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July 21, 2025
New research has uncovered important links between certain blood metabolites and ADHD by using a genetic method called Mendelian randomization. This approach leverages natural genetic differences to help identify which metabolites might actually cause changes in ADHD risk, offering stronger clues than traditional observational studies.
Key Metabolic Pathways Involved:
The study found 42 plasma metabolites with a causal relationship to ADHD. Most fall into two major groups:
Since many metabolites come from dietary sources like proteins and fats this supports the idea that diet could influence metabolic pathways involved in ADHD. However, because the study focused on genetic influences on metabolite levels, it doesn’t directly prove that dietary changes will have the same effects.
Notable Metabolites:
Five metabolites showed bidirectional links with ADHD, meaning genetic risk for ADHD also affects their levels which suggests a complex interaction between brain function and metabolism.
Twelve ADHD-related metabolites are targets of existing drugs or supplements, including:
While these findings highlight biological pathways, they don’t prove that changing diet will directly alter ADHD symptoms. Metabolite levels are shaped by genetics plus environment, lifestyle, and health factors, which require further study.
Conclusion:
This research provides stronger evidence of metabolic pathways involved in ADHD and points to new possibilities for diagnosis and treatment. Future work could explore how diet or drugs might safely adjust these metabolites to help manage ADHD.
While this study strengthens the link between amino acid and fatty acid metabolism and ADHD risk, suggesting that diet could play a role, ultimately more research is still needed before experts could use this research to give specific nutritional advice.
Shi S, Baranova A, Cao H, Zhang F. Exploring causal associations between plasma metabolites and attention-deficit/hyperactivity disorder. BMC Psychiatry. 2025 May 16;25(1):498. doi: 10.1186/s12888-025-06951-9. PMID: 40380147; PMCID: PMC12084988.
A relatively new area of ADHD research has been examining the association between ADHD and eating disorders (i.e., anorexia nervosa, bulimia nervosa, and binge-eating disorder). Nazar and colleagues conducted a systematic review and meta-analysis of extant studies.
They found only twelve studies that assessed the presence of eating disorders among people with ADHD and five that examined the prevalence of ADHD among patients with eating disorders. Although there were few studies, the total number of people studied was large, with 4,013 ADHD cases and 29,404 controls for the first set of studies and 1,044 eating disorder cases and 11,292 controls for the second set of studies. The meta-analyses of these data found that ADHD people had a 3.8-fold increased risk for an eating disorder compared with non-ADHD controls. The level of risk was similar for each of the eating disorders. Consistent with this, their second meta-analysis found that people with eating disorders had a 2.6-fold increased risk for ADHD compared with controls who did not have an eating disorder. The risk for ADHD was highest for those with binge-eating disorder (5.8-fold increased risk compared with controls).
This bidirectional association between ADHD and eating disorders provides converging evidence that this association is real and, given its magnitude, clinically significant. The results were similar for males and females and pediatric and adult populations.
We cannot tell from these data why ADHD is associated with eating disorders. Nazar et al. note that other work implicates both impulsivity and inattention in promoting bulimic symptoms, whereas inattention and hyperactivity are associated with craving. The association may also be due to the neurocognitive deficits of ADHD, which could lead to a distorted sense of self-awareness and body image.
Given that ADHD is also associated with obesity, some obese ADHD patients may have an underlying eating disorder, such as binge-eating, which has been associated with obesity in prospective studies. Also, lisdexamfetamine is FDA-approved for treating both binge eating and ADHD, which suggests the possibility that the two conditions share an underlying etiology involving the dopamine system. We do not know if treating ADHD would reduce the risk for eating disorders, as that hypothesis has not yet been tested. But such an effect would seem likely if ADHD behaviors mediate the association between the two disorders.
If we are to read what we believe on the Internet, dieting can cure many of the ills faced by humans. Much of what is written is true. Changes in dieting can be good for heart disease, diabetes, high blood pressure, and kidney stones to name just a few examples. But what about ADHD? Food elimination diets have been extensively studied for their ability to treat ADHD. They are based on the very reasonable idea that allergies or toxic reactions to foods can have effects on the brain and could lead to ADHD symptoms.
Although the idea is reasonable, it is not such an easy task to figure out what foods might cause allergic reactions that could lead to ADHD symptoms. Some proponents of elimination diets have proposed eliminating a single food, others include multiple foods, and some go as far as to allow only a few foods to be eaten to avoid all potential allergies. Most readers will wonder if such restrictive diets, even if they did work, are feasible. That is certainly a concern for very restrictive diets.
Perhaps the most well-known ADHD diet is the Feingold diet(named after its creator). This diet eliminates artificial food colorings and preservatives that have become so common in the western diet. Some have claimed that the increasing use of colorings and preservatives explains why the prevalence of ADHD is greater in Western countries and has been increasing over time. But those people have it wrong. The prevalence of ADHD is similar around the world and has not been increasing over time. That has been well documented but details must wait for another blog.
