Menthol and Mint Cigarettes and Cigars: Initiation and Progression in Youth, Young Adults and Adults in Waves 1-4 of the PATH Study, 2013-2017.

INTRODUCTION: This study examined in youth (12-17 years), young adults (18-24 years), and adults (25+ years): (1) the prevalence of the first menthol cigarette and menthol/mint cigar use among new tobacco users; (2) association between the first menthol/mint use, subsequent tobacco use, and nicotine dependence ~1 year later compared with the first non-menthol/mint use. AIMS AND METHODS: Longitudinal analysis of data from Waves 1 to 4 of the Population Assessment of Tobacco and Health (PATH) Study (2013-2017; 10 086 youth and 21 281 adults). Main outcome measures were past 12-month and past 30-day cigarette and cigar use, and nicotine dependence. RESULTS: Youth and young adult new cigarette users are more likely to smoke a menthol cigarette or indicate that they do not know the flavor compared with adults aged 25+. A greater proportion of adults aged 25+ first used menthol/mint-flavored cigars (13.4%) compared with youth (8.5%) and young adults (7.4%). Among young adults, first use of a menthol cigarette is associated with past 12-month use of cigarettes at the subsequent wave and first use of any menthol/mint-flavored cigars is associated with past 30-day use of these products at the subsequent wave in both youth and young adults. In youth and adults, there were no significant relationships between first use of a menthol/mint cigarette or cigar and nicotine dependence scores at a subsequent wave in multivariable analyses. CONCLUSIONS: The first use of menthol/mint cigarettes and cigars is associated with subsequent cigarette and cigar use in young people aged 12-24. IMPLICATIONS: This study examined the relationship between initiation with menthol cigarettes and menthol/mint cigars, subsequent tobacco use, and nicotine dependence in US youth, young adults, and adults who participated in Waves 1-4 of the Population Assessment of Tobacco and Health study. New use of menthol cigarettes was associated with greater past 12-month cigarette use in young adults and new use of menthol/mint-flavored cigars was associated with greater past 30-day cigar use in youth and young adults compared with non-menthol use. Initiation with menthol/mint cigarette and cigar products may lead to subsequent use of those products.

Trends and Associations of Menthol Cigarette Smoking Among US Middle and High School Students-National Youth Tobacco Survey, 2011-2018.

INTRODUCTION: Youth cigarette smoking decreased significantly over the last two decades in the United States. This study provides estimates and trends from 2011 to 2018 and factors associated with youth menthol and non-menthol smoking from 2016 to 2018. METHODS: Using data from the 2011-2018 National Youth Tobacco Surveys, past 30-day (current) menthol and non-menthol cigarette smoking were estimated for all youth (prevalence) and youth smokers (proportions). Trends were examined using Joinpoint regression, calculating the annual percent change (APC). Multivariate logistic regression analyses identified factors associated with menthol smoking. RESULTS: From 2011 to 2018, menthol cigarette smoking among current youth cigarette smokers significantly decreased from 57.3% to 45.7% (APC: -3.0%), while non-menthol (38.2% to 47.3% [APC: 2.9%]) and unknown menthol status (not sure\missing) (4.5% to 7.0% [APC: 7.1%]) significantly increased. Menthol cigarette smoking among high school, male, female, and non-Hispanic white current cigarette smokers decreased, but remained unchanged among middle school, non-Hispanic black, and Hispanic smokers. Significantly higher proportions of menthol cigarette smokers smoked on ≥20 days, ≥2 cigarettes per day, and ≥100 cigarettes in their lifetime compared to non-menthol smokers. Among current cigarette smokers, non-Hispanic blacks, Hispanics, flavored non-cigarette tobacco users, frequent smokers (≥20 days), those smoking 2-5 cigarettes per day, and those living with someone who uses tobacco had higher odds of menthol cigarette smoking. CONCLUSIONS: In 2018, nearly half of current youth cigarette smokers smoked menthol cigarettes. While menthol cigarette smoking declined from 2011 to 2018 among all youth and among youth smokers, there was no change in menthol cigarette smoking among non-Hispanic black, Hispanic, and middle school cigarette smokers. IMPLICATIONS: This study finds that overall cigarette and menthol cigarette smoking declined in youth from 2011 to 2018. However, menthol cigarette smoking among non-Hispanic black, Hispanic, and middle school youth cigarette smokers did not change. Information from this study can help inform efforts to reduce menthol cigarette smoking among US youth, particularly racial/ethnic minority populations.

