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US 2002O103109A1 (19) (12) Patent Application Publication (10) . No.: US 2002/0103109 A1 Glick et al. (43) Pub. Date: Aug. 1, 2002

(54) METHODS AND COMPOSITIONS FOR (52) U.S. Cl...... 514/1 TREATING DISORDERS (57) ABSTRACT (76) Inventors: Stanley D. Glick, Delmar, NY (US); A method for treating an addiction disorder (Such as an Isabelle M. Maisonneuve, Delmar, NY addiction to or dependency on , , mor (US) phine, , other , , , and/or ) in a patient is disclosed. The method includes Correspondence Address: administering to the patient a first CfB nicotinic receptor Braman & Rogalskyj, LLP antagonist and administering to the patient a second O?3. P.O. Box 352 nicotinic . The Second CB nicotinic Canandaigua, NY 14424-0352 (US) receptor antagonist is different than the first C.B. nicotinic receptor antagonist, and the first C.B. nicotinic receptor (21) Appl. No.: 10/051,770 antagonist and the Second CB nicotinic receptor antagonist are administered simultaneously or non-simultaneously. (22) Filed: Jan. 18, 2002 Compositions which include a first C.B. nicotinic receptor Related U.S. Application Data antagonist and a Second O?3 nicotinic receptor antagonist are also described. Examples of Suitable C.B. nicotinic (60) Provisional application No. 60/264,742, filed on Jan. receptor antagonists for use in the present invention's meth 29, 2001. ods and compositions include , 18-methoxy , , , , Publication Classification and phamaceutically acceptable Salts and Solvates thereof. A method of evaluating a compound for its effectiveness in (51) Int. Cl...... A61K 31/00 treating addiction disorderS is also described. Patent Application Publication Aug. 1, 2002 Sheet 1 of 7 US 2002/0103109 A1

FIGURE 1A

ACh

FIGURE B

O. - drug) (IM) Patent Application Publication Aug. 1, 2002 Sheet 2 of 7 US 2002/0103109 A1

FIGURE 2

FIGURE 3A

18MC GLU men -- GLY

FIGURE 3B

Patent Application Publication Aug. 1, 2002 Sheet 3 of 7 US 2002/0103109 A1

FIGURE 4

5HT BO 5HT 18MC ---a - --P 4-air A control f

FIGURE 5

45 Baseline 40 Treatment 35 T T

2 5

Mec 1 18MC 1 DM 5 Mec 1 Mec 1 DM 5 18MC 1 DM 5 18MC 1 Treatment Patent Application Publication Aug. 1, 2002 Sheet 4 of 7 US 2002/0103109 A1

FIGURE 6

a 35 Baseline S Treatment 2 30 9. 3 25 2 20 E 15

a.E 10 s ES C as 5 s O s Mec 1 18Mc2 DM 5 Mec 1 Mec 1 DM 5 18MC 2 DM5 18MC 2 Treatment

FIGURE 7

Baseline 1 2 O O is Treatment 1000 800 600

4 O O

2 O O s

O Mec 1 18MC 2 DM 5 Mec 1 Mec 1 DM 5 18MC 2 DM 5 18MC 2 Treatment Patent Application Publication Aug. 1, 2002. Sheet 5 of 7 US 2002/0103109 A1

FIGURE 8

45 Baseline 40 Treatment g 35 o 30 2 25 E 3. old 20 S : 15 SO 10 : 5 : O Mec 1 18Mc DM5 Bup5 Mec1 DM5 18MC1 Bup5 Bup5 Bup5 Treatment

FIGURE 9

35 Baseline a. Treatment O 30 E 25 S 2 20 E C 15 asE 10 5 e O Mec 1 18MC5 DM10 Bup 10 Mec1 DM10 18MC5 Bup 10 Bup10 Bup10 Treatment Patent Application Publication Aug. 1, 2002. Sheet 6 of 7 US 2002/0103109 A1

FIGURE 10

Baseline 1 2 O O Treatment 1000 800 i 600

400

200

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

FIGURE 11

Baseline Treatment T

2 O

s 18M .5 DM.5 Mec. 1 Mec 1 DM 5 18MC5 DM 5 18 MC 5 Treatment Patent Application Publication Aug. 1, 2002 Sheet 7 of 7 US 2002/0103109 A1

FIGURE 12

Baseline Treatment

2O

g

3. 38

g Mec. 1 18 MC5 DM 5 Bup5 Mec 1 DM.5 18MC.5 Bup5 Bup5 Bup5 Treatment US 2002/0103109 A1 Aug. 1, 2002

