The Effects of Citalopram and Thalamic Dopamine D2/3 Receptor Availability on Decision-Making and Loss Aversion in Alcohol Dependence.

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients who misuse alcohol, especially in the context of comorbid depressive symptoms. Deficits in impulse control and decision-making are linked to routine alcohol consumption and alcohol dependence. The goal of this study was to determine the effects of a single dose of citalopram on measures of impulsivity, decision-making, and/or brain dopamine receptor availability in alcohol-dependent individuals. A double-blind, placebo-controlled, within-subject, outpatient study was conducted with active alcohol-dependent (DSM-IV-TR criteria) participants (n = 12) and matched healthy controls (n = 13). Serial doses of both citalopram (40 mg) and saline were administered intravenously before laboratory tests of decision-making (Balloon Analogue Risk Task, delay discounting task, and Loss Aversion Gambling Task) and positron emission tomography with [18F]-fallypride to measure dopamine D2/3 receptor availability, separated by at least one week. Alcohol-dependent participants demonstrated greater loss aversion than healthy controls, but there were no group differences in risk taking on the Balloon Analogue Risk Task. Citalopram increased delay discounting across groups, with no group difference in the effect. There were no effects of citalopram on risk taking on the Balloon Analogue Risk Task. PET showed a negative correlation between thalamic dopamine D2/3 receptor availability and loss aversion across groups. The effect of citalopram to decrease the valuation of monetary reward as a function of delay raises the possibility that SSRIs can influence risky decision-making in clinical populations. In addition, these results suggest that altered thalamic dopamine signaling may play an important role in disproportionately valuing losses in patients with Alcohol Use Disorder. This trial is registered under ClinicalTrials.gov registration NCT01657760.

Information Transfer and Multifractal Analysis of EEG in Mild Blast-Induced TBI.

Mild, blast-induced traumatic brain injury (mbTBI) is a common combat brain injury characterized by typically normal neuroimaging findings, with unpredictable future cognitive recovery. Traditional methods of electroencephalography (EEG) analysis (e.g., spectral analysis) have not been successful in detecting the degree of cognitive and functional impairment in mbTBI. We therefore collected resting state EEG (5 minutes, 64 leads) from twelve patients with a history of mbTBI, along with repeat neuropsychological testing (D-KEFS Tower test) to compare two new methods for analyzing EEG (multifractal detrended fluctuation analysis (MF-DFA) and information transfer modeling (ITM)) with spectral analysis. For MF-DFA, we extracted relevant parameters from the resultant multifractal spectrum from all leads and compared with traditional power by frequency band for spectral analysis. For ITM, because the number of parameters from each lead far exceeded the number of subjects, we utilized a reduced set of 10 leads which were compared with spectral analysis. We utilized separate 30 second EEG segments for training and testing statistical models based upon regression tree analysis. ITM and MF-DFA models both generally had improved accuracy at correlating with relevant measures of cognitive performance as compared to spectral analytic models ITM and MF-DFA both merit additional research as analytic tools for EEG and cognition in TBI.

EEG multifractal analysis correlates with cognitive testing scores and clinical staging in mild cognitive impairment.

Alzheimer's disease and mild cognitive impairment are increasingly prevalent global health concerns in aging industrialized societies. There are only limited non-invasive biomarkers for the cognitive and functional impairment associated with dementia. Multifractal analysis of EEG has recently been proposed as having the potential to be an improved method of quantitative EEG analysis compared to existing techniques (e.g., spectral analysis). We utilized an existing database of a study of healthy elderly patients (N = 20) who were assessed with cognitive testing (Folstein Mini Mental Status Exam; MMSE) and resting state EEG (4 leads). Each subject's EEG was separated into two 30 s tracings for training and testing a statistical model against the MMSE scores. We compared multifractal detrended fluctuation analysis (MF-DFA) against Fourier Transform (FT) in the ability to produce an accurate classification and regression trees estimator for the testing EEG segments. The MF-DFA-based statistical model MMSE estimation strongly correlated with the actual MMSE when applied to the test EEG parameter dataset, whereas the corresponding FT-based model did not. Using a standardized cutoff value for MMSE-based clinical staging, the MF-DFA-based statistical model was both sensitive and specific for clinical staging of both mild Alzheimer's disease and mild cognitive impairment. MF-DFA shows promise as a method of quantitative EEG analysis to accurately estimate cognition in Alzheimer's disease.

