Search

Opioid use results in thousands of overdose deaths each year. To address this crisis, we need a better understanding of the neurobiological mechanisms that drive opioid abuse. The noninvasive imaging tools positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and manganese-enhanced magnetic resonance imaging (MEMRI) can be used to identify how brain activity responds to acute opioid exposure and adapts to chronic drug treatment. These techniques can be performed in humans and animal models, and brain networks identified in animals closely map to the human brain. Animal models have the advantage of being able to systematically examine the independent effects of opioid exposure in a controlled environment accounting for the complex factors that drive opioid misuse in humans. This review synthesizes literature that utilized noninvasive neuroimaging tools (PET, fMRI, and MEMRI) measuring brain activity correlates in animals to understand the neurobiological consequences of exposure to abused opioids. A PubMed search in September 2023 identified 25 publications. These manuscripts were divided into 4 categories based on the route and duration of drug exposure (acute/chronic, active/passive administration). Within each category, the results were generally consistent across drug and imaging protocols. These papers cover a 20-year range and highlight the advancements in neuroimaging methodology during that time. These advances have enabled researchers to achieve greater resolution of brain regions altered by opioid exposure and to identify patterns of brain activation across regions (i.e., functional connectivity) and within subregions of structures. After describing the existing literature, we suggest areas where additional research is needed. [ABSTRACT FROM AUTHOR]

Rationale: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the “psychotherapy” in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered.As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness.The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding “psychotherapy” versus “psychological support” and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored.PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration.Objectives: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the “psychotherapy” in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered.As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness.The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding “psychotherapy” versus “psychological support” and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored.PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration.Results: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the “psychotherapy” in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered.As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness.The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding “psychotherapy” versus “psychological support” and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored.PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration.Conclusions: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the “psychotherapy” in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered.As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness.The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding “psychotherapy” versus “psychological support” and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored.PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration. [ABSTRACT FROM AUTHOR]

Aim: Much research has been conducted on the acute effects of nicotine on human cognitive performance, demonstrating both enhancing and impairing cognitive effects. With the relatively recent introduction of electronic cigarettes (‘e-cigarettes’) as a smoking cessation device, little is known about the cognitive effects of e-cigarettes specifically, either as a nicotine replacement device or in the absence of nicotine. The purpose of this review was to present an overview of evidence from empirical studies on the effect of e-cigarettes on cognitive function.Guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines (PRISMA-ScR), SCOPUS, PubMed, and EBSCOhost were searched from 2006, the year e-cigarettes were introduced, to June 2023 for relevant papers, along with reference lists checked for additional papers.Seven experimental and four cross-sectional survey studies were identified and included. The majority of the studies only include regular and current cigarette smokers and primarily assessed the acute cognitive effect of e-cigarettes relative to nicotine. While the findings primarily suggest either no or positive effect of e-cigarettes on cognition in cigarette smokers, associations between e-cigarettes and cognitive impairments in memory, concentration and decision making were reported in both cigarette smokers and never-smokers.The acute cognitive effect of e-cigarettes on regular cigarette smokers appears minimal. However, long-term cognitive effect and their effects on never-smokers are unclear. Given that the increased numbers of e-cigarette users are non-smokers and/or adolescents, research with those naïve to nicotine and a developmentally vulnerable adolescent population on its long-term effect is needed.Approach: Much research has been conducted on the acute effects of nicotine on human cognitive performance, demonstrating both enhancing and impairing cognitive effects. With the relatively recent introduction of electronic cigarettes (‘e-cigarettes’) as a smoking cessation device, little is known about the cognitive effects of e-cigarettes specifically, either as a nicotine replacement device or in the absence of nicotine. The purpose of this review was to present an overview of evidence from empirical studies on the effect of e-cigarettes on cognitive function.Guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines (PRISMA-ScR), SCOPUS, PubMed, and EBSCOhost were searched from 2006, the year e-cigarettes were introduced, to June 2023 for relevant papers, along with reference lists checked for additional papers.Seven experimental and four cross-sectional survey studies were identified and included. The majority of the studies only include regular and current cigarette smokers and primarily assessed the acute cognitive effect of e-cigarettes relative to nicotine. While the findings primarily suggest either no or positive effect of e-cigarettes on cognition in cigarette smokers, associations between e-cigarettes and cognitive impairments in memory, concentration and decision making were reported in both cigarette smokers and never-smokers.The acute cognitive effect of e-cigarettes on regular cigarette smokers appears minimal. However, long-term cognitive effect and their effects on never-smokers are unclear. Given that the increased numbers of e-cigarette users are non-smokers and/or adolescents, research with those naïve to nicotine and a developmentally vulnerable adolescent population on its long-term effect is needed.Key findings: Much research has been conducted on the acute effects of nicotine on human cognitive performance, demonstrating both enhancing and impairing cognitive effects. With the relatively recent introduction of electronic cigarettes (‘e-cigarettes’) as a smoking cessation device, little is known about the cognitive effects of e-cigarettes specifically, either as a nicotine replacement device or in the absence of nicotine. The purpose of this review was to present an overview of evidence from empirical studies on the effect of e-cigarettes on cognitive function.Guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines (PRISMA-ScR), SCOPUS, PubMed, and EBSCOhost were searched from 2006, the year e-cigarettes were introduced, to June 2023 for relevant papers, along with reference lists checked for additional papers.Seven experimental and four cross-sectional survey studies were identified and included. The majority of the studies only include regular and current cigarette smokers and primarily assessed the acute cognitive effect of e-cigarettes relative to nicotine. While the findings primarily suggest either no or positive effect of e-cigarettes on cognition in cigarette smokers, associations between e-cigarettes and cognitive impairments in memory, concentration and decision making were reported in both cigarette smokers and never-smokers.The acute cognitive effect of e-cigarettes on regular cigarette smokers appears minimal. However, long-term cognitive effect and their effects on never-smokers are unclear. Given that the increased numbers of e-cigarette users are non-smokers and/or adolescents, research with those naïve to nicotine and a developmentally vulnerable adolescent population on its long-term effect is needed.Implications and conclusions: Much research has been conducted on the acute effects of nicotine on human cognitive performance, demonstrating both enhancing and impairing cognitive effects. With the relatively recent introduction of electronic cigarettes (‘e-cigarettes’) as a smoking cessation device, little is known about the cognitive effects of e-cigarettes specifically, either as a nicotine replacement device or in the absence of nicotine. The purpose of this review was to present an overview of evidence from empirical studies on the effect of e-cigarettes on cognitive function.Guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines (PRISMA-ScR), SCOPUS, PubMed, and EBSCOhost were searched from 2006, the year e-cigarettes were introduced, to June 2023 for relevant papers, along with reference lists checked for additional papers.Seven experimental and four cross-sectional survey studies were identified and included. The majority of the studies only include regular and current cigarette smokers and primarily assessed the acute cognitive effect of e-cigarettes relative to nicotine. While the findings primarily suggest either no or positive effect of e-cigarettes on cognition in cigarette smokers, associations between e-cigarettes and cognitive impairments in memory, concentration and decision making were reported in both cigarette smokers and never-smokers.The acute cognitive effect of e-cigarettes on regular cigarette smokers appears minimal. However, long-term cognitive effect and their effects on never-smokers are unclear. Given that the increased numbers of e-cigarette users are non-smokers and/or adolescents, research with those naïve to nicotine and a developmentally vulnerable adolescent population on its long-term effect is needed. [ABSTRACT FROM AUTHOR]

