US 2002001.9421A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0019421 A1 Biberman (43) Pub. Date: Feb. 14, 2002

(54) COMPOSITIONS AND THERAPY FOR Publication Classification SUBSTANCE ADDICTION

(51) Int. CI.7. ... A61K 31/44; A61K 9/00 (76) Inventor: Roni Biberman, Tel-Aviv (IL) (52) U.S. Cl...... 514/343; 424/43 Correspondence Address: Eitan, Pearl, Latzer & Cohen-Zedek (57) ABSTRACT Stal Park Inhibitors of monoamine oxidase used in combination with 2011 Crystal Drive an addictive Substance, or a pharmacological derivative or Arlington, VA 2.2202-3700 (US) analogue thereof, are useful for the treatment of Substance 9 addiction disorders. In particular, the invention discloses (21) Appl. No.: 09/898,027 compositions, and methods of use thereof, comprising Sel egiline and nicotine for the treatment of cigarette SmokerS (22) Filed: Jul. 5, 2001 wishing to abstain. The compositions and methods of use thereof include oral, inhalant, parenteral and transdermal Related U.S. Application Data patch modes of therapy, whereby the subject benefits from the combined effects of a monoamine oxidase inhibitor in (63) Non-provisional of provisional application No. combination with an addictive Substance, or derivative 60/216,366, filed on Jul. 5, 2000. thereof. US 2002/0019421 A1 Feb. 14, 2002

COMPOSITIONS AND THERAPY FOR 0006 The acetylcholine receptors appear to be of two SUBSTANCE ADDICTION general Subtypes, One Subtype appears to have nicotine as an agonist or muscarine as an agonist. Both types of receptor FIELD OF THE INVENTION are found in the central nervous System as well as the autonomic nervous System. 0001. The present invention relates to medicinal compo Sitions and methods of treating Substance addiction, in 0007. Other compounds in addition to cholinergic and particular addiction to nicotine-containing tobacco products, anticholinergic drugs have been tested for the purpose of wherein administration to an addicted subject of inhibitors attenuating withdrawal Symptoms, including craving. These of monoamine oxidase combined with co-administration of include benzodiazepines, dopamine agonists, Serotonin ago an addictive Substance is used to alleviate withdrawal Symp nists, inhibitors of dopamine carboxylase, and inhibitors of toms and to change or eliminate patterns of addictive Serotonin reuptake or of dopamine reuptake. The neurotrans Substance consumption, in particular that due to cigarette mitter dopamine has been shown to be strongly linked to the Smoking, over both short and extended periods of time. internal mechanism of pleasure Sensation mechanism of animal, including human, brains. BACKGROUND OF THE INVENTION 0008 More recently developed strategies have focused 0002 The present disclosure is related to U.S. provisional on the genetic basis of drug addiction, in particular addiction patent application No. 60/216,366, filed on Jul. 5, 2000 and to nicotine. Thus it has been hypothesized that individuals in which is hereby is incorporated herein by reference. The whom nicotine is slowly metabolized are both more likely to Statistical risk of dying from lung cancer in the United States consume fewer cigarettes or not be Smokers at all. Thus has doubled in the past thirty years for male cigarette inhibition of the metabolism of nicotine, through either SmokerS and has quadrupled for female cigarette SmokerS. inhibition of the nicotine degrading enzymes or through Lung cancer has now displaced cardiovascular disease as the inhibition of the Synthesis of nicotine degrading enzymes. Single most important cause of exceSS mortality among 0009 Inhibitors of the intracellular enzyme monoamine Smokers. Yet, about 50 million Americans continue to oxidase (monoamine oxidase) have been traditionally used Smoke. in medical therapies for the treatment of disease of the 0003. The benefits for smoking cessation are many, and central nervous System, in particular depression and Parkin are summarized in a publication entitled “The Health Ben Son's disease. The use of monoamine oxidase inhibitors in efits of Smoking Cessation: A Report of the Surgeon Gen the treatment of addiction, in particular, tobacco product eral, 1990', available from the Office on Smoking and addiction, has been recurrently Suggested although, for lack Health, Center for Disease Control, Rockville, Md. Among of conclusive data, these therapeutic compounds are not the benefits summarized are that within twenty-four hours currently endorsed for this use by the medical establishment. the chance of a heart attack decreases, within about two 0010 Most significantly, despite the introduction of nico weeks to three months lung function increases up to thirty tine replacement therapies, most frequently administered in percent, and in one year the exceSS risk of coronary heart the form of transdermal patch or nicotine gum, addiction to disease becomes half that of a Smoker. tobacco products and the associated increased morbidity and 0004 Smoking cessation programs often address both the mortality continues to be a global epidemic. physiological factor and the psychological factor. The widely available "nicotine-releasing patches' have been SUMMARY OF THE INVENTION highly advertised, and are useful for maintaining a nicotine 0011. The invention provides a pharmaceutical composi habituated patient on nicotine while addressing further the psychological factors of addiction. Craving is the most tion comprising an amount of an inhibitor of monoamine consistently observed withdrawal symptom and is probably oxidase, an amount of an addictive Substance, or derivative best described as a combination of physiological and psy thereof, and a Suitable diluent or carrier. chological factors. To treat craving for nicotine, other modes 0012. The invention provides a pharmaceutical compo of nicotine replacement therapy have been introduced, Sition comprising an amount of an inhibitor of monoamine including administration of nicotine by oral chewing gum oxidase, an amount of an addictive Substance, or derivative and by inhalation with a carrier for absorption through the thereof, and a Suitable diluent or carrier, wherein Said respiratory mucosa, including the lungs. composition is adapted to administer both the inhibitor of 0005. In addition to nicotine replacement therapy, other monoamine oxidase and the addictive Substance, or deriva pharmacological therapies have been described based on tive thereof, via the same route of administration. compounds which are expected to influence the physiologi 0013 The invention provides a pharmaceutical compo cal mechanisms common to nicotinic agents. This is the Sition comprising an amount of an inhibitor of monoamine basis for the use of compounds which interact with acetyl oxidase, an amount of an addictive Substance or derivative choline receptors, or affect levels of the neurotransmitter thereof, and a Suitable diluent or carrier, wherein Said carrier acetylcholine, as a means for reducing the desire for nicotine is an oral tablet, capsule, a comestible article, an aerosol, or other addictive drugs. Atropine and Scopolamine are nebulized vapor, Smoke, or a transdermal patch, and wherein alkaloids that block the action of acetylcholine at muscarinic Said carrier is Suitable for parenteral administration, includ receptors to produce antispasmodic, antisecretory, and anti ing intradermal, Subcutaneous, intramuscular, intravenous, parkinsonism actions. PhySoStigmine is an inhibitor of the intrathecal, Sublingual, rectal, vaginal, intraocular, transder enzyme acetylcholinesterase, thereby raising the level of mal, respiratory mucosal, or pulmonary routes of adminis acetylcholine through inhibition of its metabolism. tration. US 2002/0019421 A1 Feb. 14, 2002

0.014. The invention provides a pharmaceutical compo PharmaProjects 2806; PharmaProjects 1122; Phar Sition comprising an amount of an inhibitor of monoamine maProjects 331; PharmaProjects 4433; RS-2232; UP-614 oxidase, an amount of an addictive Substance or derivative 04, or mixtures thereof. thereof, and a Suitable diluent or carrier, wherein Said 0018. The invention provides a pharmaceutical compo addictive Substance, or derivative thereof, is nicotine and Sition, wherein Said monoamine oxidase inhibitor is Sel Said carrier is an oral tablet, capsule, a comestible article, an egiline, Said carrier is an oral tablet, a capsule, a comestible aeroSol carrier a vapor, a Smoke, or a transdermal patch and article, an aeroSol, a vapor, a Smoke, or a transdermal patch, wherein Said carrier is Suitable for parenteral administration, and wherein Said carrier is Suitable for parenteral adminis including intradermal, Subcutaneous, intramuscular, intrave tration, including intradermal, Subcutaneous, intramuscular, nous, intrathecal, Sublingual, rectal, vaginal, intraocular, intravenous, intrathecal, Sublingual, rectal, vaginal, transdermal, respiratory mucosal, or pulmonary routes of intraocular, transdermal, respiratory mucosal, or pulmonary administration, routes of administration, and Said addictive Substance, or 0.015 The invention provides a pharmaceutical compo derivative thereof, is nicotine, cotinine, a nicotinic agonist, Sition comprising an amount of an inhibitor of monoamine a derivative of nicotine, a dopamine agonist, an opiate, oxidase, an amount of an addictive Substance or derivative morphine, heroin, methadone, buprenorphine, fentanyl, thereof, and a Suitable diluent or carrier, wherein Said i naloxone, codeine, an amphetamine, metamphetamine, monoamine oxidase in inhibitor is Selegiline and Said carrier methylphenidate, methylenedioxymethamphetamine, a is an oral tablet, capsule, a comestible article, an aeroSol, a dopamine re-uptake inhibitor, an alkaloid, cocaine, or Vapor, a Smoke, or a transdermal patch, and wherein Said derivative thereof. The invention provides a pharmaceutical carrier is Suitable for parenteral administration, including composition, wherein Said monoamine oxidase inhibitor is intradermal, Subcutaneous, intramuscular, intravenous, Selegiline, wherein Said addictive Substance, or derivative intrathecal, Sublingual, rectal, vaginal, intraocular, transder thereof, is nicotine, Said carrier is an oral tablet, a capsule, mal, respiratory mucosal, or pulmonary routes of adminis a comestible article, an aeroSol, a vapor, a Smoke, or a tration. transdermal patch, wherein Said carrier is Suitable for parenteral administration, including intradermal, Subcutane 0016. The invention provides a pharmaceutical compo ous, intramuscular, intravenous, intrathecal, Sublingual, rec Sition comprising an amount of an inhibitor of monoamine tal, vaginal, intraocular, transdermal, respiratory mucosal, or oxidase, an amount of an addictive Substance, or derivative pulmonary routes of administration, and Said composition thereof, and a Suitable diluent or carrier, wherein Said further comprises at least one compound Selected from the monoamine oxidase inhibitor is Selegiline, Said addictive group consisting of an inhibitor of nicotine metabolism; a Substance, or derivative thereof, is nicotine, and said carrier nicotine antagonist; a nicotine agonist; an inhibitor of is an oral tablet, capsule, a comestible article, an aeroSol, a CYP2A6, a beta-blocker, an alpha-2 adrenergic anatagonist; Vapor, a Smoke, or a transdermal patch, and wherein Said a muscle relaxant, a benzodiazepine, an inhibitor of nicotine carrier is Suitable for parenteral administration, including metabolism; a nicotine antagonist; a peripheral nicotine intradermal, Subcutaneous, intramuscular, intravenous, anatagonist, a nicotine agonist, a dopamine agonist; a intrathecal, Sublingual, rectal, vaginal, intraocular, transder dopamine antagonist, a Serotonin agonist, a Serotonin mal, respiratory mucosal, or pulmonary routes of adminis antagonist, an antihistamine; a cannabinoid receptor antago tration. nist; a cannabinoid receptor agonist; an anticholinergic 0.017. The invention provides a pharmaceutical compo agent; an inhibitor of acetylcholine esterase; a muscarinic Sition comprising an amount of an inhibitor of monoamine antagonist; a muscarinic agonist, an opiate agonist, an opiate oxidase, an amount of an addictive Substance or derivative anatogonist, an amphetamine agonist; an amphetamine thereof, and a Suitable diluent or carrier, wherein Said antagonist, a glutamate antagonist, a NMDA antagonist, an addictive Substance, or derivative thereof, is nicotine, Said antihypertensive; an inhibitor of Serotonin transport (re carrier is an oral tablet or capsule, a comestible article, an uptake); an inhibitor of dopamine transport (re-uptake); an aeroSol, a vapor, a Smoke, or a transdermal patch, wherein inhibitior of noradrenaline transport (re-uptake); a NaSSA; Said carrier is Suitable for parenteral administration, includ an NMDA antagonist; an analgesic; a vasodilator; a calcium ing intradermal, Subcutaneous, intramuscular, intravenous, channel antagonist; a xanthine; an inhibitor of COMT (cat intrathecal, Sublingual, rectal, vaginal, intraocular, transder echol-O-methyltransferase); a steroid; a steroid hormone; a mal, respiratory mucosal, or pulmonary routes of adminis Vitamin; an inhibitor or monoamine oxidase; an antioxidant; tration, and wherein Said inhibitor of monoamine oxidase is an atypcial antidepressant, an atypical antipsychotic, an Selected from the group consisting of Selegiline, desmeth addictive Substance; a pharmacological analogue of an ylselegiline, S(+)desmethylselegiline, lazabemide, broform addictive Substance; or mixtures thereof. ine, rasagiline, LU-53439, LU-43839, idazoxan, clorgyline; 0019. The invention provides a method of treating a cimoxatone, cirazoline, befloxatone, brofaromine, bazi Subject addicted to an addictive Substance or product com naprine; MD-240928; BW-616U; BW-1370U87; CS-722; prising the Steps of co-administering to the Subject in need E-2011, harmine; harmane, norharmane, harmaline; thereof a pharmaceutical composition comprising a thera moclobemide; PharmaProjects 3975 ; RO 41-1049; peutically effective amount of Selegiline and a pharmaceu RS-8359; T-794; toloxatone; K-Y 1349; LY-51641; tical composition comprising a therapeutically effective LY-121768; M&B 9303; MDL 72394; MDL 72392; serclo remine; MD 72394, MO 1671, amiflamine; vanoxerine; amount of nicotine, thereby attenuating consumption of Said AGN 2253, iproniazid; isocarboxazid; M-3-PPC; nialamid; Substance or product. phenelZine, pargyline; tranylcypromine, budipine; carOX 0020. The invention provides a method of treating a aZone; D-1711; fezolamine; FLA-334, FLA-289; K-11566; Subject addicted to an addictive Substance or product com K-11829, metralindole; MPCPAM; PharmaProjects 227; prising the Steps of co-administering to the Subject in need US 2002/0019421 A1 Feb. 14, 2002 thereof a pharmaceutical composition comprising a thera administering to the Subject in need thereof a pharmaceutical peutically effective amount of Selegiline in oral tablet, composition comprising a therapeutically effective amount capsule, comestible dosage, aeroSol, Vapor, Smoke, or trans of Selegiline and a therapeutically effective amount of nico dermal patch dosage form, wherein Said dosage form is tine combined in a transdermal patch dosage form, thereby Suitable for parenteral administration, including intradermal, alleviating the Symptoms of nicotine withdrawal. Subcutaneous, intramuscular, intravenous, intrathecal, Sub 0027. The invention provides a method of treating a lingual, rectal, vaginal, intraocular, transdermal, respiratory Subject addicted to a tobacco product comprising the Steps of mucosal, or pulmonary routes of administration, and a co-administering to the Subject in need thereof a pharma pharmaceutical composition comprising a therapeutically ceutical composition comprising a therapeutically effective effective amount of nicotine in a transdermal patch dosage amount of Selegiline and a pharmaceutical composition form, thereby attenuating consumption of Said Substance or comprising a therapeutically effective amount of nicotine, product. thereby attenuating tobacco consumption. 0021. The invention provides a method of treating a Subject addicted to an addictive Substance or product com 0028. The invention provides a method of treating a prising the Steps of administering to the Subject in need Subject addicted to a tobacco product comprising the Steps of thereof a pharmaceutical composition comprising a thera co-administering to the Subject in need thereof a pharma peutically effective amount of Selegiline and a therapeuti ceutical composition comprising a therapeutically effective cally effective amount of nicotine combined in an oral tablet, amount of Selegiline in oral tablet, capsule, or comestible capsule, comestible, aerosol, Vapor, Smoke, or transdermal dosage form and a pharmaceutical composition comprising dosage form, wherein Said dosage form is Suitable for a therapeutically effective amount of nicotine in a transder parenteral administration, including intradermal, Subcutane mal patch dosage form, thereby attenuating tobacco con ous, intramuscular, intravenous, intrathecal, Sublingual, rec Sumption. tal, vaginal, intraocular, transdermal, respiratory mucosal, or 0029. The invention provides a method of treating a pulmonary routes of administration, thereby attenuating Subject addicted to a tobacco product comprising the Steps of consumption of Said Substance or product. co-administering to the Subject in need thereof a pharma 0022. The invention provides a method of treating the ceutical composition comprising a therapeutically effective Symptoms of nicotine withdrawal comprising the Steps of amount of Selegiline in oral tablet, capsule, or comestible co-administering to the Subject in need thereof a pharma dosage form and a pharmaceutical composition comprising ceutical composition comprising a therapeutically effective a therapeutically effective amount of nicotine in an oral amount of Selegiline, combined with a Suitable diluent or tablet, capsule, or comestible dosage form, thereby attenu carrier, and a pharmaceutical composition comprising a ating tobacco consumption. therapeutically effective amount of nicotine, combined with 0030 The invention provides a method of treating a a Suitable diluent or carrier, thereby alleviating the Symp Subject addicted to a tobacco product comprising the Steps of toms of nicotine withdrawal. co-administering to the Subject in need thereof a pharma 0023 The invention provides a method of treating the ceutical composition comprising a therapeutically effective Symptoms of nicotine withdrawal comprising the Steps of amount of Selegiline in oral tablet, capsule, or comestible co-administering to the Subject in need thereof a pharma dosage form and a pharmaceutical composition comprising ceutical composition comprising a therapeutically effective a therapeutically effective amount of nicotine in an oral amount of Selegiline in oral tablet, capsule, or comestible tablet, capsule, comestible, aeroSol, Vapor, Smoke, or trans dosage form and a pharmaceutical composition comprising dermal dosage for thereby attenuating tobacco consumption. a therapeutically effective amount of nicotine in an trans dermal patch dosage form, thereby alleviating the Symptoms 0031. The invention provides a method of treating a of nicotine withdrawal. Subject addicted to a tobacco product comprising the Steps of co-administering to the Subject in need thereof a pharma 0024. The invention provides a method of treating the ceutical composition comprising a therapeutically effective Symptoms of nicotine withdrawal comprising the Steps of amount of Selegiline in a transdermal patch dosage form and co-administering to the Subject in need thereof a pharma a pharmaceutical composition comprising a therapeutically ceutical composition a therapeutically effective amount of Selegiline in oral tablet, capsule, or comestible dosage form effective amount of nicotine in a transdermal patch dosage and a pharmaceutical composition comprising a therapeuti form, thereby attenuating tobacco consumption. cally effective amount of nicotine in an oral tablet, capsule, 0032. The invention provides a method of treating a comestible, aeroSol, Vapor, Smoke, or transdermal dosage Subject addicted to a tobacco product comprising the Steps of form, thereby alleviating the Symptoms of nicotine with administering to the Subject in need thereof a pharmaceutical drawal. composition comprising a therapeutically effective amount 0.025 The invention provides a method of treating the of Selegiline and a therapeutically effective amount of nico Symptoms of nicotine withdrawal comprising the Steps of tine combined in an oral tablet or comestible dosage form, administering to the Subject in need thereof a pharmaceutical thereby attenuating tobacco consumption. composition comprising a therapeutically effective amount 0033. The invention provides a method of treating a of Selegiline and a therapeutically effective amount of nico Subject addicted to a tobacco product comprising the Steps of tine combined in an oral tablet, capsule, or comestible administering to the Subject in need thereof a pharmaceutical dosage form, thereby alleviating the Symptoms of nicotine composition comprising a therapeutically effective amount withdrawal. of Selegiline and a therapeutically effective amount of nico 0026. The invention provides a method of treating the tine combined in a transdermal patch dosage form, thereby Symptoms of nicotine withdrawal comprising the Steps of attenuating tobacco consumption. US 2002/0019421 A1 Feb. 14, 2002