Effects of Citalopram on Cue-Induced Alcohol Craving and Thalamic D2/3 Dopamine Receptor Availability.

BACKGROUND: Selective serotonin reuptake inhibitors are often used in alcohol use disorders. Clinical trials with selective serotonin reuptake inhibitors for alcohol use disorders, however, have yielded mixed results. The goal of this project was to assess whether a single i.v. dose of a selective serotonin reuptake inhibitor reduces craving for alcohol and/or simultaneously increases striatal dopamine concentration in individuals with alcohol dependence. METHODS: Alcohol-dependent (DSM-IV-TR criteria) volunteers and matched controls (n = 10/group) underwent a double-blind, placebo-controlled, within-subjects study. Participants received i.v. citalopram (40 mg) or saline (counter-balanced) followed by a cue-induced craving assessment and [18F]-fallypride positron emission tomography scanning. RESULTS: In the alcohol-dependent individuals, the citalopram (compared with saline) resulted in decreased cue-induced craving for alcohol. For the whole study group, cue-induced alcohol craving was inversely correlated with thalamic (but not striatal) dopamine D2/3 receptor availability. CONCLUSIONS: Acute serotonin reuptake inhibition reduces cue-induced alcohol craving. Furthermore, thalamic dopamine abnormalities and the striatal hyperdopaminergic hypothesis of alcohol use disorder are supported.

Combination Extended Smoking Cessation Treatment Plus Home Visits for Smokers With Schizophrenia: A Randomized Controlled Trial.

INTRODUCTION: The majority of people with schizophrenia have a diagnosis of tobacco dependence during their lifetime. A major obstacle to reducing the burden of cigarette smoking in this population is that these smokers have lower quit rates when undergoing standard treatment compared to smokers with no mental illness. We sought to determine if combination extended treatment (COMB-EXT) and home visits (HV) would lead to improved outcomes in smokers with schizophrenia. METHODS: Thirty-four cigarette smokers with schizophrenia completed either COMB-EXT with HV, COMB-EXT without HV, or treatment as usual (TAU) (random assignment). COMB-EXT consisted of group cognitive-behavioral therapy (CBT), bupropion, nicotine patch, and nicotine lozenge, which were initiated within 2 weeks and continued for 26 weekly visits. HV consisted of biweekly visits to the home with assessment of secondhand smoke (SHS) exposure and brief behavioral therapy with participants and others in the home environment. TAU consisted of group CBT plus serial single or combination medication trials as per standard care. RESULTS: Smokers with schizophrenia who received COMB-EXT (with or without HV) had greater reductions in cigarettes per day than those treated with TAU (both ps < .01). In addition, 7-day point prevalence abstinence rates for the three groups were 45%, 20%, and 8%, respectively, which was significantly higher for COMB-EXT plus HV than TAU (χ2(1) = 4.8, p = .03). Groups did not differ significantly in the number of adverse events, and HV were easily scheduled. CONCLUSION: COMB-EXT improves outcomes for smokers with schizophrenia. HV appeared to provide additional benefit for smoking cessation in this treatment-resistant population. IMPLICATIONS: The clear benefit found here of rapidly initiated, combination, extended treatment over TAU suggests that aggressive and extended treatment should be considered in clinical practice for smokers with schizophrenia. Furthermore, HV to address SHS exposure showed initial promise for assisting smokers with schizophrenia in maintaining abstinence, indicating that this intervention may be worthy of future research.

Generalized Information Equilibrium Approaches to EEG Sleep Stage Discrimination.

