Extended observation of reduced methamphetamine use with combined naltrexone plus bupropion in the ADAPT-2 trial.

BACKGROUND AND AIMS: A 12-week placebo-controlled, sequential parallel Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial evaluated the effects of extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN) on methamphetamine (MA) use over two stages. This study reports on the previously unpublished stage 2 MA use in participants randomized at stage 1 to receive NTX + BUPN through both stages compared with those assigned to placebo. DESIGN: This is a secondary analysis of the US National Institute on Drug Abuse (NIDA) ADAPT-2 network trial. SETTING: The parent ADAPT-2 trial was carried out across multiple NIDA Clinical Trials Network (CTN) sites in the United States. PARTICIPANTS: This analysis includes 403 people with MA use disorder who participated in the ADAPT-2 CTN trial. INTERVENTION AND COMPARATOR: NTX + BUPN was compared with placebo over the course of the trial. MEASUREMENT: MA use was measured by urine drug screens conducted twice weekly for 12 weeks, then once in week 13 and once in week 16 post-treatment follow-up. FINDINGS: Participants on NTX + BUPN in stage 1 showed an additional 9.2% increase [95% confidence interval (CI), 0.09%-17.9%, P = 0.038] during stage 2 in their probability of testing negative for MA, with a total increase of 27.1% (95% CI, 13.2%-41.1%, P < 0.001) over the full 12 weeks of treatment. In contrast, participants on placebo in both stages increased in probability of testing MA-negative by a total of 11.4% (95% CI, 4.1%-18.6%, P = 0.002) over all 12 weeks. The 12-week increase among participants on NTX + BUPN was significantly greater-by 15.8% (95% CI, 4.5%-27.0%, P = 0.006)-than the increase among those on placebo. CONCLUSION: For people with methamphetamine (MA) use disorder receiving treatment with extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN), continued treatment with NTX + BUPN after 6 weeks is associated with additional reductions in MA use up to 12 weeks.

Bupropion Slow Release vs Placebo With Adaptive Incentives for Cocaine Use Disorder in Persons Receiving Methadone for Opioid Use Disorder: A Randomized Clinical Trial.

Importance: Opioid-stimulant co-use is a common problem with few evidence-based treatments. Objective: To examine bupropion slow release (SR) enhancement of a tailored abstinence incentive program for stimulant use in persons with opioid use disorder. Design, Setting, and Participants: This 26-week, double-blind, placebo-controlled randomized clinical trial with a 4-week follow-up period was conducted at 4 methadone treatment programs in Baltimore, Maryland. Included participants were persons receiving methadone for the treatment of opioid use disorder with past 3-month cocaine use and current cocaine use disorder between March 2015 and September 2019. Data were analyzed from November 2020 through August 2022. Interventions: A 6-week incentive induction period with monetary incentives for evidence of cocaine abstinence during thrice-weekly urine testing was conducted. Persons achieving 2 weeks of consecutive abstinence during induction were assigned to the relapse prevention group (20 individuals); otherwise, individuals were assigned to the abstinence initiation group (60 individuals). Participants were randomized within incentive groups to bupropion SR (150 mg oral twice daily; 40 participants) or placebo (40 participants). Incentives were available until week 26, and study medication ended week 30. Main Outcomes and Measures: The mean percentage of participants with cocaine abstinence (by negative urinalysis or self-report) during weeks 7 to 26 (ie, the incentive intervention period) and 27 to 30 (ie, the follow-up period) and the percentage of participants testing negative for cocaine at weeks 26 and 30 were assessed. Main effects of medication collapsed across incentive conditions and sensitivity analyses of medications within incentive conditions were assessed. Analyses were conducted in the modified intention-to-treat sample (ie, 80 individuals who received ≥1 dose of study medication) and completers (ie, 52 individuals who completed ≥1 visit during week 30). Results: Among 80 participants (42 Black [52.5% ] and 35 White [43.8%]; mean [SD] age, 45.7 (9.4) years; 52 males [65.0%]) receiving methadone for opioid use disorder, 40 participants were randomized to receive bupropion SR and 40 participants to receive placebo. No significant difference on urinalysis or self-reported cocaine use was observed between medication groups. Sensitivity analyses revealed differential patterns for incentive subgroups. Participants in the relapse prevention group had high abstinence (>80%; eg, during weeks 7-26 in the modified intention-to-treat analysis, 410 of 456 samples [89.9%] from participants in the bupropion SR group tested negative for cocaine) throughout the trial regardless of whether they were randomized to bupropion SR or placebo. Participants in the abstinence initiation group had better outcomes with bupropion SR than placebo throughout the trial (mean [SD] total number of samples testing negative for cocaine, 30.3 [21.6] samples for bupropion SR vs 17.1 [14.9] samples for placebo; P = .05) and more participants receiving bupropion SR than placebo were abstinent at the end of the study (20 of 30 participants [66.7%] vs 9 of 30 participants [30.0%]; P = .04). Conclusions and Relevance: In this randomized clinical trial, an overall benefit for bupropion SR vs placebo when combined with a financial abstinence incentive program was not observed. Results among incentive subgroups suggest that continued evaluation of medications, including bupropion SR, for stimulant treatment using a tailored approach that factors early abstinence into study design and interpretation may be needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02111798.

