Disclosure: The authors report no conflict of interest
Author Contributions: TQ designed the study and closely supervised the conduct of the study. ND carried out experiments and data collection. LC managed subject recruitment and data collection. ND, LDM, and TQ analyzed and interpreted data. All authors were involved in writing of the manuscript and had final approval of the submitted and published versions.
Dopamine is a neurotransmitter that mediates the reward value of food. Methylphenidate (MPH) selectively binds and inhibits the dopamine transporter, thus increasing brain dopamine levels shortly after oral administration. This investigation studied whether a single dose of MPH decreases energy intake (EI) in obese teenagers compared to placebo (P).
This study used a single-blind, placebo-controlled, within subject design. Teenagers with body mass index (BMI) ≥95th percentile underwent two identical meal tests (P or MPH) after a 10 h fast in random order. Food was weighed before and after the meals, and EI was calculated as energy content/gram of consumed foods. Total and macronutrient EI (mean ± SD) were analyzed by Mann–Whitney U and Wilcoxon tests.
Twenty-two subjects (15 females, 7 males) completed the study. Participants were 13.4 ± 2.2 years old and had BMI 34.9 ± 10.7 kg/m². EI from fat (167 vs. 203 kcal, P = 0.03) and carbohydrates (311 vs. 389 kcal, P = 0.04) was decreased for MPH compared to P meals, with a trend in decreased total EI (545 vs. 663 kcal, P = 0.06).
A single dose of MPH decreases EI from fat and carbohydrates in obese adolescents. This effect underscores the importance of central dopamine signaling on eating behavior.
Obesity is one of the most important health issues that our society is facing today. Inappropriately high energy intake (EI) plays often a key role. Although substantial strides have been made in our understanding of the mechanisms controlling appetite, effective behavioral and medical therapies are very limited. The hypothalamus integrates hormonal and neuronal signals modulating appetite, thereby serving a key role in the regulation of body weight . Homeostatic feeding is determined by energy demand, while non-homeostatic feeding is driven by pleasure or palatability associated with food preference . Behaviors associated with non-homeostatic feeding are regulated by the mesolimbic system and dopamine signaling. In fact, dopamine is the major neurotransmitter mediating the reward value of food and regulating EI. Dopamine acts as a potent inhibitor of feeding through local action in the perifornical area, ventromedial hypothalamus, and arcuate nucleus. Moreover, dopamine inhibits the expression of neuropeptide Y, a promoter of food intake .
Dopamine activity and availability are influenced by many factors such as neuronal dopamine synthetic capacity, the density of dopamine receptors, and the activity of the dopamine transporter (DAT)  which mediates reuptake of dopamine into presynaptic neuron and is a major target for pharmacologically active stimulants. DAT1 is the primary regulator of dopamine neurotransmission and is expressed in the central nervous system, primarily in brain areas that make up the dopaminergic circuits (e.g., striatum and nucleus accumbens). Methylphenidate (MPH) is a short-acting psychostimulant that alters central dopamine levels . The mechanism of MPH action is based on selective binding to DAT, leading to decreased dopamine reuptake and increased dopamine within neuronal synapses. It has been proposed that the effect of MPH on dopamine levels may impact non-homeostatic feeding behaviors. In a meal study testing the effect of MPH on EI in obese adult males, Leddy et al. demonstrated that a single dose of MPH had a 34% decrease in EI compared to placebo (P) .
The gene encoding DAT is SLC6A3 which has been mapped to chromosome 5p15.3 . Variable number tandem repeats (VNTR) polymorphisms in the 3′-untranslated region (UTR) of the dopamine transporter gene (DAT1) are associated with range of psychiatric phenotypes. The most common DAT1 genotypes are 9- and/or 10-repeats of a 40 base pair sequence (9/9, 9/10, or 10/10 combinations). The 10-repeat allele is associated with attention deficit hyperactivity disorder (ADHD) . Appetite suppression is often observed in children with ADHD treated with MPH. Leddy et al. demonstrated that children with ADHD and the 9/9 genotype had a greater dose-response reduction in caloric intake than those with the 9/10 or 10/10 genotypes . The question of whether polymorphisms in this area are associated with non-homeostatic feeding behaviors has not been addressed.