Recent advances in neuroscience have raised the hypothesis that the underlying pattern of neuronal activation which results in electroencephalography (EEG) signals is via power-law distributed neuronal avalanches, while EEG signals are nonstationary. Therefore, spectral analysis of EEG may miss many properties inherent in such signals. A complete understanding of such dynamical systems requires knowledge of the underlying nonequilibrium thermodynamics. In recent work by Fielitz and Borchardt (2011, 2014), the concept of information equilibrium (IE) in information transfer processes has successfully characterized many different systems far from thermodynamic equilibrium. We utilized a publicly available database of polysomnogram EEG data from fourteen subjects with eight different one-minute tracings of sleep stage 2 and waking and an overlapping set of eleven subjects with eight different one-minute tracings of sleep stage 3. We applied principles of IE to model EEG as a system that transfers (equilibrates) information from the time domain to scalp-recorded voltages. We find that waking consciousness is readily distinguished from sleep stages 2 and 3 by several differences in mean information transfer constants. Principles of IE applied to EEG may therefore prove to be useful in the study of changes in brain function more generally.

Discrete Scale Invariance of Human Large EEG Voltage Deflections is More Prominent in Waking than Sleep Stage 2.

Electroencephalography (EEG) is typically viewed through the lens of spectral analysis. Recently, multiple lines of evidence have demonstrated that the underlying neuronal dynamics are characterized by scale-free avalanches. These results suggest that techniques from statistical physics may be used to analyze EEG signals. We utilized a publicly available database of fourteen subjects with waking and sleep stage 2 EEG tracings per subject, and observe that power-law dynamics of critical-state neuronal avalanches are not sufficient to fully describe essential features of EEG signals. We hypothesized that this could reflect the phenomenon of discrete scale invariance (DSI) in EEG large voltage deflections (LVDs) as being more prominent in waking consciousness. We isolated LVDs, and analyzed logarithmically transformed LVD size probability density functions (PDF) to assess for DSI. We find evidence of increased DSI in waking, as opposed to sleep stage 2 consciousness. We also show that the signatures of DSI are specific for EEG LVDs, and not a general feature of fractal simulations with similar statistical properties to EEG. Removing only LVDs from waking EEG produces a reduction in power in the alpha and beta frequency bands. These findings may represent a new insight into the understanding of the cortical dynamics underlying consciousness.

A naturalistic study of the association between antidepressant treatment and outcome of smoking cessation treatment.

OBJECTIVE: Psychiatric, medical, and substance use comorbidities are highly prevalent among smokers, and many of these comorbidities have been found to be associated with reduced rate of success in clinical trials for smoking cessation. While much has been established about the best available treatments from these clinical trials, little is known about the effect of concomitant psychiatric medications on quit rates in smoking cessation programs. On the basis of results in populations with tobacco dependence and other substance use disorders, we hypothesized that smokers taking antidepressants would have a lower rate of quitting in an outpatient smoking cessation program. METHOD: We performed a naturalistic chart review of veterans (N = 144) enrolled in the Veterans Affairs Greater Los Angeles Mental Health Clinic Smoking Cessation Program from March 2011 through July 2013, who met DSM-IV-TR criteria for nicotine dependence. The primary outcome was smoking cessation with treatment, as evidenced by a patient report of at least 1 week of abstinence and an exhaled carbon monoxide level of ≤ 6 ppm (if available) at the end of acute treatment, with comparators including concomitant psychotropic medication treatment, psychiatric and medical comorbidities, and the presence of a substance use disorder history. We utilized stepwise binary logistic regression as the main statistical technique. RESULTS: We found that current antidepressant treatment (P = .003) and history of substance use disorder (P = .01) (particularly cocaine [P = .02]) were associated with a lower rate of quitting smoking. Furthermore, the association between antidepressant treatment and reduced rate of smoking cessation was primarily seen in patients with a history of substance use disorder (P = .003). CONCLUSIONS: While preliminary, these results suggest an important clinical interaction meriting future study. If these findings are confirmed, clinicians may want to consider the risk of reduced ability to quit smoking in patients with a history of substance use disorder who are taking antidepressants.

Dual role of nicotine in addiction and cognition: a review of neuroimaging studies in humans.

