The Effects of Methylphenidate on Energy Intake and Energy Expenditure
The Effects of Methylphenidate on Energy Intake and Energy Expenditure
The Problem: Obesity is one of the leading causes of chronic disease and death. The efficacy
 of diet and exercise to sustain weight loss over the long term is weak. While pharmacotherapy
 is more effective than behavior intervention in maintaining weight loss the effects are often
 not sufficient to achieve optimal health benefits. Current drug treatments may be sub-optimal
 because they do not directly target the rewarding value of food, drive to eat, food liking,
 and impulsivity for eating energy dense snack foods, all of which influences both quantity
 and quality of food intake and impacts adherence needed to maintain weight loss.

 The Solution: The limitations in current anti-obesity agents are potentially addressed by
 Methylphenidate (MPH). We showed that MPH reduces food intake, dietary fat intake, hunger and
 food reward, as increase resting energy expenditure in obese and non-obese adults;however, no
 controlled field trials have been conducted in obese individuals without ADHD.

 Objectives/Hypotheses: Primary: To test the effects of MPH on energy intake in obese men and
 women. Secondary: to examine the effects of MPH on energy expenditure, body weight,
 impulsivity, food reward, and olfaction. The investigators predict that compared to placebo,
 MPH will show reduced appetite, along with reduced impulsivity, food reward, and smell
 function.

 Deliverable: This study may be the first to establish the short-term efficacy and safety of
 using MPH for weight loss, and if successful, data will inform a larger trial that can
 potentially identify MPH as a novel therapeutic agent for treating obesity and related
 chronic diseases in a predisposed population.
Research Objectives and Hypotheses

 Primary: The primary objective of this study is to examine whether Methylphenidate (MPH) at
 dose of 0.50 mg/kg (not exceeding 100 mg/day) can lead to a sustained reduction in energy
 intake in obese adolescents and adults. Based on the investigators' pilot data in adults, it
 is predicted that daily administration of MPH for 60 consecutive days will produce reductions
 in food intake (both in lab and free-living) compared to placebo, extending our previous
 findings to a longer period of time and to obese adolescents. Prior to beginning the
 intervention, both MPH and placebo treatment groups will receive lifestyle advice (eating and
 exercise guidelines for healthy living). The primary outcome measures will rely on the
 validated measurements of energy intake (in lab lunch buffet and out of lab 3 day food menu).

 Secondary objectives/hypotheses: The effects of MPH on all components of energy expenditure
 will be investigated. Based on the investigators' pilot data, it is predicted that from
 Baseline to 60 days, MPH will increase total energy expenditure (TEE) when compared with
 placebo, mostly through greater resting energy expenditure (REE) and thermic effects of food
 (TEF). It is hypothesized that after the 60-day intervention the MPH group will experience a
 significantly attenuated reduction in REE compared to placebo. We predict that the MPH group
 will lose body weight at 2 months, whereas, it is predicted that there will be no change in
 body weight for the placebo. The investigators will also explore the effects of MPH on
 macronutrient preference and consumption, and on the rewarding value of energy dense snack
 foods. Based on previous findings, the investigators predict that MPH will reduce consumption
 of energy dense, high fat/sugar foods but have little effect on consumption of foods low in
 calories, fats or sugars. In addition, it is predicted that the reduction in intake of energy
 dense, high fat/sugar foods will be mediated by reductions in the rewarding value of food and
 impulsivity as measured by well validated computerized simulations. Also explored will be the
 effects of MPH on olfaction and it is predicted that compared to placebo, individuals taking
 MPH will have reduced smell function. It is also predicted the MPH group will show reduced
 appetite sensations, reduced rewarding value of food, reduced impulsivity for snack food, and
 reduced palatability ratings of food compared to placebo at 2 months.

 Trial Design

 The trial design will consist of a randomized, double blind, placebo-controlled 2 parallel
 arm study. The two randomly assigned treatment groups will consist of administrating a
 placebo or short-acting MPH two-times daily 1 hour before meals for a period of 2 months (60
 consecutive days). Prior to being randomized into either the placebo group or the
 experimental (MPH) group, subjects will first have had to respond to a recruitment poster,
 newspaper advertisement. Once it is determined with that initial screening that the
 participant still meets inclusion criteria, they will be invited to come to the laboratory
 for a screening visit to determine whether they meet eligibility criteria, to sign informed
 consent, and to take a test dose of MPH in order for a nurse to closely monitor any potential
 side-effects prior to starting the 2-times daily dosing of MPH or placebo.