0034. The invention provides a method of treating a 0039) Drug addiction, in particular tobacco product Subject addicted to an addictive Substance or product com addiction, is a public health epidemic of global proportions, prising the Steps of administering to the Subject in need accounting for millions of premature deaths annually. While thereof a pharmaceutical composition of the invention, treatment regimens Such as nicotine replacement therapies thereby attenuating chronic craving Symptoms of a Subject remain popular, the current best accepted Success rate for addicted to Said Substance or product. Smoking cessation provided by administration of nicotine via transdermal patch is about 20%. Possibly higher rates 0035. The invention provides a method of treating the may be obtained when respiratory routes of nicotine replace Symptoms of nicotine withdrawal comprising the Steps of ment therapy, i.e. whereby an aeroSol, a vapor, a nebulized administering to the Subject in need thereof a pharmaceutical Vapor, a particulate-containing Vapor, or a Smoke, are composition of the invention, thereby alleviating the chronic improved and implemented into clinical practice. craving Symptoms of a Subject addicted to nicotine. 0040. In addition to direct replacement therapies, other 0.036 The invention provides a method of treating a drugs have been used or Suggested to be useful for the Subject addicted to tobacco product consumption compris treatment of Substance abuse and addiction, among them ing the Steps of administering to the Subject in need thereof being the class of drugs known as monoamine oxidase a pharmaceutical composition of the invention, thereby inhibitors, including Selegiline. Combination therapy com attenuating chronic tobacco consumption. prised of administration of both nicotine and Selegiline together, by either identical or Separate routes of adminis DETAILED DESCRIPTION OF THE tration, is disclosed herein as a highly effective method for INVENTION the treatment of tobacco addiction, exhibiting a Synergistic 0037. In one aspect of the present invention, a method for effect in comparison to that of administration of either agent relieving craving in a nicotine-habituated person who is alone and achieving cessation rates of greater than 40%. abstaining from or reducing nicotine intake is provided by 0041. The invention disclosed herein comprises the com administering at least two components individually or as an bination of a monoamine oxidase inhibitor, Such as Sel admixture of first and Second components. The first com egiline, with one or more modes of nicotine replacement ponent is an inhibitor of monoamine oxidase and the Second therapy, for the treatment of addiction, in particular addic component is an addictive Substance or a non-addicitive tion to tobacco products. In particular the invention provides derivative thereof. Co-administration of the two components a pharamaceutical composition comprising an addictive or administration of a balanced admixture of the first and Substance, or a pharamceutical analogue or derivative Second components relieves craving, yet Surprisingly results thereof, in combination with an inhibitor of monoamine in Substantially no undesirable physiological changes. oxidase, for administration to the same Subject as a phar Instead, practice of the invention appears to reduce not only macological treatment, employed alone or as an adjunctive craving for nicotine, or nicotine containing tobacco prod measure, to promote the process of withdrawal from ucts, in perSons who are reducing or abstaining from nico habitual consumption of an addictive Substance or product tine intake, but appears as well to reduce other cravings wherein an addictive Substance is contained. asSociated with withdrawal Syndromes, Such as weight gain. The invention is thus useful for treating a wide range of 0042. The terms addiction, Substance addiction, Sub withdrawal Syndromes, including those encountered in Sub stance abuse, or Substance dependence are frequently used jects addicted to opiates, amphetamines, or cocaine. The interchangeably. In general, the term Substance addiction is present invention is related to U.S. provisional patent appli used herein to refer to the chronic administration, usually cation No. 60/216,366, filed on Jul. 5, 2000 and which is Self-administration, of a chemical compound, or class of hereby incorporated herein by reference. chemical compounds, which is either itself known to exert noxious effects to health and/or the route of administration 0.038 A particularly preferred composition of the inven of the compound or product thereof creates Substantial tion takes the form of a tablet, a capsule, or a comestible physiological insults, yet the Subject afflicted with the addic article for oral administration or of a patch for transdermal tion continues to crave, Seek, or administer the Substance administration wherein the first component is an inhibitor of despite the known risks to health. Such is the case with monoamine oxidase and the Second component is an addic tobacco product addiction whereby the active Substance, tive Substance, Such as nicotine, or pharmacological ana nicotine, is most typically administered via the act of inha logue thereof. The combination of the first and second lation of tobacco Smoke, as in cigarette, cigar, or pipe components is useful and effective because the first class of Smoking. Nicotine is known to be highly addictive, hence drug (specific or non-specific inhibitor of monoamine oxi the efforts to aid the afflicted subject via administration of dase) should influence the response to nicotine, or a simi purified, concentrated nicotine in the form of a transdermal larly addictive Substance, through affects on neurotransmit patch, buccoral, oral, or respiratory route which obviate the ter pathways or metabolism. AS demonstrated herein, the need to inhale noxious tobacco Smoke for acquiring the inhibitor of monoamine oxidase Selegiline is effective in desired dose of nicotine. Thus, a Subject addicted to cigarette itself to reduce the desire or craving for an addictive Smoking, or another tobacco product, may make use of the Substance, namely nicotine, Furthermore, administration of invention while attenuating or completely ceasing consump the inventive compositions comprising both classes of com tion of the offending tobacco product, and yet avoid the pounds or alternatively, co-administration of both classes of withdrawal Signs and Symptoms associated with this action, compounds by different vehicles, have been shown to lead especially craving, thus allowing the addicted Subject to to a reduced desire for nicotine, which is greater than when avoid complete or partial relapse, whereby the addicted Subjects are administered a comparative mode of therapy Subject reinstitutes the addictive behaviors associated with using only nicotine or Selegeline alone. the addictive Substance, Such as cigarette Smoking. US 2002/0019421 A1 Feb. 14, 2002

