title: Bromocriptine reduces cigarette smoking. The influence of dopamine &bgr;-hydroxylase gene polymorphism rs1611115 on levodopa/carbidopa treatment for cocaine dependence: a preliminary study Olanzapine Reduces Craving for Alcohol: A DRD4 VNTR Polymorphism by Pharmacotherapy Interaction Disulfiram effects on acute cocaine administration. Survival and cessation in injecting drug users: prospective observational study of outcomes and effect of opiate substitution treatment Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade Genetic variants altering dopamine D2 receptor expression or function modulate the risk of opiate addiction and the dosage requirements of methadone substitution Naltrexone effects on alcohol consumption in a clinical laboratory paradigm: temporal effects of drinking Naltrexone modification of drinking effects in a subacute treatment and bar-lab paradigm: influence of OPRM1 and dopamine transporter (SLC6A3) genes. Vaccine Pharmacotherapy for the Treatment of Cocaine Dependence Cocaine-Specific Antibodies Blunt the Subjective Effects of Smoked Cocaine in Humans Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. Exposure to opioid maintenance treatment reduces long-term mortality. Pharmacogenetics of antidepressant medication intolerance. The DRD4 VNTR polymorphism moderates craving after alcohol consumption. Bromocriptine in the treatment of alcoholics with the D2 dopamine receptor A1 allele Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. DBH gene as predictor of response in a cocaine vaccine clinical trial ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse Pharmacogenetic Randomized Trial for Cocaine Abuse: Disulfiram and Dopamine β-Hydroxylase Allelic association of a dopamine transporter gene polymorphism in alcohol dependence with withdrawal seizures or delirium Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial.
abstract: AIMS Animal studies have shown that nicotine releases dopamine , a neurotransmitter implicated in drug reinforcement . We hypothesized that bromocriptine would decrease smoking behavior in humans . DESIGN The study was conducted double blind and subjects ' order of dose exposure was r and omized . PARTICIPANTS The smoking behavior of 20 heavy smokers was recorded for 5 hours after ingesting placebo or one of two doses of bromocriptine ( 2.50 mg , 3.75 mg ) over three sessions ( one dose per session ) . FINDINGS There was a significant negative linear trend by dosage indicating shorter total puffing time with increasing bromocriptine dosages ( p < 0.02 ) . Other significant negative linear trends by increasing dosage include fewer number of puffs , fewer number of cigarettes smoked and mean latency to smoke after 3 hours ( expected CMAX on the drug ( all ps < 0.05 ) . There was a negative significant linear trend showing decreased plasma nicotine ( p < 0.02 ) and cotinine ( p < 0.005 ) with increasing dosages of bromocriptine . Shiffman/Jarvik Withdrawal Scale ( SJWS ) cigarette craving subscale scores decreased significantly across increasing dosages ( linear trend p < 0.02 ) . There was a significant negative linear trend ( p < 0.05 ) on the Profile of Mood States ( POMS ) Vigor and Depression subscales , with subjects reporting decreased vigor and depression with increasing bromocriptine doses . No other mood effects were observed . CONCLUSION These results support the hypothesis that dopaminergic mechanisms mediate cigarette smoking reinforcement Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine-dependent patients responding better to dopamine-enhancement pharmacotherapy . Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine & bgr;-hydroxylase ( D&bgr;H ) . Seventy-one cocaine-dependent patients who participated in a 12-week r and omized double-blind placebo-controlled trial of levodopa/carbidopa  were genotyped for the D&bgr;H gene ( DBH ) polymorphism rs1611115 . Our results showed that for patients with the low D&bgr;H activity genotypes ( CT/TT ) who received levodopa , the odds of having cocaine-positive urine decreased significantly over treatment compared with placebo-treated patients with the CT/TT genotypes ( P=0.004 ) . Individuals with the normal D&bgr;H activity genotype ( CC ) showed no differential response to levodopa . These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism Separate investigations have suggested that olanzapine , a D4 antagonist , decreases craving after a priming dose of alcohol and that the DRD4 variable number of t and em repeats ( VNTR ) polymorphism influences the expression of craving after a priming dose of alcohol . The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving based on individual differences in DRD4 VNTR in a sample of heavy social drinkers . Participants were r and omly assigned to receive olanzapine ( 5 mg ) or a control medication ( cyproheptadine , 4 mg ) prior to consuming three