Search

Background: The serotonin transporter (SERT) mRNA was previously reported to be a quantitative and pathophysiology‐based biomarker of heavy drinking in 5HTTLPR:LL genotype‐carriers treated with ondansetron. Here, we validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared it with the known biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS). Methods: Binge drinking men and women of European ancestry aged 21 to 65 years were enrolled in a 12‐day, in‐patient, randomized, double‐blind, crossover study, where they were administered three beverage doses (placebo, 0.5 g/kg [0.4 g/kg] ethanol, and 1 g/kg [0.9 g/kg] ethanol for men [women]) individually in three 4‐day periods (experiments), separated by minimum 7‐day washout period. Diet, sleep, and physical activity were controlled throughout the inpatient experiments. Twenty‐nine participants were randomized to receive beverage doses counterbalancing the sequence of treatment and gender within subgroups stratified by SERT genotypes 5HTTLPR:LL+rs25531:AA (LALA) versus 5HTTLPR:LS/SS. Peripheral venous blood was collected daily for (1) quantification of SERT mRNA (the primary outcome measure) using qRT‐PCR and (2) plasma EtG and EtS levels using tandem mass‐spectrometry. Results: The association between administered beverage dose and SERT mRNA from completers of at least one 4‐day experiment (N = 18) assessed by a linear mixed model was not statistically significant. Significant positive associations were found with beverage dose and plasma EtG, EtS and EtG/EtS ratio (β = 5.8, SE = 1.2, p < 0.0001; β = 1.3, SE = 0.6, p = 0.023; and β = 3.0, SE = 0.7, p < 0.0001, respectively; the C‐statistics for discriminating outcomes were 0.97, 0.8, and 0.92, respectively). Additionally, we observed a sequence effect with a greater placebo effect on SERT mRNA when it was administered during the first experiment (p = 0.0009), but not on EtG/EtS measures. Conclusion: The findings do not validate the use of SERT as a biomarker of heavy drinking. Larger and more innovative studies addressing the effects of placebo, race, gender, and response to treatment with serotonergic agents are needed to fully assess the utility of SERT as a biomarker of heavy and binge drinking. [ABSTRACT FROM AUTHOR]

Aims: This study compares the incidence and risk-markers of student alcohol intoxication-related emergency department (ED) visits and alcohol-related incidents reported to student affairs. Methods: Enrollment data were linked to ED visits with alcohol intoxication and to alcohol-related incidents reported to campus authorities within one year following the first (index) annual enrollment. Incidence, annual trends and associated risk markers were analyzed. Results: The cohort consisted of 204,423 students aged 16–49. Incidence rates of first ED visit with alcohol intoxication and alcohol-related incidents were 59/10,000 and 311/10,000 person-years, respectively. Both outcomes shared common risk-markers including age, gender, race/ethnicity, fraternity and sorority (FSL) membership, an existing diagnosis of depression, etc. Being an athlete was associated with a lower risk of alcohol-related ED visits, and transfer students were at lower risk for alcohol-related incidents. Conclusion: Linking enrollment data with hazardous drinking events can help in better monitoring of student hazardous drinking and targeting interventions. First longitudinal study documenting the incidence of extreme student alcohol misuse. There were rising trends in student risky drinking based on two independent datasets. Analysis identified a range of risk markers predictive of risky drinking behaviors. Linking multiple student datasets can timely identify high risk students. [ABSTRACT FROM AUTHOR]

Background/objectives: Topiramate has been studied in the treatment of substance use disorders and is often used off-label in the treatment of other disorders with impaired impulse control. We sought to determine whether impulsiveness could predict topiramate treatment response in individuals with cocaine use disorder (CUD).Methods: In a post-hoc analysis of a 12-week, double-blind, randomized, placebo-controlled trial of topiramate for CUD, we examined the relationship between response to treatment and participants' baseline score on the Barrett Impulsiveness Scale (BIS-11). During the original trial, topiramate was titrated up to 300 mg/day over 6 weeks and maintained for 6 weeks. All participants received weekly cognitive behavioral therapy.Results: Individuals with total BIS-11 scores above the median had 11.2% more cocaine-free days with topiramate versus placebo (Bonferroni corrected p = 0.047). Individuals with first-order factor scores above the median in self-control (Bonferroni corrected p = 0.020) and at or below the median in attention (Bonferroni corrected p = 0.022), and second-order factor scores at or below the median in attentional (Bonferroni corrected p = 0.024) and motor impulsiveness (Bonferroni corrected p = 0.046) were all associated with a greater improvement with topiramate.Discussion/conclusion: The results indicate an association between higher within-group impulsiveness and response to topiramate for CUD. The subscore findings may suggest a complex interaction between effectiveness and known cognitive side effects. The finding that trait impulsiveness is associated with treatment response is a promising discovery that may help guide treatment for CUD.Scientific Significance: This analysis suggests a possible endophenotype based on impulsiveness that can predict treatment response to topiramate. (Am J Addict 2019;XX:1-6). [ABSTRACT FROM AUTHOR]

Background and aims: In the United States, access to naloxone has been expanded as a measure to address growing opioid overdose mortality. The study aimed to describe the national trends in naloxone use as reported to the US poison centers (PCs). Methods: The National Poison Data System (NPDS) was queried for cases reporting naloxone therapy from 1 January 2001 to 31 December 2016. Demographic and clinical characteristics were assessed descriptively. Trends in naloxone reports were evaluated by using generalized linear mixed models that were adjusted for age, gender and random effects of the geographical census region. Cumulative incidence rates (CIR) of naloxone reports at the state‐ and national‐level were calculated. Results: There were 304 249 cases reporting naloxone therapy during the study period. The frequency of naloxone reports increased from 9498 in 2000 to 26 826 in 2016. The proportion of cases where naloxone was used prior to PC recommendation increased from 59.8% in 2000 to 81.5% in 2016. The mean number of NPDS naloxone reports per 100 000 human exposures increased from 9.6 [95% confidence interval (CI) = 6.4–14.2] to 31.7 (95% CI = 21.4–46.9, P < 0.001). Among the cases, 52.4% were female and the most frequent age group was 20–39 years (39.1%). The principal reason for a toxic exposure resulting in a naloxone report was suspected suicide (55.0%). Life‐threatening symptoms were seen in one‐fifth of the cases, with 53.9% cases being admitted to critical care units. Opioids (59.7% cases), were the most commonly reported exposure agents, with hydrocodone being most frequently reported. The national CIR of naloxone reports to the US PCs was 6.3 cases per 100 000 population, with West Virginia demonstrating the highest incidence. Conclusions: Analysis of calls to the United States poison centers indicates an increasing trend of naloxone use from 2000 to 2016. [ABSTRACT FROM AUTHOR]

