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Positive social contact predicts better health, but the mechanisms for this association remain debated. One way to explore this link is through the social regulation of emotion, particularly anticipatory anxiety. Previous research finds less neural threat response during partner handholding than when people are alone or stranger handholding. Various mechanistic accounts have been forwarded, including the hypothesis that this effect is mediated by endogenous opioid activity. This experiment critically tested the opioid hypothesis in 60 married participants and their partners. The study used a naltrexone opioid blockade in a double-blind placebo control with functional magnetic resonance imaging to determine whether endogenous opioids were necessary for handholding effects. Regulatory effects of supportive handholding manifested in threat network regions during opioid blockade, but not with placebo. Despite a surprising lack of effect in the placebo group, the overall study findings provide initial evidence that endogenous opioids may not be necessary for the social regulation of neural threat responding.

Individuals who work nonstandard schedules, such as rotating or night shifts, are more susceptible to workplace injuries, performance decrements, and reduced productivity. This population is also almost twice as likely to use illicit drugs as individuals working a standard day shift. The purpose of this study was to examine the effects of smoked marijuana on performance, mood, and sleep during simulated shift work. Ten experienced marijuana smokers completed this 23-day, within-participant residential study. They smoked a single marijuana cigarette (0, 1.9, 3.56% Δ9-THC) one hour after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an ‘off’ day. When participants smoked placebo cigarettes, psychomotor performance and subjective-effect ratings were altered during the night shift compared to the day shift: performance (e.g., vigilance) and a few subjective ratings were decreased (e.g., “Self-Confident”), whereas other ratings were increased (e.g., “Tired”). Objective and subjective measures of sleep were also disrupted, but to a lesser extent. Marijuana attenuated some performance, mood, and sleep disruptions: participants performed better on vigilance tasks, reported being less miserable and tired and sleep a greater number of minutes. Limited negative effects of marijuana were noted. These data demonstrate that abrupt shift changes produce performance, mood, and sleep decrements during night shift work and that smoked marijuana containing low to moderate Δ9-THC concentrations can offset some of these effects in frequent marijuana smokers.

This prospective, randomized, active-controlled, non-inferiority study evaluated the efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet (Zubsolv®; buprenorphine/naloxone rapidly dissolving tablet) versus generic buprenorphine for induction of opioid maintenance among dependent adults. The study, conducted at 13 sites from June 2013 to January 2014, included a 2-day blinded induction phase and a 27-day open-label stabilization/maintenance phase. During the blinded induction, patients received fixed doses of buprenorphine/naloxone rapidly dissolving tablets or generic buprenorphine. During open-label stabilization/early maintenance, all patients received buprenorphine/naloxone rapidly dissolving tablets. The primary efficacy assessment was treatment retention at day 3; buprenorphine/naloxone rapidly dissolving tablets were considered non-inferior to generic buprenorphine if the lower limit of the 95% confidence interval for the difference between the treatments was ≥-10% in patients retained on day 3. Secondary assessments included opioid withdrawal symptoms and cravings as measured using the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the opioid cravings visual analogue scale. Safety was also assessed. A total of 313 patients were randomly assigned to induction with generic buprenorphine or buprenorphine/naloxone rapidly dissolving tablets. The mean age was 38.4 years, and the mean duration of opioid dependence was 12.4 years. For the primary efficacy assessment, 235 of 256 patients (91.8%) were retained at day 3 and continued to the maintenance phase. The lower limit of the 95% confidence interval was -13.7; thus, buprenorphine/naloxone rapidly dissolving tablets did not demonstrate non-inferiority to generic buprenorphine, and significantly more patients who received induction with generic buprenorphine (122/128 [95.3%]) were retained at day 3 compared with those who received induction with buprenorphine/naloxone rapidly dissolving tablets (113/128 [88.3%]; 95% confidence interval: -13.7, -0.4; p = 0.040). The rates of clinical response, as measured by the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the visual analogue scale, were comparable among patients regardless of the induction medication. Treatment with buprenorphine/naloxone rapidly dissolving tablets was generally safe and reduced the severity of withdrawal symptoms and cravings.

