assignee: Albany Medical College, Albany, NY upon Cerebral Dopaminergic Transmission in the Rat,” (US) Brain Res., 373:324–336 (1986). Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (List continued on next page.) U.S.C. 154(b) by 0 days. Primary Examiner Marianne C. Seidel Assistant Examiner Brian-Yong S. Kwon (21) Appl. No.: 10/051,770 (74) Attorney, Agent, or Firm-Rogalskyi & Weyand, LLP (22) Filed: Jan. 18, 2002 (57) ABSTRACT (65) Prior Publication Data A method for treating an addiction disorder (Such as an US 2002/0103109 A1 Aug. 1, 2002 addiction to or dependency on , , , , other , , , Related U.S. Application Data and/or ) in a patient is disclosed. The method (60) Provisional application No. 60/264,742, filed on Jan. 29, includes administering to the patient a first C.B. nicotinic 2001. and administering to the patient a Second (51) Int. Cl...... A61K 31/44; A61 K9/70; Cla?s nicotinic receptor antagonist. The Second O?3 nico A61K 31/55; A61K 3.1/542 tinic receptor antagonist is different than the first CB nicotinic receptor antagonist, and the first CBA nicotinic (52) U.S. Cl...... 514/282; 514/343; 514/214.03; receptor antagonist and the Second O?3 nicotinic receptor 514/226.2 antagonist are administered simultaneously or non (58) Field of Search ...... 514/343,282, Simultaneously. Compositions which include a first CB 514/214.03, 226.2 nicotinic receptor antagonist and a Second C.B. nicotinic References Cited receptor antagonist are also described. Examples of Suitable (56) CB nicotinic receptor antagonists for use in the present U.S. PATENT DOCUMENTS inventions methods and compositions include , 18-methoxycoronaridine, , 5,654,281 A 8/1997 Mayer et al. 5,863,927 A 1/1999 Smith et al. , , and phamaceutically 5,965,567 A 10/1999 Archer et al. acceptable Salts and Solvates thereof. A method of evaluating 6.211,360 B1 4/2001 Glick et al. a compound for its effectiveness in treating addiction dis orders is also described. FOREIGN PATENT DOCUMENTS WO WO 99/17803 4/1999 56 Claims, 7 Drawing Sheets

. 1. 100 M) US 6,780.871 B2 Page 2

OTHER PUBLICATIONS Fryer et al., “Noncompetitive Functional Inhibition at Diverse , Human Nicotinic Receptor Sub Koyuncuoglu et al., “The Treatment of Heroin Addicts with types by Bupropion, Phencyclidine, and ,” J. Phar Dextromethorphan: A Double-blind Comparison of Dex tromethrophan with ,” Int. J. Clin. Pharma macol. Exp. Ther, 288:88-92 (1999). col. Ther, 28:147–152 (1990). Lukas et al., “International Union of Pharmacology, XX, Glick et al., “Effects and Aftereffects of Ibogaine on Mor Current Status of the Nomenclature for Nicotinic Acetyl phine Self-administration in Rats,” Europ. J. Pharmacol., Receptors and Their Subunits.” Pharmacol. Rev., 195:341–345 (1991). 51:397–401 (1999). Flores et al., “A Subtype of Nicotinic Receptor Maisonneuve et al., “Attenuation of the Reinforcing Efficacy in Rat Brain Is Comprised of 4 and 2 Subunits and Is of Morphine by 18-Methoxycoronaridine,” Euro. J. Phar Up-regulated by Chronic Nicotine Treatment,” Mol. Phar macol., 383:15–21 (1999). macol., 41:31-37 (1992). Quick et al., “3 4. Subunit-containing Nicotinic Receptors Koyuncuoglu, “The Combination of Tizanidine Markedly Dominate Function in Rat Medial Habenula Neurons.” Improves the Treatment with Dextromethorphan of Heroin Neuropharmacology, 38:769–783 (1999). Addicted Outpatients.” Int. J. Clin. Pharmacol. Ther., Reid et al., “A , Mecamylamine, 33:13-19 (1995). Reduces Cue-induced Craving in Cocaine-dependent Sub Popik et al., “NMDA Antagonist Properties of the Putative jects.” Neuropsychopharmacology, 20:297-307 (1999). Antiaddictive Drug, Ibogaine,” J. Pharmacol. Exp. Ther., Glicket al., “18-MC Reduces and Nico 275–753–760 (1995). Sweetnam et al., “Receptor Binding Profile Siggest Multiple tine Self-Administration in Rats,” NeuroReport, Mechanisms of Action Are Responsible for Ibogaine's Puta 11:2013–2015 (2000). tive Anti-addictive Activity,” Psychopharmacology, Glick et al., “18-Methoxycoronaridine (18-MC) and 118:369-376 (1995). Ibogaine: Comparison of Anti-addictive Efficacy, Toxicity Chen et al., “Ibogaine Block of the Nmda Receptor: in Vitro and Mechanisms of Action,” Ann. N.Y. Acad. Sci., and in Vivo Studies,” Neuropharmacology, 35:423-431 914:369-387 (2000). (1996). Glick et al., “Development of Novel for Drug Glick et al., “18-Methoxycoronaridine, a Non-toxic Iboga Addicition: The Legacy of an African Shrub,” Ann. N.Y. Congener: Effects of Morphine and Cocaine Self Acad. Sci., 909:88-103 (2000). administration and on Mesolimbic Release in Hernandez et al., “Dextromethorphan and its Metabolite Rats.” Brain Res., 719:29-35 (1996). Dextrorphan Block 3 4 Neuronal Nicotinic Receptors,” J. Badio et al., “Ibagaine: A Potent Noncompetitive Blocker of Pharmacol. Exp. Ther, 293:962–967 (2000). Ganglionic/Neuronal Nicotinic Receptors.” Molec. Pharma Jun et al., “Dextromethorphan Alters Methamphetamine col., 51:1–5 (1997). Self-Administration in the Rat, Pharmacol. Biochem. Pulvirenti et al., “Dextromethorphan Reduces Intravenous Behav, 67:405-409 (2000). Cocaine Self-administration in the Rat, Eur: J. Pharmacol., Levin et al., “Mecamylamine Preferentially Inhibits Cocaine 321:279-283 (1997). Rezvani et al., “Attenuation of Alcohol Consumption by a Versus Food Self-administration in Rats.” Soc. Neurosci. Novel Non-toxic Ibogaine Analog (18-Methoxycoronari Abstr., 26:1821 (2000). dine) in Alcohol Preferring Rats.” Pharmacol. Biochem. Glicket al., “Comparative Effects of Dextromethorphan and Behav, 58:615–619 (1997). Dextrorphan on Morphine, Methamphetamine, and Nicotine Ebert et al., “ as Noncompetitive N-meth Self-administration in Rats,” Europ. J. Pharmacol., yl-d-aspartate (NMDA) Antagonists,” Biochem. Pharma 422:87–90 (2001). col., 56:533–559 (1998). Klink et al., “Molecular and Physiological Diversity of Glick et al., “Mechanisms of Anti-addictive Actions of Nicotinic Acetylcholine Receptors in the Midbrain Dopam Ibogaine,” Ann. N.Y. Acad. Sci., 844, 214-226 (1998). inergic Nuclei,” J. Neurosci., 21:1452–1463 (2001). Mah et al., “Ibogaine Acts at the Nicotinic Acetylcholine Papke et al., “Analysis of Mecamylamine Steroisomers on Receptor to Inhibit Catecholamine Release,” Brain Res., Human Nicotinic Receptor Subtypes,” J. Pharmacol. Exp. 797:173–180 (1998). Ther, 297:646–656 (2001). U.S. Patent Aug. 24, 2004 Sheet 1 of 7 US 6,780,871 B2

ACh

FIGURE 1B

O. O 1 OO drug (prM) U.S. Patent Aug. 24, 2004 Sheet 2 of 7 US 6,780,871 B2

FIGURE 2 18MC ACh as

FIGURE 3A

18MC GLU

FIGURE 3B

U.S. Patent Aug. 24, 2004 Sheet 3 of 7 US 6,780,871 B2

FIGURE 4

SHT BO 5HT 18MC Occa Recr-P

A saw Control Control

toolpa 10 Sec

FIGURE 5

Baseline Treatment

Mec 1 18MC 1 DM 5 Mec 1 Mec 1 DM 5 18MC 1 DM 5 18MC 1 Treatment U.S. Patent Aug. 24, 2004 Sheet 4 of 7 US 6,780,871 B2

