WO2000006139A2

WO2000006139A2 - Use of moclobemide and metabolites for treating and preventing substance abuse

Info

Publication number: WO2000006139A2
Application number: PCT/US1999/017275
Authority: WO
Inventors: Donald F. Klein; Seth Lederman
Original assignee: Vela Pharmaceuticals Inc.
Priority date: 1998-07-31
Filing date: 1999-07-30
Publication date: 2000-02-10
Also published as: WO2000006139A3; MXPA01001180A; JP2002521432A; CA2338326A1; AU5243999A

Abstract

Methods and compositions for using moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to assist in treating or preventing physical dependence on, or withdrawal symptoms associated with alcohol and drugs, including opioids, other central nervous system depressants such as sedatives, central nervous system stimulants such as cocaine and amphetamines, and other drugs active upon the central nervous system.

Description

METHODS AND COMPOSITIONS FOR TREATING AND PREVENTING SUBSTANCE ABUSE USING MOCLOBEMIDE

This application incorporates by reference herein United States application 60/094,986, filed July 31, 1998.

1. INTRODUCTION

This invention relates to methods and compositions for treating or preventing the symptoms associated with withdrawal from substance abuse or dependence, including abuse of opioids, other central nervous system depressants such as alcohol and sedatives, and central nervous system stimulants such as cocaine and amphetamines. The present invention also relates to methods and compositions to prevent, control, or alleviate the development of physical dependence on opioids, other central nervous system depressants such as alcohol and sedatives, and central nervous system stimulants such as cocaine and amphetamines.

2. BACKGROUND OF THE INVENTION

2.1. CHEMISTRY AND PHARMACOKINETICS OF MOCLOBEMIDE

Moclobemide, or p-chloro-N- (2-morpholinoethyl) - benzamide, which is represented by the formula:

is described in U.S. Patent No. 4,210,754, to Bur ard et al . Moclobemide is a selective and reversible monoamine oxidase (MAO) subtype A inhibitor. Kettler, R. et al . , 1990, Acta Psychiatr. Scand. , Supp. 360 (82) : 101-103. Unlike other monoamine oxidase inhibitors, which irreversibly and non- selectively bind MAO and can have severe food and drug interactions that limit their therapeutic utility, moclobemide is part of a distinct class of selective MAO inhibitors that inhibit predominantly or selectively either monoamine oxidase A (MAO-A) or monoamine oxidase B (MAO-B) .

Compounds that selectively inhibit MAO-B, and thereby inhibit the degradation of dopamine, are useful for the treatment of neurological and neurodegenerative diseases of the dopa inergic pathway, such as Parkinson's disease. Livingston, M.G. and Livingston, H.M. , 1996, Drug Safety. 14 (4) :218-227. Compounds that selectively inhibit MAO-A predominantly affect the degradation of serotonin and norepinephrine, leading to increased concentrations of these neurotransmitters in synapses, and are useful for depression. Livingston and Livingston, 1996.

The in vitro binding of moclobemide to MAO-A is weak, but more than 167-fold more selective than for the MAO- B isozyme. The ex vivo binding of moclobemide to MAO-A has been demonstrated to be reversible, with sufficient dissociation to result in recovery of enzyme activity within 16 hours. Fulton, B. and Benfield, P., 1996, Drugs, 52(3) :451. This is in contrast to older, nonselective and irreversible MAO inhibitors (also referred to herein as "irreversible MAOIs" or "IMAOIs") , which irreversibly bind to either or both MAO-A and MAO-B isozymes and exhibit enzyme inhibition lasting several days. Da Prada, M. et al . , 1990. As the MAO-A inhibition in vivo is relatively short in duration, it is generally accepted to be reversible. Da Prada et al . , 1990, Acta Psychiatr. Scand. , Suppl. 360(82) .103-105.

The effects of moclobemide on monoamine metabolism and/or activity of monoaminergic neurons have been indirectly demonstrated in humans by reductions in plasma levels of the catecholamine metabolites homovanillic acid, 3,4- dihydroxyphenylacetic acid, and 3-methoxy-4- hydroxyphenylglycol and the serotonin (5-hydroxytryptamine) metabolite 5-hydroxyindoleacetic acid. In vitro , moclobemide has no appreciable affinity for muscarinic, dopaminergic, serotonergic, adrenergic, H -histaminergic, benzodiazepine or opioid receptors. Da Prada et al . , 1981, Excerpta Medica, 183-196; Da Prada et al . , 1983, Mod. Probl . Pharmacopsych.. 19:231-245; Da Prada et al . , 1984, Clin. Neuropharmacol . , 7 (Suppl. 1) :684-685.

Moclobemide is extensively distributed in the body and rapidly eliminated from plasma by metabolic conversion in the liver. After single-dose oral administration, moclobemide is almost completely absorbed; however, bioavailability ranges from 44% to 69% because of substantial first-pass metabolism. Guentert, T. . et al . , 1990, Acta Psvchiatr. Scand. , Suppl. 360 (82) : 91-93. After multiple administrations, moclobemide displays increased bioavailability (approx. 85%) , possibly due to saturation of first-pass metabolism. Id . Moclobemide is metabolized to at least 19 different metabolites, one of which has moderate MAO-A inhibitory activity. Jauch, R. et al . , 1990, Acta Psychiatr. Scand. , Suppl. 360 (82) : 87-90. Age and renal function are reported to have no significant effect on the pharmacokinetics of moclobemide; however, elimination is impaired in patients with hepatic dysfunction. Stoeckel et al . , 1990, Acta Psvchiatr. Scand. , Suppl. 360 (82) : 94-97. Thus, patients suffering from liver impairment should receive only 50% of the normal dosage. Id .