Understanding Stimulant Use and Use Disorders in a New Era.

Extending from the triple wave epidemic of opioid-related overdose deaths, a fourth wave of high mortality involving methamphetamine and cocaine use has been gathering force. This article provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments.

Internet parent-child interaction therapy (I-PCIT) in medically ill child: A case report.

INTRODUCTION: This case illustrates the feasibility, benefit, and putative enhanced ecological validity of performing internet-parent-child interaction therapy (I-PCIT) in the parent-child dyad's home for the treatment of behavior problems in medically ill children in the context of a global pandemic. PATIENT CONCERNS: Parents of a 5-year-old girl initially presented with concerns regarding inattentiveness, physical and verbal fighting with her siblings, and getting kicked out of daycare for hitting another child. Patient also had difficulties sleeping at night. DIAGNOSES: Patient was diagnosed with electrical status epilepticus in sleep, frontal lobe executive function deficit, and attention deficit hyperactivity disorder. INTERVENTIONS: Patient received a course of I-PCIT. Equipment included a cell phone with video capabilities connected to a videotelephony software program and set-up in the child's home by the parents. The treatment course included 8, 1-hour, weekly teaching/coaching sessions (7 of which were performed using I-PCIT) plus 1 follow-up booster session 6 months later. OUTCOMES: Home-based I-PCIT implementation greatly improved disruptive behaviors in a young child with electrical status epilepticus in sleep and attention deficit hyperactivity disorder. CONCLUSION: A combination of I-PCIT and methylphenidate allowed her to be successful at home and in a school setting. More research is needed on PCIT adaptations, such as home-based and internet-based PCIT, for medically ill children as well as treatment protocols for combined therapies.

Differential response to pharmacological intervention in ADHD furthers our understanding of the mechanisms of interference control.

The deficit in "interference control" found in children with Attention Deficit Hyperactivity Disorder (ADHD) could be due to two distinct processes, which are not disentangled in most studies: a larger susceptibility to activating prepotent response impulses and a deficit in suppressing them. Here, we investigated the effect of 1/ADHD and 2/ methylphenidate (MPH), on these two components of interference control. We compared interference control between untreated children with ADHD, children with ADHD under MPH, and typically developing children performing a Simon task. The main findings were that 1/ children with ADHD were more susceptible to reacting impulsively and less efficient at suppressing impulsive actions, and 2/ MPH improved the selective inhibition of impulsive actions but did not modify the strength of response impulse. This work provides an example of how pharmacological interventions and selective responses to them can be used to investigate and further our understanding of cognitive processing.

