Study objectives This project seeks to understand how an intervention based on time-restricted eating (ChronoFeeding or CF) can improve quality of life, behavior, sleep, and gut health in adults with ADHD (Attention Deficit Hyperactivity Disorder) who have alterations in their circadian rhythms. It will also study how this intervention affects biological markers, such as microbiota (gut and saliva bacteria), inflammation, and oxidative stress, in both humans and animal models. Methodology A randomized controlled pilot study will be conducted with 60 adults diagnosed with ADHD, aged between 18 and 65, who have extended eating habits (more than 14 hours a day) and sleep problems. People with chronic diseases, recent use of antibiotics (\< 6 months), or supplements that affect metabolism or sleep will be excluded. Participants will be divided into two groups: * Control group: will continue with their usual eating habits. * CF group: will reduce their eating window to 10 hours (breakfast between 9:30-10:00 a.m. and dinner between 7:30-8:00 p.m.), without changing what or how much they eat. For 12 weeks, adherence to the schedule will be assessed using food diaries and validated questionnaires on dietary habits. Clinical analyses will be performed before and after the intervention, including weight, sleep quality (measured using diaries), and psychological scales to assess symptoms of ADHD, anxiety, depression, and quality of life. Fasting blood samples will also be taken to analyze metabolic, hormonal, and inflammation markers. Factors such as the menstrual cycle, stress, environment, and medical history will be studied to better understand the effects of the intervention.
Study Rationale Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition that often persists into adulthood and is associated with a wide range of comorbidities, including mood disorders, metabolic dysfunction, and sleep disturbances. Adult ADHD remains underdiagnosed and undertreated, with current pharmacological therapies showing limited long-term efficacy and frequent side effects. Emerging evidence suggests that circadian misalignment and irregular eating patterns may exacerbate ADHD symptoms and reduce treatment responsiveness. This study investigates the hypothesis that aligning food intake with circadian rhythms-through a dietary strategy known as circadian fasting (CF)-can improve clinical outcomes in adults with ADHD. The intervention is non-invasive, non-pharmacological, and designed to modulate gut microbiota and circadian markers, potentially offering a novel therapeutic approach. Study Objectives The primary objective is to evaluate the impact of a 12-week circadian fasting protocol on cognitive and behavioral symptoms, sleep quality, circadian rhythmicity, and quality of life in adults diagnosed with ADHD. Secondary objectives include assessing changes in serum and salivary biomarkers, gut and oral microbiota composition and function, and exploring mechanistic pathways through animal and in vitro models. Study Design This is a randomized controlled pilot trial involving 60/60 adult participants diagnosed or not with ADHD. Participants will be randomly assigned to either a control group maintaining their habitual eating patterns or an intervention group following a time-restricted eating schedule (10-hour window from 9:30-10:00 AM to 7:30-8:00 PM). No restrictions will be placed on diet composition or caloric intake. Clinical assessments will be conducted at baseline and post-intervention, including validated scales for ADHD symptoms, impulsivity, sleep quality, emotional well-being, and quality of life. Actigraphy devices will be used to monitor sleep and activity cycles. Blood and saliva samples will be collected for biochemical and microbiota analysis. Microbiota and Biomarker Analysis Saliva and fecal samples will be collected at multiple time points to evaluate microbial rhythmicity and composition. Next-generation sequencing and metabolomics will be employed to identify microbial taxa and functional profiles associated with ADHD and CF intervention. Salivary cortisol and melatonin levels will be measured to assess circadian alignment. Mechanistic Studies Complementary animal studies using the spontaneously hypertensive rat (SHR) model of ADHD will assess the effects of CF on behavior, cognition, neuroinflammation, neurotransmission, and gut microbiota rhythmicity. Germ-free mice will be colonized with microbiota from ADHD patients pre- and post-intervention to evaluate causality. In vitro studies will utilize a human enteric nervous system (ENS) co-culture model to investigate the impact of ADHD-associated microbiota and CF-modulated microbiota on intestinal barrier function, oxidative stress, immune response, and neuronal activation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
SINGLE
Enrollment
60
12 consecutive weeks of circadian fasting consisting in 10/12-hour eating window and 14/12-hour fasting
Iata-Csic
Paterna, Valencia, Spain
Change in Adult ADHD Quality of Life (AAQoL) total score
The Adult ADHD Quality of Life (AAQoL) questionnaire assesses the impact of adult ADHD on a patient's life. AAQoL is a validated 29-item self-report instrument. Item responses are recorded on a 5-point Likert scale and transformed to a total score ranging from 0 to 100, where 0 represents the poorest quality of life (greatest impairment) and 100 represents the best quality of life (least impairment). Higher scores indicate better quality of life and less ADHD-related impairment. Comparison between mean change from baseline to 12 weeks in the AAQoL total score will be conducted for TRF (10-hour eating window) and control arms; analysis: between-group difference in mean change (ANCOVA adjusted for baseline score, age, sex).