The Feingold and other elimination diets have been studied by meta-analysis. This means that someone analyzed several well-controlled trials published by other people. Passing the test of meta-analysis is the strongest test of any treatment effect. When this test is applied to the best studies available, there is evidence that the exclusion of fool colorings helps reduce ADHD symptoms. But more restrictive diets are not effective. So removing artificial food colors seems like a good idea that will help reduce ADHD symptoms. But although such diets ‘work’, they do network very well. On a scale of one to 10where 10 is the best effect, drug therapy scores 9 to 10 but eliminating food colorings scores only 3 or 4. Some patients or parents of patients might want this diet change first in the hopes that it will work well for them. That is a possibility, but if that is your choice, you should not delay the more effective drug treatments for too long in the likely event that eliminating food colorings is not sufficient. You can learn more about elimination diets from Nigg, J. T., and K.Holton (2014). "Restriction and elimination diets in ADHD treatment."Child Adolesc Psychiatr Clin N Am 23(4): 937-953.
Keep in mind that the treatment guidelines from professional organizations point to ADHD drugs as the first-line treatment for ADHD. The only exception is for preschool children where medication is only the first-line treatment for severe ADHD; the guidelines recommend that other preschoolers with ADHD be treated with non-pharmacologic treatments, when available. You can learn more about non-pharmacologic treatments for ADHD from a book I recently edited: Faraone, S. V. &Antshel, K. M. (2014). ADHD: Non-Pharmacologic Interventions. Child AdolescPsychiatr Clin N Am 23, xiii-xiv.
A Swedish-Danish-Dutch team used the Swedish Medical Birth Register to identify the almost 1.7 million individuals born in the country between 1980 and 1995. Then, using the Multi-Generation Register, they identified 341,066 pairs of full siblings and 46,142 pairs of maternal half-siblings, totaling 774,416 individuals.
The team used the National Patient Register to identify diagnoses of ADHD, as well as neurodevelopmental disorders (autism spectrum disorder, developmental disorders, intellectual disability, motor disorders), externalizing psychiatric disorders (oppositional defiant and related disorders, alcohol misuse, drug misuse), and internalizing psychiatric disorders (depression, anxiety disorder, phobias, stress disorders, obsessive-compulsive disorder).
The team found that ADHD was strongly correlated with general psychopathology overall (r =0.67), as well as with the neurodevelopmental (r = 0.75), externalizing (r =0.67), and internalizing (r = 0.67) sub factors.
To tease out the effects of heredity, shared environment, and non-shared environment, a multivariate correlation model was used. Genetic variables were estimated by fixing them to correlate between siblings at their expected average gene sharing (0.5for full siblings, 0.25 for half-siblings). Non-genetic environmental components shared by siblings (such as growing up in the same family) were estimated by fixing them to correlate at 1 across full and half-siblings. Finally, non-shared environmental variables were estimated by fixing them to correlate at zero across all siblings.
This model estimated the heritability of the general psychopathology factor at 49%, with the contribution of the shared environment at 7 percent and the non-shared environment at 44%. After adjusting for the general psychopathology factor, ADHD showed a significant and moderately strong phenotypic correlation with the neurodevelopmental-specific factor (r = 0.43), and a significantly smaller correlation with the externalizing-specific factor (r = 0.25).
For phenotypic correlation between ADHD and the general psychopathology factor, genetics explained 52% of the total correlation, the non-shared environment 39%, and the shared familial environment only 9%. For the phenotypic correlation between ADHD and the neurodevelopmental-specific factor, genetics explained the entire correlation because the other two factors had competing effects that canceled each other out. For the phenotypic correlation between ADHD and the externalizing-specific factor, genetics explained 23% of the correlation, shared environment 22%, and non-shared environment 55%.
The authors concluded that "ADHD is more phenotypically and genetically linked to neurodevelopmental disorders than to externalizing and internalizing disorders, after accounting for a general psychopathology factor. ... After accounting for the general psychopathology factor, the correlation between ADHD and the neurodevelopmental-specific factor remained moderately strong, and was largely genetic in origin, suggesting substantial unique sharing of biological mechanisms among disorders. In contrast, the correlation between ADHD and the externalizing-specific factor was much smaller and was largely explained by-shared environmental effects. Lastly, the correlation between ADHD and the internalizing subfactor was almost entirely explained by the general psychopathology factor. This finding suggests that the comorbidity of ADHD and internalizing disorders are largely due to shared genetic effects and non-shared environmental influences that have effects on general psychopathology."