Background and objectives: Alcohol use disorders (AUDs) are an important cause of morbidity and mortality. Despite the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommendations that medications be considered for patients with alcohol dependence, the mainstay of treatment has been counseling. We designed a survey to assess the treatment practices of psychiatrists and family medicine (FM) physicians in an effort to identify barriers to the use of pharmacotherapy and develop strategies to increase physician knowledge and utilization of these medications. Methods: An anonymous online survey was sent to FM physicians and psychiatrists nationwide. The survey collected demographic information and assessed prescription of medications in treating AUDs, including FDA-approved medications and other medications used off-label for this purpose. We also examined factors that would lead to an increase in AUDs pharmacotherapy. Results: A total of 491 surveys were completed, with 475 responses included in the final analyses. 45.5% of participants were psychiatrists vs. 54.5% FM physicians. The 74.7% respondents had used medications to treat AUDs, with psychiatrists more likely to have prescribed acamprosate, naltrexone, and several off-label medications. FM physicians were more likely to report efficacy concerns. A majority of all physicians sampled would increase pharmacotherapy of AUDs with increased training. Discussion: In our sample, most physicians have used medications to treat AUDs. There were concerns about efficacy with all non-FDA-approved medications, but limited treatment success even with FDA-approved medications. Greater education about pharmacotherapy, including predictors for treatment response amongst patients, should help alleviate some of the uncertainties reported with medications' efficacy and lead to a more individualized treatment approach. [ABSTRACT FROM AUTHOR]

Background Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile. Methods In this double-blind, placebo-controlled clinical trial, 140 individuals who met the DSM-IV criteria for methamphetamine dependence were randomized to receive either TPM or placebo, of whom 99 consented to participate in our genome-wide expression study. The RNA samples were collected from whole blood for 50 TPM- and 49 placebo-treated participants at three time points: baseline and the ends of weeks 8 and 12. Genome-wide expression profiles and pathways of the two groups were compared for the responders and non-responders at Weeks 8 and 12. To minimize individual variations, expression of all examined genes at Weeks 8 and 12 were normalized to the values at baseline prior to identification of differentially expressed genes and pathways. Results At the single-gene level, we identified 1054, 502, 204, and 404 genes at nominal P values < 0.01 in the responders vs. non-responders at Weeks 8 and 12 for the TPM and placebo groups, respectively. Among them, expression of 159, 38, 2, and 21 genes was still significantly different after stringent Bonferroni corrections for multiple testing. Many of these genes, such as GRINA, PRKACA, PRKCI, SNAP23, and TRAK2, which are involved in glutamate receptor and GABA receptor signaling, are direct targets for TPM. In contrast, no TPM drug targets were identified in the 38 significant genes for the Week 8 placebo group. Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups. These pathways are involved in relevant physiological functions such as neuronal function/synaptic plasticity, signal transduction, cardiovascular function, and inflammation/immune function. Conclusion Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions. [ABSTRACT FROM AUTHOR]

Importance: No medication has been established as an efficacious treatment for cocaine dependence. We hypothesized that dual modulation of the mesocorticolimbic dopamine system by topiramate-a glutamate receptor antagonist and γ-aminobutyric acid receptor agonist-would result in efficacious treatment for cocaine dependence compared with placebo.Objective: To determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence.Design, Setting, and Participants: Double-blind, randomized, placebo-controlled, 12-week trial of 142 cocaine-dependent adults in clinical research facilities at the University of Virginia between November 22, 2005, and July 25, 2011.Interventions: Topiramate (n = 71) or placebo (n = 71) in escalating doses from 50 mg/d to the target maintenance dose of 300 mg/d in weeks 6 to 12, combined with weekly cognitive-behavioral treatment.Main Outcomes and Measures: For the efficacy period, weeks 6 to 12, the primary outcome was the weekly difference from baseline in the proportion of cocaine nonuse days; the secondary outcome was urinary cocaine-free weeks, and exploratory outcomes included craving and self- and observer-rated global functioning on the Clinical Global Impression scales.Results: Using an intent-to-treat analysis, topiramate was more efficacious than placebo at increasing the weekly proportion of cocaine nonuse days, irrespective of whether missing data were not or were imputed conservatively to the baseline value (13.3% vs 5.3%, 95% CI for the estimated mean difference, 1.4%-14.6%, P = .02 or 8.9% vs 3.7%, 95% CI for the estimated mean difference, 0.2%-10.1%, P = .04, respectively). Topiramate also was associated, significantly more than placebo, with increasing the likelihood of urinary cocaine-free weeks (16.6% vs 5.8%; odds ratio, 3.21; 95% CI, 1.24-8.32; P = .02), as well as decreasing craving and improving observer-rated global functioning (all P < .05).Conclusions and Relevance: Topiramate is more efficacious than placebo at increasing the mean weekly proportion of cocaine nonuse days and associated measures of clinical improvement among cocaine-dependent individuals. [ABSTRACT FROM AUTHOR]

