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PubMed2004

Urinary screening for methylphenidate (Ritalin) abuse: a comparison of liquid chromatography-tandem mass spectrometry, gas chromatography-mass spectrometry, and immunoassay methods.

OBJECTIVE: To develop a routine method for detecting methylphenidate (Ritalin) use among drug abusers using liquid chromatography-tandem mass spectrometry (LC/MS/MS). The new methodology was designed to replace less reliable and/or more expensive and time-consuming techniques (GC/MS and ELISA) currently employed in our laboratory, and to provide a combined one-step screening and confirmation LC/MS/MS method. DESIGN AND METHODS: Because methylphenidate abuse is very prevalent in Saskatchewan, there is a demand to provide high volume urine screening both to detect abuse, and to monitor compliance. Random urine samples sent for drugs of abuse testing, standards, and controls were diluted 1:100 in methanol. Diluted specimens were injected directly into an Agilent 1100 liquid chromatograph coupled to a Sciex API 2000 mass spectrometer. The method utilized selected reaction monitoring (SRM) as well as an electrospray ionization source (EIS) to detect both urinary methylphenidate and the more prevalent metabolite, ritalinic acid (RA). RESULTS: There appeared to be little or no sacrifice in sensitivity because the higher dilutions exhibited much less matrix effect. Limit of quantitation (LOQ) for methylphenidate was 100 nM and 500 nM for RA. Linear calibration curves from 100 to 1000 nM for Ritalin and 500 to 5000 nM for RA were acquired. Imprecision of spiked and true specimens did not exceed 10% and at the LOQ, it was less than 20%. CONCLUSIONS: A rapid, sensitive, reliable, and highly specific method by LC/MS/MS for detecting methylphenidate and its metabolite, RA, were developed. Both the cost and performance of the LC/MS/MS method were superior to GC/MS or ELISA, and it allows use of a single rapid procedure for both screening and confirmation.

Chromatography, Liquid↗
PubMed2006

The effect of methylphenidate on the sleep-wake cycle of brain-injured patients undergoing rehabilitation.

BACKGROUND AND PURPOSE: A number of neuro-stimulants are routinely used as part of post-acute care of hospitalized brain-injured patients. To our knowledge, the effect of these stimulants on the sleep-wake cycles of brain-injured patients undergoing rehabilitation has not been addressed. We examined the effect of one of the most commonly used neuro-stimulants, methylphenidate, on the sleep-wake behavior of brain-injured patients undergoing rehabilitation at a dedicated brain injury clinic. PATIENTS AND METHOD: For this study, records of patients admitted between January and December 1999 were scrutinized retrospectively for the data on observationally defined sleep-wake distribution. A total of 30 patients diagnosed with traumatic brain injury were identified as having been observed for a full 24h a day for at least 10 days. Some of these patients (n=17) were administered methylphenidate on clinical grounds. They served as the experimental group, while the unmedicated patients (n=13) served as controls. For the present analysis, the sleep-wake cycles were arbitrarily designated as nighttime and daytime, respectively. A cumulative sleep-wake quantity in a 24-h period was also observed. RESULT: The average number of hours of sleep during a 24-h period was not significantly different for the two cohorts. Similar trends emerged for the nighttime and daytime observations. On the whole, methylphenidate appears not to have unfavorable effects on sleep-wake cycles, presently defined as nighttime, daytime and 24-h, in the traumatic brain injury population. CONCLUSION: This study sought to gain better understanding of the effect of methylphenidate on daytime sleepiness and nighttime sleep, and the data suggest that administration of methylphenidate does not appear to have an adverse effect on sleep-wake quantity.

Adolescent↗
PubMed1998

Neuropharmacologic treatment of hemineglect: a case report comparing bromocriptine and methylphenidate.

