TYPE Systematic Review

PUBLISHED 29 November 2024

DOI 10.3389/fnut.2024.1497772

Methylphenidate can help reduce

OPEN ACCESS weight, appetite, and food
intake—a narrative review of
EDITED BY
Evelyn Frias-Toral,
Catholic University of Santiago de Guayaquil,
Ecuador

REVIEWED BY
adults’ anthropometric changes
Edna J. Nava-Gonzalez,
Autonomous University of Nuevo León,
Mexico
and feeding behaviors
Marcelo Yaffe,
Universidad de la República, Uruguay Fernand Vedrenne-Gutiérrez 1†, Sion Yu 1†, Anna Olivé-Madrigal 1†
Juan Marcos Parise-Vasco,
Universidad Tecnológica Equinoccial, and Vanessa Fuchs-Tarlovsky 2*†
Ecuador
1
School of Medicine and Health Sciences, Universidad Anáhuac, Mexico City, Mexico, 2 Department of
*CORRESPONDENCE Clinical Nutrition, Hospital General de México Eduardo Liceaga, Mexico City, Mexico
Vanessa Fuchs-Tarlovsky
vanessafuchstarlovsky@gmail.com
†
These authors have contributed equally to Introduction: Obesity constitutes a complex global health that carries several
this work comorbidities that include cardiovascular disease, diabetes, and cancer. Current
RECEIVED 17September 2024 treatments, such as lifestyle modifications and bariatric surgery, are often
ACCEPTED 18 November 2024 difficult to implement or carry risks, creating a need for alternative approaches.
PUBLISHED 29 November 2024
Methylphenidate (MPH), a drug commonly used to treat Attention Deficit and
CITATION
Hyperactivity Disorder (ADHD), has shown potential in regulating dopamine
​ edrenne-Gutiérrez F, Yu S, ​
V
Olivé-Madrigal A and ​ levels to modulate appetite and feeding behaviors.
Fuchs-Tarlovsky V (2024) Methylphenidate
Methods: This narrative review evaluated the effect of MPH in reducing food
can help reduce weight, appetite, and food
intake—a narrative review of adults’ intake, body weight, and anthropometric indicators in adults with obesity or
anthropometric changes and feeding overweight. Using the PICO method, 39 studies were selected, including 14
behaviors.
randomized controlled trials and 3 observational studies.
Front. Nutr. 11:1497772.
doi: 10.3389/fnut.2024.1497772 Results: MPH canblead to modest weight loss of 1–2% and significant appetite
COPYRIGHT suppression, with stronger effects observed in women, who reported greater
© 2024 Vedrenne-Gutiérrez, Yu, reductions in appetite and food cravings. Studies could remain underpowered
Olivé-Madrigal and Fuchs-Tarlovsky. This is an
open-access article distributed under the
to detect consistent effects in men.
terms of the Creative Commons Attribution Discussion: Even if these results suggest MPH could be an option for treating
License (CC BY). The use, distribution or
reproduction in other forums is permitted, obesity, concerns regarding its safety profile and long-term efficacy persist.
provided the original author(s) and the This review underscores the need for further investigation to confirm MPH’s
copyright owner(s) are credited and that the therapeutic potential, particularly through studies that address gender-specific
original publication in this journal is cited, in
accordance with accepted academic responses and evaluate its sustainability as a weight management tool.
practice. No use, distribution or reproduction
is permitted which does not comply with
KEYWORDS
these terms.
methylphenidate, obesity, feeding behaviors, appetite, weight

Introduction
Obesity has become a major pandemic of the 21st century (1, 2). Being overweight leads
to being in a chronic state of inflammation, which increases the risk of many serious health
problems, including heart disease, stroke, diabetes, and cancer (3, 4). Obesity also takes an
economic toll, with billions spent each year on obesity-related medical costs (1). Despite this,
obesity can be categorized as one of the most refractory conditions since lifestyle changes like
diets and exercise are challenging to maintain long-term in the actual fast-paced world (5–7).
Irreversible treatments such as bariatric surgeries are effective. Still, they carry risks and are
only suitable for selected patients (8). There is an urgent need for additional interventions to
aid individuals in achieving and maintaining a healthy body weight. Pharmacological

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treatments targeting the biological mechanisms of obesity could serve Methylphenidate (MPH) is a central nervous system stimulant
as a critical enhancement to the existing therapeutic arsenal. that increases levels of dopamine and norepinephrine in the brain by
The Mesolimbic Dopaminergic Pathway, established in the ventral inhibiting its reuptake in the presynaptic neuron. In so doing, MPH
tegmental area (VTA), is a fundamental regulator of the brain’s reward increases dopaminergic transmission in the mesolimbic (ML),
system, coordinating pleasure and reinforcement learning through mesocortical (MC), mesostriatal (MS), and infundibular (IN)
various other neural pathways (9). Its primary neurotransmitter, pathways. Methylphenidate is metabolized in the liver and is readily
dopamine, transmits signals associated with reward-related stimuli eliminated through the kidneys (14) (Figure 1). MPH is primarily
from the VTA to crucial brain regions such as the nucleus accumbens used to treat attention-deficit hyperactivity disorder (ADHD). Still, it
(NAc), amygdala, and prefrontal cortex (10). When individuals has also been investigated for its potential weight loss effects by
participate in pleasurable activities, for example, consuming food, increasing dopaminergic activity in the ML, MC, and MS pathways
dopamine is released in the NAc, triggering the feeling of satisfaction, and, ultimately, the reward system (15).
reinforcing positive feedback for motivation, and a sense of reward. Lifestyle changes should remain the primary line of obesity
This process enhances motivation and facilitates learning by treatment. However, medications could play a crucial role in aiding
associating specific actions with positive outcomes, thus shaping appetite control. Drugs that target the dopaminergic reward system
future behaviors (11). In individuals with obesity, the mesolimbic could help people lose weight and maintain their long-term health
dopaminergic system may be dysregulated. Naef et al. explained that (16). As mentioned before, MPH is one potential candidate;
these individuals showed reduced dopamine D2 receptor availability nevertheless, more research must be done to be approved by the FDA
in the striatum, suggesting a hypodopaminergic state and resulting in (17, 18). Other drugs that modulate dopamine, such as antidepressants
overconsumption of food to compensate for reduced dopamine and anxiolytics, are also being investigated (16). Ultimately, lifestyle
signaling (12). Drugs that modulate dopamine neurotransmission changes, behavioral therapy, and pharmacotherapy may be the most
could help restore normal function in this system, consequently eating effective approach to the obesity pandemic (19). Medications could
less and losing weight (13). be an essential tool to help people lose weight and improve their

