-
The Cochrane Database of Systematic... Apr 2009Few studies examined treatments for amphetamine withdrawal, although it is a common problem among amphetamine users. Its symptoms, in particular intense craving, may be... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Few studies examined treatments for amphetamine withdrawal, although it is a common problem among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse to amphetamine use. In clinical practice, medications for cocaine withdrawal are commonly used to manage amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two illicit substances are different.
OBJECTIVES
To assess the effectiveness of pharmacological alone or in combination with psychosocial treatment for amphetamine withdrawals on discontinuation rates, global state, withdrawal symptoms, craving, and other outcomes.
SEARCH STRATEGY
MEDLINE (1966 - 2008), CINAHL (1982 - 2008), PsycINFO (1806 - 2008), CENTRAL (Cochrane Library 2008 issue 2), references of obtained articles.
SELECTION CRITERIA
All randomised controlled and clinical trials evaluating pharmacological and or psychosocial treatments (alone or combined) for people with amphetamine withdrawal symptoms.
DATA COLLECTION AND ANALYSIS
Two authors evaluated and extracted data independently. The data were extracted from intention-to-treat analyses. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess dichotomous outcomes. The Weighted Mean Difference (WMD) with 95% CI was used to assess continuous outcomes.
MAIN RESULTS
Four randomised controlled trials (involving 125 participants) met the inclusion criteria for the review. Two studies found that amineptine significantly reduced discontinuation rates and improved overall clinical presentation, but did not reduce withdrawal symptoms or craving compared to placebo. The benefits of mirtazapine over placebo for reducing amphetamine withdrawal symptoms were not as clear. One study suggested that mirtazapine may reduce hyperarousal and anxiety symptoms associated with amphetamine withdrawal. A more recent study failed to find any benefit of mirtazapine over placebo on retention or on amphetamine withdrawal symptoms.
AUTHORS' CONCLUSIONS
No medication is effective for treatment of amphetamine withdrawal. Amineptine showed reduction in discontinuation rates and improvement in clinical presentation compared to placebo, but had no effect on reducing withdrawal symptoms or craving. In spite of these limited benefits, amineptine is not available for use due to concerns over abuse liability when using the drug. The benefits of mirtazapine as a withdrawal agent are less clear based on findings from two randomised controlled trials: one report showed improvements in amphetamine withdrawal symptoms over placebo; a second report showed no differences in withdrawal symptoms compared to placebo. Further potential treatment studies should examine medications that increase central nervous system activity involving dopamine, norepinephrine and/or serotonin neurotransmitters, including mirtazapine.
Topics: Amphetamine; Antidepressive Agents, Tricyclic; Dextroamphetamine; Dibenzocycloheptenes; Dopamine Uptake Inhibitors; Humans; Methamphetamine; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome
PubMed: 19370579
DOI: 10.1002/14651858.CD003021.pub2 -
Journal of Child and Adolescent... Jun 2023Amphetamines are a preferred treatment for attention-deficit/hyperactivity disorder (ADHD), with the dextroamphetamine transdermal system (d-ATS) providing an... (Randomized Controlled Trial)
Randomized Controlled Trial
d-Amphetamine Transdermal System in Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Secondary Endpoint Results and Effect Size Analyses from a Pivotal Trial.
Amphetamines are a preferred treatment for attention-deficit/hyperactivity disorder (ADHD), with the dextroamphetamine transdermal system (d-ATS) providing an alternative to oral formulations. A pivotal trial of d-ATS in children and adolescents with ADHD met primary and key secondary endpoints. This analysis reports additional endpoints and safety findings from the pivotal trial and evaluates effect size and number needed to treat (NNT) for d-ATS. In this study, a 5-week, open-label dose-optimization period (DOP) preceded a 2-week, randomized, crossover double-blind treatment period (DBP). Eligible patients received d-ATS 5 mg during the DOP, with weekly evaluations for increase to 10, 15, and 20 mg (equivalent to labeled doses of 4.5, 9, 13.5, and 18 mg/9 hours, respectively) until reaching and maintaining the optimal dose, which was utilized for the DBP. Secondary endpoints included assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression (CGI) scores. NNT was calculated for ADHD-RS-IV and CGI-Improvement (CGI-I). Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety. In total, 110 patients entered the DOP, with 106 patients randomized (DBP). During the DBP, the least-squares mean (95% confidence interval) difference for d-ATS versus placebo in ADHD-RS-IV total score was -13.1 (-16.2 to -10.0; < 0.001), with effect size of 1.1 and NNT of 3 for ADHD-RS-IV remission, ≥30% improvement, and ≥50% improvement. Significant differences between placebo and d-ATS were also observed for CPRS-R:S and CGI-I scales ( < 0.001), with NNT of 2 for CGI-I response. Most TEAEs were mild or moderate, with three leading to study discontinuation in the DOP and none in the DBP. No patients discontinued due to dermal reactions. d-ATS was effective in treating ADHD in children and adolescents, meeting all secondary endpoints, with a large effect size and NNT of 2-3 to achieve a clinically meaningful response. d-ATS was safe and well tolerated, with minimal dermal reactions. NCT01711021.
