Sustained-release Methylphenidate Research Articles

New Formulations of Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder: Pharmacokinetics, Efficacy, and Tolerability.

Psychostimulants are the recommended first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate is one of the most commonly used psychostimulants worldwide. Given that immediate-release and/or tablet/capsule formulations may decrease adherence to methylphenidate treatment, several drug companies have been developing novel long-acting and/or liquid/chewable formulations that may improve adherence as well as (for long-acting formulations) reduce abuse potential, decrease stigma associated with multiple administrations per day, and decrease the potential for adverse effects related to dosage peak. Here, we review the pharmacokinetics, efficacy, and tolerability of novel formulations of methylphenidate that are in development or have been approved by the US FDA or European Medicines Agency (EMA) in the last 5years. We searched the websites of the FDA, EMA, ClinicalTrials.gov, and the pertinent drug companies. We also searched PubMed, Ovid databases (MEDLINE, PsycINFO, Embase+Embase classic), and ISI Web of Knowledge (Web of Science [Science Citation Index Expanded], Biological Abstracts, Biosis, Food Science and Technology Abstracts) to retrieve any additional pertinent information. We found data from trials for the following compounds: (1) methylphenidate extended-release oral suspension (MEROS; NWP06, Quillivant™); (2) methylphenidate extended-release chewable capsules (NWP09, QuilliChew ER™); (3) methylphenidate hydrochloride extended-release capsules (Aptensio XR™); (4) methylphenidate extended-release orally disintegrating tablets (XR-ODT; NT-0102, Cotempla™); (5) ORADUR technology (once-daily tamper-resistant formulation) methylphenidate sustained release (SR); and (6) methylphenidate modified-release (HLD-200; Bejorna™). Overall, available evidence based on trials suggests these compounds have good efficacy and tolerability. Future research should further explore the effectiveness and tolerability of these new formulations as well as their potential to improve adherence to treatment in the 'real world' via pragmatic trials.

Awake Bruxism after Initiation of Sustained Release Methylphenidate (CONCERTA)

Attention deficit hyperactivity disorder (ADHD) is a common disorder that affecting about 5-10% of school age children. A Sustained release methylphenidate (CONCERTA) is commonly used to treat such condition in children. It has a great efficacy in ADHD children. A lot of reports have documented the relationship between MPH and sleep bruxism. However, there is a paucity of reports in the literature that documented awake bruxism as a side effect of sustained release MPH. Up to our knowledge there is only one report of its kind showing such relationships. We report the case of a 10-year - old girl who presented with awake bruxism after her third dose of sustained release MPH. It is a serious side effect of a sustained release methylphenidate (CONCERTA) that might affect health of oral cavity. So, it is important to pick it up early to prevent serious complication and improve quality of life for them.

Methylphenidate induced gynecomastia in a prepubertal boy: a case report

Methylphenidate is a frequently used treatment choice in attention deficit hyperactivity disorder. In this paper we will present a prepubertal boy who suddenly developed bilateral gynecomastia after sustained release methylphenidate (OROS MPH) treatment and we will discuss literature on this topic. Although the mechanism is not known, rare development of gynecomastia should be kept in mind in cases using methylphenidate.

Attention Deficit Disorder and Allergic Rhinitis: Are They Related?

The association between ADHD and allergy remains controversial. Our previous findings suggest that nerve growth factor may link the nervous and immune systems. The primary objective of this study was to determine if a combination of cetirizine + methylphenidate is effective in children with comorbid ADHD and allergic rhinitis. We also examined the role of nerve growth factor in these comorbidities. Our randomized, double-blind, placebo-controlled, crossover study enrolled 38 children diagnosed with comorbid ADHD and allergy using cetirizine (n = 12), sustained-release methylphenidate (n = 12), or cetirizine + methylphenidate (n = 14). Endpoints compared baseline to posttreatment evaluations for allergic rhinitis and ADHD scores. Serum nerve growth factor levels were measured using ELISA. For allergy endpoints, combination therapy produced results superior to individual therapy. For ADHD, similar scores were achieved for individual therapy; however, combination therapy resulted in improved scores. Nerve growth factor levels were downregulated following this trend. We conclude that ADHD and allergic rhinitis may have common mechanism and represent a comorbid condition that links the nervous system to the immune system. Further studies are needed.

Sustained-release methylphenidate in methamphetamine dependence treatment: a double-blind and placebo-controlled trial.