IMPORTANCE No medication has been established as an efficacious treatment for cocaine dependence. We hypothesized that dual modulation of the mesocorticolimbic dopamine system by topiramate-a glutamate receptor antagonist and y-aminobutyric acid receptor agonist-would result in efficacious treatment for cocaine dependence compared with placebo. OBJECTIVE To determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence. DESIGN, SETTING. AND PARTICIPANTS Double-blind, randomized, placebo-controlled, 12-week trial of 142 cocaine-dependent adults in clinical research facilities at the University of Virginia between November 22,2005, and July 25,2011. INTERVENTIONS Topiramate (n = 71) or placebo (n = 71) in escalating doses from 50 mg/d to the target maintenance dose of 300 mg/d in weeks 6 to 12, combined with weekly cognitive-behavioral treatment. MAIN OUTCOMES AND MEASURES For the efficacy period, weeks 6 to 12, the primary outcome was the weekly difference from baseline in the proportion of cocaine nonuse days; the secondary outcome was urinary cocaine-free weeks, and exploratory outcomes included craving and self- and observer-rated global functioning on the Clinical Global Impression scales. RESULTS Using an intent-to-treat analysis, topiramate was more efficacious than placebo at increasing the weekly proportion of cocaine nonuse days, irrespective of whether missing data were not or were imputed conservatively to the baseline value (13.3% vs 5.3%, 95% CI for the estimated mean difference, 1.4%-14.6%, P = .02 or 8.9% vs 3.7%, 95% CI for the estimated mean difference, 0.2%-10.1%, P = .04, respectively). Topiramate also was associated, significantly more than placebo, with increasing the likelihood of urinary cocaine-free weeks (16.6% vs 5.8%; odds ratio, 3.21; 95% CI, 1.24-8.32; P = .02), as well as decreasing craving and improving observer-rated global functioning (all P < .05). CONCLUSIONS AND RELEVANCE Topiramate is more efficacious than placebo at increasing the mean weekly proportion of cocaine nonuse days and associated measures of clinical improvement among cocaine-dependent individuals. [ABSTRACT FROM AUTHOR]

On the basis of the converging evidence showing regulation of drinking behavior by 5-HT receptors and the serotonin transporter, we hypothesized that the interactive effects of genetic variations in the genes HTR3A, HTR3B, and SLC6A4 confer greater susceptibility to alcohol dependence (AD) than do their effects individually. We examined the associations of AD with 22 SNPs across HTR3A, HTR3B, and two functional variants in SLC6A4 in 500 AD and 280 healthy control individuals of European descent. We found that the alleles of the low-frequency SNPs rs33940208:T in HTR3A and rs2276305:A in HTR3B were inversely and nominally significantly associated with AD with odds ratio (OR) and 95 % confidence interval of 0.212 and 0.073, 0.616 ( P = 0.004) and 0.261 and 0.088, 0.777 ( P = 0.016), respectively. Further, our gene-by-gene interaction analysis revealed that two four-variant models that differed by only one SNP carried a risk for AD (empirical P < 1 × 10 for prediction accuracy of the two models based on 10 permutations). Subsequent analysis of these two interaction models revealed an OR of 2.71 and 2.80, respectively, for AD ( P < 0.001) in carriers of genotype combinations 5′-HTTLPR:LL/LS( SLC6A4)-rs1042173:TT/TG( SLC6A4)-rs1176744:AC( HTR3B)-rs3782025:AG( HTR3B) and 5′-HTTLPR:LL/LS( SLC6A4)-rs10160548:GT/TT( HTR3A)-rs1176744:AC( HTR3B)-rs3782025:AG( HTR3B). Combining all five genotypes resulted in an OR of 3.095 ( P = 2.0 × 10) for AD. Inspired by these findings, we conducted the analysis in an independent sample, OZ-ALC-GWAS ( N = 6699), obtained from the NIH dbGAP database, which confirmed the findings, not only for all three risk genotype combinations ( Z = 4.384, P = 1.0 × 10; Z = 3.155, P = 1.6 × 10; and Z = 3.389, P = 7.0 × 10, respectively), but also protective effects for rs33940208:T ( χ = 3.316, P = 0.0686) and rs2276305:A ( χ = 7.224, P = 0.007). These findings reveal significant interactive effects among variants in SLC6A4- HTR3A- HTR3B affecting AD. Further studies are needed to confirm these findings and characterize the molecular mechanisms underlying these effects. [ABSTRACT FROM AUTHOR]

Objective: The authors previously reported that the 5'-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT3 antagonist ondansetron. In this study, they explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT3 receptors to ondansetron.Method: The authors genotyped one rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that they genotyped for SLC6A4-LL/TT in the previous randomized, double-blind, 11-week clinical trial. Participants were 283 European Americans who received oral ondansetron (4 mg/kg of body weight twice daily) or placebo along with weekly cognitive-behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed.Results: Individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (22.50; effect size=0.867), percentage of heavy drinking days (220.58%; effect size=0.780), and percentage of days abstinent (18.18%; effect size=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in the previous study) to 34%.Conclusions: The authors present initial evidence suggesting that a combined fivemarker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Additional, larger pharmacogenetic studies would help to validate these results. [ABSTRACT FROM AUTHOR]

Objective: The authors previously reported that the 5:-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT3 antagonist ondansetron. In this study, they explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT3 receptors to ondansetron. Method: The authors genotyped one rare and 18 common single-nucleotide polymorphisms in HTR3A and HTR3B in the same sample that they genotyped for SLC6A4-LL/TT in the previous randomized, double-blind, 11-week clinical trial. Participants were 283 European Americans who received oral ondansetron (4 mg/kg of body weight twice daily) or placebo along with weekly cognitive-behavioral therapy. Associations of individual and combined genotypes with treatment response on drinking outcomes were analyzed. Results: Individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942- AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (22.50; effect size=0.867), percentage of heavy drinking days (220.58%; effect size=0.780), and percentage of days abstinent (18.18%; effect size=0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in the previous study) to 34%. Conclusions: The authors present initial evidence suggesting that a combined fivemarker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Additional, larger pharmacogenetic studies would help to validate these results. [ABSTRACT FROM AUTHOR]

Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico-mesolimbic system, might reduce cocaine's abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving and preference for cocaine over money induced by low and high doses (0.325 and 0.65 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university in-patient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square cross-over design in which three experimental challenge doses of low-dose cocaine, high-dose cocaine and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pre-treatments separated by a 1-week washout period (2006-2009). After placebo pre-treatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine and monetary value of cocaine in a behavioral preference test of cocaine versus money choice. Topiramate pre-treatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine's abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate's prominent sedative effects. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled out-patient trial tested topiramate for treating methamphetamine addiction. Design Participants ( n = 140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 50 mg/day to the target maintenance of 200 mg/day in weeks 6-12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment. Setting The trial was conducted at eight medical centers in the United States. Participants One hundred and forty methamphetamine-dependent adults took part in the trial. Measurements The primary outcome was abstinence from methamphetamine during weeks 6-12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables. Findings In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6-12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization ( n = 26) had significantly greater abstinence on topiramate versus placebo during study weeks 6-12. Topiramate was safe and well tolerated. Conclusions Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent. [ABSTRACT FROM AUTHOR]