Substantial evidence demonstrates both nicotine's addiction liability and its cognition-enhancing effects. However, the neurobiological mechanisms underlying nicotine's impact on brain function and behavior remain incompletely understood. Elucidation of these mechanisms is of high clinical importance and may lead to improved therapeutics for smoking cessation as well as for a number of cognitive disorders such as schizophrenia. Neuroimaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), which make it possible to study the actions of nicotine in the human brain in vivo, play an increasingly important role in identifying these dual mechanisms of action. In this review, we summarize the current state of knowledge and discuss outstanding questions and future directions in human neuroimaging research on nicotine and tobacco. This research spans from receptor-level PET and SPECT studies demonstrating nicotine occupancy at nicotinic acetylcholine receptors (nAChRs) and upregulation of nAChRs induced by chronic smoking; through nicotine's interactions with the mesocorticolimbic dopamine system believed to mediate nicotine's reinforcing effects leading to dependence; to functional activity and connectivity fMRI studies documenting nicotine's complex behavioral and cognitive effects manifest by its actions on large-scale brain networks engaged both during task performance and at rest. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'.

Multifractal detrended fluctuation analysis of human EEG: preliminary investigation and comparison with the wavelet transform modulus maxima technique.

Recently, many lines of investigation in neuroscience and statistical physics have converged to raise the hypothesis that the underlying pattern of neuronal activation which results in electroencephalography (EEG) signals is nonlinear, with self-affine dynamics, while scalp-recorded EEG signals themselves are nonstationary. Therefore, traditional methods of EEG analysis may miss many properties inherent in such signals. Similarly, fractal analysis of EEG signals has shown scaling behaviors that may not be consistent with pure monofractal processes. In this study, we hypothesized that scalp-recorded human EEG signals may be better modeled as an underlying multifractal process. We utilized the Physionet online database, a publicly available database of human EEG signals as a standardized reference database for this study. Herein, we report the use of multifractal detrended fluctuation analysis on human EEG signals derived from waking and different sleep stages, and show evidence that supports the use of multifractal methods. Next, we compare multifractal detrended fluctuation analysis to a previously published multifractal technique, wavelet transform modulus maxima, using EEG signals from waking and sleep, and demonstrate that multifractal detrended fluctuation analysis has lower indices of variability. Finally, we report a preliminary investigation into the use of multifractal detrended fluctuation analysis as a pattern classification technique on human EEG signals from waking and different sleep stages, and demonstrate its potential utility for automatic classification of different states of consciousness. Therefore, multifractal detrended fluctuation analysis may be a useful pattern classification technique to distinguish among different states of brain function.

Poor response to sertraline in methamphetamine dependence is associated with sustained craving for methamphetamine.

BACKGROUND: Depression is common among individuals with methamphetamine (MA) use disorders. As agents that enhance serotonergic function are frequently used to treat depression, one might predict that they would be useful medications for MA dependence. However, clinical trials of serotonergic agents for MA addiction have been unsuccessful. OBJECTIVE: To identify factors that distinguish MA-dependent research participants who increased MA self-administration while receiving treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline from other groups of participants. METHOD: Using a dataset from a 12-week randomized, placebo-controlled trial of sertraline (100mg daily) for MA addiction, we identified participants who had completed at least 8 weeks of the trial (n=61 sertraline, n=68 placebo). We compared the proportions of MA-positive urine tests for weeks 8-12 of the trial for these subjects to their pre-randomization baseline, and identified those subjects who increased MA use during treatment. Using classification trees, we then assessed all data collected during the study to identify factors associated with increasing MA use during treatment with sertraline, compared to placebo. RESULTS: More subjects in the sertraline condition increased MA use during treatment (n=13) than in the placebo condition (n=5; p=0.03). Classification trees identified multiple factors from both pre-treatment and in-treatment data that were associated with increased MA use during treatment. Only elevated in-treatment craving for MA specifically characterized subjects in the sertraline group who increased their MA use. CONCLUSIONS: Some MA-abusing individuals treated with SSRIs have sustained craving with an increased propensity to relapse during treatment despite psychosocial treatment interventions.

Elevated plasma prolactin in abstinent methamphetamine-dependent subjects.