FIGURE 6

Treatment

Mec 1 18MC 2 DM5 Mec 1 Mec 1 DM 5 18MC 2 DM 5 18MC 2 Treatment

FIGURE 7

1200 Treatment 1000

Mec 1 18MC 2 DM 5 Mec 1 Mec 1 DM 5 18MC 2 DM 5 18MC 2 Treatment U.S. Patent Aug. 24, 2004 Sheet 5 of 7 US 6,780,871 B2

FIGURE 8

45 Baseline 40 Treatment

2

Mec 18Mc1 DM52. Bup5 Mec1 DM5 18Mc1 Bup5 Bup5 Bup5 Treatment

FIGURE 9

- 35 Baseline Treatment 5 30 E 25 S 20 E 15 2- 10 E. :

e O Mec 1 18MC5 DM10 Bup 10 Mec1 DM10 18MC5 Bup 10 Bup 10 Bup10 Treatment U.S. Patent Aug. 24, 2004 Sheet 6 of 7 US 6,780,871 B2

FIGURE 10

Baseline 1 2O O Treatment 1000 800 600 400 S. 200 g

Mec 1 18MC5 DM10 Bup 10 Mec1 DM10 18MC5 Bup 10 Bup 10 Bup10 Treatment

20

Mec. 1 18MC5 DM5 Mec. 18MC5 Treatment U.S. Patent Aug. 24, 2004 Sheet 7 of 7 US 6,780,871 B2