Effects of benztropine analogs on delay discounting in rats.

RATIONALE: Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability. OBJECTIVES: The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD. METHODS: Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control. RESULTS: d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding. CONCLUSIONS: AHN 1-055 may be of clinical utility in the treatment of ADHD.

Task experience eliminates catecholaminergic effects on inhibitory control - A randomized, double-blind cross-over neurophysiological study.

Catecholaminergic neural transmission plays an important role during the inhibition of prepotent responses. Methylphenidate (MPH) is an important drug that modulates the catecholaminergic system. However, theoretical considerations suggest that the effects of drugs (e.g. MPH) on cognitive control may depend on prior learning effects. Here we investigate this in a conflict-modulated Go/Nogo task and evaluate neurophysiological processes associated with this dynamic using EEG signal decomposition methods and source localization analysis. The behavioral data show that prior learning experiences eliminate effects of MPH on response inhibition processes. On a neurophysiological level, we show that MPH modulates specific processes in medial frontal brain regions. Although MPH seems to consistently modulate neurophysiological processes associated with response inhibition, this is no longer sufficient to modulate behavioral performance once learning or task familiarization processes have taken place. An important consequence of this study finding is that it may be important to adjust MPH dosage depending on learning effects in a specific setting to constantly increase cognitive control functions in that setting. This has important implications for clinical practice, since MPH is the first-line pharmacological therapy in attention-deficit hyperactivity disorder (ADHD). Cross-over study designs with constant doses of MPH can mask effects on cognitive functions. The impact of learning needs careful consideration in cross-over study designs examining catecholaminergic drug effects.

Accommodative response in children with attention deficit hyperactivity disorder (ADHD): the influence of accommodation stimulus and medication.

BACKGROUND: There are claims that ocular accommodation differs in children with attention deficit hyperactivity disorder (ADHD) compared to typically developing children. We examined whether the accommodation response in ADHD children is influenced by changing the stimulus to accommodation in an attempt modify the level of attentional engagement or by medication for the condition. METHODS: We measured the accommodative response and pupil diameter using a binocular, open-field autorefractor in non-medicated and medicated children with ADHD (n = 22, mean age = 10.1 ± 2.4 years; n = 19; mean age = 11.0 ± 3.8 years; respectively) and in an age-matched control group (n = 22; mean age = 10.6 ± 1.9 years) while participants were asked to maintain focus on (i) a high-contrast Maltese cross, (ii) a frame of a cartoon movie (picture) and (iii) a cartoon movie chosen by the participant. Each stimulus was viewed for 180 s from a distance of 25 cm, and the order of presentation was randomised. RESULTS: Greater lags of accommodation were present in the non-medicated ADHD in comparison to controls (p = 0.023, lags of 1.10 ± 0.56 D and 0.72 ± 0.57 D, respectively). No statistically significant difference in the mean accommodative lag was observed between medicated ADHD children (lag of 1.00 ± 0.44D) and controls (p = 0.104) or between medicated and non-medicated children with ADHD (p = 0.504). The visual stimulus did not influence the lag of accommodation (p = 0.491), and there were no significant group-by-stimulus interactions (p = 0.935). The variability of accommodation differed depending on the visual stimulus, with higher variability for the picture condition compared to the cartoon-movie (p < 0.001) and the Maltese cross (p = 0.006). In addition, the variability yielded statistically significant difference for the main effect of time-on-task (p = 0.027), exhibiting a higher variability over time. However, no group differences in accommodation variability were observed (p = 0.935). CONCLUSIONS: Children with ADHD have a reduced accommodative response, which is not influenced by the stimulus to accommodation. There is no marked effect of medication for ADHD on accommodation accuracy.

Amitifadine, a triple reuptake inhibitor, reduces self-administration of the opiate remifentanil in rats.

RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.

