Methylphenidate Exposure Research Articles

Methylphenidate and the risk of acute central nervous system oxygen toxicity: a rodent model and observational data in human divers.

The effects of methylphenidate, a stimulant often prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD), on the development of central nervous system oxygen toxicity (COT) have not been experimentally evaluated. The records of all pure-oxygen-rebreather divers evaluated at our institution from 1975-2022 were assessed. Cases of COT were defined as a new onset of tinnitus, tunnel vision, myoclonus, headache, nausea, loss of consciousness, or seizures resolving within 15 minutes from breathing normobaric air, and matched 4:1 with similar controls. Any medications issued to the diver in the preceding three months, including methylphenidate, were recorded. In the animal arm of this study, male mice were exposed to increasing doses of methylphenidate orally, with subsequent exposure to hyperbaric O₂ until clinically evident seizures were recorded. Seventy-five cases of COT were identified in divers, occurring at a median of 80 (range 2-240) minutes after dive initiation at a median depth of 5 m (2-13). Hypercarbia was documented in 11 (14.7%) cases. Prescription of methylphenidate in the preceding three months was not associated with increased risk (OR 0.72, 95% CI 0.16-3.32) of COT. In mice, increasing methylphenidate exposure dose was associated with significantly longer mean COT latency time being 877 s (95% CI 711-1,043) with doses of 0 mg·kg⁻¹; 1,312 s (95% CI 850-1,773) when given 0.75 mg·kg⁻¹; and 1,500 s (95% CI 988-2,012) with 5 mg·kg⁻¹ (F = 4.635, P = 0.014). Observational human data did not demonstrate an association between methylphenidate and an increased risk of COT. Methylphenidate exposure in mice prolongs COT latency and may have protective effects against COT.

Differential Impact of Serotonin Signaling Methylphenidate on Young versus Adult: Insights from Behavioral and Dorsal Raphe Nucleus Neuronal Recordings from Freely Behaving Rats.

Methylphenidate (MPD) remains a cornerstone pharmacological intervention for managing ADHD, yet its increasing usage among ordinary youth and adults outside clinical contexts necessitates a thorough investigation into its developmental effects. This study seeks to simultaneously investigate the behavioral and neuronal changes within the dorsal raphe (DR) nucleus, a center of serotonergic neurons in the mammalian brain, before and after the administration of varying doses of acute and chronic MPD in freely behaving young and adult rats implanted with DR recording electrodes. Wireless neuronal and behavioral recording systems were used over 10 consecutive experimental days. Eight groups were examined: saline, 0.6, 2.5, and 10.0 mg/kg MPD for both young and adult rats. Six daily MPD injections were administered on experimental days 1 to 6, followed by a three-day washout period and MPD re-administration on experimental day 10 (ED10). The analysis of neuronal activity recorded from 504 DR neurons (DRNs) in young rats and 356 DRNs in adult rats reveals significant age-dependent differences in acute and chronic MPD responses. This study emphasizes the importance of aligning electrophysiological evaluations with behavioral outcomes following extended MPD exposure, elucidating the critical role of DRNs and serotonin signaling in modulating MPD responses and delineating age-specific variations in young versus adult rat models.

Effects of methylphenidate on mitochondrial dynamics and bioenergetics in the prefrontal cortex of juvenile rats are sex-dependent

Methylphenidate (MPH) is a central nervous system stimulant drug and a first order prescription in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Although MPH biochemistry in neurodevelopment is not completely understood, studies showed it alters energy metabolism in rat brains. ADHD prevalence during neurodevelopment is related to males and the investigation has been mainly done in these subjects, therefore, little is known about MPH action in females and, consequently, about sexual dimorphism. In the present study we evaluated markers of mitochondrial dynamics (DRP1 and MFN2, fission and fusion, respectively), biogenesis (mtTFA) and bioenergetics (respiratory chain complexes) in prefrontal cortex of male and female juvenile rats submitted to exposure to MPH to better understand MPH effect during postnatal neurodevelopment. ATP and oxidative stress levels were also evaluated. Wistar rats received intraperitoneal injection of MPH (2.0 mg/kg) or control (saline), once a day, from 15th to 45th day of age. Results showed that MPH increased DRP1 and decreased MFN2, as well as increased mtTFA in prefrontal cortex of male rats. In female, MPH decreased NRF1 and increased Parkin, which are mitochondrial regulatory proteins. Respiratory chain complexes (complex I, SDH, complexes III and IV), ATP production and oxidative stress parameters were altered and shown to be sex-dependent. Taken together, results suggest that chronic MPH exposure at an early age in healthy animals changes mitochondrial dynamics, biogenesis and bioenergetics differently depending on the sex of the subjects.