Cannabis, the most commonly used illicit substance, exerts its primary psychoactive effect via delta-9 tetrahydrocannabinol (Δ(9) -THC) agonism of cannabinoid receptor type 1 (CB1). Some users develop a cannabis use disorder and physical dependence manifested by withdrawal symptoms during abstinence. Hence, there is growing public health concern about increasing use of a new generation of synthetic cannabinoid (SC) agonists (eg, JWH-018, CP 47,497) marketed as natural herbal incense mixtures under brand names such as "Spice" and "K2." Anecdotal reports suggest overlapping effects with marijuana when the mixtures are smoked, however, systematic evaluation of SC-related psychoactive properties and adverse effects is lacking. We conducted a systematic review of published reports on SC clinical effects in humans. Most highlight potential toxicity such as acute anxiety and psychosis. In addition, we carefully document three cases in which experienced marijuana users meeting criteria for cannabis dependence with physiologic dependence smoked SC products regularly. The SC mixture effects were reportedly similar to marijuana and well tolerated. The individuals all reported that SC product use effectively alleviated cannabis withdrawal. Biopsychosocial factors associated with SC initiation and usage by the cases help to shed light on psychopharmacologic, clinical, and public health aspects of SC product consumption. [ABSTRACT FROM AUTHOR]

Cannabis, the most commonly used illicit substance, exerts its primary psychoactive effect via delta-9 tetrahydrocannabinol (Δ9-THC) agonism of cannabinoid receptor type 1 (CB1). Some users develop a cannabis use disorder and physical dependence manifested by withdrawal symptoms during abstinence. Hence, there is growing public health concern about increasing use of a new generation of synthetic cannabinoid (SC) agonists (eg, JWH-018, CP 47,497) marketed as natural herbal incense mixtures under brand names such as 'Spice' and 'K2.' Anecdotal reports suggest overlapping effects with marijuana when the mixtures are smoked, however, systematic evaluation of SC-related psychoactive properties and adverse effects is lacking. We conducted a systematic review of published reports on SC clinical effects in humans. Most highlight potential toxicity such as acute anxiety and psychosis. In addition, we carefully document three cases in which experienced marijuana users meeting criteria for cannabis dependence with physiologic dependence smoked SC products regularly. The SC mixture effects were reportedly similar to marijuana and well tolerated. The individuals all reported that SC product use effectively alleviated cannabis withdrawal. Biopsychosocial factors associated with SC initiation and usage by the cases help to shed light on psychopharmacologic, clinical, and public health aspects of SC product consumption. (Am J Addict 2012:00:1-7) [ABSTRACT FROM AUTHOR]

Objective: Severe drinking can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT3 receptor antagonist, ondansetron. Method: The authors randomized 283 alcoholics by genotype in the 5′-regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single-nucleotide polymorphism (T/G), rs1042173, in the 3′-untranslated region, in a double-blind controlled trial. Participants received either ondansetron (4 μg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive-behavioral therapy. Results: Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (-1.53) and the percentage of days abstinent higher (9.73%) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (-1.45) and a higher percentage of days abstinent than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5′-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (-2.63) and a higher percerntage of days abstinent (16.99%) than all other genotype and treatment groups combined. Conclusions: The authors propose a new pharmacogenetic approach using ondansetron to treat severe drinking and improve abstinence in alcoholics. [ABSTRACT FROM AUTHOR]

Substance P (SP), a neurotransmitter in stress pathways, exerts its effects mainly through the neurokinin-1 receptor (NK1R). Genetic and pharmacological studies show that binding of ligands to NK1R decreases anxiety-related behaviors, and therefore, self-administration of alcohol in mice and craving for alcohol in humans. As genetic variants may result in differential expression of the receptor through various molecular mechanisms, we examined whether allelic variations in the NK1R gene are associated with alcohol dependence (AD) by genotyping 11 single-nucleotide polymorphisms (SNPs) across NK1R in alcoholic (n=271) and healthy control (n=337) participants of Caucasian descent. The AD was diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Associations of the SNPs with AD were assessed at both the individual SNP and haplotype levels. We found that genotype and allele frequencies of rs6715729, a synonymous SNP in exon 1, differed significantly in alcoholics and in controls (p=0.0006; OR (odds ratio)=6.13; 95% CI=4.06, 9.23). Haplotype analyses indicated two risk haplotypes for AD in the 5′ end of the gene, formed by the three-SNP combinations rs6715729–rs735668–rs6741029. Taken together, we conclude that polymorphisms of NK1R are significantly associated with the development of AD in Caucasian individuals. Additional studies are needed to replicate these results in other samples and to elucidate the mechanism(s) by which these polymorphisms affect NK1R function in the brain. [ABSTRACT FROM AUTHOR]

Background: We hypothesize that functional control of the serotonergic system is regulated in part by differential expression of the serotonin (5-HT) transporter (5-HTT). Alcohol-dependent individuals with the LL/LS genotype (L-carriers), compared with those with the SS genotype, have a lower 5-HT neurotransmission, which we hypothesize would be associated with higher craving for alcohol among L-carriers. We hypothesize further that acute peripheral depletion of tryptophan (5-HT’s precursor), while further reducing 5-HT function, might decrease auto-inhibition of 5-HT neuronal firing, thereby increasing 5-HT neurotransmission transiently and lowering alcohol craving. Methods: We tested these hypotheses by examining whether in 34 Hispanic alcohol-dependent individuals subjective and physiological cue craving for alcohol differed by genotype, age of onset of problem drinking, and tryptophan availability. Results: On subjective “urge to drink” and “crave for a drink,” we found a significant ( p < 0.05) main effect of genotype and cue, as well as an interaction among genotype, age of onset of problem drinking, and tryptophan depletion. For the physiological measure of pulse, there was a main effect of genotype. L-carriers had higher craving than their SS counterparts, an effect that decreased under tryptophan depletion. While craving in L-carriers increased with an earlier age of onset of problem drinking, the opposite effect was seen in those with the SS genotype. Conclusion: These results not only provide support for the hypothesis that alcoholics who are L-carriers have greater alcohol craving and possibly greater propensity for drinking but also propose that there is an important 5-HTT gene-by-environment interaction that alters cue craving response for alcohol. [ABSTRACT FROM AUTHOR]