alcoholic drinks . Participants completed subjective measures of craving and euphoria after each drink . Participants who were homozygous or heterozygous for the 7 ( or longer ) repeat allele of the DRD4 VNTR were classified as DRD4 L , while the other participants were classified as DRD4 S. The findings indicated that olanzapine reduces craving for alcohol at baseline for both DRD4 S and DRD4 L individuals , but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for DRD4 L individuals Disulfiram ( Antabuse ) is being used in outpatient clinical trials to determine its efficacy as a treatment for cocaine dependence . This inpatient r and omized , double-blind , placebo-controlled , within-subjects study was conducted to determine whether disulfiram ( placebo , 250 or 500 mg/day ) alters responses to acute intranasal cocaine ( placebo , 1 or 2 mg/kg ) administration . Effects of disulfiram on cocaine pharmacokinetics , physiological , and behavioral responses were determined . Disulfiram treatment increased plasma cocaine concentrations three to six times and significantly increased cocaine-associated cardiovascular responses , but did not significantly alter behavioral responses to cocaine . These interactions should be considered in the decision regarding disulfiram treatment in cocaine dependent patients Objectives To examine survival and long term cessation of injecting in a cohort of drug users and to assess the influence of opiate substitution treatment on these outcomes . Design Prospect i ve open cohort study . Setting A single primary care facility in Edinburgh . Participants 794 patients with a history of injecting drug use presenting between 1980 and 2007 ; 655 ( 82 % ) were followed up by interview or linkage to primary care records and mortality register  , or both , and contributed 10 390 person years at risk ; 557 ( 85 % ) had received opiate substitution treatment .  Main outcome measures Duration of injecting : years from first injection to long term cessation , defined as last injection before period of five years of non-injecting ; mortality before cessation ; overall survival . Results In the entire cohort 277 participants achieved long term cessation of injecting , and 228 died . Half of the survivors had poor health related quality of life . Median duration from first injection to death was 24 years for participants with HIV and 41 years for those without HIV . For each additional year of opiate substitution treatment the hazard of death before long term cessation fell 13 % ( 95 % confidence interval 17 % to 9 % ) after adjustment for HIV , sex , calendar period , age at first injection , and history of prison and overdose . Conversely exposure to opiate substitution treatment was inversely related to the chances of achieving long term cessation . Conclusions Opiate substitution treatment in injecting drug users in primary care reduces this risk of mortality , with survival benefits increasing with cumulative exposure to treatment . Treatment does not reduce the overall duration of injecting Objective To investigate the effect of opiate substitution treatment at the beginning and end of treatment and according to duration of treatment . Design Prospect i ve cohort study . Setting UK General Practice Research Data base Participants Primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990 - 2005 . 5577 patients with 267 003 prescriptions for opiate substitution treatment followed-up ( 17 732 years ) until one year after the expiry of their last prescription , the date of death before this time had elapsed , or the date of transfer away from the practice . Main outcome measures Mortality rates and rate ratios comparing periods in and out of treatment adjusted for sex , age , calendar year , and comorbidity ; st and ardised mortality ratios comparing opiate users ’ mortality with general population mortality rates . Results Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment ; st and ardised mortality ratios were 5.3 ( 95 % confidence interval 4.0 to 6.8 ) on treatment and 10.9 ( 9.0 to 13.1 ) off treatment . Men using opiates had approximately twice the risk of death of women ( morality rate ratio 2.0 , 1.4 to 2.9 ) . In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years : 3.1 ( 1.5 to 6.6 ) times higher ( after adjustment for sex , age group , calendar period , and comorbidity ) than the rate during the rest of time on treatment . The crude mortality rate was 4.8 per 100 person years in weeks 1 - 2 after treatment stopped , 4.3 in weeks 3 - 4 , and 0.95 during the rest of time off treatment : 9 ( 5.4 to 14.9 ) , 8 ( 4.7 to 13.7 ) , and 1.9 ( 1.3 to 2.8 ) times higher than the baseline risk of mortality during treatment . Opiate substitution treatment has a greater than 85 % chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months . Conclusions Clinicians and patients should be aware of