 Trial Procedures

 The proposed study will consist of six visits to the laboratory for a total of twenty-four
 hours, as follows: there will be an initial clinical screening visit (4 hrs), three repeated
 measures test days (6hrs each; two at baseline and one at 60 days), a mid-point visit (1hr),
 and a Lunch Box visit (10 minutes to obtain out of laboratory food). School-aged participants
 will not have to miss school to participate; if necessary, testing will be able to be
 performed over the course of the weekend. After the initial laboratory visit and informed
 consent (i.e. clinical screening visit), participants will be randomized at the Baseline 1
 visit to one of two treatment groups to either receive placebo or MPH two times daily for a 2
 month intervention period that starts at the Baseline 2 visit. In order to track physical
 activity energy expenditure, participants will be instructed to wear accelerometers for 1
 week between the in lab screening visit and the Baseline 1 visit, and then again while under
 MPH or placebo for 1 week between the mid-point visit and the Final repeated measures test
 day. Upon leaving the Baseline 1 test day (i.e. no drug or placebo) participants will receive
 a 3 day supply of food from which they will exclusively eat from until they return to the lab
 4 days later for the Baseline 2 repeated measures test day (i.e. under drug or placebo).
 Similarly, 4 days prior to the Final repeated measures test day, participants will again have
 to visit the laboratory for their "Lunch Box" visit to obtain their three days' supply of
 food from which they will eat exclusively from. Participants will return to the laboratory to
 complete the study at the Final (day 60) repeated measures test day after 3 days of eating
 from the "Lunch Boxes". For the 1 hour mid-point visit (at day 30) participants will be
 weighed and will report any perceived side-effects from the MPH or placebo. At this mid-point
 visit participants will bring in their pill container to verify compliance and to receive
 final 30 day supply of drug or placebo. At this time participants will be asked if they have
 begun any new medication or have started any over-the-counter medication as part of the
 study's safety monitoring protocol. A side-effects check list will also be provided to the
 participants upon leaving the Baseline 2 testing session; participants will be informed to
 note any perceived side-effects nightly for the first 14 days being on the study medication
 and will be instructed to notify the study coordinator as soon as specific side-effects are
 noted as being Major.

 Consent and Clinical Screening

 Initial Screening Visit (4 hours)

 Before beginning the study, a meeting between the study coordinator and the participant will
 occur in order to get consent and in order for the participant to ingest a test dose of MPH
 under the supervision of a nurse. The study coordinator will contact the participant in order
 to arrange a time for the approximately 4 hour meeting. The weight and height (thus BMI) will
 be measured upon arrival. The participant will then have to respond to questionnaires, e.g.
 the Wender-Utah Rating Scale (to assess traits compatible with ADHD), the Beck Depression
 Inventory (to assess depressive symptoms), the "Three-Factor Eating Questionnaire" (to assess
 eating style) and the Drug Abuse Screening Test (to ensure no underlying drug problem). If
 the participant is a female they cannot be pregnant to be included in the study; thus a
 pregnancy test will be administered and if it is determined that they are pregnant they will
 be referred to visit their family physician and excluded from the study. If eligible, the
 participant will be asked to read and sign the consent form. Eligible participants will then
 see a nurse who will administer the all of the measures outlined in the Case Report Form,
 e.g., a physical exam, medical history assessment, baseline vital signs, electrocardiogram
 (ECG), etc. The nurse will then administer a test dose of 0.5mg/kg of MPH and for a period of
 three hours after the ingestion of MPH the nurse will closely monitor any potential
 side-effects of the drug by measuring heart rate, blood pressure, and by following a detailed
 side-effects check-list. If at any point the participant rates and of the side effects as
 "Prohibitive", then he/she will be excluded from the study. The participant will also be
 excluded from entering the study if they demonstrate an abnormal ECG systolic or if blood
 pressure exceeds the baseline reading by 20mmHg or if diastolic blood pressure exceeds the
 baseline reading by 10mmHg, BP > 160/100, or resting pulse increased by 20 beats/minute from
 the baseline. As part of the comprehensive safety assessment to determine eligibility, the
 ECG data file that is collected will be stored via a USB external hard drive and then sent to
 CHEO cardiology to be read by a cardiologist. Once it is determined by the cardiologist that
 the ECG rhythm is normal, both the cardiologist and the QI will sign off on the Case Report
 form, indicating that the participant is eligible for enrollment. If it is determined by the
 ECG reading that the participant is not eligible, they will be called up by the study
 coordinator and told of the incidental findings and subsequently informed to visit their
 family physician to follow-up. The participant may bring the consent form home to further
 study its content before signing it. Prior to leaving the initial screening visit
 participants will be instructed on how to strap on an omni-directional accelerometer and
 instructed on how to fill out the log sheet which gathers information on when the monitors
 are worn and when they are taken off, which is needed to evaluate wear time for a seven day
 period. Participants will be instructed to return the accelerometers at their next visit,
 Baseline 1.