Objectives: The aim of the study was to evaluate treatment retention, efficacy, and preference ratings among opioid-dependent patients transitioning between a buprenorphine/naloxone rapidly dissolving sublingual tablet formulation (BNX-RDT) and BNX film. Methods: After a 2-day, blinded, fixed-dose induction with BNX-RDT (5.7/1.4 mg and 5.7/1.4 or 11.4/2.8 mg, respectively) or buprenorphine (8 mg and 8 or 16 mg, respectively), patients received open-label titrated doses of BNX-RDT or BNX film (generic buprenorphine induction group) during days 3 to 14. On day 15, patients switched treatment (using a conversion ratio of 5.7–8 mg) and continued switched treatment through day 22. Assessments included treatment retention, opioid withdrawal (Clinical and Subjective Opiate Withdrawal scales), opioid cravings (0–100 visual analog scale [VAS]), and preference ratings. Results: Of the 287 patients who switched from BNX-RDT to BNX film and 279 patients who switched from BNX film to BNX-RDT at day 15, 8.7% and 6.1% withdrew, respectively. Reductions in opioid withdrawal and cravings were similar with both formulations through day 15; after switching treatment, reductions were maintained through day 22 in both groups. Preference ratings at day 22 (patients had received both formulations) favored BNX-RDT for taste, mouthfeel, ease of administration, and overall preference (all P

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT(®)), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n= 346) who met DSM–5 criteria for at least moderate AUD were recruited across 10 US clinical sites. Participants received double-blind GE-XR (600 mg twice a day [BID]) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were pre-specified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs 21.5, respectively, p=0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSION: Overall, GE-XR at 600 mg BID did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the FDA for treating other medical conditions.

Purpose Sublingual buprenorphine and combination buprenorphine/naloxone (BNX) are effective options for the treatment of opioid dependence. A BNX sublingual tablet approved by the US Food and Drug Administration for the induction and maintenance treatment of opioid-dependence in adults was developed as a higher-bioavailability formulation, allowing for a 30% lesser dose of buprenorphine with bioequivalent systemic exposure compared with another BNX sublingual tablet formulation. No data were previously available comparing the higher-bioavailability BNX sublingual tablet to generic buprenorphine or BNX sublingual film; we therefore evaluated treatment retention during induction and stabilization with the higher-bioavailability BNX sublingual tablet versus generic buprenorphine or BNX sublingual film. Methods This multicenter, prospective, randomized, parallel-group noninferiority trial was conducted at 43 centers in the United States. Eligible patients were adults aged 18 to 65 years who met the criteria for opioid dependence and had at least mild withdrawal symptoms. On days 1 and 2, patients received blinded, fixed-dose induction with the higher-bioavailability BNX sublingual tablet or generic buprenorphine. On days 3 to 14, patients induced with BNX received open-label, titrated doses of the BNX tablet for stabilization; patients induced with buprenorphine received sublingual BNX film. Co-primary end points were treatment retention on days 3 and 15; noninferiority was concluded if the lower limit of the 95% CI of the between-group difference in treatment retention was ≥−10%. Tolerability was assessed throughout the study period. Findings A total of 758 opioid-dependent patients were included in the study (BNX sublingual tablet, 383 patients; generic buprenorphine, 375). Day-3 retention rates were 93.9% (309/329) and 92.6% (302/326) with the BNX tablet and buprenorphine, respectively (between-group difference 95% CI, −2.6 to 5.1). Day-15 retention rates were 83.0% (273/329) and 82.5% (269/326) with the BNX tablet and BNX film, respectively (between-group difference 95% CI, –5.3 to 6.3). No unexpected tolerability issues were identified; the safety profile of the BNX sublingual tablet was similar to those of generic buprenorphine and BNX film. Implications Based on the findings from this study in patients with opioid dependence , the higher-bioavailability BNX sublingual tablet formulation was noninferior to both generic buprenorphine (induction) and BNX film (stabilization). These findings suggest that BNX sublingual tablets are an efficacious and well-tolerated option for induction and early stabilization treatment of opioid dependence. ClinicalTrials.gov identifier: NCT01908842.

Background Despite growing concern about the increased rates of synthetic cannabinoid (SC) use and their effects, only limited data are available that addresses these issues. This study assessed the extent of SC product use and reported effects among a cohort of adult marijuana and tobacco users. Methods A brief telephone interview was conducted with individuals who had given permission to be contacted for future research while screening for a cannabis/nicotine dependence medication development study (NCT01204723). Results Respondents ( N = 42; 88% participation rate) were primarily young adults, male, racially diverse, and high school graduates. Nearly all currently smoked tobacco and cannabis, with 86% smoking cannabis on 5 or more days per week. Nearly all (91%) were familiar with SC products, half (50%) reported smoking SC products previously, and a substantial minority (24%) reported current use (i.e., past month). Despite a federal ban on 5 common SCs, which went into effect on March 1, 2011, a number of respondents reported continued SC product use. Common reasons reported for use included, but were not limited to, seeking a new “high” similar to that produced by marijuana and avoiding drug use detection via a positive urine screen. The primary side effects were trouble thinking clearly, headache, dry mouth, and anxiety. No significant differences were found between synthetic cannabinoid product users (ever or current) and nonusers by demographics or other characteristics. Conclusions Among current marijuana and tobacco users, SC product consumption was common and persisted despite a federal ban. The primary reasons for the use of SC-containing products seem to be to evade drug detection and to experience a marijuana-like high.