[Progression of symptoms in children with attention deficit and hyperactivity disorder in treatment with methylphenidate]. / Progresión de los síntomas en niños con trastorno por déficit de atención e hiperactividad en tratamiento con metilfenidato.

Attention deficit and hyperactivity disorder (ADHD) is a neurobiological disorder frequent in childhood. The main symptoms are attention disorder and/or impulsivity and/or hyperactivity. There are different subtypes of ADHD according to the degree of presence of these three symptoms. There are different therapeutic approaches with high proved effectiveness. Methylphenidate, a stimulant that acts through the dopaminergic and adrenergic pathways, is commonly used for the treatment of ADHD. The Strengths and Difficulties Questionnaire (SDQ) is a brief behavioural screening instrument internationally used for the screening of mental health problems in children and adolescents. It consists in a 25 items questionnaire with 5 different scales: emotional symptoms, conduct problems, hyperactivity / inattention, peer relationship problems and prosocial behaviours. The SDQ score was collected in a sample of ADHD patients with an age between 7 and 12 years. The score obtained before starting treatment with methylphenidate was compared before and after starting treatment, every 3-6 months and up to a period of 2 years. Statistical processing was performed using R, which is a free program for statistical and graphical analysis, that allows temporary analysis. The results indicate that hyperactivity improves throughout the first year of treatment, emotional symptoms and behavioral problems improve during the first 6 months of treatment, pro-social symptoms slowly improve over 2 years. Problems with partners do not improve in the analyzed time.

El trastorno por déficit de atención e hiperactividad (TDAH) es un trastorno neurobiológico frecuente en la infancia. Sus síntomas cardinales involucran a la atención y/o la impulsividad y/o la hiperactividad. Hay diferentes subtipos de TDAH según la expresividad clínica de esos tres síntomas. Hay distintas estrategias terapéuticas de alta efectividad. El metilfenidato, un estimulante que actúa en las vías dopaminérgicas y adrenérgicas, se utiliza con frecuencia en su tratamiento. El Cuestionario de Cualidades y Dificultades (SDQ) es un cuestionario de despistaje breve utilizado para la detección de problemas de salud mental en niños y adolescentes. Consta de 25 preguntas que se distribuyen en 5 escalas: sintomatología emocional, problemas de conducta, hiperactividad/inatención, problemas con los compañeros y conducta prosocial. Se recogió la puntuación del SDQ en una muestra de pacientes con TDAH con una edad situada entre los 7 y 12 años. Se comparó la puntuación obtenida antes de comenzar el tratamiento con metilfenidato y después de comenzar tratamiento, cada 3-6 meses y hasta un periodo de 2 años. Se realizó el procesamiento estadístico mediante R, que es un programa gratuito para análisis estadísticos y gráficos, y permite análisis temporales. Los resultados indican que la hiperactividad mejora a lo largo del primer año de tratamiento, la sintomatología emocional y los problemas de comportamiento mejoran durante los primeros 6 meses de tratamiento, la sintomatología prosocial mejora lentamente a lo largo de los 2 años y los problemas con compañeros no mejoran en el tiempo analizado.

Progresión de los síntomas en niños con trastorno por déficit de atención e hiperactividad en tratamiento con metilfenidato / Progression of symptoms in children with attention deficit and hyperactivity disorder in treatment with methylphenidate