the increased mortality risk at the start of opiate substitution treatment and immediately after stopping treatment . Further research is needed to investigate the effect of average duration of opiate substitution treatment on drug related mortality G*Power is a free power analysis program for a variety of statistical tests . We present extensions and improvements of the version introduced by Faul , Erdfelder , Lang , and Buchner ( 2007 ) in the domain of correlation and regression analyses . In the new version , we have added procedures to analyze the power of tests based on ( 1 ) single- sample tetrachoric correlations , ( 2 ) comparisons of dependent correlations , ( 3 ) bivariate linear regression , ( 4 ) multiple linear regression based on the r and om predictor model , ( 5 ) logistic regression  , and ( 6 ) Poisson regression . We describe these new features and provide a brief introduction to their scope and h and ling An A118 G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor 's extracellular domain . In vitro studies show that the Asp40 variant of the mu-opioid receptor binds β-endorphin three times more avidly than the more common Asn40 variant . Paraventricular corticotropin releasing hormone neurons , which activate the HPA axis , express mu-opioid receptors and are modulated by β-endorphin neurons . This preliminary study was design ed to test the hypothesis that the Asn40Asp substitution polymorphism in the mu-opioid receptor influences HPA axis activation induced by opioid receptor blockade . Thirty-nine healthy men were genotyped ( A vs. G ) and then underwent opioid receptor blockade with Naloxone . Subjects expressing the A118 G receptor variant had greater cortisol responses to opioid receptor blockade . Also , a significant difference in the rate of increase of ACTH ( slope ) between A/A and A/G was observed between 30–90 minutes as well as a significant difference in the rate of decrease after 90 minutes . Moreover , subjects expressing the variant polymorphism had lower scores on the Conscientiousness Factor and associated subscales of NEO Personality Inventory compared to subjects expressing the common receptor . Because serotonin also modulates the CRF neuron , subjects were genotyped for a functional polymorphism within the serotonin transporter gene . We did not see differences in hormone responses result ing from expression of this functional polymorphism . It is plausible that persons expressing the mu-opioid receptor variant have altered HPA axis dynamics and altered responses to other physiological processes regulated through activation of the mu-opioid receptor Aim Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling . Here , we comprehensively analyzed the DRD2 gene locus , and in addition , the ANKK1 rs1800497C > T single nucleotide polymorphism ( SNP ) , formerly known as ‘ dopamine D2 receptor Taq1A C > T polymorphism ' , for associations with the risk of opiate addiction and the methadone dosage requirements . Methods Allelic frequencies of  DRD2/ANKK1  polymorphisms were compared between 85 methadone-substituted Caucasian patients and a r and om sample of 99 healthy Caucasian controls . Within patients , the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics . Results Compared with the control group , drug users carried more frequently the minor allele of DRD2 SNP rs1076560G > T SNP ( P=0.022 , odds ratio 2.343 ) or the ATCT haplotype of DRD2 rs1799978A > G , rs1076560G > T , rs6277C > T , ANKK1 rs1800497C > T ( P=0.048 , odds ratio 2.23 ) , with similar tendencies for ANKK1 rs1800497C > T ( P=0.056 , odds ratio 2.12 ) and the TCCTCTT haplotype of DRD2 rs12364283T > C , rs1799732C del , rs4648317C > T , rs1076560G > T , rs6275C > T , rs6277C > T , and ANKK1 rs1800497C > T ( P=0.059 , odds ratio 2.31 ) . The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C > T SNP ( P=0.016 and 0.005 for average and maximum dose , respectively ) . Carriers of the variant rs6275 T allele needed higher methadone doses than noncarriers . In addition , this variant was associated with a longer time to reach the maximum methadone dose ( P=0.025 ) . Conclusion On the basis of an analysis spanning the whole gene locus , from the DRD2 promoter to the ANKK1 rs1800497C > T polymorphism , DRD2 genetic polymorphisms modulate both the risk of opiate addiction , leading to the necessity of methadone substitution therapy , and the course of this therapy in terms of dosage requirements Background This clinical laboratory study evaluated how the timing of drinking and subjective responses to alcohol are effected by the opioid antagonist naltrexone . Methods Forty non-treatment seeking alcoholics were r and omly assigned to treatment with 50 mg naltrexone or matching placebo for 7 days . On day 7 , they were administered an “ initial drink ” of alcohol ( blood alcohol levels of between 20 and 30 mg% ) in