FIGURE 1
Pharmacokinetics and pharmacodynamics of MPH. (A) MPH exists in immediate (IR), extended-release (ER), and osmotic release oral systems (OROS).
(B) MPH is readily dissolved in water. It is not absorbed in the stomach but absorbed in the intestine. IR requires to be given tid to have
pharmacokinetics similar to ER and OROS. (C) Once distributed, MPH can cross the blood–brain barrier (BBB). It inhibits Dopamine (DAT) and
Norepinephrine (NET) transporters, thus increasing the activity of noradrenergic and dopaminergic pathways. (D) MPH is metabolized into α-phenyl-2-
piperidine acetic acid by Carboxylesterase-1 (CES1A1). This metabolite has deficient biological activity and has renal elimination (12).

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health (20). With further research and development, we may see more 2010, articles without relevant outcomes, with patients receiving a
anti-obesity drugs approved in the coming years. The main objective mix of medications, or where participants had any condition that
of this narrative review is to examine the current literature on the could produce weight loss were excluded.
effects of methylphenidate (MPH) on appetite suppression and weight A total of 39 articles were selected (Figure 4). Articles could
regulation in adults with obesity or overweight. be grouped into two categories: category 1 had articles that
addressed our research question directly, and category 2 had
articles that reported weight loss, appetite changes, and other side
Methods effects related to nutrition status because of MPH when used for
other purposes. Out of the 39 articles, 17 met the inclusion and
To perform this review, a Participant-Intervention-Comparison- exclusion criteria to different extents. Of the 39 selected articles, 33
Outcome (PICO) approach was followed to answer our research (85%) were experimental or observational, 34 (90%) were carried
question. A methodological roadmap is shown in Figure 2. out on human adults, all of them were published after 2010, 26
We present a decision tree in Figure 3 to show how the search queries (67%) had a relevant anthropometric or appetite outcome, 32
were built. Six different search queries (Figure 3) were used in 4 (82%) had a methylphenidate dose declared, all of them were in
databases: PubMed, Scopus, Web of Science, and EBSCO. These English or Spanish (100%), 3 (8%) used different medications. In
databases were chosen because of the scope and breadth of journals none of the articles did participants have other weight loss
they cover. We included only articles published in English after 2010 predisposing conditions. The most common reason for rejecting an
to cover all the relevant publications in the last 10 years. Studies had article was that articles did not declare anthropometric or appetite
to be experimental and observational studies in human adults that outcomes. The studies varied in design and size, but the majority
reported objective anthropometric, appetite, or dietetic indicators or (83.3%) were randomized controlled trials (RCTs). The remaining
that reported weight loss as a side effect of MPH. MPH dosage had articles were all cohort studies. Seven studies (41.2%) were grouped
to be disclosed. Reviews, meta-analyses, conference papers, animal in category 1, while the remaining 10 (58.8%) could be grouped in
models, in-vitro studies, studies in children, articles published before category 2.

FIGURE 2
Methodology roadmap—this study followed the steps above to answer our research question. The results can be analyzed at different descriptive
levels: the type of articles found, including their design, and the actual data in the literature.

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FIGURE 3
PICO/PIO methodology decision tree—several search queries were built using Boolean operators to reach a final work batch of 95 further screened
articles.

Results had a significant effect on anthropometric indicators: Heffner et al.

(26) found a 1.6% weight decrease in participants who were trying
Effects of MPH on body weight, eating to quit smoking and took MPH versus a 1.3% weight increase in
behaviors, and appetite participants who were trying to quit smoking in the placebo group
(p < 0.001); on the other hand, Quilty et al. (25) showed that when
The present review looked at studies assessing the effects of compared to cognitive behavioral therapy (CBT), treatment with
methylphenidate (MPH) on various anthropometric and behavioral MPH produced a more considerable decrease in BMI (p = 0.01)
outcomes related to weight management, including body weight, (Table 1).
eating behaviors, and appetite in adults. Only half (n = 741.2%) of All the articles measured at least one appetite/dietetic indicator
the selected studies belonged to category 1 (18, 21–26). Weight and as an outcome. Three crossover randomized studies evaluated the
Body Mass Index (BMI) and waist circumference were the only effect of MPH on food consumption, food cravings, and appetite
studied anthropometric outcomes. Weight was an outcome in 4 variables and how this effect interacts with BMI (21), food addiction
studies (57.1%) (18, 24, 26), BMI was an outcome in 2 studies (23), and binge eating disorder (BED) (22). People with a normal
(28.6%) (24, 25), and waist circumference was an outcome in only BMI had a significant consumption reduction in snack consumption
one study (14.3%) (24). Only two studies (28.6%) found that MPH (p = 0.017), appetite ratings (p = 0.017), and food cravings

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FIGURE 4
PRISMA flowchart depicting the process of article selection.

(p < 0.0001) when receiving MPH compared to placebo. In contrast, there was a significant decrease in appetite ratings (p = 0.002), food
in people living with obesity, there was only a snack consumption cravings (p = 0.023), and snack consumption (p = 0.002) when
reduction (p < 0.0001), appetite ratings (p < 0.007), and food participants took MPH, regardless of whether they had BED or not.
cravings (p = 0.008) in women when receiving MPH but not in men There was no effect of BED on any of the variables studied. In
(21). Participants with food addiction had higher baseline food contrast, Quilty et al. (25) found that the frequency of binging
cravings and appetite than participants without good addiction episodes decreased when taking MPH in comparison with CBT
(p < 0.0001 for both). Regardless of food addiction status, all (F = 11.9, p < 0.001) and that this effect had a significant interaction
participants showed a significant decrease in appetite ratings with time (F = 2.10 p < 0.02).
(η2 = 0.157, p = 0.031) y and food cravings (η2 = 0.128, p = 0.006) Other studies replicate similar results. El Amine et al. (18) found
when given MPH compared to placebo. There was only a significant that desire to eat (p = 0.001), hunger (p = 0.001), and prospective food
interaction between food addiction and MPH for snack consumption, consumption (p = 0.003) decreased, and satiety increased (p = 0.028)
where participants without food addiction reduced their intake when in people with obesity receiving MPH when compared to placebo.
receiving MPH (η2 = 0.276, p < 0.0001) (23). In Davis et al. (22), Moreover, another study reported a gender x MPH interaction for

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TABLE 1 Summary of articles that looked at dietetic or anthropometric as a function of MPH use.