Background: The propensity for severe drinking is hypothesized to be regulated by differential expression of serotonin transporter gene (SLC6A4) in the human brain. The SLC6A4 promoter region 5-HTTLPR has been examined previously as a candidate polymorphic variant associated with severe drinking. In this study, we investigated whether other SLC6A4 single nucleotide polymorphisms (SNPs) are associated with drinking intensity among treatment-seeking alcoholics and whether these polymorphic variants result in differential SLC6A4 expression levels. Methods: We analyzed associations of drinking intensity in 275 (78.5% male) treatment-seeking alcoholics of Caucasian and Hispanic origin, with 6 SLC6A4 polymorphisms. Next, to examine the functionality of the SNP that showed a significant association with drinking intensity, we transfected the 2 alleles of rs1042173 into HeLa cell cultures and measured serotonin transporter mRNA and protein expression levels by using qRT-PCR and western blotting techniques. Results: One of the 6 polymorphisms we examined, rs1042173 in the 3′ untranslated region (3′-UTR) of SLC6A4, showed a significant association with drinking intensity. The G allele carriers for rs1042173 were associated with significantly lower drinking intensity ( p = 0.0034) compared to T-allele homozygotes. In HeLa cell cultures, the cells transfected with G allele showed a significantly higher mRNA and protein levels than the T allele-transfected cells. Conclusion: These findings suggest that the allelic variations of rs1042173 affect drinking intensity in alcoholics possibly by altering serotonin transporter expression levels. This provides additional support to the hypothesis that SLC6A4 polymorphisms play an important role in regulating propensity for severe drinking. [ABSTRACT FROM AUTHOR]

Background: Previously, we reported that ondansetron was efficacious at treating early-onset (≤25-years old) but not late-onset (≥26-years old) alcoholics in a double-blind, randomized, placebo-controlled clinical trial ( n = 321 enrolled patients, 271 of them randomized). Randomized participants underwent 11 weeks of treatment with ondansetron (1, 4, or 16 μg/kg twice daily; n = 67, 77, and 71, respectively) or identical placebo ( n = 56), plus weekly standardized group cognitive behavioral therapy. Methods: For this study, we reanalyzed the original sample to determine whether the Type A/B typological classification predicts ondansetron treatment response. In this comparative analysis, k-means clustering was applied to 19 baseline measures of drinking behavior, psychopathology, and social functioning, similar to those used by Babor in the original typological derivation. A 2-factor solution described robustly 2 groups phenomenologically consistent with Type A/B classification. Subjects were subdivided into early- and late-onset alcoholics. Results: Seventy-two percent of Type B subjects had early-onset alcoholism (EOA); 67% of Type A subjects had late-onset alcoholism (LOA). The A/B typology better discriminated 2 clusters based upon baseline severity of alcoholism. There was a significant effect ( p < 0.05) for Type B alcoholics to respond to ondansetron (4 μg/kg); however, Type A alcoholics receiving ondansetron showed no beneficial effect. Early-onset vs. late-onset classification predicted ondansetron response substantially better than Type A/B classification, which did not add to the prediction of treatment outcome. Further analyses showed that ondansetron was effective in the 33% of Type A alcoholics with EOA but ineffective in the 28% of Type B alcoholics with LOA. Conclusions: Type A/B classification best discriminates alcoholic subtypes based upon baseline severity. Early- vs. late-onset classification is, however, a better predictor of response to ondansetron treatment because it might be more closely related to fundamental neurobiological processes associated with the underlying pathophysiology of alcoholism. [ABSTRACT FROM AUTHOR]

This article presents the results of a clinical trial on the use of topiramate for treating alcoholism. Previous studies have shown that topiramate can decrease alcohol reinforcement by reducing corticomesolimbic dopamine release through at least two processes. This study sought to find out if the drug is a safe and effective drug for the treatment of alcohol dependence. The main outcome measures were reports of heavy drinking days and alcohol content of the blood. The study found that topiramate was more effective than placebo at reducing the number of heavy drinking days. Reported side effects of the medication included paresthesia, taste perversion, anorexia and difficulty with concentration. The authors find that topiramate is a promising treatment for alcoholism.

Background: Decreases in drinking behavior prior to treatment onset often occur in pharmacotherapy trials for alcohol dependence. We propose that these decreases are associated with both trait and state factors operating before initiation of treatment to influence participants’ expectation or perception of future treatment outcome. While trait factors typically include personality traits, state factors can include readiness to change and severity of drinking at screening. Understanding the characteristics of changes in drinking early in the process of entering treatment can improve clinical trials and outcomes. Our goal was to evaluate drinking behavior before initiating a randomized, double-blind pharmacotherapy clinical trial for alcohol dependence. Methods: We examined the impact of personality factors associated with gregariousness or conformity on the MacAndrew Alcoholism Scale, as well as state factors measured by the Stages-of-Change Scale (based on the University of Rhode Island Change Assessment Scale) and quantity of drinking at screening, on pre-double-blind clinical outcome (i.e., drinking reduction) among 321 male and female alcoholics enrolled in a pharmacotherapy trial. Results: A significant reduction in alcohol consumption occurred among heavy drinkers between the baseline assessment (10.3 ± 5.9 drinks per day) and the last week of single-blind placebo administration (5.3 ± 5.1 drinks per day; p < 0.001). In contrast, the reduction in alcohol consumption by nonheavy drinkers over the same period was not significant (from 3.07 ± 0.65 to 2.98 ± 2.6 drinks per day; p > 0.05). Partial correlations indicated that the significant predictors of drinking reductions during this period were: level of drinking (−0.215) and the Stages-of-Change subscales of precontemplation (−0.152), contemplation (0.144), and maintenance (−0.284). Personality factors on the MacAndrew Alcoholism Scale did not predict drinking reductions during this same period. Conclusions: Participants with higher motivation levels and greater drinking severity were most likely to reduce their drinking behavior before double-blind treatment. These state factors are important to consider when randomizing participants in trials, and are more important than trait or personality factors in accounting for the initial reduction in drinking in this population during the pretreatment period. [ABSTRACT FROM AUTHOR]