0043. The term Substance dependence usually is taken to 0048 Both nicotine and tobacco smoke are considered to refer to the psychological and behavioral aspects of chronic be dangerous to health. Nicotine has vasoconstrictive prop ingestion of a Substance known to have adverse effects on erties and probably accounts for the Substantial increased health or daily functioning. Substance dependence is thus risk for Smokers to develop ischemic vascular disease, one specific aspect of Substance addiction. leading to heart disease, Stroke, and peripheral vascular disease. Tobacco Smoke contains a multitude of known 0044) The term substance abuse usually is taken to refer carcinogens, and as well, raises blood carbon monoxide to periodic or chronic consumption of a Substance, in levels which impact negatively on hemoglobin function. particular a psychoactive Substance, the consumption of which is continued by the Subject despite the presence or 0049 Acute and chronic opiate, amphetamine, cocaine knowledge of the associated harmful effects. Substance and ethanol use are also known to produce cardiovascular abuse is thus one specific aspect of Substance addiction. disorders. Thus use of the invention is a means for mitigating the cardiovascular complications associated with Substance 0.045 An addictive substance is any compound, combi addiction disorders through providing for withdrawal from nation of compounds, or product thereof, known to be noxious addictive Substances and products thereof. addictive to an animal Subject, especially human beings. An addictive Substance is often consumed by the addicted 0050. In addition to nicotine, other psychostimulant Sub Subject in a repetitive, compulsive manner in order to obtain stances considered to be highly addicting are cocaine, heroin a mood-enhancing or mood-stimulating effect or to diminish and other opiates, the amphetamines, cocaine, caffeine, and or postpone the mood-related dysphoria and other psycho SWeetS. logical, emotional, and physical effects experienced by the addicted Subject upon discontinuation or withdrawal from 0051. The goal of therapy or treatment of Substance the ordinary Schedule of consumption of the addictive addiction is to reduce the amount and/or rate of intake of the Substance. Craving, defined as the desire for the addictive Substance over time and as well, to reduce the rate of relapse. Substance and/or the desire to partake of the behavior It is well known that individuals afflicted with an addictive patterns associated with consumption of the addictive Sub condition who Succeed in obtaining a reduction or complete stance, is a critical feature of addictive disorders. Examples cessation of intake of the Substance to which they are of addictive Substances are opiates, including heroin, mor addicted remain at a Substantial risk to relapse during the phine, codeine, and natural or Synthetic derivatives thereof; course of their lifetime. To cure, or completely eradicate, an opiate-like analgesic drugs, including fentanyl, buprenor addictive condition over the course of the lifetime of a phine, and natural or Synthetic derivatives thereof, nicotine Subject afflicted with a Substance addiction often predicates and natural or Synthetic derivatives thereof; tobacco and life-long administration of therapy, be it pharmacological, tobacco-containing products thereof, cocaine and natural or behavioral, or both. Synthetic derivatives thereof, amphetamines and natural or 0052 One important measure of the efficacy of a therapy synthetic derivatives thereof; ethyl alcohol and ethanol for addiction is the level of desire for ingesting the Sub containing products, caffeine and caffeine-containing prod stance, otherwise known as craving. Most addictive Sub ucts, and high carbohydrate diets, especially the habitual stances are clearly associated with the condition of craving consumption of Sugar products and Sweets. following a brief period of abstinence, ranging from minutes 0.046 For implementation, of the compositions and meth to days, depending upon the Substance and the individual. ods of use thereof provided by the invention, a non-addictive For many afflicted individuals, the phenomenon of craving derivative or analogue may be used in place of, or in addition may be lifelong, thus leading to the need for prolonged to, the addictive Substance. AS defined herein, a "derivative administration of therapy for addiction. thereof of an addictive Substance is a Substance which 0053 While craving is considered to be a psychological shares relevant pharmacological properties in common with or Strong mental desire which is difficult to resist, other a particular addictive Substance, So that the "derivative aspects of Substance addiction which should be targeted by thereof may be considered to be either a pharmacological Specific therapies are other acute and chronic withdrawal analogue, partial analogue, or antagonist of the addictive Symptoms in addition to craving. In the case of cocaine Substance, but which is either less addictive or non-addictive addiction, the most prominent withdrawal Symptoms are in comparison to Said addictive Substance when tested in Subjective Sensations of mild to Severe dysphora, depression, animals, including humans. Thus, for example, methadone anxiety or irritability. This is also true of amphetamine, or naloxone may be used in addition to or instead of alcohol, opiate and nicotine withdrawal. Thus, in addition to morphine, heroin, or another highly addictive opiate. reducing intake or craving, another measure of the efficacy 0047 Substance addiction is considered by many to be a of anti-addiction therapy is to diminish the undesirable life-long illness which persists long after the consumption of psychological effects associated with discontinuation or the addictive Substance is ceased. Thus, for example, ciga withdrawal from the addictive substance or product. rette Smokers, cocaine addicts, heroin addicts, alcoholics, 0054 Addictions are associated with specific symptoms and amphetamine addicts often experience one or more of withdrawal, depending upon the Substance for which relapses while attempting to abstain. These relapses may addiction had developed. For example, cigarette SmokerS occur following months or years of abstinence and are who reduce or cease tobacco product consumption fre typically invoked by experts in the field as evidence to quently experience increased appetite for food and therefore demonstrate the Strong psychological aspects of Substance are at risk for weight gain. In fact many SmokerS report that addiction. Alternatively, or in addition, individual addicts the experience or fear of weight gain significantly contrib may be genetically predisposed to the condition of Substance utes to their inability to reduce or cease their level of tobacco addiction. product consumption. Cocaine, amphetamine, and opiate US 2002/0019421 A1 Feb. 14, 2002 habits are also initiated and promulgated for their weight nyl)guinoline; harmane (1-methyl-9H-pyridol/3,4-b/indole); loSS potential. Thus the invention provides composition and norharmane; harmaline; moclobemide (Aurorix, RO therapeutic methods for the control of body weight in a 11-1163) (Roche); minaprine (3-(2-morpholino-ethy Subject addicted to a chemical Substance or product thereof, lamino)-4-methyl-6-phenylpyridazine; PharmaProjects including nicotine, amphetamines, cocaine, and opiates. 3975 (Hoechst); RO 41-1049 (N-(2-aminoethyl)-5-(3- flurophenyl)-4-thiazolecarboxemide) (Roche); RS-8359 0055. In addition, the well-known phenomena of com (+/-)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclo pulsive consumption of Sweets, although not formally clas pentad-pyrimidine) (Sankyo); T-794 (I(5R)-3-(6-(cyclco sified as a Substance addiction disorder by all medical propylmethoxy)2-napthealenyl)-5-(methoxymethyl)2-OX disciplines, has many aspects in common with other addic azolidone) (Tanabe Seiyaku); toloxatone (Humoryl, tive disorders. Thus, subjects afflicted with an addiction to Perenum, MD-690276, MD-69276) (Synthelabo); K-Y 1349 frequent episodes of craving for food, in particular Sweets, (Kalir and Youdim); LY-51641 (N-2-(o-chlorophenylxoy may benefit from the anti-craving effects of the invention. )ethylcyclopropylamine hydrochloride) (Lilly); LY-121768 0056. Other well-known withdrawal symptoms associ (N-2-o-iodophenoxy)ethylcyclopropylamine hydrochlo ated with Substance addiction are headache, Sleep distur ride) (Lilly); M&B 9303 (May & Baker); MDL 72394 bances, including hyperSomnia and insomnia, and Signs of (Marion Merrell); MDL 72392 (Marion Merrell); serclorem autonomic arousal Such as Sweating, tachycardia, diarrhea, ine (CGP-4718A) (Ciba-Geigy); MD 72394 ((E)-beta-fluo roethylene-m-tyrosine); MO 1671; amiflamine (IS-(+)4dim Stomach cramps, nausea and vomiting. ethylamino-alpha,2-dimethylphenetrhylamine (FLA-336, 0057 Nicotine addiction, as exemplified by chronic ciga FLA-668, FLA-788) (Astra); vanoxerine (boxeprazine) rette Smoking, may be taken to be a valid model for other (NovoNordisk); AGN 2253 (Nicholas Kiwi); iproniazid conditions of Substance addiction. Many Substance addic (Marsilid); isocarboxazid (Marplan) (Roche); M-3-PPC tions share certain aspects in common, as delineated above (Draxis); nialamid (Niamid); phenelzine (Nardil) (Parke with respect to craving and weight gain as withdrawal Davis); pargyline (Euronyl) (Abbott); tranylcypromine phenomena. Thus the compositions and methods for treat (Pamate) (Smith-Kline Beecham); budipine (BY-701) (t-bu ment of addiction disclosed herein may be considered useful tyl-4,4 diphenyl piperidine) (Byk Gulden); caroxazone for the treatment of Substance addiction in general, particu (Timosteni, FI-6654) (Pharmacia Upjohn, Farmitalia); larly Since they are believed to share a common physiologi D-1711 (Biocodex); fezolamine (WIN-41528-2) (N,N-dim cal mechanism attributed to the dopaminergic, and other ethyl-3,4-diphenyl-1H-pyrazole-1-propanamine-(E)-2- neurotransmitter, pathways of reward in the brain. butenedioate) (Sanofi); FLA-334 (RAN-113) (p-amino-am phetamine) (Astra); FLA-289 (FLA-299, FLA-365, FLA 0.058 Inhibitors of the intracellular enzyme monoamine 384, FLA-463, FLA-727) (p-dimethylamino-amphetamine) oxidase have been Suggested to be of value in the treatment of addiction, although to date this contention has never been (Astra); K-11566 (Pharmacia Upjohn, Farmitalia); K-11829 rigorously established by way of collection and analysis of (Pharmacia Upjohn, Farmitalia); metralindole; MPCPAM clinical data. An inhibitor of monoamine oxidase is a com (Yissum); PharmaProjects 227 (Syntex/Roche); Phar pound which either inhibits in vitro the reaction catalyzed by maProjects 2806 (Fournier); PharmaProjects 1122; Phar the enzyme, or a compound which binds to the enzyme as maProjects 3311 (Roche); PharmaProjects 4433 (Roche); demonstrated by in vitro or in vivo binding analysis. For RS-2232 (Sankyo); UP-614-04 (Bristol-Myers), hypricum purposes of the present invention, a monoamine oxidase perforatum, or mixtures thereof. inhibitor may be either a reversible or an irreversible inhibi 0059. It is understood that, although the terms, “inhibitor tor of the enzyme, Similarly, a monoamine oxidase inhibitor of monoamine oxidase' and “addictive Substance, or deriva may be either a selective or a non-selective inhibitor with tive thereof are singular, more than one inhibitor of respect to the two known isoforms of the enzyme, monoam monoamine oxidase and more than one addictive Substance, ine oxidase A and monoamine oxidase B. Examples of or derivative thereof, can be used concurrently in the meth monoamine oxidase inhibitors include, but not only, the ods of the invention. following: Selegiline (deprenyl, I-deprenyl) (R)-(-)-N,2- 0060 Inhibitors of monoamine oxidase, are generally dimethyl-N-2-propynylphenethylamine; desmethylsel employed in the medical arts as anti-depressants and as egiline; S(+)deSmethylselegiline, lazabemide, broformine; anti-parkinson agents, but when used in combination with rasagiline; LU-53439; LU-43839; idasoxan; clorgyline (N- administration of an addictive Substance, or derivative 3-(2',4'-dichlorophenoxy)-N-methylpropargylamine) (May thereof, for treatment of addiction the use is a new one. & Baker); cimoxatone, cirazoline (MD780515, Representative diseases, disorders and conditions in which MD-770222) (Synthelabo); befloxatone (MD-370503) inhibitors of monoamine oxidase are considered to have a (Synthelabo); brofaromine (Consonar, CGP-11305A) (Ciba therapeutic effect include: Parkinson's disease (either idio Geigy); bazinaprine (SR 95191) (3-(2-morpholinoethy pathic or familial), parkinsonism, depression (including lamino)-4-cyano-6-phenylpyridazine) (Sanofi); MD-240928 depression refractory to other tricyclic antidepressants, (R-3-4-((3-chlorophenyl)methoxy)phenyl-5-(methylami Selective Serotonin reuptake inhibitors), Alzheimer's dis no)methyl-2-oxazolidinone methaneSulfonate (Lilly); ease, Huntington's disease, dementia, neurodegenerative BW-616U (Burroughs Wellcome); BW-1370U87 (1-eth diseases, attention deficit disorder, migraine, narcolepsy, ylphenoxathiin-10,10-dioxide (Burroughs Wellcome); psychiatric disorders, panic disorders, Social phobias, anxi CS-722 (RS-722) ((R)4-chloro-2-(2-hydroxy-3-morpholi ety, psychoses, obsessive-compulsive disorders, obesity or nopropyl)-5-phenyl-4-isoxazolin-3-one hydrochloride (San eating disorders, body dysmorphic disorders, post-traumatic kyo); E-2011 ((5R)-3-2-((1S)-3-cyano-1-hydroxypropyl)- StreSS disorders, or conditions associated with aggression. benzothiazol-6-yl-5-methoxymethyl-2-oxazolindinone The inhibitor of monoamine oxidase is administered not (Eisai), harmine (3-phenylquinoline,3-(4-hydroxyphe only to treat Symptoms of these diseases, disorders and US 2002/0019421 A1 Feb. 14, 2002 conditions, but also to delay of prevent or delay onset or 0064. The effective amount can be administered in a worsening of Symptoms of these diseases, disorders and Series of doses Separated by appropriate intervals, Such as conditions. For example, it has been Suggested that hours, days, or weeks. Alternatively, the effective amount monoamine oxidase inhibitors can Serve as neuroprotective can be administered as a Sustained release dose, Such as by agents in Parkinson's disease. a controlled-release dosage formulation. 0061 Because Parkinson's disease is caused by prema 0065. The inhibitor of monoamine oxidase inhibitor is ture death of nerve cells in the Substantia nigra of the brain, administered in an effective amount, which is that amount use of monoamine oxidase inhibitors can reduce or eliminate necessary to alleviate, reduce, attenuate, or eliminate the premature cell death, and thereby prevent or slow down the Symptoms associated with the addictive disorder, disorder or onset of Symptoms of disease. Neuroprotection can thus be condition to be treated or to Slow disease progression. The significantly valuable in the treatment of Parkinson's dis monoamine oxidase inhibitor can also be administered pro ease, as well as other neurodegenerative diseases which are phylactically, in order to prevent Symptoms associated with caused by the death or dysfunction of cells in the central the addicitve disorder or disease, or to delay onset of nervous System. Nicotine has also been implicated as a Symptoms associated withdrawal or abstinence. If more than neuroprotective agent in Parkinson's disease. one inhibitor of monoamine oxidase inhibitor is used, the effective amount is that amount of the combination of 0.062 Although inhibitors of monoamine oxidase, in par inhibitor of monoamine oxidase inhibitors that is necessary ticular Selegiline, are reported as being effective in treating to alleviate, reduce, eliminate, prevent, or delay onset of the the foregoing conditions, neither the precise number or Symptoms associated with withdrawal or abstinence. The nature of its mechanism or mechanisms of action are known. effective amount will be determined on an individual basis, However, there is evidence that Selegiline provides neuro and will be based in part, on consideration of the particular protection or neuronal rescue, possibly by reducing oxida monoamine oxidase inhibitor, the individual's Size and tive neuronal damage, increasing the amount of the enzyme gender, the Severity of the Symptoms to be treated, the result Superoxide dismutase, and/or reducing dopamine catabo Sought, and the disease, disorder or condition to be treated lism. For example, Selegiline has been reported to act by or prevented. The effective amount will generally be an directly maintaining, preventing loSS of, and/or assisting in, amount which decreases brain monoamine oxidase activity the nerve function of animals. Thus, the compositions and by at least about 10%, preferably at least about 30%, more modes of therapy disclosed herein may be useful for the preferably at least about 50%, more preferably at least 70%, treatment of a Subject Suffering from one or more of the and more preferably up to 100%. Usually, the effective foregoing diseases, in addition to the utility as agents and amount will be between approximately 0.001 mg/kg to 1 therapies for the treatment of addiction. g/kg, preferably about 0.01 mg/kg to 10 mg/kg. For 0.063. The present invention is directed to the novel example, it was found that if the inhibitor of monoamine combination of a monoamine oxidase inhibitor administered oxidase inhibitor is clorgyline, the preferred effective together with an addictive Substance, or non-addictive amount in mice to inhibit 90% of striatal inhibitor of derivative thereof. This combination has Striking therapeutic monoamine oxidase while maintaining 50% of intestinal effects and, accordingly, is unexpectedly useful in treating inhibitor of monoamine oxidase activity is 0.6 mg/kg. One addiction and related conditions. The clinical results dis of ordinary skill in the art is able to extrapolate the preferred closed herein demonstrate that administration of Selegiline is effective amount in a Subject. The effective amount can be indeed an effective therapy for obtaining a reduction in determined by one of ordinary skill in the art, employing unwanted addictions and furthermore, that the combination Such factors and using no more than routine experimenta of Selegiline and nictoine administration is considerably tion. more effective than administration of either two agents alone. Thus, the combination of a monoamine oxidase 0066. The effective amount can be administered in a inhibitor with an addictive Substance, or a non-addictive Series of doses Separated by appropriate intervals, Such as derivative thereof, is a highly effective mode of therapy to hours, days, or weeks. Alternatively, the effective amount treat addiction. Although demonstrated herein for Selegiline can be administered as a Sustained release dose, Such as by and nicotine, other combinations incorporating members of a controlled-release dosage formulation. the same classes of compounds may be expected to be 0067. The monoamine oxidase inhibitor, or inhibitors, is equally effective. Thus, the combination of Selegiline and administered nasally, via a respiratory route or an intrapul nicotine may be expected to reduce the level of addiction to monary route, via an oral or enteral route, or via a parenteral other Substances, including opiates, cocaine, amphetamines, route, i.e., by any means other than through the gastrointes or Sweets. Alternatively, by way of example, the combina tinal tract or lungs. For example, the MAO inhibitor can be tion of Selegiline with an amphetamine may be similarly administered Subcutaneously, transdermally, intradermally, effective in reducing the number of cigarettes Smoked by an intravenously, intramuscularly, intraperitoneally, topically, addicted Smoker. It is well known that among the class of rectally, vaginally, or via an implanted reservoir. In a pre addictive Substances, many compounds manifest cross-tol ferred embodiment, the MAO inhibitor is administered erance with one another, demonstrating that these com intradermally or transdermally. The term “transdermal” pounds may behave as pharmacological analogues of one includes passive transdermal and also active electrotrans another. For treatment of any particular addictive disorder in dermal, e.g., iontophoretic or electroOSmotic, delivery. Rep any particular individual, the choice of which monoamine resentative intradermal, transdermal delivery and elec oxidase inhibitor combined with which addictive Substance, trotransdermal and other transdermal delivery means are or derivative thereof, will be determined by the nature of the described in the art. A variety of compositions of inhibitors disorder, the individual tolerance of the individual, and the of monoamine oxidase, in particular Selegiline, are disclosed knowledge and experience of the practitioner. in the art, including tablets, pills, capsules, powders, aero US 2002/0019421 A1 Feb. 14, 2002