Article Country Design Objective Sample characteristics Intervention Relevant Main findings Methodological
outcomes remarks
Davis et al. (21) Canada Cross-over To assess the effect of n = 132 Patients were given Appetite Rating: Snack consumption was equivalent While the study has a
Randomized BMI and gender on Adults between 24–45 years old. short-acting 0.5 mg/kg validated own among both genders, BMI categories, large sample size. Most
Controlled food consumption, 73.5% female of MPH as intervention. instrument with 3 and their interactions. participants were
Trial food cravings and No history of DSM IV Axis After 1 h, they were questions. Normal weight individuals significantly females, so the male
appetite after I disorders (except unipolar presented with their Food Cravings: General decreased their appetite rating group may
administering depression). favorite snack in two Food cravings (p = 0.017), food cravings (p < 0.0001), be underpowered to
Methylphenidate No history of serious medical illness. occasions (one placebo, questionnaire and snack consumption (p < 0.017) find statistical
(MPH) Not taking medications one MPH). %Snack Food regardless of gender. significance.
contraindicated against Consumption: In-lab In individuals with obesity, there was a
methylphenidate. feeding test. significant gender x day in appetite
44% of the sample had BMI < 25. ratings (p < 0.007), food cravings
56% had BMI >30. (p = 0.008), and snack consumption
19% smoked tobacco. (p < 0.0001). No changes in appetite
ratings, food cravings, or snack
consumption were seen in males, but
they were seen in females (p < 0.0001
for all).
06

Davis et al. (23) Canada Cross-over To assess whether n = 136 Patients were given Appetite Rating: Participants in the food addiction It is possible that the
Randomized food addiction status Adults between 25 and 50 years old. short-acting 0.5 mg/kg validated own group had higher baseline food craving food addiction group
Controlled and gender modulate Predominantly overweight or with of MPH as intervention. instrument with 3 scores and appetite ratings (p < 0.0001 was underpowered to
Trial food consumption, obesity. After 1 h, they were questions. for both). produce significant
food cravings and 67.7% female presented with their Food Cravings: General There was a decrease in appetite ratings differences in variables,
appetite after 17% met criteria of food addiction favorite snack in two Food cravings and craving scores between placebo so results must
administering MPH according to YFAS. Mean BMI of occasions (one placebo, questionnaire day and MPH Day (η2 = 0.157, be interpreted with
food addiction group did not differ one MPH) %Snack Food p = 0.031) and (η2 = 0.128, p = 0.006 caution, even if the
from that of the rest of the group. Consumption: In-lab respectively). The interaction between study itself has a large
No history of serious medical illness, feeding test. placebo/MPH and food addiction was sample size.
psychotic disorders, or substance Food addiction: YFAS not statistically significant.
abuse disorders. Not taking questionnaire. The interaction between placebo/MPH
medications contraindicated against and food addiction was significant for
methylphenidate. food consumption (p = 0.018). The

10.3389/fnut.2024.1497772
26 and 20% of the participants with food addiction group did not decrease
food addiction and the general their food consumption, but the
group smoked tobacco, respectively. general group did (η2 = 0.276
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p < 0.0001). Women also tended to

consume less of their snack than men
(η2 = 0.039, p = 0.022).

(Continued)
 TABLE 1 (Continued)
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Article Country Design Objective Sample characteristics Intervention Relevant Main findings Methodological
outcomes remarks
Davis et al. (22) Canada Cross-over To assess whether n = 198 Patients were given Appetite Rating: Self-reported appetite (p = 0.002), food While the study has a
Randomized having binge eating Adults between 24 and 50 years old. short-acting 0.5 mg/kg validated own cravings (p = 0.023), and snack large sample size, most
Controlled disorder (BED) All of them with overweight or of MPH as intervention. instrument with 3 consumption (p = 0.002) decreased participants were
Trial modulates food obesity. After 1 h, they were questions. significantly between placebo day and females, so lack of
consumption, 76.8% female presented with their Food Cravings: General MPH Day. There was also a significant significance in the male
appetite, and food 96 participants had binge eating favorite snack in two Food cravings day x sex interaction (p = 0.007, population should
cravings after disorder (76 females). occasions (one placebo, questionnaire p = 0.048, and p = 0.032 respectively), be taken with caution
administering MPH No history of serious medical illness, one MPH). %Snack Food showing only a decrease in female due to possible
psychotic disorders, or substance Consumption: In-lab participants (p < 0.0001 in all cases). underpowering.
abuse disorders. Not taking feeding test. BED status did not modulate the
medications contraindicated against response.
methylphenidate (MPH).

El Amine et al. Canada Randomized To determine the n = 12, randomized into a placebo Patients received short- Appetite: Visual Analog For olfaction, there is a significant Sample size is small
(18) Controlled effect of short-acting group with n = 7 (3 males and 4 acting 0.5 mg/kg of scale (desire to eat, interaction in group x time (p = 0.029), and thus not
pilot Trial MPH at 0.5 mg/kg females), and an MPH group with MPH or placebo divided hunger, prospective where participants receiving MPH generalizable; however,
during 2 months on n = 5 (2 males and 3 females). twice daily 1 h after food consumption, and increased their olfaction threshold these results look
appetite sensations, Adults between 18 and 40 years old lunch and dinner. One fullness). (M = −3.8, p = 0.017). promising for a larger
07

olfactory threshold, with BMI > 30 kg/m2 but body initial appointment and Olfaction: Sniffin’ There was a significant decrease in the scale study.
energy intake, and weight below 200 kg so as not to two measuring ®
sticks . areas under the curve for desire to eat
body weight in surpass the maximal dose of MPH appointments were Bodyweight (p = 0.001), hunger (p = 0.008), and
individuals with (100 mg/d). scheduled monthly. Height prospective food consumption
obesity All had a stable weight for the past Body composition: (p = 0.003); and an increase in fullness
6 months. None of them smoked, DXA. (p = 0.028) in the MPH group when
had ADHD, used MPH, had history Energy intake: In-lab compared to placebo.
of mental health or substance abuse feeding test. Changes in olfaction and appetite
disorders, took any medication that variables were not correlated with
could affect appetite, had any major anthropometric variables.
health problem, or reported any
food allergy