There is a growing concern about the availability of a new generation of "designer drug" stimulants that are marketed as "bath salts" and other household products. The products are not true bath salts and contain substituted cathinone stimulant substances, such as methylenedioxypyrovalerone (MDPV) and mephedrone. Calls to the American Association of Poison Control Centers regarding "bath salts" consumption began in 2010 and have continued since that time. Few reports of systematic epidemiologic surveillance or definitive clinical effects of toxicity specifically associated with "bath salts" consumption have been reported in the medical literature. The current narrative review describes the growing trend of designer substituted cathinone use, pharmacology, clinical effects, and recent regulatory changes. It is hoped that a greater understanding of the clinical effects and use patterns will help inform policy and practice.

In this report, we describe a case of intranasal "bath salts"-associated psychosis. Symptoms developed during a 3-week binge and were potentially exacerbated by oral diphenhydramine taken for insomnia. The clinical case conference includes expert discussion from 3 disciplines: emergency medicine toxicology, behavioral pharmacology, and addiction medicine. It is hoped that the discussion will provide insight into the clinical aspects and challenges of addressing acute substituted cathinone toxicity, including acute psychosis, a major adverse effect of bath salts consumption.

Topiramate, presumably through antagonism of excitatory glutaminergic pathways and facilitation of inhibitory gamma-aminobutyric acid neurons in the cortico-mesolimbic system, might reduce cocaine’s abuse liability. We tested whether topiramate (100 mg twice daily) would reduce the euphoria, subjective mood, craving, and preference for cocaine over money induced by low and high doses (0.325 and 0.650 mg/kg i.v., respectively) of experimentally administered cocaine in 24 male and female, cocaine-dependent, non-treatment-seeking research volunteers in a university inpatient laboratory. We utilized a randomized, double-blind, placebo-controlled, within-subject, Latin-square crossover design in which 3 experimental challenge doses of low-dose cocaine, high-dose cocaine, and placebo were administered in counterbalanced order after 5 days of topiramate or matching placebo pretreatments separated by a 1-week washout period (2006–2009). After placebo pretreatments, cocaine produced dose-related increases in euphoria, stimulant effects, craving for more cocaine, and monetary value of cocaine in a behavioral preference test of cocaine vs. money choice. Topiramate pretreatment reduced the cocaine-related craving and monetary value of high-dose cocaine while increasing the monetary value, euphoria, and stimulant effects of low-dose cocaine. Validated and standardized human experimental methods evaluating the potential for topiramate to alter cocaine’s abuse liability suggest that topiramate may reduce the reinforcing effects and craving induced by higher cocaine doses. Low-dose cocaine might appear to have some enhancement of its stimulant properties in the presence of topiramate’s prominent sedative effects.

Cannabis, the most commonly used illicit substance, exerts its primary psychoactive effect via delta-9 tetrahydrocannabinol (Δ(9) -THC) agonism of cannabinoid receptor type 1 (CB1). Some users develop a cannabis use disorder and physical dependence manifested by withdrawal symptoms during abstinence. Hence, there is growing public health concern about increasing use of a new generation of synthetic cannabinoid (SC) agonists (eg, JWH-018, CP 47,497) marketed as natural herbal incense mixtures under brand names such as "Spice" and "K2." Anecdotal reports suggest overlapping effects with marijuana when the mixtures are smoked, however, systematic evaluation of SC-related psychoactive properties and adverse effects is lacking. We conducted a systematic review of published reports on SC clinical effects in humans. Most highlight potential toxicity such as acute anxiety and psychosis. In addition, we carefully document three cases in which experienced marijuana users meeting criteria for cannabis dependence with physiologic dependence smoked SC products regularly. The SC mixture effects were reportedly similar to marijuana and well tolerated. The individuals all reported that SC product use effectively alleviated cannabis withdrawal. Biopsychosocial factors associated with SC initiation and usage by the cases help to shed light on psychopharmacologic, clinical, and public health aspects of SC product consumption.

Aims There are no studies directly comparing self-administration of methamphetamine and d-amphetamine by humans. This study compared intranasal methamphetamine- and d-amphetamine self-administration and characterized the mood, performance and physiological effects produced by the drugs. Design A randomized, double-blind, placebo-controlled, cross-over study. Setting An out-patient research unit at the New York State Psychiatric Institute. Participants Male recreational methamphetamine users (n = 13). Measurements Five 2-day blocks of sessions were conducted. On the first day of each block, participants ‘sampled’ a single methamphetamine or d-amphetamine dose (0, 12, 50 mg/70 kg) and a monetary reinforcer ($5 or $20). Amphetamine plasma levels, cardiovascular, mood, and psychomotor performance effects were assessed before drug administration and repeatedly thereafter. On the second day of each block, participants chose between the sampled reinforcers (drug or money). Findings There were no significant differences between the drugs on the majority of measures. Under the $5 condition, both amphetamines increased self-administration dose-dependently, with 41% drug choices overall. Under the $20 condition, only 17% drug options were selected. Both drugs increased cardiovascular activity and ‘positive’ mood, although methamphetamine produced more prominent effects on some measures (e.g. heart rate and ratings of ‘high’). Conclusions Methamphetamine and d-amphetamines appear to produce a similar dose-related profile of effects in humans, which supports their equivalence for abuse potential.