 Free and informed Consent

 During the initial screening visit, if a candidate meets the inclusion criteria, the
 coordinator will explain the research protocol to the subject. This will be done in order to
 explain in detail the requirements of the protocol and to answer all the questions from
 potential participants. If potential participants are still interested to participate in the
 study, the coordinator will then distribute, explain and answer questions regarding the
 consent form to the participant. The participant will then be asked to sign the informed
 consent letter.

 Active Investigational Product Description

 pms-METHYLPHENIDATE (methylphenidate hydrochloride) is a racemate consisting of a 1:1 mixture
 of d-methylphenidate (d-MPH) and l-methylphenidate (l-MPH). pms-METHYLPHENIDATE is a mild
 central nervous system stimulant with more prominent effects on mental than motor activities.
 The mode of action in man is not completely understood, but its stimulant effects are thought
 to be due to cortical stimulation and possibly to stimulation of the reticular activating
 system. There is neither specific evidence which clearly establishes the mechanism whereby
 methylphenidate produces its mental and behavioural effects in children, nor conclusive
 evidence regarding how these effects relate to the condition of the central nervous system
 (CNS). Methylphenidate hydrochloride is rapidly and extensively absorbed from the tablets
 following oral administration; however, owing to extensive first-pass metabolism,
 bioavailability is low (approx. 30%) and large individual differences exist (11-52%). Peak
 plasma concentrations of 10.8 and 7.8 ng/mL were observed, on average, 2 hours after
 administration of 0.30 mg/kg in children and adults, respectively. Methylphenidate is
 eliminated from the plasma with a mean half-life of 2.4 hours in children and 2.1 hours in
 adults. The apparent mean systemic clearance after an oral dose is 10.2 and 10.5 L/h/kg in
 children and adults, respectively for a 0.3 mg/kg dose, and 0.565 L/h/kg after an intravenous
 dose of the racemate in healthy adult volunteers. These data indicate that the
 pharmacokinetics of methylphenidate in hyperactive children is similar to that in healthy
 adult volunteers. The apparent distribution volume of methylphenidate in children was
 approximately 20 L/kg, with substantial variability (11-33 L/kg). The volume of distribution
 after an intravenous dose (Vss) is 2.23 L/kg for the racemate in healthy adult volunteers.

 Following oral administration of methylphenidate, 78-97% of the dose is excreted in the urine
 and 1-3% in the feces in the form of metabolites within 48-96 hours. The main urinary
 metabolite is ritalinic acid (a-phenyl-2-piperidine acetic acid, PPAA); unchanged
 methylphenidate is excreted in the urine in small quantities (<1%). Peak PPAA plasma
 concentrations occurred at approximately the same time as peak methylphenidate
 concentrations, however, levels were several-fold greater than those of the unchanged drug.
 The half-life of PPAA was approximately twice that of methylphenidate.

 Role of CHEO Pharmacy

 Section C.05.010 of the Division 5 Regulations pertains to the sponsor's (i.e. Children's
 Hospital of Eastern Ontario) obligations in regards to Good Clinical Practice. The CHEO
 pharmacy will have the following obligations-compliant with said Regulations-with respect to
 the drug/placebo management: drug acquisition and dispensing, maintenance of inventory and
 accountability and reconciliation of records, labelling of study medication, storage of
 inventory, and general records such as patient information forms and creating patient
 binders. Note that in Division 5, Health Canada mandates that records must be maintained for
 a period of 25 years, and the CHEO pharmacy will ensure the maintenance of such record
 keeping.