Rationale: Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. Objectives: In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. Results: PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. Conclusions: Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies. [ABSTRACT FROM AUTHOR]

Rationale: Drug and natural rewarding stimuli activate the mesolimbic dopaminergic system. Both methamphetamine (Meth) and copulation to satiety importantly increase dopamine (DA) release in the nucleus accumbens (NAc), but with differences in magnitude. This paper analyzes the interaction between Meth administration and the intense sexual activity associated with sexual satiety. Objectives: To evaluate possible changes in Meth-induced behavioral effects and striatal DA-related protein expression due to sexual satiety. Methods: Meth-induced locomotor activity and conditioned place preference (CPP) were tested in sexually experienced male rats that copulated to satiety (S–S) or ejaculated once (1E) the day before or displayed no sexual activity (control group; C). DA receptors and DA transporter expression were determined by western blot in the striatum of animals of all sexual conditions treated with specific Meth doses. Results: Meth's locomotor and rewarding effects were exacerbated in S–S animals, while in 1E rats, only locomotor effects were enhanced. Sexual activity, by itself, modified DA-related protein expression in the NAc core and in the caudate-putamen (CPu), while Meth treatment alone changed their expression only in the NAc shell. Meth-induced changes in the NAc shell turned in the opposite direction when animals had sexual activity, and additional changes appeared in the NAc core and CPu of S–S rats. Conclusion: Sexual satiety sensitizes rats to Meth's behavioral effects and the Meth-induced striatal DA-related protein adaptations are modified by sexual activity, evidencing cross-sensitization between both stimuli. [ABSTRACT FROM AUTHOR]

Rationale: Psychostimulants, including methylphenidate (MPH), are the mainstay of pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) in adults. Even though MPH is the most commonly used medication for ADHD these days, there are relatively few resources available that provide comprehensive insight into the pharmacological and clinical features of the compound. Objective: The aim of this paper is to provide an up-to-date outline of the pharmacology and clinical utility of MPH for ADHD in adult patients. Methods: While conducting the narrative review, we applied structured search strategies covering the two major online databases (MEDLINE and Cochrane Central Register of Controlled Trials). In addition, we performed handsearching of reference lists of relevant papers. Results: Methylphenidate exhibits multimodal mechanism of action, working primarily as a dopamine and noradrenaline reuptake inhibitor. It also protects the dopaminergic system against the ongoing 'wearing off' (by securing a substantial reserve pool of the neurotransmitter, stored in the presynaptic vesicles). In placebo-controlled trials, MPH was shown to be moderately effective both against the core ADHD symptoms (standardized mean difference [SMD], 0.49; 95% confidence interval [CI], 0.35–0.64), and the accompanying emotion regulation deficits (SMD, 0.34; 95% CI, 0.23–0.45). The most common adverse events related to long-term treatment with MPH are decreased appetite (~ 20%), dry mouth (15%), heart palpitations (13%), gastrointestinal infections (~ 10%), and agitation/feeling restless (~ 10%). Conclusions: There is substantial body of evidence to suggest that MPH is an effective and safe treatment option for adults with ADHD. [ABSTRACT FROM AUTHOR]

Rationale: The use of psychedelics for medical and recreational purposes is rising. Contextual factors such as expectancy, intention, and sensory and social environment (set and setting) are widely recognized as moderating the effects of these substances. Nevertheless, clinical trials of microdosing — the ingestion of small, sub-hallucinogenic doses of psychedelics — rarely report their set and setting. This fact suggests that such factors are not considered important in the context of microdosing. Objective: This paper challenges this assumption and makes the case for the crucial relevance of set and setting in microdosing practice. Building on set and setting theory and placebo theory, we explain why set and setting are of crucial importance in the case of microdosing. Results: This reasoning helps elucidate the role of set and setting in determining the outcomes of microdosing and helps explain some of the contradictory results that have emerged in microdosing research in recent years. Conclusion: Set and setting are important constructs to be considered especially in the context of microdosing psychedelics. By reporting set and setting, the results of microdosing research can be made more reliable and consistent. [ABSTRACT FROM AUTHOR]

Rationale: Current pharmacological approaches to treatment of post-traumatic stress disorder (PTSD) lack adequate effectiveness. As a result, identifying new molecular targets for drug development is necessary. Furthermore, fear learning and memory in PTSD can undergo different phases, such as fear acquisition, consolidation, and extinction. Each phase may involve different cellular pathways and brain regions. As a result, effective management of PTSD requires mindfulness of the timing of drug administration. One of the molecular targets currently under intense investigation is the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR). However, despite the therapeutic efficacy of drugs targeting NMDAR, their translation into clinical use has been challenging due to their various side effects. One possible solution to this problem is to target signaling proteins downstream to NMDAR to improve targeting specificity. One of these proteins is the neuronal nitric oxide synthase (nNOS), which is activated following calcium influx through the NMDAR. Objective: In this paper, we review the literature on the pharmacological modulation of nNOS in animal models of PTSD to evaluate its therapeutic potential. Furthermore, we attempt to decipher the inconsistencies observed between the findings of these studies based on the specific phase of fear learning which they had targeted. Results: Inhibition of nNOS may inhibit fear acquisition and recall, while not having a significant effect on fear consolidation and extinction. However, it may improve extinction consolidation or reconsolidation blockade. Conclusions: Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting. [ABSTRACT FROM AUTHOR]