BACKGROUND: Methamphetamine (MA) use disorders are pervasive global social problems that produce large medical and public health burdens. Abnormalities in pituitary hormonal regulation have been observed in preclinical models of substance abuse and in human substance abusers. They have, however, not been studied before in MA-dependent human subjects. OBJECTIVES: To determine if MA-dependent research volunteers differ from healthy control subjects in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, or prolactin, or in pituitary dopamine D(2) receptor availability during early abstinence from MA. METHODS: MA-dependent subjects (N = 31), who were not seeking treatment, resided on an inpatient ward for up to 5 weeks. Abstinence was confirmed by daily urine drug screening. Venous blood was sampled for plasma hormone levels, and positron emission tomography with [(18)F]fallypride was performed to determine dopamine D(2) receptor availability during the first week of abstinence. Venous blood was sampled again for hormone levels during the fourth week of abstinence. Matched healthy volunteers (N = 23) participated as a comparison group. RESULTS: MA-dependent and healthy comparison subjects did not differ in plasma ACTH or cortisol levels, but had an elevated plasma prolactin at both the first week and fourth week of abstinence. There was no group difference in pituitary dopamine D(2) receptor availability. CONCLUSION: MA-dependent individuals have abnormalities in prolactin regulation, which is not likely due to alterations in pituitary dopamine D(2) receptor availability. SCIENTIFIC SIGNIFICANCE: MA dependence is associated with elevated prolactin levels, which may contribute to medical comorbidity in afflicted individuals.

Quetiapine for the treatment of alcoholism: scientific rationale and review of the literature.

ISSUES: The development of effective treatments for alcohol use disorders represents an important public health concern. Quetiapine, a multiple receptor antagonist at 5-HT(1A) and 5-HT(2A), dopamine D(1) and D(2), histamine H(1), and adrenergic α(1) and α(2) receptors, is an atypical antipsychotic medication that has recently shown promise for the treatment of alcoholism. APPROACH: This manuscript reviews the rationale and empirical literature suggesting that quetiapine may be useful for the treatment of alcohol use disorders, including a discussion of its putative neurobiological and biobehavioural mechanisms of action. KEY FINDINGS: The effects of quetiapine on drinking outcomes may be due to its effects on mood, anxiety and sleep, which may help alleviate protracted withdrawal symptoms and address psychiatric comorbidities often associated with alcohol use disorders. IMPLICATIONS: These findings have implications to treatment development for alcoholism and suggest that the scientific study of quetiapine for alcoholism warrants further resources and attention. CONCLUSION: Quetiapine has advanced as a potentially promising pharmacotherapy for alcoholism. Additional research is needed to more clearly ascertain its clinical utility as a stand-alone treatment for this indication, as well as to identify patients who are more likely to respond favourably to this medication.

Withdrawal symptoms in abstinent methamphetamine-dependent subjects.

AIMS: Withdrawal symptoms have been linked to a propensity for relapse to drug abuse. Inasmuch as this association applies to methamphetamine (MA) abuse, an understanding of the course of MA withdrawal symptoms may help to direct treatment for MA dependence. Previous studies of symptoms manifested during abstinence from MA have been limited in size and scope. We asked (i) whether debilitating psychological and/or physical symptoms appear during the first several weeks of MA abstinence, (ii) how craving for MA evolves and (iii) whether psychiatric symptoms (e.g. depression, psychosis) persist beyond a month of abstinence. DESIGN: A study of MA-dependent participants, who initiated and maintained abstinence from the drug for up to 5 weeks, compared to a matched healthy comparison group. SETTING: In-patient research hospital ward (MA-dependent subjects) and out-patient (comparison subjects). PARTICIPANTS: Fifty-six MA-dependent and eighty-nine comparison subjects. MEASUREMENTS: Rater-assessed MA withdrawal questionnaire and self-report assessment of craving (MA-dependent subjects) and self-report assessment of psychiatric symptoms (both groups). FINDINGS: At study entry, MA-dependent subjects exhibited a wide range in severity of depressive symptoms, with the average score at a mild-moderate level of severity. Symptoms of psychosis were also prevalent. While depressive and psychotic symptoms largely resolved within a week of abstinence, craving did not decrease significantly from the time of initiating abstinence until the second week, and then continued at a reduced level to the fifth week. CONCLUSIONS: Depressive and psychotic symptoms accompany acute withdrawal from methamphetamine but resolve within 1 week. Craving is also present and lasts at least 5 weeks.

Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers.