 Safety Assessments and Trial Monitoring

 Clinical Safety Assessments

 The following assessments will be performed to determine the safety of MPH Hydrochloride:
 vital signs (blood pressure and pulse); monitoring effects/symptoms (side effects checklist).
 Those who report or show heightened blood pressure or heart rate side effects from the test
 doss of MPH at the clinical screening visit, e.g., systolic blood pressure exceeding baseline
 reading by 20mmHg, diastolic blood pressure exceeding the baseline reading by 10mmHg, BP >
 160/100, or resting pulse increased by 20 beats/minute from the baseline reading will be
 excluded from the study. Subjective side effects will be measured for 21 potential side
 effects (e.g., headache, nausea, nervousness, etc.) by having subjects rate the intensity of
 their symptoms using the following scale : 1 = none, 2 = mild, 3 = moderate, 4 = severe. A
 qualified registered nurse is present throughout the entire session. Furthermore, thorough
 emergency plans have been implemented in conjunction with the Children's Hospital of Eastern
 Ontario (e.g. code blue) and the University of Ottawa should a crisis arise. In addition, the
 research unit has been equipped with a complete first aid unit cart along with an automated
 external defibrillator in which all the employees have been trained to operate. All employees
 are also required to maintain a valid CPR-C.

 Each participant will be supplied with a "study enrollment card" that will have the study
 title, along with the emergency contact information for the CHEO pharmacy technician (in
 control of study blinding) and for the Qualified Investigator (Principal Investigator-PI ).
 This card will act as a safeguard if the participant seeks emergency medical help where it is
 required to know whether they have been taking drug or placebo, thereby acting as an aid in
 the clinical judgment to stop the treatment. The enrollment card will also act to tract
 if/when a participant needs to be unblinded to the treatment.

 Trial Management and Monitoring

 Management

 The Children's Hospital of Eastern Ontario Clinical Research Unit (CHEO-CRU) will be the
 coordinating center for this study and the University of Ottawa will the other testing site.
 The Principal Investigator and the study coordinator, along with CHEO pharmacy, will be
 responsible for the day-to-day operations of the trial. CHEO-CRU will provide the CHEO
 pharmacy with the randomization table and will resultantly be the only persons who are
 unblinded. The randomization will take place once the Initial Screening Visit is completed
 and it is determined that the participant is eligible to participate. Therefore, each
 participant will have an equal chance of being randomized to drug or placebo using a computer
 generated random number program by a member of the CRU before entering into the Baseline 1
 test day.

 Treatment discontinuation

 In the event that the subject is withdrawn from the study due to an AE, the AE will be
 recorded and reported, and the subject will be followed and treated until the abnormal
 parameter or symptom has resolved or stabilized. It is up to the clinician and the Data &
 Safety Monitoring Board to determine that the AE is either resolved or that it has reached a
 stable state, after which no further follow-up is necessary. Support for this determination
 will be documented. The reason for withdrawal from the study will be recorded on the
 appropriate case report form (CRF). If a subject is removed from the study, we will continue
 the scheduled follow-up with the subject's permission. There will be no changes to the
 follow-up schedule, except no study treatment/intervention will be administered. If at any
 point a subject no longer wishes to participate in follow-up, or after the three month
 follow-up telephone call, participation in the study will be complete. If new evidence
 emerges in the literature to indicate that our study dosage is unsafe, the study will be
 discontinued and all further qualifying patients will be offered the more effective/safer
 treatment.

 Data Safety and Monitoring Board

 The Data and Safety Monitoring Board (DSMB) is an independent group of experts who will
 function independently and at arm's length from the Study Investigators and the Steering
 Committee of the Study. The primary responsibilities of the DSMB are as follows:

 1. Review and evaluate the accumulated study data for participant safety

 2. Make recommendations to the Steering Committee based on these reviews regarding the
 continuation, modification or termination of the trial

 3. DSMB members must maintain strict confidentiality concerning all privileged trial
 results, and during all phases of DSMB review and deliberations.

 4. No member of the DSMB should have a direct involvement with the conduct of the study. No
 member should have financial, proprietary, professional or other interests that may
 affect impartial, independent decision-making by the DSMB.