Dr. Pickens was remarkably productive during this time with more than 32 basic research papers on drug self-administration as well as 29 reviews and book chapters. In possibly the most influential of these papers, Pickens and Thompson ([6]) systematically studied the effects of cocaine dose and schedule of reinforcement on cocaine self-administration. Graph Roy W. Pickens died peacefully on May 25, 2022, at his home in Glen Allen, Virginia, where he and his wife Dace Svikis have lived since 1999. [Extracted from the article]

Cannabis and its major constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being widely used to treat sleep disturbances. However, THC can cause acute cognitive and psychomotor impairment and there are concerns that driving and workplace safety might be compromised the day after evening use. Here, we examined possible ‘next day’ impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the effects of THC/CBD on insomnia disorder. Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD (‘THC/CBD’) or placebo in a randomised, double-blind, crossover trial design. Outcome measures included ‘next day’ (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug effects, and mood. We found no differences in ‘next day’ performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (p’s>0.05). In conclusion, we found a lack of notable ‘next day’ impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis. [ABSTRACT FROM AUTHOR]

The therapeutic potential of medical cannabis to treat a variety of conditions is becoming increasingly recognised. Globally, a large number of countries have now legalised cannabis for medical uses and a substantial number of patients are able to access their medications. Yet in the UK, where medical cannabis was legalised in November 2018, only a handful of NHS prescriptions have been written, meaning that most patients are unable to access the medicine. Reasons for this are manyfold and include the perceived lack of clinical evidence due to the challenges of studying medical cannabis through randomised controlled trials. In order to develop the current evidence base, the importance of incorporating real-world data (RWD) to assess the effectiveness and efficacy of medical cannabis has gradually become recognised. The current paper provides a detailed outline of Project Twenty21 (T21), the UK's first medical cannabis registry, launched in August 2020. We provide the rationale for T21 and describe the methodology before reporting the characteristics of the 'first patients' enrolled in the registry. We describe the health status of all patients enrolled into the project during its first 7 months of operation and the sociodemographic characteristics and primary presenting conditions for these patients, as well as details of the medical cannabis prescribed to these individuals. By 12th March 2021, 678 people had been enrolled into T21; the majority (64%) were male and their average age was 38.7 years (range = 18–80). The most commonly reported primary conditions were chronic pain (55.6%) and anxiety disorders (32.0%) and they reported high levels of multi-morbidity, including high rates of insomnia and depression. We also present preliminary evidence from 75 patients followed up after 3 months indicating that receipt of legal, prescribed cannabis was associated with a significant increase in self-reported health, assessed using the visual analogue scale of the EQ-5D-5L (Cohen's d =.77, 95% CI =.51–1.03). Our initial findings complement reports from other large-scale databases globally, indicating that the current RWD is building up a pattern of evidence. With many clinicians demanding better and faster evidence to inform their decisions around prescribing medical cannabis, the current and future results of T21 will expand the existing evidence base on the effectiveness of cannabis-based medical products (CBMPs). [ABSTRACT FROM AUTHOR]

The potential of mitragynine to produce physiological dependence (withdrawal) was assessed using a rapid assessment procedure with male ICR mice exposed to heroin-admixed food followed by naloxone (subcutaneously, s.c.) precipitation of withdrawal. Initial studies indicated that 3 days of exposure to 3.0 mg/g of heroin-admixed food followed by naloxone (0.6 mg/kg) reliably precipitated withdrawal jumping and weight loss. Lower concentrations of heroin-admixed food and lower doses of naloxone produced fewer withdrawal signs. A longer exposure to heroin-admixed food did not produce significantly greater amounts of jumping or weight loss. Further, these withdrawal signs were dose-dependently reversed by s.c. administration of heroin immediately following naloxone administration. Mitragynine (s.c.) also dose-dependently suppressed naloxone-precipitated withdrawal signs. Additionally, both jumping and weight loss were suppressed over a comparable range of mitragynine doses when administered by gavage with a noticeably, but not significantly, higher potency than with s.c. administration. The ED50 values for mitragynine for the suppression of withdrawal by any route (354–911 μmol/kg) were greater than the minimally effective dose that decreased locomotor activity (251 μmol/kg) and from 40- to 104-fold greater than those for heroin. The results suggest inherent opioid dependence liability of mitragynine. The in vivo potency relations between mitragynine and heroin are consistent with a conclusion of dependence-producing effects, indicated by the suppression of withdrawal, comparable to standard opioid μ-receptor agonists, differing primarily in terms of potency. The present paper provides a method for the rapid assessment of physiological dependence liability applicable to other kratom plant constituents or any potential opioid dependence-producing agents. [ABSTRACT FROM AUTHOR]

Rationale: The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance. Objective: To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance. Methods: In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks—road-tracking, car-following, and harsh-braking—using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone. Results: The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71–5.79) and 4.07 cm (90% CI: 2.02–6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94–6.69) and 24.6 ms (90% CI: 12.7–36.4), respectively. Conclusions: The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance. [ABSTRACT FROM AUTHOR]

Rationale: The regular consumption of very small doses of psychedelic drugs (known as microdosing) has been a source of growing media and community attention in recent years. However, there is currently limited clinical and social research evidence on the potential role of microdosing as therapies for mental and substance use disorders. Objectives: This paper examined subjective experiences of microdosing psychedelics to improve mental health or to cease or reduce substance use, and examined sociodemographic and other covariates of perceived improvements in mental health that individuals attributed to microdosing. Methods: An international online survey was conducted in 2018 and examined people's experiences of using psychedelics for self-reported therapeutic or enhancement purposes. This paper focuses on 1102 respondents who reported current or past experience of psychedelic microdosing. Results: Twenty-one percent of respondents reported primarily microdosing as a therapy for depression, 7% for anxiety, 9% for other mental disorders and 2% for substance use cessation or reduction. Forty-four percent of respondents perceived that their mental health was "much better" as a consequence of microdosing. In a multivariate analysis, perceived improvements in mental health from microdosing were associated with a range of variables including gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses. Conclusions: Given the promising findings of clinical trials of standard psychedelic doses as mental health therapies, clinical microdosing research is needed to determine its potential role in psychiatric treatment, and ongoing social research to better understand the use of microdosing as self-managed mental health and substance use therapies. [ABSTRACT FROM AUTHOR]