BackgroundThe objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of sustained-release methylphenidate (MPH-SR) in treatment of methamphetamine dependence.MethodsFifty-six individuals who met DSM-IV-TR criteria for methamphetamine dependence participated in this 10-week trial. The participants were randomly allocated into two groups and received 18 to 54 mg/day sustained-released methylphenidate or placebo for 10 weeks. Craving was evaluated by a visual analogue craving scale every week. Urinary screening test for methamphetamine was carried out each week. The Beck Depression Inventory-II (BDI-II) was used to monitor participant depressive symptoms at baseline and bi-weekly during the treatment period.ResultsAt the end of the trial, the MPH-SR group was less methamphetamine positive compared to the placebo group and the difference was significant (p = 0.03). By the end of the study, MPH-SR group showed significantly less craving scores compared to the placebo group [MD (95% CI) = -10.28(0.88-19.18), t(54) = 2.19, p = 0.03]. There was greater improvement in the depressive symptoms scores in the intervention group compared to the placebo group [MD (95% CI) =2.03(0.31-3.75), t (54) =2.37, p = 0.02].ConclusionSustained-released methylphenidate was safe and well tolerated among active methamphetamine users and significantly reduced methamphetamine use, craving and depressive symptoms.Trial registrationIRCT201202281556N38

Sustained-release methylphenidate for the treatment of methamphetamine dependence

Sustained-release methylphenidate for the treatment of methamphetamine dependence

Sustained-release methylphenidate in a randomized trial of treatment of methamphetamine use disorder.

No effective pharmacotherapy for methamphetamine (MA) use disorder has yet been found. This study evaluated sustained-release methylphenidate (MPH-SR) compared with placebo (PLA) for treatment of MA use disorder in people also undergoing behavioral support and motivational incentives. This was a randomized, double-blind, placebo-controlled design with MPH-SR or PLA provided for 10 weeks (active phase) followed by 4 weeks of single-blind PLA. Twice-weekly clinic visits, weekly group counseling (CBT) and motivational incentives (MI) for MA-negative urine drug screens (UDS) were included. Treatment sites were in Los Angeles, California (LA) and Honolulu, Hawaii (HH), USA. A total of 110 MA-dependent (via DSM-IV) participants (LA = 90; HH = 20). The primary outcome measure is self-reported days of MA use during the last 30 days of the active phase. Included in the current analyses are drug use (UDS and self-report), retention, craving, compliance (dosing, CBT, MI), adverse events and treatment satisfaction. No difference was found between treatment groups in self-reported days of MA use during the last 30 days of the active phase (P = 0.22). In planned secondary outcomes analyses, however, the MPH group had fewer self-reported MA use days from baseline through the active phase compared with the PLA group (P = 0.05). The MPH group also had lower craving scores and fewer marijuana-positive UDS than the PLA group in the last 30 days of the active phase. The two groups had similar retention, other drug use, adverse events and treatment satisfaction. Methylphenidate may lead to a reduction in concurrent methamphetamine use when provided as treatment for patients undergoing behavioral support for moderate to severe methamphetamine use disorder, but this requires confirmation.

A Randomized, Double-blind, 2-Period, Placebo-Controlled Crossover Trial of a Sustained-Release Methylphenidate in the Treatment of Fatigue in Cancer Patients

This study assessed the efficacy of methylphenidate versus placebo for cancer-related fatigue reduction. Other objectives were to analyze cytokine levels and to determine the effects of methylphenidate on other symptoms, cognitive function, work yield, and patients' perceptions and preferences. Patients were randomly assigned (1:1) to receive methylphenidate-placebo or placebo-methylphenidate for 4 weeks. Patients crossed over after 2 weeks. Wilcoxon signed rank tests and McNemar tests were used to assess continuous and categorical variables. The primary efficacy endpoint was change in the level of worst fatigue on the Brief Fatigue Inventory (BFI) at the end of each 2-week period. The mean baseline BFI score was moderate (5.7). Methylphenidate treatment did not affect patients' worst level of fatigue or other symptoms. Results from the Wechsler Adult Intelligence Scale Digit Symbol Test and the Hopkins Verbal Learning Test with BFI interference questions and BFI activity questions showed significant improvement in the methylphenidate-treated patients' verbal learning, memory, visual perception, analysis, and scanning speed. Patients treated with methylphenidate missed significantly fewer work hours owing to health reasons and worked significantly more hours. After 4 weeks, 64% of patients reported that methylphenidate improved their cancer-related fatigue, and 58% wanted to continue treatment. Significant difference in interleukin 6R (positive), interleukin 10 (negative), and tumor necrosis factor α (positive) was noted between the methylphenidate and the placebo group. Low-dose methylphenidate did not improve cancer-related fatigue. Patients taking methylphenidate had better cognition and were able to work more hours. Patients tolerated methylphenidate well, and the majority felt better and wanted to continue treatment.