One of the most attractive features of moclobemide is its impressive safety profile. Because it does not permanently inhibit the monoamine oxidase enzyme, it has a relatively brief pharmacological action that contributes to its clinical safety. Moclobemide ' s short plasma half life (1 to 2 hours) also contributes to its safety because it promptly degrades in the tissues thereby preventing local over-accumulations. Stoeckel et al . , 1990. Moclobemide appears to produce fewer adverse events in normal clinical use than other reversible MAOI compounds. Priest, R.G., et al . , 1995, J. Clin. Psychopharm. , 15(4), Suppl. 2: 1S-3S. The most frequently reported adverse events were psychiatric, neurologic, and gastrointestinal disorders, with hepatobiliary events occurring only rarely (Hilton, S. et al . , 1995, J. Clin. Psychopharmacol . , 15(4 Suppl. 2):76S-

83S) , and the effects of moclobemide on the sleep of healthy volunteers appear weak in comparison to other MAO inhibitors. Blois, R. et al . , 1990, Acta Psychiatr. Scand. , Suppl. 360(82) :73-75. Although moclobemide has not been extensively used in the United States, it has been used in Europe and in other countries and it is not known to produce any clinically relevant interactions with commonly prescribed drugs. Zim er, R. et al . , 1990, Acta Psvchiatr. Scand. , Suppl. 360 (82) : 84-86. Moreover, moclobemide is far less likely than traditional MAO inhibitors to induce hypertensive reactions with the concomitant administration of sympathomimetic drugs, or consumption of tyramine-rich foods. Hilton, S.E., 1997, Eur. Arch. Psychiatry Clin. Neurosci., 247:113-119; Zimmer, 1990, Acta Psvchiatr. Scand. , Suppl. 360 (82) : 81-83 ; Zimmer, Fischbach et al . , 1990, Acta Psychiatr. Scand.. Suppl. 360(82) -. 16-11 ; Zimmer, Puech et al . , 1990, Acta Psychiatr. Scand. , Suppl. 360 (82) : 78-80; Da Prada et al . , 1990, Acta Psychiatr. Scand. , Suppl. 360 (82) : 106-107. A number of studies also suggest that moclobemide is better tolerated than other compounds with anti-depressant activity. Priest, R.G., et al . , 1995. Perhaps most impressively, the fatal toxicity index of moclobemide approaches zero. Hilton et al . , 1995. Initially, the recommended doses for moclobemide therapy (i.e., to treat depression) were approximately 100 mg to 150 mg three times daily. Guentert, T. . et al . , 1990. Subsequent experience has suggested that, in view of the positive dose-response curve found with moclobemide, doses as high as 600 mg daily are increasingly efficacious and remain well-tolerated. Fitton, A. et al . , 1992, Drugs . 43(4): 561- 596.

Moclobemide¹ s excellent safety and positive tolerance profile have made it a popular anti-depressive in Canada, Europe, Australia, New Zealand, South Africa, and Latin America. Angst J. et al . , 1996, Int. Clin. Psychopharmacol. , ll(Suppl. 3):3-7; Glick, I.D. et al . , 1995 Schatzberg, A.F. and Nemeroff, C.B. (Ed.), The American Psychiatric Press Textbook of Psvchopharmacoloαy . Washington, DC, pp. 839-846)). Prescribing medications such as irreversible MAOl's with potentially harmful or deadly side effects to treat depression has traditionally caused some measure of concern among physicians, who worry that depressed patients may attempt suicide with the very medicines they are prescribing. Although moclobemide is an MAO inhibitor, as an anti-depressive, it appears to be less prone to deadly drug and food interactions and less toxic in overdose. Patients taking other MAO inhibitors must adhere to restrictive diets which require the avoidance of, inter alia , red wines, beer, aged cheese and meats, liver, yeast extracts and fava or broad beans.

Furthermore, because moclobemide ' s side-effect profile is so benign, it enjoys good compliance rates. Priest, R.G., 1990, Acta Psychiatr. Scand. , Suppl. 360 (82) : 39-41. Compliance is an integral component of successful treatment because the morbidity and mortality rates associated with untreated psychiatric illness are high. If a patient persistently rejects medical treatment for psychiatric illness because the initial experience in pharmacological intervention was bad, then the prognosis can be just as poor as if the patient had not been treated at all. When used in the treatment of major depression, moclobemide has proved itself an effective, gentle, patient- friendly drug. 2.2. THERAPEUTIC EFFICACY OF MOCLOBEMIDE

Moclobemide, sold under the tradename AURORIX™ or MANERIX™ (F. Hoffman-La Roche, Basel, Switzerland) , has been shown to be effective in the treatment of various psychiatric disorders. For example, moclobemide is marketed in Canada, Europe, Australia, New Zealand, South Africa, and Latin America as an antidepressive agent, for which it has demonstrated significant therapeutic effect in certain patient populations. Angst J. et al . , 1996; Glick, I.D. et al . , 1995. A review of the pharmacological properties and therapeutic use of moclobemide in depressive illness was published by Fulton and Benfield in Drugs, 52 (3 ): 450-478 , 1996, updating a previous review of Fitton et al . , 1992, Drugs, 43 (4) : 561-596. The preparation and use of moclobemide as an anti- depressant is described in United States Patent No. 4,210,754 to Burkard et al . In the treatment of depression, moclobemide has been shown to have similar efficacy to tricyclic antidepressants (TCAs) , selective serotonin reuptake inhibitors (SSRIs) , and nonselective, irreversible MAO inhibitors. Fulton and Benfield, 1996; Fitton et al . , 1992. In particular, moclobemide has been shown to be effective in treating elderly patients suffering from depression or age-related dementia. Wesnes, K. et al . , 1990, Acta Psychiatr. Scand. , Suppl. 360 (82) : 71-72 ; United States Patent No. 4,906,626 to Amrein et al .

Moclobemide has also been reported to be effective in the management of tobacco addiction (PCT publication WO 95/28934; PCT publication WO 90/04387), attention deficit disorder (Trott, G.E. et al . , 1992, Psychopharmacol . , 106

Suppl .: 134-136) , and anxiety disorders such as social phobia, obsessive-compulsive disorder and panic (United States Patent No. 5,371,082 to Versiani et al . ; Liebowitz, M.R. et al . , 1990, Acta Psvchiatr. Scand. , Suppl. 360 (82) : 29-34 ; Angst, J. et al . , 1996, Int. Clin. Psvchophar . , ll(Suppl. 3):3-7; Pollack, M.H. and Gould, R.A. , 1996, Int. Clin. Psvchopharm. , 11 (Suppl. 3) :71-75) .

