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The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine. Motivated by human electroencephalographic (EEG) findings, we recently reported that frontal midline delta-band power is an electrophysiological biomarker of reward surprise in humans and in mice. In the current series of experiments, we determined the impact of parametric doses of d-amphetamine on this reward-related EEG response from humans (n = 23) and mice (n = 28) performing a probabilistic learning task. In humans, d-amphetamine (placebo, 10 mg, 20 mg) boosted the Reward Positivity event-related potential (ERP) component as well as the spectral delta-band representations of this signal. In mice, d-amphetamine (placebo, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) boosted both reward and punishment ERP features, yet there was no modulation of spectral activities. In sum, the present results confirm the role of dopamine in the generation of the Reward Positivity in humans, and pave the way toward a pharmacologically valid biomarker of reward sensitivity across species.

Rationale: Behavioral economic drug purchase tasks quantify the reinforcing value of a drug (i.e., demand). Although widely used to assess demand, drug expectancies are rarely accounted for and may introduce variability across participants given diverse drug experiences. Objectives: Three experiments validated and extended previous hypothetical purchase tasks by using blinded drug dose as a reinforcing stimulus, and determined hypothetical demand for experienced effects while controlling for drug expectancies. Methods: Across three double-blind, placebo-controlled, within-subject experiments, cocaine (0, 125, 250 mg/70 kg; n=12), methamphetamine (0, 20, 40 mg; n=19), and alcohol (0, 1 g/kg alcohol; n=25) were administered and demand was assessed using the Blinded-Dose Purchase Task. Participants answered questions regarding simulated purchasing of the blinded drug dose across increasing prices. Demand metrics, subjective effects, and self-reported real-world monetary spending on drugs were evaluated. Results: Data were well modeled by the demand curve function, with significantly higher intensity (purchasing at low prices) for active drug doses compared to placebo for all experiments. Unit-price analyses revealed more persistent consumption across prices (lower α) in the higher compared to lower active dose condition for methamphetamine (a similar non-significant finding emerged for cocaine). Significant associations between demand metrics, peak subjective effects, and real-world spending on drugs also emerged across all experiments. Conclusions: Orderly demand curve data revealed differences across drug and placebo conditions, and relations to real-world measures of drug spending, and subjective effects. Unit-price analyses enabled parsimonious comparisons across doses. Results lend credence to the validity of the Blinded-Dose Purchase Task, which allows for control of drug expectancies. [ABSTRACT FROM AUTHOR]

Rationale: Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health. Objectives: This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act. Results: LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks. Conclusions: LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling. [ABSTRACT FROM AUTHOR]

RationaleUpregulation of α4β2* nicotinic acetylcholine receptors (nAChRs) is one of the most well-established effects of chronic cigarette smoking on the brain. Prior research by our group gave a preliminary indication that cigarette smokers with concomitant use of caffeine or marijuana have altered nAChR availability.ObjectiveWe sought to determine if smokers with heavy caffeine or marijuana use have different levels of α4β2* nAChRs than smokers without these drug usages.MethodsOne hundred and one positron emission tomography (PET) scans, using the radiotracer 2-FA (a ligand for β2*-containing nAChRs), were obtained from four groups of males: non-smokers without heavy caffeine or marijuana use, smokers without heavy caffeine or marijuana use, smokers with heavy caffeine use (mean four coffee cups per day), and smokers with heavy marijuana use (mean 22 days of use per month). Total distribution volume (Vt/fp) was determined for the brainstem, prefrontal cortex, and thalamus, as a measure of nAChR availability.ResultsA significant between-group effect was found, resulting from the heavy caffeine and marijuana groups having the highest Vt/fp values (especially for the brainstem and prefrontal cortex), followed by smokers without such use, followed by non-smokers. Direct between-group comparisons revealed significant differences for Vt/fp values between the smoker groups with and without heavy caffeine or marijuana use.ConclusionsSmokers with heavy caffeine or marijuana use have higher α4β2* nAChR availability than smokers without these drug usages. These findings are likely due to increased nicotine exposure but could also be due to an interaction on a cellular/molecular level.

Rationale: Misuse of dextroamphetamine occurs in work and recreational contexts. While acute drug effects broadly predict abuse liability, few studies have considered the relationship between acute effects and context. Objectives: This study examined how individual differences in acute effects of dextroamphetamine relate to desire to take dextroamphetamine again in different contexts. Methods: This secondary analysis used data from healthy adults with no history of moderate-to-severe substance use disorder, who received oral doses of placebo and dextroamphetamine (10 and 20 mg) over 3 sessions under double-blind, randomized conditions. Subjects rated subjective effects and completed reward-related behavioral tasks. Subjects rated their desire to take dextroamphetamine again in hypothetical work and recreational contexts. Multilevel models examined within-subjects change scores (10 mg-placebo; 20 mg-placebo) to determine how subjective effects and behavioral outcomes predicted desire to take dextroamphetamine again for work versus recreation. Results: Subjects reported more desire to take 20 mg dextroamphetamine again for work than for recreation. At 20 mg, there was an interaction between context and liking/wanting, such that liking/wanting predicted desire to use dextroamphetamine for work only. There was also an interaction at 20 mg between context and psychomotor speed, such that psychomotor speed predicted interest in using dextroamphetamine for recreation only. Conclusions: We found that positive subjective effects predicted desire to use dextroamphetamine again for work, while increased motor effects predicted desire to use dextroamphetamine recreationally. Hedonic effects may be perceived as advantageous when working, while increased physical energy may be preferred during recreation, suggesting that context of intended use is important when examining abuse liability. [ABSTRACT FROM AUTHOR]

Rationale: Preclinical studies demonstrate that the NK1 receptor is involved in opioid reinforcement and withdrawal expression. Few studies have examined the impact of treatment with NK1 antagonists on opioid response in humans. Objective: To explore the potential for a selective NK1 antagonist, tradipitant, to attenuate the abuse liability and reinforcing and analgesic effects of oxycodone in opioid-experienced individuals. Methods: Participants with recreational opioid use, but without opioid physical dependence, were enrolled as inpatients for ~6 weeks (n = 8). A within-subject, double-blind, randomized, placebo-controlled, crossover design was employed. The pharmacodynamic response to intranasal oxycodone across a range of doses (0 to 30 mg) was examined during two counterbalanced maintenance periods (tradipitant 0 or 85 mg/bid). Oxycodone self-administration was assessed with a modified progressive ratio procedure, and analgesia was assessed with the cold pressor test. Results: Oxycodone produced significant and dose-related increases on a broad array of prototypic opioid measures, including subjective ratings related to abuse liability (e.g., liking) and physiological outcomes (i.e., expired CO2). Oxycodone self-administration increased with increasing dose, as did analgesia. Tradipitant largely did not alter any of these effects of oxycodone, with the exception of producing a reduction in ratings of desire for opioids. Conclusions: Given that the vast majority of oxycodone effects were unchanged by tradipitant, these data do not provide support for the utility of NK1 antagonists as a potential treatment for opioid use disorder. [ABSTRACT FROM AUTHOR]