El trastorno por déficit de atención e hiperactividad (TDAH) es un trastorno neurobiológico frecuente en la infancia. Sus síntomas cardinales involucran a la atención y/o la impulsividad y/o la hiperactividad. Hay diferentes subtipos de TDAH según la expresividad clínica de esos tres síntomas. Hay distintas estrategias terapéuticas de alta efectividad. El metilfenidato, un estimulante que actúa en las vías dopaminérgicas y adrenérgicas, se utiliza con frecuencia en su tratamiento. El Cuestionario de Cualidades y Dificultades (SDQ) es un cuestionario de despistaje breve utilizado para la detección de problemas de salud mental en niños y adolescentes. Consta de 25 preguntas que se distribuyen en 5 escalas: sintomatología emocional, problemas de conducta, hiperactividad/inatención, problemas con los compañeros y conducta prosocial. Se recogió la puntuación del SDQ en una muestra de pacientes con TDAH con una edad situada entre los 7 y 12 años. Se comparó la puntuación obtenida antes de comenzar el tratamiento con metilfenidato y después de comenzar tratamiento, cada 3-6 meses y hasta un periodo de 2 años. Se realizó el procesamiento estadístico mediante R, que es un programa gratuito para análisis estadísticos y gráficos, y permite análisis temporales. Los resultados indican que la hiperactividad mejora a lo largo del primer año de tratamiento, la sintomatología emocional y los problemas de comportamiento mejoran durante los primeros 6 meses de tratamiento, la sintomatología prosocial mejora lentamente a lo largo de los 2 años y los problemas con compañeros no mejoran en el tiempo analizado.

Attention deficit and hyperactivity disorder (ADHD) is a neurobiological disorder frequent in childhood. The main symptoms are attention disorder and/or impulsivity and/or hyperactivity. There are different subtypes of ADHD according to the degree of presence of these three symptoms. There are different therapeutic approaches with high proved effectiveness. Methylphenidate, a stimulant that acts through the dopaminergic and adrenergic pathways, is commonly used for the treatment of ADHD. The Strengths and Difficulties Questionnaire (SDQ) is a brief behavioural screening instrument internationally used for the screening of mental health problems in children and adolescents. It consists in a 25 items questionnaire with 5 different scales: emotional symptoms, conduct problems, hyperactivity / inattention, peer relationship problems and prosocial behaviours. The SDQ score was collected in a sample of ADHD patients with an age between 7 and 12 years. The score obtained before starting treatment with methylphenidate was compared before and after starting treatment, every 3-6 months and up to a period of 2 years. Statistical processing was performed using R, which is a free program for statistical and graphical analysis, that allows temporary analysis. The results indicate that hyperactivity improves throughout the first year of treatment, emotional symptoms and behavioral problems improve during the first 6 months of treatment, pro-social symptoms slowly improve over 2 years. Problems with partners do not improve in the analyzed time.

Effects of ecgonine methyl ester on cognition in scopolamine-impaired and aged rats.

RATIONALE: Searches for antidotes to cocaine, and for cognition enhancers potentially applicable to Alzheimer's disease, have revealed a novel regulatory site on nicotinic acetylcholine receptors. In the presence of an agonist, inhibitors binding to this site changed the ion channel equilibrium from the open-channel form towards the closed form. Other, related, molecules could bind to the site without changing the equilibrium. These latter compounds were predicted to displace the inhibitors without affecting receptor function per se. These compounds alleviated the inhibition. One of them is ecgonine methyl ester (EME), which is generally described as inactive, but this work suggested a beneficial effect on cognition. OBJECTIVE: This in vivo study tested for cognitive enhancement by EME in scopolamine-impaired, and aged, rats. METHODS: Memory was the primary endpoint, but thigmotaxis became an important secondary endpoint in the light of observations made during the study. Impaired cognition was pharmacologically induced by scopolamine in young rats, and spontaneously present in aged rats. Learning ability before and after administration of EME was tested in Morris water maze protocols. Concentrations of EME in the brain and plasma were analyzed by gas chromatography-mass spectrometry. RESULTS: A single dose of EME reversed scopolamine impairment, indicating involvement of acetylcholine receptors. Longer-term treatment improved cognition in aged rats, with enhanced rates of learning in the absence of an exogenous cognition-impairing compound. Impairment returned with a new challenge; the improvement could be re-established with continued dosing. EME also reversed thigmotaxis seen in aged rats; thigmotaxis is believed to indicate anxiety. The concentrations of EME in the brain proved adequate drug exposure. CONCLUSIONS: Since other investigators have shown cognition impairment caused by cocaine in aged rats, this work shows that cocaine and EME have opposite effects in Morris water maze models. EME might induce cognitive enhancement and relief of anxiety in cocaine-impaired humans, and in other cognitive disorders.