Chronic Treatment with Extended Release Methylphenidate Does Not Alter Dopamine Systems or Increase Vulnerability for Cocaine Self-Administration: A Study in Nonhuman Primates

Despite the widespread use of stimulant medications for the treatment of attention deficit hyperactivity disorder, few studies have addressed their long-term effects on the developing brain or susceptibility to drug use in adolescence. Here, we determined the effects of chronic methylphenidate (MPH) treatment on brain dopamine (DA) systems, developmental milestones, and later vulnerability to substance abuse in juvenile nonhuman primates. Male rhesus monkeys (approximately 30 months old) were treated daily with either a sustained release formulation of MPH or placebo (N=8 per group). Doses were titrated to achieve initial drug blood serum levels within the therapeutic range in children and adjusted throughout the study to maintain target levels. Growth, including measures of crown-rump length and weight, was assessed before and after 1 year of treatment and after 3-5 months washout. In addition, positron emission tomography scans were performed to quantify binding availability of D2/D3 receptors and dopamine transporters (DATs). Distribution volume ratios were calculated to quantify binding of [¹⁸F]fluoroclebopride (DA D2/D3) and [¹⁸F]-(+)-N-(4-fluorobenzyl)-2β-propanoyl-3β-(4-chlorophenyl)tropane (DAT). Chronic MPH did not differentially alter the course of weight gain or other measures of growth, nor did it influence DAT or D2/D3 receptor availability after 1 year of treatment. However, after washout, the D2/D3 receptor availability of MPH-treated animals did not continue to decline at the same rate as control animals. Acquisition of intravenous cocaine self-administration was examined by first substituting saline for food reinforcement and then cocaine doses (0.001-0.1 mg/kg per injection) in ascending order. Each dose was available for at least five consecutive sessions. The lowest dose of cocaine that maintained response rates significantly higher than saline-contingent rates was operationally defined as acquisition of cocaine reinforcement. There were no differences in rates of acquisition, overall response rates, or cocaine intake as a function of cocaine dose between groups. In an animal model that closely mimics human development; chronic treatment with therapeutic doses of sustained release MPH did not have a significant influence on the regulation of DATs or D2/D3 receptors, or on standard measures of growth. Furthermore, this treatment regimen and subsequent drug washout did not have an impact on vulnerability to cocaine abuse.

A randomized, double blind, placebo-controlled crossover trial of a sustained release methylphenidate in cancer-related fatigue.

9072 Background: Cancer-related fatigue (CRF) is common and distressing. This study assessed the efficacy of OROS methylphenidate 18 mg daily (OM) vs. placebo (P) for CRF reduction. Other objectives were to compare the effects of OM vs. P on other symptoms, cognitive function, work yield, patient (pt) perceptions and preferences, and an exploratory analysis of cytokines. Methods: Initially, pts were randomly assigned (1:1) to receive OM-P or P-OM for 4 weeks (wks). Pts were crossed to the other treatment after 2 wks. Assessments were done at baseline, 2 and 4 wks. Continuous and categorical variables were assessed using Wilcoxon signed rank tests and McNemar tests, respectively. The primary efficacy end point was the change of “fatigue worst” on the Brief Fatigue Inventory (BFI) at the end of each 2 wk period. Results: 42 female breast cancer pts were enrolled (3 ineligible, 6 unevaluable); 33 pts were studied. The mean age was 58 (range, 32-79), 30% had metastasis, 82% were receiving chemotherapy (ctx), 9% hormonal therapy (ht), and 9% both ctx and ht. 94% were ECOG <1 and 52% were employed. 45% were on pain medicines and none on antidepressants. The mean baseline BFI was 5.7 (range 4.1-8.6). Fatigue worst did not differ between OM and P (p= 0.54) or in other symptoms. There was significance in WAIS-III Digit Symbol between OM and P (p=0.01), and Hopkins Verbal Learning Test with BFI interfere and BFI active (p=0.04, p=0.03, respectively). Hours (hrs) missed due to health (p=0.03) and hrs worked (p=0.04) differed in OM vs. P. At study end, pts were asked if OM improved CRF and if they wanted to stay on OM. 64% felt improved. Of these, 58% wanted to continue. There were no serious adverse events due to OM. There were differences in serum IL6 (p=0.03), IL10 (p=0.0004), and TNFα (p=0.02) among OM and P. Conclusions: Low dose OM did not show improvement in CRF on fatigue worst of BFI. Pts taking OM had better cognition and less work absences. Pts tolerated OM well and a majority felt better and wanted to continue OM. Future studies examining higher doses or longer treatment duration with OM, pt preferences and impact on productivity are necessary. Changes in serum cytokine levels should be further explored.