(Continued)

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 TABLE 1 (Continued)
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Article Country Design Objective Sample characteristics Intervention Relevant Main findings Methodological
outcomes remarks
Goldfield et al. Canada Cross-over To estimate if there is n = 120 Patients received short- Appetite variables: Significant gender x drug interaction This trial has a large
(24) Randomized gender modulates the Adults between 18 and 40 years old acting 0.5 mg/kg MPH Visual analog scale for energy intake (F = 4.9, p = 0.01) sample size with equal
Controlled effect of short-acting with BMI larger or equal than 20 kg/ at sessions. One initial (desire to eat, hunger, and carbohydrate intake (F = 8.2, gender representation.
Pilot Trial 0.5 mg/kg MPH on m2 but body weight less than 120 kg appointment, and two prospective food p = 0.02) with a greater reduction in
energy intake, to not surpass maximal dose of subsequent monthly (for consumption, and men than in women relative to placebo.
macronutrient MPH. females) or weekly (for fullness) No significant gender x drug
consumption, food 50% female males) appointments for Buffet Energy and interaction for macronutrient
preferences, appetite All non-smokers and non-tobacco measurements. micronutrient Intake preferences.
sensations and users. Participants had to eat Weight No drug x gender interaction for food
relative reinforcing from a standardized Height hedonic ratings, relative reinforcing
value of food. mixed meal buffet 1 h Waist Circumference value of food, and water intake in the
after taking the pill. BMI buffet test.
Red button pressing for No drug x gender interaction for
relative reinforcing satiety quotients of appetite sensations.
value of food. Hunger ratings between MPH and
placebo groups were not statistically
different before or after drug
08

administration.

Heffner, 2013 USA Randomized To study the effect of n = 215 OROS-MPH was ADHD diagnosis or Participants in the OROS-MPH group The study did not do
(26) Controlled Osmotic Release Oral Adults 18–55 years old. Smoking at titrated to a dose of severity: Adult ADHD lost an average of 1.6% of their body an intention-to-treat
Trial System (OROS)-MPH least 10 cigarettes/day, expired CO 72 mg/day over the first Clinical Diagnostic weight, while those in the placebo analysis along with the
on weight gain of level ≥ 8 ppm, DSM-IV ADHD 2 weeks and continued Scale and the DSM-IV group gained an average of 1.3%. completing sample
quitting smokers with Rating Scale score > 22. In good at the maximum ADHD Rating Scale. Difference was statistically significant analysis. The use of the
ADHD. physical and mental health; no tolerated dose until the Nicotine dependence: (p < 0.001). nicotine patch may
narrow angle glaucoma, tics, seizure end of the 11-week Measured by the No significant drug x gender introduce some further
disorder, Tourette syndrome. Non- treatment period. Fagerström Test for interactions percent weight change. bias to the study.
nicotine substance abuse, mood/ Participants had 11 Nicotine Dependence The group receiving OROS-MPH had a
anxiety disorders, antisocial appointments once (FTND). lower severity of hunger (M = 1.1)
personality disorder, psychosis. every week. Smoking abstinence: compared to the placebo group
Without recent treatment for In each visit, participants self-report confirmed (M = 1.6). Difference was statistically
smoking or ADHD received counseling and with CO measurement significant (p < 0.001).

10.3389/fnut.2024.1497772
a nicotine patch. Weight of <8 ppm.
assessments were Nicotine withdrawal:
conducted at baseline, Withdrawal Scale for
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week 6, and week 11. Tobacco (WST), Weight

(Continued)
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Article Country Design Objective Sample characteristics Intervention Relevant Main findings Methodological
outcomes remarks
Quilty, 2019 Canada Randomized To compare the effect n = 49 randomized into CBT group Patients on the MPH Binge Eating Behaviors: There was a significant decrease in The sample size is good
(25) Controlled of methylphenidate (n = 27) and MPH group (n = 22). group had weekly Frequency of objective binge episodes in both treatment and supposedly well
Trial versus cognitive Adult women 19–51 years old. All appointments for the binge episodes per groups (F = 11.9, p < 0.001). powered, but subgroup
behavioral therapy with BED. BMI larger or equal than first 4 weeks, then twice week, assessed by a daily BMI over time significantly decreased analyses that are non-
(CBT) on reducing 25 kg/m2. One third either a mood a week for8 weeks. MPH binge diary. in both treatment groups (F = 4.4, significant must
binge eating episodes or an anxiety disorder. None were doses were increased Quality of Life: QoL p < 0.001), but there was a significant be analyzed with
in women with BED, currently pregnant or breastfeeding, from 18 mg/day to inventory difference in BMI between treatment caution. The sample
as well as the had undergone recent 72 mg/day by week 4, Impulsivity: Impulsive groups at Week 12 with a larger weight does not represent
modulating effect of psychotherapy or behavioral and adjusted for side Behavior Scale loss in the MPH group (t = 2.73, males.
impulsivity treatment for eating/weight, had effects, with discharge to (UPPS-P) p = 0.01).
taken psychotropic medication a family physician after BMI There was a significant time ×
recently, had severe mental disorders 12 weeks. perseverance interaction that
or uncontrolled medical conditions, Patients on the CBT modulated objective binge episodes
taking medications affecting weight group had a weekly for (F = 2.10, p < 0.02); and a significant
or contraindicated for 12 weeks lasting 50 min time × negative urgency interaction
methylphenidate. each. Sessions focused modulating subjective binge episodes
on eliminating binge (F = 1.79, p = 0.049).
09

episodes, reducing
intake, restructuring
cognitions, and
preventing relapse.