Individuals who have hemineglect fail to attend to stimuli presented on the side of the body contralateral to a brain lesion. Although in animal studies the severity of neglect correlates with the degree of dopamine depletion, in hemineglect patients dopamine-enhancing medications have produced inconsistent results. We present a case of hemineglect following a right cerebrovascular accident in a 68-year-old man treated consecutively with methylphenidate and bromocriptine. Tests sensitive to neglect were administered during treatment with methylphenidate, then after all medications had been discontinued, then when the patient was taking low and moderate doses of bromocriptine, and again after all medications had been discontinued for 4 and 26 days. Methylphenidate was superior to no drug treatment. Bromocriptine produced more improvement in neglect than methylphenidate. Although the patient showed an exacerbation of his neglect after withdrawal from methylphenidate, performance gains persisted after withdrawal from bromocriptine. Treatment effects appear related to medication choice, timing of drug treatment, and the adaptability of dopaminergic receptor systems.

Brain Damage, Chronic↗
PubMed1998

Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study.

OBJECTIVE: To determine the efficacy and safety of methylphenidate in acute stroke rehabilitation. DESIGN: A prospective, randomized, double-blind, placebo-controlled study. PATIENTS AND SETTING: Twenty-one stroke patients consecutively admitted to a community-based rehabilitation unit. INTERVENTION: Three-week treatment of methylphenidate (or placebo) in conjunction with physical therapy. Methylphenidate was started at 5mg and increased gradually to 30mg (15mg at 8:00AM and 15mg at 12:00 noon), and discontinued before discharge. MAIN OUTCOME MEASURES: Mood measures included the Hamilton Depression Rating Scale (HAM-D) and Zung Self-Rating Depression Scale (ZDS). Cognitive status was evaluated using the Mini-Mental State Exam (MMSE). Motor functioning was assessed using the Fugl-Meyer Scale (FMS) and a modified version of the Functional Independence Measure (M-FIM). All measures were administered pretreatment and weekly thereafter. Side effects were measured after each increase in dosage and weekly. RESULTS: Patients receiving methylphenidate treatment scored lower on the HAM-D (F(1,18)=5.714, p=.028), lower on the ZDS (F(1,18)=4.206, p=.055), higher on the M-FIM (F(1,18)=5.374, p=.032), and higher on the FMS (F(1,9)=4.060, p=.075) than patients receiving placebo. CONCLUSION: Methylphenidate appears to be a safe and effective intervention in early poststroke rehabilitation that may expedite recovery.

Activities of Daily Living↗
PubMed1980

Gas chromatographic/mass spectrometric analysis of methylphenidate (ritalin) in serum.

A gas chromatographic/mass spectrometric (GG/MS) procedure for the determination of methylphenidate in 1 mL of serum or plasma is reported employing ethylphenidate as internal standard. A 50/50 (V/V) mixture of benzene and hexane is used to extract the methylphenidate and ethylphenidate from plasma. After evaporation of solvent the residue is redissolved in 50 microL hexane. Methyl- and ethylphenidate are then derivatized by the addition of 50 ML of trifluoroacetic anhydride and the TFA derivatives are injected into a quadrupole GC/MS for analysis. This method has a lower limit of sensitivity for methylphenidate of 2.0 micrograms/L. The between-day precision study yielded coefficients of variation of 10.4% and 14.8% at methylphenidate concentrations of 25.6 and 5.2 micrograms/L respectively. The assay has been used to investigate the pharmacokinetics of methylphenidate administered to 6 children for treatment of hyperkinesis. The study yielded ranges for volume of distribution, elimination half-life, and total body clearance of 5.0-6.8 L/kg, 1.6-2.7 hours, and 1.4-2.9 L/kg-hr respectively.

Adolescent↗
PubMed1999

Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine.

Continuous infusion of cocaine produces partial behavioral tolerance to its locomotor activating effects, while daily injections produce sensitization. Methylphenidate binds with a similar affinity to cocaine at the dopamine transporter, but has a much lower affinity for the serotonin transporter than does cocaine. This study was done to compare the effects of chronic methylphenidate with chronic cocaine. The pattern of locomotor activity over a 7 day treatment period was significantly different from cocaine. Methylphenidate elevated activity on each day, compared to saline, yet neither tolerance to a continuous infusion of the drug, nor sensitization to repeated daily injections was produced. We have previously shown that neither of these treatments with cocaine produces significant alterations in dopamine transporter density 1 day after the end of treatment. In contrast, methylphenidate injections significantly decreased dopamine transporters in rostral caudate putamen, with no change in nucleus accumbens. Continuous infusion of methylphenidate had no effect on dopamine transporters in either brain region. These findings provide further evidence that different classes of dopamine uptake inhibitors may interact with the dopamine transporter in qualitatively different manners. Furthermore, it is possible that the inhibition of serotonin uptake by cocaine may contribute to the adaptations in behavioral activity that are seen during chronic treatment.