Differential Roles of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, and Prefrontal Cortex in Regulating Response to Methylphenidate: Insights from Neuronal and Behavioral Studies in Freely Behaving Rats.

A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose-response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals' behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further increases in firing rate as compared to the initial MPD responses. The majority of neurons recorded from animals expressing behavioral tolerance responded to chronic MPD with decreases in their firing rate as compared to the initial MPD exposures. Each of the six brain areas studied-the ventral tegmental area, locus coeruleus, dorsal raphe, nucleus accumbens, prefrontal cortex, and caudate nucleus (VTA, LC, DR, NAc, PFC, and CN)-responds significantly (p < 0.001) differently to MPD, suggesting that each one of the above brain areas exhibits different roles in the response to MPD. Moreover, this study demonstrates that it is essential to evaluate neuronal activity responses to psychostimulants based on the animals' behavioral responses to acute and chronic effects of the drug from several brain areas simultaneously to obtain accurate information on each area's role in response to the drug.

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children

Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Methylphenidate (Ritalin) affects serotonin signaling differently in young compared to adults. Concomitant behavioral and neuronal recording from dorsal raphe in freely behaving rats

Currently, methylphenidate (MPD) is one of the most commonly prescribed psychostimulants for management and treatment of attention deficit hyperactivity disorder (ADHD). A rise in the consumption of MPD by “ordinary” youth and adults prompted concern regarding the ontogeny effects of acute and chronic MPD exposure. The objective of this study is to concomitantly record behavioral and neuronal activity from the dorsal raphe (DR) nucleus, a major source of serotonergic innervation in the mammalian brain before and following different doses of acute and chronic administration of MPD in freely behaving adolescent (young) and adult rats previously implanted with electrodes in the DR. A wireless recording system over 10 consecutive experimental days was used. Four experimental groups were used: saline, 0.6, 2.5, and 10.0 mg/kg MPD for young and similar groups for adult rats. Animals received one daily MPD injection on experimental days 1-6, followed by three washout days, and then drug rechallenge on experimental day 10 (ED10). 860 DR units were recorded, 356 from adult rats and 504 from young rats. The study provides experimental evidence that the responses to acute and chronic MPD were significantly different between the two age groups. Moreover, the study implies that it is essential to evaluate the electrophysiological responses to a drug based on the animal’s behavioral response to chronic drug exposure and that the DR and serotonin signaling has a significant role in the response to MPD as well as a different role in young as compared to adult rats.

Cardiovascular Safety of Atomoxetine and Methylphenidate in Patients With Attention-Deficit/Hyperactivity Disorder in Japan: A Self-Controlled Case Series Study

Objective: To investigate the association between atomoxetine or methylphenidate use and arrhythmia, heart failure (HF), stroke, and myocardial infarction (MI) in attention-deficit/hyperactivity disorder (ADHD) patients mainly focused on the people of working age. Methods: In a self-controlled case series study using a Japanese claims database, we identified events of arrhythmia, HF, stroke, and MI among 15,472 atomoxetine new users and 12,059 methylphenidate new users. Adjusted incidence rate ratios (aIRRs) of outcome events were estimated using multivariable conditional Poisson regression. Results: An increased risk of arrhythmia was observed during the first 7 days after the initial atomoxetine exposure (aIRR 6.22, 95% CI [1.90, 20.35]) and in the subsequent exposure (3.23, [1.58, 6.64]). No association was found between methylphenidate exposure and arrhythmia, nor between atomoxetine or methylphenidate exposure and HF. The limited number of stroke and MI cases prevented thorough analysis. Conclusions: Clinicians should consider monitoring for arrhythmia after patients initiating or re-initiating atomoxetine.