Topics: Humans; Adolescent; Child; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Treatment Outcome; Dose-Response Relationship, Drug; Dextroamphetamine
PubMed: 37339441
DOI: 10.1089/cap.2023.0005 -
Attention-Deficit/Hyperactivity Disorder Medications and Work Disability and Mental Health Outcomes.JAMA Network Open Mar 2024Individuals with attention-deficit/hyperactivity disorder (ADHD) often have comorbid psychiatric conditions. Relatively little is known about how specific ADHD...
IMPORTANCE
Individuals with attention-deficit/hyperactivity disorder (ADHD) often have comorbid psychiatric conditions. Relatively little is known about how specific ADHD medications are associated with overall treatment outcomes among these patients.
OBJECTIVE
To investigate the association of the use of specific ADHD medications with hospitalization outcomes and work disability among adolescents and adults with ADHD.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide register-based cohort study identified individuals (aged 16-65 years) with ADHD from Swedish nationwide registers of inpatient health care, specialized outpatient health care, sickness absence, and disability pension during the years 2006 to 2021. Data analysis was performed from November 2022 to August 2023.
EXPOSURE
Use of specific ADHD medications.
MAIN OUTCOMES AND MEASURES
The main outcome measure was psychiatric hospitalization, and secondary outcomes were suicide attempt and/or death by suicide, nonpsychiatric hospitalization, and work disability (ie, sickness absence or disability pension). The risk of outcomes between use vs nonuse periods of ADHD medications was compared in a within-individual design, where a person acts as their own control, and was analyzed with stratified Cox models.
RESULTS
A total of 221 714 persons with ADHD were included in the study cohort (mean [SD] age, 25.0 [11.2] years; 120 968 male individuals [54.6%]). Methylphenidate was the most commonly used ADHD medication (151 837 individuals [68.5%]), followed by lisdexamphetamine (78 106 individuals [35.2%]) during the follow-up (mean [SD], 7.0 [4.7] years). The following medications were associated with a decreased risk of psychiatric hospitalization: amphetamine (adjusted hazard ratio [aHR], 0.74; 95% CI, 0.61-0.90), lisdexamphetamine (aHR, 0.80; 95% CI, 0.78-0.82), ADHD drug polytherapy (aHR, 0.85; 95% CI, 0.82-0.88), dexamphetamine (aHR, 0.88; 95% CI, 0.83-0.94), and methylphenidate (aHR, 0.93; 95% CI, 0.92-0.95). No associations were found for modafinil, atomoxetine, clonidine, and guanfacine. Decreased risk of suicidal behavior was associated with the use of dexamphetamine (aHR, 0.69; 95% CI, 0.53-0.89), lisdexamphetamine (aHR, 0.76; 95% CI, 0.68-0.84), and methylphenidate (aHR, 0.92; 95% CI, 0.86-0.98). None of the medications was associated with increased risk of nonpsychiatric hospitalization; instead, use of amphetamine, lisdexamphetamine, polytherapy, dexamphetamine, methylphenidate, and atomoxetine were associated with decreased risk of nonpsychiatric hospitalization. The results regarding work disability were significant only for the use of atomoxetine (aHR, 0.89; 95% CI, 0.82-0.97), especially among adolescents and young adults aged 16 to 29 years, (aHR, 0.82; 95% CI, 0.73-0.92).