Time frame: Baseline to 12 weeks (end of intervention)
Change in sleep efficiency assessed by daily sleep diary
Mean change from baseline to week 12 in sleep efficiency (%), assessed using a daily sleep diary. Sleep efficiency is calculated as the percentage of total sleep time divided by total time spent in bed and multiplied by 100. Higher values indicate greater sleep efficiency. The outcome will be analyzed as the between-group difference in mean change from baseline to week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to 12 weeks (end of intervention)
Change in total sleep duration assessed by daily sleep diary
Mean change from baseline to week 12 in total sleep duration (hours/night), assessed using a daily sleep diary. Total sleep duration is defined as the total number of hours slept per night. The outcome will be analyzed as the between-group difference in mean change from baseline to Week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to 12 weeks (end of intervention)
Change in Conners' Adult ADHD Rating Scales (CAARS) Total Score
Mean change from baseline to week 12 in the Conners' Adult ADHD Rating Scales (CAARS) Total Score. The CAARS is a validated questionnaire used to assess the severity of attention-deficit/hyperactivity disorder (ADHD) symptoms in adults, including inattention, hyperactivity, and impulsivity. Scores are reported as T-scores, with higher scores indicating greater ADHD symptom severity and lower scores indicating fewer symptoms. Scale: T-score \<60: within normal range T-score 60-64: mildly elevated T-score 65-69: moderately elevated T-score ≥70: markedly elevated and clinically significant. The outcome will be analyzed as the between-group difference in mean change from baseline to Week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to 12 weeks (end of intervention)
Change in Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Total Score
Mean change from baseline to week 12 in the Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV) Total Score. The ADHD-RS-IV is a validated clinician-administered rating scale used to assess the severity of ADHD symptoms. Total scores range from 0 to 54, with higher scores indicating greater ADHD symptom severity and lower scores indicating fewer symptoms. The outcome will be analyzed as the between-group difference in mean change from baseline to week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to 12 weeks (end of intervention)
Change in Pittsburgh Sleep Quality Index (PSQI) Global Score
Mean change from baseline to week 12 in the Pittsburgh Sleep Quality Index (PSQI) Global Score. The PSQI is a validated self-reported measure of subjective sleep quality and consists of 19 self-rated items that generate seven component scores (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction). The seven component scores are summed to yield a Global PSQI Score ranging from 0 to 21, where lower scores indicate better sleep quality and higher scores indicate worse sleep quality. The outcome will be analyzed as the between-group difference in mean change from baseline to Week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to 12 weeks (end of intervention)
Change in mid-sleep on free days corrected for sleep debt (MSFsc) derived from the Munich Chronotype Questionnaire (MCTQ)
Mean change from baseline to week 12 in mid-sleep on free days corrected for sleep debt accumulated on workdays (MSFsc), derived from responses to the Munich Chronotype Questionnaire (MCTQ). MSFsc is a validated indicator of chronotype and circadian timing and is expressed as clock time (hours:minutes). Earlier MSFsc values indicate greater morning preference, whereas later MSFsc values indicate greater evening preference. The outcome will be analyzed as the between-group difference in mean change from baseline to week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to 12 weeks (end of intervention)
Change in salivary cortisol concentration
Mean change from baseline to week 12 in salivary cortisol concentration (µg/dL) measured from saliva samples collected at four predefined time points during the day (8am, 12pm, 4pm, 8pm). Salivary cortisol concentration will be quantified to assess changes in diurnal cortisol secretion patterns. Reference values will be obtained from literature for non-ADHD and ADHD groups.
Time frame: Baseline to 12 weeks (end of intervention)
Change in Barratt Impulsiveness Scale Version 11 (BIS-11) Total Score
Mean change from baseline to week 12 in the Barratt Impulsiveness Scale Version 11 (BIS-11) Total Score. The BIS-11 is a validated self-report questionnaire that assesses impulsivity. Total scores range from 30 to 120 points, with higher scores indicating greater impulsivity and lower scores indicating lower impulsivity. The outcome will be analyzed as the between-group difference in mean change from baseline to week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to 12 weeks (end of intervention)
Clinical Global Impression-Improvement (CGI-I) Score at week 12
Clinical improvement at week 12 assessed using the Clinical Global Impression-Improvement (CGI-I) scale, a clinician-rated measure of overall change in clinical status relative to baseline. The CGI-I score ranges from 1 to 7, where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = Much worse, 7 = Very much worse. Clinical status will be evaluated by comparing CGI-I scores between intervention and non-intervention groups at the specified assessment time point. Lower CGI-I scores indicate greater clinical improvement relative to baseline.