Background: In this paper, we reviewed translational studies concerned with environmental influences on the rewarding effects of heroin versus cocaine in rats and humans with substance use disorder. These studies show that both experienced utility ('liking') and decision utility ('wanting') of heroin and cocaine shift in opposite directions as a function of the setting in which these drugs were used. Briefly, rats and humans prefer using heroin at home but cocaine outside the home. These findings appear to challenge prevailing theories of drug reward, which focus on the notion of shared substrate of action for drug of abuse, and in particular on their shared ability to facilitate dopaminergic transmission. Aims: Thus, in the second part of the paper, we verified whether our findings could be accounted for by available computational models of reward. To account for our findings, a model must include a component that could mediate the substance-specific influence of setting on drug reward Results: It appears of the extant models that none is fully compatible with the results of our studies. Conclusions: We hope that this paper will serve as stimulus to design computational models more attuned to the complex mechanisms responsible for the rewarding effects of drugs in real-world contexts. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Acute Tryptophan Depletion in Healthy Males Attenuates Phasic Cardiac Slowing But Does Not Affect Electro-Cortical response to Negative Feedback" by F. M. Van der Veen, G. W. Mies, M. W. Van der Molen and E. A. Evers in a previous issue.

A list is presented of people who received awards for papers on original research in psychopharmacology that were cited the most in reviews published in the periodical "Psychopharmacology" between 2003 and 2006, including Danielle C. Turner, James D. Belluzzi and James N. C. Kew.

Depression is a leading cause of disability worldwide and improving its treatment is a core research priority for future programmes. A change in the view of psychological and biological processes, from seeing them as separate to complementing one another, has introduced new perspectives on pathological mechanisms of depression and treatment mode of action. This review presents a theoretical model that incorporated this novel approach, the cognitive neuropsychological hypothesis of antidepressant action. This model proposes that antidepressant treatments decrease the negative bias in the processing of emotionally salient information early in the course of antidepressant treatment, which leads to the clinically significant mood improvement later in treatment. The paper discusses the role of negative affective biases in the development of depression and response to antidepressant treatments. It also discusses whether the model can be applied to other antidepressant interventions and its potential translational value, including treatment choice, prediction of response and drug development. [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]

Comments on the article by Horowski and Dorow concerning the pharmacological effects of the compounds of beta-carboline structure with high benzodiazepine receptor-binding affinity. Sedative effects of flurazepam; Concept of inverse agonism; Electrophysiological changes in vitro by beta-carboline-3-carboxylate.

Ayahuasca is a psychoactive plant brew containing dimethyltryptamine (DMT) and monoamine oxidase inhibitors (MAOIs). It originates from the Amazon basin, where it is used primarily for ceremonial purposes. Ayahuasca tourists are now entering certain communities seeking alternative physical or psychological healing, as well as spiritual growth. Rationale: Recent evidence has shown that the similar acting psychedelic compound, psilocybin, facilitated long-term increases in trait openness following a single administration. Objectives: This paper assesses the impact of ayahuasca on personality in a traditional framework catering for ayahuasca tourists. Method: Within a mixed design, we examined the effect of ayahuasca on participants' personality (measured by the NEO Personality Inventory 3 questionnaire) across time (pre- to post-ayahuasca administration, and 6-month follow-up), relative to a comparison group (who did not ingest ayahuasca). Results: The results demonstrated significant increases in agreeableness pre- and post-ayahuasca administration and significant reductions in neuroticism in 24 participants, relative to the comparison group. Both of these changes were sustained at 6-month follow-up, and trait level increases were also observed in openness at this stage. Additionally, greater perceived mystical experience (measured using the Mystical Experience Questionnaire 30) was associated with increased reductions in neuroticism. Conclusions: These findings, which indicate a positive mediating effect of ayahuasca on personality, support the growing literature suggesting potential therapeutic avenues for serotonergic psychedelics. [ABSTRACT FROM AUTHOR]

Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a “model psychosis”; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research—and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards. [ABSTRACT FROM AUTHOR]

Rationale: Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. Objectives: In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. Methods: We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. Results: Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. Conclusions: 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia. [ABSTRACT FROM AUTHOR]

The incorporation of microeconomics concepts into studies using self-administration procedures has provided critical insights into the factors that influence consumption of a wide range of food and drug reinforcers. In particular, the fitting of demand curves to consumption data provides a powerful analytic tool for computing objective metrics of behavior that can be compared across a wide range of reward types in both human and animal experiments. The results of these analyses depend crucially on the mathematical form used to fit the data. The most common choice is an exponential form proposed by Hursh and Silberberg, which is widely used and has provided fundamental insights into relationships between cost and consumption, but it also has some disadvantages. In this paper, we first briefly review the use of demand curves to quantify the motivating effects of food and drugs, then we describe the current methodology and highlight some potential issues that arise in its application. To address these issues, we propose a new mathematical framework for the analysis of consumption data, including a new functional form for the demand curve. We show that this proposed form gives good fits to data for a range of different reinforcers and experimental protocols, while allowing for straightforward calculation of key metrics of demand, including preferred consumption level, maximum response, price at maximum response, and price elasticity of demand. We provide software implementing our entire analysis pipeline, including data fits, data visualization, and the calculation of demand metrics. [ABSTRACT FROM AUTHOR]

Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease. Objective: This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response. Methods: This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days). Results: Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment. Conclusions: Our results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer's disease (AD). [ABSTRACT FROM AUTHOR]

Background: People with schizophrenia frequently have cognitive dysfunction, which does not respond to pharmacological interventions. Varenicline has been identified as a potential treatment option for nicotinic receptor dysfunction with a potential to treat cognitive impairment in schizophrenia. Methods: We conducted a systematic review of Pubmed, Embase, Psycinfo, CINAHL and the Cochrane Schizophrenia Trial Registry for randomised controlled trials of varenicline in people with schizophrenia for cognitive dysfunction. We excluded trials among people with dementia. We then undertook a meta-analysis with the primary outcome of difference in change of cognitive measures between varenicline and placebo as well as secondary outcomes of difference in rates of adverse events. We conducted a sensitivity analysis on smoking status and study duration. Results: We included four papers in the meta-analysis (n = 339). Varenicline was not superior to placebo for overall cognition (SMD = −0.022, 95% CI −0.154–0.110; Z = −0.333; p = 0.739), attention (SMD = −0.047, 95% CI −0.199–0.104; Z = −0.613; p = 0.540), executive function (SMD = −0.060, 95% CI −0.469–0.348; Z =− 0.290; p = 0.772) or processing speed (SMD = 0.038, 95% CI −0.232–0.308; Z = 0.279; p = 0.780). There was no difference in psychotic symptoms, but varenicline was associated with higher rates of nausea. Sensitivity analyses for smoking status and study duration did not alter the results. Conclusion: Within the present literature, varenicline does not appear to be a useful target compound for improving cognitive impairment in schizophrenia. Based on these results, a trial would need over 2500 participants to be powered to show statistically significant findings. [ABSTRACT FROM AUTHOR]