Animals↗
PubMed1997

Effects of methylphenidate in children with attention deficit hyperactivity disorder: a comparison of event-related potentials between medication responders and non-responders.

Event-related potentials (ERPs) were compared among three groups, each with 13 subjects: (1) ADHD non-responders to methylphenidate treatment; (2) ADHD responders to methylphenidate treatment; and (3) normal control children. Response to methylphenidate was determined through extensive psychoeducational and cognitive assessments during a 4-week double-blind medication assessment. ERPs were recorded each week from 13 active electrodes during a visual feature detection task and a semantic classification task. Significant group effects were found for N2 and P3b latencies due to longer latencies for the ADHD children. Off medication, there were no differences between responders and non-responders. However, on methylphenidate non-responders had significantly longer P3b latencies than responders. Cognitive testing also revealed differential performance on medication between non-responders and responders on the paired-associate learning (PAL) task. Thus, both cognitive and ERP measures were found to differentiate ADHD non-responders and responders to methylphenidate treatment.

Adolescent↗
PubMed2000

Methylphenidate affects striatal dopamine differently in an animal model for attention-deficit/hyperactivity disorder--the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) is used as a model for attention-deficit/hyperactivity disorder (ADHD) because it has behavioural characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to those of ADHD. ADHD children have been shown to have reduced striatal activation in certain tasks. SHR have reduced striatal dopamine release in response to electrical stimulation. The present study set out to investigate possible long-term effects of methylphenidate treatment on dopaminergic function in striatal slices of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. Methylphenidate treatment (3 mg/kg daily for 14 days) did not normalize the decreased electrically-stimulated release of [(3)H]dopamine from SHR caudate-putamen slices nor did it affect postsynaptic D(2) receptor function. However, the second electrical stimulus caused a relatively greater release of [(3)H]dopamine from caudate-putamen slices of methylphenidate-treated SHR than from vehicle-treated SHR, suggesting that presynaptic mechanisms controlling dopamine release had been altered. Interestingly, [(3)H]dopamine release from WKY caudate-putamen slices in response to D(2) autoreceptor blockade by the antagonist, sulpiride, was selectively increased by methylphenidate treatment. This effect was not seen in SHR possibly because D(2) autoreceptor function had already been up-regulated. The results show that methylphenidate is unable to enhance D(2) autoreceptor function in SHR.

Acetylcholine↗
PubMed2002

Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users.

This study compared the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate with placebo in healthy volunteers. Sixteen non-dependent light drug users participated in six experimental sessions, receiving placebo, atomoxetine (20, 45 and 90 mg) and methylphenidate (20 and 40 mg) using a double-blind, Latin square design. Subjective drug effects were assessed using Visual Analog Scales (VAS), the Addiction Research Center Inventory (ARCI) and Adjective Rating Scales (ARS). Psychomotor performance was evaluated using the Digit Symbol Substitution Test (DSST). Physiological measures were also collected throughout the sessions. Assessments were conducted before drug administration and 30, 60, 90, 120, 150, 180 and 240 min following dosing. Forty milligrams methylphenidate produced significant increases on the stimulant portions of the VAS and ARS and the benzedrine, amphetamine, morphine-benzedrine and lysergic acid diethylamine (LSD) subscales of the ARCI relative to placebo. Ninety mg atomoxetine was reported to be unpleasurable relative to placebo as indicated by significant increases on the 'bad' and 'sick' portions of the VAS, and on the LSD subscale of the ARCI. Compared with placebo, both methylphenidate doses significantly increased systolic blood pressure (BP) and heart rate (HR). For atomoxetine, 90 mg increased diastolic BP, 45 and 90 mg increased systolic BP, and all three doses increased HR relative to placebo. Neither compound produced significant differences from placebo on DSST performance. These results suggest that atomoxetine does not induce subjective effects similar to methylphenidate and suggest that it is unlikely that atomoxetine will have abuse liability.