Methylphenidate exposure in juvenile period elicits locomotion changes and anxiolytic-like behavior in adulthood: Evidence using zebrafish as a translational model

Methylphenidate (MPH) is a central nervous system stimulant that is mainly used for Attention-Deficit/Hyperactivity Disorder (ADHD). It is well known that there is a high rate of ADHD misdiagnosis, leading to a great number of neurotypical children chronically exposed to MPH in early periods of life. This increase raises concern about possible long-lasting effects of this exposure. We aimed to evaluate whether exposure to MPH during childhood might impact adult behavioral pattern. For this purpose, we used zebrafish as a translational model considering its robustness as experimental model and fast life cycle. Fish were exposed during juvenile period (from 30 to 60 post-natal day) at MPH therapeutic concentration (2 mg L−1), and behavioral tests were performed at fish adulthood (120 post-natal day). MPH provoked slight anxiolytic-like effects and hyperlocomotion, and no differences on sociability and cortisol levels were observed. Moreover, sex did not affect any of the parameters evaluated. These results demonstrate that early chronic exposure to MPH leads to neurobehavioral adaptations that persist into adulthood in zebrafish regardless of sex, suggesting that the misuse of MPH during childhood and adolescence can alter neurobehavioral plasticity and these alterations might persist until adulthood.

Suspected Suicide Attempt and Intentional Misuse Cases Aged 50+ Involving Amphetamine or Methylphenidate and Medical Outcomes: Associations with Co-Used Other Substances

Introduction: Given the increasing adult use of amphetamine and methylphenidate and their high misuse potential, we examined suspected suicide attempts and other intentional misuse and medical outcomes and their associations with co-used other substances among amphetamine and methylphenidate exposure cases aged 50+. Methods: Using the 2015–2021 U.S. National Poison Data System (N = 7701 amphetamine and/or methylphenidate cases), we fit two generalized linear models for a Poisson distribution with a log link function, with suspected suicide attempt versus intentional misuse and major medical effect/death versus other outcomes as the dependent variables. Results: Of all amphetamine/methylphenidate exposure cases, suspected suicide attempts and intentional misuse were 28.4% and 13.2%, respectively. Benzodiazepine use was associated with a higher likelihood, but any illicit drug use was associated with a lower likelihood of suspected suicide attempts compared to intentional misuse. The type of stimulant involved (amphetamine or methylphenidate) was not significant. The co-use of antidepressants (IRR = 1.43, 95% CI = 1.16–1.76), prescription opioids (IRR = 1.48, 95% CI = 1.21–1.81), drugs for cardiovascular disease (IRR = 1.51, 95% CI = 1.20–1.90), antipsychotics (IRR = 1.26, 95% CI = 1.02–1.55), or illicit drugs (IRR = 2.40, 95% CI = 1.82–3.15) was associated with a higher likelihood of major effect/death. Conclusions: Suspected suicide attempts or intentional misuse accounted for more than 40% of amphetamine or methylphenidate exposure cases aged 50+. The higher likelihood of major effect/death in cases involving antidepressants, antipsychotics, and cardiovascular disease drugs also suggests the confounding effects of comorbid mental and physical health problems. Careful monitoring of those who were prescribed amphetamine or methylphenidate and use other substances is needed.

Effects of methylphenidate on femoral bone growth in male rats.

The use of Methylphenidate (MP) can have adverse effects on bone growth and mineralization. This study aimed to investigate the underlying pathophysiology of MP-induced skeletal deficits in growing rats using stereological and immunohistochemical methods. Male rats, aged 4weeks, were orally treated with MP through an 8-h/day water drinking protocol. The rats (n=30) were randomly divided into three groups: MP-High Dose (30/60mg/kg/day MP), MP-Low Dose (4/10mg/kg/day MP), and control (water only). After 13weeks, the femoral bones were assessed using calliper measurements, dual-energy X-ray absorptiometry, and biomechanical evaluation. The total femur volume, cartilage volume, growth zone volume, and volume fractions were determined using the Cavalieri method. Immunohistochemical analyses were conducted using alkaline phosphatase and anti-calpain antibody staining. Rats exposed to MP exhibited significant reductions in weight gain, femoral growth, bone mineralization, and biomechanical integrity compared to the control group. The total femoral volume of MP-treated rats was significantly lower than that of the control group. The MP-High Dose group showed significantly higher ratios of total cartilage volume/total femoral volume and total growth zone volume/total femoral volume than the other groups. Immunohistochemical evaluation of the growth plate revealed reduced osteoblastic activity and decreased intracellular calcium deposition with chronic MP exposure. The possible mechanism of MP-induced skeletal growth retardation may involve the inhibition of intracellular calcium deposition in chondrocytes of the hypertrophic zone in the growth plate. In this way, MP may hinder the differentiation of cartilage tissue from bone tissue, resulting in reduced bone growth and mineralization.