Rationale: As a species, humans are vulnerable to numerous mental disorders, including depression and schizophrenia. This susceptibility may be due to the evolution of our large, complex brains, or perhaps because these illnesses counterintuitively confer some adaptive advantage. Additionally, cultural and biological factors may contribute to susceptibility and variation in mental illness experience and expression. Taking a holistic perspective could strengthen our understanding of these illnesses in diverse cultural contexts. Objectives: This paper reviews some of these potential factors and contextualizes mental disorders within a biocultural framework. Results: There is growing evidence that suggests cultural norms may influence inflammation, neurotransmitters, and neurobiology, as well as the illness experience. Specific examples include variation in schizophrenia delusions between countries, differences in links between inflammation and emotion between the United States and Japan, and differences in brain activity between Caucasian and Asian participants indicating that cultural values may moderate cognitive processes related to social cognition and interoception. Conclusions: Research agendas that are grounded in an appreciation of biocultural diversity as it relates to psychiatric illness represent key areas for truly interdisciplinary research that can result in culturally sensitive treatments and highlight possible biological variation affecting medical treatment. [ABSTRACT FROM AUTHOR]

In the context of Pavlovian conditioning, two types of behaviour may emerge within the population (Flagel et al. Nature, 469(7328): 53–57, 2011). Animals may choose to engage either with the conditioned stimulus (CS), a behaviour known as sign-tracking (ST) which is sensitive to dopamine inhibition for its acquisition, or with the food cup in which the reward or unconditioned stimulus (US) will eventually be delivered, a behaviour known as goal-tracking (GT) which is dependent on dopamine for its expression only. Previous work by Lesaint et al. (PLoS Comput Biol, 10(2), 2014) offered a computational explanation for these phenomena and led to the prediction that varying the duration of the inter-trial interval (ITI) would change the relative ST-GT proportion in the population as well as phasic dopamine responses. A recent study verified this prediction, but also found a rich variance of ST and GT behaviours within the trial which goes beyond the original computational model. In this paper, we provide a computational perspective on these novel results. [ABSTRACT FROM AUTHOR]

The nascent field computational psychiatry has undergone exponential growth since its inception. To date, much of the published work has focused on choice behaviors, which are primarily modeled within a reinforcement learning framework. While this initial normative effort represents a milestone in psychiatry research, the reality is that many psychiatric disorders are defined by disturbances in subjective states (e.g., depression, anxiety) and associated beliefs (e.g., dysmorphophobia, paranoid ideation), which are not considered in normative models. In this paper, we present interoceptive inference as a candidate framework for modeling subjective—and associated belief—states in computational psychiatry. We first introduce the notion and significance of modeling subjective states in computational psychiatry. Next, we present the interoceptive inference framework, and in particular focus on the relationship between interoceptive inference (i.e., belief updating) and emotions. Lastly, we will use drug craving as an example of subjective states to demonstrate the feasibility of using interoceptive inference to model the psychopathology of subjective states. [ABSTRACT FROM AUTHOR]

Many physiological and pathological changes in brain function manifest in eye-movement control. As such, assessment of oculomotion is an invaluable part of a clinical examination and affords a non-invasive window on several key aspects of neuronal computation. While oculomotion is often used to detect deficits of the sort associated with vascular or neoplastic events; subtler (e.g. pharmacological) effects on neuronal processing also induce oculomotor changes. We have previously framed oculomotor control as part of active vision, namely, a process of inference comprising two distinct but related challenges. The first is inferring where to look, and the second is inferring how to implement the selected action. In this paper, we draw from recent theoretical work on the neuromodulatory control of active inference. This allows us to simulate the sort of changes we would expect in oculomotor behaviour, following pharmacological enhancement or suppression of key neuromodulators—in terms of deciding where to look and the ensuing trajectory of the eye movement itself. We focus upon the influence of cholinergic and GABAergic agents on the speed of saccades, and consider dopaminergic and noradrenergic effects on more complex, memory-guided, behaviour. In principle, a computational approach to understanding the relationship between pharmacology and oculomotor behaviour affords the opportunity to estimate the influence of a given pharmaceutical upon neuronal function, and to use this to optimise therapeutic interventions on an individual basis. [ABSTRACT FROM AUTHOR]

Background and rationale: Cathinones are amphetamine analogues that produce stimulant effects with rewarding properties. For many decades, synthetic cathinones have been used in the United States (USA) for abuse purposes, leading to concern about public safety by the federal government. Under the Controlled Substances Act (CSA), the federal government may place drugs with high abuse potential but no currently accepted medical use into Schedule I of the CSA. The process of scheduling an abusable drug involves both the Department of Health and Human Services (HHS), through the Food and Drug Administration (FDA) and the National Institute on Drug Abuse (NIDA), and the Department of Justice, through the Drug Enforcement Administration (DEA). Results: This paper details how numerous synthetic cathinones were placed under CSA control between 1973 and 2018, with an emphasis on 10 cathinones that were placed into Schedule I in 2017 (butylone, naphyrone, pentylone, pentedrone, 3-fluoro-N-methylcathinone (FMC), 4-FMC, 4-methyl-N-ethylcathinone, 4-methyl-pyrrolidinopropiophenone, alpha-pyrrolidinobutiophenone, and α-pyrrolidinopentiophenone). A summary is provided of the scientific and medical analysis performed by HHS, in the form of an Eight-Factor Analysis (8FA), as prescribed by the CSA. This 8FA was then evaluated and signed by the Assistant Secretary for Health at HHS and transmitted to DEA, which permanently placed the 10 cathinones into Schedule I after public notices were published into the Federal Register. Discussion and conclusions: Understanding the scientific data, analysis, and complex process utilized by the US federal government in the CSA scheduling of cathinones with abuse potential and no accepted medical use is important for transparency in governmental decision-making. [ABSTRACT FROM AUTHOR]