FIGURE 2

35 Baseline ha Treatment R 30 s 25 O 5 20 C P . au G 15 SS 10 :

5 : 2. S. Mec. 1 18MC5 DM 5 Bup5 Mec. 1 DM.5 18MC.5 Bup5 Bup5 Bup5 Treatment US 6,780,871 B2 1 2 METHODS AND COMPOSITIONS FOR is a graph showing inhibition of 1 mM ACh-evoked whole TREATING ADDICTION DISORDERS cell currents by various concentrations of various . FIG. 2 is a graph of whole-cell current VS. time showing The present invention claims the benefit of U.S. Provi sional Patent Application Serial No. 60/264,742, filed Jan. the effect of various drugs on whole-cell currents in cells 29, 2001, which is hereby incorporated by reference. expressing recombinant CB nicotinic receptors. The present invention was made with the Support of the FIGS. 3A and 3B are graphs of whole-cell current vs. time National Institute on Drug Abuse Grant No. DAO3817. The showing the effect of various drugs on whole-cell currents in Federal Government may have certain rights in this inven cells expressing recombinant NR1/2A (FIG. 3A) and NR1/ tion. 2B (FIG. 3B) receptors. FIG. 4 is a graph of whole-cell current VS. time showing FIELD OF THE INVENTION the effect of various drugs on whole-cell currents in cells The present application relates, generally, to methods of expressing recombinant 5-HT, receptorS. treating addiction disorders using Of nicotinic receptor antagonists and to compositions useful in Such treatments. FIG. 5 is a graph showing the effects of various drugs 15 and drug combinations on morphine Self-administration. BACKGROUND OF THE INVENTION FIG. 6 is a bar graph showing the effects of various drugs Drug and alcohol addiction and/or abuse and/or depen and drug combinations on methamphetamine Self dency (collectively referred to herein as “addiction administration. disorders’) is extremely common. Individuals Suffering FIG. 7 is a bar graph showing the effects of various drugs from Such are generally Subject to significant and drug combinations on responding for . Symptoms of withdrawal upon attempting to cease use of the FIG. 8 is a bar graph showing the effects of various drugs addictive Substance (whether alcohol or drugs such as and drug combinations on morphine Self-administration. cocaine, heroine, nicotine, painkillers, etc.). A number of FIG. 9 is a bar graph showing the effects of various drugs medical therapies have been tried with differing levels of and drug combinations on methamphetamine Self Success. Unfortunately, to date, none of these methods of 25 treatment have been very successful. For this and other administration. reasons, a need exists for improved methods for treating FIG. 10 is a bar graph showing the effects of various drugs addictive disorders. and drug combinations on responding for water. FIG. 11 is a bar graph showing the effects of various drugs SUMMARY OF THE INVENTION and drug combinations on nicotine Self-administration. The present invention relates to a method for treating an FIG. 12 is a bar graph showing the effects of various drugs addiction disorder in a patient. The method includes admin istering to the patient a first CB nicotinic receptor antago and drug combinations on nicotine Self-administration. nist and administering to the patient a Second C.B. nicotinic DETAILED DESCRIPTION OF THE receptor antagonist. The Second C.B. nicotinic receptor 35 INVENTION antagonist is different than the first C.B. nicotinic receptor antagonist, and the first Of nicotinic receptor antagonist The present invention relates to a method for treating an and the Second C.B. nicotinic receptor antagonist are admin addiction disorder in a patient. The method includes admin istered simultaneously or non-simultaneously. istering to the patient a first CB nicotinic receptor antago The present invention also relates to a composition which 40 nist and administering to the patient a Second CB nicotinic includes a first C.B. nicotinic receptor antagonist and a receptor antagonist. Second O?3 nicotinic receptor antagonist. In this AS used herein, “addiction disorder is meant to include composition, the Second CB nicotinic receptor antagonist a habitual or recurrent use of a Substance, Such as Stimulants, is different than the first CB nicotinic receptor antagonist. nicotine (e.g., which is meant to include all forms of nicotine The present invention also relates to a composition which 45 administration, Such as , chewing , or other includes a first compound Selected from the group consisting forms of nicotine administration), opioid (e.g., morphine and of mecamylamine, 18-methoxycoronaridine, bupropion, heroin), amphetamines, cocaine, and alcohol. It is meant to dextromethorphan, dextrorphan, and phamaceutically include, but is not meant to be limited to, a dependency on acceptable Salts and Solvates thereof, and a second C.B. the Substance. Dependency is characterized by a patient's compound Selected from the group consisting of 50 persistence in Substance use or abuse or the recurrence of mecamylamine, 18-methoxycoronaridine, bupropion, Such use or abuse in the face of negative Social or medical dextromethorphan, dextrorphan, and phamaceutically consequences of this use or abuse or in face of the patient's acceptable Salts and Solvates thereof. In this composition, declared or undeclared intent to abandon or reduce his or her the Second compound is different than the first compound. use of the Substance. A patient's dependency can be mani The present invention also relates to a method of evalu 55 fested in objective criteria or other indices of drug Seeking ating a compound for its effectiveness in treating addiction behavior, Such as repeated attempts to abandon use or abuse disorders by assessing the compounds ability to bind to of the Substance, as evidenced by, for example, past partici Cla?s nicotinic receptors. pation in encounter groups designed to reduce the partici The present invention also relates to a method for treating pants use of cocaine or , commitment to a an addiction disorder in a patient. The method includes 60 drug or alcohol rehabilitation program, arrest or conviction administering to the patient an OB, nicotinic receptor of or trafficking, hospitalization for com antagonist under conditions effective to treat the patient's plications arising from drug or alcohol use, including addiction disorder. Overdose, and the like. “Patient', as used herein, is generally meant to be a BRIEF DESCRIPTION OF THE DRAWINGS 65 human. However, it is envisioned that the method of the FIG. 1A is a graph of current VS. time showing whole-cell present invention can be used to treat addiction disorders in currents evoked by 1 mM ACh in transfected cells. FIG. 1B experimental mammals other than humans, Such as primates US 6,780,871 B2 3 4 other than humans, rats, mice, dogs, and the like. Using the nicotinic receptor. For the purposes of the present invention, methods of the present invention, mammals experimentally a compound is to be deemed as being "selective for CB addicted to drugs or alcohol can be humanely weaned from nicotinic receptors' if and only if the compound's ICso at an the Substance, and the physiological and psychological O?3 nicotinic receptor is less than (e.g., less than about 95% damage or changes which result from past drug or alcohol of, less than about 90% of, less than about 80% of, less than use can be assessed. In addition, these mammals can be used about 65% of, less than about 50% of, less than about 20% to Study the progression of or recovery from Such physi of, and/or less than about 10% of) the compound's ICso at ological and psychological damage or changes Subsequent to an another nicotinic receptor (e.g., at the C.B. nicotinic the patient's abandoning or reducing his, her, or its drug or receptor). In this regard, it should be noted that a com alcohol use. In the controlled environment of the laboratory, pound's ICso at a nicotinic receptor can be measured or the non-human mammalian patient would be allowed to otherwise deduced using whole-cell patch-clamp methods, develop drug or alcohol addiction and to maintain this Such as those described infra. addiction for a prescribed period of time. The patient's Suitable C.B. nicotinic receptor antagonists include those addiction would then be treated in accordance with the compounds which are specific for C.B. nicotinic receptors method of the present invention to cause the patient's use of 15 as well as those compounds which are not specific for CB the drug or alcohol to decrease or cease. The patient could nicotinic receptor. For the purposes of the present invention, then be monitored over time, e.g., from the time of the drug a compound is to be deemed as being “specific for CB or alcohol use cessation or reduction to ascertain long-term nicotinic receptors' if and only if the compound's ICs at an physiological or psychological changes or damage and the CB nicotinic receptor is less than about 20% of, less than patient's recovery from these changes or damage. about 15% of, less than about 10% of, less than about 8% of, “C.B. nicotinic receptor antagonist', as used herein, less than about 5% of, and/or less than about 3% of) the means a compound that directly or indirectly blockS or compound's ICso at one other nicotinic receptor (e.g., at the otherwise reduces the activity of an O?3 nicotinic receptor. O?3 nicotinic receptor), at more than one other (e.g., at two AS used herein, “C.B. nicotinic receptor is meant to include other) nicotinic receptor, or at all other nicotinic receptors. nicotinic receptors which contain three nicotinic receptor 25 In this regard, it should again be noted that a compounds Subunits and four nicotinic receptor beta Subunits, ICso at a nicotinic receptor can be measured or otherwise Such as the C.B. nicotinic receptorS described in Lucas et al. deduced using whole-cell patch-clamp methods, for Pharmacol. Rey, 51:397–401 (1999), which is hereby incor example, as described infra. porated by reference. Nicotinic receptor alpha Subunits are AS indicated above, the method of the present invention meant to include those described in GenBank Accession involves administering two different Of nicotinic receptor Nos. NM000743 (Homo sapiens) and X12434 (chicken), antagonists to the patient. For the purposes of the present which are hereby incorporated by reference. Nicotinic invention, the first Of nicotinic receptor antagonist and the receptor beta Subunits are meant to include those described Second CB nicotinic receptor antagonist are deemed to be in GenBank Accession Nos. NM000750 (Homo Sapiens) “different' if they have different chemical formulae unless and U42976 (rat), which are hereby incorporated by refer 35 the first Of nicotinic receptor