Age differences to methylphenidate-NAc neuronal and behavioral recordings from freely behaving animals.

Methylphenidate (MPD) is a psychostimulant that is widely prescribed to treat attention deficit-hyperactivity disorder, but it is abused recreationally as well. The nucleus accumbens (NAc) is part of the motivation circuit implicated in drug-seeking behaviors. The NAc neuronal activity was recorded alongside the behavioral activity from young and adult rats to determine if there are significant differences in the response to MPD. The same dose of MPD elicits behavioral sensitization in some animals and behavioral tolerance in others. In adult animals, higher doses of MPD resulted in a greater ratio of tolerance/sensitization. Animals who responded to chronic MPD with behavioral sensitization usually exhibited further increases in their NAc neuronal firing rates as well. Different upregulations of transcription factors (ΔFOSB/CREB), variable proportions of D1/D2 dopamine receptors, and modulation from other brain areas may predispose certain animals to express behavioral and neuronal sensitization versus tolerance to MPD.

Time-dependent affective disturbances in abstinent patients with methylphenidate use disorder.

BACKGROUND: Methylphenidate (MPH), also called Ritalin, is used to treat attention-deficit hyperactivity disorder (ADHD) patients. With occasional reports of subjects suffering from Methylphenidate use disorder (MPHUD), few studies analyzed the neuropsychological changes in this population. PURPOSE: This study aims to evaluate the clinical outcomes of individuals with MPHUD. METHODS: We retrospectively analyzed 61 MPH patients (aged 16-27 years) admitted to the Beijing Gaoxin Hospital drug rehabilitation program from Jan 2017 to Mar 2019. The drug use history and drug abuse motivation scale were collected at admission. Clinicians rated the Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and DSM-5 Stimulant use disorder criteria each week during the 4 weeks rehabilitation program. Correlation analyses were conducted between drug use history and affective disturbances. RESULTS: The results showed that the adolescent period is the peak for MPH exposure, and 1/3 of patients got their first exposure to MPH from their parents. MPH abstinence accompanies severe anxiety and depression symptoms, significantly alleviating after four weeks of treatment. CONCLUSIONS: MPHUD is associated with substantial affective disturbances, which warrants a more considerable sample investigation.

Relationship between long-term use of Ritalin and semen parameters in patients referred to psychiatric centres.

Some studies have shown that Ritalin can interfere with the growth and development of the reproductive system and can also have a serious and harmful effect on sperm parameters, so we decided to conduct studies in this field on the human sample. In a case-control study, 100 adult men aged 21-31 years with hyperactivity were divided into two groups of 50 past users and 50 current users and, 50 patients who had not used Ritalin before were included as the control group. Data were analysed using SPSS software, version 20. Analysis of variance, Pearson correlation coefficient, and regression analysis was used to assess the correlation between variables. The results also showed that there was a statistically significant difference between the current users and the control group in terms of sperm count, abnormality, and motility (p < .47). Comparison of the user group in the past and the control group showed that there was no statistically significant difference in terms of sperm count (p < .59), but there was a significant difference in terms of sperm motility and abnormality between the two groups (p < .001). The present study showed that long-term use of Ritalin can have negative effects on sperm parameters in humans.

Methylphenidate improves executive functions in patients with traumatic brain injuries: a feasibility trial via the idiographic approach.