Graphic Warning Labels Affect Hypothetical Cigarette Purchasing Behavior among Smokers Living with HIV.

Cigarette pack graphic warning labels (GWLs) are associated with increased knowledge of tobacco-related harms; scant research has evaluated their effects on behavior among vulnerable populations. We used a behavioral economic approach to measure the effects of GWLs and price on hypothetical cigarette purchasing behavior among HIV-positive smokers. Participants (n = 222) completed a cigarette valuation task by making hypothetical choices between GWL cigarette packs at a fixed price ($7.00) and text-only warning label cigarette packs at increasing prices ($3.50 to $14.00; $0.25 increments). More than one-quarter (28.8%) of participants paid more to avoid GWLs. The remaining participants' purchasing decisions appear to have been driven by price: 69.8% of participants chose the cheaper pack. Across all participants, overall monetary choice value observed for GWL cigarette packs (mean = $7.75) was greater than if choice was driven exclusively by price ($7.00). Most (87.4%) preferred the text-only warning label when GWL and text-only cigarette packs were equally priced. Correlation analysis indicated GWL pack preference was associated with agreement with statements that GWLs would stop individuals from having a cigarette or facilitate thoughts about quitting. These data suggest that GWLs may influence some HIV-positive smokers in such a way that they are willing to pay more to avoid seeing GWLs.

Examining the role of menthol cigarettes in progression to established smoking among youth.

BACKGROUND: Menthol, a flavoring compound added to cigarettes, makes cigarettes more appealing to youth and inexperienced smokers and increases cigarettes' abuse liability. However, limited studies are available on menthol's role in smoking progression. METHODS: To assess the association between menthol in cigarettes and progression to established smoking, we used five waves of data from the Evaluation of Public Education Campaign on Teen Tobacco Cohort Study, a nationally representative longitudinal survey of U.S. youth conducted as part of "The Real Cost" evaluation. We used discrete time survival analysis to model the occurrence of two event outcomes-progression to established, current smoking and progression to established, frequent smoking-using a logit model with a menthol use indicator as the key explanatory variable. Based on this framework, we estimated the effect of prior menthol use on the odds of smoking progression. RESULTS: In the progression to established, current smoking model, prior menthol use was significantly associated with progression [adjusted odds ratio (aOR) = 1.80, p < .05, confidence interval (CI) = (1.03-3.16)]. While results were in a similar direction for the model of progression to established, frequent smoking, the association between prior menthol use and this progression model did not reach significance [aOR = 1.56, CI = (0.80-3.03)]. CONCLUSION: The results suggest a relationship between using menthol cigarettes and progression from experimental to established, current smoking among youth. This study adds to a growing literature base that supports that menthol cigarettes, compared to nonmenthol cigarettes, put youth at increased risk for regular cigarette use.

Young adult dual combusted cigarette and e-cigarette users' anticipated responses to hypothetical e-cigarette market restrictions.

Introduction: The aim of this exploratory study was to assess young adult dual e-cigarette (EC) and combusted cigarette (CC) users' anticipated responses to hypothetical market restrictions regarding key EC characteristics. Methods: Data came from 240 young adult dual EC and CC users recruited via Amazon Mechanical Turk in June 2017. Descriptive statistics were used to report sociodemographic, CC smoking, and EC use characteristics. McNemar's chi-square tests and chi-square tests were used to assess differences between groups in terms of anticipated responses to hypothetical EC market restrictions. Results: Hypothetical regulations resulted in reported intentions to reduce EC use and increase CC use; the greatest impact was found for restrictions regarding e-liquid nicotine content, followed by flavor and ability to modify EC devices. Moreover, individuals reporting use of flavored e-liquid, high nicotine content e-liquid, and customizable EC were most likely to report intentions to reduce EC use and increase CC use. Conclusions: This work provides preliminary evidence that restrictive regulations regarding key EC characteristics may increase intentions to increase CC use among young adult dual EC and CC users.

Working Memory Training for Adolescents With Cannabis Use Disorders: A Randomized Controlled Trial.

Adolescent cannabis use is associated with working memory impairment. The present randomized controlled trial assigned adolescents ages 14 to 21 enrolled in cannabis use treatment to receive either working memory training (experimental group) or a control training (control group) as an adjunctive treatment. Cognitive function, drug use, and other outcomes were assessed before and after training. We observed few differences in cognitive, functional, or self-reported drug use outcomes as a function of training group, although tetrahydrocannabinol (THC) urinalysis results favored the experimental group. These findings are similar to previous studies in substance users, which have shown limited transfer effects for working memory training.