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energy (F = 4.9, p = 0.01) and carbohydrate (F = 8.2, p = 0.02) intake, energy balance controlled in the hypothalamus and a mechanism that
where males had more considerable reductions than females (24). is not driven by energy needs (sometimes called hedonic) that
In nine out of 10 articles in Category 2 (27–35), weight changes includes hypothalamic control but is mainly regulated in the
were studied as a side effect. Weight loss is reported in eight articles neocortex and limbic system (38). In addition, a decrease in
studying weight loss, while the remaining article reports no changes Dopamine 2 receptors (D2R) expression in the dorsal striatum and
in weight (27–29, 31–35). In only one article, weight loss was NAc has been associated with compulsive food intake in animal
measured and reported in kilograms (35). In this study, the mean models and humans (38, 39).
weight loss in the MPH group was 0.8 kg versus no weight loss in the In addition, the VTA in the midbrain projects neurons to the NAc,
placebo group (p < 0.05). One study measured the proportion of forming a complex network that will regulate food’s motivational
participants with a weight loss larger than 10% of their baseline body saliency. Food cues are categorized and prioritized as pleasurable and
weight (27). The remaining seven articles reported the proportion of compelling in these brain areas. According to Nicola (38), food’s
participants with any weight loss (28–34). The number of participants rewarding effect can be classified into three different components: the
who lost weight followed a dose–response pattern. In RCTs, at doses motivational component (wanting), the hedonic component (liking),
of 54 mg, 0.0–10.1% reported any weight loss, and at doses of 72 mg, and the learning component (reinforcement). The motivational
the interval of participants losing weight was between 0.0 and 23% component of eating has been related to the dopaminergic pathways,
(28–32). Adler et al. (27) showed that the number of participants while there is evidence that the hedonic component has an opioergic
losing over 10% of their initial body weight was 11.1% at any MPH regulation (38, 40).
dose (Table 2). The brain’s dopaminergic systems and conditioned learning drive
Regarding other relevant effects, nausea was reported in 7 studies food-seeking behaviors in humans. This means that even without
(27, 29, 31–34). Adler et al. (27) reported nausea in 11.1% of the hunger, different stimuli (i.e., smells, memories, or the sight of food)
patients at any dose with no dose–response effect. Casas et al. (29) can motivate an individual to look for food, even when it implies a
also found no dose–response effect with nausea in 17.4–18.0% of the significant effort. In addition, dopaminergic neurons in these circuits
participants. In cohort studies (33, 34, 36), the rate of nausea was appear to be regulated by hormones that regulate energy balance
between 0.43–6.5% (Table 2). Three studies reported decreased (homeostatic mechanisms). Neuropeptide Y (NPY), ghrelin, orexins,
appetite as a side effect (29, 32, 36). Two were RCTs (29, 32), and one and agouti-related peptide (AgRP) have been seen to increase
was a cohort study (36). Casas et al. (29) found a dose–response trend dopamine release, while glucagon-like peptide 1 (GLP-1), insulin, and
in reduced appetite. In this study, the prevalence of decreased leptin decrease it (38, 40).
appetite was 19.1% at 54 mg MPH and 28.3% at 72 mg MPH. Kis In rodents, Sucrose has been shown to stimulate dopamine
et al. (32) found a prevalence of decreased appetite at 54 mg MPH of transmission in the ventral striatum and olfactory bulb—cues paired
22.4%. The prevalence of decreased appetite in the cohort study was with sucrose stimuli condition dopamine release in these brain
28% (36). Anorexia was reported in only one article (31). The regions. The effects of sucrose in the dopaminergic pathways have
prevalence of anorexia in this study was 7.5% at a dose of 54 mg been compared to the effects of several drugs on the same areas. The
(Table 2). effects appear to differ in the higher speed at which dopamine activity
Some of the reviewed studies found slight differences in this subsides after sucrose is used (39).
response between genders. Women showed more significant Pleasurable stimuli activate the opioid system. Consuming
reductions in appetite, food cravings, and food consumption in palatable and calorie-dense foods stimulates μ-opioid receptors in the
response to MPH than men. This effect is consistent regardless of NAc. Activating the opioid system increases the motivational salience
the presence of BED (22) and food cravings (21, 23). The of food through a Pavlovian conditioning mechanism. Cues that
differential expression of dopamine receptors in distinct brain remind the individual of a pleasurable eating experience can further
areas can explain these sex-specific susceptibilities. Women tend reinforce dopamine release (38, 40). Figure 5 depicts the mechanisms
to have more D2Rs in the frontal cortex and striatum than men, mentioned above.
making them more sensitive to dopamine’s effect on eating Disrupted dopaminergic signaling, including decreased D2R
behaviors and, therefore, more prone to reduce their food intake expression in areas of the reward network such as the dorsal
due to MPH. striatum, the VTA, and the NAc, translates into reduced activity in
Conversely, males have more dopamine-1 receptors (D1R) in the orbitofrontal cortex and the cingulate gyrus. Since these systems
reward-processing areas such as the NAc (37) and probably overeat. regulate compulsive eating (39), their dysregulation can lead to
Moreover, when depressed, women tend to show more dopamine overeating highly palatable foods (39, 40). Given that MPH inhibits
transporter (DAT) binding, probably making it more susceptible to dopamine reuptake, it follows that enhancing dopamine’s action in
being inhibited by MPH (37). It is essential to mention that males these areas could modulate compulsive eating behaviors. Notably,
seem underrepresented in most articles that reach these conclusions. MPH has been shown to decrease the intake of dietary fats and
For this reason, more studies in males with well-powered sample sizes carbohydrates, suggesting a shift in macronutrient preference
are required. toward lower-fat options (24). This effect could help people
struggling to lose weight to improve their food choices and modify
their food composition. While this review focuses on the effects of
The mechanism of action of MPH and its MPH in adults, literature has also found similar effects on
effect on eating behaviors and body weight teenagers (41).
As previously mentioned, MPH inhibits dopamine and
Research has shown that food intake regulation comprises two norepinephrine synaptic reuptake and is available in various
mechanisms—a homeostatic hunger-satiety mechanism to regulate pharmaceutical presentations (Figure 1). The literature shows that

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Vedrenne-Gutiérrez et al.
TABLE 2 Effect of MPH on weight, and hunger studied as a side effect.