The use of irreversible monoamine oxidase inhibitors (MAOIs) has been limited by the wide range of MAOI-drug and MAOI-food interactions that are possible, particularly with sympathomimetic medications or tyramine- containing foods, resulting in hypertensive reactions. Despite their clinical benefits, this has led to a reduction in use of such medications. Even when MAOI efficacy is documented for a given condition, many practitioners are reluctant to prescribe drugs from this class because of the risk of serious adverse reactions. This appears to be so even when MAOIs are more effective than other available treatments. Perhaps due to its classification as a monoamine oxidase inhibitor, moclobemide has not been extensively studied in the United States. In fact, moclobemide is not approved by the U.S. Food and Drug Administration. Further, there remains a great need in the field of psychiatry for additional therapies to better treat the growing number of psychiatric and psychological disorders presently described in the Diagnostic and Statistical Manual of Mental Disorders. Ed. 4, (DSM-IV) , American Psychiatric Association, 1994, Washington, DC.

2.3 OPIATES AND ADDICTION

Opiates are drugs derived from opium, such as morphine, heroin, and codeine, and a wide variety of natural and semisynthetic compounds. The term "opioid" is more inclusive, applying to all agonists and antagonists with morphine-like activity, as well as to naturally occurring and synthetic opioid peptides. Opiate addiction is both a psychological and a physiological condition. In spite of the advances in recent years in the area of opiate receptors and endogenous opiate-like hormones and neurotransmitters, the dynamics and mechanisms of addiction and withdrawal remain only poorly understood. It is clear that opiate withdrawal is a state of adrenergic hyperactivity , in which neurons of the locus coeruleus become markedly activated. It is also known that three classes of opioid receptors exist, δ, K, and μ , and that there are likely subcategories within each class. Morphine and other morphine-like opioid agonists are used clinically for treatment of acute pain. They produce analgesia primarily through interaction with μ-opioid receptors, which also results in anxiolytic and euphorigenic effects. Such feelings of pleasure and euphoria motivate abuse in opioid addicted individuals, a population which includes those whose use was never legitimate, those whose use was at one time medically indicated but has escalated, and those receiving opiates in the context of medical treatment, such as for chronic pain, for whom such therapy is no longer necessary.

The mortality rate for street heroin users, the opiate of choice due to its availability and low price, is very high. Involvement in crime to support the habit, uncertainty about the dose, purity, or identity of the drug purchased on the street, and serious infections associated with sharing unsterile drugs and injection paraphernalia result in early death for many addicts. Heroin users commonly acquire bacterial infections producing skin abscesses, pulmonary infections, and endocarditis, and viral infections producing hepatitis and AIDS. Clearly, there is a need for an effective detoxification method which the addicted population will actually utilize, i.e., one that involves minimal pain and discomfort. Known detoxification methods do not meet this need. Alternatively, there is a need for drugs to assist in rendering the detoxification process less painful and unpleasant. Moreover, there presently exists no satisfactory method to prevent, control or alleviate physical opiate dependence, as by decreasing the urge for consumption thereof. 2.4 PHYSICAL OPIATE DEPENDENCE AND WITHDRAWAL

Following long-term use of opiates,' psychological dependence, physical dependence, and tolerance can develop. Physical dependence is a state that develops as a result of the adaptation produced by a resetting of homeostatic mechanisms in response to repeated drug use. Opiates affect numerous systems that were previously in equilibrium, most notably those mediated by endogenous opioids, requiring these systems to find a new balance in the presence of the inhibition or stimulation opiates cause. A person in this adapted state requires continual administration of the drug to maintain normal function. If administration of the drug is stopped abruptly, the previously affected systems experience a new imbalance, and must again readjust themselves to a new equilibrium. In the case of opiates and other central nervous system depressants, such as nicotine and alcohol, central nervous system hyperarousal is seen as the readaptive mechanism used by the body in the absence of the drug of dependence. The appearance of withdrawal symptoms when administration of the drug is stopped is the only actual evidence of physical dependence. It is estimated that 25% of those who use opiates sporadically (nondaily) will become dependent or addicted. Physical dependence is a function of the dosage schedule of the opiate, but it can be produced by very little opiate exposure, can persist for a long period after drug cessation, and will develop in every patient so exposed. In general, of those who advance to twice-daily use, the majority will become physically dependent within 6-8 weeks. Each opiate apparently has its own capacity for inducing dependence.

In a patient who is physically dependent on opiates, abrupt opiate discontinuation leads to development of the opiate withdrawal syndrome. The signs and symptoms of this syndrome are well-described. They include restlessness, lacrimation, rhinorrhea, uncontrollable yawning, perspiration, piloerection, restless sleep, and mydriasis during the first 24 hours. As the syndrome progresses, these symptoms become more severe and may be accompanied by twitching and muscle spasms, kicking movements, severe aches in the back, abdomen, and legs; abdominal and muscle cramps; hot and cold flashes; insomnia; nausea, vomiting, and diarrhea; coryza and severe sneezing; and increases in body temperature, blood pressure, respiratory rate, and heart rate (referred to hereinafter, either singly or in combination, as "withdrawal symptoms" or "withdrawal") . Some of these signs and syndromes have been incorporated into the DSM-IV-R Criteria for Opiate Withdrawal. The severity of the withdrawal is a function of which opiate was being taken, at what dose, and for how long. Thus, the degree of physical dependence will generally be reflected in the severity of the withdrawal syndrome.

The half-life of the opiate drug determines when withdrawal will begin, usually within two to three half-lives after the last opiate dose. Thus, for short half-life opiates such as morphine, withdrawal begins in 6-12 hours, whereas for long half-life opiates such as methadone, withdrawal begins in 36-48 hours. The symptoms of opiate withdrawal usually reach peak intensity in 36 to 72 hours. Without treatment, the syndrome runs its course in 5 to 7 days, although the craving for the drug may continue for months. (Fraser et al. 1961). Lingering physical effects of opiate withdrawal can appear for up to 6 months after resolution of acute symptoms.

