Modafinil Does Not Reduce Cocaine Use in Methadone-Maintained Individuals.

Introduction: There are no approved medications for the treatment of cocaine use disorder (CUD). Modafinil, a cognitive-enhancer with weak stimulant-like effects, has shown promise in initial studies as a treatment for CUD. Its potential efficacy has not been examined in individuals dually dependent on cocaine and opioids. Methods: This study examined the efficacy of modafinil, in combination with contingency management (CM), for reducing cocaine and opioid use and improving cognitive function in methadone-stabilized individuals with opioid and cocaine dependence. We conducted a 17-week, double-blind, randomized controlled trial in which participants were randomized to one of four conditions: 1) modafinil + CM; 2) modafinil + yoked-control (YC); 3) placebo +CM; or 4) placebo + YC. Additionally, all subjects received platform treatments of cognitive behavioral therapy (CBT) and methadone. While the original planned sample size was N=160, a total of 91 participants were randomized. The two primary cocaine use outcomes were percentage of urine specimens positive for cocaine and percent of days of self-reported abstinence from cocaine during treatment. Cognitive function, opioid use, and secondary cocaine use outcomes were also considered. Results: Modafinil was well-tolerated with minimal reports of adverse effects. Modafinil was no more effective than placebo in reducing cocaine or opioid use or improving cognitive performance. Conclusions: In the context of a trial with robust control conditions and platform treatments, findings did not provide support for the efficacy of modafinil treatment for the treatment of CUD in methadone-stabilized individuals with dual opioid and cocaine dependence.

Does altitude increase the risk of traumatic aortic injuries? A retrospective cohort study among six level I trauma centers in the United States.

BACKGROUND: Traumatic aortic injuries (TAIs) are rare but are associated with a high mortality. Prior studies have shown skiers and pilots, whose injuries occur at high altitudes, are at an increased risk for a TAI. The purpose of this study was to examine the effect of altitude on the incidence of TAIs across all causes of injury. METHODS: This retrospective cohort study at six Level I trauma centers (8/1/2016-1/1/2020) included adult blunt trauma patients with a chest or abdomen injury. High altitude injuries (> 5000 ft.) were compared to low altitude injuries (≤ 5000 ft.). The primary outcome was incidence of TAI. RESULTS: There were 8562 patients, 37% were at high altitude and 63% at low altitude. High altitude patients were older (p < 0.01), more often Caucasian (p < 0.01) and had a higher ISS (p < 0.01). There was a significantly greater incidence of TAI at high altitude than low altitude (1.5% vs. 1.1%, p = 0.01). The median altitude was significantly higher for patients with a TAI than for patients without a TAI (5100 ft. vs. 1400 ft., p = 0.01). After adjustment, high altitude patients had 2-fold [OR: 2.4 (1.6, 3.7)] greater odds of having a TAI than low altitude patients. CONCLUSION: TAIs were more prevalent among high altitude injuries. Providers should be aware of the increased incidence of TAIs at high altitudes particularly when there is a delay in diagnosis and transfer to a trauma center with appropriate resources to manage these critical injuries. TAI screening at high altitude trauma centers may improve survival rates.

Behavioral effects of gamma-hydroxybutyrate in humans.

Despite the therapeutic use and abuse potential of gamma-hydroxybutyrate (GHB or Xyrem), relatively few studies have examined the behavioral effects of GHB in humans under controlled laboratory conditions. Thus, this eight-session study examined in 10 non-substance-abusing volunteers the behavioral effects of GHB at each of the following doses: 0, 0.32, 0.56, 0.75, 1.0, 1.8, 2.4, 3.2 g/70 kg, orally. Order of dose testing was random, except that the first two participants received active doses in ascending order and 2.4 g/70 kg was always tested before 3.2 g/70 kg. Before drug administration and at several postdrug time points, self-report, observer report, physiological, and psychomotor performance measures were obtained. Analyses based on area under the curve showed that GHB produced dose-related increases in subjective ratings of sedative-like, stimulant-like, positive mood, and dissociative effects, but no changes in psychomotor performance measures or blood pressure. Analyses based on peak effects generally showed dose-related increases in ratings indicating sedative-like, dissociative, and drug liking, although some measures showed U-shaped dose-related changes. These initial findings suggest that GHB at doses of 0.32-3.2 g/70 kg produces dissociative, sedating and some stimulant-like effects in humans without a history of sedative abuse.

