Cannabis and cue-induced craving in cocaine-dependent individuals: A pilot study

BackgroundCannabis consumption is common among cocaine users; however, little is known about its effect on cocaine craving. The objective of this study was to assess whether cannabis co-use is associated with lower cue-induced cocaine craving in non-treatment-seeking cocaine-dependent individuals.MethodsData from twenty-eight cocaine-dependent men were analyzed in this pilot study. Cocaine-dependent subjects (n = 12) were compared with cocaine-dependent subjects who also abused or were dependent on cannabis (n = 16). After at least 72 h of cocaine abstinence, verified using the Timeline Followback and a drug screening test, subjects participated in a functional magnetic resonance imaging session during which neutral and drug cue video sequences were presented. Each sequence comprised four video blocks alternating with resting blocks. We report here subjective craving measures that were collected using the Visual Analog Scale, administered before and after each video block as per standard craving measurement paradigms.ResultsCocaine craving was successfully induced, with no significant difference in cue-induced craving between the two groups. However, post-hoc analyses revealed a significant increase in pre-video cocaine craving scores over time among individuals with cannabis use disorders.ConclusionWe could not highlight significant differences in cocaine craving induction between groups, but we observed a possible deficit in craving decay in the cocaine and cannabis group. In light of this finding, methodology of craving assessment in non-treatment-seeking users, particularly when different substances are combined, should possibly include outcomes linked to craving decay. Studies examining the association between cocaine craving decay and other outcome measures, such as relapse, are also warranted.     

A human laboratory study of the effects of quetiapine on subjective intoxication and alcohol craving

Rationale  

The available treatments for alcoholism are only modestly effective, and patients vary widely in their treatment response. Quetiapine, an atypical antipsychotic medication with antagonist activity at D1 and D2, 5-HT_1A and 5-HT_2A, H₁, and α1 and α2 receptors was shown to promote abstinence, reduce drinking days, and reduce heavy drinking days in a 12-week double-blind placebo-controlled trial.     

A nicotine antagonist, mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent subjects.

We have previously shown that nicotine enhances cue-induced cocaine craving. In the present study, the effects of a nicotine antagonist, mecamylamine, on cue-induced cocaine craving were investigated. Twenty-three cocaine-dependent patients, all cigarette smokers, were randomly assigned to mecamylamine (2.5 mg tablet) or placebo in a single-dose, placebo-controlled, crossover, double-blind study. Craving and anxiety were measured before and after cocaine cues with visual analog scales for desire to use cocaine and mood. Skin conductance, skin temperature and heart rate were recorded before and during cocaine cues. Following exposure to cocaine cues, all patients reported an increase in cocaine craving and anxiety relative to the precue measures. Cue exposure also produced an increase in skin conductance and decrease in skin temperature. The cue-induced increase in cocaine craving was reduced, while the cue-induced skin conductance and temperature responses were unaffected, by mecamylamine. These findings show that cue-induced cocaine craving is attenuated by mecamylamine. Further study on the use of mecamylamine in relapse prevention programs are suggested.     

A randomized, double-blind, placebo-controlled study of the effect of sustained-release bupropion on blood pressure in individuals with mild untreated hypertension

The effects of bupropion on blood pressure and heart rate were evaluated in a double-blind, placebo-controlled study of community volunteers with untreated mild (stage 1) hypertension (systolic blood pressure [SBP], 140-159 mm Hg, and/or diastolic blood pressure, 90-99 mm Hg). Three hundred subjects were randomly assigned (1:1:1:1) to 4 weeks of placebo or bupropion sustained release (SR) 150, 300, or 400 mg/d. Mean clinical blood pressures decreased from baseline to the end of protocol in all groups (n = 296): -6.53, -6.46, -4.20, -4.87 mm Hg for SBP; and -2.36, -2.27, -1.95, -1.55 mm Hg for diastolic blood pressure, for each group, respectively. Although decreases in mean clinical blood pressure were observed in all groups, the reduction in SBP was less on bupropion SR 300 mg/d than on placebo (-4.20 vs -6.53 mm Hg, respectively; Delta = 2.33, P = 0.020). Neither mean 24-hour ambulatory blood pressure measurements nor the proportion of subjects with clinically significant increases in blood pressure differed between any bupropion SR dose and placebo. Mean heart rate increases were small but statistically significant at 400 mg/d versus placebo (2.28 vs -0.64 beats/min; Delta = 2.92, P = 0.004). Although only minor effects on blood pressure were observed in this trial, an infrequent association of bupropion therapy and treatment-emergent hypertension cannot be ruled out.     