Methylphenidate cross-sensitization with amphetamine is dose dependent but not age dependent

Psychostimulants such as methylphenidate (MPD) and amphetamine (AMP) are often prescribed to young children and adolescents to treat behavioral disorders, or used to improve their intellectual performance in our competitive society. This is concerning as the temporal effects of how MPD exposure at a young age influences the response to MPD and AMP administration later in adulthood remains unclear. The objective of this study was to test whether MPD has the characteristics of substances that elicit behavioral symptoms of dependence and whether those effects are influenced by the initial age of MPD exposure. Three control and nine experimental groups of male rats were used. They were exposed to repetitive (chronic) 0.6, 2.5, or 10.0 mg/kg MPD in adolescence only, adulthood only, or adolescence and adulthood respectively. Then all groups were subsequently re-challenged with a single AMP dose in adulthood to test whether cross-sensitization between MPD and AMP was expressed, potentially as a result of prior MPD consumption. Exposure to 2.5 mg/kg and 10.0 mg/kg MPD in adolescence and adulthood or in adulthood alone led to cross-sensitization with AMP while exposure to 0.6 mg/kg MPD in adolescence and adulthood or in adulthood alone did not lead to cross-sensitization with AMP. Thus, these results indicate that MPD cross-sensitization with AMP is dose dependent.

Long-term methylphenidate exposure and 24-hours blood pressure and left ventricular mass in adolescents and young adults with attention deficit hyperactivity disorder

Young people with attention deficit hyperactivity disorder (ADHD) are now being treated with psychostimulant medication for longer than was previously the case and are increasingly likely to remain on methylphenidate into adolescence and adulthood. This study was designed to determine whether the long-term use of methylphenidate (MPH, immediate release or extended release) increases blood pressure and left ventricular mass (LVM) identified by echocardiography in adolescents and young adults with ADHD aged 12-25 years. In a five-site cross-sectional design two groups were compared for 24- hour blood pressure and heart rate (HR) registrations and LVM: 1) adolescents and young adults with ADHD who had been treated with MPH for > 2 years (N=162, age mean (SD) 15.6 (3.0)), and 2) adolescents and young adults with ADHD who had never been treated with methylphenidate (N=71, age mean 17.4 (4.2)). The analyses were controlled for propensity scores derived from age, sex, height, weight, and 19 relevant background variables.A blood pressure indicative of hypertension (>95th percentile) was observed in 12.2% (95% confidence interval 7.3 – 18.9%) of the participants in the MPH treated group and in 9.6% (95%CI 3.2 – 21.0%) of the MPH naïve group, with overlapping intervals. The 24-hour recorded systolic blood pressure (SBP) and HR were significantly higher during daytime in medicated individuals with ADHD than in those with unmedicated ADHD, but were similar in both groups during the night. 24-hour diastolic blood pressure (DBP) did not differ between both groups during either daytime or at night. LVM, corrected for body-surface area (LVMBSA), also did not differ between the two groups (p=0.20, controlling for confounders). Further, MPH daily dose and duration of treatment were unrelated to LVMBSA, SBP, and DBP.Long-term MPH use in adolescents and young adults with ADHD is associated with small but significant increases of SBP and HR during daytime. Given the current sample size, the proportions of hypertension do not differ significantly between MPH treated and MPH-naïve individuals with ADHD. Future studies with larger samples, longer treatment duration, and/or with within-subject designs are necessary. The results do, however, further support recommendations that highlight the importance of monitoring blood pressure and HR during MPH treatment.