Rationale: Many studies have found that ethanol intoxication and withdrawal impair initial acquisition or extinction of learned behaviors. Rapid reconditioning following extinction is a form of post-extinction re-emergence of conditioned behavior that has not been studied for its interaction with ethanol intoxication or withdrawal.Objectives: The goals of this paper were to define the parameters that allow rapid post-extinction reacquisition of fear in mice and investigate the effect of acute ethanol withdrawal and intoxication on acquisition, extinction, and post-extinction reconditioning.Methods: We examined acquisition, extinction, and post-extinction reconditioning of contextual fear in male C57BL/6 mice. Acute ethanol withdrawal occurred 6 h following a 4 g/kg injection of 20% ethanol and acute ethanol intoxication occurred 5 min following a 1.5 g/kg injection of 20% ethanol.Results: A weak context-shock pairing caused rapid reacquisition of conditioned freezing following moderate, but not extensive extinction. Acute ethanol intoxication impaired initial conditioning and acute ethanol withdrawal impaired rapid reacquisition after extinction, but not reconditioning or extinction itself.Conclusions: These findings show that rapid reconditioning occurs following moderate but not extensive extinction in C57BL/6J mice. Additionally, acute ethanol withdrawal and intoxication may differentially affect different phases of conditioning. Results are discussed in terms of current ideas about post-extinction behavior and ethanol's effects on memory. [ABSTRACT FROM AUTHOR]

The basolateral amygdala complex (BLA) and infralimbic region of the prefrontal cortex (IL) play distinct roles in the extinction of Pavlovian conditioned fear in laboratory rodents. In the past decade, research in our laboratory has examined the roles of these brain regions in the re-extinction of conditioned fear: i.e., extinction of fear that is restored through re-conditioning of the conditioned stimulus (CS) or changes in the physical and temporal context of extinction training (i.e., extinction of renewed or spontaneously recovered fear). This paper reviews this research. It has revealed two major findings. First, in contrast to the acquisition of fear extinction, which usually requires neuronal activity in the BLA but not IL, the acquisition of fear re-extinction requires neuronal activity in the IL but can occur independently of neuronal activity in the BLA. Second, the role of the IL in fear extinction is determined by the training history of the CS: i.e., if the CS was novel prior to its fear conditioning (i.e., it had not been trained), the acquisition of fear extinction does not require the IL; if, however, the prior training of the CS included a series of CS-alone exposures (e.g., if the CS had been pre-exposed), the acquisition of fear extinction was facilitated by pharmacological stimulation of the IL. Together, these results were taken to imply that a memory of CS-alone exposures is stored in the IL, survives fear conditioning of the CS, and can be retrieved and strengthened during extinction or re-extinction of that CS (regardless of whether the extinction is first- or second-learned). Hence, under these circumstances, the initial extinction of fear to the CS can be facilitated by pharmacological stimulation of the IL, and re-extinction of fear to the CS can occur in the absence of a functioning BLA. [ABSTRACT FROM AUTHOR]

It is well established that alcoholics and heavy social drinkers show a bias of attention towards alcohol-related items. Previous research suggests that there is a shared foundation of attentional bias, which is linked to attentional control settings. Specifically, attentional bias relates to a persistent selection of a Feature Search Mode which prioritises attentional bias-related information for selection and processing. However, no research has yet examined the effect of pre-existing biases on the development of an additional attentional bias. This paper seeks to discover how pre-existing biases affect the formation of a new, additional attentional bias. Twenty-five heavy and 25 light social drinkers, with and without a pre-existing bias to alcohol-related items, respectively, had an attentional bias towards the colour green induced via an information sheet. They then completed a series of one-shot change detection tasks. In the critical task, green items were present but task-irrelevant. Irrelevant green items caused significantly more interference for light than heavy social drinkers. This somewhat counter intuitive result is likely due to heavy drinkers having more experience in exerting cognitive control over attentional biases, something not previously observed in investigations of the effects of holding an attentional bias. Our findings demonstrate for the first time that an established attentional bias significantly modulates future behaviour. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Acute neuropsychological effects of MDMA and ethanol (co-)administration in healthy volunteers," by G.J. Dumont, E. Wezenberg, M. M. Valkenberg, C. A. De Jong, J. K. Buitelaar, J. M. van Gerven, and R. J. Verkes.

A letter to the editor is presented in response to the article "Binge Ethanol Administration Enhances the MDMA-Induced Long-Term 5HT Neurotoxicity in Rat Brain," in the 2007 issue.

Rationale The amygdala plays a paramount role in the modulation of anxiety and numerous studies have shown that arginine vasopressin (AVP) elicits anxiogenic effects following either its systemic or septal administration. Objectives The aim of this paper was to study the involvement of vasopressinergic neurotransmission in the amygdaloid modulation of unconditioned anxiety and to ascertain whether or not AVP receptor subtypes may have a differential role in this modulation. Methods Anxiety behavior was evaluated both in Shock-Probe Burying Test and Light-Dark Box following the bilateral microinfusion ofAVP alone orAVP together with either AVP 1a orAVP 1b receptor antagonists into the central amygdala (CeA). Results AVP microinfusion elicited at low (1 ng/side) but not at high doses (10 ng/side) anxiogenic-like responses in the Shock- Probe Burying Test but not in the Light-Dark Box. SSR149415, an AVP 1b antagonist unlike Manning compound, an AVP 1a antagonist, fully prevented AVP effects in the Shock-Probe Burying Test when it was administered simultaneously with AVP. In addition, oxytocin receptor blockade also failed to affect AVP effects. No effects of any AVP antagonist by itself were observed in both anxiety paradigms. Conclusions Our results indicate that AVP 1b receptor contribute to the amygdaloid modulation of anxiety at least in the context of the Shock-Probe Burying Test since no effects were noticed in the Light-Dark Box. It remains to the future to ascertain whether AVP receptor subtypes have indeed differential actions either in the modulation of global or specific features of unconditioned anxiety. [ABSTRACT FROM AUTHOR]