Buprenorphine induction poses a barrier for physician adoption of office-based opioid dependence treatment. We conducted a retrospective chart review of the first 41 patients inducted at a newly established outpatient treatment program to examine the induction process and determine strategies associated with greater induction efficiency. Timed withdrawal scales, medication log, and notes enabled reconstruction of the initial day of buprenorphine treatment. To assess change with experience, consecutive patients were divided into three chronological groups for analyses (Phases 1–3). The time required for induction was substantial in Phase 1 (mean 5.5 hours), but temporal efficiency improved to a mean 1.5 hours spent at the program by Phase 3 (p

Although methamphetamine and alcohol are commonly used together in a binge-like pattern, there is a dearth of empirical data investigating the repeated effects of this drug combination. The current study examined acute and residual mood, performance, and physiological effects of methamphetamine alone, alcohol alone, and the combination. Nine adult male volunteers completed this 20-day within-participant, residential laboratory study. During four 5-day blocks of sessions, participants were administered oral methamphetamine (0, 10 mg) combined with alcohol (0, 0.375, 0.75 g/kg) three times (day 2: AM, day 2: PM, and day 3: PM). Breath alcohol concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and repeatedly thereafter. Subjective and objective sleep measures were also assessed; residual effects were assessed on days 3–5 of each block. Following the first drug administration, the methamphetamine–alcohol combination produced greater elevations of heart rate and ratings of “good drug effect” compared to either drug alone. Methamphetamine attenuated alcohol-related performance decrements and feelings of intoxication, whereas alcohol attenuated methamphetamine-related sleep disruptions. By the third administration, many of these effects were significantly diminished, suggesting that participants developed tolerance. Few residual effects were observed. These data show that methamphetamine combined with alcohol produced a profile of effects that was different from the effects of either drug alone. The largely positive effects of the drug combination (i.e., greater euphoria, and fewer performance and sleep disruptions) might explain why these drugs are often used in combination.

Despite their chemical similarities, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) produce differing neurochemical and behavioral responses in animals. In humans, individual studies of methamphetamine and MDMA indicate that the drugs engender overlapping and divergent effects; there are only limited data comparing the two drugs in the same individuals.This study examined the effects of methamphetamine and MDMA using a within-subject design.Eleven adult volunteers completed this 13-day residential laboratory study, which consisted of four 3-day blocks of sessions. On the first day of each block, participants received oral methamphetamine (20, 40 mg), MDMA (100 mg), or placebo. Drug plasma concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and after. Food intake and sleep were also assessed. On subsequent days of each block, placebo was administered and residual effects were assessed.Acutely, both drugs increased cardiovascular measures and "positive" subjective effects and decreased food intake. In addition, when asked to identify each drug, participants had difficulty distinguishing between the amphetamines. The drugs also produced divergent effects: methamphetamine improved performance and disrupted sleep, while MDMA increased "negative" subjective-effect ratings. Few residual drug effects were noted for either drug.It is possible that the differences observed could explain the differential public perception and abuse potential associated with these amphetamines. Alternatively, the route of administration by which the drugs are used recreationally might account for the many of the effects attributed to these drugs (i.e., MDMA is primarily used orally, whereas methamphetamine is used by routes associated with higher abuse potential).

Rationale Previously, we reported that acute marijuana intoxication minimally affected complex cognitive performance of daily marijuana smokers. It is possible that the cognitive tests used were insensitive to marijuana-related cognitive effects. Objectives In the current study, electroencephalographic (EEG) signals were recorded as daily marijuana users performed additional tests of immediate working memory and delayed episodic memory, before and after smoking marijuana. Methods Research volunteers (N = 24), who reported smoking ∼ 24 marijuana cigarettes/week, completed this study. Participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% ∆ 9 -THC w/w), and completed additional cognitive tasks; sessions were separated by at least 72-hours. Cardiovascular and subjective effects were also assessed throughout sessions. Results Overall performance accuracy was not significantly altered by marijuana, although the drug increased response times during task performance and induced a response bias towards labeling “new” words as having been previously seen in the verbal episodic memory task. Marijuana reduced slow wave evoked potential amplitude in the episodic memory task and decreased P300 amplitude and EEG power in the alpha band in the spatial working memory task. Heart rate and “positive” subjective-effect ratings were increased in a ∆ 9 -THC concentration-dependent manner. Conclusions Relative to previous findings with infrequent marijuana users, the frequent users in the current study exhibited similar neurophysiological effects but more subtle performance effects. These data emphasize the importance of taking into account the drug-use histories of research participants and examining multiple measures when investigating marijuana-related effects on cognitive functioning.