High dose methylphenidate treatment in adult attention deficit hyperactivity disorder: a case report

IntroductionStimulant medication improves hyperactivity, inattention, and impulsivity in both pediatric and adult populations with Attention Deficit Hyperactivity Disorder (ADHD). However, data regarding the optimal dosage in adults is still limited.Case presentationWe report the case of a 38-year-old Caucasian patient who was diagnosed with Attention Deficit Hyperactivity Disorder when he was nine years old. He then received up to 10 mg methylphenidate (Ritalin®) and 20 mg sustained-release methylphenidate (Ritalin SR®) daily. When he was 13, his medication was changed to desipramine (Norpramin®), and both Ritalin® and Ritalin SR® were discontinued; and at age 18, when he developed obsessive-compulsive symptoms, his medication was changed to clomipramine (Anafranil®) 75 mg daily. Still suffering from inattention and hyperactivity, the patient began college when he was 19, but did not receive stimulant medication until three years later, when Ritalin® 60 mg daily was re-established. During the 14 months that followed, he began to use Ritalin® excessively, both orally and rectally, in dosages from 4800-6000 mg daily. Four years ago, he was referred to our outpatient service, where his Attention Deficit Hyperactivity Disorder was re-evaluated. At that point, the patient’s daily Ritalin® dosage was reduced to 200 mg daily orally, but he still experienced pronounced symptoms of, Attention Deficit Hyperactivity Disorder so this dosage was raised again. The patient’s plasma levels consistently remained between 60–187 nmol/l—within the recommended range—and signs of his obsessive-compulsive symptoms diminished with fluoxetine 40 mg daily. Finally, on a dosage of 378 mg extended-release methylphenidate (Concerta®), his symptoms of Attention Deficit Hyperactivity Disorder have improved dramatically and no further use of methylphenidate has been recorded during the 24 months preceding this report.ConclusionsSymptoms of Attention Deficit Hyperactivity Disorder (ADHD) in this adult patient, who also manifested a co-occurring obsessive compulsive disorder, dramatically improved only after application of a higher-than-normal dose of methylphenidate. We therefore suggest that clinicians consider these findings in relation to their adherence to current therapeutic guidelines.

Methylphenidate-induced erections in a prepubertal child

Methylphenidate is a medication used routinely in the management of attention deficit hyperactivity disorder. We report a case of a prepubertal child who developed unwanted erections after commencing a response-adjusted dosing regimen of sustained release methylphenidate. Despite priapism being a rare adverse reaction associated with methylphenidate, physicians and parents need to be aware as it can have significant long-term complications.

Differences in the In Vitro and In Vivo Pharmacokinetic Profiles of Once-Daily Modified-Release Methylphenidate Formulations in Canada: Examination of Current Bioequivalence Criteria