METHODS AND COMPOSITIONS FOR TREATING 0009. The present invention also relates to a method for ADDICTION DISORDERS treating an addiction disorder in a patient. The method 0001) The present invention claims the benefit of U.S. includes administering to the patient an OB, nicotinic Provisional Patent Application Serial No. 60/264,742, filed receptor antagonist under conditions effective to treat the Jan. 29, 2001, which is hereby incorporated by reference. patient's addiction disorder. 0002 The present invention was made with the support BRIEF DESCRIPTION OF THE DRAWINGS of the National Institute on Drug Abuse Grant No. DA 03817. The Federal Government may have certain rights in 0010 FIG. 1A is a graph of current vs. time showing this invention. whole-cell currents evoked by 1 mM ACh in transfected cells. FIG. 1B is a graph showing inhibition of 1 mM FIELD OF THE INVENTION ACh-evoked whole-cell currents by various concentrations of various drugs. 0003. The present application relates, generally, to meth ods of treating addiction disorders using CB. nicotinic 0011 FIG. 2 is a graph of whole-cell current vs. time receptor antagonists and to compositions useful in Such showing the effect of various drugs on whole-cell currents in treatmentS. cells expressing recombinant C.B. nicotinic receptorS. 0012 FIGS. 3A and 3B are graphs of whole-cell current BACKGROUND OF THE INVENTION VS. time showing the effect of various drugs on whole-cell 0004 Drug and alcohol addiction and/or abuse and/or currents in cells expressing recombinant NR1/2A(FIG.3A) dependency (collectively referred to herein as “addiction and NR1/2B (FIG. 3B) receptors. disorders’) is extremely common. Individuals Suffering 0013 FIG. 4 is a graph of whole-cell current vs. time from Such are generally Subject to significant showing the effect of various drugs on whole-cell currents in Symptoms of withdrawal upon attempting to cease use of the cells expressing recombinant 5-HT receptors. addictive Substance (whether alcohol or drugs such as 0014 FIG. 5 is a graph showing the effects of various cocaine, heroine, nicotine, painkillers, etc.). A number of drugs and drug combinations on Self-administra medical therapies have been tried with differing levels of tion. Success. Unfortunately, to date, none of these methods of treatment have been very successful. For this and other 0015 FIG. 6 is a bar graph showing the effects of various reasons, a need exists for improved methods for treating drugs and drug combinations on Self addictive disorders. administration. 0016 FIG. 7 is a bar graph showing the effects of various SUMMARY OF THE INVENTION drugs and drug combinations on responding for water. 0005 The present invention relates to a method for 0017 FIG. 8 is a bar graph showing the effects of various treating an addiction disorder in a patient. The method drugs and drug combinations on morphine Self-administra includes administering to the patient a first C.B. nicotinic tion. receptor antagonist and administering to the patient a Second Cla?s nicotinic receptor antagonist. The Second O?3 nico 0018 FIG. 9 is a bar graph showing the effects of various tinic receptor antagonist is different than the first CB drugs and drug combinations on methamphetamine Self nicotinic receptor antagonist, and the first CBA nicotinic administration. receptor antagonist and the Second O?3 nicotinic receptor 0019 FIG. 10 is a bar graph showing the effects of antagonist are administered Simultaneously or non-simulta various drugs and drug combinations on responding for neously. Water. 0006 The present invention also relates to a composition 0020 FIG. 11 is a bar graph showing the effects of which includes a first Of nicotinic receptor antagonist and various drugs and drug combinations on nicotine Self a Second CB nicotinic receptor antagonist. In this compo administration. Sition, the Second CB nicotinic receptor antagonist is different than the first C.B. nicotinic receptor antagonist. 0021 FIG. 12 is a bar graph showing the effects of various drugs and drug combinations on nicotine Self 0007. The present invention also relates to a composition administration. which includes a first compound Selected from the group consisting of mecamylamine, 18-methoxycoronaridine, DETAILED DESCRIPTION OF THE bupropion, dextromethorphan, dextrorphan, and phamaceu INVENTION tically acceptable Salts and Solvates thereof, and a Second C.B., compound selected from the group consisting of 0022. The present invention relates to a method for mecamylamine, 18-methoxycoronaridine, bupropion, dex treating an addiction disorder in a patient. The method tromethorphan, dextrorphan, and phamaceutically accept includes administering to the patient a first C.B. nicotinic able Salts and Solvates thereof. In this composition, the receptor antagonist and administering to the patient a Second Second compound is different than the first compound. Cla?s nicotinic receptor antagonist. 0008. The present invention also relates to a method of 0023. As used herein, “addiction disorder” is meant to evaluating a compound for its effectiveneSS in treating include a habitual or recurrent use of a Substance, Such as addiction disorders by assessing the compounds ability to Stimulants, nicotine (e.g., which is meant to include all bind to C.B. nicotinic receptors. forms of nicotine administration, Such as , chewing US 2002/0103109 A1 Aug. 1, 2002 , or other forms of nicotine administration), (which is a metabolite of dextromethorphan). Other (e.g., morphine and heroin), amphetamines, cocaine, and examples of CB nicotinic receptor antagonists that are alcohol. It is meant to include, but is not meant to be limited useful in the practice of the present invention include to, a dependency on the Substance. Dependency is charac phamaceutically acceptable Salts and Solvates (the latter of terized by a patient's persistence in Substance use or abuse which is meant to include adducts) of mecamylamine, or the recurrence of Such use or abuse in the face of negative 18-methoxycoronaridine, bupropion, dextromethorphan, Social or medical consequences of this use or abuse or in and dextrorphan. Examples of Suitable Salts include those face of the patient's declared or undeclared intent to aban derived from inorganic bases (Such as ammonium and alkali don or reduce his or her use of the Substance. A patient's and alkaline earth metal hydroxides, , bicarbon dependency can be manifested in objective criteria or other ates, and the like); Salts derived from basic organic amines indices of drug Seeking behavior, Such as repeated attempts (Such as aliphatic and aromatic amines, aliphatic diamines, to abandon use or abuse of the Substance, as evidenced by, hydroxy alkylamines, and the like), and Salts derived from for example, past participation in encounter groups designed inorganic or organic acids, Such as hydrochloric, hydrobro to reduce the participants use of cocaine or , mic, or hydroiodic acid). Bupropion hydrochloride and commitment to a drug or alcohol rehabilitation program, bupropion hydrobromide are but two examples of suitable arrest or conviction of or trafficking, hos pharmaceutically acceptable Salts that can be used in the pitalization for complications arising from drug or alcohol practice of the present invention. AS used herein, "18 use, including Overdose, and the like. methoxycoronaridine' is meant to include the parent com 0024 “Patient”, as used herein, is generally meant to be pound (i.e., 18-methoxycoronaridine per se) as well as a human. However, it is envisioned that the method of the 18-methoxycoronaridine congeners (e.g., the compounds present invention can be used to treat addiction disorders in represented by formula I in U.S. Pat. No. 6,211,360 to Glick experimental mammals other than humans, Such as primates et al., which is hereby incorporated by reference). other than humans, rats, mice, dogs, and the like. Using the 0026 Suitable C.B. nicotinic receptor antagonists methods of the present invention, mammals experimentally include those compounds which are Selective for CB addicted to drugs or alcohol can be humanely weaned from nicotinic receptors as well as those compounds which are the Substance, and the physiological and psychological not Selective for C.B. nicotinic receptor. For the purposes of damage or changes which result from past drug or alcohol the present invention, a compound is to be deemed as being use can be assessed. In addition, these mammals can be used "Selective for CB nicotinic receptors' if and only if the to Study the progression of or recovery from Such physi compound's ICs at an O?3 nicotinic receptor is less than ological and psychological damage or changes Subsequent to (e.g., less than about 95% of, less than about 90% of, less