Although intranasal methamphetamine abuse has increased, there are no published data investigating the residual effects of the drug under controlled conditions. Thus, the current study examined the residual effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Non-treatment seeking methamphetamine abusers (n = 11) completed this two-week, in-patient, within-participant, double-blind study. The study consisted of 4 two-day blocks of sessions; each block was separated by at least 24 hrs. At approximately 1000 hrs, on the first day of each block, participants received one of four intranasal methamphetamine doses (0, 12, 25, 50 mg/70 kg). Lights were turned out at 2300 hrs that evening and sleep measures were assessed. On the morning of the second day of each block, methamphetamine plasma levels, cardiovascular measures, mood, subjective reports of the previous evening's sleep, and psychomotor performance were assessed to determine residual drug effects. The larger methamphetamine doses (25 and 50 mg) markedly disrupted subjective measures of that night's sleep and some indices of next-day mood, but only the largest dose (50 mg) dose decreased objective measures of that night's sleep and increased next-day physiological measures. Methamphetamine did not produce any negative residual effects on early next-day performance. Future studies should assess methamphetamine-related residual effects following repeated doses administered over consecutive days.

Educational initiatives are needed to improve primary care substance use screening. This study assesses the impact on 24 medical residents of a 2.5-day curriculum combining experiential and manual-based training on screening for alcohol misuse and illicit drug use. A retrospective chart review of new primary care outpatients demonstrated that nearly all were asked about current alcohol use before and after curriculum participation. Adherence to national screening guidelines on quantification of alcohol consumption modestly improved (p < .05), as did inquiry about current illicit drug use (p < .05). Continued efforts are needed to enhance educational initiatives for primary care physicians.

The increasing global public health burden of heroin dependence and prescription opioid dependence warrants further expansion of treatment models. The most effective intervention for opioid dependence remains maintenance with methadone, a full mu-opioid receptor agonist, or buprenorphine, a partial mu-opioid receptor agonist.A growing body of evidence supports the use of opioid receptor agonist maintenance in office-based settings. Office-based opioid treatment (OBOT) can expand treatment access in a less stigmatized environment, which enables integrated care of co-morbid conditions. The current review primarily examines OBOT in the US, although a comparison with the British and French models is provided, given that the public health impact and implementation of OBOT will likely vary between countries because of policy and logistical differences. The comparative effectiveness of maintenance treatment in office-based and traditional programme-based models of care requires further study. Clinical and practical considerations when providing treatment for opioid dependence in traditional versus office-based settings include patient selection and monitoring, health economics, management of co-morbid conditions, and access to ancillary psychosocial treatment. OBOT is not a replacement for more structured, traditional models of care, but provides an additional opportunity to help address the tremendous public health impact of opioid dependence.

Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and ‘positive’ subjective effects, with peaks occurring approximately 5–15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses.

Objectives Individuals with HIV constitute the largest group using cannabinoids for medicinal reasons; yet, no studies have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol maintenance in HIV-positive marijuana smokers. This placebo-controlled within-subjects study evaluated marijuana and dronabinol across a range of behaviors: eating topography, mood, cognitive performance, physiologic measures, and sleep. Methods HIV-positive marijuana smokers (n = 10) completed 2 16-day inpatient phases. Each dronabinol (5 and 10 mg) and marijuana (2.0% and 3.9% Delta9-tetrahydrocannabinol [THC]) dose was administered 4 times daily for 4 days, but only 1 drug was active per day, thereby maintaining double-blind dosing. Four days of placebo washout separated each active cannabinoid condition. Results As compared with placebo, marijuana and dronabinol dose dependently increased daily caloric intake and body weight in HIV-positive marijuana smokers. All cannabinoid conditions produced significant intoxication, except for low-dose dronabinol (5 mg); the intoxication was rated positively (eg, "good drug effect") with little evidence of discomfort and no impairment of cognitive performance. Effects of marijuana and dronabinol were comparable, except that only marijuana (3.9% THC) improved ratings of sleep. Conclusions These data suggest that for HIV-positive marijuana smokers, both dronabinol (at doses 8 times current recommendations) and marijuana were well tolerated and produced substantial and comparable increases in food intake.

