Aim: Pathological gambling and comorbid alcohol dependence often occur in combination. Disulfiram is one of the proven drugs for alcohol dependence. In addition to its inhibiting acetaldehyde dehydrogenase, disulfiram inhibits dopamine β-hydroxylase and may thereby increase dopamine and decrease norepinephrine cerebral concentrations. Because there may be common neurochemical substrates and neuronal circuits for pathological gambling and addiction, we wished to explore the effect of disulfiram in gambling. Method: We describe the outcome of a patient with alcohol dependence and pathological gambling treated with disulfiram D. Results: During treatment with disulfiram, the patient reported that his desire to gamble disappeared entirely. Follow-up indicated that he has not gambled for >12 months. Conclusions: Although uncontrolled case observations should be interpreted with caution, disulfiram deserves further investigation in pathological gamblin

Bühler, Mira

Diehl, Alexander

Grosshans, Martin

Kiefer, Falk

Mann, Karl

Mutschler, Jochen

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CASE REPORTDisulﬁram, an Option for the Treatment of Pathological Gambling?Jochen Mutschler1,3,*, Mira Bühler1, Martin Grosshans1, Alexander Diehl2,Karl Mann1 and Falk Kiefer11Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg, Square J 5 68159 Mannheim,Germany, 2Department of Psychiatry, Klinikum Braunschweig, Salzdahlumer Str. 90, Braunschweig, Germany and 3University Hospital Zurich, Department ofGeneral and Social Psychiatry, Militärstrasse 8, P.O. Box 1930, CH-8021 Zürich*Corresponding Author: University Hospital Zurich, Department of General and Social Psychiatry, Militärstrasse 8, P.O. Box 1930, CH-8021 Zürich, Switzerland.Tel: +41-(0)44-296-7393; Fax: +41-(0)44-296-7469; E-mail: jochen.mutschler@puk.zh.ch(Received 21 September 2009; in revised form 9 November 2009; accepted 24 December 2009)Abstract— Aim: Pathological gambling and comorbid alcohol dependence often occur in combination. Disulﬁram is one of theproven drugs for alcohol dependence. In addition to its inhibiting acetaldehyde dehydrogenase, disulﬁram inhibits dopamine β-hydroxylase and may thereby increase dopamine and decrease norepinephrine cerebral concentrations. Because there may becommon neurochemical substrates and neuronal circuits for pathological gambling and addiction, we wished to explore the eﬀectof disulﬁram in gambling. Method: We describe the outcome of a patient with alcohol dependence and pathological gamblingtreated with disulﬁram D. Results: During treatment with disulﬁram, the patient reported that his desire to gamble disappearedentirely. Follow-up indicated that he has not gambled for >12 months. Conclusions: Although uncontrolled case observationsshould be interpreted with caution, disulﬁram deserves further investigation in pathological gambling.INTRODUCTIONPathological gambling (PG) is a public health problem char-acterized by recurrent and pathological patterns of gambling.PG is associated with a range of social and psychological pro-blems like high rates of bankruptcy, divorce, suicide andreduced quality of life. Although the lifetime prevalence rateof pathological gambling in the German population is 0.2–0.4%, it often remains unrecognized and, therefore, untreated(Wölﬂing et al., 2009). Comorbidity of DSM-IV pathologicalgambling and other psychiatric disorders are very common. Inparticular, high comorbidity rates have been reported betweenPG and drug dependence. Rates vary from 34 to 80% for sub-stance use disorders (excluding tobacco) (Hall et al., 2000;McCormick et al., 1984). The occurrence of PG in alcohol-dependent patients is at least three times higher than in thegeneral population (Hall et al., 2000). In cocaine-dependentpatients, lifetime comorbidity rates have been reported thatare even ﬁve times higher as in the general population (Hallet al., 2000). These observations suggest that common patho-physiological factors might underlie PG and drug addiction.However, this hypothesis is not proven yet.PG is currently classiﬁed as an ‘impulse control disorder(ICD) not elsewhere categorized’ in the DSM, although thecurrent diagnostic criteria indeed share many features withthose for drug dependence, including (i) continued engage-ment in a behaviour despite adverse consequences, (ii)diminished self-control over engagement in the behaviour,(iii) compulsive engagement in the behaviour and (iv) an ap-petitive urge or craving state prior to engaging in thebehaviour