A six-month, placebo-controlled trial of d-cycloserine co-administered with conventional antipsychotics in schizophrenia patients

Rationale d-Cycloserine, a partial agonist at the glycine site of the N-methyl-d-aspartate receptor, has demonstrated inconsistent efficacy for negative and cognitive symptoms of schizophrenia. The strongest evidence for efficacy has come from studies using d-cycloserine at a dose of 50 mg/day added to conventional antipsychotics in trials of 8 weeks duration or less.Objective To assess the efficacy for negative symptoms and cognitive impairment of d-cycloserine augmentation of conventional antipsychotics in a 6-month trial.Methods Fifty-five schizophrenia patients with prominent negative symptoms, treated with conventional antipsychotics, were randomly assigned to treatment with d-cycloserine 50 mg/day or placebo for 6 months in a double-blind, parallel group design.Results Twenty-six subjects completed the 6-month trial; drop-out rates did not differ between treatment groups. d-Cycloserine treatment did not differ from placebo treatment on any primary outcome measure at 8 or 24 weeks, including response of negative symptoms and performance on a cognitive battery. Serum d-cycloserine concentrations did not correlate with response of negative symptoms.Conclusion d-Cycloserine did not exhibit therapeutic effects in this trial, possibly reflecting the high drop-out rate, a narrow range of therapeutic serum concentrations, a modest magnitude of therapeutic effect for the selected outcome measures, or loss of efficacy over time. Because d-cycloserine is a partial agonist with relatively low affinity for the glycine site, the magnitude of potential therapeutic effect may be smaller than that achieved by the higher-affinity full agonists, glycine and d-serine.     

Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study

Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.     

A randomized, placebo-controlled study of the effects of naproxen, aspirin, celecoxib or clopidogrel on gastroduodenal mucosal healing

Background  Many individuals with gastroduodenal ulcers require on-going, non-steroidal anti-inflammatory drug (NSAID) or anti-platelet therapy.
Aims  To evaluate the effects of these agents on gastroduodenal mucosal healing.
Methods  Helicobacter pylori -negative volunteers were randomized to receive naproxen, celecoxib, aspirin, clopidogrel or placebo. Antral and duodenal lesions were created endoscopically with a biopsy forceps. After 7 days of medication dosing, each lesion was scored [from 0 (low) to 8 (high)] using a validated methodology. The primary endpoint was the mean injury score. The secondary endpoint was the percentage of subjects with ≥1 unhealed lesion.
Results  In all, 108 subjects completed the study. Naproxen impaired antral lesion healing more than placebo, clopidogrel, aspirin or celecoxib (mean injury score of 4.3 vs. 3.0, 2.7, 3.2, and 3.2, respectively, P  < 0.05). Naproxen impaired duodenal lesion healing more than placebo, clopidogrel or aspirin (mean injury score of 4.0 vs. 2.4, 2.6, and 2.2, respectively, P  < 0.05). More subjects taking naproxen than placebo or clopidogrel had ≥1 unhealed antral lesions (72.2% vs. 36.0% and 32.0%, respectively, P  < 0.05) and unhealed duodenal lesions (61.1% vs. 16.0% and 28.0%, respectively, P  < 0.05).
Conclusions  Naproxen may impair gastroduodenal healing more than aspirin or celecoxib in H. pylori negative subjects. Clopidogrel did not impair mucosal healing.     

Enhanced sensitivity to stress and drug/alcohol craving in abstinent cocaine-dependent individuals compared to social drinkers.

Chronic exposure to cocaine is associated with neuroadaptions in stress and reward circuits that may increase susceptibility to relapse. We examined whether there are alterations in stress response and craving in abstinent cocaine-dependent individuals compared with a demographically matched group of non-addicted socially drinking community controls. Forty treatment-engaged abstinent cocaine patients (17F/23M) and 40 controls (19F/21M) were exposed to a brief 5 min guided imagery of individually calibrated stressful situations, personal drug/alcohol-related situation and a neutral-relaxing situation, one imagery per session, presented in random order. Craving, anxiety, emotion rating scales, and physiological measures were assessed. Cocaine patients reported significantly higher and more persistent stress- and cue-induced drug/alcohol craving, negative emotions, and physiological responses compared with social drinkers. In cocaine patients, stress- and cue-induced drug craving was accompanied by increased anger, fear, sadness, heart rate, and SBP. Controls reported minimal stress-induced craving and only increases in anxiety and SBP during stress exposure. Cue-induced alcohol craving was accompanied only by an increase in relaxed state. Females reported increased stress-induced anxiety and sadness compared with males, while males were emotionally and physiologically more reactive in the cue condition. These findings are the first to document functional alterations in stress- and reward-related affect and physiology in recently abstinent cocaine patients that is marked by an enhanced sensitivity to stress- and drug-related cue exposure. These data suggest that recovery from chronic cocaine abuse could be hampered by a hyper-responsive stress- and drug-craving state that increases cocaine relapse susceptibility.     