the patient's abandoning or reducing his, her, or its drug or than about 80% of, less than about 65% of, less than about alcohol use. In the controlled environment of the laboratory, 50% of, less than about 20% of, and/or less than about 10% the non-human mammalian patient would be allowed to of) the compound's ICso at an another nicotinic receptor develop drug or alcohol addiction and to maintain this (e.g., at the CfB nicotinic receptor). In this regard, it should addiction for a prescribed period of time. The patient's be noted that a compound's ICso at a nicotinic receptor can addiction would then be treated in accordance with the be measured or otherwise deduced using whole-cell patch method of the present invention to cause the patient's use of clamp methods, Such as those described infra. the drug or alcohol to decrease or cease. The patient could then be monitored over time, e.g., from the time of the drug 0027 Suitable C.B. nicotinic receptor antagonists or alcohol use cessation or reduction to ascertain long-term include those compounds which are specific for CB nico physiological or psychological changes or damage and the tinic receptors as well as those compounds which are not patient's recovery from these changes or damage. Specific for Of nicotinic receptor. For the purposes of the 0.025 “Of nicotinic receptor antagonist', as used present invention, a compound is to be deemed as being herein, means a compound that directly or indirectly blockS “specific for O?3 nicotinic receptors' if and only if the or otherwise reduces the activity of an OB, nicotinic recep compound's ICso at an OB, nicotinic receptor is less than tor. AS used herein, "Of nicotinic receptor' is meant to about 20% of, less than about 15% of, less than about 10% include nicotinic receptors which contain three nicotinic of, less than about 8% of, less than about 5% of, and/or less receptor Subunits and four nicotinic receptor beta than about 3% of) the compound's ICso at one other nico Subunits, Such as the C.B. nicotinic receptorS described in tinic receptor (e.g., at the CB, nicotinic receptor), at more Lucas et al. Pharmacol. Rey, 51:397-401 (1999), which is than one other (e.g., at two other) nicotinic receptor, or at all hereby incorporated by reference. Nicotinic receptor alpha other nicotinic receptors. In this regard, it should again be Subunits are meant to include those described in GenBank noted that a compound's ICso at a nicotinic receptor can be Accession Nos. NM000743 (Homo Sapiens) and X12434 measured or otherwise deduced using whole-cell patch (chicken), which are hereby incorporated by reference. clamp methods, for example, as described infra. Nicotinic receptor beta Subunits are meant to include those 0028 AS indicated above, the method of the present described in GenBank Accession Nos. NM000750 (Homo invention involves administering two different C.B. nico Sapiens) and U42976 (rat), which are hereby incorporated by tinic receptor antagonists to the patient. For the purposes of reference. Examples of O?3 nicotinic receptor antagonists the present invention, the first CfB nicotinic receptor that are useful in the practice of the present invention include antagonist and the Second CB nicotinic receptor antagonist mecamylamine, 18-methoxycoronaridine (the preparation of are deemed to be “different' if they have different chemical which is described in Bandarage et al., Tetrahedron, formulae unless the first C.B. nicotinic receptor antagonist is 55:9405-9424 (1999), which is hereby incorporated by a phamaceutically acceptable Salt and/or Solvate of the reference), bupropion (also known as m-chloro-C-tert-buty Second C.B. nicotinic receptor or Vice versa. For example, laminopropiophenone), dextromethorphan, and dextrorphan the first C.B. nicotinic receptor antagonist can be mecamy US 2002/0103109 A1 Aug. 1, 2002 lamine, 18-methoxycoronaridine, bupropion, dextrometho administered before the first). When using sequential admin rphan, or dextrorphan and the Second CB nicotinic receptor istration, it is preferred that the Second-to-be-administered antagonist can be a CBA nicotinic receptor antagonist that is C. B. nicotinic receptor antagonist be administered while not Selected from the group consisting of mecamylamine, there is a Substantial amount of the first-to-be-administered 18-methoxycoronaridine, bupropion, dextromethorphan, CB nicotinic receptor antagonist present in the patient. and dextrorphan (or their pharmaceutically acceptable Salts Generally, it is preferred to administer the Second-to-be and/or Solvates). Alternatively, both the first CB nicotinic administered C-3, nicotinic receptor antagonist within 3X, receptor antagonist and the Second C.B. nicotinic receptor 2X, and/or 1X (where X is the first-to-be-administered C.B. antagonist can be Selected from the group consisting of nicotinic receptor antagonist metabolic half-life) of the time mecamylamine, 18-methoxycoronaridine, bupropion, dex at which the first-to-be-administered CB nicotinic receptor tromethorphan, dextrorphan, phamaceutically acceptable antagonist was administered. For example, the Second-to Salts thereof, phamaceutically acceptable and Solvates be-administered CB nicotinic receptor antagonist can be thereof, So long as the first and Second O?3 nicotinic administered to the patient within 4 hours, 3 hours, 2 hours, receptor antagonists are different from one another. Still 1 hour, 30 minutes, 10 minutes, and/or 5 minutes of the time alternatively, both the first and Second C.B. nicotinic recep at which the first-to-be-administered CB nicotinic receptor tor antagonists can be CfB nicotinic receptor antagonists antagonist was administered. that are not Selected from the group consisting of mecamy lamine, 18-methoxycoronaridine, bupropion, dextrometho 0032 Preferably, the first and second C.B. nicotinic rphan, and dextrorphan (or their pharmaceutically accept receptor antagonists are administered in amounts that are effective to treat the patient's addiction disorder. It will be able Salts and/or Solvates). appreciated that the actual preferred effective amount of first 0029 Illustratively, the first CB nicotinic receptor and Second CB nicotinic receptor antagonists will vary antagonist can be mecamylamine and the Second C.B. according to the Cla?s nicotinic receptor antagonists nicotinic receptor antagonist can be dextromethorphan. employed, the particular composition formulated, and the Alternatively, the first C.B. nicotinic receptor antagonist can mode of administration. Many factors that modify the CB be mecamylamine and the Second CB nicotinic receptor nicotinic receptor antagonists activity will be taken into antagonist can be dextrorphan. Still alternatively, the first account by those skilled in the art; e.g., body weight, Sex, C.B., nicotinic receptor antagonist can be mecamylamine and diet, time of administration, route of administration, rate of the Second C.B. nicotinic receptor antagonist can be excretion, condition of the patient, drug combinations, reac 18-methoxycoronaridine. Still alternatively, the first CB tion Sensitivities and Severities, Severity of addiction, and the nicotinic receptor antagonist can be mecamylamine and the Stage at which the patient is in the withdrawal process. Second Cla?s nicotinic receptor antagonist can be a Cla?s Administration of one or both of the C.B. nicotinic receptor nicotinic receptor antagonist other than 18-methoxycoro antagonists can be carried out continuously or periodically naridine. within the maximum tolerated dose. 0030) It is believed that each C.B. nicotinic receptor 0033 Illustratively, each C.B. nicotinic receptor antago antagonist modulates not only the activity of the CB nist can be administered in an amount from about 0.01 to nicotinic receptor but also the activity of “other receptors'. about 10 mg/kg of the patient's body weight per day, for It is further believed that the “other receptors” that are example, in an amount from about 0.02 to about 5 mg/kg of modulated by a particular C.B. nicotinic receptor antagonist the patient's body weight per day or in an amount from can vary depending on the nature of the particular CB about 0.1 to about 5 mg/kg of the patient's body weight per nicotinic receptor antagonist. In the practice of the present day. The optimal daily dose of each C.B. nicotinic receptor invention, it is preferred that the CfB nicotinic receptor antagonist for a particular patient can be determined by antagonists be chosen Such that the first C.B. nicotinic challenging the patient with a dose of the Substance to which receptor antagonist modulates one set of “other receptors' they are addicted, the optimal daily dose of CB nicotinic and Such that the Second C.B. nicotinic receptor antagonist