Rosmarinus officinalis and Methylphenidate Exposure Improves Cognition and Depression and Regulates Anxiety-Like Behavior in AlCl3-Induced Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurological illness that causes severe cognitive impairment. AD patients also experience at least one of the neuropsychiatric symptoms including apathy, depression, and anxiety during the course of their life. Acetylcholine esterase inhibitors are the available treatment options to alleviate cognitive deficits, whereas methylphenidate (MPH), a psychostimulant, is considered for the treatment of apathy in AD patients. Rosmarinus officinalis, a perennial herb, has been potentially known to have antioxidant and anti-inflammatory properties. The present study investigated the potential effects of MPH and R. officinalis in comparison with the standard drug, Donepezil, on cognition, anxiety, and depression in the AlCl3-induced mouse model of AD. The animals were divided into eight groups (n = 8, each). The results revealed that the MPH- and R. officinalis-treated groups significantly improved memory impairment, whereas R. officinalis substantially reduced depression and anxiety as compared with other treatment groups. MPH treatment induced an antidepressant effect and increased anxiety-like behavior. Moreover, the AlCl3 exposure led to the formation of amyloid beta (Aβ) plaques in mice hippocampus; however, none of the tested drugs caused a significant reduction in amyloid burden at the selected doses. The present study suggested the potential of R. officinalis to improve memory as well as neuropsychiatric symptoms in AD. Although R. officinalis improved cognitive abilities, it did not reduce the amyloid plaque burden, which indicates that the memory-enhancing effects of R. officinalis are due to some alternate mechanism that needs to be explored further.

Consequences of Acute or Chronic Methylphenidate Exposure Using Ex Vivo Neurochemistry and In Vivo Electrophysiology in the Prefrontal Cortex and Striatum of Rats.

Methylphenidate (MPH) is among the main drugs prescribed to treat patients with attention-deficit and hyperactivity disease (ADHD). MPH blocks both the norepinephrine and dopamine reuptake transporters (NET and DAT, respectively). Our study was aimed at further understanding the mechanisms by which MPH could modulate neurotransmitter efflux, using ex vivo radiolabelled neurotransmitter assays isolated from rats. Here, we observed significant dopamine and norepinephrine efflux from the prefrontal cortex (PFC) after MPH (100 µM) exposure. Efflux was mediated by both dopamine and norepinephrine terminals. In the striatum, MPH (100 µM) triggered dopamine efflux through both sodium- and vesicular-dependent mechanisms. Chronic MPH exposure (4 mg/kg/day/animal, voluntary oral intake) for 15 days, followed by a 28-day washout period, increased the firing rate of PFC pyramidal neurons, assessed by in vivo extracellular single-cell electrophysiological recordings, without altering the responses to locally applied NMDA, via micro-iontophoresis. Furthermore, chronic MPH treatment resulted in decreased efficiency of extracellular dopamine to modulate NMDA-induced firing activities of medium spiny neurons in the striatum, together with lower MPH-induced (100 µM) dopamine outflow, suggesting desensitization to both dopamine and MPH in striatal regions. These results indicate that MPH can modulate neurotransmitter efflux in brain regions enriched with dopamine and/or norepinephrine terminals. Further, long-lasting alterations of striatal and prefrontal neurotransmission were observed, even after extensive washout periods. Further studies will be needed to understand the clinical implications of these findings.

Prepubertal methylphenidate leads to sex-dependent differences in probabilistic discounting

Prescription psychostimulants, such as methylphenidate (MPH), have served as a first line treatment for ADHD and associated developmental disorders since 1961. Psychostimulants has been shown to improve attention, response inhibition, and reduce hyperactivity in patients with ADHD, as well as in non-clinical human populations and animals. While there is a considerable amount of preclinical research investigating the effects of stimulant medications on reward sensitivity and basic learning in male rats, less is understood about their effects in females. Further, there are competing theories on the long-term cognitive impact of MPH, specifically in children who do not have ADHD. To this end, Long-Evans female and male rats were exposed to methylphenidate (0, 2.5, 5 mg/kg, BID, IP) for 20 days during early development (PD10–29). After discontinuation of MPH into adulthood, rats (beginning PD 60) were trained and tested for risk-preference using a 2-choice probabilistic discounting task. For this task, rats were given an option between a ‘large-risky’ choice (3 sugar pellets delivered on a probabilistic VR schedule) and ‘small-certain’ choice (1 sugar pellet delivered on a FR schedule). Rats were subsequently tested on an open field conflict test. The results demonstrate that prepubertal exposure to MPH can have lasting effects on decision-making. Specifically, female rats treated with 2.5 mg/kg MPH displayed a decrease in preference for the risky option, whereas male rats treated with the same dose showed an overall increase in preference compared to sex-matched controls. Irrespective of sex, rats treated with 2.5 mg/kg MPH also demonstrated a decrease in anxiety/inhibitory behavior on the modified open field test compared to controls. These results were not due to differences in locomotor behavior. Overall, the study contributes to the growing body of evidence to suggest that MPH exposure early in development can have a sex-dependent impact on decision-making in adulthood.