antagonist is a phamaceu ence. Examples of C.B. nicotinic receptor antagonists that tically acceptable Salt and/or Solvate of the Second CB are useful in the practice of the present invention include nicotinic receptor or vice versa. For example, the first C.B. mecamylamine, 18-methoxycoronaridine (the preparation of nicotinic receptor antagonist can be mecamylamine, which is described in Bandarage et al., Tetrahedron, 18-methoxycoronaridine, bupropion, dextromethorphan, or 55:9405-9424 (1999), which is hereby incorporated by 40 dextrorphan and the Second C.B. nicotinic receptor antago reference), bupropion (also known as m-chloro-O-tert nist can be a CBA nicotinic receptor antagonist that is not butylaminopropiophenone), dextromethorphan, and dextror Selected from the group consisting of mecamylamine, phan (which is a metabolite of dextromethorphan). Other 18-methoxycoronaridine, bupropion, dextromethorphan, examples of O?3 nicotinic receptor antagonists that are and dextrorphan (or their pharmaceutically acceptable Salts useful in the practice of the present invention include 45 and/or Solvates). Alternatively, both the first CB nicotinic phamaceutically acceptable Salts and Solvates (the latter of receptor antagonist and the Second C.B. nicotinic receptor which is meant to include adducts) of mecamylamine, antagonist can be selected from the group consisting of 18-methoxycoronaridine, bupropion, dextromethorphan, mecamylamine, 18-methoxycoronaridine, bupropion, and dextrorphan. Examples of Suitable Salts include those dextromethorphan, dextrorphan, phamaceutically accept derived from inorganic bases (such as ammonium and alkali 50 able Salts thereof, phamaceutically acceptable and Solvates and alkaline earth metal hydroxides, , thereof, So long as the first and Second CB nicotinic bicarbonates, and the like); Salts derived from basic organic receptor antagonists are different from one another. Still amines (such as aliphatic and aromatic amines, aliphatic alternatively, both the first and Second C.B. nicotinic recep diamines, hydroxy alkylamines, and the like), and Salts tor antagonists can be Cla?s nicotinic receptor antagonists derived from inorganic or organic acids, Such as 55 that are not Selected from the group consisting of hydrochloric, hydrobromic, or hydroiodic acid). Bupropion mecamylamine, 18-methoxycoronaridine, bupropion, hydrochloride and bupropion hydrobromide are but two dextromethorphan, and dextrorphan (or their pharmaceuti examples of Suitable pharmaceutically acceptable Salts that cally acceptable salts and/or Solvates). can be used in the practice of the present invention. AS used Illustratively, the first C.B. nicotinic receptor antagonist herein, “18-methoxycoronaridine” is meant to include the 60 can be mecamylamine and the Second C.B. nicotinic recep parent compound (i.e., 18-methoxycoronaridine per se) as tor antagonist can be dextromethorphan. Alternatively, the well as 18-methoxycoronaridine congeners (e.g., the com first C.B. nicotinic receptor antagonist can be mecamy pounds represented by formula I in U.S. Pat. No. 6,211,360 lamine and the Second O?3 nicotinic receptor antagonist can to Glicket al., which is hereby incorporated by reference). be dextrorphan. Still alternatively, the first C.B. nicotinic Suitable C.B. nicotinic receptor antagonists include those 65 receptor antagonist can be mecamylamine and the Second compounds which are Selective for C.B. nicotinic receptors C. f a nic otinic receptor antagonist can be as well as those compounds which are not Selective for CB 18-methoxycoronaridine. Still alternatively, the first CB US 6,780,871 B2 S 6 nicotinic receptor antagonist can be mecamylamine and the Illustratively, each C.B. nicotinic receptor antagonist can Second C-3, nicotinic receptor antagonist can be a CB be administered in an amount from about 0.01 to about 10 nicotinic receptor antagonist other than mg/kg of the patient's body weight per day, for example, in 18-methoxycoronaridine. an amount from about 0.02 to about 5 mg/kg of the patient's It is believed that each C.B. nicotinic receptor antagonist body weight per day or in an amount from about 0.1 to about modulates not only the activity of the C.B. nicotinic receptor 5 mg/kg of the patient's body weight per day. The optimal but also the activity of “other receptors'. It is further daily dose of each Of nicotinic receptor antagonist for a believed that the “other receptors” that are modulated by a particular patient can be determined by challenging the particular Cla?s nicotinic receptor antagonist can vary depending on the nature of the particular Of nicotinic patient with a dose of the Substance to which they are receptor antagonist. In the practice of the present invention, addicted, the optimal daily dose of CB nicotinic receptor it is preferred that the CB nicotinic receptor antagonists be antagonist being the minimal dose at which the patient does chosen Such that the first CB nicotinic receptor antagonist not feel the effects of the challenge dose. modulates one set of “other receptors' and such that the The amount of each C.B. nicotinic receptor antagonist Second C.B. nicotinic receptor antagonist modulates can be administered in a single daily dose or in multiple another, different set of “other receptors'. One set of “other 15 doses or even continuously. Continuous administration can receptors” is considered to be different from another set of be carried out in the inpatient Setting by, for example, “other receptors' if and only if there is not a one-to-one intravenous drip, or in an outpatient Setting by providing the correspondence between the members of two sets of “other Of nicotinic receptor antagonist(s) in a slow-release receptors'. formulation, Such as in a Suspension or in microcapsules. In Also as indicated above, the first and Second CB nico the outpatient Setting, the administering is best carried out tinic receptor antagonists can be administered Simulta continuously in a Slow release formulation, or, alternatively, neously or non-simultaneously. Simultaneous administra in a Single dose. In either case, to ensure compliance with the tion is meant to include co-administration, as in the case treatment protocol, it is best that the provider actively where the two C.B. nicotinic receptor antagonists are administer (i.e. inject, etc.) each individual dose to the administered as components of a single composition as well 25 patient or, instead, that the provider observe the patient as in the case where the two C.B. nicotinic receptor antago Self-administer each dose. nists are administered in Separate compositions but at the same time (e.g., as two tablets Swallowed simultaneously or Each O?3 nicotinic receptor antagonist can be as two solutions injected Simultaneously). Non administered, individually or together, by any of the con Simultaneous administration is meant to include Sequential ventional modes of drug administration, including oral or administration (e.g., in the case where the first Of nicotinic parenteral administration. Examples of parenteral adminis receptor antagonist is administered before the second or in tration are intraventricular, intracerebral, intramuscular, the case where the Second CB nicotinic receptor antagonist intravenous, intraperitoneal, rectal, and Subcutaneous is administered before the first). When using sequential administration. administration, it is preferred that the Second-to-be 35 Each C.B. nicotinic receptor antagonist or a composition administered CB nicotinic receptor antagonist be admin containing the two can be administered alone or in combi istered while there is a Substantial amount of the first-to nation with Suitable pharmaceutical carriers or diluents. The be-administered CB nicotinic receptor antagonist present diluent or carrier ingredients should be Selected So that they in the patient. Generally, it is preferred to administer the do not diminish the therapeutic effects of the C.B. nicotinic receptor antagonists. Second-to-be-administered CB nicotinic receptor antago 40 nist within 3X, 2X, and/or 1X (where X is the first-to-be Suitable dosage forms for oral use include tablets, dis administered O?3 nicotinic receptor antagonist metabolic persible powders, granules, capsules, Suspensions, , half-life) of the time at which the first-to-be-administered and elixirs. Inert diluents and carriers for tablets include, for O?3 nicotinic receptor antagonist was administered. For example, calcium , Sodium carbonate, lactose, and example, the Second-to-be-administered CB nicotinic 45 talc. Tablets may also contain granulating and disintegrating receptor antagonist can be administered to the patient within agents, Such as Starch and alginic acid; binding agents, Such 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 10 minutes, as Starch, gelatin, and acacia, and lubricating agents, Such as and/or 5 minutes of the time at which the first-to-be Stearate, Stearic acid, and talc. Tablets may be administered O?3 nicotinic receptor antagonist was admin uncoated or may be coated by known techniques to delay istered. 