 The DSMB will be notified of all serious unexpected adverse drug reactions and all
 deaths within 5 working days of knowledge of the SAE. It is the Qualified Investigator's
 responsibility to ensure that the DSMB is apprised of all new safety information
 relevant to the study.

 The DSMB will be scheduled on a regular basis and as often as necessary. Regular reviews
 will be conducted yearly and focused primarily on safety issues. A designated third
 party analysis (prepared by a study statistician) will be delivered to the DSMB two
 weeks prior to any scheduled review. Prior to study initiation, DSMB members will review
 study protocols, informed consents, Data and Safety Monitoring Plans and other relevant
 documents as needed (case report forms, manual of procedures, etc.). During the study,
 DSMB members will review all study protocol amendments.

 Adverse Events (AE's) and Serious Adverse Events (SAE's)

 Adverse Events

 Adverse events (AEs) are defined as any symptom, sign, illness or experience that occurs
 while participating in the study, including both during admission and as an outpatient.
 Abnormal clinical results will be considered to be adverse events if the abnormality:

 -  results in study withdrawal

 -  is associated with clinical signs or symptoms

 -  leads to additional treatment or to further diagnostic tests

 -  is considered by the investigator or Data & Safety Monitoring Board to be of
 clinical significance.

 Serious Adverse Event (SAE)

 A SAE is any adverse event that at any dose:

 -  results in death

 -  is life-threatening

 -  requires inpatient hospitalization or prolongation of existing hospitalization

 -  results in persistent or significant disability or incapacity

 -  results in a congenital anomaly/birth defect

 -  other serious (important event)

 -  prolonged hospitalization, significantly beyond the expected length of stay

 -  important medical events

 Serious Unexpected Adverse drug Reactions are SAEs that are likely to be related to the
 study drug.

 Medical and scientific judgment should be exercised in deciding whether expedited
 reporting is appropriate in other situations such as important medical events that may
 not be immediately life-threatening or result in death or hospitalization but may
 jeopardize the patient or may require intervention to prevent one of the events listed
 above.

 Serious Adverse Event Reporting

 What to Report

 -  Any SAE that meets the definition of a Reportable Serious Adverse Event

 -  All life-threatening or fatal adverse events with an attribution of possible,
 probable, or definite

 The Sponsor Investigator will notify Health Canada (Office of Clinical Trials) for those
 events which meet regulatory requirements for expedited reporting, (i.e. events which
 are BOTH serious AND unexpected), AND which are thought to be related to protocol
 treatment (or for which a causal relationship with protocol treatment cannot be ruled
 out).

 Adverse Drug Reaction (ADR) report must be filed in the cases:

 -  where the ADR is neither fatal nor life-threatening, within 15 days after becoming
 aware of the information

 -  where it is fatal or life-threatening, immediately where possible and, in any
 event, within 7 days after becoming aware of the information

 -  within 8 days after having informed Health Canada of the ADR, submit as complete as
 possible, a report which an assessment of the importance and implication of any
 findings

 This includes all serious events that are unexpected and related (i.e. possibly,
 probably, or definitely) to protocol therapy. Investigators must notify their Research
 Ethics Boards (REBs) and documents related to submission must be retained in the study
 binder on site.

 The submission of these events to the local ethics board should be done as soon as
 possible (within 30 days) or per local REB requirements. REB submissions greater than 90
 days from the date of notification will be regarded as delinquent and a major deficiency
 will be assigned.

 Important medical events are those that may not be immediately life threatening, but are
 clearly of major clinical significance. They may jeopardize the subject, and may require
 intervention to prevent one of the other serious outcomes noted above.

 Monitoring of AE's/SAE's:

 Any AE that occurs between the time a study participant/parent signs the informed
 consent form and the time he/she completes the telephone follow-up (or at the time of
 early discontinuation of the subject from the study for any reason) will be captured and
 recorded. At each contact with the subject, the investigator (or designate) will seek
 information on adverse events by specific questioning and, as appropriate, by
 examination.

 The intensity of an AE is assessed as mild (usually transient in nature and generally
 not interfering with normal activities), moderate (sufficiently discomforting to
 interfere with normal activities), and severe (prevents normal activities).

 The maximum clinical intensity of all adverse events will be classified as:

 -  Mild: Signs and symptoms that can easily be tolerated or ignored.