BACKGROUND: Road traffic accidents are known to be the main cause of traumatic brain injury (TBI). TBI is also a leading cause of death and disability. This study, by means of the idiographic approach (single-case experimental designs using multiple-baseline designs), has examined whether methylphenidate (MPH - trade name Ritalin) had a differential effect on cognitive measures among patients with TBI with the sequel of acute and chronic post-concussion syndromes. The effect on gender was also explored. METHODS: In comparison with healthy controls, patients with TBI (acute and chronic) and accompanying mild cognitive impairment (MCI) were screened for their integrity of executive functioning. Twenty-four patients exhibiting executive dysfunction (ED) were then instituted with the pharmacological intervention methylphenidate (MPH). The methylphenidate was administered using an uncontrolled, open label design. RESULTS: The administration of methylphenidate impacted ED in the TBI group but had no effect on mood. Attenuation of ED was more apparent in the chronic phases of TBI. The effect on gender was not statistically significant with regard to the observed changes. CONCLUSIONS: To our knowledge, this is the first feasibility trial from the Arabian Gulf to report the performance of a TBI population with mild cognitive impairment according to the IQCODE Arabic version. This investigation confirms anecdotal observations of methylphenidate having the potential to attenuate cognitive impairment; particularly those functions that are critically involved in the integrity of executive functioning. The present feasibility trial should be followed by nomothetic studies such as those that adhere to the protocol of the randomized controlled trial. This evidence-based research is the foundation for intervention and future resource allocation by policy- or public health decision-makers.

Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects.

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.

Acute and chronic methylphenidate administration in intact and VTA-specific and nonspecific lesioned rats.

Methylphenidate (MPD) is a psychostimulant used for the treatment of ADHD and works by increasing the bioavailability of dopamine (DA) in the brain. As a major source of DA, the ventral tegmental area (VTA) served as the principal target in this study as we aimed to understand its role in modulating the acute and chronic MPD effect. Forty-eight male Sprague-Dawley rats were divided into control, sham, electrical lesion, and 6-OHDA lesion groups. Given the VTA's implication in the locomotive circuit, three locomotor indices-horizontal activity, number of stereotypy, and total distance-were used to measure the animals' behavioral response to the drug. Baseline recording was obtained on experimental day 1 (ED 1) followed by surgery on ED 2. After recovery, the behavioral recordings were resumed on ED 8. All groups received daily intraperitoneal injections of 2.5 mg/kg MPD for six days after which the animals received no treatment for 3 days. On ED 18, 2.5 mg/kg MPD was re-administered to assess for the chronic effect of the psychostimulant. Except for one index, there was an increase in locomotive activity in all experimental groups after surgery (in comparison to baseline activity), acute MPD exposure, induction with six daily doses, and after MPD re-challenge. Furthermore, the increase was greatest in the electrical VTA lesion group and lowest in the 6-OHDA VTA lesion group. In conclusion, the results of this study suggest that the VTA may not be the primary nucleus of MPD action, and the VTA plays an inhibitory role in the locomotive circuit.

Chronic oral methylphenidate treatment increases microglial activation in rats.

Methylphenidate (MP) is a widely prescribed psychostimulant used to treat attention deficit hyperactivity disorder. Previously, we established a drinking paradigm to deliver MP to rats at doses that result in pharmacokinetic profiles similar to treated patients. In the present study, adolescent male rats were assigned to one of three groups: control (water), low-dose MP (LD; 4/10 mg/kg), and high dose MP (HD; 30/60 mg/kg). Following 3 months of treatment, half of the rats in each group were euthanized, and the remaining rats received only water throughout a 1-month-long abstinence phase. In vitro autoradiography using [3H] PK 11195 was performed to measure microglial activation. HD MP rats showed increased [3H] PK 11195 binding compared to control rats in several cerebral cortical areas: primary somatosensory cortex including jaw (68.6%), upper lip (80.1%), barrel field (88.9%), and trunk (78%) regions, forelimb sensorimotor area (87.3%), secondary somatosensory cortex (72.5%), motor cortices 1 (73.2%) and 2 (69.3%), insular cortex (59.9%); as well as subcortical regions including the thalamus (62.9%), globus pallidus (79.4%) and substantia nigra (22.7%). Additionally, HD MP rats showed greater binding compared to LD MP rats in the hippocampus (60.6%), thalamus (59.6%), substantia nigra (38.5%), and motor 2 cortex (55.3%). Following abstinence, HD MP rats showed no significant differences compared to water controls; however, LD MP rats showed increased binding in pre-limbic cortex (78.1%) and ventromedial caudate putamen (113.8%). These findings indicate that chronic MP results in widespread microglial activation immediately after treatment and following the cessation of treatment in some brain regions.