Rationale: Epidemiological data indicate that drivers testing positive for an opioid drug are twice as likely to cause a fatal car crash; however, there are limited controlled data available. Objectives: The primary aim of this study was to assess the effects of a therapeutic dose range of oxycodone alone and in combination with alcohol on simulated driving performance. Methods: Healthy participants (n = 10) completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Six 7-h sessions were completed during which oxycodone (0, 5, 10 mg, p.o.) was administered 30 min before alcohol (0, 0.8 g/kg (15% less for women), p.o.) for a total of 6 test conditions. Driving assessments and participant-, observer-rated, psychomotor and physiological measures were collected in regular intervals before and after drug administration. Results: Oxycodone alone (5, 10 mg) did not produce any changes in driving outcomes or psychomotor task performance, relative to placebo (p > 0.05); however, 10 mg oxycodone produced increases in an array of subjective ratings, including sedation and impairment (p < 0.05). Alcohol alone produced driving impairment (e.g., decreased lateral control) (p < 0.05); however, oxycodone did not potentiate alcohol-related driving or subjective effects. Conclusions: These preliminary data suggest that acute doses of oxycodone (5, 10 mg) do not significantly impair acuity on laboratory-based simulated driving models; however, 10 mg oxycodone produced increases in self-reported outcomes that are not compatible with safe driving behavior (e.g., sedation, impairment). Additional controlled research is needed to determine how opioid misuse (higher doses; parenteral routes of administration) impacts driving risk. [ABSTRACT FROM AUTHOR]

Rationale: Cannabidiol (CBD) products lacking regulatory approval are being used to self-treat a myriad of conditions and for their unsubstantiated health benefits. The scientific evidence supporting these claims largely arises not from controlled clinical trials, but from the recognition that CBD has numerous biological targets. Yet, CBD is commonly consumed and often in over-the-counter products that are unapproved and of unknown composition. Epidiolex® is the only product that has undergone rigorous pharmacokinetic assessment and testing in clinical trials; it was approved as a non-scheduled drug by the U.S. Food and Drug Administration for the treatment of intractable childhood-onset seizures. However, studies investigating CBD for other medical conditions are limited in number and often lack the scientific rigor, controls, or sample sizes required to draw clinically meaningful conclusions. Although Epidiolex® is safe for human consumption, recent changes in regulation of commercially available CBD products have resulted in limited quality control and products marketed with unknown CBD bioavailability. Even scientifically rigorous studies have used different sources of CBD and different suspension vehicles for administration, making it difficult to compare results among studies and resolve mixed outcomes. Objectives: This paper reviews the molecular targets, pharmacokinetics, and safety and abuse liability of CBD; additionally, the extant evidence on its potential therapeutic effects for neurological disorders, pain, inflammation, conditions related to immune function, psychiatric disorders, and substance use are described. [ABSTRACT FROM AUTHOR]

Rationale: Behavioral disturbances (BD) are prevalent in patients with substance use disorders (SUD). Objectives: To test the hypothesis that chronic exposure to cocaine could favor the acquisition of BD that were not present in childhood. Methods: We used child and adult ADHD self-report screening scales (WURS-25 and ASRS-6, respectively, with their usual threshold) as assessment tools for significant BD. In a cross-sectional assessment of 382 patients with multiple SUD, we investigated BD and then "de novo" BD (i.e., by restricting the sample to patients below the threshold for childhood BD) (N = 214). We also tested for a gradient effect between patients' lifetime DSM IV cocaine and opioid dependence status and the prevalence of BD. Results: BD were found in 188/382 (42.9%) subjects and in 74/214 (34.6%) subjects. Three clinical factors were associated with BD in the whole sample: the number of cocaine dependence criteria (OR = 1.36 [1.14–1.64], p = 0.001), the number of opioid dependence criteria (OR = 0.69 [0.52–0.91], p = 0.010), and a personal history of using cocaine through rapid routes of administration (OR = 0.41 [0.19–0.88], p = 0.022). The same three factors were associated with "de novo" BD in the restricted sample: OR = 1.35 ([1.11–1.63], p = 0.002), OR = 0.83 ([0.70–0.99], p = 0.046), and OR 0.37 ([0.16–0.86], p = 0.022), respectively. There were significant gradients for BD according to the cocaine exposure categories in the whole (Mantel-Haenszel, p < 0.001) and in the restricted sample (Mantel-Haenszel, p = 0.002). Conclusions: Cocaine exposure was positively associated with behavioral disturbances in a dose-dependent manner in this clinical sample, whilst opioid exposure showed a negative association. [ABSTRACT FROM AUTHOR]

Rationale: Dozens of preclinical studies have reported cannabinoid agonist potentiation of the analgesic effects of μ-opioid agonists. Objectives: The aim of this study was to determine if a cannabinoid agonist could potentiate opioid analgesia in humans using several laboratory pain models. Methods: Healthy participants (n = 10) with/out current drug use/pain conditions completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Nine 8-h sessions were completed during which dronabinol (0, 2.5, 5 mg, p.o.) was administered 1 h before oxycodone (0, 5, 10 mg, p.o.) for a total of 9 test conditions. Outcomes included sensory threshold and tolerance from four experimental pain models (cold pressor, pressure algometer, hot thermode, cold hyperalgesia), along with participant- and observer-rated, performance and physiological effects. Results: Oxycodone produced miosis (p < 0.05) and analgesic responses (e.g., pressure algometer [p < 0.05]), while dronabinol did not (p > 0.05). Depending on the dose combination, dronabinol attenuated or did not alter oxycodone analgesia; for example, dronabinol (2.5 mg) decreased the analgesic effects of oxycodone (10 mg) on pressure tolerance. Conversely, dronabinol increased oxycodone subjective effects (e.g., drug liking) (p < 0.05); oxycodone (5 mg) ratings of "high" were potentiated by 5 mg dronabinol (p < 0.05; placebo = 1.1 [± 0.7]; 5 mg oxycodone = 4.7 [± 2.2]; 5 mg dronabinol = 9.9 [± 8.4]; 5 mg oxycodone + 5 mg dronabinol = 37.4 [± 11.3]). Conclusions: This study indicates that dronabinol did not enhance the analgesic effects of oxycodone and increased abuse- and impairment-related subjective effects. These data suggest that dronabinol may not be an effective or appropriate opioid adjuvant; it could potentially increase opioid dose requirements, while increasing psychoactive opioid effects. [ABSTRACT FROM AUTHOR]

Rationale: The serotonergic system has been repeatedly linked to visual attention in general, but the effects of selective serotonin reuptake inhibitor (SSRI) on specific components of visual attention remain unknown. Changes in distinct perceptual and cognitive processes are not readily evident in most attention paradigms. Objective: In this study, we isolate basic components of visual attention to investigate potential effects of longer-term SSRI administration on non-emotional aspects of visual attention in healthy males. Methods: In a randomized double-blind placebo-controlled design, 32 young healthy males were tested on multiple attentional parameters, before and after a 3-week SSRI intervention with fluoxetine (40 mg daily) or placebo. Data were modeled with a computational theory of visual attention to derive independent estimates of five distinct components of visual attention. Results: The SSRI intervention selectively and significantly lowered the threshold for conscious visual perception. Specifically, we demonstrate that this improvement does not stem from a general increase in the speed of visual processing, as previously suggested, but specifically from a change in the perceptual threshold. Conclusions: The study provides a novel description of the attentional dynamics affected by SSRI, while supporting previous findings on attentional effects of SSRI. Furthermore, it accentuates the utility of employing accuracy-based measures of attentional performance when conducting psychopharmacological research. [ABSTRACT FROM AUTHOR]