The safety and efficacy of varenicline in cocaine using smokers maintained on methadone: a pilot study.

In this double-blind, placebo-controlled trial, we compared varenicline (2 mg) to placebo for treatment for cocaine and tobacco dependence in 31 methadone-maintained subjects. Subjects received weekly counseling during the 12-week study participation. Our results indicate that varenicline is safe to give to this subject population, as there were no adverse events related to medication during this study. Varenicline was no more effective than placebo for abstinence from cocaine. Treatment with varenicline was associated with a reduced number of cigarettes smoked per day, even though subjects received only a brief education for smoking cessation. The self-report reduction in smoking was corroborated by CO levels and the Fagerström Test of Nicotine Dependence. However, self-ratings of positive mood on the Positive Affect Negative Affect Schedule did significantly decrease in the varenicline group as compared to the placebo group, although this appears to be due to randomization differences related to lifetime depression diagnosis. These preliminary findings may point to potential therapeutic value of varenicline for smoking cessation in cocaine users maintained on methadone.

Effect of PTSD diagnosis and contingency management procedures on cocaine use in dually cocaine- and opioid-dependent individuals maintained on LAAM: a retrospective analysis.

This randomized clinical trial retrospectively examined the effect of post-traumatic stress disorder (PTSD) and contingency management (CM) on cocaine use in opioid and cocaine dependent individuals maintained on high or low-dose LAAM randomly assigned to CM or a yoked-control condition. Cocaine-positive urines decreased more rapidly over time in those without PTSD versus those with PTSD in the noncontingency condition. In participants with PTSD, CM resulted in fewer cocaine-positive urines compared to the noncontingent condition. This suggests that CM may help improve the potentially worse outcomes in opioid- and cocaine-dependent individuals with PTSD compared to those without PTSD. (Am J Addict 2010;00:1-9).

ADH1A variation predisposes to personality traits and substance dependence.

Human personality traits are strong predictors or characteristics of many psychiatric disorders including substance dependence (SD). Recently, significant associations between alcohol dehydrogenase type 1A gene (ADH1A) and SD have been reported, which led us to investigate the impact of ADH1A variation on personality traits and risk of SD. Five hundred fifty-eight subjects with SD [398 European-Americans (EAs) and 160 African-Americans (AAs)], 517 college students (384 EAs and 133 European-origin Hispanics), and 448 healthy subjects (385 EAs, 48 AAs, and 15 European-origin Hispanics) participated. Personality traits were assessed in 247 subjects with SD (179 EAs and 68 AAs), all 517 college students, and 332 healthy subjects (285 EAs, 40 AAs, and 7 European-origin Hispanics). The relationships between ADH1A and personality traits were comprehensively examined using stepwise multivariate analysis of covariance (MANCOVA), and then decomposed by stepwise analysis of covariance (ANCOVA). The relationship between ADH1A and SD was examined using stepwise logistic regression analysis. Admixture effects on analyses were considered. Overall, Agreeableness and Conscientiousness were associated with the diplotypes, haplotypes, genotypes, and/or alleles of ADH1A in three of four phenotype groups including EA SD subjects, healthy subjects, and AA SD subjects (1.7 x 10(-4)

The effect of cannabis compared with alcohol on driving.

The prevalence of both alcohol and cannabis use and the high morbidity associated with motor vehicle crashes has lead to a plethora of research on the link between the two. Drunk drivers are involved in 25% of motor vehicle fatalities, and many accidents involve drivers who test positive for cannabis. Cannabis and alcohol acutely impair several driving-related skills in a dose-related fashion, but the effects of cannabis vary more between individuals than they do with alcohol because of tolerance, differences in smoking technique, and different absorptions of Delta(9)-tetrahydrocannabinol (THC), the active ingredient in marijuana. Detrimental effects of cannabis use vary in a dose-related fashion, and are more pronounced with highly automatic driving functions than with more complex tasks that require conscious control, whereas alcohol produces an opposite pattern of impairment. Because of both this and an increased awareness that they are impaired, marijuana smokers tend to compensate effectively while driving by utilizing a variety of behavioral strategies. Combining marijuana with alcohol eliminates the ability to use such strategies effectively, however, and results in impairment even at doses which would be insignificant were they of either drug alone. Epidemiological studies have been inconclusive regarding whether cannabis use causes an increased risk of accidents; in contrast, unanimity exists that alcohol use increases crash risk. Furthermore, the risk from driving under the influence of both alcohol and cannabis is greater than the risk of driving under the influence of either alone. Future research should focus on resolving contradictions posed by previous studies, and patients who smoke cannabis should be counseled to wait several hours before driving, and avoid combining the two drugs.