The purpose of the current study was to investigate the effect of a single dose of MPH on fat and carbohydrate intake and total EI in obese adolescents. In addition, we explored the potential role of DAT1 genotypes and insulin levels on total and macronutrient EI in response to MPH.
This was a randomized, single-blind, placebo-controlled, within subject study in obese adolescents recruited from pediatric practices in the urban and suburban areas of Buffalo and referred to the Pediatric Endocrinology clinic at the Women and Children's Hospital of Buffalo. Inclusion criteria were as follows: males and females aged 10-18 years with body mass index (BMI) ≥95th percentile for age and gender, pubertal Tanner stage 2 or greater, and the subject able and willing to swallow a small tablet. Subjects were excluded if they had gastrointestinal disease, dietary restrictions or food allergies to any of the test foods, psychiatric disorders including eating disorders, or neurological disorders. Subjects were also excluded if they were treated with medications that might interfere with the study outcome including stimulants, thyroid hormone replacement, or chronic oral steroids. Additional exclusion criteria were ≥5% weight loss over the past 6 months and participation in a research study within 6 months prior to enrollment. Study participants were excluded after screening if they were found to have fasting blood sugar ≥100 mg/dl, HbA1c ≥6%, or evidence of food restraint as assessed by eating behavior questionnaire. This study was approved by the Children and Youth IRB of the University at Buffalo. Parents/guardian signed informed consent and participants signed assent. All procedures were performed in accordance with the ethical standards of the responsible committee on human experimentation or with the Helsinki declaration of 1975.
After a brief explanation of the study and screening conducted over the telephone, interested subjects meeting inclusion criteria underwent screening procedures including food preference and dietary restraint questionnaires, past medical history and review of systems, physical examination including staging of pubertal maturation, anthropometric measurements, vital signs, and blood draw. Dietary restraint was measured with a modified version of the Dutch Eating Behavior Questionnaire (DEBQ) . Height was measured to the nearest 0.1 cm using a calibrated stadiometer; weight was measured to the nearest 0.1 kg using a calibrated digital scale. Blood pressure was obtained by manual sphygmomanometer with the subject sitting for 5 min. A fasting (10 h) blood sample was drawn to assess complete metabolic profile, including glucose, liver, and renal function tests, HbA1c, thyroxine (T4), thyroid stimulating hormone (TSH), and insulin. Insulin levels were analyzed by solid-phase, two-site, chemiluminescent immunometric assay using the Siemens Immulite 2000 (Kaleida Health Laboratory, Buffalo, N.Y). T4 was measured by Immulite chemiluminescent assay (Kaleida Health) and immunochemiluminometric (ICMA) assay (Quest Diagnostics, Pittsburgh, PA). TSH was measured by Chemiluminescence Enzyme Immunoassay and HbA1c was measured by HPLC (Kaleida Health and Quest Diagnostics, Pittsburgh, PA).
Eligible subjects were instructed to report to the center fasting (10 h) on two separate occasions for standardized meal tests within a window of 14-21 days. In random order, each subject received either 0.3 mg/kg MPH or P administered in identical appearing capsules prior to the test meal. The Research Pharmacy at the School of Pharmacy, University at Buffalo prepared the capsules with a powder source of 2-piperidineacetic acid, alpha-phenyl-methylester, and hydrochloride micronized methycellulose for MPH and P (Professional Compounding Centers of America). Upon arrival to the center between 7 and 9 am, the participant was placed in a quiet room, where the study procedure took place. Subjects were then given either MPH or P and provided with magazines to read for 1 h prior to the test meal. This time delay between dose administration and start of feeding test was chosen since it has been shown that oral MPH reaches peak concentration in the brain 60-90 min after administration . Participants were then offered a standard tray from which they could choose an array of breakfast options that included foods with high and low fat and carbohydrate content (Table 1). All participants were offered the same amount and variety of food at each visit in unlabeled disposable containers identifiable only by number. Subjects were instructed to consume as much or as little food as they wished. Participants were unaware that the amount of food/calories consumed would be calculated and were asked to fill out a “Test Quality Sheet” on every item they tasted by using the numbers on the container to identify the food consumed. Participants were instructed not to read, talk on the phone, or text-message during the test meal and to alert the clinician via wireless intercom when they had completed the meal. Participants were monitored by direct observation for safety reasons. After completion of the meal test, subjects were dismissed after ensuring that they did not have any significant side effects or complaints.