2.5 METHODS OF DETOXIFICATION

Until quite recently, opiate detoxification had been a relatively standard procedure whose primary purpose was to minimize or eliminate the signs and symptoms associated with opiate withdrawal syndrome via a slow taper. The most common method of treating the withdrawal syndrome of opiate addiction has traditionally been to substitute methadone, a synthetic narcotic developed during World War I, for the opiate in question, and then gradually withdraw the methadone over a 5-12 day period. This technique has been known in the United States since the work of Isbell and Vogel in 1948 (Isbell, H. and Vogel, V.H., 1948, Amer . J. Psychiat. , 105:909-914).

Two of the first alternatives to methadone treatment that were tried without overwhelming success are propranolol treatment and propoxyphene treatment. Propranolol is a beta-adrenergic blocking agent, which seems to decrease the euphoric effects of narcotics and postwithdrawal cravings (Grosz H.J., 1972, Lancet 2:564-566). However, controlled trials found only minor effects, which were determined to preclude consideration of propranolol as an adjunct to the treatment of withdrawal from opiates

(Hollister L.E., Prusmack JJ, 1974, Arch. Gen. Psychiatry, 31:695-698) .

Propoxyphene was likewise an imperfect treatment protocol, itself addictive, and, when mixed with alcohol, likely to result in severe respiratory depression (Tenat,

F.S., 1973, JAMA, 226:1012; Inaba D. et al. 1974, Am. J. Drug Alcohol Abuse, 1:67-78; Tennat F.S. et al., JAMA, 232:1019- 1022). Acupuncture (Wen H.L. and Cheung S.Y.C., 1973, Am. J. Acupuncture, 1:71-75; Whitehead, P.C., 1978, Int. J. Addict. , 13:1-16; 1), and vitamin C therapies (Libby A. and Stone I., 1977, J. Orthomolecular Psychiatr. , 6:300-308; Free V., Sanders P., 1978, J. Orthomolecular Psychiatr. , 7:264-270; U.S. Patent No. 4,500,515 to Libby, A.F.) have also been investigated as potential opiate withdrawal remedies, without much success.

The development of new medications helpful in effectuating withdrawal, such as clonidine and naltrexone, has created opportunity for significant advances in opiate detoxification protocols, a variety of which have been advocated in the literature. However, there remains a need for a method to prevent, control, or alleviate physical dependence on addictive drugs and alcohol.

2.6 ALCOHOL ADDICTION Heavy consumers of alcohol not only acquire a tolerance much like that described above for opiates, they also develop a state of physical dependence. Alcohol withdrawal is not as severe as opiate withdrawal, but includes many of the same symptoms; drug craving, tremors, irritability, nausea, sleep disturbance, tachycardia, hypertension, sweating, perceptual distortion, and seizures. Moreover, in combination with other health problems, such as malnutrition, infection, or electrolyte imbalance, the syndrome of delirium tremens becomes likely. Delirium tremens consists of severe agitation, confusion, visual hallucinations, fever, profuse sweating, tachycardia, nausea, diarrhea, and dilated pupils.

Alcohol withdrawal syndrome has been reported in subjects with moderate daily alcohol consumption for 7 to 34 days, and delirium tremens appears during withdrawal after 48-87 days of consumption (Isbell, H. et al. 1955, 0. J. Stud. Alcohol. 16:1). As might be expected, more severe withdrawal is normally associated with more drinks per day, recent alcohol use, and longer duration of alcoholism, as well as with drug use in conjunction with alcohol, and the presence of additional medical problems (Schuckit, M.A. et al., 1995, Addiction, 90:1335-1347).

Clonidine has been shown to be useful in the treatment of alcohol withdrawal (Baumgartner , G.R., and Rowen, R.C., 1987, Arch. Intern. Med. 147:1223). Naltrexone has been used as an adjunct in the treatment of alcoholism, and alcohol withdrawal, and was recently approved by the FDA as a chemical treatment for alcoholism. Naltrexone appears to block some of the reinforcing properties of alcohol and has resulted in decreased relapse rates in clinical trials. 2.7 COCAINE AND OTHER CENTRAL NERVOUS SYSTEM STIMULANTS 2.7.1 COCAINE

More than 40 million Americans are estimated to have used cocaine at sometime, with the number of addicts estimated to be around 1,700,000. Gawin, F.H. and Ellinwood, Jr., E.H., 1988, N. Engl. J. Med.. 318:1173-1182. Addiction typically results in enormous medical, psychological, social, and economic impairment. Cregler, L.L., and Mark, H. , 1986, N. Engl. J. Med. , 315:1495-1500; Isner, J.M. et al . , 1986, N. Engl. J. Med. , 315:1438-1443; Lesko, L.M. et al . , 1982, N. Engl. J. Med. , 307:1153. A key factor in cocaine's popularity is the widespread availability of relatively inexpensive cocaine in the alkaloidal (free base, "crack") form suitable for smoking and the hydrochloride powder form suitable for nasal or intravenous use. Gawin, F.H. and Ellinwood, Jr., E.H. , 1988. Drug abuse in males occurs about twice as frequently as in females. However, smoked cocaine use is particularly common in young women of childbearing age, who may use cocaine in this manner as commonly as do males. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Ed., 1996, Hardman, J.G. et ai . , eds., McGraw Hill, pp. 569-571.

Cocaine produces a dose-dependent increase in heart rate and blood pressure accompanied by increased arousal, improved performance on tasks of vigilance and alertness, and a sense of self-confidence and well-being. Wilson, M.C. et al . , 1971, Psychopharmacologia , 22:271-281; Fischman, M.W. , 1988, J. Clin. Psychiatry, 49 (Suppl. 2):7-10; Fischman, M.W. et al . , 1985, J. Pharmacol. Exp . Ther., 235:677-682. Higher doses produce euphoria, which has a brief duration and is often followed by a desire for more drug. Involuntary motor activity, stereotyped behavior, and paranoia may occur after repeated doses. Irritability and increased risk of violence are found among heavy chronic users. The half-life of cocaine in plasma is about 50 minutes, but inhalant (crack) users typically desire more cocaine after 10 to 30 minutes. Intranasal and intravenous uses also result in a high of shorter duration than would be predicted by plasma cocaine levels, suggesting that a declining plasma concentration is associated with termination of the high and resumption of cocaine seeking. Johanson, C.E., and Fischman, M.W. , 1989, Pharro. Rev. , 41:3-52. Addiction is the most common complication of cocaine use. Some users, especially intranasal users, can continue intermittent use for years. Others become compulsive users despite elaborate methods to maintain control. Stimulants tend to be used much more irregularly than opioids, nicotine and alcohol. Binge use is very common, and a binge may last hours to days, terminating only when supplies of the drug are exhausted.