 -  Moderate: Symptoms that cause discomfort but are tolerable; they cannot be ignored
 and affect concentration.

 -  Severe: Symptoms that affect usual daily activity.

 The attribution of all adverse events will be classified as:

 -  Unrelated to investigational agent/intervention

 -  Not related The AE is clearly not related to the intervention

 -  Doubtful The AE is not likely to be related to the intervention

 -  Related to investigational agent/intervention

 -  Possible The AE may be related to the intervention

 -  Probable The AE is likely related to the intervention

 -  Definite The AE is clearly related to the intervention

 An adverse drug reaction (ADR) is any untoward medical occurrence that the PI determines
 is likely related to the study drug (attribution of possible, probably, or definite).

 Feasibility

 There are no field studies looking at the effects of MPH on food intake (neither as a
 main outcome nor secondary outcome). Therefore, our only way of estimating effects sizes
 is extrapolating from our previous laboratory studies. In a laboratory study by the
 investigators, an effect size of .93 was attained in 9 obese adult males for the primary
 outcome of food intake with mean energy intake in kilocalories for MPH (0.5 mg/kg) and
 placebo of 843.5 + 393.4 and 1095.9 + 271.1, respectively. In a second study in 14
 normal weight adult males and females, an effect size of .69 was attained, favouring MPH
 (0.5 mg/kg) for food intake in an ad libitum buffet meal with mean difference in kcals
 of -133 (1099 for MPH minus 1232 for placebo), with a standard deviation of 192.0 kcals
 for the paired differences based on t-tests. Based on the more conservative effect size
 of .69, it would be possible to detect a significant difference in kcals consumed over a
 60-day period between MPH and placebo using a paired t-test with an alpha of 0.05, power
 of 0.80, with 18 participants per group. Thus, the plan to include 40 participants per
 group should enable the investigators to look at trends on other energy balance
 (secondary outcome) variables, accounting for an expected drop-out of 5-10%. The plan is
 to run 3 new participants/month, thus the experimental part of the study should last
 approximately 14 months.

 Role of Investigators/Staff

 Philippe Robaey, as Principal Investigator, is a physician and child Psychiatrist and
 Director of the ADHD clinic at CHEO. He has many years of clinical and research
 experience with MPH. Dr. Robaey will be responsible for the medical aspects of the study
 such as prescribing the study medication under double blind conditions, as well as
 overseeing the evaluation of vital sign and side effects of MPH. Dr. Eric Doucet, as
 Co-Principal Investigator (C0-PI) is a Full Professor of Human Kinetics at University of
 Ottawa, Faculty of Health Sciences. Dr. Doucet is an expert in the measurement of energy
 balance measures using the proposed methods. The study of the adult population will be
 conducted in Dr. Doucet's Behavioural Metabolic Research Unit, where our previous MPH
 cross-over trial was done, and he will oversee the coordination and supervision of the
 experimental testing procedures. Dr. Gary Goldfield, as Co-Principal Investigator
 (CO-PI), is a clinical psychologist and Investigator with the Healthy Active Living and
 Obesity Research Group at the CHEO Research Institute. He will oversee the assessment of
 psychiatric inclusion criteria evaluated by questionnaire and structured clinical
 interview, as well as the measurement of the reinforcing (rewarding) value of food. Dr.
 Jameason Cameron, as co-Principal investigator, is a postdoc and a research coordinator
 at CHEO. He has extensive experience with feeding studies and weight loss trials, and
 measures of food reward and smell function. Dr. Cameron will be responsible for the
 day-to-day testing and to supervise the PhD student who will be co-coordinating the
 study.

 Statistical Analysis

 Differences between groups (MPH vs. placebo) in energy intake and energy expenditure
 variables, as well as body weight, impulsivity, olfaction, hunger, satiety, and the
 reinforcing value of food will be evaluated by paired t-tests and repeated measures
 analyses of variance (ANOVA). Hypotheses of mechanisms linking MPH and reduced food
 intake and weight loss via reduced food reward will be explored using multiple
 regression mediational analyses as described by Baron and Kenny.