CONCLUSIONS AND RELEVANCE
In this nationwide cohort study of adolescents and adults with ADHD, the use of ADHD medication was associated with fewer hospitalizations for both psychiatric and nonpsychiatric morbidity and lower suicidal behavior.
Topics: Adolescent; Young Adult; Humans; Male; Adult; Attention Deficit Disorder with Hyperactivity; Atomoxetine Hydrochloride; Cohort Studies; Lisdexamfetamine Dimesylate; Methylphenidate; Amphetamine
PubMed: 38506810
DOI: 10.1001/jamanetworkopen.2024.2859 -
Neuropharmacology Jan 2022Nicotine enhances the rewarding effects of other environmental stimuli; this reward-enhancement encourages and maintains nicotine consumption. Nicotine use precedes...
Nicotine enhances the rewarding effects of other environmental stimuli; this reward-enhancement encourages and maintains nicotine consumption. Nicotine use precedes other psychostimulant use, but receiving a stimulant prescription also predicts future smoking. Previously, no study has investigated effects of drug exposure order in reward-enhancement, nor with nicotine and d-amphetamine. Thus, we aimed to investigate how drug exposure order impacted the reward-enhancing effects of nicotine and d-amphetamine, alone and in combination. We used 20 male and 20 female Sprague-Dawley rats. Enhancement was investigated within-subjects by examining responding maintained by a visual stimulus reinforcer following a pre-session injection of either d-amphetamine (Sal, 0.1, 0.3, or 0.6 mg/kg) or nicotine (Sal, 0.03, 0.06, 0.1, 0.3 mg/kg). Twenty rats (10 M, 10 F) completed enhancement testing with nicotine before d-amphetamine. The other 20 rats (10 M, 10 F) completed testing with d-amphetamine before nicotine. Following these phases, rats were then given two pre-session injections: one of d-amphetamine (Sal, 0.1, 0.3, or 0.6 mg/kg) and another of nicotine (Sal, 0.03, 0.06, 0.1, or 0.3 mg/kg). Experiencing amphetamine before nicotine increased reward-enhancing effects of nicotine. Females exhibited greater effects of d-amphetamine on reward-enhancement, with no effect of exposure order. During the interaction phase, receiving nicotine before amphetamine enhanced the interaction between nicotine and d-amphetamine for females whereas amphetamine before nicotine heightened this interaction for males. From this, prior and current amphetamine use, in addition to sex, should be considered when treating nicotine dependency and when examining factors driving poly-substance use involving nicotine and d-amphetamine. Keywords: Adderall, ADHD, Dexedrine, operant, smoking, polysubstance use.
Topics: Animals; Conditioning, Operant; Dextroamphetamine; Drug Combinations; Female; Humans; Male; Nicotine; Rats, Sprague-Dawley; Reinforcement, Psychology; Reward; Sex Characteristics; Substance-Related Disorders; Rats
PubMed: 34678376
DOI: 10.1016/j.neuropharm.2021.108845 -
Substance Abuse 2008Methamphetamine dependence is a serious public health problem worldwide for which there are no approved pharmacological treatments. Psychotherapy is still the mainstay... (Review)
Review
Methamphetamine dependence is a serious public health problem worldwide for which there are no approved pharmacological treatments. Psychotherapy is still the mainstay of treatment; however, relapse rates are high. The search for effective pharmacological treatment has intensified in the last decade. This review will highlight progress in pharmacological interventions to treat methamphetamine dependence as well as explore new pharmacological targets. Published data from clinical trials for stimulant addiction were searched using PubMed and summarized, as well as highlights from a recent symposium on methamphetamine pharmacotherapy presented at the ISAM 2006 meeting, including interim analysis data from an ongoing D-amphetamine study in Australia. Early pilot data are encouraging for administering D-amphetamine and methylphenidate as treatment for heavy amphetamine users. Abilify at 15 mg/day dose increased amphetamine use in an outpatient pilot study. Sertraline, ondansetron, baclofen, tyrosine, and imipramine were ineffective in proof-of-concept studies. Development of pharmacotherapy for methamphetamine dependence is still in an early stage. Data suggesting D-amphetamine and methylphenidate as effective pharmacotherapy for methamphetamine addiction will need to be confirmed by larger trials. Preclinical data suggest that use of GVG, CB1 antagonist, and lobeline are also promising therapeutic strategies.
