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NTP CERHR MON Jul 2005The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause... (Review)
Review
The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for amphetamines to cause adverse effects on reproduction and development in humans. Amphetamines evaluated were D- and D,L-amphetamine and methamphetamine. Amphetamine is approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) in persons over 3 years of age and narcolepsy; methamphetamine is approved for the treatment of ADHD in persons 6 years of age and older and for short-term treatment of obesity. Amphetamines were selected for evaluation because of 1) widespread usage in children, 2) availability of developmental studies in children and experimental animals, and 3) public concern about the effect of this stimulant on child development. The results of this evaluation on amphetamines are published in an NTP-CERHR monograph which includes: 1) the NTP Brief, 2) the Expert Panel Report on the Reproductive and Developmental Toxicity of Methylphenidate, and 3) public comments received on the Expert Panel Report. As stated in the NTP Brief, the NTP reached the following conclusions regarding the possible effects of exposure to methylphenidate on human development and reproduction. First, there is some concern for developmental effects, specifically for potential neurobehavioral alterations, from prenatal amphetamine exposure in humans both in therapeutic and non-therapeutic settings. After prenatal exposure to therapeutic doses of amphetamine, rat pups demonstrated neurobehavioral alterations. Data from human and animal studies were judged insufficient for an evaluation of the effect of amphetamine exposure on growth and other related developmental effects. Second, there is concern for methamphetamine-induced adverse developmental effects, specifically on growth and neurobehavioral development, in therapeutic and non-therapeutic settings. This conclusion is based on evidence from studies in experimental animals that prenatal and postnatal exposures to methamphetamine produce neurobehavioral alterations, small litter size, and low birth weight. Results from studies in humans suggest that methamphetamine may cause low birth weight and shortened gestation, but study confounders such as possible multiple drug usage prevent a definite conclusion. NTP-CERHR monographs are transmitted to federal and state agencies, interested parties, and the public and are available in electronic PDF format on the CERHR web site (http://cerhr.niehs.nih.gov) and in printed text or CD-ROM from the CERHR (National Institute of Environmental Health Sciences, P.O. Box 12233, MD EC-32, Research Triangle Park, NC; fax: 919-316-4511).
Topics: Amphetamine; Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Central Nervous System Stimulants; Dextroamphetamine; Female; Government Agencies; Government Programs; Humans; Infant, Low Birth Weight; Infant, Newborn; Learning; Litter Size; Memory; Methamphetamine; Narcolepsy; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Reproduction; Substance-Related Disorders
PubMed: 16130031
DOI: No ID Found -
Frontiers in Endocrinology 2022Hypothalamic obesity (HO) in children has severe health consequences. Lifestyle interventions are mostly insufficient and currently no drug treatment is approved for...
INTRODUCTION
Hypothalamic obesity (HO) in children has severe health consequences. Lifestyle interventions are mostly insufficient and currently no drug treatment is approved for children with HO. Amphetamines are known for their stimulant side-effect on resting energy expenditure (REE) and suppressing of appetite. Earlier case series have shown positive effects of amphetamines on weight in children with acquired HO. We present our experiences with dextroamphetamine treatment in the, up to now, largest cohort of children with HO.
METHODS
A retrospective cohort evaluation was performed of children with HO treated with dextroamphetamine at two academic endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive, therapy-resistant acquired or congenital HO. Anthropometrics, REE, self-reported (hyperphagic) behavior and energy level, and side effects were assessed at start and during treatment.
RESULTS
Nineteen patients with a mean age of 12.3 ± 4.0 years had been treated with dextroamphetamine. In two patients, ΔBMI SDS could not be evaluated due to short treatment duration or the simultaneous start of extensive lifestyle treatment. Mean treatment duration of the 17 evaluated patients was 23.7 ± 12.7 months. Fourteen patients ( = 10 with acquired HO, = 4 with congenital HO) responded by BMI decline or BMI stabilization (mean ΔBMI SDS of -0.6 ± 0.8, after a mean period of 22.4 ± 10.5 months). In three patients, BMI SDS increased (mean ΔBMI SDS of +0.5 ± 0.1, after a mean period of 29.7 ± 22.6 months). In 11 responders, measured REE divided by predicted REE increased with +8.9%. Thirteen patients (68.4%) reported decreased hyperphagia, improvement of energy level and/or behavior during treatment. Two patients developed hypertension during treatment, which resulted in dosage adjustment or discontinuation of treatment. Twelve children continued treatment at last moment of follow-up.