as well as tolerance and withdrawal (Potenza,2006, 2008). Similarities between PG and drug dependenceinclude not only phenomenological criteria but also epidemi-ological, clinical, genetic and neurobiological characteristics(Goudriaan et al., 2004; Potenza, 2006, 2008). Therefore,PG might best be characterized as a non-substance-relatedor behavioural addiction with a compulsive urge for a non-drug reward (Tamminga and Nestler, 2006).Recent evidence indicates that similar mechanisms are in-volved in PG and drug addiction. Neuroimaging data suggestthat in PG and drug addiction, the same brain areas are in-volved. Reduced activity in the ventral striatum and theventromedial and ventrolateral prefrontal cortex has been re-ported in PG, which is also a hallmark of drug addiction(Reuter et al., 2005). A neuroendocrinological study in casinogamblers found that gambling elevated dopamine levels inproblem gamblers more than in healthy controls (Meyer etal., 2004). The mesocorticolimbic dopaminergic system hasbeen found to be implicated in rewarding and reinforcing be-haviours. It has been suggested that PG might be related to adeﬁciency of the mesocorticolimbic dopaminergic reward sys-tem, as has been shown for drug addiction.Another hallmark of drug addiction that also holds for path-ological gambling is the inability to inhibit inappropriateresponses. Accumulating evidence points towards an impor-tant role of brain dopamine and noradrenergic systems inimpulsive behaviour. The inferior frontal gyrus is critically in-volved in response inhibition and might be particularlyimpacted by the brain’s noradrenergic system.Other preclinical studies suggest that engaging in casinogam-bling elevates activity of the hypothalamic–pituitary axis inproblem and non-problem gamblers, as indicated by increasedplasma levels of norepinephrine, cortisol and increased heartrate. Roy and colleagues found higher levels of norepineph-rine or its metabolites in urine, blood or cerebrospinal ﬂuidsamples in pathologic gamblers (Roy et al., 1988).The similarities between PG and drug addiction suggestthat patients with pathological gambling may also beneﬁtfrom medication used for the treatment of drug addiction.Pharmacotherapy research and validated treatment optionsfor PG are limited.. At the present time, there is no medicationfor treatment of PG that is approved by the Food and DrugAdministration. Controlled clinical trials provide some evi-dence for beneﬁcial eﬀects of opiate antagonists (naltrexoneand nalmefene) (Grant et al., 2006; Kim et al., 2001), N-acetyl-cysteine (Grant et al., 2007), lithium (Hollander et al.,© The Author 2010. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reservedAlcohol & Alcoholism Vol. 45, No. 2, pp. 214–216, 2010 doi: 10.1093/alcalc/agp093Advance Access publication 18 January 20102005) and selective serotonin reuptake inhibitors, which havebeen shown to reduce craving for gambling. Additionally, cog-nitive behavioural therapy has been shown to be an eﬀectivetreatment for some patients with PG. However, all these thera-pies have only limited success.Disulﬁram is well known as a treatment for alcohol depen-dence (e.g. de Sousa and de Sousa 2004, 2005; Suh et al.,2006; Laaksonen et al., 2009). Disulﬁram also helps in thetreatment of cocaine addiction (Carroll et al., 2004; Gossopand Carroll, 2006), possibly by reducing cocaine craving byincreasing neurotransmitter levels of dopamine and decreasingthe norepinephrine levels by blocking the activity of the en-zyme dopamine beta hydroxylase (DBH) involved in themetabolism of brain monoamines (Weinshenker and Schroe-der, 2007; Mutschler et al., 2009a, 2009b). As similarneurochemical disturbances have been reported in PG, disul-ﬁram might not only be eﬀective in the treatment of cocaineaddiction but also in the treatment of PG (Mutschler et al.,2009a, 2009b).We present a case in which a patient with PG and comorbidalcohol dependence was treated with disulﬁram. We suggestthat disulﬁram has the potential to reduce craving and patho-logical gambling behaviour in PG.CASE REPORTMr K. is a 48-year-old married male working as a part-timenurse. His alcohol dependence developed 25 years ago. Healso started problematic gambling at slot machines at aroundthe same time. He met all of the criteria for PG according toDSM-IV and ICD-10 for ∼20 years. The patient has no crim-inal history, but has run up about 10,000 euros in debts due toPG. Mr K is a smoker and nicotine-addicted but has never tak-en any illegal drugs.He