Sols, Suppositories, Skin patches, parenterals, and oral liq muscarinic antagonist, a muscarinic agonist, an opiate ago uids, including oil-aqueous Suspensions, Solutions, emul nist, an opiate anatogonist, an amphetamine agonist, an Sions, and Selegiline-containing Sustained release (long amphetamine antagonist, a glutamate antagonist; a NMDA acting) formulations and devices. antagonist, an antihypertensive, an inhibitor of Serotonin 0068 The compounds and methods of this invention can transport (reuptake); an inhibitor of dopamine transport be adapted to the formulation and use of the therapeutic (re-uptake); an inhibitior of noradrenaline transport (re compositions comprising an inhibitor of monoamine oxi uptake); a NaSSA, an NMDA antagonist; an analgesic; a dase and an addictive Substance, or non-addictive derivative vasodilator, a calcium channel antagonist; a Xanthine; an thereof, in admixture with conventional excipients, i.e. phar inhibitor of COMT (catechol-O-methyltransferase); a ste maceutically acceptable organic or inorganic carrier Sub roid; a Steroid hormone; a vitamin; an inhibitor or monoam stances Suitable for parenteral, enteral (e.g., oral) or topical ine oxidase; an anti-oxidant, an atypcial antidepressant, an application which do not deleteriously react with the active atypical antipsychotic, an addictive Substance; a pharmaco compounds. Suitable pharmaceutically acceptable carriers logical analogue of an addictive Substance; or mixtures include but are not limited to water, Salt Solutions, alcohols, thereof. gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates Such as lactose, amylose or 0072 The combination of an inhibitor of monoamine Starch, magnesium Stearate, talc, Silicic acid, Viscous paraf oxidase and an addictive Substance, or derivative thereof, fin, white paraffin, glycerol, alginates, hyaluronic acid, col can also be combined where desired with other active lagen, perfume oil, fatty acid monoglycerides and diglycer agents, e.g., pharmacologically active compounds of poten ides, pentaerythritol fatty acid esters, hydroxy tial value in any particular condition and any particular methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceu patient, for use as adjunctive agents in the treatment of tical preparations can be Sterilized and if desired mixed with disorders of Substance addiction. Thus the invention pro auxiliary agents, e.g., lubricants, preservatives, Stabilizers, vides for compositions comprising an amount of an inhibitor wetting agents, emulsifiers, Salts for influencing OSmotic of monoamine oxidase, an amount of an addictive Substance, preSSure, buffers, coloring, flavoring and/or aromatic Sub a Suitable diluent or carrier, wherein Said monoamine oxi stances and the like which do not deleteriously react with the dase inhibitor is Selegiline, Said carrier is a means for oral or active compounds. parenteral delivery, and Said composition further comprises at least one compound Selected from the group consisting of: 0069 Practice of the inventive method comprises admin methoXSalen, apomorphine, bromocriptine, tryptans, Suma istrating an to a Subject in need thereof of a first compound tryptan, tacrine (Cognex), mirtazapine (Remerone), ropir Selected from the group of monoamine oxidase inhibitors in plone, donepezil (Aricept), rivastigmine (Exelon, Novartis), combination with a Second compound Selected from the buproprion, (Zyban, Wellbutrin), physostigmine, physostig group of addictive Substances, including but not only, nico mine analogues, tacrine, methacholine, edrophonium, Sco tine, opiates, amphetamines, and cocaine. The first compo polamine, atropine, an opiate, an amphetamine, thiamine, a nent may be either a Specific or non-specific inhibitor of Xanthine, cotinine, mecamylamine, caffeine, propranolol, monoamine oxidase isozymes. When administered in dif levodopa, carbidopa, amantadine, metamphetamine, meth ferent vehicles through either the same or different routes of ylphenidate, methylenedioxymethamphetamine, lofeXadine, administration the method is known herein as co-adminis clonidine, yohimbine, phentolamine, moxonidine. SR tration; both administration of the compounds via the same 141716 (Synthelabo), testosterone, estradiol, progesterone, vehicle or co-administration through different vehicles are norethindrone, fentanyl, morphine, buprenorphine, Suma acceptable forms of administration when implementing the tryptin, naloxone, dextramethorphan (ALGOS), cyclazocine invention. (NIDA), lorazepam, alprazolam, nitroglycerin, buspirone, 0070 For the purpose of implementing the invention, any Scopolamine, an essential Vitamin, phySoStigmine, metha compound known as a inhibitor of monoamine oxidase and choline, edrophonium, quaternary tetraalkylammonium any compound or composition known to be an addictive Salts, 9-amino-1,2,3,4-tetrahydracridine, diisopropyl fluoro Substance, or derivative thereof, are acceptable. phosphate, paraoxon, Soman, arecoline, 4-aminopyridine, choline alfoScerate, eptastigmine, eSeridine Salicylate, gal 0071 Additional compounds which have pharmacologi antamine hydrobromide, linopirine, RS-86, Suronacrine cal actions which may serve to enhance the efficacy of the maleate, Scopolamine, atropine, benactyzine, oxybutynin, combination of an inhibitor of monoamine oxidase with an quinuclidinyl benzilate, 3-quinuclidinyl-Xanthene-9-car addictive Substance may be optionally included within the boxylate, quinuclidinyl atrolactate, or mixtures thereof. compositions and methods of administration of the inven However, not preferred are muscarinic antagonists that have tion. Examples of compounds which may serve to benefit a limited or no central antimuscarinic effects, Such as meth Subject attempting withdrawal or prolonged abstinence from octramine. an addictive Substance are the following: an inhibitor of nicotine metabolism; a nicotine antagonist; a nicotine ago 0073 While the examples provided herein describe use nist; an inhibitor of CYP2A6 a beta-blocker; an alpha-2 of the monoamine oxidase inhibitor in oral administration adrenergic anatagonist; a muscle relaxant, a benzodiazepine; and the addictive Substance in transdermal administration, an inhibitor of nicotine metabolism; a nicotine antagonist; a the Success described affords good evidence to Suppose that peripheral nicotine anatagonist; a nicotine agonist; a dopam other routes of administration, or combinations with other ine agonist, a dopamine antagonist, a Serotonin agonist, a pharmaceutical preparations, would be at least as Successful. Serotonin antagonist, an antihistamine; a cannabinoid recep The route of administration, e.g., topical, transdermal, tor antagonist; a cannabinoid receptor agonist, an anticho parenteral, oral, or inhalant, and the dosage regimen will be linergic agent; an inhibitor of acetylcholine esterase; a determined by skilled clinicians, based on factorS Such as US 2002/0019421 A1 Feb. 14, 2002

exact nature of the condition being treated, the Severity of administered up to 800 times per day for respiratory deliv the condition, the age and general physical condition of the ery, one to twenty times per day for comestible articles, one patient, and So on. to six times per day for oral tablets or capsules, one to Six times per day for injections, one to six times per day for 0.074 The inhibitor of monoamine oxidase inhibitor can transdermal patches or topical creams, one to six times per be administered in dosage formulations containing conven day for Suppositories, or by continuous circulatory System tional, non-toxic, physiologically-acceptable carriers, adju infusion for pump delivery from an internal or external vants, and/or vehicles. The formulation in which the inhibi resevoir. When the compounds are present in the same tor of monoamine oxidase inhibitor is administered will vehicle, the ratio of monoamine oxidase inhibitor to addic depend at least in part on the route by which it is adminis tive Substance, or non-addictive derivative thereof, may tered. In implementation, more than one inhibitor of range from 1:100 w/w to 100:1 w/w. Thus, for example, a monoamine oxidase may be administered, including two or transdermal patch for use in implementing the invention more monoamine oxidase inhibitors each of which exerting may comprise, for a 70 kg Subject, from 0.7 to 70 mg a selective effect on inhibition of one of the isozyme forms Selegiline and from 0.7 to 70 mg nicotine per patch dosage of the enzyme, i.e. monoamine oxidase A and monoamine unit, applied from one to four times per day. Alternatively, oxidase B. by way of example, an oral dose of Selegiline ranging from 0075. The daily dose can be administered in a single or 0.7 to 70 mg may be co-administered to the subject together multiple dosage regimen. Although the oral route of admin with a transdermal patch comprising from 0.7 to 70 mg of istration will generally be most convenient, drug may be nicotine per patch dose unit, each of which dose may be administered by the parenteral, topical, transdermal dosage administered at a rate of 1 to 6 times per day, in accordance forms, including ointments, creams and patches, intraocular, with the needs and preferences of the Subject or his/her buccal, Sublingual, intranasal, inhalation, vaginal, rectal or practitioner. other routes as well. 0079 AS used herein, the term “pharmaceutically accept 0.076 Oral dosage forms will most typically be used and able carrier refers to formulation which is Safe, and pro are preferred but other dosage forms may also be employed vides the appropriate delivery for the desired route of and may permit, for example, a continuous release of administration of an effective amount of at least one com relatively Small amounts of the active ingredient from a pound of the present invention. AS Such, all of the above Single dosage unit, Such as a transdermal patch, over the described formulations of the present invention are hereby course of one or more days. This is particularly desirable in referred to as “pharmaceutically acceptable carriers.” This the treatment of chronic conditions Such as Parkinson's term refers to as well the use of buffered formulations disease, Alzheimer's, disease, and depression. Alternatively, wherein the pH is maintained at a particular desired value, it may be desirable in conditions Such as ischemia or neural ranging from pH 3.0 to pH 10.0, in accordance with the damage to administer one or more discrete doses by a more Stability of the compounds and route of administration. direct Systemic route Such as intravenously or by inhalation. In Still other instances, localized administration, Such as via 0080 For parenteral application, particularly suitable are the intraocular route, can be indicated. injectable, Sterile Solutions, preferably oily or aqueous Solu tions, as well as Suspensions, emulsions, or implants, includ 0.077 Inhibitors of monoamine oxidase are useful when ing Suppositories. Ampoules are convenient unit dosages. administered to a Subject through a wide variety of routes of administration and dosage forms in combination with other 0081 For application by inhalation, for delivery to the drugs. For example the use of concomitant Selegiline-aman respiratory epithileum, in particular the lower respiratory tadine in oral, peroral, enteral, pulmonary, rectal, nasal, tract and lungs, Solutions or Suspensions of the compounds vaginal, lingual, intravenous, intraarterial, intracardial, mixed and aeroSolized or nebulized in the presence of the intramuscular, intraperitoneal, intracutaneous, and Subcuta appropriate carrier are Suitable. Thus the carrier may be a neous formulations has been described. In addition, a dosage Vapor, a nebulized vapor, a vapor containing particulate form comprising an outer wall impermeable to Selegiline but material, or a Smoke. permeable to external fluids. This dosage form may have 0082 For topical application, particularly for the treat applicability for the oral, Sublingual or buccal administration ment of contact dermatitis, admixture of the compounds of Selegiline. with conventional creams or delayed release patches is 0078. In general, the doses utilized for the above acceptable. described purposes will vary, but will be in an effective 0083. For enteral application, particularly suitable are amount to exert the desired anti-disease effect. AS used tablets, dragees, liquids, drops, Syrup, elixir, Suppositories, herein, the term “pharmaceutically effective amount” refers capsules, or comestible articles, Such as a gum for chewing. to an amount of a first compound, Selected from the group Taste, Sweetners, or odor agents may be added as desired. on inhibitors of monoamine oxidase, and an amount of a When indicated, Suppositories or enema formulations may Second compound, Selected from the group of addictive be the recommended route of administration. Substances, or non-addictive derivatives thereof, which will produce the desired alleviation in Symptoms or signs of 0084 Sustained or direct release compositions can be Substance addiction in a Subject when administered as either formulated, e.g., oils, liposomes, or those wherein the active a Single composition, i.e. in the Same vehicle, or when compound is protected with differentially degradable coat co-administered via either Separate routes of administration ings, e.g., by microencapsulation, multiple coatings, etc. It is or via Separate vehicles. The doses utilized for any of the also possible to freeze-dry the new compounds and use the above-described purposes will generally be from 0.001 to lyophilisates obtained, for example, for the preparation of about 1.00 milligrams per kilogram of body weight (mg/kg), products for injection. US 2002/0019421 A1 Feb. 14, 2002