CONCLUSION
In addition to supportive lifestyle interventions, dextroamphetamine treatment may improve BMI in children with HO. Furthermore, dextroamphetamines have the potential to decrease hyperphagia and improve resting energy expenditure, behavior, and energy level. In patients with acquired HO, these effects seem to be more pronounced when compared to patients with congenital HO. Future studies are needed to support these results.
Topics: Adolescent; Child; Dextroamphetamine; Energy Metabolism; Humans; Hypothalamic Diseases; Obesity; Retrospective Studies
PubMed: 35355559
DOI: 10.3389/fendo.2022.845937 -
Molecular Psychiatry Jan 2017Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis...
Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis-dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and 12 healthy controls (HC) completed two positron emission tomography scans with [C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5-7 days prior to the scans to standardize abstinence. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [C]-(+)-PHNO-binding potential (ΔBP) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBP in the striatum (P=0.002, effect size (ES)=1.48), including the associative striatum (P=0.003, ES=1.39), sensorimotor striatum (P=0.003, ES=1.41) and the pallidus (P=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence-without the confounds of any comorbidity-is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology.
Topics: Adult; Amphetamine; Brain; Cannabis; Corpus Striatum; Dextroamphetamine; Dopamine; Endocannabinoids; Female; Humans; Magnetic Resonance Imaging; Male; Marijuana Abuse; Positron-Emission Tomography
PubMed: 27001613
DOI: 10.1038/mp.2016.21 -
Behavioural Brain Research Dec 2019Procedural modifications can modulate drug effects in delay discounting, such as signaling the delay to reinforcement and altering the order in which delays are...
Procedural modifications can modulate drug effects in delay discounting, such as signaling the delay to reinforcement and altering the order in which delays are presented. Although the schedule of reinforcement can alter the rate at which animals discount a reinforcer, research has not determined if animals trained on different schedules of reinforcement are differentially affected by pharmacological manipulations. Similarly, research has not determined if using different delays to reinforcement can modulate drug effects in delay discounting. Male Sprague Dawley rats (n = 36) were split into four groups and were trained in a delay-discounting procedure. The schedule of reinforcement (fixed ratio [FR] 1 vs. FR 10) and delays to reinforcement (0, 5, 10, 20, and 50 s vs. 0, 10, 30, 60, 100 s) were manipulated for each group. Following behavioral training, rats were treated with d-amphetamine (0, 0.25, 0.5, and 1.0 mg/kg) and MK-801 (0, 0.03, and 0.06 mg/kg). Results showed that amphetamine decreased impulsive choice when a FR 1 schedule was used, but only when the short delay sequence was used. Conversely, amphetamine decreased impulsive choice when a FR 10 schedule was used, but only when rats were trained on the long delay sequence. MK-801 decreased impulsive choice in rats trained on a FR 1 schedule, regardless of delay sequence, but did not alter choice in rats trained on a FR 10 schedule. These results show that schedule of reinforcement and delay length can modulate drug effects in delay discounting.
Topics: Animals; Choice Behavior; Conditioning, Operant; Delay Discounting; Dextroamphetamine; Dizocilpine Maleate; Impulsive Behavior; Male; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Reinforcement, Psychology; Time Factors
PubMed: 31520689
DOI: 10.1016/j.bbr.2019.112228 -
Pharmacology, Biochemistry, and Behavior May 2017Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use...
Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10-18mg/kg, intramuscular (IM)) and d-amphetamine (0.032-0.32mg/kg, IM) in monkeys (n=3-4) trained to discriminate IM cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥90% cocaine-appropriate responding, in all monkeys without altering response rates. The time course of d-amphetamine's cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100min) and d-amphetamine (peak at 24h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment.
Topics: Animals; Behavior, Animal; Benzphetamine; Dextroamphetamine; Macaca mulatta; Male; Methamphetamine
PubMed: 28373066
DOI: 10.1016/j.pbb.2017.03.008 -
Journal of Neurology, Neurosurgery, and... Dec 1973The narcoleptic syndrome is a life-long and sometimes familial disorder in which there is a disturbance of the rapid eye movement phase of sleep. Patients with periodic... (Clinical Trial)
Clinical Trial
The narcoleptic syndrome is a life-long and sometimes familial disorder in which there is a disturbance of the rapid eye movement phase of sleep. Patients with periodic sleep in the daytime but no other symptoms seldom develop the narcoleptic syndrome and have a separate unrelated disorder. Twelve patients with the narcoleptic syndrome were treated separately with l(-) amphetamine and d(+) amphetamine. Both drugs abolished narcolepsy, d(+) amphetamine being slightly more potent than l(-) amphetamine. In equipotent doses, unwanted effects of nervousness and insomnia were equal in frequency. No tolerance to either preparation developed during a six month period. Cataplexy was not affected by amphetamine treatment, but was abolished in two patients when clomipramine was given together with either amphetamine.