The impact of regular marijuana use on executive cognitive abilities, including decision making, is not well understood. While cross-sectional studies have suggested that substance abusers exhibit impaired decision making, as assessed by the Iowa Gambling Task, the direct role of marijuana use in the Gambling Task performance of marijuana smokers has not been well defined. In this report, we present data on performance on a modified Gambling Task in experienced marijuana users after they had smoked marijuana under controlled laboratory conditions. A total of 36 marijuana users, who reported smoking approximately 24 marijuana cigarettes per week, completed this 3-session outpatient study. During each session, these volunteers completed the Gambling Task once at baseline and 3 times after smoking a single marijuana cigarette (0.0, 1.8, or 3.9% Delta9-THC). Marijuana cigarettes were administered in a double-blind fashion, and the sequence of Delta9-THC concentration was balanced across volunteers. Marijuana increased the time required to complete the task. However, advantageous card selection and money earned on the task were not disrupted by marijuana. These data are consistent with previous findings that indicated that speed of performance on tests of executive function, but not accuracy, is disrupted in experienced marijuana users during marijuana intoxication.

Background Expanded office-based buprenorphine opioid dependence treatment is associated with medication misuse and diversion consequences. Recurrent early refill requests may indicate misuse or diversion, although further research is needed on how to effectively recognize and address the issue in clinical practice. In the current study, patient report of damaged medication from laundering prompted evaluation of laundering on degradation of buprenorphine-containing product packages and contents. Methods Four buprenorphine product packaging approaches were assessed: 3 buprenorphine/naloxone placebo demonstration products (Suboxone and Bunavail film in foil wrappers and Zubsolv tablet in a blister pack) and Rexam-manufactured Screw-Loc closure pill container filled with a chewable aspirin as a surrogate for generic buprenorphine and buprenorphine/naloxone products. Two experimental laundering conditions, wash machine alone (W) and washer/dryer (W+D), were compared with unlaundered control (C) condition. Standard laundering settings were based on patient presentation. Products from the 2 experimental conditions and the control condition were labeled A, B, or C with counterbalanced assignment prior to visual examination of packaging and contents by the investigator who was blinded to condition. Results Packaging and contents remained intact for all products across experimental conditions, with only minor cosmetic effects compared with control. The W+D Suboxone film had 1–2 mm curling of the wrapper corners. Zubsolv blister packs had slight paper label fading (W+D > W). Bunavail W+D foil had an indentation outlining the inner film. The W+D bottle tablet had a ˜1 mm nick on one edge. No other differences were noted. After implementing more structured treatment and reviewing the results with the patient, he endorsed fabricating the laundering story to get additional medication. Conclusions Laundering is an unlikely cause of damaged buprenorphine-containing medication packaged in foil wrappers (Suboxone, Bunavail), blister pack (Zubsolv), or prescription pill bottle (generic buprenorphine or buprenorphine/naloxone products). Patient reports of such may indicate medication misuse or diversion.

This study attempts to determine how internal medicine housestaff screen and intervene for problematic alcohol and illicit drug use, as well as identify factors correlating with favorable practices. A cross-sectional survey was administered to 93 medical housestaff. Of 64 (69%) respondents, 94% reported routinely screening new patients for alcohol or illicit drug use, while only 52% routinely quantified alcohol consumption and 28% routinely used a screening instrument. Housestaff were unfamiliar with national guidelines and felt unprepared to diagnose substance use disorders, particularly prescription drug abuse. Most routinely counseled patients with alcohol (89%) or illicit-drug problems (91%), although only a third of these patients were referred for formal treatment. More thorough screening practices were associated with greater treatment optimism, while favorable referral practices were associated with greater optimism about 12-step program benefit and difficulty with management. These findings suggest areas to be addressed in residency curricula on substance abuse.

Synthetic cannabinoid use has increased in the United States. The consequences are dangerous, and public health concern about these products has led to international control efforts. This commentar...

For the primary care clinician treating patients with unhealthy alcohol use, pain syndromes are frequently clinical issues that pose unique challenges relative to the management of low risk or non-alcohol users with pain. Unhealthy alcohol use and its consequences may impact both the assessment and management of pain. Such considerations are particularly important when prescribing medications that can interact with alcohol or alcohol-related comorbidities, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioid medications. Rather than a comprehensive review of general pain management, this chapter provides recommendations on how to approach the patient with unhealthy alcohol use and pain. Special attention is devoted to the safe and effective use of opioid analgesics, given the inherent risks of interactions and misuse, and that observational studies demonstrate that patients with current or past alcohol use disorders are at higher risk for subsequent prescription opioid misuse.