receptor antagonist being the minimal dose at which the modulates another, different set of “other receptors'. One set patient does not feel the effects of the challenge dose. of “other receptors” is considered to be different from another set of “other receptors' if and only if there is not a 0034). The amount of each O?3 nicotinic receptor antago one-to-one correspondence between the members of two nist can be administered in a single daily dose or in multiple sets of “other receptors”. doses or even continuously. Continuous administration can be carried out in the inpatient Setting by, for example, 0031. Also as indicated above, the first and second C.B. intravenous drip, or in an outpatient Setting by providing the nicotinic receptor antagonists can be administered Simulta O?3 nicotinic receptor antagonist(s) in a slow-release for neously or non-simultaneously. Simultaneous administra mulation, Such as in a Suspension or in microcapsules. In the tion is meant to include co-administration, as in the case outpatient Setting, the administering is best carried out where the two CB nicotinic receptor antagonists are admin continuously in a Slow release formulation, or, alternatively, istered as components of a Single composition as well as in in a Single dose. In either case, to ensure compliance with the the case where the two CB nicotinic receptor antagonists treatment protocol, it is best that the provider actively are administered in Separate compositions but at the same administer (i.e. inject, etc.) each individual dose to the time (e.g., as two tablets Swallowed simultaneously or as patient or, instead, that the provider observe the patient two Solutions injected simultaneously). Non-simultaneous Self-administer each dose. administration is meant to include Sequential administration (e.g., in the case where the first Of nicotinic receptor 0035 Each C.B. nicotinic receptor antagonist can be antagonist is administered before the Second or in the case administered, individually or together, by any of the con where the Second C.B. nicotinic receptor antagonist is ventional modes of drug administration, including oral or US 2002/0103109 A1 Aug. 1, 2002 parenteral administration. Examples of parenteral adminis 0041) Suitable O.B. nicotinic receptor antagonists useful tration are intraventricular, intracerebral, intramuscular, in the practice of this aspect of the present invention include intravenous, intraperitoneal, rectal, and Subcutaneous those which are not mecamylamine, are not 18-methoxy administration. coronaridine, are not bupropion; are not dextromethorphan; are not dextrorphan, are not ; and are not a phama 0036) Each CfB nicotinic receptor antagonist or a com ceutically acceptable Salt or Solvate of mecamylamine, position containing the two can be administered alone or in 18-methoxycoronaridine, bupropion, dextromethorphan, combination with Suitable pharmaceutical carriers or dilu dextrorphan, or ibogaine. Additionally or alternatively, the ents. The diluent or carrier ingredients should be Selected So C.B., nicotinic receptor antagonist can be selective and/or that they do not diminish the therapeutic effects of the CB Specific for CB nicotinic receptors. Other Suitable CB nicotinic receptor antagonists. nicotinic receptor antagonists useful in the practice of this 0037 Suitable dosage forms for oral use include tablets, aspect of the present invention include those which are more dispersible powders, granules, capsules, Suspensions, Syr potent than 18-methoxycoronaridine at O?3 nicotinic recep ups, and elixirs. Inert diluents and carriers for tablets tors. For the purposes of the present invention, a compound include, for example, calcium , Sodium carbonate, is to be deemed as being “more potent than 18-methoxy lactose, and talc. Tablets may also contain granulating and coronaridine at CB nicotinic receptors' if and only if the disintegrating agents, Such as Starch and alginic acid; bind compound's ICso at an OB, nicotinic receptor is less than ing agents, Such as Starch, gelatin, and acacia, and lubricat (e.g., less than about 95% of, less than about 95% of, less ing agents, Such as Stearate, Stearic acid, and than about 80% of, less than about 65% of, less than about talc. Tablets may be uncoated or may be coated by known 50% of, less than about 20% of, and/or less than about 10% techniques to delay disintegration and absorption. Inert of) 18-methoxycoronaridine's ICso at the CB nicotinic diluents and carriers which may be used in capsules include, receptor. for example, calcium carbonate, calcium phosphate, and kaolin. Suspensions, Syrups, and elixirs may contain con 0042 Suitable C.B. nicotinic receptor antagonists useful ventional excipients, Such as methyl cellulose, tragacanth, in the practice of this aspect of the present invention can be Sodium alginate; wetting agents, Such as and poly identified using conventional drug Screening methodologies. oxyethylene Stearate; and preservatives, Such as ethyl-p- 0043. The present invention, in still another aspect hydroxybenzoate. thereof, relates to a method of evaluating a compound for its effectiveness in treating addiction disorders. The method 0.038. Dosage forms suitable for parenteral administra includes assessing the compounds ability to bind to C.B. tion include Solutions, Suspensions, dispersions, emulsions, nicotinic receptors. For example, a test compounds ability microcapsules and the like. They may also be manufactured to bind to O?3 nicotinic receptors (and hence its effective in the form of sterile solid compositions which can be ness in treating addiction disorders) can be assessed by dissolved or Suspended in Sterile injectable medium imme providing an Cla?s nicotinic receptor, contacting the test diately before use. They may contain Suspending or disperS compound with the C.B. nicotinic receptor, and determining ing agents known in the art. Where microcapsules are the amount of test compound which binds to the CB employed, they can be readily prepared by conventional nicotinic receptor. The assessment can be carried out, for microencapsulation techniques, Such as those disclosed in, example, by using a conventional binding assay (e.g., a for example, Encyclopedia of Chemical Technology, 3rd binding competition assay or an anSSay which employs a edition, volume 15, New York: John Wiley and Sons, pp. labeled test compound), or it can be carried out by deducing 470-493 (1981), which is hereby incorporated by reference. the test compounds ability to bind to C.B. nicotinic recep 0.039 The present invention, in another aspect thereof, tors from whole-cell patch-clamp Studies, Such as those relates to a composition which includes a first C.B. nicotinic described infra. The assessment can also be carried out by receptor and a second O?3 nicotinic receptor, the Second reviewing data or other information, provided by others, C.B., nicotinic receptor antagonist being different than the regarding the compounds ability to bind to C.B. nicotinic first C.B. nicotinic receptor antagonist. The meaning of receptors. The evaluation can also include other Steps, Such “C.B., nicotinic receptor antagonist", examples of Suitable as administering the compound to patients Suffering from nicotinic receptor antagonists, and methods for formulating addiction disorders and recording their progress, and/or these compositions are the Same as Set forth hereinabove. administering the compound to patients Suffering from The optimal amounts of the first and the Second CB addiction disorders recording any reported adverse side nicotinic receptor antagonists present in the composition of effects of the compound. the present invention can be determined from the optimal 0044) The present invention is further illustrated by the dosages as determined, for example, by using conventional following examples. dosage administration tests in View of the guidelines Set forth above. Illustratively, the first and Second C.B. nicotinic receptor antagonists can be present in a weight ratio of from EXAMPLES about 10:1 to about 1:10, Such as from about 5:1 to about Example 1 1:3, from about 3:1 to about 1:5, and/or from about 2:1 to about 1:2. 0045 Receptor Functional Analyses 0040. The present invention, in another aspect thereof, 0046) Human embryonic kidney 293 (HEK293) fibro also relates to a method for treating an addiction disorder in blasts (ATCC CRL1573) were cultured in minimal essential a patient by administering to the patient an OB, nicotinic medium supplemented with 10% fetal bovine serum and 2 receptor antagonist under conditions effective to treat the mM (Life Technologies, Rockville, Md.). Cells patient's addiction disorder. were plated on poly-D--coated 35 mm nunc dishes, US 2002/0103109 A1 Aug. 1, 2002