Article Country Design Objective Sample characteristics Intervention Relevant side effects reported
Adler et al. (27) USA Open label To assess the safety of n = 540 MPH dose was titrated starting at 36 mg/d Weight changes.
Randomized OROS-MPH in the long- Adults between 18–65 years old and escalated up to 108 mg depending on Proportion of participants exhibiting more than 10% weight
Controlled Trial term treatment of ADHD with ADHD. safety. There were two groups: one received loss increased in a dose–response pattern (1.3% of participants
in adults. 48% females the drug for 6 months, and the other for at 36 mg, and 18.1% at 108 mg. 11.1% at any dose). Only 0.9%
12 months. of the sample gained more than 10% of their initial weight at
any dose. This variable did not exhibit a dose–response
pattern.
Nausea.
11.1% of the sample presented with nausea at any dose. This
variable did not exhibit a dose–response pattern.

Bron et al. (28) The Netherlands Cross-over To evaluate the effect of n = 22 (12 allocated to MPH first For 6 weeks, participants received a titrated A non-quantified weight loss rate of 23% was reported in this
Randomized OROS-MPH in adult and 10 to placebo first). MPH dose starting at 36 mg/d for 7 days. study.
Controlled Trial executive functions. Mean age 30.5 with SD 7.4 years. All 36 mg weekly increments were done until
adults with ADHD. reaching 72 mg for 3 weeks.
22.7% females

Casas et al. (29) 42 European Randomized To determine the efficacy n = 279, (90 in MPH 54 mg, 92 in Dose was titrated to 54 or 72 mg according Weight changes.
locations Controlled Trial and safety of two doses (54 72 mg and 97 in placebo)- to group starting in 36 mg/d. There was Dose – response weight-loss was observed (4.1% of
11

(Managed in (Phase III) and 72 mg/d) of OROS- Adults 18–56 years old with ADHD also a placebo group. Dose was increased participants in placebo group, 10.1% in 54 mg group, and
Germany and MPH in adults with 45.7–51.1% females 7 days after initiation to the required dose. 18.5% in 72 mg group). It was not quantified.
Spain) ADHD. Trial lasted 13-week Anorexia.
Dose—response self-reported anorexia was observed (4.1% in
placebo, 6.7% in 54 mg group, and 13.0% in the 72 mg group).
Nausea.
Nausea was seen in 8.2% in placebo, 18.0% in the 54 mg
group, and 17.4% in the 72 mg group.
Appetite.
Dose – response trend in decreased appetite (5.2% in placebo,
19.1% in the 54 mg group, and 28.3% in the 72 mg group).

Edvinsson and Sweden Cohort Study To determine the safety n = 112. 51% of them in treatment. No actual intervention. Participants with Appetite
Ekselius (36) profile of MPH in adults Mean age was 35 years old at the ADHD were followed for 6 years. In the group taking MPH (n = 46) 28% of the participants
with ADHD over a long beginning and 42 years old at the reported decreased appetite

10.3389/fnut.2024.1497772
period of time. end of the study. Nausea/Vomiting
46 were taking MPH, 3 were taking In the group taking MPH (n = 46), 6.5% reported nausea or
MPH and Atomoxetine, and 8 were vomiting.
frontiersin.org

taking dexamphetamine.
37% females

(Continued)
 TABLE 2 (Continued)
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Vedrenne-Gutiérrez et al.
Article Country Design Objective Sample characteristics Intervention Relevant side effects reported
Ginsberg et al. Sweden Randomized To assess the long-term n = 30 (n = 15 for placebo and This was a 52-week trial. Dose started at No effect on body weight was observed in this study.
(30) Controlled Trial effectiveness and n = 15 for MPH group) 36 mg for 4 days, then increased to 54 mg
persistence of OROS- Adult males between 21 and for 3 days, and finally to 72 mg for 4 weeks.
MPH related side effects 61 years old. High prevalence of Those who completed the 4 weeks, entered
on cognition, motor comorbidity such as substance an open-label extension with a dose of
activity, institutional abuse, antisocial personality 1.3 mg/kg based on response and
behavior and quality of life disorder, mood and anxiety tolerability.
of male adult prison disorders.
inmates with ADHD.

Hurt et al. (31) USA Randomized To explore the effect of n = 80 (40 randomized to each This was a 6-month study comprised by 1 Anorexia
Controlled Trial OROS-MPH on smoking group). telephone pre-visit, 11 clinical visits and 1 7.5% of the participants in the MPH group presented anorexia
cessation in adults. Mean age was 38 years in the telephone follow-up. vs. 0.0% of the participants in the placebo group.
placebo group and 35.6 years in the Participants were titrated to a dose of Weight changes
OROS-MPH group. 54 mg/d for 2 weeks, and this maximum 2.5% of the participants in the MPH group lost an unknown
57.8% female dose was maintained for 8 weeks with amount of weight vs. 0.0% of the participants in the placebo
weekly assessments. group.
Nausea
5.0% of participants in the MPH group presented nausea,
12

while only 2.5% of the participants in the placebo group did.

Kis et al. (32) Germany Randomized To compare the n = 419 (randomly assigned to 4 OROS-MPH dose was titrated to 54 mg/d Decreased appetite
Controlled Trial effectiveness and safety of groups: MPH + CBT, during a 2-week period and maintained for Occurred in 22.4% of the MPH group vs. 3.8% of the Pl group
MPH and CBT in adults MPH + Clinical Management 8 weeks. Participants attended the clinic (p < 0.05)
with ADHD over a 1-year (Clin), Placebo (Pl) + CBT, weekly for counseling sessions. Nausea
period. Pl + Clin). 12.2% of the participants in the MPH group reported nausea
Mean age 35 years old (range of vs. 9.6% in the Pl group. Not statistically significant.
18–56) Abdominal discomfort
Females from 45.3 to 56% 6.3% of participants in MPH group vs. 2.9% of participants in
depending on group Pl group. Not statistically significant.
Weight changes
6.3% of participants in MPH group decreased their weight,
while only 1.9% of participants in Pl group. (p < 0.05)

10.3389/fnut.2024.1497772
Michelsen et al. The Netherlands Cohort Study To assess the n = 113 (89 had some No actual intervention. 44% of the patients Weight changes
(35) cardiovascular side effects pharmacological treatment) had extended release (ER) MPH, 9.7% A significant 0.8 kg weight decrease was observed in patients
of stimulant medications age was between 55 and 79 years were taking dexmethylphenidate (DMP), taking MPH (p < 0.05). No significant weight changes were
in older adults with 57% female and 7.1% were taking Dexamphetamine observed in other medications.
frontiersin.org

ADHD. (DAM). The observational study lasted

1 year.