Atomoxetine attenuates dextroamphetamine effects in humans.

BACKGROUND: Although preclinical studies support the contribution of the noradrenergic system activation in mediating the acute effects of amphetamines, these findings have not been followed up in clinical studies. OBJECTIVES: To examine the effects of atomoxetine, a norepinephrine transporter inhibitor, on subjective, physiological, and plasma cortisol responses to dextroamphetamine in 10 healthy volunteers. METHODS: Subjects were randomly assigned to a sequence of atomoxetine (40 mg/day) or placebo treatments each lasting for 4 days. On Day 4 of each treatment period, responses to a single 20 mg/70 kg dose of dextroamphetamine were assessed. RESULTS: Atomoxetine treatment attenuated dextroamphetamine-induced increases in systolic and diastolic blood pressure and plasma cortisol as well as the self-report ratings of "stimulated," "high," and "good drug effects." CONCLUSIONS: These findings are consistent with previous preclinical studies supporting the role of the noradrenergic system in mediating acute amphetamine responses. SCIENTIFIC SIGNIFICANCE: Atomoxetine's capacity to attenuate some of the physiological and subjective responses to dextroamphetamine supports its potential use for stimulant addiction.

Feasibility and effects of galantamine on cognition in humans with cannabis use disorder.

BACKGROUND: As long-term use of medicinal and recreational cannabis becomes more common and concentrations of delta-9-tetrahydrocannabinol (THC) in cannabis increase, it is timely to identify strategies to counteract the cognitive effects of cannabinoids. OBJECTIVE: Galantamine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease and other dementias. This study aimed to investigate the feasibility of galantamine administration to individuals with cannabis use disorder (CUD), and the effects of galantamine on cognition. We hypothesized galantamine would be well tolerated and would not have procognitive effects in the absence of acute cannabis intoxication. METHODS: Thirty individuals with CUD (73.5% male, 26.5% female) participated in a randomized, double-blind, parallel-group trial. Participants completed a baseline session followed by a 10-day outpatient treatment period, during which they received either 8 mg/day of galantamine orally or placebo. Cognitive assessments were conducted at three time points and self-reported measures that may impact cognitive performance (cannabis withdrawal, craving, and mood) were completed at six time points. RESULTS: There were no significant differences in demographic and baseline variables between groups (galantamine vs. placebo). There were no significant adverse effects from galantamine. Cannabis withdrawal and craving continuously decreased over the study. We saw evidence of a modest improvement in cognitive outcomes during the 10-day period, exemplified by a statistically significant increase in measures of response inhibition (increased median reaction time on the Stop Signal Task), and a trend for improvement in measures of attention (increased RVP A'), for both groups. Analyses did not show, however, a significant main effect for treatment or treatment-by-time interactions. CONCLUSIONS: The findings of this pilot study support the feasibility of the administration of galantamine for individuals with CUD. Adequately powered, randomized, placebo-controlled trials are required to investigate the potential of galantamine to improve cognitive deficits associated with CUD.

Substance dependence low-density whole genome association study in two distinct American populations.

Cocaine and opioid dependence are common, complex disorders with high heritability that commonly co-occur with other substance dependence disorders. Improved insight into the genetic basis of substance dependence would help elucidate its etiology and could inform its prevention and treatment. To generate new hypotheses about the genetics of substance dependence, we genotyped 5633 tagging single nucleotide polymorphism (SNP) markers in 1699 subjects from 339 African American (AA) families and 334 European American (EA) families ascertained through a sib pair meeting DSM-IV criteria for either cocaine or opioid dependence. The associations between genetic markers and five substance dependence traits (cocaine dependence, opioid dependence, cocaine-induced paranoia, alcohol dependence, and nicotine dependence) were assessed by family based association tests (FBAT). Results were ranked according to several criteria including statistical significance, concordance of results across population samples, and potential biological relevance of the implicated gene. The top-ranked result was an association of SNP rs1133503 in the MANEA gene with cocaine-induced paranoia (CIP). Our study provides an initial substance dependence trait-specific blueprint of associated regions for future candidate gene studies.