transfected by the LipofectaminePLUS method (Life Tech 0049 Naive female Long-Evans derived rats (250 g; nologies), and examined functionally between 18-48 h post Charles River, N.Y.) were maintained on a normal 12 hlight transfection. The following receptor subunit clNAS were cycle (lights on at 7:00 a.m., lights off at 7:00 p.m.). For all used: nAChR-O3 (nicotinic receptor-C3; experiments the “Principles of Laboratory Animal Care” accession no. L31621), nAChR-C4 (accession no. L31620), (NIH publication No. 85-23, revised 1985, which is hereby nAChR-B2 (accession no. L31622), nAChR-B4 (accession incorporated by reference) were followed. no. U42976), 5-HTR-A (5-HTAreceptor; accession no. M74425), NR1 (N-methyl-D-aspartate receptor 1; accession Example 3 no. X63255), NR2A (accession no. X91561), and NR2B (accession no. M91562). The nAchR and NR clones were 0050 Self-administration Procedure rat; the 5-HTR-A clone was mouse. Co-transfection of 0051. The intravenous self-administration procedure enhanced green fluorescent protein (“EGFP) (10% of total described in Glick et al., “18-MC Reduces Methamphet cDNA) provided a marker to identify transfected cells. amine and Nicotine Self-administration in Rats, NeuroRe Transfected cells were selected for EGFP expression and port 11:2013-2015 (2000) (“Glick I”), which is hereby examined by Voltage-clamp recording in the whole-cell incorporated by reference, was employed. Briefly, responses configuration using an AXopatch 200B patch-clamp ampli on either of two levers (mounted 15 cm apart on the front fier (Axon Instruments, Foster City, Calif.). Thin-walled wall of each operant test cage) were recorded on an IBM borosilicate glass microelectrodes (TW150F, World Preci compatible computer with a Med ASSociates, Inc. interface. sion Instruments, Sarasota, Fla.) had resistances of 3-5 MS2 The intravenous Self-administration System consisted of when filled with an internal solution containing (in mM): polyethylene-Silicone cannulas constructed according to the 135 CsCl, 10 CSF, 10 HEPES (N-2hydroxyethylpipera design of Weeks, "Long-term Intravenous Infusion, pp. zine-N'-(2-ethanesulfonic acid), 5 EGTA (ethylene glycol 155-168 in Myers (ed.), Methods in Psychobiology, Vol. 2, bis(3-aminoethyl -N,N,N',N'-tetraacetic acid), 1 New York: Academic Press (1972) (“Weeks”), which is MgCl, 0.5 CaCl, pH 7.2. Whole-cell capacitance and hereby incorporated by reference; Instech harnesses and Series resistance were recorded and adequately compensated Swivels; and Harvard Apparatus infusion pumps (#55-2222). using the available circuitry of the amplifier. Current Shaping of the bar-press response was initially accom responses were filtered at 1 kHz with an 8-pole Bessel filter plished by training rats to bar-press for water. Cannulas were (Cygnus Technologies, Delaware Water Gap, Pa.), digitized then implanted in the external jugular vein according to at 3 kHz, and stored on a Macintosh PowerPC-G3 computer procedures described in Weeks, which is hereby incorpo using an ITC-16 interface (Instrutech, Great Neck, N.Y.) rated by reference. Self-administration testing began with a under control of the data acquisition and analysis program 16-h nocturnal session followed by daily 1-h sessions, 5 Synapse (Synergy Research, Gaithersburg, Md.). Cells were days (Monday-Friday) a week. A lever-press response pro continuously Superfused with extracellular Solution contain duced a 10 ul infusion of drug solution (0.01 mg of morphine ing (in mM): 150 NaCl, 3 KC1, 5 HEPES, 1 MgCl, 1.8 sulfate) in about 0.2 s or a 50 ul infusion of drug solution CaCl, 10 glucose, and 0.1 mg/ml phenol red, pH 7.3 (0.025 mg of methamphetamine sulfate) in about 1s. Since (MgCl, was omitted from all solutions used for the study of all rats generally weighed 250-20g, each response delivered NMDA receptors). Drug stocks (10 mM) were made up in approximately 0.04 mg/kg of morphine or 0.1 mg/kg of dimethylsulfoxide (“DMSO”) and diluted in extracellular methamphetamine. Experiments to assess the effects of Solution immediately prior to use, final concentration of experimental treatments were begun when baseline Self DMSO was 0.2% or lower. Control, , and drug administration rates stabilized (s.10% variation from one Solutions were applied to individual cells by rapid perfusion. day to the next across 5 days), usually after 2 weeks of Solutions were driven by a Syringe pump through a flowpipe testing. Each rat typically received two or three different having 4 inputs that converge at a Single common output of treatments spaced at least one week apart. In order to approximately 100 um diameter. Rapid Switching between provide an indication of the Specificity of treatment effects inputs was achieved using a set of upstream Solenoid valves on drug Self-administration, all treatments were also admin (Lee Co., Westbrook, Conn.) under computer control; the istered to other rats bar-pressing for water (0.01 ml orally) Solution eXchange rate was ~5 mS as measured from liquid on a comparable Schedule (continuous reinforcement, 1-h junction currents. Sessions). Example 2 Example 4 0047 Chemicals and Animals 0048) 18-Methoxycoronaridine hydrochloride (1-2 0052 Drug Actions at Receptor Ion mg/kg, Albany Molecular Research, Inc., Albany, N.Y.) was channels dissolved in phosphate buffer and injected intraperitoneally 0053 Transfected HEK293 cells expressing various 15 minutes before behavioral testing. Dextromethorphan receptor subunit cDNAs were examined by whole-cell hydrobromide (5 mg/kg; Sigma/RBI, St. Louis, Mo.) was patch-clamp recording with fast perfusion of agonist and dissolved in Saline and injected Subcutaneously 20 minutes drug Solutions. We began with CB nACh receptors as these before testing. Mecamylamine hydrochloride (1 mg/kg, are the principal ganglionic nACh receptor Subtype for Sigma/RBI, St. Louis, Mo.) was dissolved in physiological which inhibition by ibogaine had previously been demon Saline and injected intraperitoneally 30 minutes before test strated (Badio et al., “Ibogaine: A Potent Noncompetitive ing. All rats received two injections. For rats that received a Blocker of Ganglionic/Neuronal Nicotinic Receptors, Single drug, half of them also received the appropriate "Molec. Pharmacol., 51:1-5 (1997); Mah et al., “Ibogaine Saline/vehicle injection corresponding to each of the other Acts at the Nicotinic to Inhibit two drugs. Catecholamine Release,” Brain Res., 797:173-180 (1998); US 2002/0103109 A1 Aug. 1, 2002 and Fryer et al., “Noncompetitive Functional Inhibition at tiple Mechanisms of Action Are Responsible for Ibogaine's Diverse, Human Nicotinic Acetylcholine Receptor Subtypes Putative Anti-addictive Activity, Psychopharmacology, by Bupropion, , and Ibogaine, J. Pharmacol. 118:369-376 (1995) (“Sweetnam”) and Chen, which are Exp. Ther, 288:88-92 (1999), which are hereby incorporated hereby incorporated by reference). Indeed, it has been by reference). Transfected HEK293 cells expressing C.B. suggested that the NMDA receptor-mediated actions of nACh receptors were voltage-clamped to -70 mV and ibogaine may be central to its putative anti-addictive prop stimulated with 1 mM ACh at 30 S intervals. ACh alone erties (Popik, which is hereby incorporated by reference). To evoked a large inward current not seen in untransfected study these, transfected HEK293 cells expressing NR1/2A cells. Application of 20 uM ibogaine or 20 uM 18-meth or NR1/2B receptors were voltage-clamped to -70 mV and Oxycoronaridine alone did not produce any response. AS stimulated with 100 uM glutamate plus 10 uM at 30 shown in FIG. 1A, co-application of either 20 uM ibogaine S intervals. Agonist application evoked a large inward cur (“IBO”) or 20 uM 18-methoxycoronaridine (“18MC”) rent not seen in untransfected cells. Application of 20 uM nearly abolished the ACh-evoked responses in all cells ibogaine or 20 uM 18-methoxycoronaridine alone did not tested (N=15). In FIG. 1A, open bars depict the timing of produce any response. Co-application of 20 uM ibogaine ACh application; filled bars depict the timing of co-appli reduced the agonist-evoked response of NR1/2A receptors cation of 20 uM IBO or 20 uM 18MC; and inhibition was by 98+3% (N=3) and of NR1/2B receptors by 95+2% (N=3); measured relative to control at the end of the drug applica inhibition by 10 uM ibogaine was 51.9% (n=3) and 82+3% tion (indicated by arrows). The inhibition developed rapidly (n=3), respectively. These data are consistent with ICso in the presence of ACh and reversed more slowly following values of 3-5 uM obtained in hippocampal neurons (Popik the removal of drug. As shown in FIG. 1B, the inhibition and Chen, which are hereby incorporated by reference). was concentration-dependent, ICso values were 0.22 uM for However, as shown in FIGS. 3A and 3B, we also found that ibogaine versus 0.75 M for 18-methoxycoronaridine, and co-application of 18-methoxycoronaridine failed to inhibit the concentration-response relationship had a Hill slope of either NR1/2A(N=3) (FIG.3A) or NR1/2B receptors (N=5) unity which is consistent with a single Site of action. More (FIG. 3B) at concentrations up to 20 uM. In FIGS. 3A and particularly, FIG. 1B shows the inhibition of 1 mM ACh 3B, open bars depict the timing of agonist application, filled evoked currents by various concentrations of IBO and bars depict the timing of co-application of 20 uM IBO or 20 18MC. The data presented in FIG. 1B are meani-SEM for luM 18MC, and inhibition was measured relative to control 3-14 cells per point, and curve fits are given for the logistic at the end of the drug application (indicated by arrows). This equation: I=I/(1+(drug/ICso)). Best fitting ICso values result necessarily calls into question any role of NMDA were 0.75 uM for IBO and 0.22 uM for 18MC. These data receptors in the putative anti-addictive actions of these confirm previous reports of the actions of ibogaine and drugs. indicate that 18-methoxycoronaridine has similar actions at 0055. There are no published