(Continued)
 Vedrenne-Gutiérrez et al. 10.3389/fnut.2024.1497772

MPH can reduce food intake and weight. This effect is seen in articles

17% of the participants in the MPH group reported nausea vs.

The study reports weight loss rate of 1.71% and nausea rate of
the maximal dose tolerated, while only 10% of participants in
48% of participants in MPH group decreased their weight at that aim to determine if MPH can help adult patients lose weight and
reduce their intake (Category 1) and in articles that evaluate different
research questions regarding the use of MPH in adults (Category 2).
Further exploring its potential effects on weight, body composition,
Relevant side effects reported

and food intake could help increase the availability of safe and
tolerable pharmacological interventions to treat obesity or
excess weight.
MPH’s effect of increasing dopaminergic activity in the ML, MC,
and MS pathways can suppress appetite and reduce food intake.
Increased dopamine release in these brain areas implies that the
4% in the Pl group.

motivational salience of food will be reduced (39, 42). As a result,

Weight changes

people with obesity or overweight taking MPH could reduce their

Pl group.

energy intake and improve their food choices (18, 41).

Nausea

0.43%.

MPH also appears to reduce appetite and food intake by

modulating olfactory sensitivity (18). These findings are interesting
No actual intervention. Dose was started at
120 mg/d (1 mg/kg maximum) for 2 weeks

0.23 mg/kg and increased to 0.45 mg/kg as

because the literature on obesity and olfaction has shown that

and then brought up to maximal dose for

individuals with obesity seem to discriminate smells less than their

MPH ER dose was titrated up to 40–

normal-weight counterparts. Impaired olfaction may delay satiety

cues, and olfactory cues could influence food choices. It is essential to
mention that it is impossible to establish a causal relationship between
per the clinic protocol.

olfaction and obesity because there may be a bidirectional association

Intervention

– impaired olfaction may alter intake and metabolism. Still, obesity

may, in turn, affect how the brain perceives smells and detection
6 weeks.

thresholds (43, 44).

Olfactory cues seem tightly linked to dopaminergic processing in
different brain regions. Sorokowska et al. (45) have shown that food
odors can increase dopaminergic activity in reward circuits such as
Females 54.8% in MPH ER group,
Sample characteristics
n = 162 (84 randomized to MPH

the anterior cingulate cortex, the putamen, and the insula, thus
influencing eating behaviors. These results seem to be supported by
Age between 18 and 71.
ER, and 78 to placebo).
Age between 18 and 56

n = 468 from 126 sites.

Rampin et al. (46), who show that food odors can further increase
and 43.6% in placebo

dopaminergic transmission in the ventral striatum.

Females 42.1%

Interestingly, the results on olfactory sensitivity in participants

with ADHD seem to be discrepant. Some studies have replicated
olfactory impairment in children with ADHD (47). However, another
study even showed that MPH cessation in children with ADHD
reduces ADHD symptoms

improves olfactory discrimination (48). More work in this area is

To determine if ER MPH

profile of MPH in adults

with ADHD attending a
and psychopathology in

needed to determine the role of olfaction in developing unwanted

To describe the safety
adults with ADHD.

eating behaviors. As it is, MPH’s dopamine reuptake inhibition could

real-world clinic.
Objective

reinforce increased olfactory detection and thus improve eating

behaviors. Also, while MPH seems to have a dose–response effect on
appetite, all doses used in the reviewed studies decreased appetite.
This means that moderate and high doses of MPH reduced energy
intake, with a notable reduction in the consumption of highly
Controlled Trial

palatable foods. This effect is replicated in older literature (49).

Cohort Study
Randomized
Design

Clinical considerations and safety issues

While promising as a potential weight-loss intervention, it is

Country

important to mention that MPH has been associated with increased

Germany

Germany

cardiovascular risk in patients who are susceptible to heart conditions

TABLE 2 (Continued)

(50). Moreover, some studies in children with ADHD have shown that
MPH has proarrhythmic properties (51). A prospective cohort study
Retz et al. (34)

Retz et al. (33)

with a three-month follow-up in 100 Iranian children with ADHD

between 6 and 11 years old found that children taking MPH had
Article

significantly higher systolic and diastolic blood pressures and

increased heart rates. There were no significant differences in the

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Vedrenne-Gutiérrez et al. 10.3389/fnut.2024.1497772

FIGURE 5
The dopaminergic model of appetite regulation explains how the brain responds to food. After consuming a palatable meal, opioid and dopaminergic
activity in the mesolimbic pathway increase, enhancing pleasure and reinforcing eating behavior. Anorexigenic peptides inhibit this dopamine activity.
In the absence of palatable food, dopamine levels remain low, but the sole thought of pleasurable food can trigger food-seeking behaviors to restore
dopamine levels. Orexigenic peptides stimulate dopamine activity (38–40).

cardiac output, QT interval, and left ventricular mass. Clinically studying the safety profile of MPH in people with obesity and
irrelevant changes in systolic and diastolic functions were also seen in overweight is of prime importance before considering it a therapeutic
children taking MPH, but the drug was determined to be safe (52). option in this population. It is also important to consider gender and
A retrospective study on 26,710 individuals between 12 to 60 years ethnic differences in dopamine receptor expression to fully understand
without ADHD using MPH matched to 225,672 controls found that the plausibility of using MPH as a treatment for obesity
there was a 41% increased risk of cardiovascular events in the group and overweight.
using MPH (50). Another retrospective study on 43,999 new MPH
users matched to 175,955 non-users found an 84% increased risk for
sudden death or ventricular arrhythmia and a 74% risk of all-cause Discussion
mortality in MPH users. There was no significant risk of stroke or
myocardial infarction, and there was no significant dose–response Since the early 2000s, several studies have found that MPH can
effect or extended vs. immediate release effect (53). lead to weight loss in individuals. A meta-analysis in 2007 of 8
In addition, a systematic review and meta-analysis analyzing randomized controlled trials found that methylphenidate treatment
the cardiovascular risk associated with medications used in resulted in an average weight loss of 2.03 kg compared to placebo
ADHD gathered 19 observational studies and nearly 4 million (55). These effects appear to be mediated by reduced appetite and
participants from different age groups. The risk of cardiovascular food intake, a competitive regulation of dopamine without the
events was not significant in stimulant users, non-stimulant users, action of eating (49, 55). This review has found similar effects in
or users of any age group, suggesting that the risk of cardiovascular newer studies. The selected studies indicate that the use of MPH can
events in stimulant users is the same as the risk in the overall produce a modest weight loss and appetite suppression, particularly
population (54). through its effects on the brain’s hedonic and sensory processing
The literature shows mixed results regarding the cardiovascular pathways and that this effect appears more pronounced in women.
risks linked to MPH. Since people with obesity have a higher rate of Side effects, such as nausea and anorexia, may also contribute to
heart comorbidities than their normal-weight counterparts, further these outcomes.