The efficacy of Ritalin in ADHD children under neurofeedback training.

Current research has shown that neurofeedback (NF) is a viable treatment for attention deficit hyperactivity disorder (ADHD), however having pharmacological approach alongside such stimulants is still inevitable. Therefore, the purpose of this study is the comparison of neurofeedback with Ritalin and without Ritalin in treating children with ADHD. This study was causal-comparative in design. Participants were children aged 5-10 years with ADHD; seven participants were in neurofeedback group with Ritalin and seven in neurofeedback without Ritalin group according to random split and parent's conformation. Clinical Q, Conner's continuous performance test (CPT), and WISC-R were used before and after treatment. For analyzing data, we used descriptive statistical and Mann Whitney U tests. Results showed that even if the two groups were modified in all components, modifications of commission and reaction time of the CPT and F4 theta/alpha of the clinical Q were more accurate in NF with Ritalin treatment rather than the other group. These findings suggest that neurofeedback is efficient in improving some of the behavioral concomitants of ADHD in children whose parents favored non-pharmacological treatment, but Ritalin and neurofeedback combination is more efficient. So, multimodal approach is strongly recommended for ADHD treatment.

Predicting the ergogenic response to methylphenidate.

PURPOSE: Methylphenidate (MPH) and other stimulants have been shown to enhance physical performance. However, stimulant research has almost exclusively been conducted in young, active persons with a normal BMI, and may not generalize to other groups. The purpose of this study was to determine whether the ergogenic response to MPH could be predicted by individual level characteristics. METHODS: We investigated whether weekly minutes of moderate-to-vigorous physical activity (MVPA), age, and BMI could predict the ergogenic response to MPH. In a double-blind, cross-over design 29 subjects (14M, 15F, 29.7 ± 9.68 years, BMI: 26.1 ± 6.82, MVPA: 568.8 ± 705.6 min) ingested MPH or placebo before performing a handgrip task. Percent change in mean force between placebo and MPH conditions was used to evaluate the extent of the ergogenic response. RESULTS: Mean force was significantly higher in MPH conditions [6.39% increase, T(25) = 3.09, p = 0.005 118.8 ± 37.96 (± SD) vs. 111.8 ± 34.99 Ns] but variable (coefficient of variation:163%). Using linear regression, we observed that min MVPA (T(25) = -2.15, ß = -0.400, p = 0.044) and age [T(25) = -3.29, ß = -0.598, p = 0.003] but not BMI [T(25) = 1.67, ß = 0.320 p = 0.109] significantly predicted percent change in mean force in MPH conditions. CONCLUSIONS: We report that lower levels of physical activity and younger age predict an improved ergogenic response to MPH and that this may be explained by differences in dopaminergic function. This study illustrates that the ergogenic response to MPH is partly dependent on individual differences such as habitual levels of physical activity and age.

Raising Awareness About Prescription and Stimulant Abuse in College Students Through On-Campus Community Involvement Projects.

As prescription stimulants become more common on college campuses, concerns have been raised about the abuse of these drugs by college students. Estimates are that up to 20% of college students abuse prescription stimulants, most often by ingesting medications not prescribed to them. In an effort to raise awareness and disseminate information about the potential harmful effects of abusing prescription stimulants, students enrolled in a Health Psychology course participated in small-group community involvement projects. This paper describes the value of such projects, details the specific projects completed by the students, how the projects were graded and assessed, and discusses the usefulness of these and similar projects in neuroscience-related courses.

D1 and D2 specific dopamine antagonist modulate the caudate nucleus neuronal responses to chronic methylphenidate exposure.

