A Clinical Trial Evaluating Fecal Microbiota Transplantation (FMT) in Adolescents With ADHD

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder affecting 5% to 7% of children globally, with up to 60% of cases persisting into adulthood. ADHD is characterized by persistent inattention, hyperactivity, and impulsivity, often leading to impairments in occupational, social, and academic functioning, while imposing profound socioeconomic burdens through direct medical costs and productivity losses. Due to current approved pharmacotherapy treatments yielding incomplete symptom relief or intolerable side effects there is an urgent need for innovative treatment options. Emerging evidence implicates the microbiota-gut-brain axis (MGBA) in ADHD, pointing to a unique, potentially dysbiotic gut microbiome profile in individuals with ADHD, marked by reduced alpha and beta diversity and fewer short-chain fatty acid producers. Thus, potentially driving ADHD pathology through low-grade inflammation, "leaky gut" and disrupted neurotransmitter precursor synthesis (dopamine, serotonin, GABA). Following promising results in autism spectrum disorder, fecal microbiota transplantation (FMT) presents a novel approach to address symptom management in ADHD. Unlike probiotics or dietary changes that introduce isolated strains, FMT systemically restructures the microbial network through competitive exclusion, restoring metabolic and ecological functions. Preclinical evidence strongly supports FMT's therapeutic potential as transplanting stool from humans with ADHD into germ-free mice induced ADHD-like behaviors and structural brain alterations in executive function regions. Conversely, transferring healthy donor stool into ADHD-like rodent models, reduced hyperactivity. However, clinical evidence is virtually nonexistent, with a single case report of a woman experiencing relief of her ADHD symptoms after FMT for a C. difficile infection. Pinpointing precise bidirectional MGBA mechanisms remains challenging due to confounding lifestyles, heterogeneous phenotypes, and microbiome complexity. Consequently, rigorous interventional trials are needed to establish true causality and disentangle the clinical impacts of a microbial reset from the disruptive effects of antibiotic pre-conditioning. This study will directly address this critical gap by conducting a randomized, placebo-controlled trial of oral FMT in an adolescent population with ADHD.

Inclusion criteria

• Between 13-17 years of age with consent of a legal guardian: Participants should be at least 13 years old and not older than 17 years at the day of screening (V1).
• Have a primary diagnosis of ADHD as confirmed by the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID).
• Be on a stable appropriate dose of an appropriate first-line pharmacological treatment for at least 8 weeks prior to the day of screening (V1).

a. First line pharmacotherapy treatment will be defined based on the CADDRA guidelines [63] and include the following

Amphetamine-based psychostimulants:

i. Mixed amphetamine salts (amphetamine and dextroamphetamine) ii. Lisdexamfetamine dimesylate

Methylphenidate-based psychostimulants:

i. Methylphenidate hydrochloride, Methylphenidate hydrochloride (extended release, multilayer release capsules) ii. Methylphenidate hydrochloride (extended release, OROS tablets) iii. Methylphenidate hydrochloride (controlled release, multi-layer beat capsules) iv. Methylphenidate hydrochloride (extended-release oral suspension)

• Have a score of ≥ 18 on the inattention subset (questions 1-9) and/or the hyperactivity/impulsivity subset (questions 10-18) of the SNAP-IV 26-Item Parent Rating Scale on the day of screening (V1) and the baseline visit (V2).
• Able to communicate and complete study assessments in English.
• Able to comply with all protocol procedures.
• Consenting guardian

Exclusion criteria

• Participant meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) Criteria for the following conditions according to the MINI-KID:

• Diagnosis of a Substance Use Disorder within the last 3 months prior to screening. *(Criteria should include Alcohol and Non-Alcohol substances except Cannabis)
• Moderate or severe Substance Use Disorder for Cannabis use in the last 3 months
• Currently active high suicidality. Eligibility of Participants who meet criteria for moderate suicidality is determined by clinical judgment of Principal Investigator.
• Active Anorexia Nervosa or Bulimia Nervosa in the last 3 months.
• Tic Disorders
• Psychosis
• Obsessive Compulsive Disorder
• Bipolar Disorder
• Conduct Disorder
• Participant has a score of ≥ 8 on the oppositional defiant subset of the SNAP-IV 26-Item Parent Rating Scale (questions 19-26) on the day of screening (V1).
• Intellectual or learning disability based on previous documented diagnosis or clinical judgment of Principal Investigator.
• Documented diagnosis of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) or Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS).
• Documented diagnosis of schizophrenia or schizoaffective disorder.
• Documented diagnosis of Autism Spectrum Disorder (ASD) or currently undergoing assessment for suspected ASD.
• Use of systemic antibiotics for medical purposes within the last 3 months prior to the day of screening (V1).
• Use of prebiotics or probiotics for medical purposes for more than 2 weeks within the last 3 months prior to the day of screening (V1).

a) Eligibility and required washout period of participants with use of over-the-counter prebiotics or probiotics will be determined by clinical judgment of Principal Investigator.

• Use of experimental drugs in the last 3 months prior to the day of screening (V1).
• Documented clinical diagnosis of inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, and/or celiac disease.
• Documented diagnosis of conditions causing immunosuppression and/or currently receiving immunosuppressive treatments.
• Documented clinical diagnosis of significant bleeding disorders.
• History of oropharyngeal dysphagia or other swallowing disorder, and/or self or study partner reported difficulty with taking oral capsules or pills.
• Breastfeeding, pregnant or seeking to get pregnant during the course of this study. Female participants of childbearing age should be using an acceptable method of birth control (implants, injectable, combined oral contraceptives, IUDs, barrier contraceptives, sexual abstinence, or a vasectomized partner) for the duration of their participation in the trial.
• Participants who are currently hospitalized or institutionalized.
• Reported allergy to Vancomycin or Nitazoxanide
• Hepatic dysfunction:

A) Documented history or current diagnosis of an acute or chronic hepatic disease (e.g., cirrhosis, hepatitis, hepatic impairment) OR

B) Abnormal - Liver Function Tests (LFTs): Screening laboratory results indicating clinically significant hepatic dysfunction:

• Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) ≥3 the Upper Normal Limit (UNL)
• Total Bilirubin > 1.5 × ULN (except in cases of documented Gilbert's Syndrome) 19. Renal dysfunction: A) Diagnosed Renal Disease: Any documented medical history or current diagnosis of kidney disease, acute kidney injury, or other clinically significant renal impairment. OR B) Abnormal Renal Function Tests: Screening laboratory results indicating significant renal dysfunction. Creatinine > 1.5 × ULN*

• Potential participants presenting with mild, non-clinically significant laboratory abnormalities (e.g., AST/ALT between 1.0 and 3.0 × ULN, or isolated borderline creatinine variations confirmation of enrollment into the study will be dependent of the study physician.