Abstinence following intermittent methylphenidate exposure dose-dependently modifies brain glucose metabolism in the rat brain.

Methylphenidate (MP) is a psychostimulant chronically prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). Additionally, MP users may take breaks from using the medication during "drug holidays," which may include short-term or long-term breaks from medication. The present study utilized fluorodeoxyglucose (FDG) positron emission tomography (PET) to analyze the effects of chronic oral MP use and abstinence on brain glucose metabolism (BGluM) in rats at two different doses: high dose (HD) and low dose (LD). The schedule of treatment was 3weeks on-treatment and 1week off-treatment for a period of 13weeks, followed by an abstinence period of 4 total weeks. Results showed that chronic MP treatment using this schedule did not lead to significant changes in BGluM when comparing the control to HD MP groups. However, significant activation in BGluM was observed after periods of abstinence between control and HD MP rats in the following brain regions: the trigeminal nucleus, reticular nucleus, inferior olive, lemniscus, mesencephalic reticular formation, inferior colliculus, and several areas of the cerebellum. These brain regions and functional brain circuit play a role in facial sensory function, the auditory pathway, organizing connections between the thalamus and cortex, motor learning, auditory function, control over eye movement, auditory information integration, and both motor and cognitive functions. These results, when considered with previous studies, indicate that MP schedule of use may have differing effects on BGluM. BGluM following long-term MP use was dependent on MP dose and schedule of use in rats. This study was conducted in non-ADHD model rats with the aim to establish an understanding of the effects of MP itself, especially given the growing chronic off-label and prescribed use of MP. Further studies are needed for analysis of the drug's effects on an ADHD model.

Association between Attention Deficit Hyperactivity Disorder Medication and Depression: A 10-year Follow-up Self-controlled Case Study.

ObjectiveThere is clinical concern that the stimulant methylphenidate (MPH) might increase the risk of depression, particularly in children. This study aimed to investigate the association between MPH use and the risk of depression.MethodsA population-based electronic medical records database was used. We obtained claims data for prescription of ADHD medication, diagnosis of depression, and prescription of antidepressant medication between January 2007 and December 2016 for 43,259 individuals aged 6 to 19 who were diagnosed with ADHD between July 1, 2007 and December 31, 2007. The final analysis was based on 2,330 eligible participants. A self-controlled case series design was used to identify risk factors for major depressive disorder (MDD).ResultsAn elevated MDD risk was found during the 90 days before MPH exposure, with an incidence rate ratio (IRR) of 12.12 (95% confidence interval [95% CI] 10.06−14.61, p < 0.0001). During methylphenidate treatment, the IRR was 18.06 with a 95% CI of 16.67 to 19.56 (p < 0.0001), but it returned to baseline levels after day 31 of MPH treatment discontinuation. The IRR for patients aged 6 to 9 years was 13.11 (95% CI 9.58−17.95) during the 90 days before MPH exposure, and 17.7 (95% CI 15.6−20.08) during MPH treatment, but returned to baseline levels after discontinuation of MPH treatment.ConclusionWe confirmed the temporal relationship between depression and methylphenidate use in young people with ADHD. Though the absolute risk is low, the risk of depression should be carefully considered, particularly in the period directly following the start of methylphenidate treatment.

Physiologically-Based Pharmacokinetic Modeling to Predict Methylphenidate Exposure Affected by Interplay Among Carboxylesterase 1 Pharmacogenetics, Drug-Drug Interactions, and Sex