 Data Management

 All "source document" data collected from the study visits, except data that would
 indicate randomization assignment, will be maintained in a secure location within the
 Children's Hospital of Eastern Ontario. The investigator will verify that all data
 entries in the CRF are accurate and correct. Data collection is the responsibility of
 the research staff at the site under the supervision of the Principal Investigator.
 During the study the investigator will maintain complete and accurate documentation for
 the study and keep all original source documents. All adverse events will be graded,
 assessed by severity and causality and reviewed by the site investigator. Original
 subject records (source documents) will be reviewed during the course of the monitoring
 to verify the accuracy of the CRF's. This review will be conducted according to the peer
 monitoring plan. The Investigator(s) institutions(s) will permit trial-related
 monitoring, audits, REB(s) review and regulatory inspections(s) by providing direct
 access to source data and documentation. The medical (hospital/practice) records for
 each patient should contain information to provide a means by which study data can be
 verified. Patient information collected electronically will be available for review when
 the study site is monitored or audited. Entry of these data in SPSS will be performed
 primarily by the PhD student, but partly by the co-Principal investigators. Subjects
 will be assigned a code number to maintain blinding to data management staff, with the
 corresponding list of names associated with subject codes kept by the pharmacist in a
 secure filing cabinet. Databases will be stored on a secure server, with nightly backup.

 Publication Plan

 By the end of the second year of the study the investigators plan on publishing 2
 peer-review articles, one at the international journal Physiology and Behavior
 highlighting the secondary metabolic outcomes, and the other at the American Journal of
 Clinical Nutrition, highlighting the main outcome of the influence of MPH on appetite.

 Ethical Considerations

 This study will be conducted according to Canadian and international standards of Good
 Clinical Practice and the Health Canada, Food and Drug Act, Part C, Division 5, Drugs
 for clinical Trials Involving Human Subjects, and in full conformance with principles of
 the "Declaration of Helsinki". The CHEO research institute policies and standard
 operating procedures will also be followed. This protocol and any amendments will be
 submitted to the CHEO REB for formal approval to conduct the study. The decision of the
 REB concerning the conduct of the study will be made in writing to the investigator. All
 participants for this study will be provided a consent form and assent form if
 applicable, describing this study and providing sufficient information for participants
 to make an informed decision about their participation in this study. The consent form
 will be submitted with the protocol for review and approval by the REB. The formal
 consent of a participant, using the REB-approved consent form, will be obtained before
 that participant is submitted to any study procedure. The consent form must be signed by
 the participant or legally acceptable surrogate, and the investigator-designated
 research professional obtaining the consent.
Inclusion Criteria:

 -  males and females 16 to 40 years old

 -  BMI in the obese category (above 29.9kg/m2)

 -  willing to comply with procedures, and sign informed consent forms

 -  able to swallow a placebo pill that will be used in the study (same size as study
 drug)

 Exclusion Criteria:

 -  smoker (the main outcome is energy intake and smoking is known to impact appetite)

 -  known serious food allergies, including lactose

 -  history of previous MPH use or allergy to MPH

 -  history of ADHD or current diagnosis of an axis 1 psychiatric disorder (e.g.,
 depression, panic disorder, schizophrenia) as measured by self-report, the Wender-Utah
 Rating Scale52-54 and the Beck Depression Inventory

 -  current use of antidepressants, thyroid medication, or any medication that could
 affect appetite

 -  high blood pressure

 -  pre-existing cardiovascular disorders including uncontrolled hypertension, angina
 pectoris, arterial occlusive disease, heart failure, cardiomypathies, myocardial
 infarction, and cardiac arrhythmia

 -  diabetes

 -  excessive use of alcohol or alcoholism, or current addictions to opiates, cocaine or
 stimulants as measured by the Drug Abuse Screening Test;

 -  not a restrained eater based on cut-score (11 or higher) on Three Factor Eating
 Questionnaire56

 -  glaucoma

 -  personal or family history of seizure disorders

 -  currently taking MAO inhibitors, pressor agents, coumarin, anticonvulsants,
 phenylbutazone, or tricyclic antidepressants

 -  history of thyroid disease

 -  personal or family history of motor tics or Tourettes's Syndrome

 -  not pregnant, as determined by commercially available pregnancy test taken by female
 participants prior to test dose of MPH.

 -  after the test dose of MPH, systolic blood pressure exceeding baseline reading by
 20mmHg, diastolic blood pressure exceeding the baseline reading by 10mmHg, BP >
 160/100, or resting pulse increased by 20 beats/minute from the baseline.