Adolescent↗
PubMed1986

Development of enantioselective gas chromatographic quantitation assay for dl-threo-methylphenidate in biological fluids.

An enantioselective gas chromatographic quantitation assay was developed for the enantiomers of dl-threo-methylphenidate in plasma and urine. dl-threo-Methylphenidate and the internal standard were acylated with N-heptafluorobutyryl-1-prolylchloride under Schotten-Baumann conditions prior to gas chromatographic separation on achiral mixed stationary phases. The derivatives were detected by means of a nitrogen-phosphorus detector. Linear and reproducible calibration curves were obtained over the concentration ranges 0.43-43.25 and 2.16-216.25 ng/ml enantiomer in plasma or urine, respectively. This enantioselective gas chromatographic quantitation assay was applied in a single oral dose disposition study of dl-threo-methylphenidate in a healthy adult volunteer. Stereoselective differences were observed in the plasma concentration-time profiles and cumulative urinary excretion profiles following oral doses of 20 and 40 mg of dl-threo-methylphenidate hydrochloride. Only d-threo-methylphenidate was detectable in plasma after 4 h.

Adult↗
PubMed1999

Effect of methylphenidate on attention in children with attention deficit hyperactivity disorder (ADHD): ERP evidence.

Methylphenidate is the most common treatment for attention deficit hyperactivity disorder (ADHD) and has been shown to improve attention and behaviour. However, the precise nature of methylphenidate on specific aspects of attention at different dose levels remains unclear. We studied methylphenidate effects in ADHD from a neurophysiological perspective, recording event-related potentials (ERPs) during attention task performance in normal controls and children with ADHD under different dose conditions. Twenty children with ADHD and 20 age matched controls were assessed with a continuous performance task requiring subjects to identify repeating alphabetic characters. ERPs and behavioural measures were recorded and analyzed for trials where a correct response was made. The ADHD group was assessed off drug (baseline) and on placebo, low (0.28 mg/kg) and high (0.56 mg/kg) dose levels of methylphenidate. The results showed that the ADHD group at baseline was more impulsive and inattentive than controls and had shorter P2 and N2 latencies and longer P3 latencies. Low dose methylphenidate was associated with reduced impulsivity (fewer false alarms) and decreased P3 latencies, whereas the higher dose level was associated with reduced impulsivity and less inattention (more hits), as well as increased P2 and N2 latencies and decreased P3 latencies. Amplitudes were unaffected and there were no adverse effects of the higher dose for any of the children. These results suggest differential dosage effects and a dissociation between dose levels and aspects of processing.

Attention↗
PubMed2005

Immediate effects of methylphenidate on cognitive attention skills of children with attention-deficit-hyperactivity disorder.

This study investigated the immediate effects of stimulant medication (methylphenidate) on cognitive attention processes in children with attention-deficit-hyperactivity disorder (ADHD). Thirteen males and two females (mean age 9 y 5 mo, SD 18.3 mo) with a diagnosis of ADHD and who were to be prescribed methylphenidate were assessed twice on one day with the Test of Everyday Attention for Children, a neuropsychological battery designed to tap different aspects of cognitive attention. Between assessments, the children were administered methylphenidate (10 mg). Each child had at least average intelligence (IQ 80 or over, as measured by the Wechsler Intelligence Scale for Children-III UK) and was on no other medication. A group of 16 children, who were matched for age, sex, and intelligence, also performed the cognitive tests twice on the same day to control for practice effects of testing. At the first assessment, children with ADHD demonstrated significant impairments in several aspects of cognitive attention in comparison with the control group, particularly sustained attention. After administration of methylphenidate for the children with ADHD, they showed significant improvements in their performance on measures of cognitive attention compared to controls. The immediate effects of methylphenidate and the significance of measuring cognitive aspects of attention as well as behavioural measures are discussed.

