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T R Kosten

Publications and source records attributed to T R Kosten.

At least 55 records · Page 3Linked to original sources

Pharmacotherapy of cerebral ischemia in cocaine dependence.

This paper will examine how cerebral perfusion deficits in cocaine abusers may be a target for pharmacotherapy. The review covers five areas: (1) cerebral ischemia and neuropsychological impairment in cocaine abusers, (2) neuroimaging evidence for cerebral perfusion defects in cocaine abusers, (3) mechanisms for cocaine induced cerebral thrombosis, (4) neurotoxicity from cerebral ischemia and excitatory amino acids, (5) glutamate antagonists as potential treatment agents for cocaine induced neurotoxicity. Several pharmacotherapies are suggested including antiplatelet agents and excitatory amino acid (EAA) antagonists such as lamotrigine. Clinical trials in cocaine abusers with cerebral perfusion defects are indicated and EAA antagonists hold promise as they are developed for stroke treatment.

Aspirin↗

[123I]beta-CIT SPECT imaging of dopamine transporter availability after mazindol administration in human cocaine addicts.

The in vivo potency of mazindol for binding to striatal dopamine transporters (DAT) was assessed by [123I]beta-CIT ([123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n = 12) underwent three SPECT scans; one before, between, and after subchronic (1 week) administration of 2 mg/day and 4 mg/day mazindol. For each scan, subjects were injected with [123I]beta-CIT and imaged 24 h later under equilibrium conditions. Results showed a statistically significant main effect of mazindol dose (df = 2, F = 10.30, P < 0.001, repeated measures ANOVA) in reducing the specific to non-displaceable equilibrium partition coefficient, V3'' (a measure proportional to DAT binding potential). Regression analysis of the logit transformed data enabled estimation of the 50% displacement dose of mazindol (ED50 = 30mg/day). These data suggest that low doses of mazindol (i.e., 2-4 mg) occupy a small percentage (i.e., < 25%) of DAT in human cocaine abusers and that much higher, potentially intolerable doses (i.e., > or = 30 mg/day) may be required to antagonize significantly cocaine binding in vivo.

Adult↗

A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic.

PURPOSE: Buprenorphine is an alternative to methadone for the maintenance treatment of heroine dependence and may be effective on a thrice weekly basis. Our objective was to evaluate the effect of thrice weekly buprenorphine maintenance for the treatment of heroin dependence in a primary care clinic on retention in treatment and illicit opioid use. SUBJECTS AND METHODS: Opioid-dependent patients were randomly assigned to receive thrice weekly buprenorphine maintenance in a primary care clinic that was affiliated with a drug treatment program (n = 23) or in a traditional drug treatment program (n = 23) in a 12-week clinical trial. Primary outcomes were retention in treatment and urine toxicology for opioids; secondary outcomes were opioid withdrawal symptoms and toxicology for cocaine. RESULTS: Retention during the 12-week study was higher in the primary care setting (78%, 18 of 23) than in the drug treatment setting (52%, 12 of 23; P = 0.06). Patients admitted to primary care had lower rates of opioid use based on overall urine toxicology (63% versus 85%, P < 0.01) and were more likely to achieve 3 or more consecutive weeks of abstinence (43% versus 13%, P = 0.02). Cocaine use was similar in both settings. CONCLUSIONS: Buprenorphine maintenance is an effective treatment for heroin dependence in a primary care setting.

Adult↗

Neurobiological similarities in depression and drug dependence: a self-medication hypothesis.

