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Addiction (Abingdon, England) Feb 2024There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD.
METHODS
Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables.
RESULTS
Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention.
CONCLUSIONS
Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.
Topics: Humans; Central Nervous System Stimulants; Methylphenidate; Substance-Related Disorders; Amphetamines; Prescriptions; Randomized Controlled Trials as Topic
PubMed: 37880829
DOI: 10.1111/add.16347 -
Neuropharmacology Dec 2023Rats communicate through auditory signals in the ultrasonic range, so-called ultrasonic vocalizations (USV). Short, high-frequency 50-kHz USV are associated with...
Acute anxiogenic effects of escitalopram are associated with mild alterations in D-amphetamine-induced behavior and social approach evoked by playback of 50-kHz ultrasonic vocalizations in rats.
Rats communicate through auditory signals in the ultrasonic range, so-called ultrasonic vocalizations (USV). Short, high-frequency 50-kHz USV are associated with positive affective states and are emitted in appetitive situations, often rewarding social interactions, such as rough-and-tumble play and mating. Exaggerated levels of 50-kHz USV emission can be observed in response to psychostimulants, most notably d-amphetamine (AMPH). There is robust evidence suggesting that 50-kHz USV serve as affiliative signals and help to maintain or re-establish social proximity. A key neurotransmitter involved in behavioral regulation is serotonin (5-hydroxytryptamine, 5-HT). This includes both, the regulation of anxiety-related behavior and ultrasonic communication. Here, we show that acute treatment with the selective 5-HT reuptake inhibitor (SSRI) escitalopram (ESC) leads to increased anxiety-related behavior in the elevated plus maze and tested whether such acute anxiogenic effects of ESC result in alterations in ultrasonic communication in sender and/or receiver. To this aim, we conducted a dose-response study in male rats and assessed AMPH-induced hyperactivity and 50-kHz ultrasonic calling in the sender and social approach behavior evoked by playback of pro-social 50-kHz USV in the receiver. Acute ESC treatment affected both, sender and receiver. This was reflected in a lack of AMPH-induced changes in acoustic features of 50-kHz USV and absence of social exploratory behavior evoked by 50-kHz USV playback, respectively. Albeit the SSRI effects were relatively mild, this supports the notion that the 5-HT system is involved in the regulation of a key aspect of the social behavior repertoire of rodents, namely socio-affective communication through 50-kHz USV.
Topics: Rats; Male; Animals; Ultrasonics; Dextroamphetamine; Vocalization, Animal; Escitalopram; Serotonin; Amphetamine; Social Behavior; Rodentia
PubMed: 37813275
DOI: 10.1016/j.neuropharm.2023.109734 -
Behavioural Brain Research Oct 2023Despite the increasingly pervasive use of chemogenetic tools in preclinical neuroscience research, the in vivo pharmacology of DREADD agonists remains poorly understood.... (Comparative Study)
Comparative Study
RATIONALE
Despite the increasingly pervasive use of chemogenetic tools in preclinical neuroscience research, the in vivo pharmacology of DREADD agonists remains poorly understood. The pharmacological effects of any ligand acting at receptors, engineered or endogenous, are influenced by numerous factors including potency, time course, and receptor selectivity. Thus, rigorous comparison of the potency and time course of available DREADD ligands may provide an empirical foundation for ligand selection.
OBJECTIVES
Compare the behavioral pharmacology of three different DREADD ligands clozapine-N-oxide (CNO), compound 21 (C21), and deschloroclozapine (DCZ) in a locomotor activity assay in tyrosine hydroxylase:cre recombinase (TH:Cre) male and female rats.
METHODS
Locomotor activity in nine adult TH:Cre Sprague-Dawley rats (5 female, 4 male) was monitored for two hours following administration of d-amphetamine (vehicle, 0.1-3.2 mg/kg, IP), DCZ (vehicle, 0.32-320 µg/kg, IP), CNO (vehicle, 0.32-10 mg/kg), and C21 (vehicle, 0.1-3.2 mg/kg, IP). Behavioral sessions were conducted twice per week prior to and starting three weeks after bilateral intra-VTA hM3Dq DREADD virus injection.