Rationale: Better means to control placebo effects are key to optimizing treatment outcomes. Dopamine-based reward and learning mechanisms have been hypothesized to drive placebo effects. Here, we tested whether dopamine augmentation can modulate learned placebo effects.Methods: We performed a randomized, double-blind parallel group study with 70 healthy adult participants to test whether a single oral dose of the dopamine precursor levodopa/carbidopa (100/25 mg) administered before the acquisition of conditioned placebo analgesia enhances the placebo response in an established experimental placebo model using heat pain.Results: Overall, the observed levels of placebo analgesia in our sample were low and not statistically significant. Levodopa, compared to placebo, only led to a marginal increase in placebo analgesia. Female participants tended to show larger placebo responses than male participants. Within the female subgroup, levodopa showed small-to-moderate effects on placebo analgesia; however, this effect was not statistically significant.Conclusions: In summary, the present study could not provide evidence for a placebo augmenting effect of levodopa-enhanced dopamine levels in healthy subjects. Further studies are needed to elucidate whether placebo enhancement can be achieved through dopamine augmentation. [ABSTRACT FROM AUTHOR]

Rationale: Disruption of auditory event-related evoked potentials (ERPs) P300 and mismatch negativity (MMN), electrophysiological markers of attentive and pre-attentive cognitive processing, is repeatedly described in psychosis and schizophrenia. Similar findings were observed in a glutamatergic model of psychosis, but the role of serotonergic 5-HT2A receptors in information processing is less clear.Objectives: We studied ERPs in a serotonergic model of psychosis, induced by psilocybin, a psychedelic with 5-HT2A/C agonistic properties, in healthy volunteers.Methods: Twenty subjects (10M/10F) were given 0.26 mg/kg of psilocybin orally in a placebo-controlled, double-blind, cross-over design. ERPs (P300, MMN) were registered during the peak of intoxication. Correlations between measured electrophysiological variables and psilocin serum levels and neuropsychological effects were also analyzed.Results: Psilocybin induced robust psychedelic effects and psychotic-like symptoms, decreased P300 amplitude (p = 0.009) but did not affect the MMN. Psilocybin’s disruptive effect on P300 correlated with the intensity of the psychedelic state, which was dependent on the psilocin serum levels. We also observed a decrease in N100 amplitude (p = 0.039) in the P300 paradigm and a negative correlation between P300 and MMN amplitude (p = 0.014).Conclusions: Even though pre-attentive cognition (MMN) was not affected, processing at the early perceptual level (N100) and in higher-order cognition (P300) was significantly disrupted by psilocybin. Our results have implications for the role of 5-HT2A receptors in altered information processing in psychosis and schizophrenia. [ABSTRACT FROM AUTHOR]

Background: The theory of behavioral tolerance to alcohol posits that greater experience with drinking to intoxication leads to less impaired cognitive and psychomotor performance. However, the degree to which behavioral tolerance develops or changes over time in adults due to repeated heavy alcohol drinking has not been clearly demonstrated. Method: We examined data from the first 6 years of the Chicago Social Drinking Project to test whether chronic heavy drinkers (HDs; n = 86) and light drinkers (LDs; n = 69) exhibit behavioral tolerance or changes in perceived impairment at two testing phases in early adulthood. Tasks were the Grooved Pegboard and Digit Symbol Substitution Test (DSST) given at initial testing and then repeated in a re-examination phase 5 years later. Alcohol (0.8 g/kg) and placebo were administered at separate sessions in each phase for a total of 620 individual laboratory sessions. Results: HDs exhibited less impairment over time on the Pegboard task but not on the DSST, while LDs did not exhibit behavioral tolerance on either task. HDs reported persistently lower perceived impairment compared to LDs. Conclusions: These findings demonstrate that behavioral tolerance in HDs is evident over time on rote fine motor skills (Pegboard) but not more complex skills integrating motor speed, encoding, and short-term memory (DSST). The results have implications for our understanding of alcohol-induced impairments across neurobehavioral processes in heavy drinkers and their ongoing risks for alcohol-related consequences over time. [ABSTRACT FROM AUTHOR]

Rationale: Combining alcohol and caffeine is associated with increased alcohol consumption, but no prospective experimental studies have examined whether added caffeine increases alcohol consumption. Objectives: This study examined how caffeine alters alcohol self-administration and subjective reinforcing effects in healthy adults. Methods: Thirty-one participants completed six double-blind alcohol self-administration sessions: three sessions with alcohol only (e.g., beverage A) and three sessions with alcohol and caffeine (e.g., beverage B). Participants chose which beverage to consume on a subsequent session (e.g., beverage A or B). The effects of caffeine on overall beverage choice, number of self-administered drinks, subjective ratings (e.g., Biphasic Alcohol Effects Scale), and psychomotor performance were examined. Results: A majority of participants (65%) chose to drink the alcohol beverage containing caffeine on their final self-administration session. Caffeine did not increase the number of self-administered drinks. Caffeine significantly increased stimulant effects, decreased sedative effects, and attenuated decreases in psychomotor performance attributable to alcohol. Relative to nonchoosers, caffeine choosers reported overall lower stimulant ratings and reported greater drinking behavior prior to the study. Conclusions: Although caffeine did not increase the number of self-administered drinks, most participants chose the alcohol beverage containing caffeine. Given the differences in subjective ratings and pre-existing differences in self-reported alcohol consumption for caffeine choosers and nonchoosers, these data suggest that decreased stimulant effects of alcohol and heavier self-reported drinking may predict subsequent choice of combined caffeine and alcohol beverages. These predictors may identify individuals who would benefit from efforts to reduce risk behaviors associated with combining alcohol and caffeine. [ABSTRACT FROM AUTHOR]

Rationale: Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. Objectives: We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. Methods: We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. Results: Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. Conclusions: In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials. [ABSTRACT FROM AUTHOR]

Rationale: Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD). Objective: We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment. Method: A total of 148 children, 4-5 years old, were classified into groups as follows: ADHD group ( n = 107, DSM-IV-TR criteria) and a control group (CG, n = 41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63 ± 2.3 months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0). Results: Morning BDNF (36.36 ± 11.62 ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78 ± 11.92 vs PAD 26.41 ± 11.55 ng/ml). The hyperactive-impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms. Conclusions: Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients. [ABSTRACT FROM AUTHOR]

Rationale: The beneficial effects of nicotinic acetylcholine receptor (nAChR) agonists on cognitive performance have been widely shown. Paradoxically, recent preclinical studies employing extremely low doses of nAChR antagonists have also found cognitive enhancement, perhaps pointing to a novel treatment mechanism for cognitive deficits. Objectives: The aim was to test whether low doses of the nAChR antagonist mecamylamine would benefit performance in human volunteers. Methods: The study employed a double-blind within-subject design. Over four separate days, healthy adult non-smokers ( n = 23) were tested with placebo and three trace doses of mecamylamine (0.25-1 mg, p.o.), adjusted for body weight. Participants performed three computerized tasks: a task of spatial selective attention and stimulus detection, the rapid visual information processing task (RVIPT) taxing sustained attention and working memory, and a change detection short-term memory task. Subjective state and vital signs were assessed repeatedly. Results: Mecamylamine did not improve performance in any of the tasks. Any trends that were observed instead pointed toward performance impairment. Mecamylamine also had no effects on subjective state or vital signs. Conclusions: The present results do not support the hypothesized cognitive-enhancing potential of low doses of mecamylamine. Contrary to preclinical reports, these findings speak against low-dose nAChR antagonism as a novel avenue for treating cognitive deficits. [ABSTRACT FROM AUTHOR]

