WO2006032146A1 - The use of a modafinil compound for the treatment of problem gambling - Google Patents

Abstract

The invention is directed to methods for the treatment of problem gambling, impulse control disorders, and/or disorders for which boredom proneness and/or impulsivity are prominent risk factors. The method comprises the administration of a modafinil compound to a patient in need of such treatment. The invention also discloses the use and methods of use of a modafinil compound for the reduction of the primed motivation to gamble, decrease of the reinforcing effect of gambling, reduction of enjoyment of slot machine gambling, production of improvement in inhibitory control following the gambling episode, and production of a more rapid adoption of a low risk gambling strategy.

Description

The Use of a Modafinil Compound for the Treatment of Problem Gambling Field of Invention

The present invention generally relates to the use of drugs for the treatment of psychiatric disorders. More specifically, the invention describes methods for the treatment of certain impulse control disorders and addictions characterized by boredom proneness or impulsivity.

Background

Psychiatrists will often classify a disorder according to its symptoms and not the neurochemistry responsible for the symptom. This is often because a lot is not known about the neurochemical pathways involved with each symptom, or different neurochemical pathways may be responsible for similar symptoms. The pharmacological treatment of disorders, therefore, often becomes an attempt at a treatment of the neurochemical pathologies which cause the predominant symptoms.

Disorders may be classified, for example, as impulse control disorders, substance use disorders (e.g., substance abuse, substance dependence), etc. Impulse control disorders are often described as being harmful behaviors performed in response to irresistible impulses. Substance use disorders ^• are often described as a physiological dependence between a person and some chemical stimulus. Two symptoms which may occur in these or other disorders are boredom proneness (apathy) and impulsivity.

Boredom proneness and impulsivity are two neurocognitive dimensions which are prominent in problem gamblers (also known as pathological gamblers). Between 2 and 5% of the general population meet clinical criteria for problem gambling. The number of newly diagnosed cases is growing rapidly as the availability of gambling activities, including Internet venues, continues to increase. The consequences of problem gambling are often severe, including job loss, marital breakdown and, in some cases, suicide. At present, there is no medication specifically indicated for the treatment of problem gambling. Existing medications for gambling are drawn from the pharmacopoeia of other disorders. None of these medications address the psychostimulant profile of effects produced by gambling. As well, none of these medications specifically addresses impulsivity or boredom proneness/apathy.

Psychiatric medications frequently have variable effects across individuals or sub-types of patients suffering from a particular disorder. For example, people with major depressive disorder may or may not suffer with concomitant anxiety. In such cases, the efficacy of the antidepressant may depend upon the degree to which it addresses the anxiety dimension as well as the primary depressive symptoms. In the case of Impulse Control Disorders, it is possible that the impulsivity is fairly circumscribed and manifests only with respect to their particular clinical concern. Thus, a problem gambler may be highly impulsive in gambling situations but have normal impulse control with respect to food or alcohol.

Patients diagnosed with problem or 'pathological' gambling are considered to suffer from an Impulse Control Disorder under the Diagnostic and Statistical Manual of Mental Disorders IV-TR (DSM-IV-TR; American Psychiatric Association, 2000). By definition, individuals who meet

DSM-IV criteria for a gambling disorder are clinically impulsive. However, impulsivity is a multi¬ dimensional construct both in terms of the cognitive-behavioral processes that mediate it, and its manifestations outside the laboratory.

Modafinil (benzhydrylsulphinylacetamide) and modafinil compounds are an interesting new class of compound which act as stimulants. Modafinil, marketed as Provigil(R), Modiodal(R), Vigil(R), Alertec(R), and Modasomil(R), is a stimulant medication with diverse neurochemical effects. This drug is currently approved for the treatment of narcolepsy. It may also have a therapeutic effect in attention deficit hyperactivity disorder (ADHD) and, as an adjunct to conventional antidepressants in depression with prominent apathy. It is also currently being tested as a pharmacotherapy for cocaine addiction. Pre-clinical evidence with cocaine abusers indicates that modafinil is well- tolerated, has low abuse liability, and reduces some of the rewarding effects of cocaine.

A number of patents teach various uses of modafinil. For example, US#6,488,164 teaches compositions including modafinil for treatment of ADHD and multiple sclerosis fatigue. US #6,455,588 teaches compositions including modafinil for treatment of eating disorders and for appetite stimulation. US #5,612,379 teaches the application of modafinil for treatment of sleep apneas and ventilatory disorders. US# 5,401,776 relates to the use of modafinil for the treatment of urinary and fecal incontinence. Patent number 00547952/EP-B 1 describes the use of modafinil for the manufacture of an antiischemic medicament. Patent number 00462004/EP-B 1 teaches the use of modafinil for the production of a medicament intended for treating degenerative diseases of the central nervous system such as Parkinson's disease. According to the PCT Application. NO.- 00104317/US, modafinil is shown to be effective in improving or restoring cognitive function in humans or other mammals when administered at doses that are substantially lower than optimal wakefulness-promoting doses. US patent #6,323,236 teaches the use of sulfamate derivatives for treatment of impulse control disorders (including pathological gambling). None of the above prior art, however, describes the use of benzhydrylsulphinylacetamide for the treatment of disorders characterized by the symptoms of boredom proneness and impulsivity.

The role of medication in the treatment of pathological gambling is reviewed by Richard Rosenthal in eGambling, the Electronic Journal of Gambling Issues, February 2004. According to this review, problem gamblers are mainly treated pharmacologically for comorbid conditions (e.g. depression). None of the existing medications used to treat problem gambling specifically addresses impulsivity or boredom proneness. A medication tailored specifically to the neurochemical and behavioral features of problem gambling would have considerable medical and public health benefits.

Summary of Invention

According to one aspect of the invention, there is provided a method for treating problem gambling comprising administering to a human afflicted with problem gambling a therapeutically effective amount of a modafinil compound. The modafinil compound may be modafinil or adrafinil.

Another aspect of the invention provides for a method for treating impulse control disorders comprising administering to a mammal afflicted with such a disorder a therapeutically effective amount of a modafinil compound. The disorder may be problem gambling. The modafinil compound may be modafinil or adrafinil.

Another aspect of the invention provides for a method for treating disorders for which boredom proneness and/or impulsivity is a prominent risk factor comprising administering to a mammal afflicted with such a disorder a therapeutically effective amount of a modafinil compound. The disorder may be problem gambling. The modafinil compound may be modafinil or adrafinil.

Another aspect of the invention provides for a method wherein the modafinil compound reduces the primed motivation to gamble, and/or decreases the reinforcing effect of gambling, and/or reduces enjoyment of slot machine gambling, and/or produces improvement in inhibitory control following the gambling episode, and/or produces a more rapid adoption of a low risk gambling strategy. The modafinil compound may be modafinil or adrafinil.

According to another aspect of the invention, the methods provided herein further provide that the therapeutically effective amount of the modafinil compound is in the range of about 100 to about 800 mg per day, more particularly in the range of about 150 to about 600 mg per day, even more particularly in the range of about 200 to about 400 mg per day. The therapeutically effective amount may be administered once or twice a day, for example. It may be administered orally or transdermally. The modafinil compound may be modafinil or adrafinil.

According to yet another aspect of the invention, there is provided a use of a therapeutically effective amount of modafinil compound for the treatment of problem gambling, or for the manufacture of a medicament for use in the treatment of problem gambling. The modafinil compound may be modafinil or adrafinil. ^■ - - According to yet another aspect of the invention, there is provided a use of a therapeutically effective amount of modafinil compound for the treatment of impulse control disorders, or for the manufacture of a medicament for use in the treatment of problem gambling. The modafinil compound may be modafinil or adrafinil.

According to yet another aspect of the invention, there is provided a use of a therapeutically effective amount of modafinil compound for the treatment of disorders for which boredom proneness and/or impulsivity is a prominent risk factor, or for the manufacture of a medicament for use in the treatment of problem gambling. The modafinil compound may be modafinil or adrafinil.