Epidemiological and clinical data indicate high comorbidity between depression and drug dependence that may reflect an attempt to self-medicate with drugs of abuse. The present review examines whether these two psychiatric disorders are related by attempting to identify similarities in the neurobiology of depression and drug dependence. Emphasis is put on the neuromechanisms that may mediate specific core symptoms of both disorders that reflect alterations in reward and motivational processes. First, the epidemiological and clinical data on the comorbidity of the two disorders are reviewed briefly. Then, the neuroadaptations associated with psychomotor stimulant, opiate, ethanol, nicotine, and benzodiazepine dependence in animals are reviewed. Finally, the neurotransmitter systems whose function appears to be altered in depression (i.e., serotonin, norepinephrine, acetylcholine, dopamine, gamma-aminobutyric acid, corticotropin releasing factor, neuropeptide Y, and somatostatin), as revealed primarily by animal studies, are discussed. It is concluded that drug dependence and depression may be associated with alterations in some of the same neurotransmitter systems and, in particular, with alterations of neurotransmitter function in limbic-related brain structures. Thus, these two psychiatric disorders may be linked by some shared neurobiology. Nevertheless, it remains unclear whether drug abuse and depression are different symptomatic expressions of the same preexisting neurobiological abnormalities, or whether repeated drug abuse leads to the abnormalities mediating depression (i.e., drug-induced depressions). The hypothesis of self-medication of non-drug- and drug-induced depressions with drugs of abuse is also discussed as a potentially important explanatory concept in understanding the observed clinical comorbidity of these two psychiatric disorders.

Animals↗

When is less treatment better? The role of social anxiety in matching methadone patients to psychosocial treatments.

In response to a need to match drug users to the most appropriate and cost-effective level of care, it was hypothesized the socially anxious methadone-maintained patients would attain greater benefit from coping skills training provided in the context of a low-intensity enhanced standard methadone maintenance intervention (E-STD) than in the context of a high-intensity, socially demanding day treatment program (DTP). Social anxiety was assessed in 307 methadone-maintained patients using the Social Anxiety and Distress Scale prior to randomization to either E-STD or DTP. The hypothesis was supported: Socially anxious patients were drug free longer during treatment, were more likely to be abstinent at treatment completion, and had greater reductions in HIV risk behaviors if assigned to the lower intensity intervention, which was provided at 1/3 the cost of the DTP.

Adolescent↗

Hydromorphone-naloxone combinations in opioid-dependent humans under a naloxone novel-response discrimination procedure.

Naloxone-hydromorphone combinations were tested in participants trained to discriminate naloxone from placebo under a novel-response drug discrimination procedure while maintained on methadone. Naloxone alone produced dose-related increases in naloxone-appropriate responding, little or no "novel"-appropriate responding, and increases in opioid antagonist adjective ratings (n = 5). Hydromorphone alone produced dose-related increases in novel-appropriate responding, little or no naloxone-appropriate responding, and increases in opioid agonist adjective ratings (n = 6). When combined with naloxone, hydromorphone produced dose-related decreases in naloxone-appropriate responding and antagonist adjective ratings (n = 6). These findings are consistent with nonhuman data and suggest that this procedure may be useful as a human laboratory model of opioid withdrawal.

Adult↗

Prognostic factors in Buprenorphine- versus methadone-maintained patients.

This study a) compared the effects of buprenorphine versus methadone maintenance on benzodiazepine and alcohol use and b) evaluated the prognostic significance of gender and psychopathology and their interaction with maintenance treatment. Eighty male and 36 female patients were randomly assigned to daily sublingual buprenorphine (4 or 12 mg) or oral methadone (20 or 65 mg). Maintenance medication was not associated with significant differences in alcohol or benzodiazepine use. Rates of abstinence from illicit opioids were significantly higher for females, within the buprenorphine 4-mg group, females also had significantly better retention, lower rates of opioid-positive urine samples, and higher rates of abstinence from illicit opioids. Lifetime sedative dependence was associated with significantly better retention, decreased rates of cocaine-positive urine samples, and increased rates of cocaine abstinence; among buprenorphine- but not methadone-maintained patients, it was also associated with increased rates of abstinence from illicit opioids.

Adult↗

Depression and stimulant dependence: neurobiology and pharmacotherapy.

Depressive disorder rates in stimulant-dependent individuals are substantially higher than community rates. Further, depressive symptoms are considered a major component of stimulant withdrawal. The comorbidity of these disorders may reflect shared neurochemical alterations in the function of serotonin, dopamine, and peptide systems, such as corticotropin releasing factor (CRF) and neuropeptide Y (NPY). These alterations are observed in patients, and in animal models of depression and stimulant dependence, particularly in limbic brain structures. This shared neurobiology does not seem to result from significant shared heritability or genetic linkage; stimulants may induce changes in neurobiology that are similar to those found in depression, and these changes might provide a therapeutic target. Stimulant-dependent patients with a depressive disorder may be a specific subpopulation for antidepressant trials, and they might reduce their stimulant abuse when treated with antidepressants. Nevertheless, concomitant dependence on alcohol or opioids may influence this response, and antidepressants appear to be more effective for depression in combined stimulant and opioid dependence than in combined stimulant and alcohol dependence.