Background: Rodent models highlight the key role of μ-opioid receptor (MOR) signaling in palatable food consumption. In humans, however, the effects of MOR stimulation on eating and food liking remain unclear. Objectives: Here, we tested sweet pleasantness experience in humans following MOR drug manipulations. We hypothesized that behaviors regulated by the endogenous MOR system would be enhanced by MOR agonism and decreased by antagonism. In line with rodent findings, we expected the strongest drug effects for the sweetest (high-calorie) sucrose stimuli. As very sweet stimuli are considered aversive by many people (called sweet dislikers), we also assessed whether MOR manipulations affect pleasantness ratings of sucrose-water stimuli differently depending on subjective and objective value. Methods: In a bidirectional psychopharmacological cross-over study, 49 healthy men underwent a sweet taste paradigm following double-blind administration of the MOR agonist morphine, placebo, and the opioid antagonist naltrexone. Results: As hypothesized, MOR stimulation with morphine increased pleasantness of the sweetest of five sucrose solutions, without enhancing pleasantness of the lower-sucrose solutions. For opioid antagonism, an opposite pattern was observed for the sweetest drink only. The observed drug effects on pleasantness of the sweetest drink did not differ between sweet likers and dislikers. Conclusions: The bidirectional effect of agonist and antagonist treatment aligns with rodent findings showing that MOR manipulations most strongly affect the highest-calorie foods. We speculate that the MOR system promotes survival in part by increasing concordance between the objective (caloric) and subjective (hedonic) value of food stimuli, so that feeding behavior becomes more focused on the richest food available. [ABSTRACT FROM AUTHOR]

Rationale: Contextual stimuli present during drug experiences become associated with the drug through Pavlovian conditioning and are thought to sustain drug-seeking behavior. Thus, extinction of conditioned responses is an important target for treatment. To date, acquisition and extinction to drug-paired cues have been studied in animal models or drug-dependent individuals, but rarely in non-drug users. Objective: We have recently developed a procedure to study acquisition of conditioned responses after single doses of methamphetamine (MA) in healthy volunteers. Here, we examined extinction of these responses and their persistence after conditioning. Methods: Healthy adults (18-35 years; N = 20) received two pairings of audio-visual stimuli with MA (20 mg oral) or placebo. Responses to stimuli were assessed before and after conditioning, using three tasks: behavioral preference, attentional bias, and subjective 'liking.' Results: Subjects exhibited behavioral preference for the drug-paired stimuli at the first post-conditioning test, but this declined rapidly on subsequent extinction tests. They also exhibited a bias to initially look towards the drug-paired stimuli at the first post-test session, but not thereafter. Subjects who experienced more positive subjective drug effects during conditioning exhibited a smaller decline in preference during the extinction phase. Further, longer inter-session intervals during the extinction phase were associated with less extinction of the behavioral preference measure. Conclusions: Conditioned responses after two pairings with MA extinguish quickly, and are influenced by both subjective drug effects and the extinction interval. Characterizing and refining this conditioning procedure will aid in understanding the acquisition and extinction processes of drug-related conditioned responses in humans. [ABSTRACT FROM AUTHOR]

Rationale: Long-term heavy cannabis users (cannabis users) who are not acutely intoxicated have diminished subconscious neural responsiveness to affective stimuli. Objective: This study sought to determine if abnormal processing extends to the conscious evaluation of emotional stimuli. Methods: Functional magnetic resonance imaging (fMRI) was used to examine brain activity as cannabis users ( N = 16) and non-cannabis-using controls ( N = 17) evaluated and categorized standardized International Affective Picture System (IAPS) stimuli. Individual judgments were used to isolate activity during the evaluation of emotional (i.e., emotional evaluation) or neutral (i.e., neutral evaluation) stimuli. Within- and between-group analyses were performed. Results: Both groups judged the same stimuli as emotional and had activations in visual, midbrain, and middle cingulate cortices during emotional evaluation, relative to neutral. Within-group analyses also revealed amygdalar and inferior frontal gyrus activations in controls, but not cannabis users, and medial prefrontal cortex (mPFC) deactivations in cannabis users, but not controls, during emotional evaluation, relative to neutral. Between-group comparisons found that mPFC activity during positive and negative evaluation was significantly hypoactive in cannabis users, relative to controls. Conclusions: Abnormal neural processing of affective content extends to the level of consciousness in cannabis users. The hypoactive mPFC responses observed resembles the attenuated mPFC responses found during increased non-affective cognitive load in prior research. These findings suggest that abnormal mPFC singling in cannabis users during emotional evaluation might be associated with increased non-affective cognitive load. [ABSTRACT FROM AUTHOR]

Background: Ayahuasca is a psychotropic plant tea used for ritual purposes by the indigenous populations of the Amazon. In the last two decades, its use has expanded worldwide. The tea contains the psychedelic 5-HT receptor agonist N, N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties. Acute administration induces an introspective dream-like experience characterized by visions and autobiographic and emotional memories. Studies of long-term users have suggested its therapeutic potential, reporting that its use has helped individuals abandon the consumption of addictive drugs. Furthermore, recent open-label studies in patients with treatment-resistant depression found that a single ayahuasca dose induced a rapid antidepressant effect that was maintained weeks after administration. Here, we conducted an exploratory study of the psychological mechanisms that could underlie the beneficial effects of ayahuasca. Methods: We assessed a group of 25 individuals before and 24 h after an ayahuasca session using two instruments designed to measure mindfulness capacities: The Five Facets Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ). Results: Ayahuasca intake led to significant increases in two facets of the FFMQ indicating a reduction in judgmental processing of experiences and in inner reactivity. It also led to a significant increase in decentering ability as measured by the EQ. These changes are classic goals of conventional mindfulness training, and the scores obtained are in the range of those observed after extensive mindfulness practice. Conclusions: The present findings support the claim that ayahuasca has therapeutic potential and suggest that this potential is due to an increase in mindfulness capacities. [ABSTRACT FROM AUTHOR]

Rationale: There is evidence that glucose temporarily enhances cognition and that processes dependent on the hippocampus may be particularly sensitive. As the hippocampus plays a key role in binding processes, we examined the influence of glucose on memory for object-location bindings. Objective: This study aims to study how glucose modifies performance on an object-location memory task, a task that draws heavily on hippocampal function. Methods: Thirty-one participants received 30 g glucose or placebo in a single 1-h session. After seeing between 3 and 10 objects (words or shapes) at different locations in a 9 × 9 matrix, participants attempted to immediately reproduce the display on a blank 9 × 9 matrix. Blood glucose was measured before drink ingestion, mid-way through the session, and at the end of the session. Results: Glucose significantly improves object-location binding ( d = 1.08) and location memory ( d = 0.83), but not object memory ( d = 0.51). Increasing working memory load impairs object memory and object-location binding, and word-location binding is more successful than shape-location binding, but the glucose improvement is robust across all difficulty manipulations. Within the glucose group, higher levels of circulating glucose are correlated with better binding memory and remembering the locations of successfully recalled objects. Conclusions: The glucose improvements identified are consistent with a facilitative impact on hippocampal function. The findings are discussed in the context of the relationship between cognitive processes, hippocampal function, and the implications for glucose's mode of action. [ABSTRACT FROM AUTHOR]

Rationale: Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known. Objective: In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype. Methods: A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning. Results: Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning. Conclusions: These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene. [ABSTRACT FROM AUTHOR]

