Barbara J. Mason

An Evidence Based Review of Acute and Long-Term Effects of Cannabis Use on Executive Cognitive Functions

Cannabis use may impair cognitive functions on a number of levels—from basic motor coordination to more complex executive function tasks, such as the ability to plan, organize, solve problems, make decisions, remember, and control emotions and behavior. These deficits differ in severity depending on the quantity, recency, age of onset, and duration of marijuana use. Understanding how cannabis use impairs executive function is important for clinicians. Individuals with cannabis-related impairment in executive functions have been found to have trouble learning and applying the skills required for successful recovery, putting them at increased risk for relapse to cannabis use. Here, we review the research on the acute, residual, and long-term effects of cannabis use on executive functions and discuss the implications for treatment.

Effects of calcium supplementation on serum lipid concentrations in normal older women:: A randomized controlled trial

PURPOSE To determine the effect of supplementation with calcium citrate on circulating lipid concentrations in normal older women. SUBJECTS AND METHODS As part of a study of the effects of calcium supplementation on fractures, we randomly assigned 223 postmenopausal women (mean [+/- SD] age, 72 +/- 4 years), who were not receiving therapy for hyperlipidemia or osteoporosis, to receive calcium (1 g/d, n = 111) or placebo (n = 112) for 1 year. Fasting serum lipid concentrations, including high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, were obtained at baseline, and at 2, 6, and 12 months. RESULTS After 12 months, HDL cholesterol levels and the HDL cholesterol to LDL cholesterol ratio had increased more in the calcium group than in the placebo group (mean between-group differences in change from baseline: for HDL cholesterol, 0.09 mmol/L (95% confidence interval [CI]: 0.02 to 0.17; P = 0.01); for HDL/LDL cholesterol ratio, 0.05 (95% CI: 0.02 to 0.08; P = 0.001). This was largely due to a 7% increase in HDL cholesterol levels in the calcium group, with a nonsignificant 6% decline in LDL cholesterol levels. There was no significant treatment effect on triglyceride level (P = 0.48). CONCLUSION Calcium citrate supplementation causes beneficial changes in circulating lipids in postmenopausal women. This suggests that a reappraisal of the indications for calcium supplementation is necessary, and that its cost effectiveness may have been underestimated.

Gabapentin treatment for alcohol dependence: a randomized clinical trial.

IMPORTANCE Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics. OBJECTIVE To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid-modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner. DESIGN, PARTICIPANTS AND SETTING A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital. INTERVENTIONS Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling. MAIN OUTCOMES AND MEASURES Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study. RESULTS Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups. CONCLUSIONS AND RELEVANCE Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00391716.

Randomized Controlled Trial of Calcium Supplementation in Healthy, Nonosteoporotic, Older Men

BACKGROUND There is no consistent evidence, to our knowledge, that calcium supplementation affects bone mineral density (BMD) in men, despite male osteoporosis being a common clinical problem. METHODS To determine the effects of calcium supplementation (600 mg/d, 1200 mg/d, or placebo) on BMD in men, we conducted a double-blind, randomized controlled trial for a 2-year period at an academic clinical research center. A total of 323 healthy men at least 40 years old (mean age, 57 years) were recruited by newspaper advertisement. Complete follow-up was achieved in 96% of subjects. RESULTS The BMD increased at all sites in the group receiving calcium, 1200 mg/d, by 1% to 1.5% more than those receiving placebo. The results for the group receiving calcium, 600 mg/d, were not different from the placebo group at any BMD site. There was no interaction between the BMD treatment effect and either age or dietary calcium intake. There were dosage-related, sustained decreases in serum parathyroid hormone (P < .001), total alkaline phosphatase activity (P = .01), and procollagen type 1 N-terminal propeptide (P < .001) amounting to 25%, 8%, and 20%, respectively, in the group receiving calcium, 1200 mg/d, at 2 years. Tooth loss, constipation, and cramps were unaffected by calcium supplementation, falls tended to be less frequent in the group receiving calcium, 1200 mg/d, but vascular events tended to be more common in the groups receiving calcium vs the group receiving placebo. CONCLUSION Calcium, 1200 mg/d, has effects on BMD in men comparable with those found in postmenopausal women but a dosage of 600 mg/d is ineffective for treating BMD. TRIAL REGISTRATION actr.org.au Identifier: 012605000274673.

A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults

There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18–65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis–Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.

A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone.

Acamprosate and naltrexone have each demonstrated safety and efficacy for alcohol dependence in placebo-controlled clinical trials. There is scientific and clinical interest in evaluating these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes. Thus, this is the first human pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Twenty-four normal, healthy adult volunteers participated in a double-blind, multiple dose, within subjects, randomized, 3-way crossover drug interaction study of the standard therapeutic dose of acamprosate (2 g/d) and the standard therapeutic dose of naltrexone (50 mg/d), given alone and in combination, with seven days per treatment condition and seven days washout between treatments. Blood samples were collected on a standardized schedule for pharmacokinetic analysis of naltrexone, 6-β-naltrexol, and acamprosate. A computerized assessment system evaluated potential drug effects on cognitive functioning. Coadministration of acamprosate with naltrexone significantly increased the rate and extent of absorption of acamprosate, as indicated by an average 33% increase in acamprosate maximum plasma concentration, 33% reduction in time to maximum plasma concentration, and 25% increase in area under the plasma concentration-time curve. Acamprosate did not affect the pharmacokinetic parameters of naltrexone or 6-β-naltrexol. A complete absence of negative interactions on measures of safety and cognitive function supports the absence of a contraindication to co-administration of acamprosate and naltrexone in clinical practice.