BackgroundCurrent Canadian bioequivalence criteria rely on rate and extent of drug exposure, that is, Cmax and AUC. In the case of complex modified-release formulations, these criteria may not address pharmacokinetic differences with potential therapeutic and tolerability implications. ObjectiveThis study was performed to characterize in vitro dissolution and in vivo pharmacokinetic profiles of three modified-release formulations of methylphenidate (MPH) marketed in Canada, two of which meet the criteria for assuming bioequivalence as defined by Health Canada: MPH extended-release (ER-C) and osmotic controlled-release oral-delivery-system (OROS-MPH). MethodsIn vitro dissolution tests were performed using 54-mg OROS-MPH, 54-mg MPH ER-C, and 20-mg MPH sustained-release (SR) tablets. In vivo pharmacokinetics of single oral doses of 54 mg OROS-MPH, 54 mg MPH ER-C, and 60 mg MPH-SR were evaluated in an open-label, randomized, crossover study in healthy subjects. Plasma samples were collected up to 24 hours after administration of the drug. ResultsIn vitro dose-corrected release profiles of MPH ER-C and MPH-SR tablets were similar (<10% difference), whereas OROS-MPH exhibited a profile distinct from that of the other formulations. Twenty-four subjects completed the pharmacokinetic study and were included in the analyses. Analysis of Cmax and AUC of MPH showed that OROS-MPH and MPH ER-C met the criteria for assumed bioequivalence according to Health Canada guidelines. However, partial AUCs exhibited significant differences between the two formulations, which were supported by ratios of MPH concentrations over time. Comparison of MPH ER-C with MPH-SR (dose corrected) also satisfied bioequivalence criteria. ConclusionsThe pharmacokinetic data suggest that in vitro and in vivo profiles of OROS-MPH and MPH ER-C are distinct. However, using traditional criteria for bioequivalence, MPH ER-C would be assumed bioequivalent to both OROS-MPH and MPH-SR. Inclusion of partial AUCs as additional criteria could aid in ensuring therapeutic equivalence. ClinicalTrials.gov identifier: NCT01118702.

Pharmacological Treatments for Cocaine Dependence: Is There Something New?

There is no specific and approved treatment, by regulatory authorities, for cocaine dependence. Therefore, developing new medications for the treatment of this disease continues to be a research priority. Recent advances in neurobiology and brain imaging studies have suggested several promising pharmacological approaches. Literature searches were conducted for the period from January 1990 to February 2011 using PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov, which are the main electronic sources of ongoing trials. Recent controlled clinical studies have highlighted some very promising medications, especially glutamatergic (N-Acetylcysteine, modafinil, topiramate) and GABAergic (vigabatrin) agents, agonist replacement therapy (sustained-release methylphenidate, d-amphetamine) and dopamine agents (disulfiram). Additionally, immunotherapy is a new and promising pharmacological approach. Promising pharmacological approaches have emerged for the treatment of cocaine dependence, but larger, randomized, placebo-controlled studies are needed for some medications. Preclinical studies suggest new targets of interest in cocaine dependence. The optimal therapeutic platform is the combination of pharmacotherapies with behavioral therapies.

Methylphenidate enhances prepulse inhibition during processing of task-relevant stimuli in attention-deficit/hyperactivity disorder

ADHD is characterized by inattention, hyperactivity, and disinhibition, including the inability to screen out distracting stimuli. Prepulse inhibition (PPI) of startle indexes a related gating process and is enhanced during attended compared to ignored stimuli. We predicted that PPI during attended stimuli would be enhanced by the stimulant methylphenidate (MPH) and that this effect would be moderated by baseline PPI. Children with ADHD (n=36) completed a baseline day and a randomized, double-blind medication trial (placebo vs. sustained release MPH). Bilateral startle eyeblink EMG was measured during a tone discrimination task. MPH enhanced PPI during attended, but not during ignored stimuli. Extending findings that pretreatment functioning moderates stimulant effects on PPI, this effect tended to be inversely related to baseline PPI. These data fit with the clinical literature on ADHD and the hypothesis that MPH enhances interference control for important environmental stimuli.

Sustained release methylphenidate for the treatment of ADHD in amphetamine abusers: A pilot study

The efficacy of stimulant treatment in patients with substance use disorders and comorbid attention deficit hyperactivity disorder (ADHD) has been tested for cocaine and alcohol dependence but so far no studies have been conducted in amphetamine dependent individuals. The present trial was a pilot study aiming to test the feasibility of treating amphetamine dependent patients with comorbid ADHD with central stimulant medication. The study was a double-blind, placebo controlled trial with parallel groups design comparing the efficacy of a fixed dose (72 mg) of OROS methylphenidate (MPH) with placebo (PL) in reducing ADHD symptoms in currently abstinent adults with amphetamine dependence and ADHD. Twenty-four treatment seeking patients who met the DSM IV criteria for amphetamine dependence and ADHD were randomized to MPH/PL. The trial was conducted at an outpatient facility with twice weekly visits, measuring ADHD symptoms and drug use. Patients rated their ADHD symptoms on a weekly basis and provided supervised urine specimens for drug toxicology twice weekly. All patients participated in weekly sessions of a skills training programme. Both the groups significantly reduced their self-rated ADHD symptoms during the 12-week treatment but there was no difference between the two treatment arms. Drug use, both measured by urine toxicology and self-report did not differ between the groups. No difference was found between the two groups with regards to craving for amphetamine or in retention in treatment. Larger studies with higher doses combined with individual dosage and longer follow-up periods are warranted.