Topics: Adult; Amphetamine; Antidepressive Agents; Cataplexy; Dextroamphetamine; Electroencephalography; Evaluation Studies as Topic; Female; Hallucinations; Humans; Isomerism; Male; Middle Aged; Narcolepsy; Placebos; Sleep Initiation and Maintenance Disorders; Sleep Stages; Sleep Wake Disorders; Sleep, REM; Sweating; Tremor
PubMed: 4359162
DOI: 10.1136/jnnp.36.6.1076 -
Alcoholism, Clinical and Experimental... Feb 2013Considerable evidence suggests that sensitivity to the stimulant effects of alcohol and other drugs is a risk marker for heavy or problematic use of those substances. A... (Clinical Trial)
Clinical Trial
BACKGROUND
Considerable evidence suggests that sensitivity to the stimulant effects of alcohol and other drugs is a risk marker for heavy or problematic use of those substances. A separate body of research implicates negative emotionality. The goal of the present study was to evaluate the independent and interactive effects of the stimulant response, assessed with an amphetamine challenge, and negative emotionality on alcohol and drug use.
METHODS
Healthy young women and men completed the Multidimensional Personality Questionnaire (MPQ) and an inventory assessing alcohol and other drug use. Subsequently, the effects of 10-mg d-amphetamine were determined in the laboratory using the Stimulant scale of the Biphasic Alcohol Effects Scale. Hierarchical regression analyses evaluated the effects of amphetamine response and the MPQ factor Negative Emotionality on measures of substance use.
RESULTS
The amphetamine response moderated relationships between negative emotionality and alcohol use: in combination with a robust amphetamine response (i.e., enhanced stimulant effects as compared with baseline), negative emotionality predicted greater alcohol consumption, more episodes of binge drinking, and more frequent intoxication in regression models. A strong stimulant response independently predicted having used an illicit drug, and there was a trend for it to predict having used alcohol. Negative emotionality alone was not associated with any measure of alcohol or drug use.
CONCLUSIONS
Consistent with the idea that emotion-based behavioral dysregulation promotes reward seeking, a high level of negative emotionality was associated with maladaptive alcohol use when it co-occurred with sensitivity to drug-based reward. The findings contribute to our understanding of how differences in personality may interact with those in drug response to affect alcohol use.
Topics: Adolescent; Adult; Alcohol Drinking; Central Nervous System Stimulants; Dextroamphetamine; Drug Users; Emotions; Female; Humans; Male; Personality Inventory
PubMed: 23240777
DOI: 10.1111/j.1530-0277.2012.01935.x -
Experimental and Clinical... Apr 2020Drug self-administration procedures are the gold standard for laboratory research to study mechanisms of drug use disorders and evaluate candidate medications. However,...
Pharmacological validation of a translational model of cocaine use disorder: Effects of d-amphetamine maintenance on choice between intravenous cocaine and a nondrug alternative in humans and rhesus monkeys.
Drug self-administration procedures are the gold standard for laboratory research to study mechanisms of drug use disorders and evaluate candidate medications. However, preclinical-to-clinical translation has been hampered by a lack of coordination. To address this limitation, we previously developed homologous intravenous (IV) cocaine choice self-administration procedures in rhesus monkeys and humans, and then demonstrated their functional equivalence. The present studies sought to determine the sensitivity of these procedures to d-amphetamine maintenance. Three (N = 3) rhesus monkeys with histories of cocaine self-administration and 16 (N = 16) humans with cocaine use disorder completed the studies. Monkeys were maintained on IV d-amphetamine (0, 0.019, 0.037 and 0.074 mg/kg/h), and then completed 7 sessions during each condition in which they completed 9 choice trials to receive 0.14 mg/kg/injection IV cocaine (corresponding to 10 mg/70 kg in humans) or 10 food pellets under independent, concurrent progressive-ratio schedules. Humans were maintained on oral extended release d-amphetamine (0, 30 and 60 mg/day, corresponding to the lowest 3 doses in monkeys) and participated in 12 sessions in which they chose money ($6.00) or IV cocaine (0, 3, 10 and 30 mg/70 kg). Blood samples were taken to compare d-amphetamine plasma levels across species. In monkeys and humans, d-amphetamine reduced the number of cocaine choices and produced comparable blood levels at equivalent daily doses. d-Amphetamine had similar efficacy, though lower potency, at reducing choice for an equivalent cocaine dose in monkeys relative to humans. These coordinated studies support the utility of these procedures as a translational model for cocaine use disorder. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Topics: Administration, Intravenous; Adolescent; Adult; Animals; Choice Behavior; Cocaine; Cocaine-Related Disorders; Dextroamphetamine; Female; Humans; Macaca mulatta; Male; Middle Aged; Self Administration; Young Adult
PubMed: 31259593
DOI: 10.1037/pha0000302 -
Journal of Child and Adolescent... Apr 2020Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in...