0085. It will be appreciated that the actual preferred 0092. Several different pharmaceutical preparations of amounts of active compound in a specific case will vary nicotine are available, including transdermal patches com according to the Specific compound being utilized, the prising nicotine, comestibles (gum for chewing) comprising particular compositions formulated, the mode of application, nicotine, and inhalants for mucosal and pulmonary delivery and the particular situs and organism being treated. Dosages comprising nicotine. These preparations are available for the for a given host can be determined using conventional purpose of treatment of addiction to tobacco products as considerations, e.g., by customary comparison of the differ nicotine replacement therapy. ential activities of the Subject compounds and of a known 0093. In addition, nicotine may be administered: by tablet agent, e.g., by means of an appropriate, conventional phar form, for absorption through the gastrointestinal tract, macological protocol. although this route has generally not been preferred due to 0086) Without further elaboration, it is believed that one Side effects and inferior absorption. However, for purposes skilled in the art can, using the preceding description, utilize of the present invention, this route of administration may the present invention to its fullest extent. The following also be considered a useful method of therapy when co preferred Specific embodiments are, therefore, to be con administered with a monoamine oxidase inhibitor. Strued as merely illustrative, and not limitative of the 0094 Nicotine and at least one monoamine oxidase remainder of the disclosure in any way whatsoever. inhibitor, Such as Selegiline, may be co-administered though different routes of administration, as described herein for 0.087 Pharmaceutical compositions containing an inhibi orally administered Selegiline and transdermally adminis tor of monoamine oxidase and an addictive Substance or tered nicotine, or, as an alternative, these compounds may be non-addictive derivative thereof, can be prepared according administered through the same route of administration for to conventional techniques. For example, preparations for achieving the object of the invention which is to aid and parenteral routes of administration of the combination, e.g., facilitate for a Subject the process of withdrawal from an intramuscular, intradermal, Subcutaneous, intravenous and addictive Substance, in particular nicotine containing intraarterial routes, can employ Sterile isotonic Saline Solu tobacco products. Thus, both Selegiline and nicotine may be tions. Sterile isotonic buffered solutions can also be co-administered to a Subject via transdermal route employ employed for intraocular administration. ing the use for this purpose of transdermal patches contain 0088 Transdermal dosage unit forms of inhibitors of ing Selegiline and nicotine to achieve the same results as monoamine oxidase inhibitors can be prepared utilizing a described herein for co-administration of these compounds variety of previously techniques known in the art. For in the treatment of a Subject in need thereof. example, a monolithic patch structure can be utilized in 0.095 The present invention also provides for pharma which the compound is directly incorporated into the adhe ceutical compositions comprising both nicotine and at least Sive and this mixture is cast onto a backing sheet. Alterna one monoamine oxidase inhibitor. Thus, for purposes of tively, the drug can be incorporated as an acid addition Salt implementing the invention, a pharmaceutical composition into a multilayer patch which effects a conversion of the Salt comprising nicotine and at least one monoamine oxidase to the free base. inhibitor, Such as Selegiline, may be administered to a 0089. In a particularly preferred embodiment, the present Subject addicted to a Substance, Such as nicotine, or a invention is directed to a transdermal delivery composition nicotine-containing tobacco product, Such as cigarettes, for comprising Selegine and nicotine in a single patch for use in the purpose of facilitating a desired reduction in the level of treating a condition in a human related to addiction to a nicotine or tobacco product consumption. substance and the desire to diminish or otherwise modify the 0096. A Single pharmaceutical composition comprising intake of that Substance. Transdermal patches comprising nicotine, or a pharmacologically active derivative thereof, either nicotine or Selegiline have been developed and one and a monoamine oxidase inhibitor, has distinct advantages skilled in the art may readily adapt these carrier forms to a to that of administering these therapeutic agents through Single patch comprising both compounds. Patches compris different routes or through the Same route of administration ing a combination of Selegiline, or another inhibitor of but as Separate compositions. A pharmaceutical composition monoamine oxidase, and an addictive Substance, or deriva comprising both types of agents has the advantage of tives thereof, other than nicotine, are also objects of the Simplification of the treatment regimen with respect to the invention, and may be readily prepared by one skilled in the Subject, who would therefore require the administration of a pharmaceutical arts. Single tablet or patch comprising both nicotine and an effective monoamine oxidase inhibitor, Such as Selegiline, 0090 Subjects treatable by the present preparations and instead of two separate tablets or Separate patches, for methods include both human and non-human Subjects for example. Combination of nicotine, or an pharmacologically which therapeutic effects of combination therapy with an equivalent derivative thereof, and an effective monoamine inhibitor of monoamine oxidase and an addictive Substance oxidase inhibitor as a single pharmaceutical composition or derivative thereof are useful. Accordingly, the composi affords an improved means for implementing the treatment tions and methods above provide especially useful therapies of a subject in need of administration of both types of for mammals, especially humans. compounds for the purpose of treating addiction, Since it is 0.091 For the purpose of the present invention, forms of well known that administration of a single pharmaceutical delivery of pharmaceutical preparations of monoamine oxi composition is often better tolerated, enhances Subject com dase inhibitors, including oral, parenteral, topical, transder pliance, and prevents Subject confusion when compared to mal patch, and inhalation are Suitable as an agent adminis the co-administration of two different compositions. tered in a therapy regimen when co-administered with a 0097 Thus the invention provides for a pharmaceutical preparation of nicotine. composition comprising nicotine, or a pharmacologically US 2002/0019421 A1 Feb. 14, 2002

equivalent derivative or Salt thereof, and an effective cally administered twice a day while Selegiline or phenelzine monoamine oxidase inhibitor, together with a pharmaceuti are typically administered once a day. cally Suitable diluent or carrier. 0102) In broader use of the inventive composition, per 0098. A preferred embodiment of the invention is a Sons attempting to abstain from nicotine intake will probably pharmaceutical composition comprising nicotine, or a phar Self-medicate. A recommended dose for Self-medication is macologically equivalent derivative or Salt thereof, and an likely a maximum of about six capsules per day, each effective monoamine oxidase inhibitor, together with a phar comprising an inhibitor of monoamine oxidase, an addici maceutically Suitable diluent or carrier, wherein the tive Substance or a derivative thereof, and a physiologically monoamine oxidase inhibitor is Selegiline and the carrier is acceptable diluent or carrier, administered at the rate of a transdermal patch. The incorporation of nicotine or equiva about one capsule per hour to one per three hours. Alterna lent derivative thereof, and Selegiline, or equivalent thereof, tively, as one embodiment of the invention, a Subject may as a single pharmaceutical composition in the form of a partake of a nicotine-containing product Such as a dispenser transdermal patch together with Suitable diluents and other of nicotine in vapor, Smoke, aeroSol, particulate aeroSol, or carriers necessary to achieve therapeutic levels of these nebulized form, in a desired manner in accordance with the compounds for the purpose of treating a Subject addicted to Subjects's needs for Self-medication while, at the Same time, a Substance, in particular, tobacco products, may be readily taking from one to Six daily doses of a monoamine oxidase carried out by one with knowledge and Skill in the art. inhibitor. 0099 Successful use of the compositions and methods 0103) The amount of monoamine oxidase inhibitor to be above requires employment of an effective amount of both administered for treating a Subject addicted to a Substance or the inhibitor of monoamine oxidase and the addictive Sub product, Such as a tobacco product, is a function of Several stance or non-addictive derivative therof. Both the monoam factors and may be modified in accordance with one or more ine OXdiase inhibitor and the addictive Substance may be of these factors to achieve the desired result. Among the equipotent in achieving the desired effect, yet the combina factors which determine the amount of monoamine oxidase tion does not necessarily require a commensurately inhibitor to be administered are the Specific type of increased dosage to obtain the same level of therapeutic monoamine oxidase inhibitor to administered, the traditional response confered by either compound individually. Thus, clinical or manufacturer recommended dose, the individual dosages necessary to attain a Selegiline-like therapeutic tolerance of the patient, the co-administration of other effect may actually be lower when the monoamine oxidase medications, and the extent of therapeutic effect achieved at inhibitor is employed in combination with nicotine. The any particular dose. Thus, a typical Starting dose may be Same appears to be true for nicotine, as the combination with decreased due to patient intolerance, Such as experiencing a Selegiline appears to allow for a dose reduction of nicotine Side effect of the medication, or a typical Starting dose may Sooner than when nicotine is used alone. Thus the risk of be increase due to lack of desired response. adverse effects of either the monoamine oxidase inhibitor or 0104. The therapeutic response due to treatment by co of the addictive Substance are minimized due to the potency administration of a monoamine oxidase inhibitor with nico of the two when administered in combination. tine, according to the present invention, may be either a 0100 Co-administration of pharmaceutically active com Subjective report or objective measure of the level of con pounds, i.e. drugs, is defined herein as administration to a Sumption of the addictive Substance. Thus, when used for Subject of two or more active compounds wherein each treating a Subject addicted to tobacco to product, the compound is administered to a Subject within a time proX response may be assessed by the Subject's report of a imity such that the subject is exposed to the effects of the decrease in the consumption of the tobacco product or a drugs at the same time. Thus co-administration may be reduced Sense of craving for the tobacco product, or both. implemented by administering pharmaceutical compositions 0105. Another type of therapeutic response provided by of two different drugs either Simultaneously, or each drug implementation of the invention, which may be in addition preparation at different hours of the same day or week, to a reduction in crabing, is the Subject's experience of a provided that the Subject is exposed to the effects of each reduction in other discomforting withdrawal signs or Symp compound at the same time. The effects of a pharmaceuti toms experienced by the Subject who is in the process of cally active compound on a Subject may be measured either attempting to discontinue, attenuate, or curtail his or her by Subjective report, i.e. the Subject reports a decreased level of addictive Substance consumption. Such a with craving for nicotine, or through measurement of tissue levels drawal State may be characterized by anxiety, irritability, of the administered Substance or metabolites thereof or poor concentration, restlessness, impatience, depressed through other means, Such as measuring the level of inhi mood, insomnia or hyperSomnia, enhanced thirst, enhanced bition of the activity of the enzyme monoamine oxidase or appetite, gain of body weight, Sexual dysfunction, or craving measuring the degree of occupancy of binding Sites in the or consumption of another Substance or product, in particu brain through the use of isotopically labeled monoamine lar a Substance or product known to have addictive potential oxidase compounds or derivatives thereof. for the Subject. It is known that, in Subjects addicted to Substances Such as ethanol, cocaine, amphetamines, or opi 0101. In preferred embodiment, the invention entails at ates, craving for these addictive Substances may be partially least once daily administration of a monoamine oxidase releaved by Self-administration of a nicotine-containing inhibitor, although alternate-dosing regimens may produce tobacco product, in particular cigarette Smoking. the same results in terms of Subjective effects or measurable tissue levels. The rate of dosing of the monoamine oxidase 0106 A preferred mode of the invention is for the treat inhibitor is also a function of the Specific active compound ment of a Subject who is addicted to tobacco product, Such employed. Thus, by way of example, meclobomide is typi as cigarette, cigar, or pipe Smoking. The type of therapeutic US 2002/0019421 A1 Feb. 14, 2002