Background: Previous research on emotional correlates of individual differences in subjective responses to d-amphetamine has focused on relatively broad personality traits. Yet, emotional functioning is best characterized by several narrow subcomponents, each of which may contribute uniquely to amphetamine response. Here, we examine several specific subdomains of emotional functioning in relation to acute amphetamine response. Method: At a baseline session, healthy stimulant-naive volunteers ( N = 97) completed measures of several subdomains of baseline trait emotional functioning and then completed two counterbalanced experimental sessions during which they received a single oral dose of 20 mg d-amphetamine or placebo. Acute subjective drug response measures were completed at repeated intervals before and after drug administration. Data from subjective measures that were significantly modulated by amphetamine were reduced using principal component analysis (amphetamine or placebo) into three higher-order factors of 'positive mood,' 'arousal,' and 'drug high.' Amphetamine did not significantly alter any 'negative' subjective states. Separate multiple regression analyses were conducted regressing these three drug factors on baseline trait emotional functioning scales. Results: The combined set of trait emotional functioning indicators accounted for approximately 22 % of the variance in acute amphetamine-induced positive mood changes. Greater anticipatory pleasure and greater anxious distress each uniquely predicted greater amphetamine-induced positive mood. Trait emotional functioning did not significantly predict amphetamine-induced changes in arousal or drug high. Discussion: Emotional traits appear to moderate drug-induced positive mood but not other dimensions of amphetamine effects. Different facets of emotional functioning may differentially modulate amphetamine's subjective effect profile. [ABSTRACT FROM AUTHOR]

Rationale: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. Objectives: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT receptors, dopamine D receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Methods: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT receptors, D receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. Results: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT receptors and low occupancy of striatal D receptors (~12 %). D receptor occupancy increased with dose and significantly correlated with plasma concentrations ( r = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D receptors and 33 % of striatal serotonin transporters. Conclusions: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials. [ABSTRACT FROM AUTHOR]

Rationale: Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions. Objective: The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine. Methods: In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed. Results: Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis. Conclusions: We present indirect evidence that MTNX crosses the blood-brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question. [ABSTRACT FROM AUTHOR]

Rationale: Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear. Objectives: This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans. Methods: Following intake assessment, 28 healthy male and female adults, aged 18-29 years, underwent two consecutive 90-min positron emission tomography studies with high specific activity [C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg). Results: Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress. Conclusions: Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse. [ABSTRACT FROM AUTHOR]

Rationale: Drug purchasing tasks have been successfully used to examine demand for hypothetical consumption of abused drugs including heroin, nicotine, and alcohol. In these tasks, drug users make hypothetical choices whether to buy drugs, and if so, at what quantity, at various potential prices. These tasks allow for behavioral economic assessment of that drug's intensity of demand (preferred level of consumption at extremely low prices) and demand elasticity (sensitivity of consumption to price), among other metrics. However, a purchasing task for cocaine in cocaine-dependent individuals has not been investigated. Objectives: This study examined a novel Cocaine Purchasing Task and the relation between resulting demand metrics and self-reported cocaine use data. Methods: Participants completed a questionnaire assessing hypothetical purchases of cocaine units at prices ranging from $0.01 to $1,000. Demand curves were generated from responses on the Cocaine Purchasing Task. Correlations compared metrics from the demand curve to measures of real-world cocaine use. Results: Group and individual data were well modeled by a demand curve function. The validity of the Cocaine Purchasing Task was supported by a significant correlation between the demand curve metrics of demand intensity and O (determined from Cocaine Purchasing Task data) and self-reported measures of cocaine use. Partial correlations revealed that after controlling for demand intensity, demand elasticity and the related measure, P, were significantly correlated with real-world cocaine use. Conclusions: Results indicate that the Cocaine Purchasing Task produces orderly demand curve data, and that these data relate to real-world measures of cocaine use. [ABSTRACT FROM AUTHOR]

Rationale: Some recent pharmacoepidemiological studies revealed an elevated risk of driving accidents after opioid analgesics uses. Among analgesics, codeine is often associated with paracetamol in numerous pharmaceutical specialties. Objectives: The objective of this study was to evaluate the dose-effect relationship of three usual therapeutic doses of codeine/paracetamol on driving ability, psychomotor performance, subjective alertness, in link with blood concentrations in healthy young volunteers. Methods: Driving performance, responses to psychomotor vigilance tests, and scales reflecting alertness were evaluated during the morning after drug intake in a double-blind, randomized, placebo-controlled study. Sixteen healthy volunteers (23.4 ± 2.7 years old, 8 men and 8 women) participated in this balanced, cross-over study. Three doses of codeine/paracetamol (20/400, 40/800, 60/1200 mg) were evaluated against placebo. Two blood samples were collected, 1 and 4 h after drug intake. In serum, codeine and morphine concentrations were determined in serum using high-performance liquid chromatography electrospray ionization-tandem mass spectrometry, and paracetamol concentrations using fluorescence polarization immunoassay. Results: Driving and psychomotor performance were not affected by any of the three codeine/paracetamol doses. However, significant, though modest, correlations were observed between the driving parameters and both morphine and codeine blood concentrations. Conclusions: This study did not reveal any significant impairment in performance due to the three therapeutic doses used in healthy young volunteers. However, the relationships between drug blood concentration and behavioral measures suggest that an inter-subject variability in blood concentration may influence the power of the observed drug effect. [ABSTRACT FROM AUTHOR]

Rationale: Chronic dysregulation of hypothalamus-pituitary-adrenal (HPA) axis activity is related to several neuropsychiatric disorders. Studies suggest that cortisol response to stress has a strong genetic etiology, and that FK506 binding protein 5 (FKBP5) and G-protein coupled type-I CRH receptor (CRHR1) are key proteins regulating response. Variations in the genes encoding these proteins, FKBP5 and CRHR1, have been associated with several neuropsychiatric disorders. Objectives: We examined variation in these genes in relation to cortisol response to psychological stress in one of the largest Trier Social Stress Test (TSST) cohorts yet examined. Methods: A total of 368 healthy, young adults underwent the TSST. Salivary cortisol was measured at multiple time points before and after the stressor. Nine variants in FKBP5 and four in CRHR1 were assessed. Single marker analyses were conducted. Secondary analyses assessed haplotypes and interaction with stress-related variables. Results: The strongest association was for rs4713902 in FKBP5 with baseline cortisol ( p = 0.0004). We also identified a male-specific effect of FKBP5 polymorphisms on peak response and response area under the curve ( p = 0.0028 for rs3800374). In CRHR1, rs7209436, rs110402, and rs242924 were nominally associated with peak response ( p = 0.0029-0.0047). We observed interactions between trait anxiety and rs7209436 and rs110402 in CRHR1 in association with baseline cortisol ( p = 0.0272 and p = 0.0483, respectively). Conclusions: We show association of variants in FKBP5 and CRHR1 with cortisol response to psychosocial stress. These variants were previously shown to be associated with neuropsychiatric disorders. These findings have implications for interindividual variation in HPA axis activity and potentially for the etiology of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Rationale: Many addictive drugs are known to have effects on learning and memory, and these effects could motivate future drug use. Specifically, addictive drugs may affect memory of emotional events and experiences in ways that are attractive to some users. However, few studies have investigated the effects of addictive drugs on emotional memory in humans. Objectives: This study examined the effects of the memory-enhancing drug dextroamphetamine (AMP) and the memory-impairing drug Δ-tetrahydrocannabinol (THC) on emotional memory in healthy volunteers. Methods: Participants completed three experimental sessions across which they received capsules containing placebo and two doses of either AMP (10 and 20 mg; N = 25) or THC (7.5 and 15 mg; N = 25) before viewing pictures of positive (pleasant), neutral, and negative (unpleasant) scenes. Memory for the pictures was assessed 2 days later, under drug-free conditions. Results: Relative to placebo, memory for emotional pictures was improved by AMP and impaired by THC, but neither drug significantly affected memory for unemotional pictures. Positive memory biases were not observed with either drug, and there was no indication that the drugs' memory effects were directly related to their subjective or physiological effects alone. Conclusions: This study provides the first clear evidence that stimulant drugs can preferentially strengthen, and cannabinoids can preferentially impair, memory for emotional events in humans. Although addictive drugs do not appear to positively bias memory, the possibility remains that these drugs' effects on emotional memory could influence drug use among certain individuals. [ABSTRACT FROM AUTHOR]