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The interpretation of these findings is limited by several factors: Conclusion

study heterogeneity, small sample sizes, and lack of long-term data
make it challenging to generalize results. Additionally, none of the Methylphenidate appears to suppress appetite and reduce food
reviewed studies evaluated MPH in combination with lifestyle or intake in adults with obesity or overweight. This effect appeared to
dietary interventions, which are commonly prescribed together with be more pronounced in women. Given the current state of the
weight-loss drugs in clinical practice. MPH’s association with evidence, it is not possible to determine if men are less sensitive to the
cardiovascular risks highlights the need for caution, especially in anorexigenic effects of MPH or if the sample was underpowered.
patients with obesity who may already have an elevated risk of heart MPH also seems to influence macronutrient preferences, reducing fat
disease. While MPH shows potential as an adjunct therapy for weight and carbohydrate intake. These effects could be mediated by increased
management, further research is essential to confirm its safety and dopamine levels, which affect the reward value of food. Overall, MPH
efficacy in broader, more diverse populations and to determine its shows promise as a potential pharmacological intervention for weight
suitability for long-term use. management in obese and overweight individuals.
Some examples of real-world include one using a Phentermine Current studies are limited by small sample sizes, design
+ Topiramate combination for the treatment of obesity in heterogeneity, short follow-up periods, and lack of integral
adolescents included a lifestyle intervention for both placebo and accompanying interventions. To build a robust evidence base, future
experimental groups. This study showed a maximum BMI loss of research should prioritize large-scale randomized controlled trials
10.44% after 56 weeks of treatment (56). Another trial using focusing on the long-term efficacy and safety of MPH in diverse
glucagon-like peptide-1 (GLP-1) agonists in patients with type-2 populations. Studies assessing cardiovascular risks in individuals with
diabetes in the “real world” found that over 67% of the participants obesity and MPH’s impact over extended periods are especially
lost more than 5% of their initial body weight at 72 weeks without important. Furthermore, analyzing the effect of MPH in combination
explicitly offering lifestyle interventions, and mean weight loss was with lifestyle modifications or other anorexigenic/weight-loss
2.2% (57). This is comparable with the magnitude of weight loss medications could provide further answers into its possible role within
found in the articles in this review, which was around 1.6% (26). a comprehensive weight management strategy. Understanding optimal
Also, the proportion of participants losing over 10% of their initial dosing and the role of gender differences in MPH’s effects on appetite
body weight was around 11% in Adler et al. (27). However, another and weight regulation also remain unanswered issues that need
article using GLP-1 agonists plus lifestyle interventions found that future addressing.
an exercise intervention increased the number of participants
losing weight 3.7 times compared to the control group and that
exercise protected participants from regaining weight after Data availability statement
treatment (58).
Another area that limits discussion is that it is difficult to compare The original contributions presented in the study are included in
the selected studies given their heterogeneity and that three articles the article/supplementary material, further inquiries can be directed
appear to come from the same cohort (21–23). Furthermore, to the corresponding author.
measurements, doses, and MPH presentations are not standardized
across the studies. Also, it is essential to remember that none of the
studies in Category 1 addressed any adverse effects of MPH that may Author contributions
become relevant in people with obesity.
MPH is not the first drug with noradrenergic/dopaminergic FV-G: Conceptualization, Investigation, Methodology, Writing –
activity to be considered to promote weight loss in individuals original draft, Writing – review & editing. SY: Writing – original draft,
with obesity or overweight. Amphetamine derivatives, Writing – review & editing. AO-M: Writing – original draft, Writing
phentermine, bupropion (all enhancing norepinephrine and – review & editing. VF-T: Conceptualization, Resources, Supervision,
dopamine activity through different mechanisms), and Writing – original draft, Writing – review & editing.
sibutramine (a serotonin and norepinephrine reuptake inhibitor),
among others, have been used alone or in combination to promote
weight loss. Similar drugs that are currently approved for weight Funding
loss come in combination. Examples include Phentermine +
Topiramate (an antiseizure drug with multiple targets) and The author(s) declare that no financial support was received for
Bupropion + Naltrexone (a μ-opioid receptor antagonist used in the research, authorship, and/or publication of this article.
higher doses to treat alcohol cravings) (20). Given its similar
pharmacodynamic profile and moderate weight-loss-inducing
properties, MPH could be a good candidate for further study. Conflict of interest
While MPH does enhance dopamine activity in reward-processing
brain areas and the evidence does show that MPH can decrease The authors declare that the research was conducted in the
weight and promote anorexia, more studies are needed to fully absence of any commercial or financial relationships that could
uncover adverse effects in people with obesity who may be at risk be construed as a potential conflict of interest.
of cardiovascular events, the optimal doses to promote weight loss The author(s) declared that they were an editorial board member
in different populations, and its potential to be combined with of Frontiers, at the time of submission. This had no impact on the peer
other drugs. review process and the final decision.

Frontiers in Nutrition 15 frontiersin.org

Vedrenne-Gutiérrez et al. 10.3389/fnut.2024.1497772

Publisher’s note or those of the publisher, the editors and the reviewers. Any
product that may be evaluated in this article, or claim that may
All claims expressed in this article are solely those of the authors be made by its manufacturer, is not guaranteed or endorsed by
and do not necessarily represent those of their affiliated organizations, the publisher.

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