Since cocaine typically is used intermittently, even heavy users go through frequent periods of withdrawal or "crash." The symptoms of withdrawal seen in users admitted to hospital include dysphoria, depression, sleepiness, fatigue, cocaine craving, and brady-cardia. Careful studies of cocaine users during withdrawal show gradual diminution of these symptoms over 1 to 3 weeks (Satel, S.L., et al . , 1991, Am. J. Psychiatry, 148:1712-1716). Cocaine frequently is used in combination with other drugs, such as heroin. Alcohol is another drug that cocaine users take to reduce the irritability experienced during heavy cocaine use. Some develop alcohol addiction in addition to their cocaine problem. Other risks of cocaine use, beyond the potential for addiction, involve cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasσconstriction, and seizures. Death from trauma also is associated with cocaine use (Marzuk, P.M., et al . , 1995, K _. Engl. J. Med. , 332:1753-1757). Pregnant cocaine users may experience premature labor and abruptio placentae (Chasnoff, I.J., et al . , 1989, JAMA, 261:1741-1744). Reports of developmental abnormalities in infants born to cocaine-using women are confounded by prematurity, multiple drug exposure, and poor pre- and postnatal care. Since cocaine withdrawal is generally mild, treatment of withdrawal symptoms has not been well-explored. Desipramine is a tricyclic antidepressant that has been tested in several double-blind trials among cocaine addicts. Like cocaine, desipramine inhibits monoamine neurotransmitter reuptake, but its principal effects are on norepinephrine reuptake. It was hypothesized that desipramine could relieve some of the withdrawal symptoms of cocaine dependence and reduce the desire for cocaine during the vulnerable period following cessation of cocaine use. This drug showed efficacy in a group of patients who were primarily white collar intranasal cocaine users (Gawin, F.H., et al . 1989, Arch of Gen Psychiatry, 46:117-121). The majority of subsequent studies of desipramine using more severely ill cocaine addicts have been negative. Goodman and Gilman, p. 571.

Several other classes of medications have been tried in this disorder. Examples are: amantadine, a dopaminergic drug that has been reported to aid in detoxification (Alterman, A.I. et al . , 1992, Drug Alcohol Depend. , 31:19-29); fluoxetine, a selective serotonin reuptake antagonist that has been reported to reduce cocaine use (Batki, S.L., et al . , 1993, J. Clin. Psychopharmacol .. 13:243-250); and buprenorphine, a partial opioid agonist that has been found to reduce cocaine self-administration in monkeys (Mello, N.K. et al . , 1989, Science, 245:859-862). Thus far, all of the studies of medications to treat addiction and to help prevent relapse to cocaine dependence have revealed modest benefits at best. Thus, there remains a need for a compound that can be used reliably in the treatment of cocaine addiction. 2.7.2 OTHER CNS STIMULANTS

Subjective effects similar to cocaine's are produced by, for example, amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate and diethylproprion (sometimes referred to herein, collectively, as "CNS stimulants"). Amphetamines increase synaptic dopamine primarily by stimulating presynaptic release rather than by blockade of reuptake, as is the case with cocaine (Goodman and Gilman, p. 571) . Intravenous or smoked methamphetamine produces an abuse/dependence syndrome similar to that of cocaine.

In contrast, oral stimulants, such as those prescribed in a weight-reduction program, have short-term efficacy because of tolerance development. Only a small proportion of patients introduced to these stimulants to facilitate weight reduction subsequently exhibit drug-seeking behavior to obtain the stimulant effects of the anorectic medication. These patients may meet diagnostic criteria for abuse or addiction. Cathinone, a compound similar to amphetamine, is used widely in Africa for its stimulant properties. Recently, methcathinone, a congener with similar effects, has been synthesized in the United States. Again, there remains a need for a compound that can be used reliably to treat, prevent, and control addiction to, and withdrawal from, CNS stimulants.

3. SUMMARY OF THE INVENTION

The present invention is useful in treating and preventing the symptoms associated with withdrawal from abuse of or dependence on opioids, other central nervous system (CNS) depressants, including alcohol and sedatives, CNS stimulants such as cocaine and amphetamines. The present invention is also useful in treating or preventing the symptoms associated with withdrawal from abuse of or dependence on other drugs that act upon the central nervous system but which are not generally categorized as pure "stimulants" or "depressants," including marijuana, barbiturates, and psychedelic agents such as lysergic acid diethylamide (LSD) , phencyclidine (PCP) , methylenedioxymethamphetamine (MDMA, Ecstasy), N,N- dimethylamine, and psilocybin. The present invention is also useful in preventing, controlling, or alleviating the development of physical dependence on drugs or alcohol. The present invention relates to the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition for treating or preventing certain psychiatric and medical disorders. Moclobemide, or moclobemide metabolite, or moclobemide derivative according to this invention may be in the form of a pharmaceutically acceptable salt, hydrate, or solvate.

Hereinafter, the term "moclobemide, moclobemide metabolite or moclobemide derivative," includes moclobemide, a metabolite of moclobemide, or a derivative of moclobemide; or a prodrug of moclobemide, a metabolite of moclobemide, or a derivative of moclobemide; or pharmaceutically acceptable salt, hydrate, solvate of moclobemide, a metabolite of moclobemide, a derivative of moclobemide; or prodrug thereof. The present invention also encompasses the use of a composition in the methods of this invention, wherein the composition comprises moclobemide, a metabolite of moclobemide, or a derivative of moclobemide together with a pharmaceutically acceptable carrier. Moclobemide metabolites according to this invention are those with MAO-A inhibitor activity, such as moclobemide- N-oxide. The invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in treating or preventing the symptoms associated with withdrawal from substance abuse or dependence, including abuse of or dependence on opioids, other CNS depressants such as alcohol and sedatives, and CNS stimulants such as cocaine and amphetamines. Thus, one embodiment of the present invention relates to the treatment of such withdrawal symptoms by administration of a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to a human.