Rationale: Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the plant Salvia divinorum, which has increased in popularity as a recreational drug over the past decade. Few human studies have examined salvinorin A. Objective: This double-blind, placebo-controlled study evaluated the dose-related effects of inhaled salvinorin A in individuals with histories of hallucinogen use. Methods: Eight healthy hallucinogen-using adults inhaled up to 16 doses of salvinorin A (0.375-21 μg/kg) in ascending order. Physiological, behavioral, and subjective effects were assessed every 2 min for 60 min after administration. Qualitative subjective effects were assessed retrospectively via questionnaires at the end of sessions. Persisting effects were assessed 1 month later. Results: Orderly dose-related effects peaked at 2 min and then rapidly dissipated, replicating previous findings. Subjective effects were intense, with maximal drug strength ratings or unresponsiveness frequently observed at high doses. Questionnaires assessing qualitative effects (Hallucinogen Rating Scale, Pharmacological Class Questionnaire) suggested some overlap with serotonergically mediated classic hallucinogens. Salvinorin A also produced dose-related dissociative effects and impairments in recall/recognition memory. At 1-month follow-up, there was no evidence of persisting adverse effects. Participants reported that salvinorin A effects were qualitatively different from other drugs. Conclusions: Salvinorin A produces a unique profile of subjective and cognitive effects, including strong dissociative effects and memory impairment, which only partially overlap with classic hallucinogen effects. Along with nonhuman studies of salvinorin A, these results are important for understanding the neurobiology of the kappa opioid system and may ultimately have important therapeutic applications. [ABSTRACT FROM AUTHOR]

Objective: We previously demonstrated that short-term treatment with a standardized kudzu extract (NPI-031) reduced alcohol drinking by men and women in a natural setting. The present study was conducted in nontreatment-seeking heavy drinkers to assess the safety and efficacy of 4 weeks of kudzu extract in an outpatient setting. Method: This randomized between-subject, double-blind, placebo-controlled study involved 2 weeks of baseline, 4 weeks of treatment, and 2 weeks of follow-up. Seventeen men (21-33 years) who reported drinking 27.6 ± 6.5 drinks/week with a diagnosis of alcohol abuse/dependence took either kudzu extract (250 mg isoflavones, t.i.d.) or matched placebo on a daily basis. They reported alcohol consumption and desire to use alcohol using a wrist actigraphy device; twice weekly laboratory visits were scheduled to monitor medication adherence and adverse events. Results: Medication adherence was excellent and there were no adverse events and changes in vital signs, blood chemistry, and renal or liver function. There was no effect on alcohol craving, but kudzu extract significantly reduced the number of drinks consumed each week by 34-57 %, reduced the number of heavy drinking days, and significantly increased the percent of days abstinent and the number of consecutive days of abstinence. Conclusions: A standardized formulation of kudzu extract produced minimal side effects, was well-tolerated, and resulted in a modest reduction in alcohol consumption in young nontreatment-seeking heavy drinkers. Additional studies using treatment-seeking alcohol-dependent persons will be necessary to determine the usefulness of this herbal preparation in reducing alcohol use in other populations. [ABSTRACT FROM AUTHOR]

Rationale: In laboratory animals, the biological stressor yohimbine (α-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking. Objectives: This clinical study tested whether yohimbine increases opioid-seeking behavior. Methods: Ten heroin-dependent, buprenorphine-stabilized (8 mg/day) volunteers sampled two doses of hydromorphone [12 and 24 mg IM in counterbalanced order, labeled drug A (session 1) and drug B (session 2)]. During each of six later sessions (within-subject, double-blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (drug A or B) vs money ($2) following different oral yohimbine pretreatment doses (0, 16.2, and 32.4 mg). Results: Behavioral economic demand intensity and peak responding ( O) were significantly higher for hydromorphone 2 than 1 mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units ( P = 909, 3,647, and 3,225 for placebo, 16.2, and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units ( P = 2,656, 3,193, and 3,615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic ≈ 15 and diastolic ≈ 10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood. Conclusions: These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose. [ABSTRACT FROM AUTHOR]

Rationale: We test methods to advance (shift earlier) circadian rhythms without producing misalignment between rhythms and sleep. We previously tested (1) a gradually advancing sleep/dark schedule plus morning bright light and afternoon/evening melatonin and (2) the same sleep schedule with only morning bright light. Now we report on the same sleep schedule with only afternoon/evening melatonin. Objectives: This study aims to examine phase advances, sleepiness, and performance in response to melatonin compared to placebo. Methods: Twelve adults (five female individuals) aged 20-45 years (mean ± SD = 28.3 ± 7.3 years) completed this within-subjects placebo-controlled counterbalanced study. The participants slept on fixed 8-h sleep schedules for nine days. Then, sleep/dark was advanced by 1 h/day for three consecutive days of treatment. The participants took 3 mg of melatonin or placebo 11 h before baseline sleep midpoint (the optimal time to produce phase advances) on the first treatment day and 1 h earlier on each subsequent day. We measured the dim light melatonin onset before and after treatment. The participants rated subjective symptoms throughout the study. They completed the Psychomotor Vigilance Task and rated sleepiness from 1 h before pill ingestion until bedtime on each treatment day. Results: Melatonin produced significantly larger advances (1.3 ± 0.7 h) compared to placebo (0.7 ± 0.7 h); however, in the hours between melatonin ingestion and bed, melatonin caused sleepiness and performance decrements. Conclusions: Adding afternoon/evening melatonin to the gradually advancing sleep schedule increased the phase advance, but given the side effects, like sleepiness, it is better to use morning bright light and perhaps a lower dose of melatonin. [ABSTRACT FROM AUTHOR]

Rationale: Recent studies on reinforcer valuation in social situations have informed research on mental illness. Social temporal discounting may be a way to examine effects of social context on the devaluation of delayed reinforcers. In prior research with non-drug-using groups, we demonstrated that individuals discount delayed rewards less rapidly (i.e., value the future more) for a group of which they are a member than they do for themselves alone. Objectives: The current study examined how cigarette smoking and level of alcohol use relate to rates of delay and social temporal discounting. Methods: In this study, we used crowd-sourcing technology to contact a large number of individuals ( N = 796). Some of these individuals were hazardous-to-harmful drinkers ( n = 269), whereas others were non-problem drinkers ( n = 523); some were smokers ( n = 182), whereas others were nonsmokers ( n = 614). Delay discounting questionnaires for individual rewards (me now, me later) and for group rewards (we now, we later; me now, we later) were used to measure individuals' discounting rates across various social contexts. Results: Our analyses found that smokers discounted delayed rewards more rapidly than controls under all conditions. However, hazardous-to-harmful drinkers discounted delayed rewards significantly more rapidly than the non-problem drinkers under the individual condition, but not under the social conditions. Conclusions: This finding suggests that the use of different abused drugs may be associated with excessive discounting in the individual condition and has selective effects when discounting for a group in the social conditions. [ABSTRACT FROM AUTHOR]