Cannabis, the most commonly used illicit substance, exerts its primary psychoactive effect via delta-9 tetrahydrocannabinol (Δ(9) -THC) agonism of cannabinoid receptor type 1 (CB1). Some users develop a cannabis use disorder and physical dependence manifested by withdrawal symptoms during abstinence. Hence, there is growing public health concern about increasing use of a new generation of synthetic cannabinoid (SC) agonists (eg, JWH-018, CP 47,497) marketed as natural herbal incense mixtures under brand names such as "Spice" and "K2." Anecdotal reports suggest overlapping effects with marijuana when the mixtures are smoked, however, systematic evaluation of SC-related psychoactive properties and adverse effects is lacking. We conducted a systematic review of published reports on SC clinical effects in humans. Most highlight potential toxicity such as acute anxiety and psychosis. In addition, we carefully document three cases in which experienced marijuana users meeting criteria for cannabis dependence with physiologic dependence smoked SC products regularly. The SC mixture effects were reportedly similar to marijuana and well tolerated. The individuals all reported that SC product use effectively alleviated cannabis withdrawal. Biopsychosocial factors associated with SC initiation and usage by the cases help to shed light on psychopharmacologic, clinical, and public health aspects of SC product consumption.

Buprenorphine induction poses a barrier for physician adoption of office-based opioid dependence treatment. We conducted a retrospective chart review of the first 41 patients inducted at a newly established outpatient treatment program to examine the induction process and determine strategies associated with greater induction efficiency. Timed withdrawal scales, medication log, and notes enabled reconstruction of the initial day of buprenorphine treatment. To assess change with experience, consecutive patients were divided into three chronological groups for analyses (Phases 1-3). The time required for induction was substantial in Phase 1 (mean 5.5 hours), but temporal efficiency improved to a mean 1.5 hours spent at the program by Phase 3 (p .001). Phase 2-3 patients arrived to the program after significantly longer opioid abstinence and were in greater withdrawal, with mean Clinical Opioid Withdrawal Scale scores of 6, 10, and 10 for Phases 1-3, respectively (p .01). Patients in the later phases had less time delay to medication initiation, 5 minutes in Phase 3 compared to 133 minutes in Phase 1 (p .001). The mean 7-mg buprenorphine dose administered in the office did not differ between groups, but occurred over a smaller time interval for later phases indicating more rapid titration. Patients in the later phases had more rapid withdrawal relief after buprenorphine initiation and were more likely to have used preinduction ancillary withdrawal medication. The study sheds light on the induction barrier and provides practical procedural information to inform clinical guidelines and hopefully mitigate procedural aspects of the induction barrier.

Dronabinol (Δ9tetrahydrocannabinol) is approved for HIV-related anorexia, yet, little is known about its effects in HIV-positive marijuana smokers. HIV-negative marijuana smokers require higher than recommended dronabinol doses to experience expected effects. Employing a within-subjects, double-blind, placebo-controlled design, we assessed the effects of repeated high-dose dronabinol in HIV-positive marijuana smokers taking antiretroviral medication. Participants (N = 7), who smoked marijuana 4.2 ± 2.3 days/week, resided in a residential laboratory for two 16-day stays, receiving dronabinol (10 mg QID) in one stay and placebo in the other. Efficacy was assessed with objectively verified food intake and body weight. Tolerability was measured with sleep, subjective, and cognitive assessments. For analyses, each inpatient stay was divided into two phases, days 1–8 and 9–16; we compared dronabinol’s effects with placebo in each 8-day phase to investigate tolerance. Despite sustained increases in self-reported food cravings, dronabinol only increased caloric intake in the initial 8 days of dosing. Similarly, sleep quality was improved only in the first 8 days of dosing. Dronabinol’s mood-enhancing effects were sustained across the 16-day inpatient stay. Dronabinol was well tolerated, causing few negative subjective or cognitive effects. In HIV-positive marijuana smokers, high dronabinol doses safely and effectively increased caloric intake. However, repeated high-dose dronabinol appeared to result in selective tolerance to these effects. These findings indicate that HIV-positive individuals who smoke marijuana may require higher dronabinol doses than are recommended by the FDA. Future research to establish optimal dosing regimens, and reduce the development of tolerance, is required.

Physician adoption of buprenorphine treatment of opioid dependence may be limited in part by concerns regarding the induction process. Although national guidelines recommend observed induction, some physicians utilize unobserved induction outside the office. The aim of this pilot randomized clinical trial was to assess preliminary safety and effectiveness of unobserved versus observed office buprenorphine/naloxone induction among patients entering a 12-week primary care maintenance study. Participants (N=20) with DSM-IV opioid dependence were randomly assigned to unobserved or office induction, stratifying by past buprenorphine use. All patients received verbal and written instructions. A withdrawal scale was used during initiation and to monitor treatment response. Clinic visits occurred weekly for 4 weeks then decreased to monthly. The primary outcome, successful induction one week after the initial clinic visit, was defined as retention in buprenorphine/naloxone treatment and being withdrawal free. Secondary outcomes included prolonged withdrawal beyond 2 days after medication initiation and stabilization at week 4, defined as being in treatment without illicit opioid use for the preceding 2 weeks. Outcome results were similar in the two groups: 6/10 (60%) successfully inducted in each group, 3/10 (30%) experienced prolonged withdrawal, and 4/10 (40%) stabilized by week 4. These pilot study results suggest comparable safety and effectiveness of unobserved and office induction and point toward utilization of non-inferiority design during future definitive protocol development. By addressing an important barrier for physician adoption, further validation of the unobserved buprenorphine induction method will hopefully lead to increased availability of effective opioid dependence treatment.