Attention↗
PubMed2004

Quantitative mass spectrometric determination of methylphenidate concentration in urine using an electrospray ionization source integrated with a polymer microchip.

We have demonstrated the use of a simple microfabricated electrospray ionization source for coupling microfluidic chips to mass spectrometry (MS). A polymer-based microchip, coupled to a triple quadrupole mass spectrometer, has been employed for direct infusion quantitative bioanalysis of methylphenidate (Ritalin) extracted from human urine samples. The approach used a microfabricated polymer electrospray emitter to couple a microfluidic channel to a stable electrospray ionization source. The microchip was fabricated from cycloolefin plastic plate by hot embossing and thermal bonding. This microfluidic chip contained two independent microfluidic channels, integrated with two corresponding electrospray emitters and an internal gold electrode. Liquid-liquid extraction was used to prepare urine samples, spiked with methylphenidate. A trideuterated analogue of methylphenidate (methylphenidate-d(3)) was used as the internal standard for the analysis. The system showed good electrospray stability and reproducibility with different spray tips. Four different electrospray tips were used to analyze the same sample, and the results showed very small variation with a relative standard deviation of 1.4%. A standard curve prepared for methylphenidate in urine (R(2) = 0.999) was linear over the range of 0.4-800 ng/mL. The precision of the quality control samples for three different concentrations ranged from 19.1% at 20 ng/mL, 3.2% at 200 ng/mL, to 3.5% at 667 ng/mL while the accuracy was 96.3% at 20 ng/mL, 101.2% at 200 ng/mL, and 101.6% at 667 ng/mL. No system carryover was detected even when the same device was used for sequential analysis. These results suggest the potential of this microdevice for MS-based quantitative analysis in drug discovery and development.

Electrophoresis, Microchip↗
PubMed2002

[Waived EEG diagnosis before administration and during drug therapy with methylphenidate: dangerous or justifiable?].

OBJECTIVES: The issue of whether or not to perform an EEG before or during therapy with psychostimulants currently is a topic of controversial discussion. Only a few studies have described the types of EEG alterations that occur in patients without epilepsy who are being treated with psychostimulants. The aim of our study was to assess the types of change in the EEG that occur before and during this treatment so as to be able to formulate recommendations for EEGs in children with ADHD. METHODS: The EEGs of 124 children and adolescents with ADHD before and during treatment with methylphenidate were analyzed retrospectively. RESULTS: In summary the rate of hypersynchronous activity (HSA) during therapy with methylphenidate does not increase. Patients on antiepileptic medication did not show any increased rates of seizures or HSA. CONCLUSIONS: Whether or not methylphenidate medication influences the occurrence of epileptic seizures remains unsettled. Given the data from this study, we would conclude that an EEG during therapy with methylphenidate is not necessary. Before commencing a planned methylphenidate therapy, however, an EEG should be performed.

Adolescent↗
PubMed2004

Reinforcing and subjective effects of methylphenidate: dose and time in bed.

So that reinforcing and subjective effects of methylphenidate as a function of dose and level of sleepiness could be evaluated, 21 volunteers received methylphenidate (5, 10, or 20 mg) or placebo on 2 sampling days. After 4 and 8 hr time in bed (TIB), they chose their preferred capsule on 5 days. Methylphenidate was chosen more frequently after 4 hr TIB (60%) than it was after 8 hr TIB (33%). The strongest preference (68%) was seen in the 10-mg group. At 10 and 20 mg, stimulant-like subjective effects were reported. The 10-mg group was more adversely affected by the restricted bedtime and showed more pronounced drug effects with methylphenidate. These results indicate that sleepiness modulates the reinforcing and subjective effects of methylphenidate.

Adult↗
PubMed2004

Influence of methylphenidate on eating in obese men.