The present invention also encompasses the use of moclobemide or a moclobemide composition in preventing, controlling, or alleviating the development of physical dependence on drugs or alcohol. Thus, one embodiment of the present invention relates to the administration of a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to a human in need of the prevention of physical drug or alcohol dependence. Another embodiment of the invention relates to methods of controlling the consumption or intake of opioids, CNS depressants, or CNS stimulants by administering to a human in need of such therapy an effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.

The use of other benzamide derivatives to treat or prevent physical dependence, or to treat or prevent withdrawal symptoms or to control consumption is also encompassed by the present invention. In particular, the use of p-iodo-N- (2-morpholinoethyl) -benzamide, p-fluoro-N- (2- morpholinoethyl) -benzamide, p-bromo-N- (2-morpholinoethyl) - benzamide, 4-chloro-N- (2-morpholinoethyl) -benzamide, and p- chloro-N- (2-morpholinoethyl) -benzamide-N-oxide is contemplated. Each of these compounds and salts thereof, is structurally similar to moclobemide and can be used with the present methods, although moclobemide is preferred.

The present invention further encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in conjunction with traditional or known detoxification methods to treat or prevent withdrawal symptoms in a human by administering moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to said human, before, during, or after the other detoxification methods. The present invention also encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in conjunction with other pharmacologically active compounds, such as known antidepressants, with tricyclic antidepressants being preferred. Such known antidepressant compounds include tricyclic antidepressants such as amitriptyline, clomipramine, doxepin, imipramine, (+) -trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, and protryptiline; seretonin-reuptake inhibitors such as (+) -fluoxetine, fluvoxamine, paroxetine, sertraline, and (+) -venlafaxine; atypical antidepressants such as bupropion, nefazodone, and trazodone; and other monoamine oxidase inhibitors, such as phenelzine, tranylcypromine, and (-) -selgiline, either singly or in combination. In particular, the present invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in conjunction with other known antidepressants without the resulting negative drug interactions commonly associated with MAOI's.

Except when used in the treatment or prevention of dependence on or withdrawal from certain central nervous system sedatives, when the administration of additional sedatives may be counterindicated, as would be easily determined by one of skill in the art, the present invention further encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in conjunction with benzodiazepines, including, without limitation, alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, σxazepam, quazepam, temazepam, and triazolam. The present invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat or prevent physical dependence, or to treat or prevent withdrawal symptoms, either alone or in conjunction with other means of detoxification, in all potential human patient populations, including men, women, children and the elderly. The invention further encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to prevent, control, or alleviate physical dependence on multiple addictive substances at once, or to prevent or treat symptoms associated with simultaneous withdrawal from dependence on multiple substances.

4. DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of treating the symptoms associated with withdrawal from abuse of or dependence on opioids, other central nervous system depressants, such as alcohol and sedatives, or CNS stimulants, such as cocaine and amphetamine, in a human, which comprises administering to said human suffering from withdrawal symptoms a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.

The present invention also encompasses a method of preventing the development of withdrawal symptoms in a human who is dependent on substances such as opioids, other central nervous system depressants such as alcohol and sedatives, or CNS stimulants, such as cocaine and amphetamine, which comprises administering to said human likely to suffer withdrawal symptoms a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition. The present invention further encompasses a method to prevent, control, or alleviate physical dependence on drugs or alcohol in a human who is using addictive drugs or alcohol, which comprises administering to said human a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition. Moreover, the invention encompasses a method of controlling consumption of the above-mentioned substances by the administration of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition. Moclobemide, as well as certain other moclobemide derivatives, can be synthesized according to the method described in United States Patent No. 4,210,754 to Burkard et al . , and in United States Patent No. 4,906,626 to Amrein et al . , which are incorporated by reference herein in their entirety.

The moclobemide metabolite known as moclobemide-N- oxide which can be represented by the formula:

has been shown to have MAO-A nhibitory activity, and its use in the treatment or prevention of substance abuse and the symptoms associated with the withdrawal from abuse of or dependence on opioids, other CNS depressants, such as alcohol and sedatives, or CNS stimulants, such as cocaine and amphetamine is also encompassed by the present invention. Prodrugs, i.e. drugs that are metabolized in vivo into the active agent, and methods for making prodrugs are readily know in the art (e.g., Balant, L.P., "Prodrugs for the Improvement of Drug Absorption Via Different Routes of Administration," Eur. J. Drug Metab. Pharmacokinet . 15:143-153 (1990); and Bundgaard, H., "Novel Chemical

Approaches in Prodrug Design," Drugs of the Future 16:443-458 (1991) ; incorporated by reference herein) . In one embodiment, derivatives according to this invention have MAOI activity.

The magnitude of a prophylactic or therapeutic dose of the active ingredient (e . g. , moclobemide, a moclobemide metabolite, a moclobemide derivative) in the treatment or prevention of physical dependence or withdrawal symptoms will vary with the severity of the patient's consumption, dependence, or symptoms, and the route of administration. The dose and dose frequency will also vary according to the age, weight and response of the individual patient. In general, the recommended daily dose range for the conditions described herein lies within the range of from about 50 rag to about 1200 mg per day, generally divided equally into doses given one to four times a day. Preferably, a daily dose range should be between 150 mg and 900 mg per day, usually divided equally into a two to four times a day dosing. Most preferably, a daily dose range should be between 150 mg and 600 mg per day, usually divided equally into a two to four times a day dosing. It may be necessary to use dosages outside these ranges in some cases, and the treating physician will know how to increase, decrease or interrupt treatment based upon patient response. The various terms described above such as "therapeutically effective amount," are encompassed by the above-described dosage amounts and dose frequency schedule.