50 disintegration and absorption. Inert diluents and carriers Preferably, the first and Second CB nicotinic receptor which may be used in capsules include, for example, cal antagonists are administered in amounts that are effective to cium carbonate, calcium phosphate, and kaolin. treat the patient's addiction disorder. It will be appreciated Suspensions, Syrups, and elixirs may contain conventional that the actual preferred effective amount of first and Second excipients, Such as methyl cellulose, tragacanth, Sodium CB nicotinic receptor antagonists will vary according to 55 alginate, wetting agents, Such as and polyoxyethyl the C.B. nicotinic receptor antagonists employed, the par ene Stearate; and preservatives, Such as ethyl-p- ticular composition formulated, and the mode of adminis hydroxybenzoate. tration. Many factors that modify the CBA nicotinic receptor Dosage forms Suitable for parenteral administration antagonists activity will be taken into account by those include Solutions, Suspensions, dispersions, emulsions, skilled in the art, e.g., body weight, Sex, diet, time of 60 microcapsules and the like. They may also be manufactured administration, route of administration, rate of , in the form of sterile solid compositions which can be condition of the patient, drug combinations, reaction Sensi dissolved or Suspended in Sterile injectable medium imme tivities and Severities, Severity of addiction, and the Stage at diately before use. They may contain Suspending or disperS which the patient is in the withdrawal process. Administra ing agents known in the art. Where microcapsules are tion of one or both of the CB nicotinic receptor antagonists 65 employed, they can be readily prepared by conventional can be carried out continuously or periodically within the microencapsulation techniques, Such as those disclosed in, maximum tolerated dose. for example, Encyclopedia of Chemical Technology, 3rd US 6,780,871 B2 7 8 edition, volume 15, New York: John Wiley and Sons, pp. assessment can also be carried out by reviewing data or other 470-493 (1981), which is hereby incorporated by reference. information, provided by others, regarding the compounds The present invention, in another aspect thereof, relates to ability to bind to C.B. nicotinic receptors. The evaluation a composition which includes a first C.B. nicotinic receptor can also include other StepS, Such as administering the and a Second O?3 nicotinic receptor, the Second CB compound to patients Suffering from addiction disorders and nicotinic receptor antagonist being different than the first recording their progress, and/or administering the compound Cla?s nicotinic receptor antagonist. The meaning of "CfB to patients Suffering from addiction disorders recording any nicotinic receptor antagonist', examples of Suitable nicotinic reported adverse Side effects of the compound. receptor antagonists, and methods for formulating these The present invention is further illustrated by the follow compositions are the same as Set forth hereinabove. The ing examples. optimal amounts of the first and the Second C.B. nicotinic receptor antagonists present in the composition of the EXAMPLES present invention can be determined from the optimal dos ages as determined, for example, by using conventional Example 1 dosage administration tests in View of the guidelines Set 15 Receptor Functional Analyses forth above. Illustratively, the first and Second C.B. nicotinic receptor antagonists can be present in a weight ratio of from Human embryonic 293 (HEK293) fibroblasts about 10:1 to about 1:10, Such as from about 5:1 to about (ATCC CRL1573) were cultured in minimal essential 1:3, from about 3:1 to about 1:5, and/or from about 2:1 to medium supplemented with 10% fetal bovine serum and 2 about 1:2. mM (Life Technologies, Rockville, Md.). Cells The present invention, in another aspect thereof, also were plated on poly-D--coated 35 mm nunc dishes, relates to a method for treating an addiction disorder in a transfected by the Lipofectamine PLUS method (Life patient by administering to the patient an OB, nicotinic Technologies), and examined functionally between 18–48 h receptor antagonist under conditions effective to treat the post transfection. The following receptor subunit cDNAS patient's addiction disorder. 25 were used: nAChR-C3 (nicotinic -C3; accession no. L31621), nAChR-C4 (accession no. L31620), Suitable C.B. nicotinic receptor antagonists useful in the nAChR-B2 (accession no. L31622), nAChR-B4 (accession practice of this aspect of the present invention include those no. U42976), 5-HTR-A (5-HT, receptor; accession no. which are not me camylamine; are not M74425), NR1 (N-methyl-D-aspartate receptor 1; accession 18-methoxycoronaridine, are not bupropion; are not deX no. X63255), NR2A (accession no. X91561), and NR2B tromethorphan, are not dextrorphan, are not ibogaine; and (accession no. M91562). The nAchR and NR clones were are not a phamaceutically acceptable Salt or Solvate of rat; the 5-HTR-A clone was mouse. Co-transfection of mecamylamine, 18-methoxycoronaridine, bupropion, enhanced green fluorescent protein (“EGFP) (10% of total dextromethorphan, dextrorphan, or ibogaine. Additionally cDNA) provided a marker to identify transfected cells. or alternatively, the CB nicotinic receptor antagonist can 35 Transfected cells were selected for EGFP expression and be selective and/or specific for C.B. nicotinic receptors. examined by Voltage-clamp recording in the whole-cell Other Suitable C.B. nicotinic receptor antagonists useful in configuration using an AXopatch 200B patch-clamp ampli the practice of this aspect of the present invention include those which are more potent than 18-methoxycoronaridine fier (Axon Instruments, Foster City, Calif.). Thin-walled at CB nicotinic receptors. For the purposes of the present borosilicate glass microelectrodes (TW150F, World Preci 40 sion Instruments, Sarasota, Fla.) had resistances of 3–5 MS2 invention, a compound is to be deemed as being “more when filled with an internal solution containing (in mM): potent than 18-methoxycoronaridine at CB nicotinic recep 135 CsCl, 10 CsF, 10 HEPES (N-2-hydroxyethyl tors' if and only if the compound's ICs at an O?3 nicotinic -N'-(2-ethanesulfonic acid), 5 EGTA (ethylene receptor is less than (e.g., less than about 95% of, less than glycol-bis B-aminoethyl -N,N,N',N'-tetraacetic acid), about 95% of, less than about 80% of, less than about 65% 45 1 MgCl, 0.5 CaCl, pH 7.2. Whole-cell capacitance and of, less than about 50% of, less than about 20% of, and/or Series resistance were recorded and adequately compensated less than about 10% of) 18-methoxycoronaridine’s ICso at using the available circuitry of the amplifier. Current the CBA nicotinic receptor. responses were filtered at 1 kHz with an 8-pole Bessel filter Suitable C.B. nicotinic receptor antagonists useful in the (Cygnus Technologies, Delaware Water Gap, Pa.), digitized practice of this aspect of the present invention can be 50 at 3 kHz, and stored on a Macintosh PowerPC-G3 computer identified using conventional drug Screening methodologies. using an ITC-16 interface (Instrutech, Great Neck, N.Y.) The present invention, in Still another aspect thereof, under control of the data acquisition and analysis program relates to a method of evaluating a compound for its effec Synapse (Synergy Research, Gaithersburg, Md.). Cells were tiveness in treating addiction disorders. The method includes continuously Superfused with extracellular Solution contain assessing the compounds ability to bind to C.B. nicotinic 55 ing (in mM): 150 NaCl, 3 KC1, 5 HEPES, 1 MgCl, 1.8 receptors. For example, a test compounds ability to bind to CaCl, 10 glucose, and 0.1 mg/ml phenol red, pH 7.3 O?3 nicotinic receptors (and hence its effectiveness in (MgCl, was omitted from all solutions used for the study of treating addiction disorders) can be assessed by providing an NMDA receptors). Drug stocks (10 mM) were made up in CB nicotinic receptor, contacting the test compound with dimethylsulfoxide (“DMSO”) and diluted in extracellular the C.B. nicotinic receptor, and determining the amount of 60 Solution immediately prior to use, final concentration of test compound which binds to the CfB nicotinic receptor. DMSO was 0.2% or lower. Control, , and drug The assessment can be carried out, for example, by using a Solutions were applied to individual cells by rapid perfusion. conventional binding assay (e.g., a binding competition Solutions were driven by a Syringe pump through a flowpipe assay or an anSSay which employs a labeled test compound), having 4 inputs that converge at a Single common output of or it can be carried out by deducing the test compounds 65 approximately 100 um diameter. Rapid Switching between ability to bind to C.B. nicotinic receptors from whole-cell inputS was achieved using a Set of upstream Solenoid valves patch-clamp Studies, Such as those described infra. The (Lee Co., Westbrook, Conn.) under computer control; the US 6,780,871 B2 9 10 Solution eXchange rate was ~5 mS as measured from liquid Example 4 junction currents. Drug Actions at Receptor Ion Example 2 channels 5 Transfected HEK293 cells expressing various receptor Chemicals and Animals subunit cDNAs were examined by whole-cell patch-clamp 18-Methoxycoronaridine hydrochloride (1-2 mg/kg; recording with fast perfusion of agonist and drug Solutions. Albany Molecular Research, Inc., Albany, N.Y.) was dis We began with CB nACh receptors as these are the Solved in phosphate buffer and injected intraperitoneally 15 principal ganglionic nACh receptor Subtype for which inhi minutes before behavioral testing. Dextromethorphan bition by ibogaine had previously been demonstrated (Badio hydrobromide (5 mg/kg; Sigma/RBI, St. Louis, Mo.) was et al., “Ibogaine: A Potent Noncompetitive Blocker of dissolved in Saline and injected Subcutaneously 20 minutes Ganglionic/Neuronal Nicotinic Receptors,” Molec. before testing. Mecamylamine hydrochloride (1 mg/kg, Pharmacol, 51:1-5 (1997); Mah et al., “Ibogaine Acts at the Sigma/RBI, St. Louis, Mo.) was dissolved in physiological Nicotinic Acetylcholine Receptor to Inhibit Catecholamine Saline and injected intraperitoneally 30 minutes before test 15 Release,” Brain Res., 797:173–180 (1998); and Fryer et al., ing. All rats received two injections. For rats that received a “Noncompetitive Functional Inhibition at Diverse, Human Single drug, half of them also received the appropriate Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Saline/vehicle injection corresponding to each of the other Phencyclidine, and Ibogaine,” J. Pharmacol. Exp. Ther, two drugs. 288:88-92 (1999), which are hereby incorporated by Naive female Long-Evans derived rats (250 g; Charles reference). Transfected HEK293 cells expressing CB River, N.Y.) were maintained on a normal 12 h light cycle nACh receptors were voltage-clamped to -70 mV and (lights on at 7:00 a.m., lights off at 7:00 p.m.). For all stimulated with 1 mM ACh at 30 S intervals. ACh alone experiments the “Principles of Laboratory Animal Care” evoked a large inward current not seen in untransfected (NIH publication No. 85-23, revised 1985, which is hereby cells. Application of 20 uM ibogaine or 20 uM incorporated by reference) were followed. 