The psychostimulant, methylphenidate (MPD), is the first line treatment as a pharmacotherapy to treat behavioral disorders such as attention deficit hyperactivity disorder (ADHD). MPD is commonly misused in non-ADHD (normal) youth and young adults both as a recreational drug and for cognitive enhancing effects to improve their grades. MPD is known to act on the reward circuit; including the caudate nucleus (CN). The CN is comprised of medium spiny neurons containing largely dopamine (DA) D1 and D2 receptors. It has been widely shown that the DA system plays an important role in the response to MPD exposure. We investigated the role of both D1 and D2 DA receptors in the CN response to chronic MPD administration using specific D1 and D2 DA antagonist. Four groups of young adult, male SD rats were used: a saline (control) and three MPD dose groups (0.6, 2.5, and 10.0 mg/kg). The experiment lasted 11 consecutive days. Each MPD dose group was randomly divided into two subgroups to receive either a 0.4 mg/kg SCH-23390 selective D1 DA antagonist or a 0.3 mg/kg raclopride selective D2 DA antagonist prior to their final (repetitive) MPD rechallenge administration. It was observed that selective D1 DA antagonist (SCH-23390) given 30 min prior to the last MPD exposure at ED11 partially reduced or prevented the effect induced by MPD exposure in CN neuronal firing rates across all MPD doses. Selective D2 DA antagonist (raclopride) resulted in less obvious trends; some CN neuronal firing rates exhibited a slight increase in all MPD doses.

Monitoring of threo-methylphenidate enantiomers in oral fluid by capillary electrophoresis with head-column field-amplified sample injection.

Threo-methylphenidate is a chiral psychostimulant drug widely prescribed to treat attention-deficit hyperactivity disorder in children and adolescents. An enantioselective CE-based assay with head-column field-amplified sample stacking for analysis of threo-methylphenidate enantiomers in liquid/liquid extracts of oral fluid is described. Analytes are electrokinetically injected across a short water plug placed at the capillary inlet and become stacked at the interface between plug and buffer. Enantiomeric separation occurs within a few minutes in a pH 3.0 phosphate/triethanolamine buffer containing 20 mg/mL (2-hydroxypropyl)-ß-CD as chiral selector. The assay with six point multilevel internal calibration provides a linear response for each enantiomer in the 10-200 ng/mL concentration range, is simple, inexpensive, and reproducible, and has an LOQ of 5 ng/mL. It was applied to oral fluid patient samples that were collected up to 12 h after intake of an immediate release tablet and two different extended release formulations with racemic methylphenidate. Drug profiles could thereby be assessed in a stereoselective way. Almost no levorotary threo-methylphenidate enantiomer was detected after intake of the two extended release formulations, whereas this enantiomer was detected during the first 2.5 h after intake of the immediate release preparation. The noninvasive collection of oral fluid is an attractive alternative to plasma for the monitoring of methylphenidate exposure in the pediatric community.

Trends in attention deficit hyperactivity disorder drugs consumption, Israel, 2005-2012.

PURPOSE: The aim of this study was to describe trends in attention deficit hyperactivity disorder (ADHD) drugs consumption in Israel (Ritalin, Concerta, Daytrana, Vyvanse, Focalin, and Adderall) over the 8 years, 2005-2012, and to explore explanations for changes in amounts and patterns of the utilization. METHODS: Data for the period from 2005 to 2012 were extracted from the database maintained by the Israel Ministry of Health's Pharmaceutical Administration. The data were converted into a defined daily dose (DDD) per 1000 inhabitants per day. RESULTS: Consumption of all ADHD drugs covered by Israel's national health care system doubled over the study period, from 4.02 DDD/1000 inhabitants/day in 2005 to 9.92 DDD/1000 inhabitants/day in 2012. This rise was largely due to a fivefold increase in Concerta consumption (from 0.46 DDD/1000 inhabitants/day in 2005 to 2.28 DDD/1000 inhabitants/day in 2012) and a threefold increase in Ritalin consumption (from 1.43 DDD/1000 inhabitants/day in 2005 to 4.84 DDD/1000 inhabitants/day in 2012). Adderall (amphetamine mixed salts) consumption rose by 30% for the same period. A substantial trend was noted for increased utilization of high-dose formulations together with proportional decline in low-dose consumption. In the same period, cost of the medications has been reduced an average by 20-25%. CONCLUSIONS: There has been a drastic rise in ADHD drugs consumption in Israel over 2005-2012. This has been associated with substantial reduction in cost and changes in the pattern of prescribing that characterized by increased prescription of high-dose long-acting preparations of ADHD drugs and decreased prescription of their low-dose, short-acting formulations.