On the pathophysiology and treatment of akinetic mutism.

Akinetic mutism (AM) is a rare neurological disorder characterized by the presence of an intact level of consciousness and sensorimotor capacity, but with a simultaneous decrease in goal-directed behavior and emotions. Patients are in a wakeful state of profound apathy, seemingly indifferent to pain, thirst, or hunger. It represents the far end within the spectrum of disorders of diminished motivation. In recent years, more has become known about the functional roles of neurocircuits and neurotransmitters associated with human motivational behavior. More specific, there is an increasing body of behavioral evidence that links specific damage of functional frontal-subcortical organization to the occurrence of distinct neurological deficits. In this review, we combine evidence from lesion studies and neurophysiological evidence in animals, imaging studies in humans, and clinical investigations in patients with AM to form an integrative theory of its pathophysiology. Moreover, the specific pharmacological interventions that have been used to treat AM and their rationales are reviewed, providing a comprehensive overview for use in clinical practice.

Methylphenidate modifies reward cue responses in adults with ADHD: An fMRI study.

Attention deficit hyperactivity disorder (ADHD) has been associated with neural hyposensitivity to reward-predicting cues. Methylphenidate is widely used in the management of the disorder's symptoms, but its effects on reward sensitivity in ADHD are unknown. The current study used fMRI to measure striatal responses to reward-predicting cues in adults with ADHD on and off methylphenidate and a control group, during a classical conditioning task. Responses to cued reward were also explored. Larger differences in the ventral striatum activation to reward cues versus non-reward cues were observed when the ADHD participants were on methylphenidate compared to placebo. In response to cued-reward outcome, an exploratory analysis showed methylphenidate reduced the BOLD time-series correlation between the dorsal striatum and dorsal medial prefrontal cortex. Methylphenidate's therapeutic effects may be mediated by altering reward processing in individuals with ADHD.

A randomized clinical trial on the effects of bupropion and buprenorphine on the reduction of methamphetamine craving.

BACKGROUND: The purpose of this study was to compare the effect of 300 mg of bupropion and 8 mg of buprenorphine per day on the treatment of methamphetamine withdrawal cravings over a 2-week treatment interval. METHOD: Sixty-five methamphetamine-dependent men who met the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) criteria for methamphetamine dependence and withdrawal were randomly divided into two groups. Subjects randomly received 300 mg of bupropion or 8 mg of buprenorphine per day in a psychiatric ward. Of the 65 subjects, 35 (53.8%) received buprenorphine and 30 (46.2%) received bupropion. The subjects were assessed by using methamphetamine craving score, interview, and negative urine drug test. FINDINGS: There were no statistically significant differences between the two groups in regard to age, education, duration of methamphetamine dependency, marital status, employment, and income. The mean ages were 32.8 years (standard deviation (SD) = 7.26, range = 22 to 59) for the buprenorphine group and 32.21 years (SD = 8.45, range = 17 to 51) for the bupropion group. All 65 patients completed the 2-week study. Both medications were effective in the reduction of methamphetamine cravings. Reduction of craving in the buprenorphine group was significantly more than the bupropion group (P = 0.011). Overall, a significant main effect of day (P <0.001) and group (P = 0.011) and a non-significant group-by-day interaction (P >0.05) were detected. CONCLUSIONS: The results support the safety and effectiveness of buprenorphine and bupropion in the treatment of methamphetamine withdrawal craving. Administration of 8 mg of buprenorphine per day can be recommended for the treatment of methamphetamine withdrawal cravings. We should note that it is to be expected that craving decreases over time without any medication. So the conclusion may not be that bupropion and buprenorphine both lower the craving. As the buprenorphine is superior to bupropion, only buprenorphine does so for sure. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT) registration number: IRCT2015010320540N1 . Date registered: April 10, 2015.