25 18-methoxycoronaridine alone did not produce any response. AS shown in FIG. 1A, co-application of either 20 Example 3 uM ibogaine (“IBO”) or 20 uM 18-methoxycoronaridine (“18MC) nearly abolished the ACh-evoked responses in all Self-administration Procedure cells tested (N=15). In FIG. 1A, open bars depict the timing The intravenous Self-administration procedure described of ACh application; filled bars depict the timing of in Glick et al., “18-MC Reduces Methamphetamine and co-application of 20 uM IBO or 20 uM 18MC; and inhibi Nicotine Self-administration in Rats,” NeuroReport tion was measured relative to control at the end of the drug 11:2013–2015 (2000) (“Glick I"), which is hereby incorpo application (indicated by arrows). The inhibition developed rated by reference, was employed. Briefly, responses on rapidly in the presence of ACh and reversed more slowly either of two levers (mounted 15 cm apart on the front wall 35 following the removal of drug. As shown in FIG. 1B, the of each operant test cage) were recorded on an IBM com inhibition was concentration-dependent, ICso values were patible computer with a Med ASSociates, Inc. interface. The 0.22 uM for ibogaine versus 0.75 uM for intravenous Self-administration System consisted of 18-methoxycoronaridine, and the concentration-response polyethylene-Silicone cannulas constructed according to the relationship had a Hill slope of unity which is consistent design of Weeks, "Long-term Intravenous Infusion, pp. 40 with a single site of action. More particularly, FIG. 1B 155-168 in Myers (ed.), Methods in Psychobiology, Vol. 2, shows the inhibition of 1 mM ACh-evoked currents by New York: Academic Press (1972) (“Weeks”), which is various concentrations of IBO and 18MC. The data pre hereby incorporated by reference; Instech harnesses and sented in FIG. 1B are meant-SEM for 3-14 cells per point, Swivels; and Harvard Apparatus infusion pumps (#55-2222). and curve fits are given for the logistic equation: I=I/(1+ Shaping of the bar-press response was initially accom 45 (drug/ICs)). Best fitting ICso values were 0.75 uM for plished by training rats to bar-press for water. Cannulas were IBO and 0.22 uM for 18MC. These data confirm previous then implanted in the external jugular vein according to reports of the actions of ibogaine and indicate that procedures described in Weeks, which is hereby incorpo 18-methoxycoronaridine has similar actions at ganglionic rated by reference. Self-administration testing began with a nACh receptors. Results were somewhat different, however, 16-h nocturnal session followed by daily 1-h sessions, 5 50 at neuronal nACh receptors. In this case, transfected days (Monday-Friday) a week. A lever-press response pro HEK293 cells expressing CB nACh receptors were duced a 10 ul infusion of drug solution (0.01 mg of morphine voltage-clamped to -70 mV and stimulated with 300 uM sulfate) in about 0.2 s or a 50 ul infusion of drug solution ACh at 30s intervals. ACh alone evoked an inward current (0.025 mg of methamphetamine sulfate) in about 1 S. Since whereas application of 20 uM ibogaine or 20 uM all rats generally weighed 250-20g, each response delivered 55 18-methoxycoronaridine alone did not produce any approximately 0.04 mg/kg of morphine or 0.1 mg/kg of response. Co-application of 5 uM ibogaine inhibited the methamphetamine. Experiments to assess the effects of ACh-evoked response by 61+4% (n=5) whereas 5 uM experimental treatments were begun when baseline Self 18-methoxycoronaridine produced no apparent inhibition administration rates stabilized (s.10% variation from one (N=6). This is shown in FIG. 2, where open bars depict the day to the next across 5 days), usually after 2 weeks of 60 timing of ACh application and filled bars depict the timing testing. Each rat typically received two or three different of co-application of 20 uM IBO or 20 uM 18MC. Because treatments spaced at least one week apart. In order to of the relatively rapid desensitization of the CB response, provide an indication of the Specificity of treatment effects inhibition was measured relative to control (Superimposed on drug Self-administration, all treatments were also admin curve fits) during drug application (arrows). At higher drug istered to other rats bar-pressing for water (0.01 ml orally) 65 concentrations (20 uM), ibogaine inhibition reached 93+3% on a comparable Schedule (continuous reinforcement, 1-h (N=7) versus only 8 +4% by 18-methoxycoronaridine Sessions). (N=6). These data Suggest the ICso for ibogaine at CB US 6,780,871 B2 11 12 nACh receptors is on the order of 1-5 uM and that drugs have similar potencies at 5-HT, receptors with ICso 18-methoxycoronaridine is considerably less potent values of approximately 20 uM. (ICsod20 um) at this neuronal nACh receptor Subtype. Another known action of ibogaine involves the inhibition Example 5 of NMDA-type glutamate receptors (Popik et al., “NMDA 5 Antagonist Properties of the Putative Antiaddictive Drug, Effect of Mecamylamine, 18-Methoxycoronaridine, Ibogaine,” J. Pharmacol. Exp. Ther, 275:753–760 (1995) Dextromethorphan, Mecamylamine/18 (“Popik”) and Chen et al., “Ibogaine Block of the NMDA Methoxycoronaridine, Mecamylamine/ Receptor: In Vitro and In Vivo Studies,” Dextromethorphan, and Dextromethorphan/18 Neuropharmacology, 35:423–431 (1996) (“Chen”), which Methoxycoronaridine Drug Treatments on are hereby incorporated by reference), presumably by inter Morphine and Methamphetamine Self action with the PCP/MK-801 (phencyclidine/) administration binding site (Sweetnam et al., “Receptor Binding Profile FIGS. 5-7 show the effects of mecamylamine, Suggests Multiple Mechanisms of Action Are Responsible 18-methoxy corona ridine, de Xtrome thorphan, for Ibogaine's Putative Anti-addictive Activity,” 15 mecamylamine/18-methoxycoronaridine, mecamylamine/ Psychopharmacology, 118:369-376 (1995) (“Sweetnam”) de Xtrome thorphan, and de Xtrome thorphan? 18 and Chen, which are hereby incorporated by reference). methoxycoronaridine drug treatments on morphine and Indeed, it has been suggested that the NMDA receptor methamphetamine Self-administration and on responding for mediated actions of ibogaine may be central to its putative anti-addictive properties (Popik, which is hereby incorpo Water. rated by reference). To study these, transfected HEK293 More particularly, FIG. 5 shows the effects of the drugs cells expressing NR1/2A or NR1/2B receptors were voltage and drug combinations on morphine Self-administration. Rats were administered two of the following treatments clamped to -70 mV and stimulated with 100 uM glutamate before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec plus 10 uM at 30 S intervals. Agonist application 1'), 18-methoxycoronaridine (1 mg/kg i.p., 15 min) (“18MC evoked a large inward current not seen in untransfected 25 cells. Application of 20 uM ibogaine or 20 uM 1'), dextromethorphan (5 mg/kg. s.c., 20 min) (“DM 5”), or 18-methoxycoronaridine alone did not produce any vehicle (Saline for mecamylamine and dextromethorphan; response. Co-application of 20 uM ibogaine reduced the phosphate buffer for 18-methoxycoronaridine). Each data agonist-evoked response of NR1/2A receptors by 98+3% point represents the mean (tS.E.M.) percent of baseline of (N=3) and of NR1/2B receptors by 95+2% (N=3); inhibition 6-8 rats. Significant differences between baseline and treat by 10 uM ibogaine was 51.9% (n=3) and 82+3% (n=3), ment are indicated by an asterisk (paired t-test, respectively. These data are consistent with ICs values of P-0.01–0.001). 3-5uM obtained in hippocampal neurons (Popik and Chen, FIG. 6 shows the effects of the drugs and drug combina which are hereby incorporated by reference). However, as tions on methamphetamine Self-administration. Rats were shown in FIGS. 3A and 3B, we also found that 35 administered two of the following treatments before testing: co-application of 18-methoxycoronaridine failed to inhibit mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1), either NR1/2A(N=3) (FIG. 3A) or NR1/2B receptors (N=5) 18-methoxycoronaridine (2 mg/kg i.p., 15 min) (“18MC2), (FIG. 3B) at concentrations up to 20 uM. In FIGS. 3A and dextromethorphan (5 mg/kg. s.c., 20 min) (“DM 5”), or 3B, open bars depict the timing of agonist application, filled vehicle (Saline for mecamylamine and dextromethorphan; bars depict the timing of co-application of 20 uM IBO or 20 40 phosphate buffer for 18-methoxycoronaridine). Each data luM 18MC, and inhibition was measured relative to control point represents the mean (tS.E.M.) percent of baseline of at the end of the drug application (indicated by arrows). This 6-7 rats. Significant differences between baseline and treat result necessarily calls into question any role of NMDA ment are indicated by an asterisk (paired t-test, P-0.01). receptors in the putative anti-addictive actions of these FIG. 7 shows the effects of the drugs and drug combina drugs. 45 tions on responding for water. Rats were administered two There are no published Studies examining the effects of of the following treatments before testing: mecamylamine (1 ibogaine on 5-HT receptor function. Although Some action mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (2 may be expected based on competition binding Studies mg/kg i.p., 15 min) (“18MC 2'), dextromethorphan (5 (Sweetnam, which is hereby incorporated by reference), it mg/kg. s.c., 20 min) ("DM 5”), or vehicle (saline for remains to be seen whether ibogaine binding to these 50 mecamylamine and dextromethorphan; phosphate buffer for receptors activates, inhibits, or otherwise alters channel 18-methoxycoronaridine). Each data point represents the function. Likewise, the effects of 18-methoxycoronaridine mean (+S.E.M.) percent of baseline of 6 rats. on 5-HT, receptor function have not been examined. Trans All three drug combinations (i.e., mecamylamine/18 fected HEK293 cells expressing 5-HT, receptors were methoxycoronaridine, mecamylamine/dextromethorphan, voltage-clamped to -70 mV and stimulated with 100 uM 55 and dextromethorphan/18-methoxycoronaridine), but none at 30s intervals. Serotonin alone evoked an inward of the drugs administered alone, Significantly decreased current not seen in untransfected cells. Application of 20 uM morphine and methamphetamine Self-administration while ibogaine or 20 uM 18-methoxycoronaridine alone did not having no effect on responding for water. The particular produce any response, indicating that neither is an agonist at doses of 18-methoxycoronaridine, dextromethorphan, and 5-HT, receptors. Co-application of 20 uM ibogaine or 20 uM 60 mecamylamine Selected for Study were, in each instance, 18-methoxycoronaridine inhibited serotonin-evoked based on the respective dose-response functions. The doses responses by 53+3% (N=8) versus 50+3% (N=4), respec of 18-methoxycoronaridine (1 and 2 mg/kg) were approxi tively. This is shown in FIG. 4, where open bars depict the mately one-fifth of those required to decrease morphine timing of agonist application, filled bars depict the timing of (Glick et al., “18-Methoxycoronaridine, a Non-toxic Iboga co-application of 20 uM IBO or 20 uM 18MC, and inhibi 65 Alkaloid Congener: Effects on Morphine and Cocaine Self tion was measured relative to control at the end of the drug administration and on Mesolimbic Dopamine Release in application (indicated by arrows). Thus, it appears that these Rats.” Brain Res., 719:29-35 (1996), which is hereby incor US 6,780,871 B2 13 14 porated by reference) and methamphetamine (Glick I, which All three drug combinations (i.e., mecamylamine/ is hereby incorporated by reference) self-administration, bu propion, de Xtrome thorphan/bupropion, and respectively, when administered alone. The dose of dex 18-methoxycoronaridine/bupropion), but none of the drugs tromethorphan (5 mg/kg) was one-half to one-fourth of that administered alone, Significantly decreased morphine and necessary to decrease morphine and methamphetamine Self methamphetamine Self-administration while having no administration (Glick et al., “Comparative Effects of Dex effect on responding for water. tromethorphan and Dextrorphan on Morphine, Methamphetamine, and Nicotine Self-administration in Example 7 Rats,” Europ. J. Pharmacol., 422:87–90 (2001), which is hereby incorporated by reference), respectively, when Effect of Drugs and Drug Combinations on administered alone. The dose of mecamylamine (1 mg/kg) Nicotine Self-administration was one-third of that required to decrease either morphine or FIGS. 11 and 12 show the effects of mecamylamine, methamphetamine Self-administration, and, at a dose of 3 18-methoxycoronaridine, dextromethorphan, bupropion, mg/kg, mecamylamine also decreaseS responding for water mecamylamine/18-methoxycoronaridine, mecamylamine/ (data not shown). Lastly, although FIG. 7 only shows results 15 de Xtrome thorphan, and de Xtrome thorphan? 