studies examining the ganglionic nACh receptors. Results were Somewhat differ effects of ibogaine on 5-HT, receptor function. Although ent, however, at neuronal nACh receptors. In this case, Some action may be expected based on competition binding transfected HEK293 cells expressing CB nACh receptors studies (Sweetnam, which is hereby incorporated by refer were voltage-clamped to -70 mV and stimulated with 300 ence), it remains to be seen whether ibogaine binding to luM ACh at 30 s intervals. ACh alone evoked an inward these receptorS activates, inhibits, or otherwise alters chan current whereas application of 20 uM ibogaine or 20 uM nel function. Likewise, the effects of 18-methoxycoronari 18-methoxycoronaridine alone did not produce any dine on 5-HT, receptor function have not been examined. response. Co-application of 5 uM ibogaine inhibited the Transfected HEK293 cells expressing 5-HTA receptors ACh-evoked response by 61+4% (n=5) whereas 5 uM were voltage-clamped to -70 mV and stimulated with 100 18-methoxycoronaridine produced no apparent inhibition luM at 30 s intervals. Serotonin alone evoked an (N=6). This is shown in FIG. 2, where open bars depict the inward current not seen in untransfected cells. Application timing of ACh application and filled bars depict the timing of 20 uM ibogaine or 20 uM 18-methoxycoronaridine alone of co-application of 20 uM IBO or 20 uM 18MC. Because did not produce any response, indicating that neither is an of the relatively rapid desensitization of the O?3 response, agonist at 5-HT, receptors. Co-application of 20 uM inhibition was measured relative to control (Superimposed ibogaine or 20 uM 18-methoxycoronaridine inhibited sero curve fits) during drug application (arrows). At higher drug tonin-evoked responses by 53+3% (N=8) versus 50+3% concentrations (20 uM), ibogaine inhibition reached 93+3% (N=4), respectively. This is shown in FIG. 4, where open (N=7) versus only 8 +4% by 18-methoxycoronaridine bars depict the timing of agonist application, filled bars (N=6). These data Suggest the ICs for ibogaine at CB depict the timing of co-application of 20 uM IBO or 20 uM nACh receptors is on the order of 1-5 uM and that 18-meth 18MC, and inhibition was measured relative to control at the oxycoronaridine is considerably less potent (ICso>20 um) at end of the drug application (indicated by arrows). Thus, it this neuronal nACh receptor Subtype. appears that these drugs have Similar potencies at 5-HT 0.054 Another known action of ibogaine involves the receptors with ICso values of approximately 20 um. inhibition of NMDA-type glutamate receptors (Popik et al., Example 5 “NMDA Antagonist Properties of the Putative Antiaddictive Drug, Ibogaine, J. Pharmacol. Exp. Ther, 275:753-760 0056 Effect of Mecamylamine, 18-Methoxycoronari (1995) (“Popik”) and Chen et al., “Ibogaine Block of the dine, Dextromethorphan, Mecamylamine/18-Methoxycoro NMDA Receptor: In Vitro and In Vivo Studies,'Neurophar naridine, Mecamylamine/Dextromethorphan, and Dex macology, 35:423-431 (1996) (“Chen”), which are hereby tromethorphan/18-Methoxycoronaridine Drug Treatments incorporated by reference), presumably by interaction with on Morphine and Methamphetamine Self-administration the PCP/MK-801 (phencyclidine/) binding site 0057 FIGS. 5-7 show the effects of mecamylamine, (Sweetnam et al., “Receptor Binding Profile Suggests Mul 18-methoxycoronaridine, dextromethorphan, mecamy US 2002/0103109 A1 Aug. 1, 2002 lamine/18-methoxycoronaridine, mecamylamine/dex The dose of mecamylamine (1 mg/kg) was one-third of that tromethorphan, and dextromethorphan/18-methoxycoro required to decrease either morphine or methamphetamine naridine drug treatments on morphine and Self-administration, and, at a dose of 3 mg/kg, mecamy methamphetamine Self-administration and on responding for lamine also decreases responding for water (data not Water. shown). Lastly, although FIG. 7 only shows results with the 2 mg/kg dosage of 18-methoxycoronaridine, Virtually iden 0.058 More particularly, FIG. 5 shows the effects of the tical results were found with 1 mg/kg. drugs and drug combinations on morphine Self-administra tion. Rats were administered two of the following treatments Example 6 before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 0062) Effect of Mecamylamine, 18-Methoxycoronari 1'), 18-methoxycoronaridine (1 mg/kg i.p., 15 min) (“18MC dine, Dextromethorphan, Bupropion, Mecamylamine/Bu 1'), dextromethorphan (5 mg/kg. s.c., 20 min) (“DM 5”), or propion, Dextromethorphan/Bupropion, and 18-Methoxy vehicle (Saline for mecamylamine and dextromethorphan; coronaridine/Bupropion Drug Treatments on Morphine and phosphate buffer for 18-methoxycoronaridine). Each data Methamphetamine Self-administration point represents the mean (tS.E.M.) percent of baseline of 0063 FIGS. 8-10 show the effects of mecamylamine, 6-8 rats. Significant differences between baseline and treat 18-methoxycoronaridine, dextromethorphan, bupropion, ment are indicated by an asterisk (paired t-test, P-0.01 mecamylamine/bupropion, dextromethorphan?bupropion, 0.001). and 18-methoxycoronaridine/bupropion drug treatments on 0059 FIG. 6 shows the effects of the drugs and drug morphine and methamphetamine Self-administration and on combinations on methamphetamine Self-administration. responding for water. Rats were administered two of the following treatments 0064.) More particularly, FIG. 8 shows the effects of the before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec drugs and drug combinations on morphine Self-administra 1'), 18-methoxycoronaridine (2 mg/kg i.p., 15 min) (“18MC tion. Rats were administered two of the following treatments 2”), dextromethorphan (5 mg/kg, s.c., 20 min) (“DM 5”), or before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec vehicle (Saline for mecamylamine and dextromethorphan; 1'), 18-methoxycoronaridine (1 mg/kg i.p., 15 min) phosphate buffer for 18-methoxycoronaridine). Each data (“18MC1'), dextromethorphan (5 mg/kg, s.c., 20 min) point represents the mean (tS.E.M.) percent of baseline of (“DM5”), bupropion (5 mg/kg i.p., 15 min) (“Bup5”), or 6-7 rats. Significant differences between baseline and treat vehicle (Saline for mecamylamine, dextromethorphan and ment are indicated by an asterisk (paired t-test, P-0.01). bupropion; phosphate buffer for 18-methoxycoronaridine). 0060 FIG. 7 shows the effects of the drugs and drug Each data point represents the mean (tS.E.M.) percent of combinations on responding for water. Rats were adminis baseline of 5-8 rats. Significant differences between baseline tered two of the following treatments before testing: and treatment are indicated by an asterisk (paired t-test), mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1), 18-meth P-0.05-0.01). oxycoronaridine (2 mg/kg i.p., 15 min) (“18MC 2'), dex 0065 FIG. 9 shows the effects of the drugs and drug tromethorphan (5 mg/kg, s.c., 20 min) (“DM 5”), or vehicle combinations on methamphetamine Self-administration. (Saline for mecamylamine and dextromethorphan; phos Rats were administered two of the following treatments phate buffer for 18-methoxycoronaridine). Each data point before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec represents the mean (+S.E.M.) percent of baseline of 6 rats. 1'), 18-methoxycoronaridine (5 mg/kg i.p., 15 min) (“18MC5'), dextromethorphan (10 mg/kg. s.c., 20 min) 0061 All three drug combinations (i.e., mecamylamine/ (“DM10”), bupropion (10 mg/kg i.p., 15 min) (“Bup10”), or 18-methoxycoronaridine, mecamylamine/dextromethor vehicle (Saline for mecamylamine, dextromethorphan and phan, and dextromethorphan/18-methoxycoronaridine), but bupropion; phosphate buffer for 18-methoxycoronaridine). none of the drugs administered alone, Significantly Each data point represents the mean (tS.E.M.) percent of decreased morphine and methamphetamine Self-administra baseline of 5-9 rats. Significant differences between baseline tion while having no effect on responding for water. The particular doses of 18-methoxycoronaridine, dextromethor and treatment are indicated by an asterisk (paired t-test, phan, and mecamylamine Selected for Study were, in each P-0.01). instance, based on the respective dose-response functions. 0.066 FIG. 10 shows the effects of the drugs and drug The doses of 18-methoxycoronaridine (1 and 2 mg/kg) were combinations on responding for water. Rats were adminis approximately one-fifth of those required to decrease mor tered two of the following treatments before testing: phine (Glick et al., “18-Methoxycoronaridine, a Non-toxic mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1), 18-meth Iboga Congener: Effects on Morphine and Cocaine oxycoronaridine (5 mg/kg i.p., 15 min) (“18MC5”), dex Self-administration and on Mesolimbic Release tromethorphan (10 mg/kg, s.c., 20 min) (“DM10”), bupro in Rats.” Brain Res., 719:29-35 (1996), which is hereby pion (10 mg/kg i.p., 15 min) (“Bup10), or vehicle (saline incorporated by reference) and methamphetamine (Glick I, for mecamylamine, dextromethorphan and bupropion; phos which is hereby incorporated by reference) self-administra phate buffer for 18-methoxycoronaridine). Each data point tion, respectively, when administered alone. The dose of represents the mean (tS.E.M.) percent of baseline of 6-7 dextromethorphan (5 mg/kg) was one-half to one-fourth of ratS. that necessary to decrease morphine and methamphetamine 0067 All three drug combinations (i.e., mecamylamine/ self-administration (Glick et al., “Comparative Effects of bupropion, dextromethorphan?bupropion, and 18-methoxy Dextromethorphan and Dextrorphan on Morphine, Metham coronaridine/bupropion), but none of the drugs administered phetamine, and Nicotine Self-administration in Rats, Europ. alone, Significantly decreased morphine and methamphet J. Pharmacol., 422:87–90 (2001), which is hereby incorpo amine Self-administration while having no effect on rated by reference), respectively, when administered alone. responding for water. US 2002/0103109 A1 Aug. 1, 2002