According to yet another aspect of the invention, there is provided a use of a therapeutically effective amount of modafinil compound for reduction of the primed motivation to gamble, and/or decrease of the reinforcing effect of gambling, and/or reduction of enj oyment of slot machine gambling, and/or production of improvement in inhibitory control following the gambling episode, and/or production of a more rapid adoption of a low risk gambling strategy, or the manufacture of a medicament for the uses described above. The therapeutically effective amount of the modafinil compound may be in the range of about 100 to about 800 mg per day, more particularly in the range of about 150 to about 600 mg per day, even more particularly in the range of about 200 to about 400 mg per day. The therapeutically effective amount may be administered once or twice a day, for example. It may be administered orally or transdermally. The modafinil compound may be modafinil or adrafinil.

Brief Description of Figures

Figures IA and IB show the mean modified visual analog scale (m-VAS) ratings of gambling- induced reward on three sub-scales under modafinil and placebo for subjects who received the drug on session 1 and session 2 in an example demonstrating the present invention.

Figure 2 shows the mean Desire to Gamble ratings under each Treatment, collapsed across Time - pre-game, post-game (modafinil's effects were consistent across Time), and indicates that modafinil significantly decreased the Desire to Gamble associated with playing the slot machine game in an example demonstrating the present invention.

Figure 3 shows that modafinil was associated with relatively higher Confidence ratings than placebo in an example demonstrating the present invention. Figure 4 shows that the Treatment effect for betting behavior during the 15 -minute slot machine game reflected a significantly smaller mean bet size (number of credits wagered) per trial under modafmil versus placebo in an example demonstrating the present invention.

Figure 5 shows the mean Stop Signal Reaction Time (SSRT) scores under each Treatment and indicates that SSRT scores tended to be faster (smaller) under modafmil than placebo in an example demonstrating the present invention.

Figure 6 plots the mean deck selection values on the Bechara Gambling Task under modafinil and placebo in an example demonstrating the present invention. Higher values indicate less risky deck selections.

Figure 7 plots the mean blood pressure values at pre-capsule baseline through to 30 min after completion of the slot machine game under modafinil and placebo in an example demonstrating the present invention..

Description of the Invention

The present invention relates to the treatment of disorders for which boredom proneness is a prominent risk factor. More particularly, the treatment of disorders for which both boredom proneness and impulsivity are prominent risk factors. Boredom proneness and impulsivity are two neurocognitive dimensions that are especially prominent in problem gamblers. The treatment comprises administering modafinil compounds to people assessed by a qualified professional as being problem or pathological gamblers, with special emphasis on reducing boredom proneness or boredom proneness and impulsivity.

The tendency to problem gambling may exist in a patient on its own (idiopathic), in association with another disorder or ailment (co-morbid), or may be induced by drug therapy of another ailment or disorder. For example, patients with Parkinson's disease may exhibit the tendency to gamble when being treated with certain conventional medications, e.g. dopamine substitution therapy, including but not limited to, dopamine receptor agonists.

Impulsivity is associated with a failure to modulate behaviour in accord with its consequences (e.g., unduly risky bets, or persistence in gambling despite appreciable losses). Boredom proneness is characterized by an inability to experience pleasure or stimulation from everyday activities, and is associated with seeking of pharmacotherapy by older gamblers.

The inventors hypothesize that gambling activity is mediated by neurochemical processes similar to those that underlie the reinforcing effects of conventional stimulant drugs, like cocaine or amphetamine. Prior research has suggested that disturbances in the brain chemical, dopamine may be involved in the risk for problem gambling and in the pathological motivation to gamble. The chemical properties of modafmil may be suitable for the treatment of disorders involving disturbances in dopamine function. To date, no medication appears to have been tested or used for the purpose of rectifying disturbances in dopamine function in problem gamblers. The unique neurochemical and cognitive-behavioral profile of modafmil strongly suggests that it can accomplish this goal, without leading to abuse of the medication itself or other secondary pathology. It appears that modafmil may be suitable to treat problem gambling, and may be particularly valuable or efficacious for the large sub-set of problem gamblers characterized by high impulsivity and/or boredom proneness.

Further, the ability of modafϊnil to reduce the rewarding effects of a drug stimulus (cocaine) in cocaine abusers, along with its ability to improve executive function (sensitivity to response contingencies, inhibitory control) in patients with Attention Deficit Hyperactivity Disorder (ADHD), suggests that, among individuals who have an Impulse Control Disorder (e.g., pathological gambling), those who also report a pervasive pattern of impulsivity, as measured by self-report indices like the Eysenck Impulsiveness Scale (Eysenck & Eysenck, 1978) will show relatively greater benefit than those who have an Impulse Control Disorder with low overall impulsivity on such indices. Neither Cocaine Abuse/Dependence nor ADHD is an Impulse Control Disorder within the American Psychiatric Association's diagnostic scheme, although, like numerous other psychiatric disorders, Cocaine Abuse/Dependence and ADHD often involve impulsivity as well. It is hypothesized that individuals who have an Impulse Control Disorder and report high levels of Boredom Proneness will receive benefit from modafinil compared to those who have an Impulse Control Disorder like problem/pathological gambling but report low levels of Boredom Proneness.

Modafinil has therapeutic effects for individuals with an Impulse Control Disorder like problem/pathological gambling, irrespective of their other characteristics. It is further thought that the degree of modafiniPs therapeutic effect will be most pronounced for those who also score high on overall impulsivity or boredom proneness.

The beneficial effects of modafinil on impulse control and mood brightening are evident after a single dose. Current medications used with problem gamblers often take weeks to become effective, in the case of antidepressants. In the case of naltrexone, there is no evidence of mood brightening and there may even be a mood dampening effect. Thus, modafinil appears to afford a distinct advantage over these existing medications, which have been prescribed for problem gambling, in terms of its rate of therapeutic onset and lack of apparent mood dampening effects. There are few, if any, medications with an established ability to reduce impulsivity in addictions or substance use disorders. This reflects the fact that the neurochemical effects of the addictive reinforcer often interfere with any impulse-modulating effects of the medication. Modafinil has the potential to enhance general (tonic) dopamine function so that the "spike" in (phasic) dopamine produced by an addictive reinforcer (e.g., gambling) is not experienced as intensely as if tonic dopamine levels were lower. This spike is often the neurochemical eliciting stimulus for compulsive seeking (craving), or persistent use (loss of control) of the addictive reinforcer. There is a theoretical basis for predicting that a drug, like modafinil, that enhances tonic dopamine function, will reduce the priming or reinforcing effects of gambling activity.

As used herein, the term "modafinil compound" may include a racemic mixture comprising benzhydrylsulfmylacetic acid and/or esters and/or salts, and or isomers, including stereoisomers, thereof, or may be in an acid form, such as a metabolic acid of modafinil or a benzhydrylsulfmylacetic acid, a sulfone form, a hydroxylated form (such as adrafinil), a conjugated form such as a modafinil compound conjugated to a protein, a polysaccharide, a glucuronide or a sulfate, or a polymorphic form, it may include compounds containing isosteric replacements of the phenyl groups or other functional group of modafinil, and polymorphic species or analogs of modafinil, or derivatives of cogeners and prodrugs. In preferred embodiments, the modafinil compound is modafinil. Modafinil is 2-(benzhydryl-sulfinyl)acetamide, and is also known as 2[(diphenylmethyl)sulfinyl]acetamide. Prodrugs are known in the art as compounds that are converted to the active agent (modafinil) in the body of a subject. See US 2002/0082301, published June 27, 2002, the entire specification of which is incorporated herein by reference.

In addition, compounds with substantially the same mechanism of action as modafinil for the treatment of problem gambling fall within the scope of this invention.

Compounds with substantially the same mechanism of action as modafinil for the treatment impulse control disorders and/or disorders for which impulsivity and/or boredom proneness is a prominent risk factor are also included in the scope of this invention.