Vascular effects of naftidrofuryl in a randomized placebo-controlled double-blind study

In a randomized, placebo-controlled, double-blind, crossover study in 10 volunteers it was demonstrated that intravenous administration of 200 mg naftidrofuryl (Dusodril, Praxilene) produced a slight but significant increase in the erythrocyte column diameters of conjunctival arterioles (mean diameter 17.5 +/- 7.6 microns) of 6.9% which persisted until 1 h after administration. The venules (mean diameter of the erythrocyte column 35.4 +/- 11.5 microns) are not significantly affected at the concentration tested. In their time course the results are in good agreement with the former measurements of the peripheral resistance and with the kinetic characteristic of the drug.     

A double blind, placebo-controlled study of the effects of post-retrieval propranolol on reconsolidation of memory for craving and cue reactivity in cocaine dependent humans

Rationale/objectives

This study examined the effects of propranolol vs. placebo, administered immediately after a “retrieval” session of cocaine cue exposure (CCE), on craving and physiological responses occurring 24 h later during a subsequent “test” session of CCE. It was hypothesized that compared to placebo-treated cocaine-dependent (CD) individuals, propranolol-treated CD individuals would evidence attenuated craving and physiological reactivity during the test session. Secondarily, it was expected that group differences identified in the test session would be evident at a 1-week follow-up CCE session. Exploratory analyses of treatment effects on cocaine use were also performed at follow-up.

Methods

CD participants received either 40 mg propranolol or placebo immediately following a “retrieval” CCE session. The next day, participants received a “test” session of CCE that was identical to the “retrieval” session except no medication was administered. Participants underwent a “follow-up” CCE session 1 week later. Craving and other reactivity measures were obtained at multiple time points during the CCE sessions.

Results

Propranolol- vs. placebo-treated participants evidenced significantly greater attenuation of craving and cardiovascular reactivity during the test session. Analysis of the follow-up CCE session data did not reveal any group differences. Although there was no evidence of treatment effects on cocaine use during follow-up, this study was insufficiently powered to rigorously evaluate differential cocaine use.

Conclusions

This double-blind, placebo-controlled laboratory study provides the first evidence that propranolol administration following CCE may modulate memories for learning processes that subserve cocaine craving/cue reactivity in CD humans. Alternative interpretations of the findings were considered, and implications of the results for treatment were noted.     

The impact of craving and impulsivity on aggression in detoxified cocaine-dependent patients

Patients with substance use disorders are frequently associated with impulsivity that may underlie elevated levels life-threatening types of behavior, including aggression. In addition, craving is a prominent feature of addiction and appears to be closely related to impulsivity. This study assessed the unique contribution of cocaine craving and impulsivity in predicting aggression by means of correlational and mediational analyses. Forty inpatient detoxified cocaine-dependent patients and 40 matched healthy controls were enrolled. These participants filled out the Obsessive Compulsive Drug Use Scale, the Dickman Impulsivity Inventory, and the Aggression Questionnaire. The patient group showed elevated levels of impulsivity and aggression as compared with the control group. Although cocaine craving is positively correlated with both impulsivity and aggression, craving did not mediate the relationship between both constructs. It is concluded that craving does not have an impact on the relationship between impulsivity and trait aggression in this patient sample.     

Varenicline effects on drinking,craving and neural reward processing among non-treatment-seeking alcohol-dependent individuals

Rationale

The α4β2 nicotinic acetylcholine receptor partial agonist varenicline has been reported to reduce drinking among both heavy-drinking smokers and primary alcoholics, and this effect may be related to varenicline-mediated reduction of alcohol craving. Among smokers, varenicline has been reported to modulate cigarette cue-elicited brain activation in several reward-related areas.

Objectives

This pilot study tested varenicline’s effects on drinking, alcohol craving, and alcohol cue-elicited activation of reward-related brain areas among non-treatment-seeking alcohol-dependent individuals.

Methods

Thirty-five such individuals (mean age?=?30, 57 % male, 76 % heavy drinking days in the past month, 15 smokers) were randomized to either varenicline (titrated to 2 mg) or placebo for 14 days, and were administered an alcohol cue reactivity fMRI task on day 14. A priori regions of interest (ROIs) were bilateral and medial orbitofrontal cortex (OFC), right ventral striatum (VS), and medial prefrontal cortex (mPFC).