Topics: Antipsychotic Agents; Aripiprazole; Bupropion; Central Nervous System Stimulants; Dextroamphetamine; Drug Therapy; Humans; Lobeline; Methamphetamine; Methylphenidate; Narcotic Antagonists; Nicotinic Agonists; Piperazines; Prevalence; Quinolones; Recurrence; Substance-Related Disorders
PubMed: 19042205
DOI: 10.1080/08897070802218554 -
Journal of Attention Disorders May 2023To evaluate the real-world efficacy, safety, and functional outcomes of PRC-063 (multilayer-release methylphenidate) versus lisdexamfetamine (LDX) in ADHD subjects in a...
Real-World Efficacy and Safety of Extended-Release Methylphenidate (PRC-063) in the Treatment of ADHD in Pediatric and Adult Subjects: Results of a Phase IV Multicenter Comparison With Lisdexamfetamine Dimesylate.
OBJECTIVE
To evaluate the real-world efficacy, safety, and functional outcomes of PRC-063 (multilayer-release methylphenidate) versus lisdexamfetamine (LDX) in ADHD subjects in a phase IV, open-label study.
METHOD
The primary endpoint was the change in the ADHD-DSM-5 Rating Scale (ADHD-5-RS) total score from baseline to Month 4. Secondary endpoints included a non-inferiority comparison between PRC-063 and LDX and measures of functioning and evening behavior.
RESULTS
One hundred forty-three pediatric and 112 adult subjects were enrolled. Mean ADHD-5-RS scores (standard deviation) were reduced in pediatric (-16.6 [10.4]) and adult (-14.8 [10.6]) subjects treated with PRC-063 ( < .001). PRC-063 was non-inferior to LDX in the pediatric population but not in the adult population. Significant improvements were demonstrated in quality of life and functionality. Both medications were well-tolerated; more adverse events led to study discontinuation in pediatric subjects treated with LDX versus PRC-063.
CONCLUSION
PRC-063 and LDX significantly improved ADHD symptomatology and functioning and were well-tolerated.
Topics: Humans; Adult; Child; Lisdexamfetamine Dimesylate; Attention Deficit Disorder with Hyperactivity; Methylphenidate; Central Nervous System Stimulants; Dextroamphetamine; Quality of Life; Treatment Outcome; Double-Blind Method; Dose-Response Relationship, Drug
PubMed: 37144295
DOI: 10.1177/10870547231172767 -
Physiology & Behavior May 2023Psychostimulant drugs increase behavioral, cardiac and brain responses in humans and other animals. Acute food deprivation or chronic food restriction potentiates the...
Psychostimulant drugs increase behavioral, cardiac and brain responses in humans and other animals. Acute food deprivation or chronic food restriction potentiates the stimulatory effects of abused drugs and increases the propensity for relapse to drug seeking in drug-experienced animals. The mechanisms by which hunger affects cardiac and behavioral activities are only beginning to be elucidated. Moreover, changes in motor neuron activities at the single neuron level induced by psychostimulants, and their modulation by food restriction, remain unknown. Here we investigated how food deprivation affects responses to d-amphetamine by measuring locomotor activity, cardiac output, and individual motor neuron activity in zebrafish larvae. We used wild-type larval zebrafish to record behavioral and cardiac responses and the larvae of Tg(mnx1:GCaMP5) transgenic zebrafish to record motor neuron responses. Physiological state gated responses to d-amphetamine. That is, d-amphetamine evoked significant increases in motor behavior (swimming distances), heart rate and motor neuron firing frequency in food-deprived but not fed zebrafish larvae. The results extend the finding that signals arising from food deprivation are a key potentiator of the drug responses induced by d-amphetamine to the zebrafish model. The larval zebrafish is an ideal model to further elucidate this interaction and identify key neuronal substrates that may increase vulnerability to drug reinforcement, drug-seeking and relapse.