The modafinil compound may be formulated in dosage forms such as liquid oral preparations including suitable carriers, solid oral preparations including suitable carriers, such as tablets, capsule, pills, and powder forms, syrups, liquid parenteral forms, including solutions and suspensions, in a suitable carrier. Suitable solutions, for example, are described in U.S. Patent No. 6,919,378, which is incorporated herein by reference. It may also be formulated as a modified release, controlled release, sustained release, pulsatile release, extended release, or delayed extended release solid formulation, tablet capsule, granulation caplet, layered tablet, all of which is described in U.S. patent application publication 2005/0095294, the entire specification of which is incorporated herein by reference.

The modafinil compound may be administered to the patient through various routes, such as orally, by suppository, transdermally, or parenterally, or through other methods known in the field of drug delivery or administration.

Dosage regimes of the modafinil compound for the treatment of problem gambling disorders for which boredom proneness and/or impulsivity are prominent risk factors include the administration of an oral dose of about 20 mg to about 1000 mg, more particularly about 50 mg to 700 mg, more particularly about 150 mg to about 600 mg, more particularly about 200 mg to 400 mg, and even more particularly about 100 mg or about 200 mg of modafinil, administered once, twice, three times or more a day as specified by a physician. It is also conceivable that modafinil compounds could be administered on a weekly, bi-weekly or monthly basis using an extended release modified release, controlled release, sustained release, pulsatile release, extended release, delayed extended release formulation, depot injection, or transdermally via a patch, for example. This would circumvent the problem of non-compliance with prescription (failure to take the medication) in order to facilitate gambling during periods of decreased motivation to refrain from gambling (e.g., during periods of stress).

Kits comprising a suitable formulation of a modafinil compound and instructions for use are considered within the scope of this invention. For example, a kit comprising solid formulations or a patch as described above with instructions for use can be made.

Example 1

Evidence from an initial sample of 6 (1 female) problem gamblers clearly demonstrates that modafinil modulates critical subjective, cognitive, and behavioral responses to gambling activity in problem gamblers. Subjects underwent a placebo controlled, double-blind, counterbalanced assessment of modafinil (acute oral dose of 200 mg) versus placebo on 2 procedurally identical test sessions held 1 week apart. The critical manipulation was participation in a 15 -minute episode of gambling on an actual, casino-style slot machine in a mock-bar laboratory. The rewarding effects of the game as well as its effect on motivation to gamble (i.e., priming), inhibitory control on The Stop-Signal Task (Logan et al 1997), and physiological reactivity were evaluated under drug and placebo. The effects of modafinil on risky decision making (sensitivity to reward and punishment) on The Bechara Gambling Task (Bechara et al. 2001) were also assessed. Although this sample included subjects with varying degrees of Impulsivity and Boredom Proneness, the number of individuals with these different psychological profiles was not sufficient to conduct a statistical analysis in order to evaluate the effects of Impulsivity and Boredom Proneness on responses to modafinil. See example 2 for sub-type study that addresses this issue.

RESEARCH DESIGN

Type of Design and Sub-Groups of Problem Gamblers. We assessed the effects of a 200-mg oral dose of modafinil in a placebo-controlled, fully counterbalanced, double blind, between-within design. The within-subjects factor was Treatment: drug vs. placebo. The between-subjects factor was Sequence of Treatment: Half of the subjects received modafinil on test session 1 and placebo on test session 2; the other half received the treatments in reverse order.

Subjects Subjects were 6 problem gamblers as defined by scores > 5 on the South Oaks Gambling Screen (SOGS; Lesieur & Blume, 1987) and on the DSM-IV (APA, 1994).

Each subject underwent two procedurally identical (except for drug treatment) test sessions. On each session, subjects received their assigned drug treatment and underwent a 15-minute gambling episode on a slot-machine version Electronic Gaming Device (EGD). Subjective, cognitive, and behavioral indices were assessed at multiple time points throughout each session (see details below).

General Reliability and Validity of Tasks and Dependent Measures.

Modified visual analogue scales Modified Visual Analogue Scales (m-VAS; 0-10) measure (a) Desire to Gamble, (b) Confidence to Refrain from Gambling. M-VAS ratings are widely used tools for assessing drug effects (Fischman & Foltin, 1991), and their sensitivity to drug effects in problem gamblers has been validated in our two previous drug studies (Zack & Poulos, 2004; Zack, Poulos & Desmond, 2004). M-VAS ratings also assess the subjective pleasurable or rewarding effects of the gambling episode (i.e., Enjoyment, Excitement, and perceived 'High'). M- VAS measures of gambling reward have been validated in previous published studies (Loba, Stewart, Klein, & Blackburn, 2001), as well as in our recent haloperidol study (Zack, Poulos & Desmond, 2004).

M-VAS Measure of Interest in Everyday Activities To assess the effects of modafinil on subjective (i.e., state) boredom proneness during the test sessions, we used an m-VAS scale (0-10) to rate agreement with the following statement: "Right now, I could find interest in any one of a variety of everyday activities."

Addiction Research Center Inventory (ARCI) Relevant sub-scales of the ARCI (Haertzen, 1965) assess responses to the drug treatment at several points within each test session (see Session Timeline below). The ARCI is a standardized index of drug effects that measures a range of subjective, mental, emotional and physical responses to psychoactive drugs. The ARCI has been used to assess the modulating effects of modafϊnil on subjective responses to cocaine (Dackis et al., 2003).

Stop Signal Task We use the most recent version of the Stop-Signal Task, which employs an algorithm to compute mean inhibitory latency to the stop signal (also known as Stop Signal

Reaction Time; SSRT). This task provides a behavioral index of inhibitory control: The faster the SSRT, the better is the inhibitory control. Performance on this task has been shown to correlate positively with scores on the Eysenck Impulsiveness Scale in heterogeneous samples (Logan, Schachar, & Tannock, 1997). The task has been widely validated in terms of its sensitivity to drug effects, including modafinil, as well as in clinical populations (e.g., ADHD patients; For details, see Turner et al. 2004).

Gambling/Slot Machine Episode As in previous laboratory gambling studies (Loba et al., 2001), subjects are given cash credits with which to bet. They are required to play for 15 minutes. Play stops if a subject exhausts all credits. To increase validity and provide an incentive to do well on the slot machine, subjects are advised that they will receive a monetary bonus at the end of the study proportional to the number of credits they win on each session. This is also noted in the consent form. For ethical reasons, all subjects in fact receive an identical bonus of $80 ($40 x 2 sessions) in addition to their participation fee. We use an Electronic Gaming Device of the type currently used in Ontario (Cash Crop, WMS Gaming Inc., Detroit MI), and gambling occurs in an authentic setting, a mock bar currently in place at The Centre for Addiction and Mental Health.

Bechara Gambling Task. (See footnote 'a' to Timeline below for details on its use in this study). We use this task primarily to cross-validate our results with those of previous studies in problem gamblers (Petry, 2001). The task measures sensitivity to reward and punishment and has been found to discriminate between clinically impulsive subjects and healthy controls (Bechara et al., 2001). The appropriate task parameters have been established in numerous prior studies (e.g., Petry, 2001; Bechara, Dolan, & Hindes, 2002). Thus, The Bechara Gambling Task also has excellent validity and reliability for the purposes of this study. Specifically, The Bechara Task measures the tendency to pursue large monetary gains, which entail large monetary losses or to pursue modest monetary gains, which entail modest losses. Subjects choose from among four decks of playing cards, with some decks involving high stakes and some more moderate stakes. The goal is to maximize winnings at the end of the game. Selecting from high stakes decks eventually leads to a net deficit, whereas selecting from low stakes decks eventually leads to a modest net gain. Over trials, subjects learn to choose from those decks that provide the best net outcome. Problem gamblers as well as drug and alcohol abusers display deficits in optimal performance on this game as reflected by a delay in the shift towards consistent selection of low stakes decks (Bechara, 2003; Petry, 2001).

