Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood, affecting an estimated 5% of children and adolescents globally. Persistence into adulthood is common, with prevalence estimated to be about 2.5%.
Due to the negative health effects it causes and the significant financial burden on healthcare and society, alternative treatment approaches beyond medication have been investigated.
Research is increasingly focused on the bidirectional signaling between the gut and the brain, which may affect neurodevelopmental disorders such as ADHD. Gut microbiota modification through the use of probiotics in ADHD patients may present a novel therapy.
This blog explores the evidence for the role of gut microbiota in the pathophysiology of ADHD and then describes research on gut microbiome-targeted interventions—mainly the use of probiotics— in ADHD.
ADHD, in brief
ADHD is marked by an ongoing pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development and often persists into adulthood. Untreated ADHD can result in significant issues including academic struggles, social problems, accidents, strained family ties, and career disorganization.
The disorder’s complex etiology involves genetic predispositions primarily while various environmental influences, including perinatal complications like prematurity and low birthweight, as well as psychosocial factors such as adoption and neglect, are thought to contribute. These conditions can lead to neurobiological dysfunctions affecting catecholaminergic neurotransmission. In essence, altered levels of brain chemicals such as dopamine and norepinephrine (catecholamines) can cause inflammation and oxidative stress which damage neurons and worsen symptoms of ADHD.
For nearly a century, psychostimulants have remained the primary medications for addressing ADHD symptoms. These medications largely comprise methylphenidate and amphetamine formulations, which share similar mechanisms of action. Methylphenidate blocks dopamine and norepinephrine transporters, boosting catecholamine transmission, while amphetamine inhibits these transporters and enhances dopamine efflux from presynaptic terminals. However, the lasting impact of these treatments on crucial educational, vocational, and social results remains unclear. Additionally, low adherence, particularly after prolonged use during adolescence, exacerbates these effects. Additionally, ADHD medications increase the likelihood of reduced appetite, weight loss, and abdominal discomfort in children and adolescents.
Emerging research shows the involvement of changes and imbalances in the intestinal microbiota in ADHD.
ADHD and the gut microbiome
The gut-brain axis is currently under study in ADHD due to the evidence on how gut microbiota can influence brain activity bidirectionally. Dysbiosis, an imbalance in microbiota composition, may lead to inflammation, compromised gut permeability, microbial translocation, systemic inflammation, and oxidative stress, affecting neural cells and ADHD-related neurotransmitters.
Indeed, several studies have observed links between gut microbiome composition and ADHD.
The first reported microbial composition differences were in Dutch young adults with ADHD where Bifidobacterium was seen to be significantly increased in the ADHD cohort. An increased abundance of Bifidobacterium was also observed in a later study. The authors suggested a possible influence on dopamine-related pathways that may lead to reduced reward anticipation, a hallmark of ADHD.
However, a decreased abundance of Bifidobacterium species bacteria in infants diagnosed later with ADHD was observed in one study, which may reflect delayed maturation of the microbiome in ADHD.
In addition, research revealed a higher abundance of Bacteroidaceae in adolescents with ADHD which was later supported by another study.
A reduced amount of Faecalibacterium was also found in ADHD patients in two studies. As Faecalibacterium is known for its anti-inflammatory products, its relative scarcity could possibly lead to an overproduction of pro-inflammatory cytokines, which is found in children with ADHD.
Additionally, a recent study noted significant associations between Clostridiales and ADHD, consistent with findings of alterations in related microbial taxa in other studies.
Gut microbes, fatty acids, and sleep
Fatty acids
Omega-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) influence neurotransmission and neuroprotection, potentially ameliorating ADHD symptoms and neuroinflammation. Studies show that individuals with ADHD often have lower omega-3 PUFA levels and higher omega-6:omega-3 ratios than controls, suggesting potential benefits from the administration of probiotics that may boost omega-3 PUFA,
The interplay between omega-3 PUFAs and the gut microbiome, affecting fatty acid profiles and microbial composition, may provide new avenues for ADHD treatment, targeting neurotransmitter pathways and gut health to improve symptoms and inflammation.
Sleep
Sleep disorders, common in children with ADHD, impact cognitive and behavioral functioning, potentially exacerbated by delayed circadian rhythms associated with melatonin secretion. Research indicates a bidirectional relationship between gut microbiota and sleep, with disruptions in microbial composition potentially contributing to altered melatonin levels, suggesting a role for gut-brain axis interactions in ADHD-related sleep disturbances.
Probiotic interventions
The involvement of the gut microbiome-gut-brain axis in ADHD pathophysiology suggests its potential as a therapeutic target, particularly through probiotic interventions. Reviewers report that clinical trials exploring probiotic supplementation in ADHD have shown mixed results; while some studies demonstrated reductions in ADHD risk alongside improvements in cognitive function and behavior, others presented ambiguous findings with limited consistency across interventions and outcome measures. Let’s take a look at some of these studies:
A 2023 study found that specific strains of Lactobacillus acidophilus supplementation combined with medication (atomoxetine) for 3 months had a beneficial impact on ADHD symptoms and certain aspects of cognitive performance.