Ritanserin in the treatment of alcohol dependence – a multi-center clinical trial

Abstract Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT2 receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects’ QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence.

Effects of calcium supplementation on lipids, blood pressure, and body composition in healthy older men: a randomized controlled trial

BACKGROUND Calcium supplementation has been suggested to have beneficial effects on serum lipids, blood pressure, and body weight, but these possibilities have not been rigorously assessed in men. OBJECTIVE This study evaluated the effect of calcium supplementation on the change in the ratio of HDL to LDL cholesterol (primary endpoint) and on changes in cholesterol fractions, triglycerides, blood pressure, and body composition (secondary endpoints). DESIGN We carried out a randomized controlled trial of calcium supplementation in 323 generally healthy men over a period of 2 y. Subjects were randomly assigned to take placebo, 600 mg Ca/d, or 1200 mg Ca/d. RESULTS There was no significant treatment effect on the ratio of HDL to LDL cholesterol (P = 0.47) nor on weight, fat mass, lean mass, triglycerides, or total, LDL, or HDL cholesterol (P > 0.28 for all). There were downward trends in systolic and diastolic blood pressures within the calcium-supplemented groups, but there were no significant treatment effects over the whole trial period (P > 0.60). In a post hoc analysis of those with baseline calcium intakes below the median value (785 mg/d), blood pressures showed borderline treatment effects (P = 0.05-0.06 for changes at 2 y in those who received 1200 mg Ca/d compared with placebo: systolic, -4.2 mm Hg; diastolic, -3.3 mm Hg). Low magnesium intake showed a similar interaction. No treatment effects on weight or body composition were found. CONCLUSIONS These data do not show significant effects of calcium supplementation on serum lipids or body composition. Calcium supplementation in those with low dietary intakes may benefit blood pressure control. This trial was registered with the Australian Clinical Trials Registry as ACTRN 012605000274673.

Sertraline treatment of co-occurring alcohol dependence and major depression.

Background: Major depressive disorder occurs commonly in association with alcohol dependence, both in clinical samples and in the community. Efforts to treat major depressive disorder in alcoholics with antidepressants have yielded mixed results. This multicenter, double-blind, placebo-controlled trial of sertraline was designed to address many of the potential methodological shortcomings of studies of co-occurring disorders. Method: Following a 1-week, single-blind, placebo lead-in period, 328 patients with co-occurring major depressive disorder and alcohol dependence were randomly assigned to receive 10 weeks of treatment with sertraline (at a maximum dose of 200 mg/d) or matching placebo. Randomization was stratified, based on whether initially elevated scores on the 17-item Hamilton Depression Rating Scale declined with cessation of heavy drinking, resulting in a sample of 189 patients with Hamilton Depression Rating Scale scores ≥17 (group A) and 139 patients with Hamilton Depression Rating Scale scores ≤16 (group B). Results: Both depressive symptoms and alcohol consumption decreased substantially over time in both groups. There were no reliable medication group differences on depressive symptoms or drinking behavior in either group A or B patients. Conclusion: Despite careful attention to methodological considerations, this study does not provide consistent support for the use of sertraline to treat co-occurring major depressive disorder and alcohol dependence. The high rate of response among placebo-treated patients may help to explain these findings. Further research is needed to identify efficacious treatments for patients with these commonly co-occurring disorders.

Acamprosate for the Treatment of Alcohol Dependence: A Review of Double-Blind, Placebo-Controlled Trials

Acamprosate (calcium acetyl-homotaurine) is a synthetic compound that crosses the blood-brain barrier and has a chemical structure similar to that of the naturally occurring amino acid neuromediators, homotaurine and g-aminobutyric acid (GABA). Acamprosate appears to act primarily by restoring normal n-methyl-d-aspartate (NMDA) receptor tone in the glutamate system, and has been shown to have a specific dose-dependent effect on decreasing voluntary alcohol intake in animals with no effects on food and water consumption. The safety and efficacy of acamprosate in alcohol-dependent outpatients is currently under evaluation in the United States. Acamprosate has been available by prescription since 1989 in France and more recently in most European and Latin American coutries as well as Australia, South Africa, and Hong Kong. More than 4 million people have been treated with acamprosate since it became commercially available. The purpose of this article is to review all available double-blind, placebo-controlled clinical trials evaluating the safety and efficacy of acamprosate treatment of alcohol dependence. This work encompasses 16 controlled clinical trials conducted across 11 European countries and involves more than 4,500 outpatients with alcohol dependence. Fourteen of 16 studies found alcohol-dependent patients treated with acamprosate had a significantly greater rate of treatment completion, time to first drink, abstinence rate, and/or cumulative abstinence duration than patients treated with placebo. Additionally, a multinational open-label study of acamprosate in 1,281 patients with alcohol dependence found acamprosate to be equally effective across four major psychosocial concomitant treatment programs in maintaining abstinence and reducing consumption during any periods of relapse. An absence of known strong predictors of response to acamprosate, in conjunction with a modest but consistent effect on prolonging abstinence, and an excellent safety profile, lend support to the use of acamprosate across a broad range of patients with alcohol dependence.