Betting Behavior during Gambling/Slot Machine Episode Size of bets (credits wagered) per trial during the gambling episode provides an ecologically valid measure of gambling intensity (Ladouceur et al., 1991). Bet size has also been shown to be sensitive to drug effects in our haloperidol study (Zack, Poulos & Desmond, 2004).

Physiological Effects Heart rate and blood pressure are monitored every 30 minutes, using an unobtrusive wrist cuff (Model HEM-601, Omron Inc., Vernon Hills, IL).

Test Session Timeline. The sequence of events on the two test sessions was identical (see Table 1 below); the only difference was the contents of the capsule: 200-mg modafϊnil or placebo. Testing was timed to correspond with peak blood levels of oral modafϊnil, which occur at 2-3 hrs post- ingestion (Robertson & Hellriegel, 2003). This conforms to previous research on acute effects of modafϊnil (Turner et al., 2003, 2004)

Table 1. Timeline of events on each test session.

^aThe Bechara Gambling Task is not amenable to repeated measures testing because of a strong learning component. Thus, the effects of modafmil on this task is assessed between-subjects, with full counterbalancing with drug treatment and order.

Results: 1. Modafmil reduced primed desire to gamble associated with playing the slot machine game. (Electronic Gaming Device; EGD) during the gambling episode.

2. Modafmil reduced the reported enjoyment of the slot machine game.

3. Modafmil reduced the intensity of gambling behavior in terms of mean credits wagered per trial during the slot machine game.

4. Modafmil produced a trend (p = .075) towards reduced post-gambling inhibitory impairment on The Stop Signal Task (i.e., led to improved impulse control).

Methodology

Sampling. Subjects were recruited by newspaper ads. They were prescreened by telephone on DSM-IV criteria for PG and on the SOGS, Eysenck Impulsiveness Scale, and Boredom Proneness Scale. Those who meet inclusion criteria were invited to attend an interview. Subjects identified as problem gamblers were advised that treatment referrals are available. For ethical reasons, subjects currently in treatment were ineligible for the study.

At the interview, subjects completed a battery of questionnaires: The Canadian Problem Gambling Index (CPGI; Ferris & Wynne, 2001); The Twenty Questions of Gamblers Anonymous, an international index with good psychometric properties (Ursua & Uribelarrea, 1998); The Alcohol Dependence Scale (ADS; Ross, Gavin, & Skinner, 1990) Alcohol Timeline Followback (Sobell & Sobell, 1992); Hamilton-Depression and Anxiety scales (Hamilton, 1959, 1960). These scales enabled us to control for the possible effects of these background variables on experimental measures by analysis of covariance. We also re-administered the SOGS, DSM-FV checklist, Eysenck Impulsiveness Scale, and Boredom Proneness scale at the interview.

Following the interview, subjects attended a physician's exam. Urine and blood tests were also screened for the presence of psychoactive drugs at this time. Volunteers with any disorder that counter-indicated modafmil administration were excluded. In addition, individuals who were mentally or physically ill, including drug or alcohol dependence or ADHD based on DSM-IV, or who were taking a medication that could interact with modafmil were excluded from the study. - Individuals whose blood or urine screens indicated drug use were also excluded. Procedure. Subjects came to The Centre for Addiction and Mental Health on 4 separate occasions: a screening interview, a physician's exam, and 2 procedurally identical test sessions. A minimum inter-session interval of 1 week precluded drug carryover effects. Subjects were instructed to abstain from alcohol for 24 hours prior to each test session, and the absence of alcohol was determined by breathalyzer (J-4X ALERT, Alcohol Countermeasures Inc., Mississauga, ON) at the beginning of each test session. They arrived at the laboratory at 8: 15 AM, having fasted overnight. Subjects underwent the experimental procedure in the sequence specified in the Test Session Timeline (see above). They remained under observation until 5:00 PM, and were examined by medical personnel to ensure safety to dismiss, before being sent home by pre-paid taxi.

Statistical Power. Modafmil (200-mg) significantly reduced the euphoric effects of cocaine on the ARCI (Dackis et al., 2003) with an effect size of d = 0.56, relative to placebo. This serves as our estimated effect size for the main overall effect of Treatment.

Data Analysis. A series of 2 (Treatment: Modafmil, Placebo) x 2 (Treatment Sequence: Drug on Session 1, Drug on Session 2) analyses of variance assessed the relevant dependent variables. In cases where pre-capsule baseline state could be meaningfully assessed (e.g., Desire to Gamble), these scores were included as covariates to isolate the effects of the drug treatment. In cases where tests occurred at multiple times during each test session (e.g., Desire to Gamble, Blood Pressure, etc), Time of Test served as an additional within-subjects variable in the variance analyses. In cases where multiple indices tapped different elements of the Treatment effect (e.g., m-VAS effects of slot machine game; sub-scales on Profile of Mood States), Sub-scale was included as another within-subjects factor in the variance analysis.

Drug Treatment (200-mg oral modafmil, placebo) was counterbalanced across the 2 test sessions.

The findings from this initial sample support the hypotheses and reveal a broad range of benefits for modafmil in problem gamblers.

RESULTS

Subject characteristics are described in Table 1 below, followed by inferential statistics on the effects of modafmil. Subject Characteristics

The table shows that all subjects met formal diagnostic criteria for pathological gambling as defined by a score > 5 on the DSM-IV checklist (American Psychiatric Association 1994), and a score > 5 on The South Oaks Gambling Screen (SOGS; Lesieur and Blume 1987). On average they spent 60% of their income on gambling, which is 20 times the normative expenditure on all forms of entertainment in the general Canadian population. They displayed generally modest levels of Impulsiveness (for this population) on the Eysenck scale (10 is published mean/ø7" problem gamblers), with slightly higher levels on the Boredom Proneness Scale (15 is published mean for problem gamblers). There was no evidence of problem drinking on the Alcohol Dependence Scale or depression on the Hamilton Depression Scale.

Perceived Effects of the Capsule

A 2 (Treatment: Drug, Placebo) x 2 (Treatment Sequence: Drug on Session 1, Drug on Session 2) x 3 (Sub-scale) ANOVA assessed self-reported Good Effects, Bad Effects, and Desire to Take Again for modafinil and inert capsule on the modified visual analog scales (m-VAS) at post- capsule peak blood drug levels. The analysis yielded no significant effects involving Treatment, p's > .30. Mean (SD) m-VAS scores (0-10; Not at All - Extremely) for Good Effects were 1.8 (3.1) under modafinil and 1.0 (2.5) under placebo; for Bad Effects, 0 (0) under modafinil 0.8 (1.6) under placebo; and for Desire to Take Again were 1.8 (3.3) under modafinil and 0.7 (1.2) under placebo. A 2 x 2 ANCOVA of m-VAS 'Interest in Everyday Activities' at post-capsule peak, controlling for pre-capsule baseline, also yielded no significant effects involving Treatment, p's > .47. Mean (SD) m-VAS scores were 5.4 (3.4) under modafinil and 4.2 (1.0) under placebo.

A 2 x 2 x 7 (Sub-scale) ANOVA of scores on the Profile of Mood States (POMS) yielded no significant effects involving Treatment, p's > .56. Consistent with the wake-promoting effects of an anti-narcoleptic drug, the mean (SD) score on the Vigor sub-scale was higher under modafinil, 7.5 (6.1), than placebo, 4.1 (6.4). A parallel 2 x 2 x 7 ANOVA of sub-scale scores on the Addiction Research Center Inventory (ARCI) of psychoactive drug effects yielded no significant effects involving Treatment, p's > .40, with no discernible pattern across sub-scales.

These results are consistent with those of previous research that found no evidence of abuse liability, and also little evidence of reported unpleasant effects of modafinil in substance abusers or healthy controls (Myrick et al. 2004, Rush et al. 2002).