a bar-like setting . In a r and om fashion , half of the subjects in each group ( naltrexone and placebo ) had either immediate or delayed ( 40 min ) access to up to 8 additional mini-drinks over a 2-h period . In the delayed group subjective reactions to alcohol were measured prior to access to more drinks . Results In the immediate access condition , subjects had similar drinking patterns , irrespective of whether they were taking naltrexone or placebo . However , in the delayed condition , naltrexone-treated subjects consumed fewer drinks and had a slower progression of drinking . There was a positive relationship between alcohol-induced stimulation and the number of drinks consumed in the placebo subjects but a negative correlation in the naltrexone subjects . Conclusions These data suggest that the effectiveness of naltrexone on alcohol consumption may be somewhat dependent on pattern of consumption . Since naltrexone seems to disrupt the connection between alcohol-induced stimulation and further alcohol consumption , there may be a time-critical period between drinks necessary for alcoholics to benefit from its effects . These findings are consistent with clinical trial data that suggest a potential synergistic effect between relapse prevention therapies and opiate antagonist pharmacotherapy BACKGROUND Naltrexone is moderately effective for the treatment of alcohol dependence , but there is great individual variability . The opioid receptor ( OPRM1 ) single nucleotide polymorphism ( SNP ) asn40asp has been shown to alter alcohol and naltrexone response in animals and humans . In addition , the brain opioid and dopamine systems interact and might underlie drinking and craving . This study investigated the effects of the OPRM1 SNP and dopamine transporter ( DAT ) variable number of t and em repeat ( VNTR ) genetic differences on drinking , alcohol effects , and naltrexone response under controlled conditions in nontreatment-seeking alcoholics . METHODS Two hundred and sixty-five nontreatment-seeking individuals with alcohol dependence were genotyped a priori for the OPRM1 asn40asp SNP and post hoc for DAT ( SLC6A3 ) 9 and 10 VNTRs . Asp40 carriers ( n = 43 ) and matched asn40 homozygotes ( n = 40 ) were r and omized to naltrexone or placebo for 7 days before receiving a priming drink and limited-access alcohol consumption in a bar-lab setting . Effects of genotypes on natural drinking as well as drinking , alcohol effects , and response to naltrexone in the bar-lab setting were examined by genotype . RESULTS There were no significant main effects of naltrexone or OPRM1 genotype , or any medication by OPRM1 interaction , on drinking variables . However , in individuals who had at least one DAT 9 VNTR , and who were also OPRM1 asn40 homozygotes , naltrexone reduced drinks/d consumed under natural conditions ( p = 0.006 ) , but not in the bar-lab . OPRM1 asn40 homozygotes ( p = 0.028 ) and DAT 9 VNTR carriers ( p = 0.032 ) had more stimulation to alcohol after the priming drink . CONCLUSIONS This study does not support a salient role for the OPRM1 asp40 alone in predicting drinking or naltrexone effects . However , although exploratory and in need of replication , it introduces the possibility that epistasis between the OPRM1 gene and DAT gene might need to be taken into account when examining differential genetic response to alcohol or medication treatment , especially in early-stage alcoholics BACKGROUND Cocaine abuse has no established pharmacotherapy , but active immunotherapy with a cocaine vaccine shows promise as a therapeutic intervention . METHODS An open label , fourteen week , dose-escalation study evaluated the safety , immunogenicity , and clinical efficacy of a novel human cocaine vaccine ( TA-CD ) in eighteen cocaine dependent subjects . Ten subjects ( 400 microg total dose group ) received four-100 microg injections over the course of eight weeks . Subsequently , eight subjects ( 2000 microg total dose group ) received five-400 microg vaccinations over twelve weeks . Intent to treat analysis of thrice weekly urine toxicologies and cocaine antibody titers were compared . RESULTS Sixteen of 18 subjects completed the study . There were no serious adverse reactions and the vaccine was well tolerated . The 2000 microg total dose group had a significantly higher mean antibody titer response ( 2000 units ) as compared to the 400 microg total dose group ( 1000 units ) ( p = .05 ) . The 2000 microg group was more likely to maintain cocaine free urines than those in the 400 microg group ( Z = -3.12 , p = .002 ) . Despite relapse in both groups , most reported an attenuation of cocaine 's usual euphoric effects at the six month follow-up time points ( 63 % in the 400 microg and 100 % in the 2000 microg groups ) . CONCLUSIONS The conjugated cocaine vaccine was well tolerated and cocaine specific antibodies persisted at