Example 7 administering to the patient a Second C.B. nicotinic recep tor antagonist, wherein the Second CB nicotinic 0068. Effect of Drugs and Drug Combinations on Nico receptor antagonist is different than the first CB tine Self-administration nicotinic receptor antagonist and wherein the first Of 0069 FIGS. 11 and 12 show the effects of mecamy nicotinic receptor antagonist and the Second CB nico lamine, 18-methoxycoronaridine, dextromethorphan, bupro tinic receptor antagonist are administered simulta pion, mecamylamine/18-methoxycoronaridine, mecamy neously or non-simultaneously. lamine/dextromethorphan, and dextromethorphan/18 2. A method according to claim 1, wherein the addiction methoxycoronaridine, mecamylamine/bupropion, disorder is nicotine addiction. dextromethorphan/bupropion, and 18-methoxycoronaridine/ 3. A method according to claim 1, wherein the addiction bupropion drug treatments on nicotine Self-administration. disorder is opioid addiction. 0070 More particularly, FIG. 11 shows the effects of 4. A method according to claim 1, wherein the addiction mecamylamine, 18-methoxycoronaridine, dextromethor disorder is heroin addiction. phan, mecamylamine/18-methoxycoronaridine, mecamy 5. A method according to claim 1, wherein the addiction lamine/dextromethorphan, and dextromethorphan/18-meth disorder is amphetamine addiction. Oxycoronaridine, on nicotine Self-administration. Rats were 6. A method according to claim 1, wherein the addiction administered two of the following treatments before testing: disorder is cocaine addiction. mecamylamine (0.1 mg/kg i.p., 30 min) (“Mec 0.1”), 7. A method according to claim 1, wherein the addiction 18-methoxycoronaridine (0.5 mg/kg i.p., 15 min) (“18MC disorder is alcohol addiction. 0.5”), dextromethorphan (0.5 mg/kg, s.c., 20 min) (“DM 8. A method according to claim 1, wherein the first CB 0.5”), or vehicle (saline for mecamylamine and dex nicotinic receptor antagonist and the Second C.B. nicotinic tromethorphan; phosphate buffer for 18-methoxycoronari receptor antagonist are administered simultaneously. dine). Each data point represents the mean (tS.E.M.) per 9. A method according to claim 1, wherein the first Of cent of baseline of 5-7 rats. Significant differences between nicotinic receptor antagonist and the Second C.B. nicotinic baseline and treatment are indicated by an asterisk (paired receptor antagonist are administered simultaneously by t-test, P-0.01). administering a composition comprising the first C.B. nico 0071 FIG. 12 shows the effects of mecamylamine, tinic receptor antagonist and the Second C.B. nicotinic 18-methoxycoronaridine, dextromethorphan, bupropion, receptor antagonist. mecamylamine/bupropion, dextromethorphan?bupropion, 10. A method according to claim 1, wherein the first CB and 18-methoxycoronaridine/bupropion drug treatments on nicotinic receptor antagonist and the Second C.B. nicotinic nicotine Self-administration. Rats were administered two of receptor antagonist are administered Sequentially, in either the following treatments before testing: mecamylamine (0.1 order, within 4 hours of one another. mg/kg i.p., 30 min) (“Mec 0.1”), 18-methoxycoronaridine 11. A method according to claim 1, wherein the first CB (0.5 mg/kg i.p., 15 min) (“18MC 0.5"), dextromethorphan nicotinic receptor antagonist is administered in an amount of (0.5 mg/kg. s.c., 20 min) (“DM 0.5”), bupropion (5 mg/kg from about 0.01 to about 10 mg/kg of the patient's body i.p., 15 min) (“Bup5”), or vehicle (saline for mecamylamine, weight per day and wherein the Second C.B. nicotinic dextromethorphan and bupropion; phosphate buffer for receptor antagonist is administered in an amount of from 18-methoxycoronaridine). Each data point represents the about 0.01 to about 10 mg/kg of the patient's body weight mean (+S.E.M.) percent of baseline of 5-8 rats. Significant per day. differences between baseline and treatment are indicated by 12. A method according to claim 1, wherein the first CB an asterisk (paired t-test, P-0.01). nicotinic receptor antagonist is administered in an amount of 0072 All six drug combinations (i.e., mecamylamine/18 from about 0.1 to about 5 mg/kg of the patient’s body weight methoxycoronaridine, mecamylamine/dextromethorphan, per day and wherein the Second CB nicotinic receptor dextromethorphan/18-methoxycoronaridine, mecamy antagonist is administered in an amount of from about 0.1 to lamine/bupropion, dextromethorphan/bupropion, and about 5 mg/kg of the patient's body weight per day. 18-methoxycoronaridine/bupropion), but none of the drugs 13. A method according to claim 1, wherein the first Of administered alone, Significantly decreased nicotine Self nicotinic receptor antagonist is Selected from the group administration. Control experiments showed that these drug consisting of mecamylamine, 18-methoxycoronaridine, combinations had no significant effect on responding for bupropion, dextromethorphan, dextrorphan, and phamaceu Water. tically acceptable Salts and Solvates thereof. 14. A method according to claim 1, wherein the Second 0.073 Although the invention has been described in detail C.B., nicotinic receptor antagonist is selected from the group for the purpose of illustration, it is understood that Such consisting of mecamylamine, 18-methoxycoronaridine, detail is Solely for that purpose, and variations can be made bupropion, dextromethorphan, dextrorphan, and phamaceu therein by those skilled in the art without departing from the tically acceptable Salts and Solvates thereof. spirit and scope of the invention which is defined by the 15. A method according to claim 1, wherein each of the following claims. first and Second C.B. nicotinic receptor antagonists is inde pendently Selected from the group consisting of mecamy What is claimed is: lamine, 18-methoxycoronaridine, bupropion, dextrometho 1. A method for treating an addiction disorder in a patient, rphan, dextrorphan, and phamaceutically acceptable Salts Said method comprising: and Solvates thereof. administering to the patient a first CB nicotinic receptor 16. A method according to claim 1, wherein the first CB antagonist; and nicotinic receptor antagonist is mecamylamine. US 2002/0103109 A1 Aug. 1, 2002