Effects of Modafinil on Rewarding Effects of the Slot Machine Game

A 2 x 2 x 3 (Sub-scale) ANOVA assessed perceived Enjoyment, Excitement and 'High' induced by the 15-minute Slot Machine Game. The analysis yielded a significant Treatment Sequence x Sub-scale interaction, F (2, 8) = 9.95, p = .007, a significant Treatment x Sub-scale interaction, F (2, 8) = 4.77, p = .043, and a significant three-way interaction of these factors, F (2, 8) = 6.16, p = .024.

Figures IA and IB show the m-VAS ratings of gambling-induced reward on each sub-scale under modafinil and placebo for subjects who received the drug on session 1 and session 2, respectively.

Figure IA shows that subjects who received the drug on session 1 reported significantly lower Enjoyment and significantly lower Excitement from playing the game under modafinil than placebo (simple effects, p's < .05). Figure IB shows that subjects who received the drug on test session 2 reported significantly lower Enjoyment from the slot-machine game under modafinil than placebo (p < .05), whereas scores on the other two sub-scales did not differ significantly as a function of treatment.

Inspection of Figures IA and IB reveals that the Treatment Sequence x Sub-scale interaction reflected lower ratings on the High sub-scale relative to the other sub-scales under each Treatment (drug, placebo) in subjects who received the drug on session 2 (Figure IB), whereas subjects who received the drug on session 1 (Figure IA) exhibited High scores that were comparable to, or larger than, those of the other sub-scales.

The Treatment x Sub-scale interaction reflected lower ratings of Enjoyment under modafinil than placebo regardless of Treatment Sequence. The 3-way interaction arose because, along with the lower Enjoyment scores, modafinil led to lower scores on the Excitement sub-scale in subjects who received the drug on session 1.

In sum, these results show that modafinil led to a consistent and significant reduction in self- reported Enjoyment of a slot machine game in problem gamblers. Effects of Modafinil on Primed Motivation to Gamble induced by Slot Machine Game

A 2 x 2 x 2 (Time of Test) ANCOVA assessed Desire to Gamble before and after the slot machine game under modafinil and placebo, while controlling for individual differences in pre-capsule baseline Desire ratings.

The analysis yielded a significant main effect of Treatment, F (1, 2) = 20.11, p = .046, and no other significant effects, p's > .098. Figure 2 shows the mean Desire ratings under each Treatment, collapsed across Time of Test (pre-game, post-game), and indicates that modafinil significantly decreased the Desire to Gamble associated with playing the slot machine game.

A parallel ANCOVA of Self-Efficacy ratings, as measured by Confidence to Refrain from Gambling ("if a casino were right across the street"), yielded no significant effects, p's > .15. Although the effects were not significant, Figure 3 shows that modafinil was associated with relatively higher Confidence ratings than placebo, indicating a trend toward greater self-efficacy to refrain from gambling under the drug. Self-efficacy is often used as a measure of vulnerability to cue-induced relapse. Therefore, these findings suggest that problem gamblers felt more confident to avoid relapse in the face of salient cues for gambling under modafinil.

Taken together, these findings indicate that modafinil reduced primed motivation to gamble associated with participating in an episode of slot machine gambling in problem gamblers.

Effects of Modafinil on Betting Behavior during Slot Machine Game

A series of 2 x 2 ANOVA's assessed the number of trials played (speed of play), number of credits wagered per trial (mean bet size) and maximum credits wagered on a single trial during the slot machine game. The ANOVA's for speed of play and maximum bet size yielded no significant effects, p's > .47. The mean (SD) number of trials played was 98.2 (28.0) under placebo and 103.5 (22.4) under modafinil. The mean (SD) maximum bet size was 28.7 (15.2) credits under placebo and 28.2 (19.3) credits under modafinil. The maximum possible wager on a trial is 45 credits.

The ANOVA of credits wagered per trial yielded a main effect of Treatment, F (1, 4) = 7.87, p = .049, and no other significant effects, p's > .085. Figure 4 shows that the Treatment effect reflected a significantly smaller mean bet size per trial under modafinil versus placebo.

Effects of Modafinil on Inhibitory Control Following the Slot Machine Game

A 2 x 2 ANOVA of Stop Signal Reaction Time (SSRT) scores on The Stop-Signal Task (Logan et al 1997) assessed inhibitory control under modafinil and placebo. Although the analysis yielded no significant effects, the Treatment effect was marginal (p = .075). Figure 5 shows the mean SSRT scores under each treatment and indicates that SSRT scores tended to be faster (smaller) under modafmil than placebo.

SSRT reflects the time required to recruit the inhibitory (Stop) process and pre-empt the overt key¬ press response. SSRT controls for individual differences in overt reaction time to the Go signal (visual stimulus). In general, the faster the SSRT, the more efficient is the Stop process. Thus, these results are consistent with those of Turner et al (2004) for ADHD patients, and indicate that modafmil induced a marginally significant improvement in inhibitory control following the slot machine game in problem gamblers. As noted above, inhibitory control on The Stop Signal Task correlates reliably with self-report measures of (trait) Impulsivity in large samples (Logan et al., 1997).

The Bechara Gambling Task: Effects of Modafinil on Sensitivity to Reward and Punishment:

As noted above, The Bechara Gambling Task measures relative sensitivity to reward and punishment and associated risk-taking when these outcomes are salient. The Task includes 4 decks of cards from which to choose on each of 100 trials. Decks 1 and 2 on the Task are high stakes decks, which yield large monetary gains but also entail large losses. Selection from these decks eventually leads to a net deficit. Decks 3 and 4 are low stakes decks, which yield more modest gains but also more modest losses, and lead to a net gain at the end of the 100 trials. Adoption of the optimal strategy (to ensure a net gain) is reflected by the tendency to select from Decks 3 and 4. Over trials this tendency can be illustrated by an increase in mean deck number (i.e., towards 3 and 4 and away from 1 or 2). To assess this tendency, deck selection value was aggregated into blocks of 10 consecutive trials, with block score reflecting the mean deck number (1-4) from that block. Higher mean deck selection scores for the block indicate lower risk behavior.

As noted in the procedure section above, due to a large learning component, The Bechara Gambling Task could only be administered to each subject once. The task was administered after all other measures on test session 2. Thus, the effects of modafinil are measured between-subjects as opposed to within-subjects.

A 2 (Treatment) x 10 (Trial Block) ANOVA of deck selections over the course of the 100 trials yielded no significant effects, p's > .37. Figure 6 plots the mean deck selection values under modafinil and placebo. The figure shows that mean selection value was equivalent in Block 1 but diverged between trial Blocks 2 and 7, and converged again in Block 8.

Since higher mean deck selection values reflect a more conservative strategy on the task, Figure 6 suggests that modafinil was associated with rapid adoption of a low risk strategy. In contrast, sύbj ects under placebo took several blocks before adopting the low risk strategy required to achieve a net gain at the end of the task. These findings are consistent with those seen in ADHD patients, who adopted a more conservative strategy on a decision-making task under an acute 200- mg dose of modafinil versus placebo (Turner et al. 2004)

Physiological Reactivity: Systolic Blood Pressure A 2 x 2 x lO (Time of Test) ANOVA of systolic blood pressure scores taken at 30-min intervals from 0830 hrs to 1300 hrs yielded a significant main effect of Treatment, F (1, 4) = 88.94, p = .001, and no other significant effects involving Treatment, p's > .13.

Figure 7 plots the mean blood pressure values at pre-capsule baseline through to 30 min after completion of the slot machine game under modafmil and placebo. The figure shows that modafinil led to a clear and consistent elevation in blood pressure, in line with its established pressor effects. Inspection of the profile of scores under placebo also shows that the slot machine game was associated with a marked elevation in blood pressure, indicating heightened sympathetic activation. In contrast, there was only minor fluctuation in blood pressure due to the game under modafinil.