The importance of training physicians to effectively assess and manage substance use disorders has become increasingly recognized. Studies highlighting the effort to enhance curricula are described and common practices identified. Preferable curricula incorporate interactive teaching methods along with experiential and didactic components. Addiction specialists serve an important role in training programs designed for medical students and residents (ie, role models) and practicing physicians (ie, clinical support). Further integration of online training into current programs may expand and enhance training opportunities.

To evaluate buprenorphine training methodology, we surveyed physicians who had completed a combined online and in person buprenorphine curriculum. Of 53/70 (76%) survey respondents, 57% were psychiatrists and 40% generalists. On a scale of 1 (very poor) to 7 (superlative), the overall training rated a mean of 5.8. The online course (5.0) rated lower than in person training components (p

Common complaints among shift workers are sleep disruptions and increased sleepiness while working, which may contribute to shift workers being more susceptible to diminished performance and work-related accidents. The purpose of this double-blind, within-participant study was to examine the effects of the alerting agent modafinil on cognitive/psychomotor performance, mood, and measures of sleep during simulated shift work. In all, 11 participants completed this 23-day residential laboratory study. They received a single oral modafinil dose (0, 200, 400 mg) 1 h after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an ‘off’ day. When participants received placebo, cognitive performance and subjective ratings of mood were disrupted during the night shift, relative to the day shift. Objective and subjective measures of sleep were also disrupted, but to a lesser extent. Modafinil reversed disruptions in cognitive performance and mood during the night shift. While modafinil produced few effects on sleep measures during the night shift, the largest dose produced several sleep alterations during the day shift. These data demonstrate that abrupt shift changes produced cognitive performance impairments and mood disruptions during night shift work. Therapeutic doses of modafinil attenuated night-shift-associated disruptions, but the larger dose produced some sleep impairments when administered during day-shift work.

No studies to date have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol in HIV(+) marijuana smokers.The aim of this study was to compare dronabinol (0, 10, 20, 30 mg p.o.) and marijuana [0.0, 1.8, 2.8, 3.9% Delta(9)-tetrahydrocannabinol (THC)] in two samples of HIV(+) marijuana smokers: those with (n=15) and those without (n=15) a clinically significant loss of muscle mass (90% body cell mass/height), which is one component of AIDS wasting.Mood, physical symptoms, self-selected food intake, cardiovascular data, and cognitive task performance were measured before and repeatedly after dronabinol and marijuana administration in eight 7-h sessions. Marijuana and dronabinol were administered in randomized order using a within-subject, staggered, double-dummy design.As compared to placebo, (1) marijuana (1.8, 2.8, 3.9% THC) and the lower dronabinol doses (10, 20 mg) were well tolerated (e.g., few physical symptoms, significant increases in ratings of "good drug effect") in both groups of participants; the highest dose of dronabinol (30 mg) was poorly tolerated in a subset of participants; (2) marijuana and dronabinol significantly increased caloric intake in the low bioelectrical impedance analysis (BIA) group but not in the normal BIA group; and (3) drug effects on cognitive performance were minor.These data suggest that for experienced marijuana smokers with clinically significant muscle mass loss, both dronabinol (at acute doses at least four to eight times the current recommendation) and marijuana produce substantial and comparable increases in food intake without producing adverse effects.

Recent designer drugs, also known as “legal highs,” include substituted cathinones (e.g., mephedrone, methylone, and methylenedioxypyrovalerone, often referred to as “bath salts”); synthetic cannabinoids (SCs; e.g., Spice); and synthetic hallucinogens (25I-NBOMe, or N-bomb). Compound availability has evolved rapidly to evade legal regulation and detection by routine drug testing. Young adults are the primary users, but trends are changing rapidly; use has become popular among members of the military. Acute toxicity is common and often manifests with a constellation of psychiatric and medical effects, which may be severe (e.g., anxiety, agitation, psychosis, and tachycardia), and multiple deaths have been reported with each of these types of designer drugs. Clinicians should keep designer drugs in mind when evaluating substance use in young adults or in anyone presenting with acute neuropsychiatric complaints. Treatment of acute intoxication involves supportive care targeting manifesting signs and symptoms. Long-term treatment of designer drug use disorder can be challenging and is complicated by a lack of evidence to guide treatment.