Aims Having demonstrated previously the efficacy of topiramate—a sulfamate-substituted fructopyranose derivative—as pharmacotherapy for treating alcohol dependence, promoting abstinence and reducing the harmful psychosocial consequences of drinking, we investigated whether topiramate also promoted ‘safe’ levels of drinking: ≤ 1 and ≤ 2 standard drinks/day for women and men, respectively, among alcohol-dependent individuals. Design, setting and participants In a double-blind, randomized, controlled, 12-week clinical trial conducted in San Antonio, Texas, 75 alcohol-dependent adults received topiramate and 75 received placebo as an adjunct to weekly standardized medication compliance management. Measurements For this secondary analysis of data from that trial, we calculated, based on self-reports, specific intervals of up to 30 days of continuous ‘safe’ drinking for each subject. Findings The average longest ‘safe’ drinking period was 16.7 days for topiramate recipients versus 8.9 days for placebo recipients. By day 50 of treatment, 44% versus 26.4% had achieved ≥ 7 and 30.8% versus 10% had achieved ≥ 14 continuous ‘safe’ drinking days. Similarly, topiramate increased the relative likelihood of continuous ‘safe’ drinking from 77% for ≥ 7 days [relative risk (RR) for achieving continuous ‘safe’ drinking = 1.77] to threefold for ≥ 14 days (RR = 3.37) and fourfold for ≥ 28 days (RR = 4.07). Thus, participants who received topiramate were more likely to achieve longer periods of ‘safe’ drinking compared with those who received placebo. Conclusions For alcohol-dependent individuals who drank within an abstinence-oriented treatment program, topiramate promoted ‘safe’ drinking. Topiramate’s potential to decrease the public health consequences of hazardous drinking needs to be established in future long-term studies. [ABSTRACT FROM AUTHOR]

This article represents the proceedings of a symposium presented at the 158th Annual Meeting of the American Psychiatric Association held in Atlanta, Georgia, on May 24, 2005. The organizer/chairman was Bankole A. Johnson, DSc, MD, PhD. The presentations included the following: (1) Neuropharmacological Basis of Alcohol Dependence, by George F. Koob, PhD; (2) Recent Developments in the Genetics of Alcohol Dependence, by Marc A. Schuckit, MD; (3) New Pharmacological Strategies for Treating Alcohol Dependence, by Barbara J. Mason, PhD; (4) New Medications: The Use of Anticonvulsants, Both Alone and in Combination, with Various Forms of Psychotherapy, by Bankole A. Johnson, DSc, MD, PhD; and (5) Differential Effects of Pharmacological Agents on Craving, by Nassima Ait-Daoud, MD. [ABSTRACT FROM AUTHOR]

Background Previously, our group has shown that topiramate, a sulfamate-substituted fructopyranose derivative, is an effective treatment for alcohol dependence. Herein, we extend that proof-of-concept study by determining whether cigarette-smoking, alcohol-dependent individuals from the earlier study also experienced improved smoking outcomes. Methods As a subgroup analysis of a larger double-blind, randomized, controlled, 12-week study comparing topiramate vs placebo as treatment for alcohol dependence, a 12-week clinical trial compared topiramate vs placebo in 94 cigarette-smoking, alcohol-dependent individuals. Of these, 45 were assigned to receive topiramate (escalating dose from 25 to 300 mg/d) and the remaining 49 had placebo as an adjunct to weekly standardized medication compliance management. The primary outcome was smoking cessation ascertained by self-report and confirmed by the level of serum cotinine (nicotine’s major metabolite). Results Topiramate recipients were significantly more likely than placebo recipients to abstain from smoking (odds ratio, 4.46; 95% confidence interval, 1.08-18.39; P = .04). Using a serum cotinine level of 28 ng/mL or lower to segregate nonsmokers from smokers, we found that the topiramate group had 4.97 times the odds of being nonsmokers (95% confidence interval, 1.1-23.4;P = .04). Smoking cessation rates for topiramate recipients were 19.4% and 16.7% at weeks 9 and 12, respectively, compared with 6.9% at both time points for placebo recipients. Conclusion In this trial, topiramate (up to 300 mg/d) showed potential as a safe and promising medication for the treatment of cigarette smoking in alcohol-dependent individuals. [ABSTRACT FROM AUTHOR]

Cocaine-induced hypoperfusion, a risk factor for ischemic stroke, has not been fully characterized during experimental drug-taking among individuals with cocaine use disorder. We sought to examine cocaine's dose-dependent, time-related effects on cerebral blood flow. In a double-blind, randomized human laboratory study with a counterbalanced order of drug administration, 31 male and female subjects with cocaine use disorder were divided into two groups receiving either (a) low-dose cocaine (0.325 mg/kg intravenously) or placebo (N=15) or (b) high-dose cocaine (0.650 mg/kg intravenously) or placebo (N=16). The different dose conditions were administered on test days separated by a rest period of ≥48 h. Cerebral blood flow was assessed quantitatively using H2O15 positron emission tomography. Experimentally administered low- and high-dose cocaine conditions versus their corresponding placebo conditions were associated with global and regional hypoperfusion. The trend for high- versus low-dose cocaine to be associated with greater hypoperfusion achieved statistical significance only for the dopamine-rich sublobar and midbrain regions. Cocaine's hypoperfusion effects were maximal at 8 mins after infusion (i.e., at about the expected peak of intravenous cocaine levels) and had mostly dissipated by 32 mins after infusion. Although hypoperfusion occurred throughout the brain, the left hemispheric dopamine-rich sublobar region was the most severely affected. Cocaine-induced cerebral hypoperfusion is associated with the time course of its pharmacological effects, and dopamine-rich areas, particularly in the left hemisphere, may be most vulnerable. Increasingly larger doses of cocaine may be associated with greater risk for ischemic stroke.Journal of Cerebral Blood Flow & Metabolism (2005) 25, 928–936. doi:10.1038/sj.jcbfm.9600093 Published online 9 March 2005 [ABSTRACT FROM AUTHOR]