Methamphetamine is a highly addictive stimulant and long-term exposure leads to reductions in dopamine. One therapeutic strategy is to develop and test compounds that normalize dopamine. The primary aim of this study was to determine the safety of modafinil treatment during methamphetamine exposure in a controlled clinical setting. Methamphetamine-dependent volunteers (N=13), who were not seeking treatment, were randomized to receive either modafinil (200mg, PO) or matching placebo over three days (Days 1-3 or Days 8-10). On Day 1, subjects were randomized to modafinil or placebo in the morning, and then 3 and 6h later received infusions of methamphetamine (0 and 30 mg, i.v.), after which cardiovascular and subjective effects were assessed. On Day 3, participants completed i.v. self-administration sessions during which they made 10 choices for low doses of methamphetamine (3mg, i.v.) or saline. Days 4-7 were used as a washout period. On Day 8 participants were assigned to the alternate study medication (placebo or modafinil), and the same testing procedures were repeated through Day 10. The data reveal that modafinil treatment was well-tolerated and not associated with increased incidence of adverse events. In general, modafinil reduced by approximately 25% ratings of methamphetamine-induced "Any Drug Effect", "High", and "Want Methamphetamine", and reduced total number of choices for methamphetamine and monetary value of methamphetamine, though none of these measures reached statistical significance. Given these encouraging, though non-significant trends, the primary conclusion is that it appears safe to proceed with modafinil in further clinical evaluations of therapeutic efficacy.

Pilot safety evaluation of varenicline for the treatment of methamphetamine dependence.

Despite the worldwide extent of methamphetamine dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Animal research suggests that enhancement of central cholinergic activity, possibly at nicotinic acetylcholine receptors (nAChRs), can reduce methamphetamine-related behaviors. Further, preliminary findings indicate that rivastigmine, a cholinesterase inhibitor, may reduce craving for methamphetamine after administration of the drug in human subjects. We therefore performed a double-blind, placebo-controlled, crossover pilot study of the safety and tolerability of varenicline in eight methamphetamine-dependent research subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4b2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over one week to reach 1 mg twice daily, and then was co-administered with 30 mg methamphetamine, delivered in 10 intravenous (iv) infusions of 3 mg each. Varenicline was found to be safe in combination with iv methamphetamine, producing no cardiac rhythm disturbances or alterations in vital sign parameters. No adverse neuropsychiatric sequelae were detected either during varenicline titration or following administration of methamphetamine. The results suggest that varenicline warrants further investigation as a potential treatment for methamphetamine dependence.

The cardiovascular and subjective effects of methamphetamine combined with gamma-vinyl-gamma-aminobutyric acid (GVG) in non-treatment seeking methamphetamine-dependent volunteers.

Gamma-vinyl-gamma-aminobutyric acid (GVG) elevates central nervous system gamma-aminobutyric acid (GABA) levels by irreversibly inhibiting GABA transaminase. An open-label clinical trial in humans suggested that GVG may reduce cocaine and methamphetamine use. To test safety and to obtain preliminary data on efficacy of GVG for treating methamphetamine dependence, we conducted a double-blind, placebo-controlled, parallel group study of GVG interaction with the cardiovascular and subjective effects produced by methamphetamine. Non-treatment seeking methamphetamine-dependent volunteers received either GVG (N=8) or placebo (N=9) by random assignment. GVG treatment was initiated at 1 g/day and increased to 5 g/day. After reaching the target dose of 5 g/day, participants received methamphetamine (15+30 mg, IV), and cardiovascular and subjective effects were assessed. No serious adverse events were noted, and the total number of adverse events was similar between the treatment groups. Considering the full time course and peak effects independently, no significant differences were detected between the groups for systolic or diastolic blood pressures, or heart rate, following methamphetamine exposure. Some methamphetamine-induced cardiovascular changes approached significance (p<0.10) and may warrant attention in future trials. Methamphetamine-induced subjective effects ("any drug effect", "high", "crave methamphetamine") were statistically similar between GVG and placebo treatment groups. Pharmacokinetic data indicate that GVG treatment did not alter methamphetamine or amphetamine plasma levels, and there was no association between methamphetamine or amphetamine plasma levels and peak cardiovascular effects. Taken together, the data indicate that GVG treatment is generally well tolerated but not efficacious in attenuating the positive subjective effects of methamphetamine in the laboratory.