RESULTS
d-Amphetamine significantly increased locomotor activity pre- and post-DREADD virus injection. DCZ, CNO, and C21 did not alter locomotor activity pre-DREADD virus injection. There was no significant effect of DCZ, CNO, and C21 on locomotor activity post-DREADD virus injection; however, large individual differences in both behavioral response and receptor expression were observed.
CONCLUSIONS
Large individual variability was observed in both DREADD agonist behavioral effects and receptor expression. These results suggest further basic research would facilitate the utility of these chemogenetic tools for behavioral neuroscience research.
Topics: Animals; Female; Male; Rats; Clozapine; Dextroamphetamine; Imidazoles; Ligands; Locomotion; Rats, Sprague-Dawley; Sulfonamides; Thiophenes; Tyrosine 3-Monooxygenase; Ventral Tegmental Area
PubMed: 37722510
DOI: 10.1016/j.bbr.2023.114674 -
The International Journal on Drug Policy Oct 2023As safer supply programs expand in Canada, stimulant safer supply is often overlooked despite the harms and criminalization faced by people who use stimulants.
Preferred stimulant safer supply and associations with methamphetamine preference among people who use stimulants in British Columbia: Findings from a 2021 cross-sectional survey.
BACKGROUND
As safer supply programs expand in Canada, stimulant safer supply is often overlooked despite the harms and criminalization faced by people who use stimulants.
METHODS
The 2021 Harm Reduction Client Survey was administered at 17 harm reduction sites around British Columbia, Canada. The survey included a question about what specific substance participants would want to receive as stimulant safer supply. We investigated preference of stimulant safer substance by looking at frequency of stated preference and by using multivariable logistic regression to understand factors associated with the most frequently chosen substance.
RESULTS
Of 330 participants who reported a stimulant safer supply preference, 58.5% (n = 193) chose crystal methamphetamine, 13% (n = 43) crack cocaine and 12.4% (n = 41) cocaine powder. The options that were available by prescription at the time of data collection were chosen by under 11% of participants (dextroamphetamine n = 21, methylphenidate n = 15). A preference for crystal methamphetamine was associated with being 29 and under compared to 50 and over (AOR: 3.96, 95% CI: 1.42-11.07, p-value: 0.01); self-identifying as a cis man versus a cis woman (AOR: 1.75, 95% CI: 1.03-2.97, p-value: 0.04); and using drugs every day (AOR: 15.43, 95% CI: 3.38-70.51, p-value: < 0.01) or a few times a week (AOR: 8.90, 95% CI: 1.78-44.44, p-value: 0.01) compared to a few times a month.
CONCLUSIONS
Preference of stimulant safer supply is associated with age, gender, and substance use characteristics. Safer supply programs that offer limited substances risk being poorly accessed, resulting in a continued reliance on an unregulated supply. Moreover, programs that do not offer a range of substances can contribute to health inequities.
PubMed: 37708585
DOI: 10.1016/j.drugpo.2023.104186 -
Journal of Cognitive Neuroscience Nov 2023Limbic and motor integration is enabled by a mesial temporal to motor cortex network. Parkinson disease (PD) is characterized by a loss of dorsal striatal dopamine but...
Limbic and motor integration is enabled by a mesial temporal to motor cortex network. Parkinson disease (PD) is characterized by a loss of dorsal striatal dopamine but relative preservation of mesolimbic dopamine early in disease, along with changes to motor action control. Here, we studied 47 patients with PD using the Simon conflict task and [18F]fallypride PET imaging. Additionally, a cohort of 16 patients participated in a single-blinded dextroamphetamine (dAMPH) study. Task performance was evaluated using the diffusion model for conflict tasks, which allows for an assessment of interpretable action control processes. First, a voxel-wise examination disclosed a negative relationship, such that longer non-decision time is associated with reduced D2-like binding potential (BPND) in the bilateral putamen, left globus pallidus, and right insula. Second, an ROI analysis revealed a positive relationship, such that shorter non-decision time is associated with reduced D2-like BPND in the amygdala and ventromedial OFC. The difference in non-decision time between off-dAMPH and on-dAMPH trials was positively associated with D2-like BPND in the globus pallidus. These findings support the idea that dysfunction of the traditional striatal-motor loop underlies action control deficits but also suggest that a compensatory parallel limbic-motor loop regulates motor output.
Topics: Humans; Corpus Striatum; Dopamine; Parkinson Disease; Positron-Emission Tomography; Receptors, Dopamine D2
PubMed: 37677065
DOI: 10.1162/jocn_a_02048 -
The Journal of Neuroscience : the... Oct 2023Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the...
Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effort-based decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior. A core feature of attention-deficit/hyperactivity disorder (ADHD) is thought to be a heightened aversion to effort. Surprisingly, however, the degree to which effort sensitivity is impaired in ADHD has rarely been tested. More broadly, the relative efficacy of catecholamines in motivating the investment of cognitive and physical effort is unclear. We tested 20 individuals with ADHD ON and OFF amphetamines, and compared their behavior on an effort-based decision-making task to 24 controls. When tested OFF medication, the ADHD group was less cognitively and physically motivated than controls. However, amphetamines led to a comparable increase in motivation across both domains. This demonstrates the efficacy of catecholamines in facilitating domain-general effort, and highlights the broader potential of such drugs to treat disorders of motivation.
Topics: Male; Female; Humans; Attention Deficit Disorder with Hyperactivity; Motivation; Amphetamines; Lisdexamfetamine Dimesylate; Catecholamines; Central Nervous System Stimulants
PubMed: 37666665
DOI: 10.1523/JNEUROSCI.0982-23.2023 -
Basic & Clinical Pharmacology &... Nov 2023Monoamine transporters are of great interest for their role in the physiological activity of the body and their link to mental and behavioural disorders. Currently,...
Monoamine transporters are of great interest for their role in the physiological activity of the body and their link to mental and behavioural disorders. Currently, static well-plate assays or manual perfusion systems are used to characterize the interaction of psychostimulants, antidepressants and drugs of abuse with the transporters but still suffer from significant drawbacks caused by lack of automation, for example, low reproducibility, non-comparability of results. An automated microfluidic platform was developed to address the need for more standardized procedures for cell-based assays. An automated system was used to control and drive the simultaneous perfusion of 12 channels on a microfluidic chip, establishing a more standardized protocol to perform release assays to study monoamine transporter-mediated substrate efflux. D-Amphetamine, GBR12909 (norepinephrine transporter) and p-chloroamphetamine, paroxetine (serotonin transporter) were used as control compounds to validate the system. The platform was able to produce the expected releasing (D-Amphetamine, p-chloroamphetamine) or inhibiting (GBR12909, paroxetine) profiles for the two transporters. The reduction of manual operation and introduction of automated flow control enabled the implementation of stronger standardized protocols and the possibility of obtaining higher throughput by increasing parallelization.
Topics: Microfluidics; p-Chloroamphetamine; Paroxetine; Reproducibility of Results; Membrane Transport Proteins; Perfusion; Dextroamphetamine
PubMed: 37658634
DOI: 10.1111/bcpt.13940 -
Frontiers in Pharmacology 2023Methylphenidate, atomoxetine, and Amphetamine are the three most commonly used medications approved by the United States Food and Drug Administration (FDA) for the...
Safety profiles of methylphenidate, amphetamine, and atomoxetine: analysis of spontaneous reports submitted to the food and drug administration adverse event reporting system.
Methylphenidate, atomoxetine, and Amphetamine are the three most commonly used medications approved by the United States Food and Drug Administration (FDA) for the treatment of attention deficit/hyperactivity disorder (ADHD). However, a comprehensive analysis of their safety profiles across various age groups and genders in real-world contexts has yet to be conducted. In this study, a pharmacovigilance analysis was performed using the FDA Adverse Event Reporting System (FAERS) database to examine differences in adverse events between methylphenidate, atomoxetine, and Amphetamine. From January 2014 to September 2022, FAERS reports listing "Methylphenidate," "Dexmethylphenidate," "Atomoxetine," "Amphetamine," "Lisdexamfetamine," "Dextroamphetamine," and "Methamphetamine" as primary suspects were analyzed after removing duplicate reports. We used the standardized Medical Dictionary for Regulatory Activities (MedDRA) query generalized search for adverse events at the preferred term level based on case reports. After filtering duplicate reports, disproportionality analysis was used to detect safety signals according to the proportional reporting ratio (PRR). In order to delve into potential safety concerns, we undertook a two-step analysis of the data. Initially, the data was segmented based on age cohorts: 0-5 years, 6-12 years, 13-18 years, and individuals aged ≥19 years. Following this, after partitioning the data into males and females within the 0-18 years age