Background: Massive hypertensive crises relating to cerebrovascular accidents such as strokes or ruptured aneurysms, or cardiovascular dysfunction and toxicity, are an important cause of morbidity and mortality associated with cocaine or methamphetamine use. Experimentally administered, pharmacologically effective doses of cocaine and methamphetamine may serve as a model for studying the effects of these drugs on hemodynamic response and for examining the potential utility of the antihypertensive and dihydropyridine-class calcium channel antagonist isradipine to block these effects. We therefore examined, in two separate experiments of similar design conducted contemporaneously, the hemodynamic effects of cocaine or methamphetamine in the presence and absence of isradipine. Methods: In both experiments (total N = 31), isradipine pretreatment was provided to cocaine- or methamphetamine-dependent male and female subjects before intravenous administration of low and high doses of cocaine (0.325 or 0.650 mg/kg) or methamphetamine (15 or 30 mg), respectively, on separate test days. Results: Both cocaine and methamphetamine administration produced predicted elevations in blood pressure (with peak response between 1 and 3 min after infusion). Apart from tachycardia, no arrhythmias were reported. Isradipine significantly reduced stimulant-associated increases in all measures of blood pressure except pulse pressure, but tended to enhance the effects of these drugs on heart rate. Conclusions: Clinical studies are needed to determine whether isradipine is therapeutically efficacious in preventing hypertensive crises and the associated cerebrovascular and cardiovascular sequelae in cocaine- or methamphetamine-dependent individuals. As there is no established pharmacotherapy for treating cocaine or methamphetamine dependence, identification of a medication that reduces the harmful medical consequences of these drugs would be scientifically and clinically important. [Copyright &y& Elsevier]

Presents a study on the effects of isradipine on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition. Objectives of the study; Study methods; Results.

Study Objective. To compare the relative bioavailability of an extemporaneous ondanselron capsule formulation with that of an identical dose of the commercially available solution formulation. Design. Open-label, randomized, two-way crossover study. Setting. University-affiliated research laboratory. Subjects. Sixteen (eight men, eight women) healthy, nonsmoking volunteers. Intervention. Participants were randomly assigned to receive a 4-mg dose of either the commercially available ondanselron solution or the extemporaneous ondansetron capsule formulation. Blood sampling was performed over 12 hours after dosing Alter a washout period of at least days, each participant was switched to the alternate formulation, and blood sampling was repealed. Measurements and Main Results. Ondansetron was well absorbed after administration of both formulations, with the solution achieving a faster rate of drug absorption over the first hour of dosing. After the peak plasma concentration was achieved, the plasma concentration-time curves of both formulations declined at a similar steady rate. There were no significant differences in pharmacokinetic parameters between the two formulations. and the relative bioavailability of the capsule versus the solution formulation was 101%. Conclusions. Similar concentration-time curves and pharmacokinetic parameters were achieved with the two formulations. The commercially available solution would be a useful alternative formulation for administration of low-dose ondansetron in research and clinical settings. [ABSTRACT FROM AUTHOR]

Rationale: Early onset alcoholics (EOA) differ from late onset alcoholics (LOA) by having greater serotonergic abnormality, familial history, and a range of antisocial behaviors. Previously, we showed that ondansetron, a selective 5-HT[sub 3] antagonist, effectively treated EOA. Proximate motivational drives such as craving could have determined drinking behavior. We therefore investigated whether ondansetron treatment would reduce alcohol craving significantly among EOA. Objectives: We tested the hypothesis that the craving outcomes of EOA, compared with LOA, would be differentially improved by ondansetron. We also tested the prediction that craving would be significantly correlated with drinking behavior. Methods: We studied a cohort of 253 out of 321 enrolled alcohol dependent subjects. These 253 subjects were entered into a 1-week lead-in single-blind placebo period followed by 11 weeks of double-blind outpatient treatment. Study design was a 2 (EOA versus LOA)×4 medication dose (placebo, or ondansetron 1, 4, or 16 µg/kg b.i.d)×13 (visits) factorial analysis of variance. Craving was measured at each visit using seven visual analogue scales. Subjects received 12 weekly sessions of standardized group cognitive behavioral therapy. Results: Data reduction by factor analysis of the visual analog scale items yielded one dimension, overall craving. Ondansetron 4 µg/kg b.i.d. reduced overall craving significantly among EOA. In contrast, ondansetron (1 µg/kg b.i.d.) increased craving significantly in LOA. Decreased overall craving was positively correlated with reduced drinking and negatively associated with increased abstinence. Conclusions: Compared with placebo, ondansetron (4 µg/kg b.i.d.) was associated with significant reductions in overall craving in EOA but not LOA, presumably by ameliorating serotonergic abnormality. [ABSTRACT FROM AUTHOR]

Examines the use of dihydropyridine-class calcium channel antagonists in preventing cocaine induced cerebral ischemia. Physiological effects of cocaine abuse; Regulation of cerebral blood flow by dopamine innervated neurons; Causes of cerebral ischemia.