OBJECTIVE: Rapid synaptic dopamine transport or reduced brain dopamine receptor signaling may influence energy intake. Methylphenidate, a dopamine reuptake inhibitor, increases brain synaptic dopamine and produces anorexia, suggesting that it may reduce energy intake. We investigated the effects of two doses of short-acting methylphenidate on energy intake over one meal in obese adult males. RESEARCH METHODS AND PROCEDURES: Nine obese males (>85th BMI percentile) ingested a placebo or a moderate dose (0.5 mg/kg) or a high dose (1.0 mg/kg) of methylphenidate in a within-subject double-blind acute laboratory study. One hour after ingestion, pizza consumption was measured in a naturalistic laboratory setting. RESULTS: Participants reduced energy intake by 23% for the moderate dose vs. the placebo (p < 0.02), but there was no significant difference for the high dose vs. the moderate dose (p > 0.05). Participants consumed 34% fewer kilocalories after ingesting the lowest effective dose of methylphenidate compared with placebo (725.7 +/- 404.5 vs.1095 +/- 271.1 kcal, p < 0.01). Seven of nine subjects responded to the moderate dose. The increase in perceived drug effect above placebo was correlated with the reduction in energy intake for both the moderate (r = -0.85, p = 0.004) and the high (r = -0.75 p = 0.021) doses. Hunger scores were not different across drug doses or placebo before drug administration. DISCUSSION: Methylphenidate reduced energy intake of a highly palatable food over one meal by one-third in obese adult males. Dopamine transport inhibition may be an effective component of a comprehensive treatment for obesity.

Adult↗
PubMed2005

Topography of methylphenidate (ritalin)-induced gene regulation in the striatum: differential effects on c-fos, substance P and opioid peptides.

Dopamine action alters gene regulation in striatal neurons. Methylphenidate increases extracellular levels of dopamine. We investigated the effects of acute methylphenidate treatment on gene expression in the striatum of adult rats. Molecular changes were mapped in 23 striatal sectors mostly defined by their predominant cortical inputs in order to determine the functional domains affected. Acute administration of 5 and 10 mg/kg (i.p.) of methylphenidate produced robust increases in the expression of the transcription factor c-fos and the neuropeptide substance P. Borderline effects were found with 2 mg/kg, but not with 0.5 mg/kg. For 5 mg/kg, c-fos mRNA levels peaked at 40 min and returned to baseline by 3 h after injection, while substance P mRNA levels peaked at 40-60 min and were back near control levels by 24 h. These molecular changes occurred in most sectors of the caudate-putamen, but were maximal in dorsal sectors that receive sensorimotor and medial agranular cortical inputs, on middle to caudal levels. In rostral and ventral striatal sectors, changes in c-fos and substance P expression were weaker or absent. No effects were seen in the nucleus accumbens, with the exception of c-fos induction in the lateral part of the shell. In contrast to c-fos and substance P, acute methylphenidate treatment had minimal effects on the opioid peptides dynorphin and enkephalin. These results demonstrate that acute methylphenidate alters the expression of c-fos and substance P preferentially in the sensorimotor striatum. These molecular changes are similar, but not identical, to those produced by other psychostimulants.

Animals↗
PubMed1996

Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat.

Much experimental and clinical data suggest that the pharmacological profile of modafinil, a newly discovered waking substance, differs from those of amphetamine and methylphenidate, two classical psychostimulants. The brain targets on which modafinil acts to induce wakefulness, however, remain unknown. A double-blind study using the protooncogene c-fos as experimental marker in the cat was, therefore, carried out to identify the potential target neurons of modafinil and compare them with those for amphetamine and methylphenidate. Cats were sacrificed after a single oral administration of amphetamine, methylphenidate, or modafinil at equivalent doses for wake induction (1, 2.5, or 5 mg/kg, respectively) and brain sections examined for Fos by immunocytochemistry. Administration of either amphetamine or methylphenidate evoked Fos-like immunoreactivity in a large number of neurons in the striatum and whole cortex, especially in the caudate nucleus and mediofrontal cortex, which are known to be dopaminergic targets. In contrast, administration of modafinil resulted in the labeling of few cells in these structures, but did induce marked Fos labeling in neurons of the anterior hypothalamic nucleus and adjacent areas. These results provide evidence for the potential brain targets of modafinil, which differ from those of amphetamine or methylphenidate, and suggest that modafinil induces wakefulness by mechanisms distinct from those of the two stimulants.

Amphetamine↗