was treated for alcohol dependence for the ﬁrst time∼10 years ago. He has undergone 28 inpatient detoxiﬁcations.In 2000, he had long-term residential treatment for alcohol de-pendence. Afterwards, he participated in a self-help group ona regular basis but did not receive speciﬁc treatment for PG.He remained completely abstinent from alcohol for 6–7months. However, he continued to gamble during those alco-hol-abstinent months.After the ﬁrst contact with our team in 2008, he was treatedfor 5 weeks in our inpatient department, which specializes inaddiction medicine. The treatment included behavioural ther-apy as well as relapse prevention medication with disulﬁram(dosage 500 mg/3 days per week). The patient tolerated themedication without any side eﬀects (apart from short-term,moderate fatigue at the beginning of the treatment).After discharge from our inpatient treatment, we continuedtreating the patient over a period of 12 months in our outpa-tient programme for chronic alcohol patients. The disulﬁrammedication was supervised by a physician three times perweek, establishing a therapeutic ritual with high frequencyof short-term individual contacts. During this therapeutic rit-ual, the therapist praised the patient for taking disulﬁram andfor maintaining abstinence, thereby providing continuous rein-forcement of an alcohol-free lifestyle. Additionally, alternativecoping skills were developed and breathalyzer tests to monitorabstinence from alcohol were conducted. Throughout thistreatment, the patient reported that not only craving for alco-hol had disappeared but that he surprisingly had no urge togamble anymore.In conclusion, we found that, since initiating the supervisedtreatment with disulﬁram, the patient has been abstinent fromalcohol and gambling for >12 months.DISCUSSIONThis case report suggests that disulﬁram might provide treat-ment in PG. Disulﬁram helps in the treatment of alcoholism,cocaine addiction, human cancers and fungal infections(Brewer, 1990; Suh et al., 2006; Cvek and Dvorak, 2008).For more than half a century, disulﬁram has been successfullyused for alcohol aversion therapy (Brewer, 1993). Disulﬁr-am’s pharmacokinetics have been extensively studied; italso has a good safety record (Suh et al., 2006). It is a well-known vicious circle that substance use may lead to moregambling and more gambling may lead to substance use. Per-sonality traits like impulsivity and reward sensitivity maycontribute to excessive engagement in both behaviours.In the presented case, the patient has abstained from alcoholconsumption for >12 months now and, notably, he has notgambled either since treatment with disulﬁram started. Onepossible explanation might be that the patient was abstinentfrom alcohol. However, it can be argued that the patientwas treated for alcohol dependence several times, but PGwas never markedly aﬀected. Furthermore, despite numerousprevious detoxiﬁcations, the patient had never been treatedwith supervised disulﬁram before.Psychological aspects of the supervised disulﬁram therapyand the high placebo response rate seen in treatment studies ofpathological gambling may have contributed to the good clin-ical outcome, and this is a methodological limitation of thiscase report.However, we propose that a possible neurobiological con-tributant might be that disulﬁram directly modulates rewardsensitivity and craving for gambling by increasing the levelof the brain chemical dopamine and decreasing the norepi-nephrine levels through blocking the activity of the DBH,which metabolizes brain monoamines (Mutschler et al.,2009a, 2009b). Most strikingly, these two neurotransmittersystems are thought to be altered in PG (Reuter et al., 2005;Roy et al., 1988).The disappearance of the patient’s desire to gamble duringtreatment with disulﬁram points towards the potential of disul-ﬁram in reward modulation in PG, similar to that described inthe treatment of cocaine dependence (Mutschler et al., 2009a,2009b). Our preliminary clinical data support the hypothesisthat disulﬁram aﬀects the desire to gamble, thereby promotinggambling abstinence. The possible involvement of DBH wasmentioned above.Previous studies in drug-dependent patients and patientswith PG have shown that a combination of pharmacologicaltreatment in combination with psychosocial treatment meth-ods, group therapies or contingency management therapiesis more eﬀective than either treatment alone (Oakley-Browneet al., 2000; Pallesen et al., 2007). 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