Summary of Findings

Overall, the findings from the measures of self-report, cognitive-inhibitory control, betting behavior on the slot machine and risk-taking provide an internally consistent and clear pattern of evidence. The following effects were observed: (1) modafinil significantly decreased self- reported Desire to Gamble before and after the slot machine game; (2) modafinil significantly decreased self-reported Enjoyment of the slot machine game; (3) modafinil significantly reduced mean bet size (credits wagered per trial) during the slot machine game; (4) modafinil induced a trend (p =.075) toward better inhibitory control following the slot machine game, as measured by The Stop-Signal Task; (5) modafinil was associated with more rapid adoption of a low-risk strategy on The Bechara Gambling Task.; (6) there was no evidence of abuse liability or reported unpleasant effects of modafinil. These findings indicate that modafinil has significant therapeutic potential as a medication for the treatment of problem gambling.

On its own, modafinil had no subjectively hedonic or unpleasant effects. This is consistent with previous research on modafinil' s low abuse liability and generally good tolerability at therapeutic doses.

Theoretical models of addiction have distinguished between the pleasurable properties of an addictive reinforcer ('liking') and the motivation to seek or obtain that reinforcer ('wanting') (Robinson and Berridge 2001). The present results provide support for the position that modafinil reduces both the 'liking' and the 'wanting' of gambling activity in problem gamblers. As such, they provide a strong basis to proceed towards patenting modafmil as the first medication explicitly indicated for the treatment of problem gambling.

Implications and Applications to Impulse Control Disorders.

Problem gambling (i.e., 'Pathological Gambling') is formally classified as anjmpulse Control Disorder (DSM-IV-TR, American Psychiatric Association, 2000). As such, problem gambling shares important symptom profiles and processes (e.g., priming, disinhibition) with other Impulse Control Disorders, such as kleptomania, and pyromania (and possibly with compulsive shopping or compulsive sexuality). Like problem gambling, there is no medication that is specifically indicated for, or consistently effective in, treating these disorders. The present evidence provides a rational basis for proposing that modafmil will be effective in treating these other Impulse Control Disorders as well.

Further aspects of the invention will now be illustrated by way of a prophetic example.

Example 2

An acute oral dose of 200-mg modafmil is administered to problem gamblers and the effect is evaluated on responses to a 15 -minute slot machine gambling episode.

Type of Design and Sub-Groups of Problem Gamblers. We assess the effects of a 200-mg oral dose of modafmil in a placebo-controlled, fully counterbalanced, double blind, between-within design. The within-subjects factor is Treatment: drug vs. placebo. Half of the subjects receive modafmil on test session 1 and placebo on test session 2; the other half receive the treatments in reverse order. The fundamental difference between this prophetic example (Example 2) and the empirical study described in Example 1 is the examination of sub-type effects on the magnitude of the Treatment effect. Specifically, Example 2 involves assessment of subjects as a function of trait Impulsivity and Boredom Proneness as outlined below.

Subjects Subjects are 40 problem gamblers as defined by scores > 5 on the South Oaks Gambling Screen (SOGS; Lesieur & Blume, 1987) and on the DSM-IV (APA, 1994). Subjects are stratified based on mean scores for problem gamblers from previous research on the Eysenck Impulsiveness Scale (Eysenck & Eysenck, 1978), and Boredom Proneness Scale (Farmer & Sundberg, 1986). Specifically, subjects are divided into two sub-groups on each dimension: High (> Published Mean) vs. Low (< Published Mean).

Given that Impulsivity and Boredom Proneness share only -25% of variance (Watt & Vodanovich, 1992), it is possible to recruit subjects who fall into each of the 4 possible combinations of high vs. low Impulsivity x Boredom Proneness (n = 10/cell of the 2 x 2 matrix: High/High, High/Low, Low/High, Low/Low). We realize that a perfect distribution of scores across the two dimensions is difficult to achieve. Nevertheless, a modest asymmetry will not affect the validity of statistical comparisons. In addition, any differences in weighting of the 4 cells will be automatically accounted for by the regression analyses (see Data Analysis section below).

As in the study described in Example 1, each subject undergoes two procedurally identical (except for drug treatment) test sessions. On each session, subjects receive their assigned drug treatment and undergo a 15-minute gambling episode on a slot-machine game. Subjective and behavioral indices are assessed at multiple time points throughout each session in a manner identical to that described above for Example 1.

Results a. Modafϊnil reduces motivation to gamble and reduces the pleasurable reinforcing e effects of the slot machine game during the 15-minute gambling episode. b. These effects (a) are greater in High vs. Low Impulsive subjects and in High vs. Low Boredom Proneness subjects.

c. Modafϊnil reduces mean bet size (credits wagered) during slot machine game.

d. This effect (c) is greater in High vs. Low Impulsive subjects and in High vs. Low Boredom Proneness subjects.

b. e. Modafinil reduces post-slot machine inhibitory impairment on the Stop Signal

Task (i.e., state impulsivity). f. This effect (e) is greater in High vs. Low Impulsive subjects.

g. Modafϊnil leads to faster adoption of low-risk deck selection strategy on Bechara Gambling Task.

h. This effect (g) is greater in High vs. Low Impulsive subjects

i. Modafϊnil significantly increases reported Interest in Everyday Activities.

j. This effect (i) is greater in High vs. Low Boredom Proneness subjects.

Methodology

Methodology used in Example 2 is identical to that described in Example 1 apart from sub-types analysis and counterbalancing of subtypes across drug treatment sequence. Data Analysis. Mean Effects A series of 2 (Treatment: Drug, Placebo) x 2 (Impulsivity Sub-Group: High, Low) x 2 (Boredom Proneness Sub-Group: High, Low) analyses of variance (ANOVA's) assess the effects of modafinil on the subjective, cognitive, and gambling behaviour variables. Additional variables (e.g., word type in the reading task) are also be included, as appropriate. Simple effects analyses (Winer, 1971) isolate the source of interactions. Where appropriate, co- variates are included in the ANOVA's to control for possible effects of trait variables (e.g., alcohol use), and state variables such as level of success on the slot machine. Multivariate ANOVA's assess heart rate and blood pressure on each test session.

Individual Differences For key dependent measures (i.e., those specified above for Results i - j ), hierarchical multiple linear regression analyses assess the relationship between the effects of Treatment (drug minus placebo) and the two primary predictors: Impulsivity and Boredom Proneness. Scores on the relevant dependent measure under placebo are entered in stage 1 to remove shared variance between test (drug) and baseline (placebo), which can confound the effects of other variables (Cohen & Cohen, 1983). Ratings on the Eysenck Impulsiveness scale and Boredom Proneness scale are entered next in stage 2. The interaction of Impulsiveness and

Boredom Proneness, as assessed by the product of ratings on these two scales, is entered in stage 3. This interaction product term enables us to assess the possibility that there is a compound effect of combined Impulsivity and Boredom Proneness on response to modafinil over and above the unique effects of either predictor alone.

Statistical Power. To estimate the effect size for Sub-Groups (i.e., Treatment x Sub-Group interaction), we utilize the effect sizes previously found for 200-mg modafinil on sensitivity to response contingencies in a risk-taking/decision-making task. A direct comparison of the effect size for performance in healthy volunteers (i.e., Low Impulsivity; [Turner et al., 2003]) vs. ADHD patients (i.e., High Impulsivity; [Turner et al., 2004]) revealed that the differential effect of 200- mg (i.e., the between-groups effect) was d = 0.47. This serves as our best estimate of effect size for the hypothesized effect of sub-groups in this study. The required sample size to detect this interaction with 80% power (α= .05, two-tailed) as determined by SPSS Sample Power 2, is N = 40. This N provides 93% power to detect the main overall effect of Treatment.

Note: There do not appear to be any data upon which to base our effect size for high vs. low Boredom Proneness. In such cases, it is recommended to use Cohen's estimated effect sizes

(Cohen, 1977). By this approach, our proposed effect size for sub-groups is considered moderate.