Antidepressive Agents↗

Elevated striatal dopamine transporters during acute cocaine abstinence as measured by [123I] beta-CIT SPECT.

OBJECTIVE: The authors examined whether striatal dopamine transporters were altered in acutely (96 hours or less) abstinent cocaine-abusing subjects, as suggested by postmortem studies. METHOD: [123I] beta-CIT and single photon emission computed tomography were used to assess striatal dopamine transporter levels in 28 cocaine-abusing subjects and 24 comparison subjects matched as a group for age and gender. RESULTS: Results showed a significant (approximately 20%) elevation in striatal V3" values in acutely abstinent cocaine-abusing subjects relative to comparison subjects. An inverse correlation between dopamine transporter level and Hamilton Depression Rating Scale score was also observed. CONCLUSIONS: These findings indicate more modest elevations in striatal dopamine transporters in cocaine-abusing subjects than noted in previous postmortem reports and suggest a possible relationship between cocaine-related depression and dopamine transporter binding.

Adult↗

A preliminary investigation of lamotrigine for cocaine abuse in HIV-seropositive patients.

Theoretical considerations as well as pre-clinical data suggest a potential role for glutamate-inhibiting agents in the treatment of cocaine addiction. At present, however, there is little clinical data to inform the use of these agents for this application. In this preliminary study eighteen HIV-seropositive cocaine dependent, opiate-agonist maintained patients received lamotrigine (300 mg/day), an indirect glutamate release inhibitor, on either a standard (n = 8) or accelerated (n = 10) induction schedule for 12 weeks. Results showed a significant decrease in percentage of cocaine-positive urine screens in the standard induction lamotrigine group but not in the accelerated induction group. There were fewer reports of side-effects and fewer dropouts in the standard-induction lamotrigine group compared to the accelerated induction group. Neuropsychological assessments suggested a decrement in the Trail Making Tests, but no other decreases in cognitive functioning. We conclude that standard-induction lamotrigine warrants further investigation for the treatment of cocaine abuse in this patient population.

Adult↗

The pharmacotherapy of relapse prevention using anticonvulsants.

This review of anticonvulsants for relapse prevention in substance abusers focuses on a series of clinical trials among cocaine abusers. Based on a preclinical rationale linking kindling with drug craving, several studies by Halikas et al. found reductions in cocaine use and craving among "compliant" subjects with blood levels above 4 mu/ml. Three independent randomized trials found no difference from placebo in cocaine use, although treatment retention may be higher during the first 6 weeks, and alcohol use might be less at follow-up after medication discontinuation.

Anticonvulsants↗

Effect of LAAM dose on opiate use in opioid-dependent patients. A pilot study.

The authors conducted a 16-week study with nine opioid-dependent individuals (six male; four white/two African American/three Hispanic; age 36.8 +/- 2.2 years). Participants were assigned to either a low-dose (165 mg/week; n = 5) or high-dose (330 mg/week; n = 4) Levo-alpha-acetylmethadol (LAAM) condition according to a randomized, double-blind, within-subjects crossover design, such that they were inducted onto one maintenance dose for 4 weeks and then were crossed over to receive the converse for 4 weeks. Subsequently, individuals underwent detoxification from LAAM. Eight of nine participants completed the study protocol. The proportion of urine samples positive for opiates was 0.22 +/- 0.08 and 0.53 +/- 0.12, under the high- and low-dose conditions, respectively (F = 11.8; P = 0.01). These results show that LAAM dose regimen affects the degree of abstinence from opioids.

Adult↗

Effects of d-amphetamine and caffeine in humans under a cocaine discrimination procedure.