Abstract Rationale Impulsive choice is often measured with delay discounting paradigms. Because there are multiple discounting procedures, as well as different statistical analyses that can be applied to data generated from these paradigms, there are some inconsistencies in the literature regarding drug effects on impulsive choice. Objectives The goal of the current paper is to review the methodological and analytic approaches used to measure discounting and to discuss how these differences can account for differential drug effects observed across studies. Results Because some procedures/analyses use a single data point as the dependent variable, changes in this value following pharmacological treatment may be interpreted as alterations in sensitivity to delayed reinforcement, but when other procedures/analyses are used, no changes in behavior are observed. Even when multiple data points are included, some studies show that the statistical analysis (e.g., ANOVA on raw proportion of responses vs. using hyperbolic/exponential functions) can lead to different interpretations. Finally, procedural differences (e.g., delay presentation order, signaling the delay to reinforcement, etc.) in the same discounting paradigm can alter how drugs affect sensitivity to delayed reinforcement. Conclusions Future studies should utilize paradigms that allow one to observe alterations in responding at each delay (e.g., concurrent-chains schedules). Concerning statistical analyses, using parameter estimates derived from nonlinear functions or incorporating the generalized matching law can allow one to determine if drugs affect sensitivity to delayed reinforcement or impair discrimination of the large and small magnitude reinforcers. Using these approaches can help further our understanding of the neurochemical underpinnings of delay discounting. [ABSTRACT FROM AUTHOR]

Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science. [ABSTRACT FROM AUTHOR]

Rationale: Hyperprolactinemia is a highly prevalent adverse effect of many antipsychotic agents, with potentially serious health consequences. Several guidelines have been developed for the management of this condition; yet, their concordance has not been evaluated. Objectives: The objectives of this paper were (1) to review current clinical guidelines; (2) to review key systematic evidence for management; and (3) based on our findings, to develop an integrated management recommendation specific to male and female patients who are otherwise clinically stabilised on antipsychotics. Methods: We performed searches of Medline and EMBASE, supplemented with guideline-specific database and general web searches, to identify clinical guidelines containing specific recommendations for antipsychotic-induced hyperprolactinemia, produced/updated 01/01/2010-15/09/2016. A separate systematic search was performed to identify emerging management approaches described in reviews and meta-analyses published ≥ 2010. Results: There is some consensus among guidelines relating to baseline PRL screening (8/12 guidelines), screening for differential diagnosis (7/12) and discontinuing/switching PRL-raising agent (7/12). Guidelines otherwise diverge substantially regarding most aspects of screening, monitoring and management (e.g. treatment with dopamine agonists). There is an omission of clear sex-specific recommendations. Systematic literature on management approaches is promising; more research is needed. An integrated management recommendation is presented to guide sex-specific clinical response to antipsychotic-induced hyperprolactinemia. Key aspects include asymptomatic hyperprolactinemia monitoring and fertility considerations with PRL normalisation. Conclusion: Further empirical work is key to shaping robust guidelines for antipsychotic-induced hyperprolactinemia. The integrated management recommendation can assist clinician and patient decision-making, with the goal of balancing effective psychiatric treatment while minimising PRL-related adverse health effects in male and female patients. [ABSTRACT FROM AUTHOR]

Rationale: Knowing how stress manifests in the lives of people with substance-use disorders could help inform mobile 'just in time' treatment. Objectives: The purpose of this paper is to examine discrete episodes of stress, as distinct from the fluctuations in background stress assessed in most EMA studies. Methods: For up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated an entry whenever they experienced a stressful event (SE) and when randomly prompted (RP) three times daily. Participants reported the severity of stress and craving and the context of the report (location, activities, companions). Decomposition of covariance was used to separate within-person from between-person effects; r sizes below are within-person. Results: Participants (158 of 182; 87%) made 1787 stress-event entries. Craving for opioids increased with stress severity ( r = 0.50). Stress events tended to occur in social company (with acquaintances, 0.63, friends, 0.17, or on the phone, 0.41) rather than with family (spouse, −0.14; child, −0.18), and in places with more overall activity (bars, 0.32; outside, 0.28; walking, 0.28) and more likelihood of unexpected experiences (with strangers, 0.17). Being on the internet was slightly protective (−0.22). Our prior finding that being at the workplace protects against background stress in our participants was partly supported in these stressful-event data. Conclusions: The contexts of specific stressful events differ from those we have seen in prior studies of ongoing background stress. However, both are associated with drug craving. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol hangover may be defined as an adverse effect of heavy alcohol consumption present after sufficient time has elapsed for the alcohol to have been eliminated from the blood. Understanding how hangover may impair performance is important for public safety; yet, there is relatively little hangover research. This paper outlines good practice for future studies. Objectives: This paper presents a critical analysis of hangover methodology for surveys or studies of effects on cognition with human subjects and provides suggestions for optimum research practice for laboratory-based and naturalistic alcohol hangover studies. Results: Four hangover symptom scales have been developed and subjected to psychometric testing. For retrospective assessment, we recommend the Hangover Symptoms Scale (HSS) or the Alcohol Hangover Severity Scale (AHSS). For concurrent assessment of hangover symptoms, we recommend either the Acute Hangover Scale (AHS), the five-item version of the HSS, or the AHSS. In research aiming to assess the cognitive effects of alcohol hangover, we suggest focusing on the cognitive domains of attention, memory and executive function, and we specify a number of tests within these cognitive domains that are likely to be sensitive to any decrements due to hangover. Finally, we argue that naturalistic studies should assess biological markers to improve the accuracy of estimates of alcohol consumption. Specifically, we recommend the assessment of ethyl glucuronide (EtG) for this purpose. Conclusions: Recommendations are made with respect to assessing hangover symptoms, cognitive effects of hangover and biological markers of alcohol consumption. [ABSTRACT FROM AUTHOR]

Rationale: We have shown that differences in the level of neural activation to stimuli associated with smoking vs. natural rewards, a biomarker related to reward sensitivity, predict treatment outcome. Objectives: This paper examined whether this biomarker moderates the impact of bupropion or varenicline on smoking cessation. Methods: Prior to treatment randomization, smokers ( N = 180) in a placebo-controlled trial using bupropion and varenicline completed event-related potential recording (late positive potential, LPP) while viewing pleasant (P), cigarette (C)-related, and other pictures. We used Bayesian models to estimate the probability of interaction between treatment and the LPP for both efficacy and comparative effectiveness analyses. Results: Efficacy analysis showed that smokers with more neural activation to pleasant vs. cigarette-related stimuli (P > C) had a 98-99% chance of achieving greater abstinence than placebo (OR >1.00), using either medication from the end of treatment (EOT, primary outcome) through the 3-month follow-up. Relative to placebo, smokers with higher activation to cigarette-related vs. pleasant stimuli (C > P) had a 99% chance of increased benefit from varenicline at both time points (OR >1), but only 67 and 43% with bupropion at the EOT and 3-month follow-up, respectively. Comparative effectiveness analysis found that smokers with the C > P activation pattern had a 95-98% chance of benefit from varenicline vs. bupropion, while P > C smokers had a 50-58% chance of similar improvement with varenicline at the EOT and 3 months. Conclusions: Varenicline appears to be the treatment of choice for smokers with the C > P pattern of neural activation, while for those showing P > C, varenicline and bupropion have similar efficacy. [ABSTRACT FROM AUTHOR]