For use in treating or preventing physical dependence or withdrawal symptoms, the physician will generally prescribe the period of treatment and frequency of dose of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition on a patient-by- patient basis. In general, however, treatment or prevention of substance abuse or dependence with moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition may be carried out for as long a period as necessary, either in a single, uninterrupted session or in discrete sessions. Most preferably, moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition therapy may be carried out for a period of at least 4 weeks. Moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition may also be administered before, along with, or after traditional methods used to detoxify patients from substance abuse or dependence. When used to prevent, control, or alleviate the development of physical dependence on a substance, moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition therapy should overlap temporally with the period of consumption of the addictive substance, but may commence prior to that period, and/or continue after that period ends. Moreover, moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition therapy may be used to control or alleviate physical dependence that already exists, but that is minimal, and, therefore, unlikely to cause clinically significant withdrawal symptoms. For example, a regular drinker of alcohol who is only slightly physically dependent on alcohol may benefit from the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition therapy to prevent any increase in physical dependence, even though such an individual may be unlikely to suffer withdrawal should he stop drinking alcohol.

Any suitable route of administration may be employed for providing the patient with an effective dosage of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition. For example, oral, rectal, parenteral, transdermal, subcutaneous, sublingual, intranasal, intramuscular, intrathecal and the like may be employed as appropriate. Dosage forms include tablets, coated tablets, caplets, capsules (e.g., hard gelatine capsules) troches, dragees, dispersions, suspensions, solutions, patches and the like, including sustained release formulations well known in the art. See, e . g.- Introduction to Pharmaceutical Dosage Forms. 1985, Ansel, H.C., Lea and Febiger, Philadelphia, PA; Remington's Pharmaceutical Sciences, 1995, Mack Publ. Co., Easton, PA.

The compositions of the present invention may also comprise other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.

Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include maleic, acetic, benzene-sulfonic (besylate) , benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are hydrobromic, hydrochloric, maleic, phosphoric, and sulfuric acids.

The compositions include compositions suitable for oral, rectal, transdermal, sublingual, and parenteral administration (including subcutaneous, intramuscular, intrathecal and intravenous) , although the most suitable route in any given case will depend on the nature and severity of the condition being treated. The most preferred route of administration of the present invention is the oral route. The composition may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In the case where an oral composition is employed, a suitable dosage range for use is, e . g . , from about 50 mg to about 1200 mg per day, generally divided equally into a one to four times a day dosing, preferably from about 150 mg to about 900 mg per day, generally divided equally into a two to four times a day dosing and most preferably from about 150 mg to about 600 mg per day, generally divided equally into a two to four times a day dosing. Patients may be upward titrated from below to within this dose range to achieve satisfactory control or prevention of symptoms as appropriate.

In practical use, moclobemide, a moclobemide metabolite, or a moclobemide derivative can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e . g . , oral or parenteral (including intravenous injections or infusions) . In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, for example, suspensions, elixirs and solutions; or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, stabilizers, diluents, granulating agents, lubricants, binders, fillers, disintegrating agents and the like in the case of oral solid preparations such as, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. The preferred solid oral preparation is tablets. The most preferred solid oral preparation is coated tablets. Because of their ease of administration tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. The preparation of coated tablets, sachets, and hard gelatin capsules containing moclobemide as the active ingredient is described in United States Patent No. 4,906,626, which is incorporated herein by reference. In addition to the common dosage forms set out above, the compounds of the present invention- may also be administered by controlled release or sustained release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200, 4,008,719, 4,687,660, and 4,769,027, the disclosures of which are hereby incorporated by reference. Preferred controlled release or sustained release tablets suitable for use with moclobemide are described in U.S. Patent No. 5,427,798, which is incorporated herein by reference.

Pharmaceutical stabilizers may also be used to stabilize compositions comprising moclobemide, a moclobemide metabolite, or a moclobemide derivative or salts thereof; acceptable stabilizers include but are not limited to L- cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid and L- cysteine dihydrochloride. See, e . g . U.S. Patent No. 5,358,970, which is incorporated herein by reference. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more of a binder, filler, stabilizer, lubricant, inert diluent, and/or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 50 mg to about 300 mg of the active ingredient, and each cachet or capsule contains from about 50 mg to about 300 mg of the active ingredient. In a preferred embodiment, the tablet, cachet or capsule contains one of four dosages: about 50 mg, about 75 mg, about 100 mg, and about 150 mg of active ingredient. The invention is further defined by reference to the following examples describing in detail the preparation of the compound and compositions of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and to methods, may be practiced without departing from the purpose and interest of this invention.

5. EXAMPLES

5.1 EXAMPLE 1

ORAL FORMULATION

Coated Tablets:

Formula Quantity per Tablet (mg.)

moclobemide 50.0

Lactose 74.0 Corn Starch 35.0

Water (per thousand Tablets) 30.0 ml

Magnesium Stearate 1.0

Corn Starch 25.0

The water evaporates during manufacture.

The active ingredient (moclobemide, a moclobemide metabolite, a moclobemide derivative) is blended with the lactose until a uniform blend is formed. The smaller quantity of corn starch is blended with a suitable quantity of water to form a corn starch paste. This is then mixed with said uniform blend until a uniform wet mass is formed. The remaining corn starch is added to the resulting wet mass and mixed until uniform granules are obtained. The granules are then screened through a suitable milling machine, using a 1/4 inch stainless steel screen. The milled granules are then dried in a suitable drying oven until the desired moisture content is obtained. The dried granules are then milled through a suitable milling machine using 1/4 mesh stainless steel screen. The magnesium stearate is then blended and the resulting mixture is compressed into tablets of desired shape, thickness, hardness and disintegration.

Tablets are coated by standard aqueous or nonaqueous techniques. For example, 2.5 mg of hydroxypropymethylcellulose can be dissolved in 25 mg of deionized water. An aqueous (10 mg) suspension of 1.88 mg talc, 0.5 mg of titanium dioxide, 0.1 mg of yellow iron oxide, and 0.02 mg of red iron oxide is stirred into this solution. The coating suspension is sprayed on the tablets and the coated tablets are dried overnight at 45^*C.

5.2 EXAMPLE 2 ORAL FORMULATION

Capsules:

Formula Quantity per capsule in mg.

B

Active ingredient moclobemide 25 50 75

Lactose 149.5 124.5 374 Corn Starch 25 25 50 Magnesium Stearate 0.5 0.5 1.0 Compression Weight 200.0 200.0 500.0

The active ingredient (moclobemide) , lactose, and corn starch are blended until uniform; then the magnesium stearate is blended into the resulting powder. The resulting mixture is encapsulated into suitably sized two-piece hard gelatin capsules.