Rationale: Salvia divinorum has been used for centuries, and nontraditional use in modern societies is increasing. Inebriation and aftereffects of use are poorly documented in the scientific literature. Objectives: This double-blind, placebo-controlled, randomized study analyzed subjective experiences of salvinorin A (SA) inebriation and consequences of use after 8 weeks. Methods: Thirty middle-aged, well-educated, hallucinogen-experienced participants smoked either 1,017 or 100 μg SA 2 weeks apart in counterbalanced order. Vital signs were recorded before and after inhalation. A researcher rated participants' behavior during sessions. Participants completed the Hallucinogen Rating Scale (HRS) assessing inebriation immediately after each session. Differences were analyzed between groups as functions of dose and time. After 8 weeks, participants were interviewed to determine reported consequences and aftereffects. Results: Participants talked, laughed, and moved more often on an active dose. All six HRS clusters were significantly elevated on an active dose indicating hallucinogenic experiences. No significant adverse events were observed or reported by participants. Conclusions: The present results indicate similarities as well as differences between the subjective effects of S. divinorum and other hallucinogens. As a selective kappa opioid receptor agonist, SA may be useful for expanding understanding of the psychopharmacology and psychology of hallucinogenic states beyond serotonergic mechanisms. [ABSTRACT FROM AUTHOR]

Rationale: Several psychoactive drugs are known to influence episodic memory. However, these drugs' effects on false memory, or the tendency to incorrectly remember nonstudied information, remain poorly understood. Objectives: Here, we examined the effects of two commonly used psychoactive drugs, one with memory-enhancing properties (dextroamphetamine; AMP), and another with memory-impairing properties (Δ-tetrahydrocannabinol; THC), on false memory using the Deese/Roediger-McDermott (DRM) illusion. Methods: Two parallel studies were conducted in which healthy volunteers received either AMP (0, 10, and 20 mg) or THC (0, 7.5, and 15 mg) in within-subjects, randomized, double-blind designs. Participants studied DRM word lists under the influence of the drugs, and their recognition memory for the studied words was tested 2 days later, under sober conditions. Results: As expected, AMP increased memory of studied words relative to placebo, and THC reduced memory of studied words. Although neither drug significantly affected false memory relative to placebo, AMP increased false memory relative to THC. Across participants, both drugs' effects on true memory were positively correlated with their effects on false memory. Conclusions: Our results indicate that AMP and THC have opposing effects on true memory, and these effects appear to correspond to similar, albeit more subtle, effects on false memory. These findings are consistent with previous research using the DRM illusion and provide further evidence that psychoactive drugs can affect the encoding processes that ultimately result in the creation of false memories. [ABSTRACT FROM AUTHOR]

Rationale: Nicotine has been shown to improve both memory and attention when assessed through speeded motor responses. Since very few studies have assessed effects of nicotine on visual attention using measures that are uncontaminated by motoric effects, nicotine's attentional effects may, at least partially, be due to speeding of motor function. Objectives: Using an unspeeded, accuracy-based test, the CombiTVA paradigm, we examined whether nicotine enhances attention when it is measured independently of motor processing. Methods: We modelled data with a computational theory of visual attention (TVA; Bundesen ) so as to derive independent estimates of several distinct components of attention from performance of the single task: threshold of visual perception, perceptual processing speed, visual short-term memory storage capacity and top-down controlled selectivity. Acute effects of nicotine (2 mg gum) on performance were assessed in 24 healthy young non-smokers in a placebo-controlled counterbalanced, crossover design. Chronic effects of nicotine were investigated in 24 age- and education-matched minimally deprived smokers. Results: Both an acute dose of nicotine in non-smokers and chronic nicotine use in temporarily abstaining smokers improved perceptual thresholds but slowed subsequent perceptual speed. Moreover, both acute and chronic nicotine use reduced attentional selectivity though visual short-term memory capacity was unimpaired. Conclusions: Nicotine differentially affected discrete components of visual attention, with acute and chronic doses revealing identical patterns of performance. We challenge prior reports of nicotine-induced speeding of information processing by showing, for the first time, that nicotine slows down perceptual processing speed when assessed using accuracy-based measures of cognitive performance. [ABSTRACT FROM AUTHOR]

Rationale: Quantitative real-time data on the stress experienced by drug misusers in their daily lives may provide additional insight into stress's role in drug use. Objective: The purpose of this study is to evaluate stress in relation to craving, mood, relapse-trigger exposure, and cocaine use in cocaine-dependent outpatients. Methods: Methadone-maintained cocaine- and heroin-abusing outpatients ( N = 114) provided ecological momentary assessment data on handheld computers. Ratings of stress were compared to those of craving and mood and past-hour exposure to putative drug-use triggers in randomly prompted entries and in the 5 h prior to participant-initiated cocaine use reports. Results: Stress had significant positive relationships with current ratings of craving for cocaine, heroin, and tobacco and with ratings of tiredness, boredom, and irritation, and had significant negative relationships with ratings of happiness and relaxation. Stress was significantly greater in entries in which participants also reported past-hour exposure to negative-mood triggers, most of the drug-exposure triggers, or any trigger involving thoughts about drugs (e.g., tempted out of the blue). The linear increase in stress during the 5-h preceding individual episodes of cocaine use was not significant ( p = 0.12), though there was a trend for such an increase before the use episodes that participants attributed to stressful states when they occurred ( p = 0.87). Conclusions: The findings suggest a complex role of stress in addiction. Stress reported in real time in the natural environment showed strong cross-sectional momentary relationships with craving, mood, and exposure to drug-use trigger. However, the prospective association between stress ratings and cocaine-use episodes was, at best, weak. [ABSTRACT FROM AUTHOR]

Background: Despite early promise in phase II, the performance of the NK1 receptor antagonist aprepitant in subsequent clinical trials has been disappointing. Healthy volunteer models of emotional processing offer a potential means by which novel drugs can be screened prior to clinical trials. Here, we consider the effect of 7 days of treatment with aprepitant in such a model. Method: Healthy volunteers ( n = 32) were randomised to receive 7-day treatment with aprepitant (125 mg) or placebo. On the seventh day, participants completed a battery of tasks measuring emotional processing previously demonstrated to be sensitive to conventional antidepressant drugs. The tasks included facial expression recognition, emotional categorisation and memory, attentional dot-probe and emotion potentiated startle task. Results: Aprepitant abolished the emotionally potentiated startle effect and increased recognition memory for emotionally positive versus negative stimuli. In addition, the drug decreased attention to negative relative to positive emotional stimuli on the masked version of the dot-probe task. These effects were seen in the absence of any change in subjective mood. There were no effects on emotional categorisation, recall or on facial expression recognition. Conclusion: These results suggest that NK1 receptor antagonism does affect some aspects of emotional processing and, in particular, that it has anxiolytic-like effects. The profile of effects reported here is, however, more limited than that found in response to conventional antidepressant treatment, and this may explain disappointing results at clinical trial. Healthy volunteer models of emotional processing may be useful in closing the gap between preclinical and clinical trials. [ABSTRACT FROM AUTHOR]

Rationale: 'Party Pills' containing benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) have been used in a recreational context since the 1990s and, prior to April 2008, were legally available in New Zealand. Taken together, they have been reported to produce a 'high' similar to that produced by 3,4-methylenedioxymethamphetamine (MDMA). Objectives: There has been little research on the subjective effects of piperazines in humans. The purpose of this study is to further investigate the subjective and physiological responses following an oral dose of BZP combined with TFMPP in males. Methods: In a randomised, double-blind, placebo-controlled study the subjective and physiological effects of BZP/TFMPP were investigated in 36 healthy, non-smoking males (mean age 22 ± 4 years). Participants were tested before and approximately 120 min after administration of a single dose of placebo ( n = 16) or 100/30 mg BZP/TFMPP ( n = 20). Participants were required to comment on the subjective effects using three rating scales-the Addiction Research Centre Inventory (ARCI), the Visual Analogue Scale (VAS) and the Profile of Mood States (POMS). Participants' blood pressure, heart rate and body temperature were also measured. Results: Statistical analysis using repeated-measures analysis of variance (ANOVA) and planned comparisons revealed that BZP/TFMPP significantly increases blood pressure and heart rate ( p < 0.05). Likewise, the subjective rating scales revealed that BZP/TFMPP has significant dexamphetamine-like effects, increases dysphoria and feelings of self-confidence ( p < 0.05). Conclusion: These physiological and subjective data reflect clear similarities between the effects of BZP/TFMPP and commonly known stimulants such as dexamphetamine and MDMA. [ABSTRACT FROM AUTHOR]