Table 1. Breakfast menu and nutritional information for meal test foods (ad libitum food intake task)
Low calories foods
High calorie foods
Volume (cups, number)
Volume (cups, number)
Dannon Yogurt Light & Fit
Dannon laCreme Yogurt
Dole Apple & Caramel Creme
Kellogg's Special K cereal
Post Banana Nut Crunch
Nature Valley granola bars
Snack well's sugar free cookie
Milano milk chocolate cookies
Lays Light Chips
1 ½ cups
Lays classic chips
1 ½ cups
Food was weighed to the nearest 0.1 g using the Scout Pro 45001 electronic scale (Ohaus Scale Corporation) before and after the meal, and the weight of the empty containers subtracted. The scale was calibrated daily. Energy content was calculated based on food labels. Energy from carbohydrates (CHO) and fat and total EI were calculated. Mean ± standard deviations (SD) were calculated for each group for every meal. Mann–Whitney U and Wilcoxon tests were used to compare EI between treatment groups. P-values of ≤ 0.05 were accepted as statistically significant (SPSS Version 8).
At the first test-meal visit, prior to the study drug administration, a DNA sample was collected using a buccal brush. DAT1 VNTR polymorphism analysis was performed as previously described . Briefly, DNA was isolated and PCR was performed. PCR products were separated on a 6% acrylamide gel, and alleles were differentiated by size.
Figure 1 illustrates the recruitment, screening, and disposition of study participants. After telephone pre-screening of 89 subjects who were potentially eligible based on BMI and age criteria, 45 were invited to be come to our center for screening procedures. Twenty nine out of 33 subjects (88%) who underwent screening were eligible for the study; however, five participants failed to initiate the study, and two subjects were excluded due to poor cooperation at the time of the first meal test. The data from 22 completers (7 males and 15 females) were analyzed and are presented.
Table 2 shows the characteristics of the study participants. Subjects had a mean age of 13.4 ± 2.2 years. With respect to pubertal status, 9 participants were Tanner stage II and III (41%) and 13 participants were Tanner stage IV or V (59%). Minority groups were well represented (36%). The absolute mean BMI was 34.9 ± 10.7 kg/m2, and the mean BMI Z-score was 2.3 ± 0.4. Fasting insulin levels ranged from 5 to 68 uIU/ml with the mean fasting insulin level being 17.9 ± 13.8 uIU/ml; nine subjects had elevated fasting insulin levels ≥15 uIU/ml. Figure 2 shows EI from CHO and fats and total EI following MPH or P. For all subjects, total EI following MPH treatment was 545 ± 235 kcal compared to 663 ± 329 kcal for P (P = 0.06). EI from CHO (MPH 311 ± 134, P 389 ± 211 kcal; P = 0.04) and fat (MPH 167 ± 79, P 203 ± 93 kcal; P = 0.03) was lower following MPH treatment compared to P. Eight subjects consumed >100 kcal less during the MPH meal compared to the P meal; seven subjects consuming at least 200 kcal less in response to MPH. Five subjects consumed >100 kcal more during the MPH meal compared to the P meal; however, no subject consumed >200 kcal during the MPH meal compared to the P meal. The range in response between the meals (P vs. MPH) was +184 to −1206 kcal with an average decrease in total EI of 118 ± 293 kcal (data not shown).
Table 2. Baseline characteristics for the study participants (N = 22)
Mean age (years)
13.4 ± 2.2
Data are expressed as absolute number or mean ± SD.
BMI SDU: Body mass index standard deviation unit
Tanner stage II/III/IV/V
2.3 ± 0.4
Fasting Insulin (mIU/ml)
17.9 ± 13.8
There was no significant difference in EI between male and female subjects (data not shown). When the subjects were stratified based on Tanner staging into early pubertal (T2-T3, n = 9) and late pubertal (T4-T5, n = 13) groups, there was not a difference in EI between the two groups. However, total EI decreased with MPH in the late pubertal group (P 757 ± 373 vs. MPH 584 ± 242; P < 0.05); similar effects on EI in response to MPH were not seen in the early pubertal group. EI from CHO (P 450 ± 242 vs. MPH 336 ± 131; P <0.02) and fat (P 226 ± 100 vs. MPH 177 ± 87; P < 0.015) were also lower following MPH treatment compared to P in the late pubertal group.