Behavioral Characteristics of Modafinil. Impulsivity and Boredom Proneness (i.e., apathy/anhedonia) are two neurocognitive dimensions strongly linked with problem gambling (Blaszczynski, McConaghy, & Frankova, 1990; Vitaro, Arseneault, & Tremblay, 1999). Modafinil has been found to modulate processes underlying both of these behavioral dimensions. However, to our knowledge, this has never been demonstrated in problem gamblers or in individuals with an impulse control disorder, as defined by DSM-IV (American Psychiatric Association, 1994).

First, modafmil improves inhibitory control, both in clinical subjects with ADHD and in healthy volunteers. (Note: ADHD is not classified as an Impulse Control Disorder in DSM-IV). In adults with ADHD, an acute oral dose of 200 mg modafmil significantly improved performance on a Stop-Signal Task (Turner et al., 2004). This task is widely used as a behavioral index of impulse control and correlates well with trait impulsivity on The Eysenck Impulsiveness Scale (Logan et al., 1997). In the study of healthy volunteers with normative levels of inhibitory control, doses of 100-mg and 200-mg modafinil produced dose-dependent improvements in performance on the Stop-Signal Task (Turner et al., 2003). There are additional findings from the aforementioned study of modafinil in adults with ADHD that are relevant to the present proposal. In a risk- taking/decision making task "patients were significantly more sensitive to the decision-making contingencies when receiving modafinil" (Turner et al., 2004, p. 1035). Specifically, relative to placebo, modafinil increased the frequency of choosing the most likely outcome at high odds ratios rather than low odds ratios (i.e., increased the frequency of safe bets). In other words, these ADHD patients were more cautious in making a gambling-like decision under a dose of modafinil.

A second key behavioral feature of modafinil is its mood brightening effects. Healthy volunteers report feeling significantly more alert, attentive, and energetic under the drug (Turner et al., 2003). Moreover, modafinil has been shown to have significant therapeutic effects as an adjunct to SSRI antidepressants in the treatment of depression with prominent apathy (Markovitz & Wagner, 2003). This is consistent with a beneficial effect of modafinil on anhedonia and reduced sensitivity to environmental stimuli.

All documents referred to herein are incorporated herein by reference into this specification as though reproduced herein in their entirety.

References

1. American Psychiatric Association. (2000) Diagnostic and statistical manual of mental disorders-Text Revision, ( 4^th ed), APA, Washington, DC.

2. Bechara A. (2003). Risky business: emotion, decision-making, and addiction. J Gambl Stud 19: 23-51.]

3. Bechara A, Dolan S, Denburg N, Hindes A, Anderson SW, Nathan PE. (2001) Decision- making deficits, linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers. Neuropsychologia. 39:376-389.

4. Bechara A, Dolan S, Hindes A. (2002) Decision-making and addiction (part II): myopia ^* for the future or hypersensitivity to reward? Neuropsychologia. 2002;40(l 0) : 1690-705.

5. Blaszczynski A, McConaghy N, Frankova A. (1990). Boredom proneness in pathological gambling. Psychol Rep. 67: 35-42.

6. Blood Pressure Monitor, Model HEM-601, Omron Inc., Vernon Hills, IL.

7. Cohen J, Cohen P. (1983) Applied multiple regression/correlation for the behavioral sciences. Erlbaum, Hillsdale, NJ.

8. Cohen J. (1977) Statistical power analysis for behavioral sciences, 2^nd ed. Academic Press, New York.

9. Dackis CA, Lynch KG, Yu E, Samaha FF, Kampman KM, Cornish JW, Rowan A, Poole S, White L, O'Brien CP. (2003) Modafmil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend. 70: 29-37.

10. Eysenck SB, Eysenck HJ. (1978). Impulsiveness and venturesomeness: their position in a dimensional system of personality description. Dec;43(3 Pt 2): 1247-55.

11. Eysenck, SBG, Eysenck HJ. (1978). Impulsiveness and venturesomeness: their position in a dimensional system of personality description. Psychol Rep 43: 1247-1255.

12. Farmer R, Sundberg ND. (1986). Boredom proneness~the development and correlates of a new scale. J Pers Assess. 50, 4-17.

13. Ferris J, Wynne HJ. (2001). The Canadian problem gambling index: final report. Edmonton, AB: AADAC.

14. Fischman MW, Foltin RW. (1991) Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict. 86:1563-1570.

15. Haertzen CA. (1965) Addiction Research Center Inventory (ARCI): development of a general drug estimation scale. J Nerv Ment Dis. 141:300-307.

16. Hamilton MA (1959) The assessment of anxiety states by rating. Br J Med Psychol 32: 51- 55

17. Hamilton MA (1960) A rating scale for depression J Neurol Neurosurg Psychiatry 23: 56- 62 18. J-4X A.L.E.R.T. Model Breathalyser. Alcohol Countermeasures Inc. Mississauga, ON.

19. Ladouceur R, Gaboury A, Bujold A, Lachance N, Tremblay S. (1991) Ecological validity of laboratory studies of videopoker gaming. J Gambling Stud 7: 109-116

20. Lesieur HR, Blume SB. (1987). The South Oaks Gambling Screen (SOGS): A new instrument for identification of pathological gamblers. Am J Psychiatry 144: 1184-1188.

21. Loba P, Stewart SH, Klein RM, Blackburn JR (2001). Manipulations of the features of standard video lottery terminal (VLT) games: Effects in pathological and non-pathological gamblers. J Gamb Stud 17: 297-320.

22. Logan GD, Schachar RJ, TannockR. (1997). Impulsivity and inhibitory control. Psychol Sci, 8, 60-64.

23. Markovitz PJ, Wagner S. (2003). An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol. 23, 207-209.

24. Myrick H, Malcom R, Taylor B, LaRowe S. (2004) Modafinil: preclinical, clinical, and post marketing surveillance— a review of abuse liability issues. Ann Clin Psychiatrhy 16:101-109.

25. Petry NM. (2001) Substance abuse, pathological gambling, and impulsiveness. Drug Alcohol Depend. 63: 29-38.

26. Robertson P Jr, Hellriegel ET. (2003) Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 42: 123-137.

27. Robinson TE, Berridge KC. (2001) Incentive-sensitization and addiction. Addiction 96:103-114.

28. Ross HE, Gavin DR, Skinner HA. (1990). Diagnostic validity of the MAST and the Alcohol Dependence Scale in the assessment of DSM-III alcohol disorders. J Stud AIc, 51: 506-513.

29. Rush CR, Kelly TH, Hays LR, Baker RW, Wooten AF. (2002) Acute behavioral and physiological effects of modafinil in drug abusers. Behav Pharmacol. 13: 105-115.

30. Sobell LC, Sobell MB. (1992). Timeline followback: A technique for assessing self- reported alcohol consumption. In: Litten RZ, Allen J (eds), Measuring alcohol consumption: Psychosocial and biological methods (pp. 41-72) Humana, Totowa, NJ.

31. Turner DC, Clark L, Dowson J, Robbins TW, Sahaldan BJ. (2004) Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry. 55:1031-1040.

32. Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ. (2003). Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology 165, 260-269.

33. Ursua MP, Uribelarrea LL. (1998) 20 questions of Gambler Anonymous: A psychometric study with population of Spain. J Gambling Stud 14: 3-15.

34. Vitaro F, Arseneault L, Tremblay RE. (1999) Impulsivity predicts problem gambling in low SES adolescent males. Addiction. 94, 565-575. 35. Watt JD, Vodanovich SJ. (1992). Relationship between boredom proneness and impulsivity. Psychol Rep. 70: 688-690.

36. Winer BJ. (1971) Statistical principles in experimental design, 2^nd ed. McGraw-Hill, NY.

37. Zack M, Poulos CX. (2004 )Amphetamine primes motivation to gamble and gambling- related semantic networks in problem gamblers. Neuropsychopharmacology. 29:195-207.