group, and similarly for those aged ≥19 years, further analysis was conducted. The pharmacovigilance analysis uncovered substantial safety signals in the standardized MedDRA queries. Methylphenidate was associated with dyskinesia (PRR = 21.15), myocardial infarction (PRR = 12.32), and hypertension (PRR = 8.95) in children aged 0-5, 6-12, and 13-18 years, respectively, as well as neonatal exposures via breast milk (PRR = 14.10) in adults aged ≥19 years. Atomoxetine was linked to hostility/aggression (PRR = 15.77), taste and smell disorders (PRR = 6.75), and hostility/aggression (PRR = 6.74) in children aged 0-5, 6-12, and 13-18 years, respectively, as well as hostility/aggression (PRR = 14.00) in adults aged ≥19 years. Amphetamine was associated with psychosis and psychotic disorders (PRR = 16.78), hostility/aggression (PRR = 4.39), and Other ischaemic heart disease (PRR = 10.77) in children aged 0-5 years, 6-12 years, and 13-18 years, respectively, and hostility/aggression in adults aged ≥19 years (PRR = 9.16). Significant and noteworthy adverse event signals were also identified at the preferred term level. Specifically, methylphenidate was associated with myocardial infarction, acute myocardial infarction, coronary artery dissection, electrocardiogram QT prolonged, growth retardation, self-destructive behavior, suicidal ideation, and completed suicide. Atomoxetine was linked to electrocardiogram QT prolonged, growth retardation, and tic. Amphetamine was recorded for coronary artery dissection, suicidal ideation, and completed suicide. It was observed that male patients, including both children and adults, showed a more significant and frequent occurrence of adverse events compared to females, particularly in terms of cardiac disorders. The intensity and quantity of adverse event signals were distinctly different between the two genders, with males having a higher number of signals. All detected safety signals were confirmed using signals obtained from the disproportionality analysis. This pharmacovigilance analysis demonstrated significant variations in the safety profiles of methylphenidate, atomoxetine, and Amphetamine across different age groups and between different genders. Following an in-depth analysis of the FAERS database, we discerned prominent safety signals. Notably, the strength of the signals associated with coronary artery dissection induced by methylphenidate and amphetamine, as well as those related to suicide, demand particular attention. Consequently, it remains imperative to persist in monitoring these medications, assessing the associated risks, and carrying out comparative studies particularly geared towards ADHD drugs.
PubMed: 37645441
DOI: 10.3389/fphar.2023.1208456 -
Neuropsychopharmacology : Official... Jan 2024Effort-based decision-making is impaired in multiple psychopathologies leading to significant impacts on the daily life of patients. Preclinical studies of this...
Refining the study of decision-making in animals: differential effects of d-amphetamine and haloperidol in a novel touchscreen-automated Rearing-Effort Discounting (RED) task and the Fixed-Ratio Effort Discounting (FRED) task.
Effort-based decision-making is impaired in multiple psychopathologies leading to significant impacts on the daily life of patients. Preclinical studies of this important transdiagnostic symptom in rodents are hampered, however, by limitations present in currently available decision-making tests, including the presence of delayed reinforcement and off-target cognitive demands. Such possible confounding factors can complicate the interpretation of results in terms of decision-making per se. In this study we addressed this problem using a novel touchscreen Rearing-Effort Discounting (RED) task in which mice choose between two single-touch responses: rearing up to touch an increasingly higher positioned stimulus to obtain a High Reward (HR) or touching a lower stimulus to obtain a Low Reward (LR). To explore the putative advantages of this new approach, RED was compared with a touchscreen version of the well-studied Fixed Ratio-based Effort Discounting (FRED) task, in which multiple touches are required to obtain an HR, and a single response is required to obtain an LR. Results from dopaminergic (haloperidol and d-amphetamine), behavioral (changes in the order of effort demand; fixed-ratio schedule in FRED or response height in RED), and dietary manipulations (reward devaluation by pre-feeding) were consistent with the presence of variables that may complicate interpretation of conventional decision-making tasks, and demonstrate how RED appears to minimize such variables.
Topics: Humans; Mice; Animals; Haloperidol; Dextroamphetamine; Reinforcement, Psychology; Reward; Dopamine Antagonists; Decision Making; Motivation
PubMed: 37644210
DOI: 10.1038/s41386-023-01707-z