Additionally, Bifidobacterium bifidum supplementation in children with ADHD, showed improvements in symptoms and weight gain, suggesting a link between gut microbiota composition and ADHD, though further randomized controlled trials are needed to validate the findings.
Several studies found positive results with Lacticaseibacillus rhamnosus:
- In a 2015 prospective study, 75 infants were randomized to receive L. rhamnosus or placebo during the first six months of life. At the age of 13 y, ADHD or a mild form of autism was diagnosed in 17% of children in the placebo group and none in the probiotic group.
- A more recent randomized control trial showed that children and adolescents with ADHD who had received L. rhamnosus supplementation showed better self-reported health-related quality of life scores.
- In another study, researchers noted beneficial outcomes from supplementing with the same strain of L. rhamnosus on cognitive abilities in children and teenagers, leading to a decreased likelihood of ADHD development.
However, a 2024 meta-analysis of seven trials involving 379 participants found no significant improvement in ADHD symptoms with probiotic supplementation compared to placebo, but there were notable differences in effect size between studies using probiotics as an adjunct to methylphenidate versus those using probiotics alone and between studies using multiple strains versus single-strain regimens.
Importantly, significant disparities are evident across studies, with differences in sample demographics, intervention methods, and outcome assessments, underscoring the necessity for additional research to clarify the therapeutic possibilities and mechanisms of probiotic interventions in managing ADHD.
Takeaway
ADHD, affecting around 5% of children and adolescents globally and which can persist into adulthood, poses significant health and societal burdens. Research into the gut-brain axis suggests modifying gut microbiota through probiotics could offer a novel treatment avenue. Studies link gut microbiome changes to ADHD, potentially contributing to inflammation and neurotransmitter dysregulation. Omega-3 PUFAs and sleep disturbances also impact ADHD, with interactions with the gut microbiome offering new treatment possibilities. While some studies show promising results with probiotics, others are inconclusive, necessitating further research to understand their therapeutic potential in managing ADHD.
Key references
Aarts, Esther et al. “Gut microbiome in ADHD and its relation to neural reward anticipation.” PloS one vol. 12,9 e0183509. 1 Sep. 2017, doi:10.1371/journal.pone.0183509
Adler, Lisa D, and Andrew A Nierenberg. “Review of medication adherence in children and adults with ADHD.” Postgraduate medicine vol. 122,1 (2010): 184-91. doi:10.3810/pgm.2010.01.2112
Boonchooduang, Nonglak et al. “Possible links between gut-microbiota and attention-deficit/hyperactivity disorders in children and adolescents.” European journal of nutrition vol. 59,8 (2020): 3391-3403. doi:10.1007/s00394-020-02383-1
Bundgaard-Nielsen, Caspar et al. “Gut microbiota profiles of autism spectrum disorder and attention deficit/hyperactivity disorder: A systematic literature review.” Gut microbes vol. 11,5 (2020): 1172-1187. doi:10.1080/19490976.2020.1748258
Carabotti, Marilia et al. “The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.” Annals of gastroenterology vol. 28,2 (2015): 203-209.
Cenit, María Carmen et al. “Gut microbiota and attention deficit hyperactivity disorder: new perspectives for a challenging condition.” European child & adolescent psychiatry vol. 26,9 (2017): 1081-1092. doi:10.1007/s00787-017-0969-z
Chang, Zheng et al. “Risks and Benefits of Attention-Deficit/Hyperactivity Disorder Medication on Behavioral and Neuropsychiatric Outcomes: A Qualitative Review of Pharmacoepidemiology Studies Using Linked Prescription Databases.” Biological psychiatry vol. 86,5 (2019): 335-343. doi:10.1016/j.biopsych.2019.04.009
Checa-Ros, Ana et al. “Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications.” Nutrients vol. 13,1 249. 16 Jan. 2021, doi:10.3390/nu13010249
Cheng, Shiqiang et al. “Identifying psychiatric disorder-associated gut microbiota using microbiota-related gene set enrichment analysis.” Briefings in bioinformatics vol. 21,3 (2020): 1016-1022. doi:10.1093/bib/bbz034
Corona, Juan Carlos. “Role of Oxidative Stress and Neuroinflammation in Attention-Deficit/Hyperactivity Disorder.” Antioxidants (Basel, Switzerland) vol. 9,11 1039. 23 Oct. 2020, doi:10.3390/antiox9111039
Dam, Sarita A et al. “The Role of the Gut-Brain Axis in Attention-Deficit/Hyperactivity Disorder.” Gastroenterology clinics of North America vol. 48,3 (2019): 407-431. doi:10.1016/j.gtc.2019.05.001
Del Campo, Natalia et al. “The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder.” Biological psychiatry vol. 69,12 (2011): e145-57. doi:10.1016/j.biopsych.2011.02.036
Dyall, Simon C. “Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA.” Frontiers in aging neuroscience vol. 7 52. 21 Apr. 2015, doi:10.3389/fnagi.2015.00052
Elhossiny, Reham M et al. “Assessment of probiotic strain Lactobacillus acidophilus LB supplementation as adjunctive management of attention-deficit hyperactivity disorder in children and adolescents: a randomized controlled clinical trial.” BMC psychiatry vol. 23,1 823. 9 Nov. 2023, doi:10.1186/s12888-023-05324-4
Holmskov, Mathilde et al. “Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.” PloS one vol. 12,6 e0178187. 15 Jun. 2017, doi:10.1371/journal.pone.0178187
Kalenik, Anna et al. “Gut microbiota and probiotic therapy in ADHD: A review of current knowledge.” Progress in neuro-psychopharmacology & biological psychiatry vol. 110 (2021): 110277. doi:10.1016/j.pnpbp.2021.110277
Kumperscak, Hojka Gregoric et al. “A Pilot Randomized Control Trial With the Probiotic Strain Lactobacillus rhamnosus GG (LGG) in ADHD: Children and Adolescents Report Better Health-Related Quality of Life.” Frontiers in psychiatry vol. 11 181. 17 Mar. 2020, doi:10.3389/fpsyt.2020.00181
LaChance, Laura et al. “Omega-6 to Omega-3 Fatty Acid Ratio in Patients with ADHD: A Meta-Analysis.” Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l’Academie canadienne de psychiatrie de l’enfant et de l’adolescent vol. 25,2 (2016): 87-96.