18 with the 2 mg/kg dosage of 18-methoxycoronaridine, Virtu methoxy , me camylamine/bu propion, ally identical results were found with 1 mg/kg. dextromethorphan/bupropion, and 18-methoxycoronaridine/ Example 6 bupropion drug treatments on nicotine Self-administration. More particularly, FIG. 11 shows the effects of Effect of Mecamylamine, 18-Methoxycoronaridine, me c a my la mine, 18-methoxy corona ridine, Dextromethorphan, Bupropion, Mecamylamine/ de Xtro me th orphan, me c a my lamine / 18 Bupropion, Dextromethorphan/Bupropion, and 18 methoxycoronaridine, mecamylamine/dextromethorphan, Methoxycoronaridine/Bupropion Drug Treatments and dextromethorphan/18-methoxycoronaridine, on nico on Morphine and Methamphetamine Self tine self-administration. Rats were administered two of the administration 25 following treatments before testing: mecamylamine (0.1 FIGS. 8-10 show the effects of mecamylamine, mg/kg i.p., 30 min) (“Mec 0.1”), 18-methoxycoronaridine 18-methoxycoronaridine, dextromethorphan, bupropion, (0.5 mg/kg i.p., 15 min) (“18MC 0.5"), dextromethorphan mecamylamine/bupropion, dextromethorphan/bupropion, (0.5 mg/kg, s.c., 20 min) (“DM 0.5"), or vehicle (saline for and 18-methoxycoronaridine/bupropion drug treatments on mecamylamine and dextromethorphan; phosphate buffer for morphine and methamphetamine Self-administration and on 18-methoxycoronaridine). Each data point represents the responding for water. mean (tS.E.M.) percent of baseline of 5-7 rats. Significant More particularly, FIG. 8 shows the effects of the drugs differences between baseline and treatment are indicated by and drug combinations on morphine Self-administration. an asterisk (paired t-test, P-0.01). Rats were administered two of the following treatments 35 FIG. 12 shows the effects of mec amylamine, before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 18-methoxycoronaridine, dextromethorphan, bupropion, 1'), 18-methoxycoronaridine (1 mg/kg i.p., 15 min) mecamylamine/bupropion, dextromethorphan/bupropion, (“18MC1'), dextromethorphan (5 mg/kg. s.c., 20 min) and 18-methoxycoronaridine/bupropion drug treatments on (“DM5”), bupropion (5 mg/kg i.p., 15 min) (“Bup5”), or nicotine Self-administration. Rats were administered two of vehicle (Saline for mecamylamine, dextromethorphan and the following treatments before testing: mecamylamine (0.1 bupropion; phosphate buffer for 18-methoxycoronaridine). 40 mg/kg i.p., 30 min) (“Mec 0.1”), 18-methoxycoronaridine Each data point represents the mean (tS.E.M.) percent of (0.5 mg/kg i.p., 15 min) (“18MC 0.5"), dextromethorphan baseline of 5-8 rats. Significant differences between base (0.5 mg/kg. s.c., 20 min) (“DM 0.5"), bupropion (5 mg/kg line and treatment are indicated by an asterisk (paired t-test), i.p., 15 min) (“Bup5”), or vehicle (saline for mecamylamine, P-0.05–0.01). 45 dextromethorphan and bupropion; phosphate buffer for FIG. 9 shows the effects of the drugs and drug combina 18-methoxycoronaridine). Each data point represents the tions on methamphetamine Self-administration. Rats were mean (+S.E.M.) percent of baseline of 5-8 rats. Significant administered two of the following treatments before testing: differences between baseline and treatment are indicated by mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1), an asterisk (paired t-test, P-0.01). 18-methoxycoronaridine (5 mg/kg i.p., 15 min) (*18MC5"), 50 All six drug combinations (i.e., mecamylamine/18 dextromethorphan (10 mg/kg, s.c., 20 min) (“DM10”), methoxycoronaridine, mecamylamine/dextromethorphan, bupropion (10 mg/kg i.p., 15 min) (“Bup10”), or vehicle de Xtro me thorphan / 18-methoxy corona ridine, (Saline for mecamylamine, dextromethorphan and bupro mecamylamine/bupropion, dextromethorphan/bupropion, pion; phosphate buffer for 18-methoxycoronaridine). Each and 18-methoxycoronaridine/bupropion), but none of the data point represents the mean (tS.E.M.) percent of baseline 55 drugs administered alone, Significantly decreased nicotine of 5-9 rats. Significant differences between baseline and Self-administration. Control experiments showed that these treatment are indicated by an asterisk (paired t-test, P-0.01). drug combinations had no significant effect on responding FIG. 10 shows the effects of the drugs and drug combi for water. nations on responding for water. Rats were administered two Although the invention has been described in detail for of the following treatments before testing: mecamylamine (1 60 the purpose of illustration, it is understood that Such detail mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (5 is Solely for that purpose, and variations can be made therein mg/kg i.p., 15 min) (*18MC5'), dextromethorphan (10 by those skilled in the art without departing from the spirit mg/kg. s.c., 20 min) (“DM10”), bupropion (10 mg/kg i.p., 15 and scope of the invention which is defined by the following min) (“Bup 10'), or vehicle (saline for mecamylamine, dex claims. tromethorphan and bupropion; phosphate buffer for 65 What is claimed is: 18-methoxycoronaridine). Each data point represents the 1. A composition comprising a first CfB nicotinic recep mean (+S.E.M.) percent of baseline of 6-7 rats. tor antagonist and a Second C.B. nicotinic receptor US 6,780,871 B2 15 16 antagonist, wherein Said first CBA nicotinic receptor antago receptor antagonist is administered in an amount of from nist is 18-methoxycoronaridine or a pharmaceutically about 0.1 to about 5 mg/kg of the patient's body weight per acceptable Salt or Solvate thereof and Said Second CB day. nicotinic receptor antagonist is mecamylamine or a pharma 15. A composition comprising a first C.B. nicotinic recep ceutically acceptable Salt or Solvate thereof. tor antagonist and a Second C.B. nicotinic receptor 2. A composition according to claim 1, wherein Said first antagonist, wherein Said first CfB nicotinic receptor antago O?3 nicotinic receptor antagonist and Said Second CB nist is 18-methoxycoronaridine or a pharmaceutically nicotinic receptor antagonist are present in a weight ratio of acceptable Salt or Solvate thereof and Said Second CB from about 10:1 to about 1:10. nicotinic receptor antagonist is dextromethorphan or a phar 3. A composition according to claim 1, wherein Said first maceutically acceptable Salt or Solvate thereof. Cla?s nicotinic receptor antagonist and Said Second Cla?s 16. A composition according to claim 15, wherein Said nicotinic receptor antagonist are present in a weight ratio of first Cla?s nicotinic receptor antagonist and Said Second Cla?s from about 5:1 to about 1:5. nicotinic receptor antagonist are present in a weight ratio of 4. A composition according to claim 1, wherein Said from about 10:1 to about 1:10. composition is in the form of a tablet, capsule, granular 15 17. A composition according to claim 15, wherein Said dispersible powder, Suspension, , or elixir. first Of nicotinic receptor antagonist and Said Second CB 5. A composition according to claim 1, wherein Said nicotinic receptor antagonist are present in a weight ratio of composition is in the form of a tablet or capsule and wherein from about 5:1 to about 1:5. Said composition further comprises an inert diluent, a granu 18. A composition according to claim 15, wherein Said lating agent, a disintegrating agent, a lubricating agent, or composition is in the form of a tablet, capsule, granular combinations thereof. dispersible powder, Suspension, Syrup, or elixir. 6. A method for treating nicotine addiction in a patient, 19. A composition according to claim 15, wherein said Said method comprising: administering to the patient a composition is in the form of a tablet or capsule and wherein composition according to claim 1. Said composition further comprises an inert diluent, a granu 7. A method according to claim 6, wherein the first CB 25 lating agent, a disintegrating agent, a lubricating agent, or nicotinic receptor antagonist is administered in an amount of combinations thereof. from about 0.01 to about 10 mg/kg of the patient's body 20. A method for treating nicotine addiction in a patient, weight per day and wherein the Second C.B. nicotinic Said method comprising: administering to the patient a receptor antagonist is administered in an amount of from composition according to claim 15. about 0.01 to about 10 mg/kg of the patient’s body weight 21. A method according to claim 20, wherein the first per day. CB nicotinic receptor antagonist is administered in an 8. A method according to claim 6, wherein the first CB amount of from about 0.01 to about 10 mg/kg of the patient’s nicotinic receptor antagonist is administered in an amount of body weight per day and wherein the Second O?3 nicotinic from about 0.1 to about 5 mg/kg of the patient’s body weight receptor antagonist is administered in an amount of from per day and wherein the Second CB nicotinic receptor 35 about 0.01 to about 10 mg/kg of the patient's body weight antagonist is administered in an amount of from about 0.1 to per day. about 5 mg/kg of the patient's body weight per day. 22. A method according to claim 20, wherein the first 9. A method for treating amphetamine addiction in a CB nicotinic receptor antagonist is administered in an patient, Said method comprising: administering to the patient amount of from about 0.1 to about 5 mg/kg of the patient's a composition according to claim 1. 