least six months . The likelihood of using cocaine decreased in subjects who received the more intense vaccination schedule BACKGROUND Rates of relapse among cocaine-dependent patients are high , and new treatment approaches are needed . Clinical data demonstrate that a cocaine vaccine ( TA-CD ) produces selective anticocaine antibodies , yet the impact of these antibodies on cocaine 's direct effects is unknown . The objective of this human laboratory study was to measure the relationship between antibody titers and the effects of smoked cocaine on ratings of intoxication , craving , and cardiovascular effects . METHODS Ten cocaine-dependent men not seeking drug treatment spent 2 nights per week for 13 weeks inpatient where the effects of cocaine ( 0 mg , 25 mg , 50 mg ) were determined before vaccination and at weekly intervals thereafter . Two doses of TA-CD ( 82 microg , n = 4 ; 360 microg , n = 6 ) were administered at weeks 1 , 3 , 5 , and 9 . RESULTS Peak plasma antibody levels , which were highly variable , significantly predicted cocaine 's effects . Those individuals in the upper half of antibody production had an immediate ( within 4 minutes of cocaine smoking ) and robust ( 55%-81 % ) reduction in ratings of good drug effect and cocaine quality , while those in the lower half showed only a nonsignificant attenuation ( 6%-26 % ) . Self-reported cocaine use while participants were outpatient tended to decrease as a function of antibody titer ( p < .12 ) . By contrast , higher antibody levels predicted significantly greater cocaine-induced tachycardia . CONCLUSIONS The TA-CD vaccine substantially decreased smoked cocaine 's intoxicating effects in those generating sufficient antibody . These data support further testing of cocaine immunotherapy as a treatment for cocaine dependence AIMS Cocaine use by patients on methadone maintenance treatment is a widespread problem and is associated with a poorer prognosis . Recent studies have evaluated disulfiram as a treatment for individuals with comorbid alcohol and cocaine abuse . We evaluated the efficacy of disulfiram for cocaine dependence , both with and without co-morbid alcohol abuse , in a group of methadone-maintained opioid addicts . DESIGN R and omized double-blind , placebo-controlled trial . SETTING Urban methadone maintenance clinic . PARTICIPANTS Sixty-seven cocaine-dependent , methadone-maintained , opioid-dependent subjects ( 52 % female ; 51 % Caucasian ) . INTERVENTION Study medication , either disulfiram or placebo , was placed directly in the methadone to ensure compliance for 12 weeks . MEASUREMENTS Primary outcome measures included weekly assessment s of the frequency and quantity of drug and alcohol use , weekly urine toxicology screens and breathalyzer readings . FINDINGS Disulfiram treated subjects decreased the quantity and frequency of cocaine use significantly more than those treated with placebo .  Alcohol use was minimal for all subjects regardless of the medication . CONCLUSIONS Disulfiram may be an effective pharmacotherapy for cocaine abuse among methadone-maintained opioid addicts , even in those individuals without co-morbid alcohol abuse . Disulfiram inhibits dopamine beta-hydroxylase result ing in an excess of dopamine and decreased synthesis of norepinephrine . Since cocaine is a potent catecholamine re-uptake inhibitor , disulfiram may blunt cocaine craving or alter the " high " , result ing in a decreased desire to use cocaine AIMS To ( i ) examine the predictors of mortality in a r and omized study of methadone versus buprenorphine maintenance treatment ; ( ii ) compare the survival experience of the r and omized subject groups ; and ( iii ) describe the causes of death . DESIGN Ten-year longitudinal follow-up of mortality among participants in a r and omized trial of methadone versus buprenorphine maintenance treatment .  SETTING Recruitment through three clinics for a r and omized trial of buprenorphine versus methadone maintenance . PARTICIPANTS A total of 405 heroin-dependent ( DSM-IV ) participants aged 18 years and above who consented to participate in original study . MEASUREMENTS Baseline data from original r and omized study ; date s and causes of death through data linkage with Births , Deaths and Marriages registries ; and longitudinal treatment exposure via State health departments . Predictors of mortality examined through survival analysis . FINDINGS There was an overall mortality rate of 8.84 deaths per 1000 person-years of follow-up and causes of death were comparable with the literature . Increased exposure to episodes of opioid treatment longer than 7 days reduced the risk of mortality ; there was no differential mortality among methadone versus buprenorphine participants . More dependent , heavier users of heroin at baseline had a lower risk of death , and also higher exposure to opioid treatment . Older participants r and omized to buprenorphine treatment had significantly improved survival . Aboriginal or Torres Strait Isl and er participants had a higher risk of death . CONCLUSIONS Increased exposure to opioid maintenance treatment reduces the risk of death in opioid-dependent people . There was no differential reduction between buprenorphine and methadone . Previous studies suggesting differential effects may have been affected by biases in patient selection OBJECTIVE The authors sought to identify genetic markers for antidepressant medication intolerance . Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 ( CYP2D6 ) has been postulated to underlie antidepressant intolerance ( pharmacokinetic effect ) . However , variation in genes encoding serotonin receptors could also explain antidepressant side effects ( pharmacodynamic effect ) . METHOD An 8-week , double-blind , r and omized pharmacogenetic study compared the widely prescribed antidepressants paroxetine ( a selective serotonin reuptake inhibitor [ SSRI ] ) and mirtazapine ( not an SSRI ) in 246 elderly patients with major depression . Genotypes were determined for the 102 T/C single nucleotide polymorphism ( SNP ) in the serotonin 2A ( 5-HT(2A ) ) locus ( HTR2A ) , previously associated with psychotropic medication treatment outcome . Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene . Clinical outcomes included treatment discontinuations , adverse events , medication compliance , and change in mood . RESULTS Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype . There was a significant linear relationship between the number of C alleles and the probability of discontinuation . Side effect severity in paroxetine-treated patients with the C/C genotype was also greater . In contrast , HTR2A 102 T/C genotype had no effect on mirtazapine side effects . CYP2D6 genotype did not predict treatment outcome for either medication . CONCLUSIONS Pharmacodynamic differences among patients due to variant 5-HT(2A ) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance . Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome Recent research has suggested that alterations in mesolimbic dopamine neurotransmission are central to the development and expression of craving for alcohol . Because the D4 dopamine receptor gene , variable numbers of t and em repeats ( DRD4 VNTR ) polymorphism putatively expresses functional differences in dopamine receptors , the present study tested whether this polymorphism influences the effects of a priming dose of alcohol on craving .  Participants consumed 3 alcoholic drinks or 3 control drinks and completed measures of craving  after each drink .  Participants who were homozygous or heterozygous for the 7 ( or longer ) repeat allele were classified as DRD4 L , whereas the other participants were classified as DRD4 S. Results suggested that DRD4 L participants demonstrated significantly higher craving after consumption of alcohol as compared with the control beverage Various types of alcoholics have been described and heredity has been shown to be involved in some of these types . An important role of the mesolimbic dopamine system has been suggested in the reinforcing effects of alcohol and recent molecular genetic studies are implicating the gene for the D2 dopamine receptor ( DRD2 ) in alcoholism . In a double-blind study , bromocriptine , a DRD2 agonist , or placebo was administered to alcoholics with either the A1 ( A1/A1 and A1/A2 genotypes ) or only the A2 ( A2/A2 genotype ) allele of the DRD2 gene . The greatest improvement in craving and anxiety occurred in the bromocriptine-treated A1 alcoholics and attrition was highest in the placebo-treated A1 alcoholics . The feasibility of a pharmacogenetic approach in treating certain types of alcoholics is suggested AIMS To evaluate disulfiram and three forms of manual guided psychotherapy for individuals with cocaine dependence and concurrent alcohol abuse or dependence . DESIGN R and omized controlled trial . SETTING Urban substance abuse treatment center . PARTICIPANTS One hundred and twenty-two cocaine/alcohol abusers ( 27 % female ; 61 % African-American or Hispanic ) . INTERVENTIONS One of five treatments delivered over 12 weeks : cognitive behavioral treatment ( CBT ) plus disulfiram ; Twelve Step facilitation ( TSF ) plus disulfiram ; clinical management ( CM ) plus disulfiram ; CBT plus no medication ; TSF plus no medication . MEASUREMENTS Duration of continuous abstinence from cocaine or alcohol ; frequency and quantity of cocaine and alcohol use by week , verified by urine toxicology and breathalyzer screens . FINDINGS Disulfiram treatment was associated with significantly better retention in treatment , as well as longer duration of abstinence from alcohol and cocaine use . The two active psychotherapies ( CBT and TSF ) were associated with reduced cocaine use over time compared with