ADHD, psychostimulants, and sleep disorders: Is there a link?

Sleep difficulties occur in a high percentage of children and adults with attention-deficit/hyperactivity disorder (ADHD). Poor sleep worsens cognitive difficulties; ADHD children who sleep poorly have increased school absenteeism, and their caregivers are more often late for work. This article will review new findings in ADHD sleep disorder studies and the impact of psychostimulant treatment on sleep-related problems. Insomnia is frequently reported as a side effect when stimulants are initiated but is usually mild to moderate in severity and improves during the first week of treatment. Polysomnography shows improvement in sleep latency and overall sleep efficiency when ADHD adults are treated with methylphenidate twice a day. A large clinical trial in ADHD children found no difference in overall sleep parameters between placebo and sustained-release methylphenidate. Similarly, an adult lisdexamfetamine trial found no change in overall sleep efficiency with significant improvement in daytime function.

Stimulant-induced changes in smoking and caloric intake: Influence of rate of onset

Rate-of-onset modulates the subject-rated effects of stimulants. Results of two studies from our laboratory demonstrate that immediate-release methylphenidate increases smoking and decreases caloric intake. Whether rate-of-onset influences the effects of methylphenidate on smoking and eating is unknown. The present experiment examined the influence of a range of doses of immediate- (7.5–30 mg) and sustained-release (18–72 mg) methylphenidate as well as placebo on smoking and eating. Eight cigarette smokers participated. A double-dummy drug administration procedure was used to maintain the double blind because immediate-release methylphenidate produces peak plasma concentrations 1.5–2 h and the sustained-release formulation produces peak plasma concentrations 6–8 h after oral administration. Smoking and eating were assessed for 4 h across the predicted peak effects of both methylphenidate formulations. Measures of smoking included total cigarettes, puffs, and carbon monoxide levels. Snacks and decaffeinated beverages were available ad libitum and caloric intake was monitored during the four-hour smoking session. Immediate- and sustained-release methylphenidate increased smoking and decreased caloric intake. The effects of methylphenidate generally did not vary as a function of formulation. The results of this study may have important implications for the treatment of disorders that require stimulant medications. Smoking should be monitored in patients that are prescribed stimulant medications, regardless of the formulation type.

Prescribe sustained-release phenylphenidate by brand

My colleagues and I are responsible for treating more than 1,500 patients with attention-deficit hyperactivity disorder (ADHD), many of whom are receiving drug therapy. The predominant treatment is methylphenidate in immediate-release and sustained-release forms. When prescribing sustained-release methylphenidate, I have always prescribed by brand, notably Concerta XL, Equasym XL and Medikinet XL. Because of their differing release profiles, these products have different clinical effects.

Treatment of cocaine dependent treatment seekers with adult ADHD: Double-blind comparison of methylphenidate and placebo

The purpose of this double-blind 14-week trial was to compare the efficacy of sustained-release methylphenidate (MPH) to placebo (PBO) in treating adult attention deficit hyperactivity disorder (ADHD) symptoms in current cocaine dependent (CD) treatment seekers. The randomized sample consisted of 106 participants who were predominately male (83%) and 60% Caucasian, 14% Hispanic, 20% African-American and 6% other. All participants met DSM-IV criteria for ADHD and CD. There were no significant demographic differences between the two treatment groups. All participants received weekly individual cognitive behavioral therapy. There was no difference in retention rate based on treatment group ( p = .91). The majority of the PBO group and the MPH group reported >30% improvement in their ADHD symptoms (55% versus 47%), with no significant difference between the two groups ( p = .44). Using a combined outcome measure (>30% reduction in ADHD symptoms and CGI <3), the response rates were similar for both groups (28% PBO versus 30% MPH; p = .83). Longitudinal analyses of the urine toxicology data using generalized estimating equations, revealed a decrease in the probability of cocaine positive urine samples during the trial for the MPH group compared to the PBO group ( p = .001). Further analysis suggested that for the MPH group, ADHD treatment responders, based on a semi structured clinical interview, were more likely to have a reduction in cocaine use compared to the non-ADHD responders. Although sustained-release MPH did not show superiority over PBO in treating ADHD symptoms, this trial provides some evidence that improvement in ADHD symptoms (clinician rated) among those patients receiving MPH, but not placebo, was associated with a reduction in cocaine use.