"Everything's a Challenge": An Interview Study of ADHD Individuals in the Midst of the Prescription Stimulant Shortage.

BACKGROUND: The shortage of prescription stimulants is an ongoing issue that is impacting the ability of individuals with ADHD to access their medication. Amidst concerns that this shortage may have a substantial impact on individuals' ability to manage their symptoms effectively, this research seeks to understand the experiences and consequences for those affected. METHODS: In this study, we interviewed individuals with ADHD who have been directly impacted by the stimulant shortage. Thematic analysis focused on identifying common themes related to challenges with medication access and the resulting effects on daily living. RESULTS: The study uncovered significant difficulties in accessing ADHD medication due to current shortages, leading to disruptions in the management of ADHD symptoms and subsequent detriments to individuals' professional, educational, and personal lives. Systematic controls aimed at reducing non-medical use were found to exacerbate these access issues, inadvertently compounding the challenges faced by those using medication for legitimate medical needs. Individuals also described ways they coped with the shortage, with some seeking ADHD medication via unofficial channels. CONCLUSION: Our findings highlight the urgency of addressing stimulant shortages to safeguard the wellbeing of individuals with ADHD. This study also calls for a critical review of policy measures regulating stimulant medication access, and their effectiveness at reducing non-medical use given the unintended consequences these regulations appear to have on individuals prescribed these medications for therapeutic purposes.

A Rare Phenomenon, Recurrent Acute Dystonia after Withdrawal of 'Methylphenidate-immediate Release Form': A Pediatric Case with ADHD.

Drug-induced acute dystonia is usually associated with combination therapies of neuroleptics, but rarely with the withdrawal or rebound effect of various psychotrops. Very sparse reports have described acute dystonia as a methylphenidate withdrawal (rebound effect), particularly in combination modalities. However, there is no case report or research regarding acute dystonia related to the withdrawal of the short-acting methylphenidate-immediate release form (MPH-IR) in the case of monotherapy of MPH-IR or a combination with guanfacine. Herein, a pediatric case of recurrent acute dystonia with two separate phenomena, locating orolingual and oromandibular/lower extremities, is presented as a withdrawal adverse reaction occurring after abrupt discontinuation of MPH-IR when under a combination therapy with guanfacine. Various options such as anticholinergic agents, re-administrating MPH, or turning to monotherapy from combination modalities, can be suggested in treatment, as well as only hydration may also have the benefit of resolving the symptoms, as in the current case. Practitioners should be aware of all possible adverse effects of MPH, even the rebound effect of short-acting forms.

Brain talk: power and negotiation in children's discourse about self, brain and behaviour.

This article examines children's discourse about self, brain and behaviour, focusing on the dynamics of power, knowledge and responsibility articulated by children. The empirical data discussed in this article are drawn from the study of Voices on Identity, Childhood, Ethics and Stimulants, which included interviews with 151 US and UK children, a subset of whom had a diagnosis of attention deficit/hyperactivity disorder. Despite their contact with psychiatric explanations and psychotropic drugs for their behaviour, children's discursive engagements with the brain show significant evidence of agency and negotiated responsibility. These engagements suggest the limitations of current concepts that describe a collapse of the self into the brain in an age of neurocentrism. Empirical investigation is needed in order to develop agent-centred conceptual and theoretical frameworks that describe and evaluate the harms and benefits of treating children with psychotropic drugs and other brain-based technologies.