Abstract Rationale: Previously, we have reported that the combination of ondansetron (a 5-HT[sub 3] antagonist) and naltrexone (a mu opioid antagonist) appears to act synergistically at improving the drinking outcomes of early onset alcoholics (EOA), a subtype of alcoholic characterized by developing problem-drinking earlier, antisocial behaviors, high familial loading, and biological disease predisposition. Presumably, this medication combination counteracts the interaction between activated central 5-HT[sub 3] receptors and the endogenous opioid system during the mediation of alcohol-induced reward. We now hypothesize further that an important mechanism by which the combination diminishes alcohol consumption is through a reduction in craving. Objective: To determine whether the combination of naltrexone and ondansetron is superior to a placebo at reducing craving among EOA, and the relationship between craving and drinking behavior in both treatment groups. Methods: We conducted an 8-week double-blind placebo-controlled clinical trial in which 10 EOA were randomized to receive ondansetron (4 pg/kg b.i.d.) + naltrexone (25 mg b.i.d.) and 10 EOA had a placebo (total n=20) as an adjunct to weekly standardized group cognitive behavioral therapy. Craving was measured by using the obsessive compulsive drinking scale (OCDS). Results: Craving ratings were scored on four subscales which where derived empirically by principal component structure... [ABSTRACT FROM AUTHOR]

Presents a study to test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by 5-HT3 (serotonin) antagonist ondansetron. Design; Settings; Main Outcome Measures; Results; Conclusion that ondansetron is an effective treatment for patients with early-onset alcoholism.

Background: Individuals considered to be early onset alcoholics (EOA) are characterized by an early onset age, a broad range of antisocial behaviors, high familial loading, and presumed biological disease predisposition. Ondansetron, a 5-HT3 antagonist, improves drinking outcomes and increases abstinence rates among EOA. Individuals with high familial loading for developing alcoholism have lower levels of β-endorphin and demonstrate a more pronounced increase in β-endorphin levels in response to alcohol administration compared with individuals who do not have alcoholic relatives. The propensity for naltrexone (a mu opioid antagonist) to reduce alcohol's rewarding effects and drinking in humans is greatest in individuals with high familial loading. Predicated on the added knowledge that 5-HT3 receptors may themselves mediate alcohol reward via activation of the endogenous opioid system, we hypothesized that the combination of ondansetron and naltrexone would act synergistically and would be an effective treatment in EOA. Methods: We conducted an 8-week double-blind placebo controlled clinical trial in which 20 EOA were randomized to receive ondansetron (4 μg/kg twice a day) + naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized group Cognitive Behavioral Therapy. Results: At endpoint, subjects who received ondansetron + naltrexone ( n= 10), compared with those who received placebo ( n= 10), had fewer drinks/day (covariate adjusted mean 0.99 ± 0.60 vs. 3.68 ± 0.63; F 1, 16 = 9.35, p= 0.008; effect size = 1.42), drinks/drinking day (covariate adjusted mean 3.14 ± 0.87 vs. 6.76 ± 0.71; F 1, 13 = 10.45, p= 0.007; effect size = 1.71), and a trend toward increased percent days abstinent (covariate adjusted mean 69.76 ± 8.64 vs. 48.24 ± 9.12; F 1, 16 = 3.58, p= 0.08; effect size = 0.88). Conclusions: Ondansetron plus naltrexone seems to synergistically improve the drinking outcomes of EOA. Larger scale studies that test these medications, both alone and together, among various alcoholic subtypes are needed to establish and extend these promising findings. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Dopamine (DA) pathways in the midbrain mediate d-methamphetamine's rewarding effects associated with its abuse liability. Isradipine, a dihydropyridine-class calcium channel antagonist, reduces the rewarding effects of psychostimulants such as cocaine and d-amphetamine, presumably by antagonizing these central DA pathways. This is the first experiment to test the hypothesis that the rewarding effects of dmethamphetamine, like other psychostimulants, can be reduced by isradipine. Objective: We studied the effects of high dose isradipine (0.21 mg/kg orally), on the positive subjective effects associated with the abuse liability of low and high dose d-methamphetamine (0.21 mg/kg and 0.42 mg/kg orally, respectively). Methods: Using a double-blind, double-dummy, placebo-controlled, Latin-Square, cross-over design, 18 healthy male and female volunteers received each of the following six treatments separated by a rest period of 2-7 days: a) placebo+placebo; b) low-dose d-methamphetamine+placebo); c) highdose d-methamphetamine+placebo; d) high dose isradipine+placebo); e) low-dose d-methamphetamine+high dose isradipine, and f) high-dose d-methamphetamine+high dose isradipine. Results: d-Methamphetamine produced orderly increases in positive subjective measures of both stimulation and mood. Pre-treatment with isradipine significantly reduced some of these positive subjective effects and craving for d-methamphetamine. Conclusion: Isradipine as an anti-reward or craving reducing medication is a promising therapeutic agent for the treatment of d-methamphetamine dependence. [ABSTRACT FROM AUTHOR]

Background: Recently, we showed by using self-report that combining ondansetron (4 μg/kg twice a day) and naltrexone (25 mg twice a day) was effective at reducing drinking and increasing abstinence among early-onset alcoholics (EOAs), who are characterized by a range of antisocial behaviors and high biological and familial disease predisposition. Here, we investigated whether the self-reported differences in drinking would be corroborated by measurements of serum carbohydrate-deficient transferrin (CDT) level, a sensitive, reliable, and well-validated marker of transient alcohol consumption. Method: An 8-week double-blind clinical trial was performed in which 20 EOAs were randomized to receive ondansetron (4 μg/kg twice a day) and naltrexone (25 mg twice a day) or placebo as an adjunct to weekly standardized cognitive behavioral therapy. Serum CDT was assessed at weeks 0 (baseline), 4, and 8. Results: Log serum CDT was significantly lower in the ondansetron and naltrexone group (group mean, 1.44 ± 0.076) compared with the placebo group (group mean, 1.82 ± 0.113), as evidenced by a main effect of group [ F (1,15) = 7.2, p= 0.017; effect size = 0.32], visit [ F (1,16) = 11.2, p= 0.004; effect size = 0.41], and an interaction between group and visit [ F (1,16) = 27.54, p < 0.001; effect size = 0.63]. Conclusions: The combination of ondansetron plus naltrexone was superior to placebo at reducing serum CDT. This corroborated our self-reported drinking data and demonstrated that the medication combination is an effective treatment for EOAs. [ABSTRACT FROM AUTHOR]

A reply by Bankole A. Johnson, Nassima Ait-Daoud, Raymond F. Anton, Domenic A. Ciraulo, Henry R. Kranzler, Karl Mann, Stephanie S. O'Malley and Robert M. Swift to letters to the editor about their article "Topiramate for treating alcohol dependence: a randomized controlled trial," in a previous issue is presented.