supportive psychotherapy ( CM ) . Cocaine and alcohol use were strongly related throughout treatment , particularly for subjects treated with disulfiram . CONCLUSIONS For the large proportion of cocaine-dependent individuals who also abuse alcohol , disulfiram combined with outpatient psychotherapy may be a promising treatment strategy . This study underlines ( a ) the significance of alcohol use among treatment-seeking cocaine abusers , ( b ) the promise of the strategy of treating co-morbid disorders among drug-dependent individuals , and ( c ) the importance of combining psychotherapy and pharmacotherapy in the treatment of drug use disorders We examined a pharmacogenetic association of the dopamine β-hydroxylase ( DBH ) gene with a response to an  anti-cocaine vaccine that was tested in a recent clinical trial . This gene is associated with cocaine-induced paranoia , which has a slower onset than the euphoria from cocaine . The vaccine reduced euphoria by slowing the entry of cocaine into the brain , but it may not reduce aversive symptoms like paranoia . A 16-week Phase IIb r and omized double-blind placebo-controlled trial of 114 cocaine and opioid dependent subjects who received five vaccinations over the first 12 weeks was examined . We genotyped 71 subjects for the rs1611115 ( -1021C > T ) variant of the DBH gene and compared vaccine to placebo subjects on cocaine-free urines . Using repeated measures analysis of variance , corrected for population structure , vaccine pharmacotherapy reduced cocaine positive urines significantly based on DBH genotype . Patients with the low DβH level genotype dropped from 77 % to 51 % on vaccine ( p=0.0001 ) , while those with the normal DβH level genotype dropped from 83 % to 72 % . Placebo showed no effect on cocaine use overall or by genotype . This study indicates that a patient 's DBH genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence Objective Disulfiram is a potential cocaine addiction pharmacotherapy . Since dopamine deficiency has been found with cocaine addiction , our objective was to examine whether functional variants in the ankyrin repeat and kinase domain-containing 1 ( ANKK1 ) and /or the dopamine receptor D2 ( DRD2 ) genes interact with response to treatment with disulfiram . Material s and methods Cocaine and opioid codependent ( DSM-IV ) patients were stabilized on methadone and subsequently r and omized into treatment groups – disulfiram ( 250 mg/day , N=31 ) or placebo ( N=37 ) . They were genotyped for ANKK1 ( rs1800497 ) and DRD2 ( rs2283265 ) polymorphisms , and the data were evaluated for an association between a cocaine-free state , as assessed by cocaine-free urine sample s , and disulfiram treatment . Data were analyzed using repeated measures analysis of variance corrected for population structure . Results Patients with CT or TT ANKK1 genotypes dropped from 80 to 52 % cocaine-positive urines on disulfiram ( N=13 ; P⩽0.0001 ) , whereas those on placebo ( N=20 ) showed no treatment effect . Patients carrying the CC ANKK1 genotype showed no effect on treatment with disulfiram ( N=18 ) or placebo ( N=17 ) . The GT/TT DRD2 genotype group showed a significant decrease in the number of cocaine-positive urine sample s on disulfiram ( N=9 ; 67–48 % ; P⩽0.0001 ) , whereas the GG DRD2 genotype group showed only a marginal decrease ( N=23 ; 84–63 % ; P=0.04 ) . Genotype pattern analysis revealed that individuals carrying at least one minor allele in either gene responded better to disulfiram treatment ( N=13 ; P⩽0.0001 ) compared with individuals carrying only the major alleles ( N=17 ) . Conclusion A patient ’s genotype for ANKK1 , DRD2 , or both , may be used to identify individuals for whom disulfiram may be an effective pharmacotherapy for cocaine dependence BACKGROUND Disulfiram has been an effective cocaine addiction pharmacotherapy , and one of its possible mechanisms of efficacy is through copper chelation and inhibition of an enzyme involved in catecholamine metabolism , dopamine β-hydroxylase ( DβH ) , which converts dopamine to norepinephrine . A variant in the gene encoding DβH leads to reduced DβH activity , and as such , disulfiram might not be an effective treatment of cocaine dependence for individuals with this variant . This study explored that potential matching . METHODS Seventy-four cocaine- and opioid-codependent ( DSM-V ) subjects were stabilized on methadone for 2 weeks and subsequently r and omized into disulfiram ( 250 mg/day , n = 34 ) and placebo groups ( n = 40 ) for 10 weeks . We genotyped the DBH gene polymorphism , -1021C/T ( rs1611115 ) , that reduces DβH enzyme levels and evaluated its role for increasing cocaine free urines  with disulfiram . RESULTS With repeated measures analysis of variance , corrected for population structure , disulfiram pharmacotherapy  reduced cocaine-positive urines from 80 % to 62 % ( p = .0001 ) , and this disulfiram efficacy differed by DBH genotype group . Patients with the normal DβH level genotype dropped from 84 % to 56 % on disulfiram ( p = .0001 ) , whereas those with the low DBH level genotype showed no disulfiram effect . CONCLUSIONS This study indicates that the DBH genotype of a patient could be used to identify a subset of individuals for which disulfiram treatment might be an effective pharmacotherapy for cocaine dependence Hereditary factors confer susceptibility to alcohol dependence . Alcohol mediates its reinforcing effects by enhancing dopamine activity in the mesolimbic dopamine system . The role of the dopamine transporter in terminating dopaminergic activity in synaptic neurotransmission suggests that variants of the dopamine transporter gene ( DAT1 ) might contribute to individual differences in vulnerability to addictive behavior . Our population -based association study investigated whether variants of DAT1 confer susceptibility to alcohol dependence in 293 alcoholics and clinical ly more homogeneous subgroups formed by : positive family history , early age-at-onset , delirium , withdrawal seizures , antisocial tendencies , type 1 and 2 alcoholics . Analyzing a VNTR polymorphism in the 3 ' untranslated region of DAT1 , we found a significantly increased prevalence of the nine-repeat allele in 93 alcoholics displaying withdrawal seizures or delirium  , compared with 93 ethnically matched nonalcoholic controls ( p = 0.003 ; OR = 2.44 ; 95 % confidence interval : 1.35 - 4.43 ) . Our data provide evidence that a major genetic determinant of DAT1 influences vulnerability to severe alcohol withdrawal symptoms CONTEXT Disulfiram has emerged as a promising treatment for cocaine dependence , but it has not yet been evaluated in general population s of cocaine users . OBJECTIVES To compare the effectiveness of disulfiram therapy with that of a placebo condition in reducing cocaine use and to compare the effectiveness of 2 active behavioral therapies-cognitive behavior therapy ( CBT ) and interpersonal psychotherapy (IPT)-in reducing cocaine use . DESIGN R and omized , placebo-controlled , double-masked ( for medication condition ) , factorial ( 2 x 2 ) trial with 4 treatment conditions : disulfiram plus CBT , disulfiram plus IPT , placebo plus CBT , and placebo plus IPT . SETTING A community-based outpatient substance abuse treatment program . PATIENTS A total of 121 individuals meeting the criteria for current cocaine dependence . INTERVENTIONS Patients received either disulfiram ( 250 mg/d ) or placebo in identical capsules . Medication compliance was monitored using a riboflavin marker procedure . Both behavioral therapies ( CBT and IPT ) were manual guided and were delivered in individual sessions for 12 weeks . MAIN OUTCOME MEASURES R and om regression analyses of self-reported frequency of cocaine use and results of urine toxicology screens . RESULTS Participants assigned to disulfiram reduced their cocaine use significantly more than those assigned to placebo , and those assigned to CBT reduced their cocaine use significantly more than those assigned to IPT ( P<.01 for both ) . Findings were consistent across all study sample s ( eg , intention to treat , treatment initiators , and treatment completers ) . Benefits of disulfiram use and CBT were most pronounced for participants who were not alcohol dependent at baseline or who fully abstained from drinking alcohol during treatment . Adverse effects experienced by participants who received disulfiram were mild and were not considerably different from those experienced by participants who received placebo . CONCLUSIONS Disulfiram and CBT are effective therapies for general population s of cocaine-dependent individuals . Disulfiram seems to exert a direct effect on cocaine use rather than through reducing concurrent alcohol use
target: Polymorphisms of the DRD2 , ANKK1 , DAT1 , DBH , and DRD4 genes have been found to moderate the effects of pharmacotherapy  of alcohol , opioid , and cocaine use disorders .
  The integration of genetic information with clinical data will inform health professionals of the most efficacious pharmacotherapeutic intervention for substance use disorders .
background: Substance use disorders have significant personal , familial , and societal consequences .
  Despite the serious consequences of substance use , only a few therapies are effective in treating substance use disorders , thus highlighting a need for improved treatment practice s. Substance use treatment response depends on multiple factors such as genetic , biological , and social factors .
  It is essential that each component is represented in treatment plans .
  The dopaminergic system plays a critical role in the pharmacotherapy for addictions , and an underst and ing of the role of variation of genes involved in this system is essential for its success .