40 body weight per day and wherein the Second O?3 nicotinic 10. A method according to claim 9, wherein the first C.B. receptor antagonist is administered in an amount of from nicotinic receptor antagonist is administered in an amount of about 0.1 to about 5 mg/kg of the patient's body weight per from about 0.01 to about 10 mg/kg of the patient's body day. weight per day and wherein the Second C.B. nicotinic 23. A method for treating amphetamine addiction in a receptor antagonist is administered in an amount of from 45 patient, Said method comprising: administering to the patient about 0.01 to about 10 mg/kg of the patient’s body weight a composition according to claim 15. per day. 24. A method according to claim 23, wherein the first 11. A method according to claim 9, wherein the first CB CB nicotinic receptor antagonist is administered in an nicotinic receptor antagonist is administered in an amount of amount of from about 0.01 to about 10 mg/kg of the patient's from about 0.1 to about 5 mg/kg of the patient’s body weight 50 body weight per day and wherein the Second CB nicotinic per day and wherein the Second C.B. nicotinic receptor receptor antagonist is administered in an amount of from antagonist is administered in an amount of from about 0.1 to about 0.01 to about 10 mg/kg of the patient's body weight about 5 mg/kg of the patient's body weight per day. per day. 12. A method for treating opioid addiction in a patient, 25. A method according to claim 23, wherein the first Said method comprising: administering to the patient a 55 CB nicotinic receptor antagonist is administered in an composition according to claim 1. amount of from about 0.1 to about 5 mg/kg of the patient's 13. A method according to claim 12, wherein the first body weight per day and wherein the Second CB nicotinic CB nicotinic receptor antagonist is administered in an receptor antagonist is administered in an amount of from amount of from about 0.01 to about 10 mg/kg of the patient's about 0.1 to about 5 mg/kg of the patient's body weight per body weight per day and wherein the Second CB nicotinic 60 day. receptor antagonist is administered in an amount of from 26. A method for treating opioid addiction in a patient, about 0.01 to about 10 mg/kg of the patient’s body weight Said method comprising: administering to the patient a per day. composition according to claim 15. 14. A method according to claim 12, wherein the first 27. A method according to claim 25, wherein the first CB nicotinic receptor antagonist is administered in an 65 CB nicotinic receptor antagonist is administered in an amount of from about 0.1 to about 5 mg/kg of the patient's amount of from about 0.01 to about 10 mg/kg of the patient's body weight per day and wherein the Second CB nicotinic body weight per day and wherein the Second CB nicotinic US 6,780,871 B2 17 18 receptor antagonist is administered in an amount of from 40. A method for treating opioid addiction in a patient, about 0.01 to about 10 mg/kg of the patient’s body weight Said method comprising: administering to the patient a per day. composition according to claim 29. 28. A method according to claim 26, wherein the first 41. A method according to claim 40, wherein the first CB nicotinic receptor antagonist is administered in an CB nicotinic receptor antagonist is administered in an amount of from about 0.1 to about 5 mg/kg of the patient's amount of from about 0.01 to about 10 mg/kg of the patient's body weight per day and wherein the Second O?3 nicotinic body weight per day and wherein the Second O?3 nicotinic receptor antagonist is administered in an amount of from receptor antagonist is administered in an amount of from about 0.1 to about 5 mg/kg of the patient's body weight per about 0.01 to about 10 mg/kg of the patients body weight per day. day. 29. A composition comprising a first C.B. nicotinic recep 42. A method according to claim 40, wherein the first tor antagonist and a Second C.B. nicotinic receptor CB nicotinic receptor antagonist is administered in an antagonist, wherein Said first CBA nicotinic receptor antago amount of from about 0.1 to about 5 mg/kg of the patient's nist is 18-methoxycoronaridine or a pharmaceutically body weight per day and wherein the Second O?3 nicotinic acceptable Salt or Solvate thereof and Said Second CB 15 receptor antagonist is administered in an amount of from nicotinic receptor antagonist is bupropion or a pharmaceu about 0.1 to about 5 mg/kg of the patient's body weight per tically acceptable Salt or Solvate thereof. day. 30. A composition according to claim 29, wherein said 43. A composition comprising a first C.B. nicotinic recep first Cla?s nicotinic receptor antagonist and Said Second Cla?s tor antagonist and a Second C.B. nicotinic receptor nicotinic receptor antagonist are present in a weight ratio of antagonist, wherein Said first CfB nicotinic receptor antago from about 10:1 to about 1:10. nist is mecamylamine or a pharmaceutically acceptable Salt 31. A composition according to claim 29, wherein Said or Solvate thereof and Said Second CB nicotinic receptor first Of nicotinic receptor antagonist and Said Second CB antagonist is dextromethorphan or a pharmaceutically nicotinic receptor antagonist are present in a weight ratio of acceptable Salt or Solvate thereof. from about 5:1 to about 1:5. 25 44. A composition according to claim 43, wherein Said 32. A composition according to claim 29, wherein Said first Cla?s nicotinic receptor antagonist and Said Second Cla?s composition is in the form of a tablet, capsule, granular nicotinic receptor antagonist are present in a weight ratio of dispersible powder, Suspension, Syrup, or elixir. from about 10:1 to about 1:10. 33. A composition according to claim 29, wherein Said 45. A composition according to claim 43, wherein Said composition is in the form of a tablet or capsule and wherein first Of nicotinic receptor antagonist and Said Second CB Said composition further comprises an inert diluent, a granu nicotinic receptor antagonist are present in a weight ratio of lating agent, a disintegrating agent, a lubricating agent, or from about 5:1 to about 1:5. combinations thereof. 46. A composition according to claim 43, wherein Said 34. A method for treating nicotine addiction in a patient, composition is in the form of a tablet, capsule, granular Said method comprising: administering to the patient a 35 dispersible powder, Suspension, Syrup, or elixir. composition according to claim 29. 47. A composition according to claim 43, wherein Said 35. A method according to claim 34, wherein the first composition is in the form of a tablet or capsule and wherein CB nicotinic receptor antagonist is administered in an Said composition further comprises an inert diluent, a granu amount of from about 0.01 to about 10 mg/kg of the patient's lating agent, a disintegrating agent, a lubricating agent, or body weight per day and wherein the Second O?3 nicotinic 40 combinations thereof. receptor antagonist is administered in an amount of from 48. A method for treating nicotine addiction in a patient, about 0.01 to about 10 mg/kg of the patient’s body weight Said method comprising: administering to the patient a per day. composition according to claim 43. 36. A method according to claim 34, wherein the first 49. A method according to claim 48, wherein the first CB nicotinic receptor antagonist is administered in an 45 CB nicotinic receptor antagonist is administered in an amount of from about 0.1 to about 5 mg/kg of the patient's amount of from about 0.01 to about 10 mg/kg of the patient's body weight per day and wherein the Second O?3 nicotinic body weight per day and wherein the Second O?3 nicotinic receptor antagonist is administered in an amount of from receptor antagonist is administered in an amount of from about 0.1 to about 5 mg/kg of the patient's body weight per about 0.01 to about 10 mg/kg of the patient's body weight day. 50 per day. 37. A method for treating amphetamine addiction in a 50. A method according to claim 48, wherein the first patient, Said method comprising: administering to the patient CB nicotinic receptor antagonist is administered in an a composition according to claim 29. amount of from about 0.1 to about 5 mg/kg of the patient's 38. A method according to claim 37, wherein the first body weight per day and wherein the Second O?3 nicotinic CB nicotinic receptor antagonist is administered in an 55 receptor antagonist is administered in an amount of from amount of from about 0.01 to about 10 mg/kg of the patient's about 0.1 to about 5 mg/kg of the patient's body weight per body weight per day and wherein the Second CB nicotinic day. receptor antagonist is administered in an amount of from 51. A method for treating amphetamine addiction in a about 0.01 to about 10 mg/kg of the patient’s body weight patient, Said method comprising: administering to the patient per day. 60 a composition according to claim 43. 39. A method according to claim 37, wherein the first 52. A method according to claim 51, wherein the first CB nicotinic receptor antagonist is administered in an CB nicotinic receptor antagonist is administered in an amount of from about 0.1 to about 5 mg/kg of the patient's amount of from about 0.01 to about 10 mg/kg of the patient's body weight per day and wherein the Second CB nicotinic body weight per day and wherein the Second CB nicotinic receptor antagonist is administered in an amount of from 65 receptor antagonist is administered in an amount of from about 0.1 to about 5 mg/kg of the patient's body weight per about 0.01 to about 10 mg/kg of the patient's body weight day. per day. US 6,780,871 B2 19 20 53. A method according to claim 51, wherein the first body weight per day and wherein the Second CB nicotinic O?3 nicotinic receptor antagonist is administered in an receptor antagonist is administered in an amount of from amount of from about 0.1 to about 5 mg/kg of the patient's about 0.01 to about 10 mg/kg of the patient's body weight body weight per day and wherein the Second CB nicotinic per day. receptor antagonist is administered in an amount of from 56. A method according to claim 54, wherein the first about 0.1 to about 5 mg/kg of the patient's body weight per CB nicotinic receptor antagonist is administered in an day. amount of from about 0.1 to about 5 mg/kg of the patient's 54. A method for treating opioid addiction in a patient, body weight per day and wherein the Second CB nicotinic Said method comprising: administering to the patient a receptor antagonist is administered in an amount of from composition according to claim 43. about 0.1 to about 5 mg/kg of the patient's body weight per 55. A method according to claim 54, wherein the first day. CB nicotinic receptor antagonist is administered in an amount of from about 0.01 to about 10 mg/kg of the patient's