Rationale: Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high, and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. Objective: The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. Results: Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. Conclusions: Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence, they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many 'off-target' effects to be used clinically. However, newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence. [ABSTRACT FROM AUTHOR]

Rationale: The mildly euphoric and cognitive enhancing effects of nicotine play a role in the initiation of smoking, while dysphoria and anxiety associated with smoking cessation contribute to relapse. After the acute withdrawal phase, smoking cues, a few cigarettes (i.e., lapse), and stressors can cause relapse. Human and animal studies have shown that neuropeptides play a critical role in nicotine addiction. Objectives: The goal of this paper is to describe the role of neuropeptide systems in the initiation of nicotine intake, nicotine withdrawal, and the reinstatement of extinguished nicotine seeking. Results: The reviewed studies indicate that several drugs that target neuropeptide systems diminish the rewarding effects of nicotine by preventing the activation of dopaminergic systems. Other peptide-based drugs diminish the hyperactivity of brain stress systems and diminish withdrawal-associated symptom severity. Blockade of hypocretin-1 and nociceptin receptors and stimulation of galanin and neurotensin receptors diminishes the rewarding effects of nicotine. Both corticotropin-releasing factor type 1 and kappa-opioid receptor antagonists diminish dysphoria and anxiety-like behavior associated with nicotine withdrawal and inhibit stress-induced reinstatement of nicotine seeking. Furthermore, blockade of vasopressin 1b receptors diminishes dysphoria during nicotine withdrawal, and melanocortin 4 receptor blockade prevents stress-induced reinstatement of nicotine seeking. The role of neuropeptide systems in nicotine-primed and cue-induced reinstatement is largely unexplored, but there is evidence for a role of hypocretin-1 receptors in cue-induced reinstatement of nicotine seeking. Conclusion: Drugs that target neuropeptide systems might decrease the euphoric effects of smoking and improve relapse rates by diminishing withdrawal symptoms and improving stress resilience. [ABSTRACT FROM AUTHOR]

Objective: This paper provides an overview of the role of type 2 metabotropic glutamate receptors (mGluR2) in addiction and behaviors reflecting addictive processes. Results: AZD8529, an mGluR2 positive allosteric modulator (PAM), failed to separate from placebo in a phase II schizophrenia trial. The demonstration by Athina Markou's laboratory that AZD8529 attenuated both nicotine self-administration and cue-induced reinstatement was a key factor in the decision to move this compound into a smoking cessation study. Conclusion: Here, we highlight Markou laboratory's contribution to this project, as well as several innovative features of the phase II clinical trial that has already completed enrollment with top line results expected in early 2017. [ABSTRACT FROM AUTHOR]

This paper is a personal account on the discovery and characterization of the 5-HT receptor (first known as the 5-HT receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HTR, the 5-HTR was discovered while studying the pharmacological features and the distribution of [H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [H]mesulergine-labelling to the rat choroid plexus. [H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT binding, the new binding site was called 5-HT because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HTR (later named 5-HT) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HTR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HTR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HTR splice variants. Intense research led to therapeutically active 5-HT receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HTR antagonists/inverse agonists. Agomelatine, a 5-HTR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HTR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HTR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HTR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HTR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HTR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HTR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain. [ABSTRACT FROM AUTHOR]

Rationale: Cannabis is the most commonly used illicit drug among pregnant women. Since the endocannabinoid system plays a crucial role in brain development, maternal exposure to cannabis derivatives might result in long-lasting neurobehavioral abnormalities in the exposed offspring. It is difficult to detect these effects, and their underlying neurobiological mechanisms, in clinical cohorts, because of their intrinsic methodological and interpretative issues. Objectives: The present paper reviews relevant rodent studies examining the long-term behavioral consequences of exposure to cannabinoid compounds during pregnancy and/or lactation. Results: Maternal exposure to even low doses of cannabinoid compounds results in atypical locomotor activity, cognitive impairments, altered emotional behavior, and enhanced sensitivity to drugs of abuse in the adult rodent offspring. Some of the observed behavioral abnormalities might be related to alterations in stress hormone levels induced by maternal cannabis exposure. Conclusions: There is increasing evidence from animal studies showing that cannabinoid drugs are neuroteratogens which induce enduring neurobehavioral abnormalities in the exposed offspring. Several preclinical findings reviewed in this paper are in line with clinical studies reporting hyperactivity, cognitive impairments and altered emotionality in humans exposed in utero to cannabis. Conversely, genetic, environmental and social factors could also influence the neurobiological effects of early cannabis exposure in humans. [ABSTRACT FROM AUTHOR]

Rationale: Early Life Stress (ELS) increases risk for both adult traumatization and posttraumatic stress disorder (PTSD). Adult PTSD may also reflect a continuation of a response to an earlier exposure to adversity. Given similarities between neuroendocrine aspects of PTSD and ELS, such as in reduced cortisol signaling and glucocorticoid receptor (GR) responsiveness, some aspects of the biology of PTSD may reflect biological correlates of risk. Objectives: This paper will examine how empirical findings regarding the biological basis of ELS can inform our understanding of the neuroendocrinology of PTSD. This paper will also propose a hypothetical model to guide future research that integrates genetic, epigenetic, neuroendocrine, and psychological observations to understand the contribution of ELS neurobiology to PTSD. Results: Recent genetic findings demonstrate heritable aspects of at least some of these cortisol-related disturbances. Furthermore, ELS may produce at least some of the PTSD-associated changes in glucocorticoid responsiveness through epigenetic mechanisms such as developmental programming. These, then, may contribute to enduring changes in stress responsiveness as well as enhanced risk for adult exposure and PTSD. Conclusion: Molecular mechanisms associated with gene x environment interactions or GR programming are essential in explaining current observations in the neuroendocrinology of PTSD that have been difficult to understand through the lens of contemporary stress theory. [ABSTRACT FROM AUTHOR]