Disulfiram enhances subjective effects of dextroamphetamine in humans.

Disulfiram has shown promise in several clinical trials for cocaine addiction, but its potential utility in the treatment of amphetamine addiction has not been examined. The goal of this study was to determine the effects of disulfiram on acute physiological and subjective responses to dextroamphetamine in healthy volunteers. Five male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects were randomly assigned to a sequence of disulfiram (250 mg/day) or placebo treatments each lasting for 4 days. Day four of each treatment period was the experimental session, in which subjects orally ingested a single dose of dextroamphetamine (20 mg/70 kg). Outcome measures included heart rate, blood pressure, plasma cortisol and prolactin, subjective and performance on the Sustained Attention to Response Test (SART). Disulfiram did not affect dextroamphetamine-induced increases in heart rate, blood pressure, cortisol, or prolactin. Disulfiram did enhance some of the subjective effects of dextroamphetamine including ratings of "high," "anxious," "bad drug effects," "want more drug" and "drug liking" and was also associated with decreased performance in the SART test. How these enhanced subjective amphetamine responses affect cocaine use behavior remains to be determined in future clinical trials.

Preliminary study of buprenorphine and bupropion for opioid-dependent smokers.

In this double-blind, placebo-controlled trial, bupropion (BUPRO, 300 mg/day) was compared to placebo (PBO) for the concurrent treatment of opioid and tobacco addiction in 40 opioid-dependent smokers stabilized on buprenorphine (BUPRE, 24 mg/day). Participants received contingent, monetary reinforcement for abstinence from smoking, illicit opioids, and cocaine. Significant differences in treatment retention were observed (BUPRE+BUPRO, 58%; BUPRE+PBO, 90%). BUPRO treatment was not more effective than placebo for abstinence from tobacco, opioids, or cocaine in BUPRE-stabilized patients. These preliminary findings do not support the efficacy of BUPRO, in combination with BUPRE, for the concurrent treatment of opioid and tobacco addiction.

Genomewide linkage scan for nicotine dependence: identification of a chromosome 5 risk locus.

BACKGROUND: Nicotine dependence (ND) is costly to societies worldwide, moderately heritable, and genetically complex. Risk loci can be identified with genetic linkage analysis independent of prior physiological hypotheses. METHODS: We completed a genomewide linkage scan to map loci increasing risk for DSM-IV ND and for a quantitative assessment of ND as measured by the Fagerstrom Test for Nicotine Dependence (FTND) in a set of 634 small nuclear families ascertained on the basis of multiple individuals affected with cocaine or opioid dependence. Of these, 507 had at least two subjects affected with ND. There are two distinct populations within this sample, European-Americans (EAs) and African-Americans (AAs). RESULTS: A region on chromosome 5 was identified as containing a gene that affects risk for ND on the basis of FTND score in the AA part of our sample (logarithm of the odds [lod] score 3.04; empirically determined to be genomewide-significant, p = .0374; point p = .0001). The highest lod score observed in the EA part of the sample was on chromosome 7 (lod score 2.73). Several other "possible" risk loci were identified in either AA or EA subjects, with many of these in proximity to previously suggested risk loci from other clinical samples. Three nominally significant single-nucleotide polymorphism associations were found at the peptidylglycine alpha-amidating monooxygenase (PAM) locus under the chromosome 5 linkage peak, also in the AA part of the sample. CONCLUSIONS: These data add to the growing evidence for locations for ND risk loci, add a novel statistically significant locus important in AAs, and suggest a gene that might be contributing to this linkage signal.

Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population.