response provided by implementation of the invention, and per, manganese, aluminum Salts and the like. Particularly which may be in addition to a reduction in craving, is the preferred are the ammonium, potassium, Sodium, calcium Subject's experience of a reduction in other discomforting and magnesium Salts. Salts derived from pharmaceutically withdrawal Signs or Symptoms experienced by the Subject acceptable organic non-toxic bases include Salts of primary, who is in the process of attempting to discontinue, attenuate, Secondary, and tertiary amines, Substituted amines including or curtail his or her level of tobacco product consumption. naturally occurring Substituted amines, cyclic amines and Thus, in the case of tobacco product addiction, the Symp basic ion exchange resins, Such as isopropylamine, trim toms of nicotine withdrawal may be characterized by anxi ethylamine, diethylamine, triethylamine, tripropylamine, ety, irritability, poor concentration, restleSSness, impatience, and ethanolamine are also Suitable for forming the compo depressed mood, insomnia or hyperSomnia, enhanced thirst, Sitions of the invention. enhanced appetite, gain of body weight, Sexual dysfunction, 0110 Compositions for use in the inventive method for craving for the tobacco product to which the Subject is relieving craving may also be formed as tablets or capsules addicted, craving or consumption of another tobacco prod Suitable for oral administration and have the first and Second uct, craving or consumption of another product comprising components admixed therein. The quantities of first and nicotine, or craving or consumption of another Substance, in Second components So admixed are wherein a dose com particular a Substance known to have addictive potential for prised by one or more tablets, is effective substantially to the Subject. relieve craving for a duration of time, preferably Several 0107 A significant advantage of the present invention is hours, most preferably about three hours or more. the co-administration of a monoamine oxidase inhibitor, 0111 Tablets, capsules, and comestible articles of the Such as Selegiline, and nicotine replacement therapy, Such as invention optionally include one or more pharmacologically a transdermal nicotine patch, for treating a Subject addicted Suitable component or components Such as buffering agent, to tobacco products and in need of Specific therapy to reduce preservative (e.g. antioxidants), excipients and/or tabletting the level of consumption thereof, including achieving a State agents, flavoring agents, and the like. Suitable Such compo of complete abstinence. Moreover, while both monoamine nents are well-known to the tabletting art. oxidase inhibitors, as demonstrated herein for Selegiline, and 0112 Composition embodiments of the invention were nicotine replacement therapies, Such as administration of a formulated and administered to patients by a treating phy transdermal patch, are effective modalities for a treating a Sician as will now be described for purposes of illustrating Subject addicted to tobacco products, the administration to a the invention. Subject of the two types of drug together, i.e. co-adminis tration of Selegiline and nicotine, affords therapeutic results 0113. In general, the compounds of the invention will be which surpass the efficacy of either form of therapy when administered to the warm blooded mammal as pharmaceu administered alone. Thus the co-administration of a tical compositions comprising a pharmaceutically accept monoamine oxidase inhibitor and a nicotine replacement able diluent or carrier. The pharmaceutical compositions regiment, as disclosed below for co-administration to Sub may be prepared by known procedures using well-known jects in need thereof of Selegiline and nicotine transdermal and readily available ingredients. In making the composi patch, comprises a Synergistic combination previously unan tions, the active ingredient will usually be mixed with a ticipated in the art. carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, Sachet, paper, or other 0108) Herein it is disclosed that administration of the container. When the carrier Serves as a diluent, it may be a monoamine oxidase inhibitor Selegiline, which is specific in Solid, Semi-Solid, or liquid material which acts as a vehicle, low doses for the monoamine oxidase-B isoform of the excipient, or medium for the active ingredient. The compo enzyme, is comparable to nicotine replacement therapy for Sitions can be in the form of tablets, pills, powders, lozenges, the treatment of tobacco product addiction. Of paramount Sachets, cachets, capsules, Soft or hard gleatin capsules, Significance is the finding, as disclosed herein, that when Sterile injectable Solutions, comestibles, elixirs, Suspensions, administered as combination therapy, Selegiline and nicotine emulsions, Solutions, Syrups, aerosols, vapors, Smokes, or are Synergistic in the ability to treat the affliction of tobacco ointments containing, for example, up to 30% by weight of product addiction, the combination achieving greater reduc active compound, and packaged accordingly, including Ster tions in cigarette consumption than would be expected from ile packaged powders. the sum of each form of therapy administered individually. 0114 Some examples of Suitable carriers, excipients, and 0109 Pharmaceutically acceptable acid addition salts for diluents include lactose, dextrose, Sucrose, Sorbitol, manni use in the compositions of the invention are those Salts tol, Starches, gum, acacia, calcium phosphate, alginates, which retain the biological effectiveness and properties of fragacanth, gelatin, calcium Silicate, micro-crystalline cel the free bases and which are not biologically or otherwise lulose, polyvinylpyrrollidone, cellulose, water Syrup, methyl undesirable, formed with inorganic acids Such as hydrochlo cellulose, methyl and propyl hydroxy-benzoates, talc, mag ric acid, hydrobromic acid, Sulfuric acid, nitric acid, phos nesium Stearate, and mineral oil. The formulations can phoric acid and the like, and organic acids Such as acetic additionally include lubricating agents, wetting agents, acid, propionic acid, glycolic acid, pyruvic acid, Oxalic acid, emulsifying and Suspending agents, preserving agents, maleic acid, malonic acid, Succinic acid, fumaric acid, Sweetening agents, or flavoring agents. Compositions may tartaric acid, citric acid, benzoic acid, cinnamic acid, man be formulated So as to provide quick, Sustained, or delayed delic acid, methaneSulfonic acid, ethaneSulfonic acid, release of the active ingredient after administration to the p-tolueneSulfonic acid, Salicylic acid and the like. Pharma patient by employing procedures well known in the art. ceutically acceptable base addition Salts include those 0115 The following formulation example is illustrative derived from inorganic baseS Such as Sodium, potassium, only and is not intended to limit the Scope of the invention lithium, ammonium, calcium, magnesium, iron, Zinc, cop in any way. US 2002/0019421 A1 Feb. 14, 2002

CLINICAL EXAMPLES TABLE 2 0.116) To demonstrate the therapeutic effect of selegiline and of a combination of Selegiline and nicotine in the Selegiline Alone and In Combination with Nicotine treatment of a Subject addicted to tobacco products, the Sub results of two experimental clinical trials are disclosed ject Weeks from Quit Day herein for the first time. No. -2 0 1. 2 3 4 5 6 7 8 9 0117 Experiment One 1. Cig?wk 140 O O 3 O O O O - - leC S S S S S S S - - 0118. An experimental clinical trial was performed to 2 Cig?wk 150 O O O O O O O O O assess the effect of Selegiline alone and in combination with leC S S S S - - - - - 3 Cig?wk 105 O O O O O O O O O co-administration of nicotine. Neither the use of Selegiline leC S S S S S S S S - alone nor in combination with nicotine has been previously 4. Cig?wk 140 21 21 25 25 25 14 21 21 21 tested or implemented for the treatment of Substance addic leC S S S S S SN S S S tion and is disclosed herein for the first time. 5 Cig?wk 140 140 ------leC S ------6 Cig?wk 210 210 ------TABLE 1. leC S ------7 Cig?wk 140 35 70 ------Initial Characteristics of the Trial Subjects leC S S ------8 Cigfwk 140 O O O O O O O O - leC SN SN SN SN SN SN SN SN - Average Beck 9 Cig?wk 140 O O O O O 21 35 6.O 25 Patient Consumption Pack Tolerance Depression leC N N N N N N N N SN No. Age Sex (cigarettesfalay) Years Scorer Inventory:

1. 40 M 2O 2O 7 2 0121 Legend 2 39 F 25 25 6 7 0.122 S=Selegiline; N=nicotine; SN=Selegiline and 3 3O M 15 1O 4 9 nicotine, --=none 4 55 F 2O 40 6 2 5 39 M 2O 22 5 2O 0123 Med=medication; Cig/wk=cigarettes consumed 6 55 F 3O 50 7 O per week, -----trial dropout 7 37 M 2O 2O 8 6 0124 cigarettes Smoked. One subject (No. 8) initially, 8 35 M 2O 16 5 O receiving both Selegiline and nicotine replacement, had not 9 39 M 25 3O 7 3 Smoked a single cigarette during the first eight weeks of the Study. One Subject (No.9) receiving just nicotine patch alone iFagerstrom Tolerance Score (0-11); Beck Depression Inventory (0-63) resumed Smoking after the fifth week of abstinence, but following the addition of oral Selegiline, reduced the daily 0119). In this prospective open trial subjects addicted to consumption of cigarettes Smoked. In addition, Subject No. chronic cigarette Smoking were administered either oral 4 reduced her daily cigarette intake even further upon adding Selegiline tablets (Jumex, Janssen, Belgium) 5 mg. b.i.d. or administration of nicotine patch at the Sixth week of the quit administered, for Subjects 8 and 9, combined co-adminis day, Later she discontinued the patch, expressing that she tration of both oral Selegiline and nicotine replacement wished to continue Smoking her three post-meal cigarettes therapy via transdermal patch. Subjects were then monitored per day. for their level of tobacco product consumption during the 0.125 Surprisingly, while the efficacy of tobacco replace course of the next 8 weeks. The study protocol relied on the ment therapy, when administered as Sole therapy in the form Subjective report of the patient for measurement of the of transdermal patch, is known to be about 20%, and that for therapy outcome, i.e. reporting of level of cigarette con Selegiline as Sole therapy, as demonstrated above, is about Sumption was elicited from the participating Subjects at 30%, as disclosed herein in Table 2, 100% of the subjects weekly intervals intervals throughout the course of the Study, receiving the combined therapy were treated Successfully, unless the patient was using nictotine replacement therapy. i.e. abstaining or significantly reducing their level of ciga Initial, trial entry levels of craving were determined by rette Smoking while undergoing co-administration of the two administration of the Fagerström Tolerance Score exam, pharmaceutical compositions. while initial level of mood was monitored by administering 0.126 The results of the study presented herein demon the Beck Depression Inventory. These initial characteristics Strate firstly that administration of Selegiline is effective of the patient characteristics are Summarized in Table 1. treatment for Substance addiction, namely cigarette Smok ing. Moreover, the combination of Selegiline and nicotine is 0120) Following one week on the medication, the Sub more Superior to either drug alone when used for this jects were instructed to quit Smoking on "quit day', as purpose, and addition of Selegiline to nicotine replacement predetermined at the initiation of the Study. AS shown in therapy is a Synergistic use of the combination, particularly Table 2, below, three Subjects taking Selegiline alone Suc effective when used to treat Smokers who wish to further cessfully abstained from cigarette Smoking while three other attenuate their level of cigarette consumption when under patients did not respond and eventually left the Study. One going nicotine replacement therapy alone as an abstinence Subject Significantly reduced the number of promoting therapy. US 2002/0019421 A1 Feb. 14, 2002

0127. In this study, at follow-up one year from the negative on each of the four occasions conducted following initiation of treatment, Subjects no. 2, 8 and 9 continued to conclusion of the initial eight week patch therapy. demonstrate continuous abstinence from Smoking, provid 0.135 According to these results, the success rate of ing a success rate of 100% for the inventive combination of combination therapy is 33%, a figure which is much higher Selegeline with nicotine patch compared to 14.2% for than that reported for either Selegeline alone (14.2%, See Selegeline alone. above) or nicotine patch alone (9.8%-N. Eng J Med 1999; 0128. According to these results, the success rate of 340:685-91), and which indicates a synergism for the inven combination therapy is 100%, a figure which is much higher tive combination of Selegeline and nicotine patch regimen. than that reported for either Selegeline alone (14.2%, See above) or nicotine patch alone (9.8% N. Eng J Med 1999: TABLE 3 340:685-91), and which indicates a synergism for the inven Characteristics of Quitters (Continous Abstinence from Smoking) tive combination of Selegeline and nicotine patch regimen. Treated by Oral Selegeline and Nicotine Patch Combination Therapy 0129. Experiment Two Continuous Participant abstinence 0130. The second experiment is a randomized double O. Gender Age Pack-years (months) blind placebo controlled clinical trial wherein subjects 1. F 42 36 12 received either Selegiline in oral tablet form, or a placebo, 2 M 29 15 12 initiating administration of this drug one week prior to the 3 F 40 25 12 date Set for Self-induced reduction or cessation of tobacco 4 F 38 3O 12 product consumption, in this case cigarette Smoking. Four 5 M 35 24 6 6 F 42 13 6 hundred chronic Smokers of both Sexes Subjects addicted to 7 M 47 29 6 chronic cigarette Smoking are planned to enter the Study; 50 8 M 51 40 6 patients have been recruited already. 9 M 36 2O 6 1O M 51 33 6 0131 Subjects were admitted to the study after undergo 11 M 47 45 6 ing medical examination including anamnesis or other medi 12 M 38 29 6 cal conditions and other forms of Substance abuse and all 13 F 43 48 6 14 M 43 26 6 signed informed consent, including the use of placebo in 15 F 49 90 6 place of Selegiline. All of the Subjects admitted to the Study Were chronic cigarette Smokers, consuming at least 15 cigarettes daily for the preceding year, but in otherwise general good physical and free of concomitant medication What we claim is: use. The Study was approved and Subjected to regulation by 1. A pharmaceutical composition comprising an amount both a hospital Helsinki committee and the Israel Ministry of of an inhibitor of monoamine oxidase, an amount of an Health. addictive Substance or derivative thereof, and a Suitable diluent or carrier. 0132) Subjects were assigned to one of two groups: oral 2. A composition as of claim 1, wherein Said composition Selegeline tablet 5 mg (Jumex, Jansson, Belgium) twice a is adapted to administer both the inhibitor of monoamine day for 26 weeks in combination with nicotine Skin patch for oxidase and the addictive Substance, or derivative thereof, 8 weeks or oral placebo twice a day for 26 weeks combined via the same route of administration. with nicotine skin patch for 8 weeks. Self-reported absti 3. A composition as of claim 1, wherein Said carrier is an nence, urine cotinine levels, Safety laboratory parameters oral tablet, capsule, or comestible article. and adverse events were monitored at regular intervals. 4. A composition as of claim 1, wherein Said carrier is an 0133. During the initial phase of the trial, half of the aeroSol, nebulized vapor, or Smoke. patients were administered either Selegiline tablets taken as 5. A composition as of claim 1, wherein Said carrier is a 5 mg tablet twice a day, once in the morning and once in the transdermal patch. afternoon. Alternately, to the Second half of patients, instead 6. A composition as of claim 1, wherein Said carrier is of Selegiline, a placebo tablet was provided, identical in Suitable for parenteral administration, including intradermal, shape, colour, marking, weight, and size to the Selegiline Subcutaneous, intramuscular, intravenous, intrathecal, Sub containing tablets. In all cases the physician investigator lingual, rectal, vaginal, intraocular, transdermal, respiratory Supervising the trial was blinded to the identity of the active mucosal, or pulmonary routes of administration. Selegiline tablet vs the placebo tablet. 7. A composition as of claim 1, wherein Said addictive Substance, or derivative thereof, is nicotine and Said carrier 0134. According to the initial results of this long term is an oral tablet, capsule, or comestible article. abstinence Study, a high degree of Success was noted for 8. A composition of claim 1, wherein Said addictive SmokerStreated with the combination therapy of oral Selege Substance, or derivative thereof, is nicotine and Said carrier line and nicotine patch (first 8 weeks only) regimen. From is an aeroSol, Vapor, or Smoke carrier. among a group of 45 Smokers who participated in the 9. A composition as of claim 1, wherein Said addictive long-term clinical trial, 15 SmokerS demonstrated continous Substance, or derivative thereof, is nicotine and Said carrier abstinence from smoking, as shown in Table 3 below. In this is a transdermal patch. Study, participants were interviewed once every two weeks 10. A composition as of claim 1, wherein Said addictive for the first three months and then at six months and twelve Substance, or derivative thereof, is nicotine and Said carrier months (where applicable) from the intiation of treatment. In is Suitable for parenteral administration, including intrader addition to Self-reporting, urinalysis for co-nicotine was mal, Subcutaneous, intramuscular, intravenous, intrathecal, US 2002/0019421 A1 Feb. 14, 2002