17. A method according to claim 1, wherein the Second 32. A composition according to claim 21, wherein Said C.B., nicotinic receptor antagonist is dextromethorphan. composition is in the form of a tablet, capsule, granular 18. A method according to claim 1, wherein the Second dispersible powder, Suspension, Syrup, or elixir. C.B., nicotinic receptor antagonist is dextrorphan. 33. A composition according to claim 21, wherein Said 19. A method according to claim 1, wherein the first CB composition is in the form of a tablet or capsule and wherein nicotinic receptor antagonist is mecamylamine and wherein Said composition further comprises an inert diluent, a granu the Second C.B. nicotinic receptor antagonist is dex lating agent, a disintegrating agent, a lubricating agent, or tromethorphan. combinations thereof. 20. A method according to claim 1, wherein the first O?3. 34. A composition comprising: nicotinic receptor antagonist is mecamylamine and wherein a first compound Selected from the group consisting of the Second O?3 nicotinic receptor antagonist is dextrorphan. mecamylamine, 18-methoxycoronaridine, bupropion, 21. A composition comprising: dextromethorphan, dextrorphan, and phamaceutically a first Cla?s nicotinic receptor antagonist, and acceptable Salts and Solvates thereof, and a Second CB nicotinic receptor antagonist, wherein the a Second CB compound selected from the group con Second O?3 nicotinic receptor antagonist is different Sisting of mecamylamine, 18-methoxycoronaridine, than the first CBA nicotinic receptor antagonist. bupropion, dextromethorphan, dextrorphan, and pha 22. A composition according to claim 21, wherein Said maceutically acceptable Salts and Solvates thereof; first Cla?s nicotinic receptor antagonist and Said Second Cla?s wherein the second compound is different than the first nicotinic receptor antagonist are present in a weight ratio of compound. from about 10:1 to about 1:10. 35. A method of evaluating a compound for its effective 23. A composition according to claim 21, wherein Said neSS in treating addiction disorders, Said method comprising: first Of nicotinic receptor antagonist and Said Second CB assessing the compounds ability to bind to CB nicotinic nicotinic receptor antagonist are present in a weight ratio of receptors. from about 5:1 to about 1:5. 36. A method according to claim 35, wherein Said assess 24. A composition according to claim 21, wherein Said ing comprises: first CBA nicotinic receptor antagonist is Selected from the group consisting of mecamylamine, 18-methoxycoronari providing an O?3 nicotinic receptor, and dine, bupropion, dextromethorphan, dextrorphan, and pha contacting the test compound with the C.B. nicotinic maceutically acceptable Salts and Solvates thereof. receptor, and 25. A composition according to claim 21, wherein said Second O?3 nicotinic receptor antagonist is selected from determining the amount of test compound which binds to the group consisting of mecamylamine, 18-methoxycoro the Cla?s nicotinic receptor. naridine, bupropion, dextromethorphan, dextrorphan, and 37. A method for treating an addiction disorder in a phamaceutically acceptable Salts and Solvates thereof. patient, Said method comprising: 26. A composition according to claim 21, wherein each of administering to the patient an OB, nicotinic receptor said first and said Second CB nicotinic receptor antagonists antagonist under conditions effective to treat the is independently Selected from the group consisting of patient's addiction disorder. mecamylamine, 18-methoxycoronaridine, bupropion, dex 38. A method according to claim 37, wherein the CB tromethorphan, dextrorphan, and phamaceutically accept nicotinic receptor antagonist is not mecamylamine, is not able salts and Solvates thereof. 18-methoxycoronaridine, is not bupropion; is not deX 27. A composition according to claim 21, wherein Said tromethorphan, is not dextrorphan, is not ibogaine; and is first CBA nicotinic receptor antagonist is mecamylamine. not a phamaceutically acceptable Salt or Solvate of mecamy 28. A composition according to claim 21, wherein Said lamine, 18-methoxycoronaridine, bupropion, dextrometho Second CB nicotinic receptor antagonist is dextromethor rphan, dextrorphan, or ibogaine. phan. 39. A method according to claim 37, wherein the CB 29. A composition according to claim 21, wherein Said nicotinic receptor antagonist is selective for O?3 nicotinic Second C.B. nicotinic receptor antagonist is dextrorphan. receptors. 30. A composition according to claim 21, wherein Said 40. A method according to claim 37, wherein the CfB first C.B. nicotinic receptor antagonist is mecamylamine and nicotinic receptor antagonist is specific for C.B. nicotinic wherein said Second C.B. nicotinic receptor antagonist is receptors. dextromethorphan. 41. A method according to claim 37, wherein the CB 31. A composition according to claim 21, wherein Said nicotinic receptor antagonist is more potent than 18-meth first C.B. nicotinic receptor antagonist is mecamylamine and oxycoronaridine at CB nicotinic receptors. wherein Said Second C.B. nicotinic receptor antagonist is dextrorphan. k k k k k