This study examined further the pharmacological specificity of an oral cocaine discriminative stimulus in humans. Five male cocaine-abusing volunteers (two African-American/three Caucasian) were trained to discriminate between a low dose of cocaine hydrochloride (80 mg/70 kg, p.o.) and placebo. Once the criterion for discrimination was met (i.e. > or = 80% correct responding for four consecutive sessions), dose-effect curves were determined for the dopamine reuptake inhibitor cocaine (20, 40, 80, 120 mg/70 kg, p.o.), the indirect dopamine agonist d-amphetamine (5, 10, 20 mg/70 kg, p.o.) and the adenosine antagonist caffeine (150, 300, 600 mg/70 kg, p.o.). Cocaine, d-amphetamine and caffeine each produced dose-related increases in cocaine-appropriate responding. Each compound produced at least a trend towards increases in a few stimulant-like self-reports and vital signs. When the relationship between cocaine-appropriate responding and self-reports were examined, cocaine and d-amphetamine, but not caffeine, had a similar profile of significant associations between discriminative performance and stimulant-like self-reports. These results suggest that, although the cocaine discriminative stimulus (80 mg/70 kg) is not specific only to stimulants with primarily dopaminergic actions, its pharmacological specificity may be more clearly defined when the relationship between discrimination and self-reports is examined.

Adult↗

Three methods of opioid detoxification in a primary care setting. A randomized trial.

BACKGROUND: Opioid detoxification in a primary care setting followed by ongoing substance abuse treatment may be appropriate for selected opioid-dependent patients. OBJECTIVE: To compare three pharmacologic protocols for opioid detoxification in a primary care setting. DESIGN: Randomized, double-blind clinical trial with random assignment to treatment protocols. SETTING: A free-standing primary care clinic affiliated with drug treatment programs. PATIENTS: 162 heroin-dependent patients. INTERVENTIONS: Three detoxification protocols: donidine, combined donidine and naltrexone, and buprenorphine. MEASUREMENTS: Successful detoxification (that is, when study participants received a full opioid-blocking dose [50 mg] of naltrexone), treatment retention (8 days), and withdrawal symptoms. RESULTS: Overall, 65% of participants (36 of 55) who received clonidine, 81% (44 of 54) who received combined clonidine and naltrexone, and 81% (43 of 53) who received buprenorphine were successfully detoxified. Retention did not differ significantly across the groups: 65% of participants (36 of 55) who received clonidine, 54% (29 of 54) who received combined clonidine and naltrexone, and 60% (32 of 53) who received buprenorphine. Participants who received buprenorphine had a significantly lower mean withdrawal symptom score than those who received clonidine or combined clonidine and naltrexone. CONCLUSIONS: Participants in the combined clonidine and naltrexone group and those in the buprenorphine group were more likely to complete detoxification, although retention at 8 days did not differ among the groups. Participants who were assigned to the buprenorphine group experienced less severe withdrawal symptoms than those assigned to the other two groups.

Adolescent↗

Effect of alpha-methyl-para-tyrosine on response to cocaine challenge.

This study evaluated the effect of an acute reduction in catecholamine synthesis produced by alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor, on cocaine-induced euphoria. In a blinded, placebo-controlled study, AMPT (1 g p.o. T.I.D.) was given to 10 non-treatment-seeking cocaine abusers prior to intranasal administration of 2 mg/kg cocaine. AMPT, but not placebo, reduced plasma levels of the dopamine metabolite homovanillic acid and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol. AMPT also elevated prolactin levels, indicating inhibition of the tuberoinfundibular dopamine system. AMPT pretreatment produced a trend toward diminished cocaine "high" AMPT also tended to lower heart rate and blood pressure responses to cocaine, but had no effect on serum cocaine levels. Although we cannot rule out the therapeutic potential of the depletion strategy, our results with AMPT alone, at this dose, do not strongly support it.

Administration, Oral↗

Guanine nucleotide binding proteins in opioid-dependent patients.

Guanine nucleotide binding (G) protein levels and functioning in the platelets of 19 methadone-maintained patients were compared to age and sex matched, normal controls. We found that in the methadone patients, G alpha s-levels were significantly higher, while the levels of G alpha i 1/2 and pertussis toxin catalyzed [32P]ADP ribosylation were significantly lower compared to control subjects in platelet membranes. We have further found that when all three of these biochemical indicators were combined in a discriminant function analysis, 79% of the methadone patients were correctly classified and 83% of the controls were correctly classified.

Adenosine Diphosphate Ribose↗