Time frame: Baseline to 12 weeks (end of intervention)
Proportion of participants achieving ≥80% adherence to the assigned intervention
Percentage of participants achieving at least 80% adherence to the assigned intervention over the 12-week study period, assessed using participant adherence logs, digital monitoring records, and investigator review.
Time frame: Baseline to 12 weeks (end of intervention)
Change in relative abundance of selected gut microbial taxa assessed by 16S rRNA gene sequencing
Mean change from baseline to week 12 in the relative abundance (%) of predefined bacterial genera, assessed by 16S rRNA gene sequencing of stool samples. Relative abundance represents the proportion of sequencing reads assigned to each taxon.
Time frame: Baseline to week 12 (end of intervention)
Change in gut microbial alpha diversity assessed by 16S rRNA gene sequencing
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Mean change from baseline to week 12 in gut microbial alpha diversity, assessed by 16S rRNA gene sequencing of stool samples. Alpha diversity will be quantified using the Shannon Diversity Index (unitless), a measure of within-sample microbial diversity. Higher values indicate greater microbial diversity.
Time frame: Baseline to 12 weeks (end of intervention)
Change in gut microbial beta diversity assessed by 16S rRNA gene sequencing
Change from baseline to week 12 in gut microbial beta diversity, assessed by 16S rRNA gene sequencing of stool samples. Beta diversity will be evaluated using a distance-based metric (e.g., Bray-Curtis dissimilarity; unitless) to characterize differences in overall microbial community composition between samples.
Time frame: Baseline to week 12 (end of intervention)
Change in fecal short-chain fatty acid concentrations
Mean change from baseline to week 12 in fecal short-chain fatty acid (SCFA) concentrations (µmol/g stool), measured in stool samples. SCFAs may include acetate, propionate, and butyrate.
Time frame: Baseline to week 12 (end of intervention)
Changes in fecal calprotectin
Mean change from baseline to week 12 in fecal calprotectin concentration (µg/g). The primary analysis will compare the change from baseline to week 12 between the TRF (10-hour eating window) and control groups.
Time frame: Baseline to week 12 (end of intervention)
Changes in serum lipid profile biomarkers
Mean change from baseline to week 12 in serum lipid biomarkers measured by clinical laboratory assays, including: Total cholesterol (mg/dL); HDL cholesterol (mg/dL); LDL cholesterol (mg/dL); VLDL cholesterol (mg/dL); Triglycerides (mg/dL)
Time frame: Baseline to 12 weeks (end of intervention)
Change in serum corticotropin (ACTH) concentration
Mean change from baseline to week 12 in serum corticotropin (ACTH) levels (pg/mL) measured using standard clinical laboratory methods.
Time frame: Baseline to 12 weeks (end of intervention)
Changes in serum protein biomarkers
Mean change from baseline to week 12 in serum protein biomarkers measured by clinical laboratory assays, including: Albumin (g/dL) and Total protein (g/dL)
Time frame: Baseline to 12 weeks (end of intervention)
Change in serum IL6
Mean change from baseline to week 12 in serum IL6 concentration (pg/mL) using standard clinical laboratory methods.
Time frame: Baseline to 12 weeks (end of intervention)
Changes in serum electrolyte biomarkers
Mean change from baseline to week 12 in serum electrolyte biomarkers measured using standard clinical laboratory methods. Biomarkers will be analyzed individually and reported in their respective units and include: Sodium (mEq/L) Potassium (mEq/L) Chloride (mEq/L)
Time frame: Baseline to week 12 (end of intervention)
Change in body weight
Mean change from baseline to week 12 in body weight (kg) measured using a calibrated scale. Lower values indicate weight loss, whereas higher values indicate weight gain relative to baseline.
Time frame: Baseline to 12 weeks (end of intervention)
Changes in Body Mass Index
Mean change from baseline to week 12 in Body Mass Index (BMI), calculated as body weight in kilograms divided by height in meters squared (kg/m²).
Time frame: Baseline to week 12 (end of intervention)
Change in Transepithelial Electrical Resistance (TEER)
Change in intestinal barrier integrity assessed by transepithelial electrical resistance (TEER) in in vitro models following exposure to intervention-derived fecal samples. TEER is expressed in Ω·cm², with higher values indicating greater epithelial barrier integrity.
Time frame: 24 months