CONTEXT: No effective pharmacotherapies exist for cocaine dependence, although contingency management (CM) has demonstrated efficacy. OBJECTIVE: To compare the efficacy of bupropion hydrochloride and CM for reducing cocaine use in methadone hydrochloride-maintained individuals. DESIGN: This 25-week, placebo-controlled, double-blind trial randomly assigned participants to 1 of 4 treatment conditions: CM and placebo (CMP), CM and 300 mg/d of bupropion hydrochloride (CMB), voucher control and placebo (VCP), or voucher control and bupropion (VCB). SETTING: Outpatient clinic at the Veterans Affairs Connecticut Healthcare System. PARTICIPANTS: A total of 106 opiate-dependent, cocaine-abusing individuals. INTERVENTIONS: All study participants received methadone hydrochloride (range, 60-120 mg). Participants receiving bupropion hydrochloride were given 300 mg/d beginning at week 3. In the CM conditions, each urine sample negative for both opioids and cocaine resulted in a monetary-based voucher that increased for consecutively drug-free urine samples during weeks 1 to 13. Completion of abstinence-related activities also resulted in a voucher. During weeks 14 to 25, only completion of activities was reinforced in the CM group, regardless of sample results. The voucher control groups received vouchers for submitting urine samples, regardless of results, throughout the study. MAIN OUTCOME MEASURE: Thrice-weekly urine toxicologic test results for cocaine and heroin. RESULTS: Groups did not differ in baseline characteristics or retention rates. Opiate use decreased significantly, with all treatment groups attaining equivalent amounts of opiate use at the end of the study. In the CMB group, the proportion of cocaine-positive samples significantly decreased during weeks 3 to 13 (P<.001) relative to week 3 and remained low during weeks 14 to 25. In the CMP group, cocaine use significantly increased during weeks 3 to 13 (P<.001) relative to week 3, but then cocaine use significantly decreased relative to the initial slope during weeks 14 to 25 (P<.001). In contrast, by treatment end, the VCB and VCP groups showed no significant improvement in cocaine use. CONCLUSION: These findings suggest that combining CM with bupropion for the treatment of cocaine addiction may significantly improve outcomes relative to bupropion alone.

Progesterone effects on cocaine use in male cocaine users maintained on methadone: a randomized, double-blind, pilot study.

Previously, the authors reported that progesterone treatment attenuated reports of cocaine-induced high in male and female cocaine users. In this pilot clinical trial, the authors tested the safety and efficacy of oral progesterone as a treatment for cocaine dependence in methadone-stabilized male cocaine users. This was a 10-week, randomized, double-blind, placebo-controlled trial. Forty-five male methadone-stabilized cocaine users were randomized to receive placebo (n=15) or progesterone (n=30) for 9 weeks. The progesterone dose was gradually increased from 100 mg to 300 mg twice daily by Week 4 and maintained through Week 10. Treatment retention for the clinical trial was 80%, without significant group differences (log rank=2.4, p=.12). Hierarchical linear modeling estimates of obtaining a cocaine positive urine result across 10 weeks showed a very slight reduction in cocaine use for the progesterone group (Z=-2.89, p<.004). The placebo group showed a slight increase in cocaine use from Week 1 to Week 10 (Z=2.72, p<.007). These slopes significantly differed from each other (Z=-3.83, p<.0001). Overall, the placebo group showed significantly lower probability of having a cocaine positive urine result at treatment's end (Weeks 9 and 10) compared with the progesterone group (0.60 vs. 0.73; U=4837, p<.04). These preliminary findings do not support the efficacy of progesterone in male cocaine users. The efficacy of progesterone in female cocaine users remains to be determined in future studies.

Carvedilol does not reduce cocaine use in methadone-maintained cocaine users.

INTRODUCTION: The goal of this study was too test the efficacy of carvedilol (CAR), an adrenergic blocker, for reducing cocaine use in individuals with cocaine use disorder (CUD). We conducted a 17-week, double-blind, randomized controlled trial with 3 treatment arms: 25mg CAR, 50mg CAR, and placebo. METHODS: One hundred and six treatment-seeking opioid and cocaine-dependent participants, who were also maintained on methadone during study participation, were randomized to placebo (n=34), 25mg/day CAR (n=37) or 50mg/day CAR (n=35). The main outcome measures were cocaine and opioid use as assessed by urine drug screening and self-reported drug use. RESULTS: No significant group differences were found for treatment retention with 56% of the placebo, 76% of the 25mg and 66% of the 50mg CAR groups (p>0.05) completing treatment. The percentage (SD) of cocaine positive urines during the trial showed an overall treatment effect: 59.2 (38.9) for the placebo, 50.8 (33.8) for the 25mg and 75.1 (33.2) for the 50mg CAR group. In post hoc comparisons, neither the 25 nor 50mg CAR condition differed significantly from the placebo; however, the 25mg CAR group had a significantly lower proportion of cocaine-positive urines than the 50mg group. No significant group differences were found for the percentage of self-reported days of cocaine abstinence during the trial: 72.9 (25.3) for placebo, 72.9 (29) for CAR 25mg, and 59.3 (31.7) for CAR 50mg. Significant groups differences in the proportion of opioid positive urines submitted were not observed (p>0.05). Baseline cocaine withdrawal severity did not predict treatment response (p>0.05). CONCLUSIONS: These findings did not support the efficacy of CAR for the treatment of cocaine use in cocaine and opioid dependent participants maintained on methadone. Further, CAR doses >25mg should not be used to avoid possible increases in cocaine and opioid use.

Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder.

BACKGROUND: Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, the effect of these medications on alcohol use outcomes and on psychiatric symptoms is still unknown in patients with co-occurring disorders post-traumatic stress disorder (PTSD). METHODS: Patients (n = 254) with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in a medication study at three Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram; and (2) double-blind randomization to naltrexone or placebo. This resulted in four groups: (1) naltrexone alone; (2) placebo alone; (3) disulfiram and naltrexone; or (4) disulfiram and placebo. Outcomes were measures of alcohol use, PTSD symptoms, alcohol craving, GGT levels and adverse events. RESULTS: 93 individuals (36.6%) met DSM-IV criteria for PTSD. Subjects with PTSD had better alcohol outcomes with active medication (naltrexone, disulfiram or the combination) than they did on placebo; overall psychiatric symptoms of PTSD improved. Individuals with PTSD were more likely to report some side effects when treated with the combination. CONCLUSIONS: The results of this study suggest that disulfiram and naltrexone are effective and safe for individuals with PTSD and comorbid alcohol dependence.

Effects of topiramate in combination with intravenous nicotine in overnight abstinent smokers.

RATIONALE: Topiramate, an anticonvulsant medication, may be effective as a treatment for alcohol and cocaine addiction. While a recent clinical study has demonstrated the potential utility of topiramate for smoking cessation in alcohol-dependent smokers, the effects of topiramate on tobacco addiction have not been systematically examined in humans. OBJECTIVES: To determine topiramate's effects on acute physiological and subjective responses to intravenous (IV) nicotine in overnight abstinent smokers. METHODS: Seven male and five female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. Before each session, participants were treated orally with either a single 25 or 50 mg topiramate dose or with placebo. Starting 2 h following the medication treatment, participants received an IV saline injection, followed by 0.5 and 1.0 mg/70 kg IV nicotine. RESULTS: Topiramate treatment at 50 mg, compared to 25 mg or placebo, attenuated heart rate increases induced by nicotine. Topiramate, compared to placebo, enhanced the ratings of subjective effects from nicotine including "drug strength," "good effects," "head rush," and "drug liking." Topiramate treatment did not affect performance on the Stroop test. CONCLUSIONS: These results suggest that topiramate may enhance the subjective effects of nicotine and attenuate the heart rate response to nicotine. While the exact mechanisms are unclear, enhancement of the dopaminergic system and attenuation of the noradrenergic system may mediate the topiramate's effects on the subjective and cardiovascular responses to nicotine, respectively. The utility of topiramate for smoking cessation needs to be examined further in controlled clinical trials.

Vaccine pharmacotherapy for the treatment of cocaine dependence.

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.

Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders.

BACKGROUND: Disulfiram and naltrexone are approved by the Food and Drug Administration (FDA) for the treatment of alcoholism, but these agents have not been rigorously evaluated in dually diagnosed individuals. METHOD: Two-hundred and fifty-four patients with an Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at three Veterans Administration outpatient clinics. Randomization included assignment to one of four groups: 1) naltrexone alone; 2) placebo alone; 3) (open-label) disulfiram and (blinded) naltrexone; or 4) (open-label) disulfiram and (blinded) placebo. Medication compliance was evaluated using the Microelectric Events Monitoring System. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms, alcohol craving, g-GGT levels and adverse events. RESULTS: There was a high rate of abstinence across groups. Subjects treated with an active medication had significantly more consecutive weeks of abstinence and less craving than those treated with placebo, but there were no significant group differences in other measures of alcohol consumption. There was no advantage of the combination of both medications. CONCLUSIONS: These data suggest a modest advantage for the use of disulfiram and naltrexone for this group of dually diagnosed alcohol-dependent individuals but did not suggest an advantage in the combination.