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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 -
Biological Psychiatry. Cognitive... May 2024While the exploration of serotonergic psychedelics as psychiatric medicines deepens, so does the pressure to better understand how these compounds act on the brain. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
While the exploration of serotonergic psychedelics as psychiatric medicines deepens, so does the pressure to better understand how these compounds act on the brain.
METHODS
We used a double-blind, placebo-controlled, crossover design and administered lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and d-amphetamine in 25 healthy participants. By using spectral dynamic causal modeling, we mapped substance-induced changes in effective connectivity between the thalamus and different cortex types (unimodal vs. transmodal) derived from a previous study with resting-state functional magnetic resonance imaging data. Due to the distinct pharmacological modes of action of the 3 substances, we were able to investigate specific effects mainly driven by different neurotransmitter systems on thalamocortical and corticothalamic interactions.
RESULTS
Compared with placebo, all 3 substances increased the effective connectivity from the thalamus to specific unimodal cortices, whereas the influence of these cortices on the thalamus was reduced. These results indicate increased bottom-up and decreased top-down information flow between the thalamus and some unimodal cortices. However, for the amphetamines, we found the opposite effects when examining the effective connectivity with transmodal cortices, including parts of the salience network. Intriguingly, LSD increased the effective connectivity from the thalamus to both unimodal and transmodal cortices, indicating a breach in the hierarchical organization of ongoing brain activity.
CONCLUSIONS
The results advance our knowledge about the action of psychedelics on the brain and refine current models aiming to explain the underlying neurobiological processes.
Topics: Humans; Lysergic Acid Diethylamide; N-Methyl-3,4-methylenedioxyamphetamine; Thalamus; Male; Double-Blind Method; Adult; Magnetic Resonance Imaging; Hallucinogens; Dextroamphetamine; Cross-Over Studies; Female; Cerebral Cortex; Young Adult; Neural Pathways; Connectome
PubMed: 37532129
DOI: 10.1016/j.bpsc.2023.07.010