38. Zack, M., Poulos, C. X., Desmond, R. C. (2004). Partial dopamine blockade by haloperidol increases the reinforcing effects of a gambling episode in problem gamblers. Annual conference of The Alberta Gaming Research Institute. May, Banff, Alberta.

Claims

We Claim:

1. A method for treating problem gambling comprising administering to a human afflicted with problem gambling a therapeutically effective amount of a modafϊnil compound.

2. A method for treating impulse control disorders comprising administering to a mammal afflicted with such a disorder a therapeutically effective amount of a modafϊnil compound.

3. A method for treating disorders for which boredom proneness is a prominent risk factor comprising administering to a mammal afflicted with such a disorder a therapeutically effective amount of a modafinil compound.

4. A method for treating disorders for which impulsivity is a prominent risk factor comprising administering to a mammal afflicted with such a disorder a therapeutically effective amount of a modafinil compound.

5. A method for treating disorders for which both boredom proneness and impulsivity are prominent risk factors comprising administering to a mammal afflicted with such a disorder a therapeutically effective amount of a modafϊnil compound.

6. A method according to any of claims 2 to 5 wherein the disorder is problem gambling.

7. A method according to any of claims 1 to 6 wherein the modafϊnil compound reduces the primed motivation to gamble.

8. A method according to any of claims 1 to 6 wherein the modafϊnil compound decreases the reinforcing effect of gambling.

9. A method according to any of claims 1 to 6 wherein the modafinil compound reduces enjoyment of slot machine gambling.

10. A method according to any of claims 1 to 6 wherein the modafinil compound produces improvement in inhibitory control following the gambling episode.

11. A method according to any of claims 1 to 6 wherein the modafinil compound produces a more rapid adoption of a low risk gambling strategy.

12. A method according to any of claims 1 to 11 wherein the therapeutically effective amount is in the range of about 100 to about 800 mg per day.

13. A method according to any of claims 1 to 12 wherein the therapeutically effective amount is in the range of about 150 to about 600 mg per day.

14. A method according to any of claims 1 to 13 wherein the therapeutically effective amount is in the range of about 200 to about 400 mg per day.

15. A method according to any of claims 1 to 14 wherein the therapeutically effective amount is administered a number of times a day selected from the group consisting of once, twice, and three a day.

16. A method according to any of claims 1 to 14 wherein the therapeutically effective amount is administered twice a day.

17. A method according to any of claims 1 to 16 wherein the therapeutically effective amount is administered orally.

18. A method according to any of claims 1 to 16 wherein the therapeutically effective amount is administered transdermally.

19. A method according to any of claims 1 to 18 wherein the modafinil compound is modafinil.

20. A method according to any of claims 1 to 18 wherein the modafinil compound is adrafmil.

21. A method for treating problem gambling comprising administering to a mammal afflicted with problem gambling a therapeutically effective amount of modafinil.

22. A method for treating problem gambling comprising administering to a mammal afflicted with problem gambling a therapeutically effective amount of adrafmil.

23. Use of a therapeutically effective amount of a modafinil compound for the treatment of problem gambling.

24. Use of a therapeutically effective amount of a modafinil compound for the treatment of impulse control disorders.

25. Use of a therapeutically effective amount of a modafinil compound for the treatment of disorders for which boredom proneness is a prominent risk factor.

26. Use of a therapeutically effective amount of a modafinil compound for the treatment of disorders for which impulsivity is a prominent risk factor.

27. Use of a therapeutically effective amount of a modafinil compound for the treatment of disorders for which both boredom proneness and impulsivity are prominent risk factors.

28. The use according to any of claims 24 to 27 wherein the disorder is problem gambling.

29. The use according to any of claims 23 to 28 wherein the modafinil compound reduces the primed motivation to gamble.

30. The use according to any of claims 23 to 28 wherein the modafinil compound decreases the reinforcing effect of gambling.

31. The use according to any of claims 23 to 28 wherein the modafinil compound reduces enjoyment of slot machine gambling.

32. The use according to any of claims 23 to 28 wherein the modafinil compound produces improvement in inhibitory control following the gambling episode.

33. The use according to any of claims 23 to 28 wherein the modafinil compound produces a more rapid adoption of a low risk gambling strategy.

34. The use according to any of claims 23 to 33 wherein the therapeutically effective amount is in the range of about 100 to about 800 mg per day.

35. The use according to any of claims 23 to 34 wherein the therapeutically effective amount is in the range of about 150 to about 600 mg per day.

36. The use according to any of claims 23 to 35 wherein the therapeutically effective amount is in the range of about 200 to about 400 mg per day.

37. The use according to any of claims 23 to 36 wherein the therapeutically effective amount is administered once a day.

38. The use according to any of claims 23 to 36 wherein the therapeutically effective amount is administered twice a day.

39. The use according to any of claims 23 to 38 wherein the therapeutically effective amount is administered orally.

40. The use according to any of claims 23 to 38 wherein the therapeutically effective amount is administered transdermally.

41. The use according to any of claims 23 to 40 wherein the modafinil compound is modafinil.

42. The use according to any of claims 23 to 40 wherein the modafinil compound is adrafinil.

43. A use of a therapeutically effective amount of modafinil for the treatment of problem gambling.

44. A use of a therapeutically effective amount of adrafinil for the treatment of problem gambling.

45. Use of a therapeutically effective amount of a modafinil compound for the manufacture of a medicament for the treatment of problem gambling.

46. Use of a therapeutically effective amount of a modafinil compound for the manufacture of a medicament for the treatment impulse control disorders.

47. Use of a therapeutically effective amount of a modafinil compound for the manufacture of a medicament for the treatment of disorders for which boredom proneness is a prominent risk factor.

48. Use of a therapeutically effective amount of a modafinil compound for the manufacture of a medicament for the treatment of disorders for which impulsivity is a prominent risk factor.

49. Use of a therapeutically effective amount of a modafmil compound for the manufacture of a medicament for the treatment of disorders for which both boredom proneness and impulsivity are prominent risk factors.

50. The use according to any of claims 46 to 49 wherein the disorder is problem gambling.

51. The use according to any of claims 45 to 50 wherein the modafmil compound reduces the primed motivation to gamble.

52. The use according to any of claims 45 to 50 wherein the modafmil compound decreases the reinforcing effect of gambling.

53. The use according to any of claims 45 to 50 wherein the modafmil compound reduces enjoyment of slot machine gambling.

54. The use according to any of claims 45 to 50 wherein the modafmil compound produces improvement in inhibitory control following the gambling episode.

55. The use according to any of claims 45 to 50 wherein the modafmil compound produces a more rapid adoption of a low risk gambling strategy.

56. The use according to any of claims 45 to 55 wherein the therapeutically effective amount is in the range of about 100 to about 800 mg per day.

57. The use according to any of claims 45 to 56 wherein the therapeutically effective amount is in the range of about 150 to about 600 mg per day.

58. The use according to any of claims 45 to 57 wherein the therapeutically effective amount is in the range of about 200 to about 400 mg per day.

59. The use according to any of claims 45 to 58 wherein the therapeutically effective amount is administered once a day.

60. The use according to any of claims 45 to 59 wherein the therapeutically effective amount is administered twice a day.

61. The use according to any of claims 45 to 60 wherein the therapeutically effective amount is administered orally.

62. The use according to any of claims 45 to 60 wherein the therapeutically effective amount is administered transdermally.

63. The use according to any of claims 45 to 62 wherein the modafinil compound is modafinil.

64. The use according to any of claims 45 to 62 wherein the modafinil compound is adrafinil.

65. Use of a therapeutically effective amount of modafinil for the manufacture of a medicament for the treatment of problem gambling.

66. Use of a therapeutically effective amount of adrafinil for the manufacture of a medicament for the treatment of problem gambling.

67. Use of a compound with a substantially the same mechanism of action as modafinil for the treatment of problem gambling.