Describe the safety and tolerability of lisdexamfetamine dimesylate (LDX) and provide data on clinical effects for efficacy-related endpoints and pharmacokinetics in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD). This phase 2, multicenter, open-label, dose-optimization study (ClinicalTrials.gov registry: NCT02402166) was conducted at seven U.S. sites between April 15, 2015, and June 30, 2016. Children (4-5 years of age) meeting criteria for ADHD and having ADHD Rating Scale-IV Preschool version (ADHD-RS-IV-PS) total scores ≥28 (boys) or ≥24 (girls) were eligible. Open-label LDX (8-week duration) was initiated at 5 mg and titrated to 30 mg until achieving an optimal dose. Assessments included treatment-emergent adverse events (TEAEs), vital sign changes, ADHD-RS-IV-PS total score changes, and pharmacokinetic evaluations. Among 24 participants, the most frequently reported TEAE was decreased appetite (8/24; 33%). At week 8/early termination, mean (standard deviation) systolic and diastolic blood pressure and pulse changes from baseline were -1.1 (7.31) and 1.5 (6.93) mmHg and -0.8 (12.75) bpm, respectively. The mean (95% confidence interval) change from baseline ADHD-RS-IV-PS total score at the final on-treatment assessment was -26.1 (-32.2 to -20.0). Pharmacokinetic parameters of amphetamine, a major active metabolite of LDX, were characterized: -amphetamine exposure increased with LDX dose; mean and , respectively, ranged from 4.00 to 4.23 hours and 7.18 to 8.46 hours. In preschool-aged children with ADHD, LDX was generally well tolerated and reduced ADHD symptoms, consistent with observations in children 6-17 years of age. Based on these findings, a starting LDX dose as low as 5 mg in phase 3 studies in preschool-aged children is supported.
Topics: Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child, Preschool; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Lisdexamfetamine Dimesylate; Male; Psychiatric Status Rating Scales; Treatment Outcome
PubMed: 32233956
DOI: 10.1089/cap.2019.0117 -
Experimental and Clinical... Apr 2022Recent advances in diagnostic research identified that individuals with higher impulsivity and sensation-seeking scores tend to report more positive subjective responses...
Recent advances in diagnostic research identified that individuals with higher impulsivity and sensation-seeking scores tend to report more positive subjective responses to stimulant drugs such as amphetamine. The current exploratory study hypothesized that differences in underlying mesocorticolimbic circuitry may mediate the relationship between personality and responses to stimulants due to its previously established implication in reward processes as well as the overlap between its dopaminergic projections and the pharmacodynamics of many stimulants. Forty participants (20 female) were recruited with relatively high- and low-impulsivity and sensation-seeking scores as defined by the Zuckerman-Kuhlman Personality Questionnaire (Form IIIR; Zuckerman, Kuhlman, Joireman, Teta, & Kraft, 1993) for a double-blind, placebo-controlled, intranasal amphetamine administration study conducted within an MRI scanner. Active state seed-to-voxel connectivity analyses assessed the effects of amphetamine, personality, subjective responses to amphetamine, and their interactions with mesocorticolimbic seeds on data collected during monetary incentive delay and go/no-go task performance. Results indicated that amphetamine administration largely disrupted brain activity as evidenced by connectivity values shifting toward no correlation among brain stem, striatal, and frontal cortex regions. Additionally, associations of impulsivity and connectivity between ventral tegmental and medial orbitofrontal as well as lateral orbitofrontal and putamen regions were inverted from negative to positive during the placebo and amphetamine conditions, respectively. Personality was unrelated to subjective responses to amphetamine. Results are interpreted as providing evidence of underlying differences in mesocorticolimbic circuitry being a potential target for requisite diagnostic and treatment strategies implicated with stimulant use disorders, but further research is needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Topics: Amphetamine; Dextroamphetamine; Double-Blind Method; Exploratory Behavior; Female; Humans; Impulsive Behavior; Male; Sensation
PubMed: 33764102
DOI: 10.1037/pha0000406