Rationale: Although hypnotics are primarily used by older people, the residual effects the morning after a single nighttime intake of the two most commonly prescribed hypnotics, zolpidem (Zp) and zopiclone (Zc), on older middle-aged drivers have not been evaluated and compared. Methods: Sixteen healthy subjects, 55 to 65 years of age, participated in this double-blind, balanced, cross-over study. Zc (7.5 mg), Zp (10 mg) and flunitrazepam (Fln) (1 mg) or a placebo was administered at each subject's home at 11.00 pm. The next morning, at 9.00 am, the subjects had to drive in a simulated monotonous driving environment for 1 h. During each morning session, two blood samples were collected, and subjective feelings of alertness were completed three times. Results: In comparison to placebo, Zp and Zc equivalently and significantly impaired the standard deviation of lateral position, the standard deviation of speed and the number of road exits. Detectable blood concentrations were found with Zp in 11 subjects at 8.30 am and at 1.30 pm. The subjective alertness factor was significantly impaired with Zp. Conclusions: This is the first study revealing residual effects of Zp on driving performance in ageing drivers which are similar to that of Zc. Studying the effects of medication in different age ranges appears useful to complete the studies on behavioural-pharmacological effects of medication. To reduce the incidence of driving accidents due to prescription drugs, patients should be warned at the time of treatment initiation that they should avoid driving. [ABSTRACT FROM AUTHOR]

Rationale: Smoking cues are theorized to be conditioned stimuli (CSs) formed by repeated pairing with drug. Smoking paraphernalia can elicit subjective and physiological responses in smokers, indicative of positive affect and motivation to consume. Although these responses are probably the result of conditioning, direct evidence from human conditioning studies with physiological measures of motivational valence is rare. Objective: The present study investigated the motivational properties of experimentally conditioned cues for smoking. Methods: Thirty-nine smokers completed a differential conditioning protocol. Abstract pictures were used as CSs and single puffs on a cigarette as unconditioned stimulus (US). Skin conductance responses and facial electromyography of the zygomatic, corrugator, and orbicularis oris muscles were measured during conditioning. Results: The conditioned cue for smoking (CS+) elicited stronger skin conductance responses and more activity of the zygomatic and orbicularis oris muscles than the CS−. Conclusions: These results support the notion that through pairing with smoking, neutral stimuli acquire the ability to elicit preparatory physiological responses, which are assumed to play an important role in the maintenance of addiction and relapse in the natural environment. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine (METH) is a widely abused psychostimulant that is associated with neurotoxicity and neurocognitive impairments in adults. However, the effects of METH use on neurocognitive performance of adolescents are unclear. Methods: Fifty-four adolescent METH users and 74 age-matched comparison subjects (ages 12 to 23 years) were evaluated with a battery of neuropsychological tests. The cognitive domains evaluated include psychomotor (Symbol Digit, Trail Making), executive function (Stroop Interference task, Wisconsin Card Sort task), fine-motor speed (Grooved Pegboard), memory (Digit span and Auditory Verbal Learning Task), as well as attention and working memory (California Computerized Assessment package). Results: METH users were slower on the Stroop Interference task than the comparison subjects (F(1,114) = 4.33, p = 0.03). METH subjects also performed worse than controls on the Wechsler Adult Intelligence Scale III/Wechsler Intelligence Scale for Children IV (WAIS/WISC) Matrices task (F(1,114) = 4.37, p = 0.04) and performed significantly worse on the Peg Board task than the comparison subjects for both the dominant (F(1,114) = 7.56, p = 0.01) and non-dominant (F(1,114) = 6.75, p = 0.01). Lastly, length of abstinence was associated with improved performance on the Peg Board test with the dominant had ( r = −0.34), as well as the WAIS/WISC Forward Digit Span task ( r = 0.38) Conclusions: METH use is associated with impaired executive functions in adolescent users. [ABSTRACT FROM AUTHOR]

Trifluoromethylphenyl piperazine (TFMPP) is an active constituent of a relatively new group of recreational drugs known as ‘party pills’. TFMPP has been anecdotally reported to induce mild psychedelic effects similar to lysergic acid diethylamide and psilocybin. There has been no research about the subjective effects of TFMPP in humans. This study aimed to investigate the subjective effects of TFMPP in human males. A randomised, double-blind, placebo-controlled trial design was used to investigate the subjective effects of TFMPP in 30 healthy, non-smoking male volunteers (mean age 24 ± 4 years). Participants were randomised into two groups and given either TFMPP 60 mg ( n = 15) or placebo ( n = 15). Each participant completed three rating scales, the Addiction Research Centre Inventory (ARCI), the Profile of Mood States (POMS) and the Visual Analogue Scales (VAS), both before and 120 min after drug administration. Results from the ARCI indicated that TFMPP produced increases in ‘dysphoria’ and ‘dexamphetamine-like effects’. TFMPP also increased ratings of ‘tension/anxiety’ and ‘confusion/bewilderment’ as rated on the POMS. Results from the VAS indicated increases in ‘drug liking’, ‘high’ and ‘stimulated’ ratings relevant to placebo. Increased ratings of ‘dexamphetamine-like effects’, ‘tension/anxiety’, ‘stimulated’ and ‘high’ following TFMPP administration resemble the subjective effects of common amphetamine-type stimulants. However, increases in ‘dysphoria’ and ‘confusion/bewilderment’ ratings following TFMPP are more commonly associated with drugs that have greater effects on serotonin release, binding and reuptake such as 1-[3-chlorophenyl]-piperazine, fenfluramine and lysergic acid diethylamide. [ABSTRACT FROM AUTHOR]

Buprenorphine is a partial mu opioid receptor agonist with clinical efficacy as a pharmacotherapy for opioid dependence. A sublingual combination formulation was developed containing buprenorphine and naloxone with the intent of decreasing abuse liability in opioid-dependent individuals. However, the addition of naloxone may not limit abuse potential of this medication when taken by individuals without opioid physical dependence. The present study investigated the effects of buprenorphine alone and in combination with naloxone administered intramuscularly and sublingually to non-dependent opioid abusers. In a within-subject crossover design, non-dependent opioid-experienced volunteers ( N = 8) were administered acute doses of buprenorphine (4, 8, and 16 mg) and buprenorphine/naloxone (4/1, 8/2, and 16/4 mg) via both intramuscular and sublingual routes, intramuscular hydromorphone (2 and 4 mg as an opioid agonist control), and placebo, for a total of 15 drug conditions. Laboratory sessions were conducted twice per week using a double-blind, double-dummy design. Buprenorphine and buprenorphine/naloxone engendered effects similar to hydromorphone. Intramuscular administration produced a greater magnitude of effects compared to the sublingual route at the intermediate dose of buprenorphine and at both the low and high doses of the buprenorphine/naloxone combination. The addition of naloxone did not significantly alter the effects of buprenorphine. These results suggest that buprenorphine and buprenorphine/naloxone have similar abuse potential in non-dependent opioid abusers, and that the addition of naloxone at these doses and in this dose ratio confers no evident advantage for decreasing the abuse potential of intramuscular or sublingual buprenorphine in this population. [ABSTRACT FROM AUTHOR]