Perceived risk of developing smoking-related disease among persons living with HIV.

Perceived risk of smoking is associated with smoking status, interest in quitting, cessation attempts, and quit success. Research is needed to explore risk perceptions of developing smoking-related disease among persons living with HIV (PLWH). Data came from 267 HIV-positive smokers who completed an online survey assessing perceived health risks associated with (a) generic smoking status; (b) generic non-smoking status; (c) their own personal current smoking; and (d) a hypothetical situation in which they were a non-smoker. PLWH perceived greater risk associated with their current smoking versus hypothetical personal non-smoking (p's < 0.001), and greater risks associated with generic smoking status compared with their current smoking (p's < 0.001). Being on HIV medication (ß = 0.65, 95% CI = 0.17, 1.12), interest in quitting smoking (ß = 0.89, 95% CI = 0.45, 1.32), and having an HIV healthcare provider who has recommended cessation (ß = 1.04, 95% CI = 0.42, 1.67) were positively associated with perceived risk of developing smoking-related diseases. Findings have implications for developing targeted interventions to correct misperceptions regarding the health risks of smoking among PLWH, a population at particular risk for smoking and smoking-related morbidity and mortality.

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats.

BACKGROUND/AIMS: The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-D-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. METHODS: Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. RESULTS: Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. CONCLUSIONS: Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders.

Behavioral economic substitutability of e-cigarettes, tobacco cigarettes, and nicotine gum.

The public health impact of e-cigarettes may depend on their substitutability for tobacco cigarettes. Dual users of e-cigarettes and tobacco cigarettes completed purchasing tasks in which they specified daily use levels under hypothetical conditions that varied the availability and price of e-cigarettes, tobacco cigarettes, and nicotine gum (for those with nicotine gum experience). When either e-cigarettes or tobacco cigarettes were the only available commodity, as price per puff increased, purchasing decreased, revealing similar reinforcement profiles. When available concurrently, as the price of tobacco puffs increased, purchasing of tobacco puffs decreased while purchasing of fixed-price e-cigarette puffs increased. Among those with nicotine gum experience, when the price of tobacco puffs was closest to the actual market value of tobacco puffs, e-cigarette availability decreased median tobacco puff purchases by 44% compared to when tobacco was available alone. In contrast, nicotine gum availability caused no decrease in tobacco puff purchases. E-cigarettes may serve as a behavioral economic substitute for tobacco cigarettes, and may be a superior substitute compared to nicotine gum in their ability to decrease tobacco use. Although important questions remain regarding the health impacts of e-cigarettes, these data are consistent with the possibility that e-cigarettes may serve as smoking cessation/reduction aids.

Positive smoking cessation-related interactions with HIV care providers increase the likelihood of interest in cessation among HIV-positive cigarette smokers.

Smoking cessation has proven to be a challenge for HIV-positive smokers. Patient and provider characteristics may provide barriers to smoking cessation. We aimed to identify characteristics associated with interest in cessation as well as characterize use of, current interest in, and provider recommendations for smoking cessation modalities. Data came from 275 HIV-positive smokers recruited online. Half (49.1%) of the sample was interested in quitting; daily smoking was associated with decreased likelihood of interest in cessation, whereas making a lifetime quit attempt, receiving encouragement to quit from an HIV care provider, and greater frequency of discussions regarding cessation with HIV care providers were associated with increased likelihood of interest in cessation. Nicotine replacement therapy was the most commonly used (42.9%), generated the most interest (59.1%), and was the most commonly clinician-recommended (70.7%) cessation modality. Findings emphasize the importance of the healthcare provider-patient relationship for smoking cessation promotion in HIV-positive smokers.

Knowledge about nicotine among HIV-positive smokers: Implications for tobacco regulatory science policy.

The present paper describes the general knowledge of smoking and nicotine among a sample of current smokers living with HIV (n=271) who were recruited via Amazon Mechanical Turk. Descriptive statistics were used to report sociodemographic and smoking characteristics, as well as knowledge about smoking and nicotine. The sample was comprised of relatively light smokers, both in terms of cigarettes per day (M=8.1, SD=9.7) and dependence (67.5% had low dependence according to the Heaviness of Smoking Index). The majority of participants correctly identified smoking as being a potential cause of various smoking-related conditions and correctly identified constituents in cigarette smoke. However, a majority of participants also misattributed nicotine as being a potential cause of smoking-related illness. Accurate knowledge about nicotine was low. These misperceptions are of particular concern for vulnerable populations, such as persons living with HIV, who are disproportionately burdened by the prevalence of smoking and associated morbidities and mortality. These misperceptions could have unintended consequences in the wake of a potential nicotine reduction policy, such that reduced nicotine content products are perceived as safer than normal nicotine content products currently available for sale. Additionally, incorrect knowledge about nicotine has implications for the uptake and continued use of nicotine replacement therapy.