Results of VNTR polymorphisms from DAT1 genotyping are shown in Table 3. The majority of subjects carried either the 10/10 or 9/10 alleles. DAT1 genotype did not predict EI from fat or CHO or total EI intake (data not shown).
Table 3. DAT1 genotype distribution for study cohort
MPH is one of the most common medications used for treatment of children and adults with ADHD. Appetite suppression and weight loss are well described side effects of MPH and likely are mediated by MPH decreasing neuronal dopamine reuptake with subsequent increased dopamine levels in the neuronal synapses. PET data shows that >50% of dopamine receptors are blocked by MPH doses of 0.25 mg/kg, which is in the therapeutic dose range used for ADHD (0.3-0.6 mg/kg) . Leddy et al. demonstrated that a single dose (0.5 mg/kg) of MPH reduced EI by 34% in seven out of nine adult obese males . The study presented here demonstrates that, in obese adolescents, EI from fat and CHO is significantly decreased with a single acute dose of MPH of 0.3 mg/kg, a dose lower than used in the adult study. This dose was chosen based on previous studies in children which showed a 15% reduction in caloric intake following a single 0.3 mg/kg dose of MPH , and it represents a standard initial MPH dose used for treatment of ADHD in children. Indeed, none of the study participants experienced adverse events from MPH administration. In addition, we were able to show a trend toward reductions in total EI following MPH, although this did not attain statistical significance (P = 0.06). Although total EI did not show a significant decline in our study group, 8/22 subjects demonstrated a clinically relevant decrease in caloric intake (at least 100-200 kcal) in response to MPH. If this decrease in EI were sustained, it would translate to ∼5% weight loss over the course of a year, an amount which has been demonstrated to impact risks for development of Type 2 diabetes, hypertension, and atherogenic lipid profiles .
The failure to demonstrate a difference in total EI is likely due to the small sample size and variability in caloric intake among subjects in our study. It should be noted that MPH is administered two to three times a day in the typical treatment regimen of adolescents with ADHD. Leddy et al. showed significant MPH dose-response reduction in appetite among children with ADHD . Thus, it is possible that a higher single dose or multiple doses of MPH would decrease EI to a greater degree in obese adolescents.
Puberty is a physiologic anabolic state characterized by insulin resistance due to increased growth hormone and sex steroid secretion. Obesity exacerbates insulin resistance further. In our population, we demonstrated that MPH had a greater effect on EI in obese adolescents in late puberty. We were unable to demonstrate a correlation between fasting insulin levels and response to MPH, likely because of the low sample number. Future studies focusing on subjects in late puberty could explore associations between insulin sensitivity and response to MPH.
Individual responses to central nervous system stimulants are highly variable in humans. In fact, our data demonstrates that some subjects had minimal or no response to MPH, while others had as much as a 70% decrease in total EI (not shown). We postulated that differences in VNTR polymorphisms encoded by the DAT1 gene may contribute to differences in EI observed in obese youth. Based on the literature, the frequencies on DAT1 genotypes in general population are 5-10%, 32.5-42.5%, and 46.2-57.5% for 9/9, 9/10, and 10/10 VNTR polymorphisms, respectively . Davis et al. showed that adult subjects with binge eating disorder and at least one copy of the 9-repeat allele (9/9 or 9/10 DAT1 genotype) have greater appetite suppression after a single oral dose of MPH (0.5 mg/kg to max dose of 50 mg) compared to either a control group or patients with binge eating disorder and the 10/10 DAT1 genotype . In this study, participants exhibited DAT1 allele frequencies similar to those observed in the general population. In addition, there was no association between DAT1 genotype and EI responses to MPH. It should be noted that this aim was exploratory in nature due to the small numbers of subjects within each genotype.
In conclusion, this study provides data demonstrating that a single low dose of MPH lowers EI from fat and CHO in obese teenagers. Additional research is needed to explore acute versus chronic MPH effects on EI in obese subjects. Moreover, a wider range of doses should be studied to determine the lowest effective dose influencing EI from fat and CHO as well as whether higher doses would successfully reduce total EI in obese teenagers.
The authors would like to thank Dara Farber for valuable contribution to the study, Louise M. Cooper, R.Ph, MS and her laboratory for preparing study medication and placebo capsules, and Sherry Ortiz for her assistance in the manuscript preparation.