Background and objectiveThe pharmacokinetics (PK) of methylphenidate (MPH) differ significantly among individuals. Carboxylesterase 1 (CES1) is the primary enzyme metabolizing MPH, and its function is affected by genetic variants, drug-drug interaction (DDI), and sex. The object of this study is to evaluate CES1 pharmacogenetics as related to MPH metabolism using human liver samples and develop a physiologically-based pharmacokinetic (PBPK) modeling approach to investigate the influence of CES1 genotypes and other factors on MPH PK. MethodsThe effect of the CES1 variant G143E (rs71647871) on MPH metabolism was studied utilizing 102 individual human liver S9 (HLS9) fraction samples. PBPK models were developed using the population-based PBPK software PK-Sim® by incorporating the HLS9 incubation data. The established models were applied to simulate MPH PK profiles under various clinical scenarios, including different genotypes, drug-alcohol interactions, and the difference between males and females. ResultsThe HLS9 incubation study showed that subjects heterozygous for the CES1 variant G143E metabolized MPH at a rate of approximately 50% of that in non-carriers. The developed PBPK models successfully predicted the exposure alteration of MPH from the G143E genetic variant, ethanol-MPH DDI, and sex. Importantly, the study suggests that male G143E carriers who are alcohol consumers are at a higher risk of MPH overexposure. ConclusionPBPK modeling provides a means for better understanding the mechanisms underlying interindividual variability in MPH PK and PD and could be utilized to develop a safer and more effective MPH pharmacotherapy regimen.

Prediction of Carboxylesterase 1-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models.

The use of cannabis products has increased substantially. Cannabis products have been perceived and investigated as potential treatments for attention-deficit/hyperactivity disorder (ADHD). Accordingly, co-administration of cannabis products and methylphenidate (MPH), a first-line medication for ADHD, is possible. Oral MPH undergoes extensive presystemic metabolism by carboxylesterase 1 (CES1), a hepatic enzyme which can be inhibited by two prominent cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This prompts further investigation into the likelihood of clinical interactions between MPH and these two cannabinoids through CES1 inhibition. In the present study, inhibition parameters were obtained from a human liver S9 system and then incorporated into static and physiologically-based pharmacokinetic (PBPK) models for prediction of potential clinical significance. The inhibition of MPH hydrolysis by THC and CBD was reversible, with estimated unbound inhibition constants (Ki,u) of 0.031 and 0.091 µM, respectively. The static model predicted a mild increase in MPH exposure by concurrent THC (34%) and CBD (94%) from smoking a cannabis cigarette and ingestion of prescriptive CBD, respectively. PBPK models suggested no significant interactions between single doses of MPH and CBD (2.5 - 10 mg/kg) when administered simultaneously, while a mild interaction (area under drug concentration-time curve increased by up to 55% and maximum concentration by up to 45%) is likely if multiple doses of CBD (10 mg/kg twice daily) are administered. In conclusion, the pharmacokinetic disposition of MPH can be potentially influenced by THC and CBD under certain clinical scenarios. Whether the magnitude of predicted interactions translates into clinically relevant outcomes requires verification in an appropriately designed clinical study. SIGNIFICANCE STATEMENT: This work demonstrated a potential mechanism of drug-drug interactions between methylphenidate (MPH) and two major cannabinoids (Δ9-tetrahydrocannabinol [THC] and cannabidiol [CBD]) not previously reported. We predicted a mild interaction between MPH and THC when the cannabinoid exposure occurred via cannabis smoking. Mild interactions between MPH and CBD were predicted with multiple oral administrations of CBD.

Prescription Stimulants and the Risk of Psychosis: A Systematic Review of Observational Studies.

Stimulants can cause psychotic symptoms at high doses and with parenteral use, but it remains uncertain whether the clinical use of prescription stimulants (PS) at therapeutic doses precipitates psychosis or influences long-term psychosis risk. Although serious, psychosis is a relatively uncommon event that is difficult to detect in brief randomized controlled trials. There have been several large-scale observational studies of PS and psychosis risk, which have not been reviewed; therefore, we conducted a systematic review of observational studies of PS and psychosis risk in adults and children. We conducted a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered with International Prospective Register of Systematic Reviews (CRD42021243484). Eligible studies were longitudinal observational studies, either cohort or case-control, published in English that reported on PS exposure and risk of psychotic events or disorders. Risk of bias assessments were performed with the ROBINS-I instrument. There were 10,736 reports screened, and 8 were ultimately included (n = 232,567 patients): 4 retrospective cohort studies, 1 nested case-control study, 2 self-controlled case series, and 1 prospective cohort study. Exposure to methylphenidate (MPH) was more commonly studied than amphetamine (AMPH). In the 3 studies with lowest risk of bias, there was no effect of MPH exposure on psychosis risk, but there was evidence for increased risk with AMPH in 1 study. We conclude that observational studies do not support a clear-cut effect of prescribed MPH on psychosis risk but that AMPH has been less well studied and may increase psychosis risk.