Results

Despite good medication adherence, varenicline did not reduce heavy drinking days or other drinking parameters. It did, however, increase self-reported control over alcohol-related thoughts and reduced cue-elicited activation bilaterally in the OFC, but not in other brain areas.

Conclusions

These data indicate that varenicline reduces alcohol craving and some of the neural substrates of alcohol cue reactivity. However, varenicline effects on drinking mediated by cue-elicited brain activation and craving might be best observed among treatment-seekers motivated to reduce their alcohol consumption.     

A randomized, double-blind, placebo-controlled study of ritanserin pharmacotherapy for cocaine dependence

Eighty cocaine-dependent individuals enrolled in outpatient treatment took part in a randomized, double-blind, placebo-controlled trial of ritanserin, a 5-HT(2) antagonist, as an adjunct therapy. Participants attended an outpatient day hospital therapy program each day and received tablets containing placebo or 10 mg ritanserin for a 4-week period. Primary outcome measures included retention in treatment, urine drug tests, and self-reports of craving. Secondary outcome measures were depression scores on the Beck and Hamilton inventories, negative mood as measured by the Profile of Mood States, and life functioning as measured by the Addiction Severity Index. Although participants showed improvement over the 4 weeks, there were no group differences on any of the measures. These results fail to support the use of ritanserin as a complement to outpatient psychosocial therapy for cocaine dependence.     

A double-blind, randomized, placebo-controlled comparison of the metabolic effects of low-dose hydrochlorothiazide and indapamide

To compare the metabolic effects of indapamide (I) and hydrochlorothiazide (HCTZ) at equivalent hypotensive doses, 11 hypertensive patients (5 male, 8 black, aged 56 +/- 8 yr--mean +/- SEM) having serum uric acid concentrations greater than 8.0 mg/dL while receiving previous therapy with thiazides, received 28-day courses of placebo, indapamide (2.5 mg/d), and HCTZ (25 mg/d) in randomized, double-blind, double-crossover design. Supine and standing blood pressures, weight, pulse rates and sera were obtained after each 28 day period. Blood pressures and weights were lowered (P less than .001 and 0.01, respectively) equally by the diuretics: supine blood pressures fell from 168 +/- 4/104 +/- 2 (placebo) to 153 +/- 4/93 +/- 2 (HCTZ) and 155 +/- 4/94 +/- 2 mm Hg (I); standing blood pressures (after 2 minutes upright) also decreased: 171 +/- 5/104 +/- 2 (placebo) to 156 +/- 5/93 +/- 2 (HCTZ) and 157 +/- 4/94 +/- 2 mm Hg (I). There was a statistically significant difference (P less than .05) across treatments by analysis of variance in both uric acid and potassium concentrations: serum urate (in mg/dL) was lowest with placebo (7.1 +/- 0.3), and rose to 8.3 +/- 0.2 with HCTZ (P less than .001 compared with placebo by paired t test), and 8.1 +/- 0.2 with I (P less than .005 vs. placebo). The urate concentration with I was significantly lower than that with HCTZ (P less than .02), but the magnitude of the difference was small (0.2 mg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Performance on the Stroop predicts treatment compliance in cocaine-dependent individuals.

Treatment dropout is a problem of great prevalence and stands as an obstacle to recovery in cocaine-dependent (CD) individuals. Treatment attrition in CD individuals may result from impairments in cognitive control, which can be reliably measured by the Stroop color-word interference task. The present analyses contrasted baseline performance on the color-naming, word-reading, and interference subtests of the Stroop task in CD subjects who completed a cocaine treatment trial (completers: N=50) and those who dropped out of the trial before completion (non-completers: N=24). A logistic regression analysis was used to predict trial completion using three models with the following variables: the Stroop task subscale scores (Stroop model); the Hamilton depression rating scale (HDRS) scores (HDRS model); and both the Stroop task subscale scores and HDRS scores (Stroop and HDRS model). Each model was able to significantly predict group membership (completers vs non-completers) better than a model based on a simple constant (HDRS model p=0.02, Stroop model p=0.006, and Stroop and HDRS model p=0.003). Models using the Stroop preformed better than the HDRS model. These findings suggest that the Stroop task can be used to identify cocaine-dependent subjects at risk for treatment dropout. The Stroop task is a widely available, reliable, and valid instrument that can be easily employed to identify and tailor interventions of at risk individuals in the hope of improving treatment compliance.