Sublingual, rectal, vaginal, intraocular, transdermal, respira BW-1370U87; CS-722; E-2011; harmine; harmane, norhar tory mucosal, or pulmonary routes of administration. mane; harmaline; moclobemide; PharmaProjects 3975; RO 11. A composition of claim 1, wherein Said monoamine 41-1049; RS-8359; T-794; toloxatone; K-Y 1349; oxidase inhibitor is Selegiline and Said carrier is an oral LY-51641; LY-121768; M&B 9303; MDL 72394; MDL tablet, capsule, or comestible article. 72392; Sercloremine; MD 72394, MO 1671, amiflamine; 12. A composition as of claim 1, wherein Said monoamine vanoxerine; AGN 2253; iproniazid; isocarboxazid; M-3- oxidase inhibitor is Selegiline and Said carrier is an aeroSol, PPC, nialamid; phenelZine, pargyline; tranylcypromine, Vapor, or Smoke carrier. budipine; caroxazone; D-1711; fezolamine; FLA-334, FLA 13. A composition of claim 1, wherein Said monoamine 289; K-11566: K-1 1829; metralindole; MPCPAM; Phar oxidase inhibitor is Selegiline and Said carrier is a transder maProjects 227; PharmaProjects 2806; PharmaProjects mal patch. 1122; PharmaProjects 331; PharmaProjects 4433; RS-2232; 14. A composition as of claim 1, wherein Said monoamine UP-614-04, or mixtures thereof. oxidase inhibitor is Selegiline and Said carrier is Suitable for 21. A composition as of claim 1, wherein Said addictive parenteral administration, including intradermal, Subcutane Substance, or derivative thereof, is nicotine, Said carrier is a ous, intramuscular, Intravenous, intrathecal, Sublingual, rec transdermal patch, and Said inhibitor of monoamine oxidase tal, vaginal, intraocular, transdermal, respiratory mucosal, or is Selected from the group consisting of Selegiline, desm pulmonary routes of administration. ethylselegiline, S(+)desmethylselegiline, lazabemide, bro 15. A composition as of claim 1, wherein Said monoamine formine, rasagiline, LU-53439, LU-43839, idazoxan, clor oxidase inhibitor is Selegiline, Said addictive Substance, or gyline, cimoxatone, cirazoline, befloxatone, brofaromine; derivative thereof, is nicotine, and Said carrier is an oral bazinaprine; MD-240928; BW-616U; BW-1370U87; tablet, capsule, or comestible article. CS-722, E-2011, harmane, harmane, norharmane, harma 16. A composition as of claim 1, wherein Said monoamine line; moclobemide; PharmaProjects 3975; RO 41-1049; oxidase inhibitor is Selegiline, Said addictive Substance, or RS-8359; T-794; toloxatone; K-Y 1349; LY-51641; derivative thereof, is nicotine, and Said carrier is an aeroSol, LY-121768, M&B 9303; MDL 72394; MDL 72392; serclo Vapor, or Smoke carrier. remine; MD 72394, MO 1671, amiflamine; vanoxerine; 17. A composition as of claim 1, wherein Said monoamine AGN 2253; iproniazid; isocarboxazid; M-3-PPC; nialamid; oxidase inhibitor is Selegiline, Said addictive Substance, or phenelZine, pargyline; tranylcypromine, budipine; carOX derivative thereof, is nicotine, and Said carrier is a transder aZone; D-1711; fezolamine; FLA-334, FLA-289; K-11566; mal patch. K-1 1829; metralindole; MPCPAM; PharmaProjects 227; 18. A composition as of claim 1, wherein said monoamine PharmaProjects 2806; PharmaProjects 1122; Phar oxidase inhibitor is Selegiline, Said addictive Substance, or maProjects 331; PharmaProjects 4433; RS-2232; UP-614 derivative thereof, is nicotine, and Said carrier is Suitable for 04, or mixtures thereof. parenteral administration, including intradermal, Subcutane 22. A composition as of claim 1, wherein Said addictive ous, intramuscular, intravenous, intrathecal, Sublingual, rec Substance, or derivative thereof, is nicotine, Said carrier is tal, vaginal, intraocular, transdermal, respiratory mucosal, or Suitable for parenteral administration, including intradermal, pulmonary routes of administration. Subcutaneous, intramuscular, intravenous, intrathecal, Sub 19. A composition as of claim 1, wherein said addictive lingual, rectal, vaginal, intraocular, transdermal, respiratory Substance, or derivative thereof, is nicotine, Said carrier is an mucosal, or pulmonary routes of administration, and Said oral tablet, capsule, or comestible article, and Said inhibitor inhibitor of monoamine oxidase is Selected from the group of monoamine oxidase is Selected from the group consisting consisting of Selegiline, desmethylselegiline, S(+)desmeth of Selegiline, desmethylselegiline, S(+)desmethylselegiline, ylselegiline, lazabemide, broformine, rasagiline, LU-53439, lazabemide, broformine, rasagiline, LU-53439, LU-43839, LU-43839, idaZOXan, clorgyline, cimoxatone, cirazoline; idaZOXan, clorgyline, cimoxatone, cirazoline; befloxatone; befloxatone; brofaromine; bazinaprine; MD-240928; brofaromine; bazinaprine; MD-240928; BW-616U; BW-616U; BW-137OU87; CS-722; E-2011; harmine; har BW-1370U87; CS-722; E-2011; harmine; harmane, norhar mane, norharmane, harmaline, moclobemide, Phar mane; harmaline; moclobemide; PharmaProjects 3975; RO maProjects 3975; RO 41-1049; RS-8359; T-794; toloxatone; 41-1049; RS-8359; T-794; toloxatone; K-Y 1349; K-Y 1349; LY-51641; LY-121768; M&B 9303; MDL 72394; LY-51641; LY-121768; M&B 9303; MDL 72394; MDL MDL 72392; sercloremine; MD 72394, MO 1671, ami 72392; Sercloremine; MD 72394, MO 1671, amiflamine; flamine; vanoxerine; AGN 2253; iproniazid; isocarboxazid; vanoxerine; AGN 2253; iproniazid; isocarboxazid; M-3- M-3-PPC; nialamid; phenelzine; pargyline; tranylcyprom PPC, nialamid; phenelZine, pargyline; tranylcypromine, ine, budipine; caroxazone; D-1711; fezolamine; FLA-334; budipine; caroxazone; D-1711; fezolamine; FLA-334, FLA FLA-289; K-11566; K11829; metralindole MPCPAM; Phar 289; K-11566: K-1 1829; metralindole; MPCPAM; Phar maProjects 227; PharmaProjects 2806; PharmaProjects maProjects 227; PharmaProjects 2806; PharmaProjects 1122; PharmaProjects 331; PharmaProjects 4433; RS-2232; 1122; PharmaProjects 331; PharmaProjects 4433; RS-2232; UP-614-04, or mixtures thereof. UP-614-04, or mixtures thereof. 23. A composition as of claim 1, wherein Said monoamine 20. A composition as of claim 1, wherein Said addictive oxidase inhibitor is Selegiline, Said carrier is an oral tablet, Substance, or derivative thereof, is nicotine, Said carrier is an capsule, or comestible article, and Said addictive Substance aeroSol, Vapor, or Smoke carrier, and Said inhibitor of is nicotine, cotinine, a nicotinic agonist, a derivative of monoamine oxidase is Selected from the group consisting of nicotine, a dopamine agonist, an opiate, morphine, heroin, Selegiline, desmethylselegiline, S(+)desmethylselegiline, methadone, buprenorphine, fentanyl, naloxone, codeine, an lazabemide, broformine, rasagiline LU-53439, LU-43839, amphetamine, metamphetamine, methylphenidate, methyl idaZOXan, clorgyline, cimoxatone, cirazoline; befloxatone; enedioxymethamphetamine, a dopamine re-uptake inhibitor, brofaromine; bazinaprine; MD-240928; BW616U; an alkaloid, cocaine, or derivative thereof. US 2002/0019421 A1 Feb. 14, 2002