Initial feasibility and validity of a prospective memory training program in a substance use treatment population.

Individuals with substance use disorders have shown deficits in the ability to implement future intentions, called prospective memory. Deficits in prospective memory and working memory, a critical underlying component of prospective memory, likely contribute to substance use treatment failures. Thus, improvement of prospective memory and working memory in substance use patients is an innovative target for intervention. We sought to develop a feasible and valid prospective memory training program that incorporates working memory training and may serve as a useful adjunct to substance use disorder treatment. We administered a single session of the novel prospective memory and working memory training program to participants (n = 22; 13 men, 9 women) enrolled in outpatient substance use disorder treatment and correlated performance to existing measures of prospective memory and working memory. Generally accurate prospective memory performance in a single session suggests feasibility in a substance use treatment population. However, training difficulty should be increased to avoid ceiling effects across repeated sessions. Consistent with existing literature, we observed superior performance on event-based relative to time-based prospective memory tasks. Performance on the prospective memory and working memory training components correlated with validated assessments of prospective memory and working memory, respectively. Correlations between novel memory training program performance and established measures suggest that our training engages appropriate cognitive processes. Further, differential event- and time-based prospective memory task performance suggests internal validity of our training. These data support the development of this intervention as an adjunctive therapy for substance use disorders. (PsycINFO Database Record

Resting-state EEG, impulsiveness, and personality in daily and nondaily smokers.

OBJECTIVES: Resting EEG is sensitive to transient, acute effects of nicotine administration and abstinence, but the chronic effects of smoking on EEG are poorly characterized. This study measures the resting EEG profile of chronic smokers in a non-deprived, non-peak state to test whether differences in smoking behavior and personality traits affect pharmaco-EEG response. METHODS: Resting EEG, impulsiveness, and personality measures were collected from daily smokers (n=22), nondaily smokers (n=31), and non-smokers (n=30). RESULTS: Daily smokers had reduced resting delta and alpha EEG power and higher impulsiveness (Barratt Impulsiveness Scale) compared to nondaily smokers and non-smokers. Both daily and nondaily smokers discounted delayed rewards more steeply, reported lower conscientiousness (NEO-FFI), and reported greater disinhibition and experience seeking (Sensation Seeking Scale) than non-smokers. Nondaily smokers reported greater sensory hedonia than nonsmokers. CONCLUSIONS: Altered resting EEG power in daily smokers demonstrates differences in neural signaling that correlated with greater smoking behavior and dependence. Although nondaily smokers share some characteristics with daily smokers that may predict smoking initiation and maintenance, they differ on measures of impulsiveness and resting EEG power. SIGNIFICANCE: Resting EEG in non-deprived chronic smokers provides a standard for comparison to peak and trough nicotine states and may serve as a biomarker for nicotine dependence, relapse risk, and recovery.

Characterizing use patterns and perceptions of relative harm in dual users of electronic and tobacco cigarettes.

Awareness and use of electronic cigarettes (e-cigarettes) is increasing. Questions regarding positive (e.g., smoking reduction/cessation) and negative (e.g., delay of cessation) potential public health consequences of e-cigarettes may be informed by studying dual users of e-cigarettes and tobacco cigarettes. A cross-sectional online survey assessed demographics, product use patterns, and beliefs about relative product benefits and harms among dual users (n = 350) in the United States using the website Amazon Mechanical Turk. Compared to tobacco cigarettes, e-cigarettes were used less often and were associated with lower dependence. Participants reported a 30% reduction in self-reported tobacco cigarette smoking since beginning to use e-cigarettes. Reported primary reasons for e-cigarette use were harm reduction and smoking cessation. E-cigarette use was reported as more likely in settings with smoking restrictions and when others' health could be adversely affected. Conversely, participants reported having used tobacco cigarettes more often than e-cigarettes in hedonic situations (e.g., after eating, drinking coffee or alcohol, or having sex), outdoors, or when stressed. Participants were twice as likely to report wanting to quit tobacco cigarettes compared to e-cigarettes in the next year and intended to quit tobacco cigarettes sooner. Tobacco cigarettes were described as more harmful and addictive, but also as more enjoyable than e-cigarettes. Participants provided evidence consistent with both positive and negative public health consequences of e-cigarettes, highlighting the need for experimental research, including laboratory studies and clinical trials. Policies should consider potential public health benefits of e-cigarettes, in addition to potential harms.