Topics: Animals; Humans; Dextroamphetamine; Zebrafish; Larva; Heart Rate; Central Nervous System Stimulants; Locomotion; Motor Neurons; Transcription Factors; Homeodomain Proteins
PubMed: 36889488
DOI: 10.1016/j.physbeh.2023.114144 -
British Journal of Pharmacology Sep 2022Rats emit 50-kHz ultrasonic vocalizations (USV) in appetitive situations, reflecting a positive affective state. Particularly high rates of 50-kHz USV are elicited by... (Review)
Review
Rats emit 50-kHz ultrasonic vocalizations (USV) in appetitive situations, reflecting a positive affective state. Particularly high rates of 50-kHz USV are elicited by the psychostimulant d-amphetamine. Exaggerated 50-kHz USV emission evoked by d-amphetamine is modulated by dopamine, noradrenaline and 5-hydroxytyrptamine receptor ligands and inhibited by the mood stabilizer lithium, the gold standard anti-manic drug for treating bipolar disorder. This indicates that exaggerated 50-kHz USV emission can serve as a reliable and valid measure for assessing mania-like elevated mood in rats with sufficient translational power for gaining a better understanding of relevant pathophysiological mechanisms and the identification of new therapeutic targets. The improved capacity to study the effects of anti-manic pharmacological interventions on a broader range of behaviours by including exaggerated 50-kHz USV emission as preclinical outcome measure complementary to locomotor hyperactivity will refine rodent models for mania. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.
Topics: Amphetamine; Animals; Antimanic Agents; Dextroamphetamine; Mania; Rats; Ultrasonics; Vocalization, Animal
PubMed: 33830495
DOI: 10.1111/bph.15487 -
Neuropsychopharmacology : Official... May 2021Effort-related decision-making and reward learning are both dopamine-dependent, but preclinical research suggests they depend on different dopamine signaling dynamics....
Effort-related decision-making and reward learning are both dopamine-dependent, but preclinical research suggests they depend on different dopamine signaling dynamics. Therefore, the same dose of a dopaminergic medication could have differential effects on effort for reward vs. reward learning. However, no study has tested how effort and reward learning respond to the same dopaminergic medication within subjects. The current study aimed to test the effect of therapeutic doses of d-amphetamine on effort for reward and reward learning in the same healthy volunteers. Participants (n = 30) completed the Effort Expenditure for Reward Task (EEfRT) measure of effort-related decision-making, and the Probabilistic Reward Task (PRT) measure of reward learning, under placebo and two doses of d-amphetamine (10 mg, and 20 mg). Secondarily, we examined whether the individual characteristics of baseline working memory and willingness to exert effort for reward moderated the effects of d-amphetamine. d-Amphetamine increased willingness to exert effort, particularly at low to intermediate expected values of reward. Computational modeling analyses suggested this was due to decreased effort discounting rather than probability discounting or decision consistency. Both baseline effort and working memory emerged as moderators of this effect, such that d-amphetamine increased effort more in individuals with lower working memory and lower baseline effort, also primarily at low to intermediate expected values of reward. In contrast, d-amphetamine had no significant effect on reward learning. These results have implications for treatment of neuropsychiatric disorders, which may be characterized by multiple underlying reward dysfunctions.
Topics: Decision Making; Dextroamphetamine; Humans; Motivation; Reinforcement, Psychology; Reward
PubMed: 32722661
DOI: 10.1038/s41386-020-0779-8 -
Brain : a Journal of Neurology Oct 2022Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson's disease. Reduced ventral striatum dopamine receptor availability, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson's disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson's disease population. Here, we applied 18F-fallypride PET studies to assess striatal and extrastriatal D2-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson's disease patients with impulsive-compulsive behaviours would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D2 autoreceptors would underlie this response. Twenty patients with Parkinson's disease (mean age = 64.1 ± 5.8 years) both with (n = 10) and without (n = 10) impulsive-compulsive behaviours, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an OFF dopamine state. All completed PET imaging with 18F-fallypride, a high-affinity D2-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise and region of interest analyses revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum correlated positively with patient-reported participation in reward-based behaviours, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson's disease Rating Scale. In participants without impulsive-compulsive behaviours, baseline midbrain D2 receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviours. These findings emphasize that reward-based behaviours in Parkinson's disease are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviours.
Topics: Aged; Humans; Middle Aged; Amphetamine; Autoreceptors; Dextroamphetamine; Dopamine; Impulsive Behavior; Ligands; Parkinson Disease; Receptors, Dopamine D2; Single-Blind Method; Ventral Striatum
PubMed: 34951464
DOI: 10.1093/brain/awab487