24. A composition as of claim 1, wherein Said monoamine prises at least one compound Selected from the group oxidase inhibitor is Selegiline, Said carrier is an aeroSol, consisting of an inhibitor of nicotine metabolism; a nicotine Vapor, or Smoke carrier, and Said addictive Substance, or antagonist, a nicotine agonist; an inhibitor of CYP2A6, derivative thereof, is nicotine, cotinine, a nicotinic agonist, beta-blocker; an alpha-2 adrenergic anatagonist, a muscle a derivative of nicotine, a dopamine agonist, an opiate, relaxant, a benzodiazepine; an inhibitor of nicotine metabo morphine, heroin, methadone, buprenorphine, fentanyl, lism; a nicotine antagonist; a peripheral nicotine anatagonist; naloxone, codeine, an amphetamine, metamphetamine, a nicotine agonist, a dopamine agonist; a dopamine antago methylphenidate, methylenedioxymethamphetamine, a nist; a Serotonin agonist; a Serotonin antagonist, an antihis dopamine re-uptake inhibitor, an alkaloid, cocaine, or tamine; a cannabinoid receptor antagonist; a cannabinoid derivative thereof. receptor agonist; an anticholinergic agent; an inhibitor of 25. A composition as of claim 1, wherein Said monoamine acetylcholine esterase a muscarinic antagonist; a muscarinic oxidase inhibitor is Selegiline, Said carrier is a transdermal agonist, an opiate agonist, an opiate anatogonist; an amphet patch, and Said addictive Substance, or derivative thereof, is amine agonist, an amphetamine antagonist; a glutamate nicotine, cotinine, a nicotinic agonist, a derivative of nico antagonist, a NMDA antagonist, an antihypertensive; an tine, a dopamine agonist, an opiate, morphine, heroin, inhibitor of Serotonin transport (re-uptake); an inhibitor of methadone, buprenorphine, fentanyl, naloxone, codeine, an dopamine transport (re-uptake); an inhibitior of noradrena amphetamine, metamphetamine, methylphenidate, methyl line transport (re-uptake); a NaSSA; an NMDA antagonist; enedioxymethamphetamine, a dopamine re-uptake inhibitor, an analgesic, a vasodilator; a calcium channel antagonist; a an alkaloid, cocaine, or derivative thereof. Xanthine; an inhibitor of COMT (catechol-O-methyltrans 26. A composition as of claim 1, wherein Said monoamine ferase); a steroid; a steroid hormone; a vitamin; an inhibitor oxidase inhibitor is Selegiline, Said carrier is Suitable for or monoamine oxidase; an anti-oxidant; an atypcial antide parenteral administration, including intradermal, Subcutane preSSant; an atypical antipsychotic, an addictive Substance: ous, intramuscular, intravenous, intrathecal, Sublingual, rec a pharmacological analogue of an addictive Substance; or tal, vaginal, intraocular, transdermal, respiratory mucosal, or mixtures thereof. pulmonary routes of administration, and Said addictive Sub 29. A composition as of claim 1, wherein Said monoamine stance, or derivative thereof, is nicotine, cotinine, a nicotinic oxidase inhibitor is Selegiline, Said addictive Substance, or agonist, a derivative of nicotine, a dopamine agonist, an derivative thereof, is nicotine, Said carrier is a transdermal opiate, morphine, heroin, methadone, buprenorphine, fenta patch, and Said composition further comprises at least one nyl, naloxone, codeine, an amphetamine, metamphetamine, compound Selected from the group consisting of an inhibi methylphenidate, methylenedioxymethamphetamine, a tor of nicotine metabolism; a nicotine antagonist; a nicotine dopamine re-uptake inhibitor, an alkaloid, cocaine, or agonist; an inhibitor of CYP2A6, a beta-blocker; an alpha-2 derivative thereof. adrenergic anatagonist; a muscle relaxant, a benzodiazepine; 27. A composition of claim 1, wherein Said monoamine an inhibitor of nicotine metabolism; a nicotine antagonist; a oxidase inhibitor is Selegiline, Said addictive Substance, or peripheral nicotine antagonist, a nicotine agonist; a dopam derivative thereof, is nicotine, Said carrier is an oral tablet ine agonist, a dopamine antagonist, a Serotonin agonist, a capsule, or comestible article, and Said composition further Serotonin antagonist, an antihistamine; a cannabinoid recep comprises at least one compound Selected from the group tor antagonist; a cannabinoid receptor agonist, an anticho consisting of an inhibitor of nicotine metabolism; a nicotine linergic agent; an inhibitor of acetylcholine esterase, a antagonist, a nicotine agonist; an inhibitor of CYP2A6, a muscarinic antagonist, a muscarinic agonist, an opiate ago beta-blocker; an alpha-2 adrenergic anatagonist, a muscle nist, an opiate anatogonist; an amphetamine agonist, an relaxant, a benzodiazepine; an inhibitor of nicotine metabo amphetamine antagonist, a glutamate antagonist; a NMDA lism; a nicotine antagonist; a peripheral nicotine anatagonist; antagonist, an antihypertensive, an inhibitor of Serotonin a nicotine agonist, a dopamine agonist; a dopamine antago transport (re-uptake); an inhibitor of dopamine transport nist; a Serotonin agonist; a Serotonin antagonist, an antihis (re-uptake); an inhibitior of noradrenaline transport (re tamine; a cannabinoid receptor antagonist; a cannabinoid uptake); a NaSSA, an NMDA antagonist; an analgesic; a receptor agonist; an anticholinergic agent; an inhibitor of vasodilator, a calcium channel antagonist; a Xanthine; an acetylcholine esterase; a muscarinic antagonist, a muscar inhibitor of COMT (catechol-O-methyltransferase); a ste inic agonist, an opiate agonist, an opiate anatogonist, an roid; a Steroid hormone; a vitamin; an inhibitor or monoam amphetamine agonist, an amphetamine antagonist, a ine oxidase; an anti-oxidant, an atypical antidepressant, an glutamate antagonist, a NMDA antagonist; an antihyperten atypical antipsychotic, an addictive Substance; a pharmaco Sive, an inhibitor of Serotonin transport (re-uptake); an logical analogue of an addictive Substance; or mixtures inhibitor of dopamine transport (re-uptake); an inhibitior of thereof. noradrenaline transport (re-uptake); a NaSSA; an NMDA 30. A composition as of claim 1, wherein Said monoamine antagonist, an analgesic; a vasodilator; a calcium channel oxidase inhibitor is Selegiline, Said addictive Substance, or antagonist; a xanthine; an inhibitor of COMT (catechol-O- derivative thereof, is nicotine, Said carrier is Suitable for methyltransferase); a steroid; a steroid hormone; a vitamin, parenteral administration, including intradermal, Subcutane an inhibitor or monoamine oxidase; an anti-oxidant; an ous, intramuscular, intravenous, intrathecal, Sublingual, rec atypcial antidepressant, an atypical antipsychotic, an addic tal, vaginal, intraocular, transdermal, respiratory mucosal, or tive Substance, a pharmacological analogue of an addictive pulmonary routes of administration, and Said composition Substance; or mixtures thereof. further comprises at least one compound Selected from the 28. A composition as of claim 1, wherein Said monoamine group consisting of an inhibitor of nicotine metabolism; a oxidase inhibitor is Selegiline, Said addictive Substance, or nicotine antagonist; a nicotine agonist; an inhibitor of derivative thereof, is nicotine, Said carrier is an aeroSol, CYP2A6, a beta-blocker, an alpha-2 adrenergic anatagonist; Vapor, or Smoke carrier, and Said composition further com a muscle relaxant, a benzodiazepine, an inhibitor of nicotine US 2002/0019421 A1 Feb. 14, 2002 metabolism; a nicotine antagonist; a peripheral nicotine to the Subject in need thereof a pharmaceutical composition anatagonist, a nicotine agonist; a dopamine agonist, a comprising a therapeutically effective amount of Selegiline dopamine antagonist; a Serotonin agonist, a Serotonin and a therapeutically effective amount of nicotine combined antagonist, an antihistamine; a cannabinoid receptor antago in an oral tablet, capsule, or comestible dosage form, thereby nist; a cannabinoid receptor agonist; an anticholinergic attenuating consumption of Said Substance or product. agent; an inhibitor of acetylcholine esterase; a muscarinic 37. A method of treating a subject addicted an addictive antagonist, a muscarinic agonist, an opiate agonist, an opiate Substance or product comprising the Steps of administering anatogonist; an amphetamine agonist; an amphetamine to the Subject in need thereof a pharmaceutical composition antagonist, a glutamate antagonist, a NMDA antagonist; an comprising a therapeutically effective amount of Selegiline antihypertensive; an inhibitor of Serotonin transport (re and a therapeutically effective amount of nicotine combined uptake); an inhibitor of dopamine transport (re-uptake); an in a transdermal patch dosage form, thereby attenuating inhibitor of noradrenaline transport (re-uptake); a NaSSA; consumption of Said Substance or product. an NMDA antagonist; an analgesic; a vasodilator, a calcium 38. A method of treating the symptoms of nicotine with channel antagonist; a xanthine; an inhibitor of COMT (cat drawal comprising the Steps of co-administering to the echol-O-methyltransferase); a steroid; a steroid hormone; a Subject in need thereof a pharmaceutical composition com Vitamin; an inhibitor or monoamine oxidase; an anti-oxi prising a therapeutically effective amount of Selegiline, dant; an atypcial antidepressant, an atypical antipsychotic, combined with a Suitable diluent or carrier, and a pharma an addictive Substance, a pharmacological analogue of an ceutical composition comprising a therapeutically effective addictive Substance, or mixtures thereof. amount of nicotine, combined with a Suitable diluent or 31. A method of treating a Subject addicted to an addictive carrier, thereby alleviating the Symptoms of nicotine with Substance or product comprising the Steps if co-administer drawal. ing to the Subject in need thereof a pharmaceutical compo 39. A method of treating the symptoms of nicotine with Sition comprising a therapeutically effective amount of Sel drawal comprising the Steps of co-administering to the egiline and a pharmaceutical composition comprising a Subject in need thereof a pharmaceutical composition com therapeutically effective amount of nicotine, thereby attenu prising a therapeutically effective amount of Selegiline in ating consumption of Said Substance or product. oral tablet, capsule, or comestible dosage form and a phar 32. A method of treating a Subject addicted to an addictive maceutical composition comprising a therapeutically effec Substance or product comprising the Steps of co-administer tive amount of nicotine in a transdermal patch dosage form, ing to the Subject in need thereof a pharmaceutical compo thereby alleviating the Symptoms of nicotine withdrawal. Sition comprising a therapeutically effective amount of Sel 40. A method of treating the symptoms of nicotine with egiline in oral tablet, capsule, or comestible dosage form and drawal comprising the Steps of co-administering to the a pharmaceutical composition comprising a therapeutically Subject in need thereof a pharmaceutical composition a effective amount of nicotine in a transdermal patch dosage therapeutically effective amount of Selegiline in oral tablet, form, thereby attenuating consumption of Said Substance or capsule, or comestible dosage form and a pharmaceutical product. composition comprising a therapeutically effective amount 33. A method of treating a subject addicted to an addictive of nicotine in an oral tablet, capsule, or comestible dosage Substance or product comprising the Steps of co-administer form, thereby alleviating the Symptoms of nicotine with ing to the Subject in need thereof a pharmaceutical compo drawal. Sition comprising a therapeutically effective amount of Sel 41. A method of treating the Symptoms of nicotine with egiline in oral tablet, capsule, or comestible article form and drawal comprising the Steps of co-administering to the a pharmaceutical composition comprising a therapeutically Subject in need thereof a pharmaceutical composition com effective amount of nicotine in oral tablet, capsule, or prising a therapeutically effective amount of Selegiline in comestible article form, thereby attenuating consumption of oral dosage form and a pharmaceutical composition com Said Substance or product. prising a therapeutically effective amount of nicotine in an 34. A method of treating a Subject addicted to an addictive aeroSol, Vapor, or Smoke dosage form, thereby alleviating Substance or product comprising the Steps of co-administer the Symptoms of nicotine withdrawal. ing to the Subject in need thereof a pharmaceutical compo 42. A method of treating the Symptoms of nicotine with Sition comprising a therapeutically effective amount of Sel drawal comprising the Steps of co-administering to the egiline in oral tablet or comestible dosage form and a Subject in need thereof a pharmaceutical composition com pharmaceutical composition comprising a therapeutically prising a therapeutically effective amount of Selegiline in a effective amount of nicotine in an aeroSol, Vapor, or Smoke transdermal patch dosage form and a pharmaceutical com dosage form, thereby attenuating consumption of Said Sub position comprising a therapeutically effective amount of stance or product. nicotine in a transdermal patch dosage form, thereby alle 35. A method of treating a subject addicted to an addictive viating the Symptoms of nicotine withdrawal. Substance or product comprising the Steps of co-administer 43. A method of treating the symptoms of nicotine with ing to the Subject in need thereof a pharmaceutical compo drawal comprising the Steps of administering to the Subject Sition comprising a therapeutically effective amount of Sel in need thereof a pharmaceutical composition comprising a egiline in a transdermal patch dosage form and a therapeutically effective amount of Selegiline and a thera pharmaceutical composition comprising a therapeutically peutically effective amount of nicotine combined in an oral effective amount of nicotine in a transdermal patch dosage tablet, capsule, or comestible dosage form, thereby allevi form, thereby attenuating consumption of Said Substance or ating the Symptoms of nicotine withdrawal. product. 44. A method of treating the Symptoms of nicotine with 36. A method of treating a Subject addicted to an addictive drawal comprising the Steps of administering to the Subject Substance or product comprising the Steps of administering in need thereof a pharmaceutical composition comprising a US 2002/0019421 A1 Feb. 14, 2002 therapeutically effective amount of Selegiline and a thera to the Subject in need thereof a pharmaceutical composition peutically effective amount of nicotine combined in a trans of claims 3, 7, 11, 15, 19, 23, or 27, thereby attenuating dermal patch dosage form, thereby alleviating the Symptoms chronic craving Symptoms of a Subject addicted to Said of nicotine withdrawal. Substance or product. 45. A method of treating a Subject addicted to a tobacco 54. A method of treating a subject addicted to an addictive product comprising the Steps of co-administering to the Substance or product comprising the Steps of administering Subject in need thereof a pharmaceutical composition com to the Subject in need thereof a pharmaceutical composition prising a therapeutically effective amount of Selegiline and of claims 4, 8, 12, 16, 20, 24, or 28, thereby attenuating a pharmaceutical composition comprising a therapeutically chronic craving Symptoms of a Subject addicted to Substance effective amount of nicotine, thereby attenuating tobacco or product. consumption. 55. A method of treating a subject addicted to an addictive 46. A method of treating a Subject addicted to a tobacco Substance or product comprising the Steps of administering product comprising the Steps of co-administering to the to the Subject in need thereof a pharmaceutical composition Subject in need thereof a pharmaceutical composition com of claims 5, 9, 13, 17, 21, 25, or 29, thereby attenuating prising a therapeutically effective amount of Selegiline in chronic craving Symptoms of a Subject addicted to Said oral tablet, capsule, or comestible dosage form and a phar Substance or product. maceutical composition comprising a therapeutically effec 56. A method of treating a subject addicted to an addictive tive amount of nicotine in a transdermal patch dosage form, Substance or product comprising the Steps of administering thereby attenuating tobacco consumption. to the Subject in need thereof a pharmaceutical composition 47. A method of treating a Subject addicted to a tobacco of claims 6, 10, 14. 18, 22, 26, or 30, thereby attenuating product comprising the Steps of co-administering to the chronic craving Symptoms of a Subject addicted to Said Subject in need thereof a pharmaceutical composition com Substance or product. prising a therapeutically effective amount of Selegiline in 57. A method of treating the symptoms of nicotine with oral tablet, capsule, or comestible dosage form and a phar drawal comprising the Steps of administering to the Subject maceutical composition comprising a therapeutically effec in need thereof a pharmaceutical composition of claims 1 or tive amount of nicotine in an oral tablet, capsule, or comes 2, thereby alleviating the chronic craving Symptoms of a tible dosage form, thereby attenuating tobacco consumption. Subject addicted to nicotine. 48. A method of treating a Subject addicted to a tobacco 58. A method of treating the symptoms of nicotine with product comprising the Steps of co-administering to the drawal comprising the Steps of administering to the Subject Subject in need thereof a pharmaceutical composition com in need thereof a pharmaceutical composition of claims 3, 7, prising a therapeutically effective amount of Selegiline in 11, 15, 19, 23, or 27, thereby alleviating the chronic craving oral tablet, capsule, or comestible dosage form and a phar Symptoms of a Subject addicted to nicotine. maceutical composition comprising a therapeutically effec 59. A method of treating the symptoms of nicotine with tive amount of nicotine in an aeroSol, Vapor, or Smoke drawal comprising the Steps of administering to the Subject dosage form, thereby attenuating tobacco consumption. in need thereof a pharmaceutical composition of claims 4, 8, 49. A method of treating a subject addicted to a tobacco 12, 16, 20, 24, or 28, thereby alleviating the chronic craving product comprising the Steps of co-administering to the Symptoms of a Subject addicted to nicotine. Subject in need thereof a pharmaceutical composition com 60. A method of treating the symptoms of nicotine with prising a therapeutically effective amount of Selegiline in a drawal comprising the Steps of administering to the Subject transdermal patch dosage form and a pharmaceutical com in need thereof a pharmaceutical composition of claims 5, 9, position comprising a therapeutically effective amount of 13, 17, 21, 25, or 29, thereby alleviating the chronic craving nicotine in a transdermal patch dosage form, thereby attenu Symptoms of a Subject addicted to nicotine. ating tobacco consumption. 61. A method of treating the symptoms of nicotine with 50. A method of treating a subject addicted to a tobacco drawal comprising the Steps of administering to the Subject product comprising the Steps of administering to the Subject in need thereof a pharmaceutical composition of claims 6, in need thereof a pharmaceutical composition comprising a 10, 14, 18, 22, 26, or 30, thereby alleviating the chronic therapeutically effective amount of Selegiline and a thera craving Symptoms of a Subject addicted to nicotine. peutically effective amount of nicotine combined in an oral 62. A method of treating a Subject addicted to tobacco tablet, capsule, or comestible dosage form, thereby attenu product consumption comprising the Steps of administering ating tobacco consumption. to the Subject in need thereof a pharmaceutical composition 51. A method of treating a Subject addicted to a tobacco of claims 1 or 2, thereby attenuating chronic tobacco con product comprising the Steps of administering to the Subject Sumption. in need thereof a pharmaceutical composition comprising a 63. A method of treating a Subject addicted to tobacco therapeutically effective amount of Selegiline and a thera product consumption comprising the Steps of administering peutically effective amount of nicotine combined in a trans to the Subject in need thereof a pharmaceutical composition dermal patch dosage form, thereby attenuating tobacco of claims 3, 7, 11, 15, 19, 23, or 27, thereby attenuating consumption. chronic tobacco consumption. 52. A method of treating a Subject addicted to an addictive 64. A method of treating a Subject addicted to tobacco Substance or product comprising the Steps of administering product consumption comprising the Steps of administering to the Subject in need thereof a pharmaceutical composition to the Subject in need thereof a pharmaceutical composition of claims 1 or 2, thereby attenuating chronic craving Symp of claims 4, 8, 12, 16, 20, 24, or 28, thereby attenuating toms of a Subject addicted to Said Substance or product. chronic tobacco consumption. 53. A method of treating a subject addicted to an addictive 65. A method of treating a subject addicted to tobacco Substance or product comprising the Steps of administering product consumption comprising the Steps of administering US 2002/0019421 A1 Feb. 14, 2002 19 to the Subject in need thereof a pharmaceutical composition to the Subject in need thereof a pharmaceutical composition of claims 5, 9, 13, 17, 21, 25, or 29, thereby attenuating of claims 6, 10, 14, 18, 22, 26, or 30, thereby attenuating chronic tobacco consumption. chronic tobacco consumption. 66. A method of treating a Subject addicted to tobacco product consumption comprising the Steps of administering k . . . .