A randomized controlled trial of the effects of working memory training in methadone maintenance patients.

OBJECTIVE: Working memory impairment in individuals with chronic opioid dependence can play a major role in cognitive and treatment outcomes. Cognitive training targeting working memory shows promise for improved function in substance use disorders. To date, cognitive training has not been incorporated as an adjunctive treatment for opioid dependence. METHODS: Methadone maintenance patients were randomly assigned to experimental (n=28) or active control (n=28) 25-session computerized training and run in parallel. Cognitive and drug use outcomes were assessed before and after training. RESULTS: Participants in the experimental condition showed performance improvements on two of four working memory measures, and both groups improved on a third measure of working memory performance. Less frequent drug use was found in the experimental group than in the control group post-training. In contrast to previous findings with stimulant users, no significant effect of working memory training on delay discounting was found using either hypothetical or real rewards. There were no group differences on working memory outcome measures that were dissimilar from the training tasks, suggesting that another mechanism (e.g., increased distress tolerance) may have driven drug use results. CONCLUSIONS: Working memory training improves performance on some measures of working memory in methadone maintenance patients, and may impact drug use outcomes. Working memory training shows promise in patients with substance use disorders; however, further research is needed to understand the mechanisms through which performance is improved and drug use outcomes are impacted.

Phencyclidine Disrupts the Auditory Steady State Response in Rats.

The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule.

Topiramate impairs cognitive function in methadone-maintained individuals with concurrent cocaine dependence.

Topiramate is being investigated as a potential pharmacotherapy for the treatment of addictive disorders. However, its cognitive side effects raise concerns about its use, especially in populations with cognitive impairment, such as persons with chronic substance use disorders. This study investigated topiramate's cognitive effects in individuals dually dependent on cocaine and opioids as part of a double-blind, randomized, controlled trial of topiramate for cocaine dependence treatment. After 5 weeks of stabilization on daily oral methadone (M = 96 mg), participants were randomized to topiramate (n = 18) or placebo (n = 22). Cognitive testing took place at 2 time points: study weeks 4 through 5 to assess baseline performance and 10 to 13 weeks later to assess performance during stable dosing (300 mg topiramate or placebo). All participants were maintained on methadone at both testing times, and testing occurred 2 hours after the daily methadone plus topiramate/placebo administration. The topiramate and placebo groups did not differ on sex, level of education, premorbid intelligence, methadone dose, or illicit drug use. Topiramate slowed psychomotor and information processing speed, worsened divided attention, reduced n-back working memory accuracy, and increased the false alarm rate in recognition memory. Topiramate had no effects on visual processing, other measures of psychomotor function, risk-taking, self-control, Sternberg working memory, free recall, and metamemory. These findings indicate that topiramate may cause cognitive impairment in this population. This effect may limit its acceptability and use as a treatment in individuals with chronic opioid and cocaine use disorders, among whom preexisting cognitive impairments are common. (PsycINFO Database Record

Cognitive performance in methadone maintenance patients: effects of time relative to dosing and maintenance dose level.

Given the long-term nature of methadone maintenance treatment, it is important to assess the extent of cognitive side effects. This study investigated cognitive and psychomotor performance in 51 methadone maintenance patients (MMP) as a function of time since last methadone dose and maintenance dose level. MMP maintained on doses ranging from 40 to 200 mg (mean = 97 mg) completed a battery of psychomotor and cognitive measures across 2 sessions, during peak and trough states, in a double-blind crossover design. Peak sessions were associated with worse performance on measures of sensory processing, psychomotor speed, divided attention, and working memory, compared with trough sessions. The effects of maintenance dose were mixed, with higher dose resulting in worse performance on aspects of attention and working memory, improved performance on executive function, and no effects on several measures. Longer treatment duration was associated with better performance on some measures, but was also associated with increased sensitivity to time since last dose (i.e., worse performance at peak vs. trough) on some measures. The results suggest that cognitive functioning can fluctuate as a function of time since last dose even in MMP who have been maintained on stable doses for an extended time (mean duration in treatment = 4 years), but worsened performance at peak is limited to a subset of functions and may not be clinically significant at these modest levels of behavioral effect. For patients on stable methadone maintenance doses, maintenance at higher doses may not significantly increase the risk of performance impairment.