5.3 EXAMPLE 3 ORAL FORMULATION

Tablets

Formula Quantity per Tablet in mg.

A B C

Active ingredient, moclobemide 20 40 100 lactose BP 134.5 114.5 309.0 starch BP 30.0 30.0 60.0 Pre-gelatinized Maize Starch BP 15.0 15.0 30.0 magnesium stearate 0.5 0.5 1.0 Compression Weight 200.0 200.0 500.0

The active ingredient (moclobemide) is sieved through a suitable sieve and blended with lactose, starch, and pre-gelatinized maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using punches.

Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit. In particular, single unit dosage forms of moclobemide in 50, 100, 150, and 200 mg are preferred and can be easily manufactured by those of skill in the art. For example, tablets of the following composition, as described in U.S. Patent No. 4,210,754,

incorporated herein in its entirety, may be prepared by methods known to those of skill in the art:

Tablets

Formula Quantity per Tablet in mg.

Active ingredient, moclobemide 50 . . 0

Lactose 95 , . 0

Maize starch 100 . . 0

Talc 4 , . 5

Magnesium stearate 0 . . 5

Weight per tablet 250.0

The embodiments of the present invention described above are intended to be merely exemplary and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the present invention and are covered by the following claims.

The contents of all references described herein are hereby incorporated by reference. Throughout this specification and claims, the word "comprise," or variations such as "comprises" or "comprising, " will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers .

Other embodiments are within the following claims.

Claims

What is claimed is:

1. A method of treating or preventing symptoms associated with withdrawal from dependence on drugs or alcohol in a human, which comprises administering to a human who is physically dependent on a drug or on alcohol a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.

2. A method to prevent, control, or alleviate physical dependence on a drug or on alcohol in a human, which comprises administering to said human in need of prevention, control, or alleviation an amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition, said amount being sufficient to prevent, control, or alleviate said physical dependence.

3. The method of claim 1 or 2 wherein moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition is administered orally or parentally.

4. The method of claim 3 wherein moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition is administered orally as a tablet or a capsule.

5. The method of claim 1 wherein moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition is administered transdermally as a transdermal patch.

6. The method of claim 1 or 2 wherein the amount administered is from about 50 mg to about 1200 mg.

7. The method of claim 6 wherein the amount administered is from about 150 mg to about 900 mg.

8. The method of claim 7 wherein the amount administered is from about 150 mg to about 600 mg.

9. The method of claim 1 or 2 wherein the amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition is administered together with a pharmaceutically acceptable carrier.

10. The method of claim 1 or 2 wherein moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition is administered in a sustained or controlled release formulation.

11. The method of claim 1 or 2 wherein said administration is made one to four times per day.

12. The method of claim 1 or claim 2 wherein said administration continues for a period of at least 4 weeks.

13. The method of claim 1 or claim 2 further comprising treating said human with an antidepressant .

14. The method of claim 13 wherein the antidepressant is a tricyclic antidepressant.

15. The method of claim 14 wherein the tricyclic antidepressant is selected from the group consisting of amitriptyline, clomipramine, doxepin, imipramine, (+)- imipramine, amoxapine, desipramine, maprotiline, nortriptyline, protryptiline.

16. The method of claim 13 wherein the antidepressant is selected from the group consisting of (+) -fluoxetine, fluvoxamine, paroxetine, sertraline, (+) - venlafaxine, bupropion, nefazodone, trazodone, phenelzine, tranylcypromine, and (-) -selegiline.

17. The method of claim 1 or claim 2 further comprising treating said human with a benzodiazepine.

18. The method of claim 17 wherein the benzodiazepine is selected from the group consisting of alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, and triazolam.

19. The method of claim 1 or claim 2 wherein the drug is a central nervous system depressant.

20. The method of claim 19 wherein the central nervous system depressant is selected from the group consisting of opioids, sedatives, marijuana, and depressants.

21. The method of claim 1 or claim 2 wherein the drug is a central nervous system stimulant.

22. The method of claim 21 wherein the central nervous system stimulant is selected from the group consisting of cocaine, amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate and diethylproprion .

23. The method of claim 1 or claim 2 wherein the drug is selected from the group consisting of marijuana, barbiturates, lysergic acid diethylamide (LSD) , phencyclidine (PCP) , methylenedioxymethamphetamine (MDMA, Ecstasy) , N,N- dimethylamine, and psilocybin.

24. A method of controlling the consumption of alcohol or a drug in a human which comprises administering a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to said human.

25. The method of claim 24 wherein the drug is selected from the group consisting of opioids, sedatives, marijuana, depressants, cocaine, amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate, diethylproprion, barbiturates, lysergic acid diethylamide (LSD) , phencyclidine (PCP) , methylenedioxymethamphetamine (MDMA, Ecstasy), N,N- dimethylamine, and psilocybin

26. A method of treating or preventing symptoms associated with withdrawal from dependence on drugs or alcohol in a human, which comprises administering to said human a therapeutically effective amount of a compound selected from the group consisting of p-iodo-N-(2- morpholinoethyl) -benzamide, p-fluoro-N- (2-morpholinoethyl) - benzamide, p-bromo-N- (2-morpholinoethyl) -benzamide, 4-chloro- N- (2-morpholinoethyl) -benzamide, pharmaceutically acceptable salts thereof, and p-chloro-N- (2-morpholinoethyl) -benzamide- N-oxide.

27. A method to prevent, control, or alleviate physical dependence on a drug or alcohol in a human, which comprises administering to said human a therapeutically effective amount of a compound selected from the group consisting of p-iodo-N- (2-morpholinoethyl) -benzamide, p- fluoro-N- (2-morpholinoethyl) -benzamide, p-bromo-N- (2- morpholinoethyl) -benzamide, 4-chloro-N- (2-morpholinoethyl) - benzamide, pharmaceutically acceptable salts thereof, and p- chloro-N- (2-morpholinoethyl) -benzamide-N^'-oxide.