Liang, Shun-Chin et al. “Therapeutic efficacy of probiotics for symptoms of attention-deficit hyperactivity disorder in children and adolescents: meta-analysis.” BJPsych open vol. 10,1 e36. 25 Jan. 2024, doi:10.1192/bjo.2023.645
Ligezka, Anna N et al. “A systematic review of microbiome changes and impact of probiotic supplementation in children and adolescents with neuropsychiatric disorders.” Progress in neuro-psychopharmacology & biological psychiatry vol. 108 (2021): 110187. doi:10.1016/j.pnpbp.2020.110187
Matenchuk, Brittany A et al. “Sleep, circadian rhythm, and gut microbiota.” Sleep medicine reviews vol. 53 (2020): 101340. doi:10.1016/j.smrv.2020.101340
Mathee, Kalai et al. “The gut microbiome and neuropsychiatric disorders: implications for attention deficit hyperactivity disorder (ADHD).” Journal of medical microbiology vol. 69,1 (2020): 14-24. doi:10.1099/jmm.0.001112
Pärtty, Anna et al. “A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial.” Pediatric research vol. 77,6 (2015): 823-8. doi:10.1038/pr.2015.51
Posner, Jonathan et al. “Attention-deficit hyperactivity disorder.” Lancet (London, England) vol. 395,10222 (2020): 450-462. doi:10.1016/S0140-6736(19)33004-1
Prehn-Kristensen, Alexander et al. “Reduced microbiome alpha diversity in young patients with ADHD.” PloS one vol. 13,7 e0200728. 12 Jul. 2018, doi:10.1371/journal.pone.0200728
Rianda, D et al. “Effect of probiotic supplementation on cognitive function in children and adolescents: a systematic review of randomised trials.” Beneficial microbes vol. 10,8 (2019): 873-882. doi:10.3920/BM2019.0068
Salvi, Virginio et al. “ADHD and Bipolar Disorder in Adulthood: Clinical and Treatment Implications.” Medicina (Kaunas, Lithuania) vol. 57,5 466. 10 May. 2021, doi:10.3390/medicina57050466
Sandgren, Anna M, and Robert J M Brummer. “ADHD-originating in the gut? The emergence of a new explanatory model.” Medical hypotheses vol. 120 (2018): 135-145. doi:10.1016/j.mehy.2018.08.022
Song, Peige et al. “The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis.” Journal of global health vol. 11 04009. 11 Feb. 2021, doi:10.7189/jogh.11.04009
Stevens, Aaron J et al. “Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder.” Scientific reports vol. 9,1 10128. 12 Jul. 2019, doi:10.1038/s41598-019-46146-3
Sukmajaya, Alverina Cynthia et al. “Systematic review of gut microbiota and attention-deficit hyperactivity disorder (ADHD).” Annals of general psychiatry vol. 20,1 12. 16 Feb. 2021, doi:10.1186/s12991-021-00330-w
Wang, Liang-Jen et al. “Effect of Bifidobacterium bifidum on Clinical Characteristics and Gut Microbiota in Attention-Deficit/Hyperactivity Disorder.” Journal of personalized medicine vol. 12,2 227. 7 Feb. 2022, doi:10.3390/jpm12020227
Wang, Liang-Jen et al. “Gut microbiota and dietary patterns in children with attention-deficit/hyperactivity disorder.” European child & adolescent psychiatry vol. 29,3 (2020): 287-297. doi:10.1007/s00787-019-01352-2
Yin, Huimei et al. “Relationship between sleep disorders and attention-deficit-hyperactivity disorder in children.” Frontiers in pediatrics vol. 10 919572. 22 Jul. 2022, doi:10.3389/fped.2022.919572