Preparation and structural analysis of (±)-threo-ritalinic acid.

Hydrolysis of the methyl ester (±)-threo-methyl phenidate afforded the free acid in 40% yield, viz. (±)-threo-ritalinic acid, C13H17NO2. Hydrolysis and subsequent crystallization were accomplished at pH values between 5 and 7 to yield colourless prisms which were analysed by X-ray crystallography. Crystals of (±)-threo-ritalinic acid belong to the P21/n space group and form intermolecular hydrogen bonds. An antiperiplanar disposition of the H atoms of the (HOOC-)CH-CHpy group (py is pyridine) was found in both the solid (diffraction analysis) and solution state (NMR analysis). It was also determined that (±)-threo-ritalinic acid conforms to the minimization of negative gauche(+)-gauche(-) interactions.

A new mechanistic insight into the association between environmental perfluorooctane sulfonic acid (PFOS) exposure and attention deficit and hyperactivity disorder (ADHD)-like behavior.

Perfluorooctane sulfonic acid (PFOS) is one of the main residual environmental pollutants that threaten human health. PFOS exposure is positively correlated with the prevalence of attention deficit hyperactivity disorder (ADHD); however, the underlying mechanism is unknown. Given that dopamine (DA) is a crucial target for PFOS and that its dysfunction is a key role in ADHD development, it is speculated that PFOS exposure contributes to the occurrence of ADHD to some extent by disrupting DA homeostasis. To establish the relationship between PFOS exposure, DA dysfunction, and ADHD-like behavior, adult zebrafish were exposed to PFOS for 21 days using PFOS concentrations in the serum of patients with ADHD as the reference exposure dose. Results showed that PFOS caused ADHD-like behaviors, with the presence of the slightly elevated percentage of time spent in movement and prolonged time spent in reaching the target zone in the T-maze. Hyperactivity and cognitive ability impairment were more severe with increasing PFOS concentrations. Further investigation showed that PFOS exposure resulted in a decrease in the DA content, accompanied by a decrease in the number of dopaminergic neurons and a disturbance in the transcription profiles of genes associated with the dopaminergic system. Treatment with Ritalin effectively alleviated PFOS-induced ADHD-like behavior and restored DA levels, number of dopaminergic neurons, and expression of DA metabolism-related genes, suggesting that PFOS exposure induced ADHD-like behavior by triggering DA secretion disorder. This study enriches our understanding of the pathogenic mechanisms underlying ADHD development and emphasizes the importance of focusing on the health risks pertaining to environmental exposure.

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.

Behavioral, Neurochemical and Developmental Effects of Chronic Oral Methylphenidate: A Review.

The majority of animal studies on methylphenidate (MP) use intraperitoneal (IP) injections, subcutaneous (SC) injections, or the oral gavage route of administration. While all these methods allow for delivery of MP, it is the oral route that is clinically relevant. IP injections commonly deliver an immediate and maximum dose of MP due to their quick absorption. This quick-localized effect can give timely results but will only display a small window of the psychostimulant's effects on the animal model. On the opposite side of the spectrum, a SC injection does not accurately represent the pathophysiology of an oral exposure because the metabolic rate of the drug would be much slower. The oral-gavage method, while providing an oral route, possesses some adverse effects such as potential animal injury and can be stressful to the animal compared to voluntary drinking. It is thus important to allow the animal to have free consumption of MP, and drinking it to more accurately mirror human treatment. The use of a two-bottle drinking method allows for this. Rodents typically have a faster metabolism than humans, which means this needs to be considered when administering MP orally while reaching target pharmacokinetic levels in plasma. With this oral two-bottle approach, the pathophysiological effects of MP on development, behavior, neurochemistry and brain function can be studied. The present review summarizes these effects of oral MP which have important implications in medicine.