The countervailing forces behind France's low Ritalin consumption.

In recent decades pharmaceutical consumption has skyrocketed, growing from $43 US billion in 1985 to over $1143 billion in 2017. In trying to understand the source of this growth, social scientists have identified the key actors driving medication use and the processes through which they are driving it. However, much less attention has been devoted to understanding the forces that constrain medication consumption. This information is crucial for developing a deeper understanding of medication consumption, one that explains how context mediates the ability of key actors to shape medication consumption. To address this gap, I examine France's low consumption of psychostimulants to treat ADHD symptoms. France is a strategic case to analyze because it diverges dramatically from comparative cases: while 7% of U.S. children are medicated with psychostimulants, the same is true for only 0.2% of French children. To explain the French case I use the theory of countervailing powers. Informed by interviews with key informants, the French medical literature on psychostimulants and secondary sources, I explain how the state, medical experts and consumers have acted as countervailing forces against pharmaceutical interests. In doing so, I provide deeper insight about how context can limit the pharmaceutical industry's power.

Antidepressants Reduced Risk of Mortality in Patients With Diabetes Mellitus: A Population-Based Cohort Study in Taiwan.

CONTEXT: The effect of antidepressant (ATD) use on mortality in patients with diabetes mellitus (DM) has not yet been sufficiently studied, although comorbid depression is common in this population. OBJECTIVE: To explore the impact of ATDs on mortality among DM patients. DESIGN: A retrospective cohort study in a national database. SETTING: This population-based study used the National Health Insurance Research Database in Taiwan. Since 2000, we identified 53,412 cases of newly diagnosed patients with DM and depression. Patient cases were followed for assessing mortality until 2013. MAIN OUTCOME MEASURE: The association between mortality and ATD use was explored adjusting for cumulative dosing. RESULTS: Using the time-dependent Cox regression model, ATD use was associated with significantly reduced mortality among patients with DM [in the highest dose group: hazard ratio (HR), 0.65; 95% CI, 0.59 to 0.71]. Further analysis showed that differences in mortality existed across ATD categories: selective serotonin reuptake inhibitors (HR, 0.63; 95% CI, 0.56 to 0.71), serotonin-norepinephrine reuptake inhibitors (HR, 0.58; 95% CI, 0.44 to 0.78), norepinephrine-dopamine reuptake inhibitors (HR, 0.20; 95% CI, 0.07 to 0.63), mirtazapine (HR, 0.60; 95% CI, 0.45 to 0.82), tricyclic/tetracyclic antidepressants (HR, 0.73; 95% CI, 0.54 to 0.97), and trazodone (HR, 0.52; 95% CI, 0.29 to 0.91). However, reversible inhibitor of monoamine oxidase A (RIMA) was found to be associated with an increase, rather than a decrease, in total mortality (HR, 1.48; 95% CI, 1.09 to 1.99). CONCLUSION: Most ATDs, but not RIMA, were associated with significantly reduced mortality among a population with comorbid DM and depression.

Solriamfetol for the treatment of excessive daytime sleepiness associated with narcolepsy.

Introduction: Narcolepsy is a chronic disabling condition, excessive daytime somnolence is the main symptoms of it. There is currently no cure for narcolepsy, and hence there is a great need for new treatment options. Solriamfetol is a new selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects. The purpose of this paper is to review solriamfetol. Areas covered: The chemical property, mechanism of action, pharmacokinetics, clinical efficacy, and safety of solriamfetol are introduced in this paper. Expert opinion: Solriamfetol can bind to dopamine and norepinephrine transporters and inhibit reuptake of dopamine and norepinephrine. Clinical trials showed that solriamfetol could significantly improve the ability to stay awake and subjective symptoms of excessive sleepiness in adults with narcolepsy. Solriamfetol was well tolerated. Very common adverse reactions were headache, nausea, decreased appetite, insomnia, and anxiety.