For many ADHD patients, getting properly diagnosed and starting meds is only half the battle. The next step is figuring out the exact right dose. Historically, clinical guidelines have provided scant guidance on this critical step. This lack of direction can inadvertently foster two extremes in clinical practice: therapeutic inertia (settling for a subtherapeutic dose that leaves symptoms undertreated) or uncritical escalation (driving doses higher and higher beyond licensed limits without meaningful benefit).
To clear up this pharmacological gray area, an international team of researchers published the first comprehensive dose-effect network meta-analysis of ADHD medications in The Lancet Psychiatry. By pulling together a massive vault of clinical trial data, they mapped out exactly how efficacy and tolerability shift as doses increase.
Traditional meta-analyses evaluate head-to-head, pairwise data, comparing one drug at a specific dose directly against a placebo. However, this study utilized an advanced Bayesian hierarchical network model using restricted cubic splines.
This mathematical framework allowed the researchers to combine both direct trial data and indirect evidence simultaneously across 113 double-blind randomized controlled trials (RCTs). In total, the study evaluated data from 14,138 children/adolescents and 11,016 adults. By standardizing various formulations into basic equivalents (e.g., converting amphetamines to dextroamphetamine equivalents), they created a clear, unified map of dose ranges.
The study yielded distinct dose-response curves depending on the patient's age and the specific medication class. Rather than a linear trend in which "more medicine equals more benefit," most treatments reach a clear statistical plateau or ceiling.
For Children and Adolescents (under 18)
In the pediatric population, medications hit clear peak efficacy boundaries:
For both amphetamines and guanfacine, escalating the dosage past these points resulted in U-shaped curves, meaning further dose hikes yielded diminishing group-level symptom reduction.
For Adults (18 and older)
Adult profiles showed slightly different trajectories:
The ultimate goal of this landmark analysis is to guide shared decision-making between clinicians, patients, and families. The results send a dual message to the medical community:
A medication's true efficacy hinges on its tolerability, typically measured by how often patients discontinue treatment due to severe side effects. For amphetamines, this dropout risk scales linearly with dosage, notably exceeding placebo in children above 25 mg/day and becoming prominent in adults past 50 mg/day. In contrast, methylphenidate shows no clear dose-dependent dropout risk in pediatric patients, whereas adults face a steep risk curve: increasing the dose from 60 mg/day to 90 mg/day raises the dropout risk from 7.3% to 10.0% for only modest symptom relief. Finally, youth taking guanfacine experience a sharp climb in discontinuation risks, reaching a 9.8% median risk at 4 mg/day before data limitations obscure further trends.
The authors strongly emphasize that these findings represent group averages. Because individual metabolism, genetics, and comorbidities vary widely, some specific patients may legitimately require and tolerate higher off-label doses. However, if an unusually high dose is needed, the study suggests it should prompt a careful clinical pause, either to reassess for co-occurring conditions (like anxiety, autism, or sleep disorders) or to manage realistic expectations regarding what the medication can achieve.
The persistent shortage of ADHD medications has been more than a simple annoyance for patients at the pharmacy; the inconsistent availability of these medications has had deep impacts on the daily lives of those struggling without them. While public discourse has pointed fingers at over-prescribing or at restrictive DEA quotas, a recent economic evaluation in JAMA Health Forum suggests we’ve been looking in the wrong direction for an answer to what is causing this.
The reality of the shortage is less about increased demand and more about a fragile, globalized supply chain that snapped at a critical link.
Debunking the "Quota Myth":
The prevailing narrative suggested that the Drug Enforcement Administration (DEA) was stifling production by refusing to raise quotas. However, the data tells a different story. In 2022, manufacturers collectively met only about 70% of their allotted production quotas.
So we know that the problem wasn't that this DEA quota ceiling was too low. In fact, most manufacturers couldn't even reach it. Even when accounting for exports and domestic retail, production remained significantly below the legal limit. Even if the DEA had doubled its quotas, these medications still likely wouldn't have magically appeared on pharmacy shelves.
The most striking finding in the study is the correlation between the shortage and a sharp decline in the import of raw Active Pharmaceutical Ingredients (APIs). For the past decade, Germany has accounted for over 85% of US amphetamine imports. In 2022, these imports dropped by approximately 36.7%. When the API doesn't arrive at the factory, production for medium and small manufacturers grinds to a halt. Unlike larger pharmaceutical giants, these smaller players often lack the inventory cushion or flexibility to quickly pivot to a new supplier.
When the primary supply of amphetamine-based stimulants (like Adderall) faltered, it triggered a secondary crisis. Patients and clinicians, seeking alternatives, shifted toward lisdexamfetamine (Vyvanse) and methylphenidate (Ritalin/Concerta).
If we view this shortage purely through a regulatory or clinical lens, we miss the underlying cause of the crisis. The pharmaceutical industry has become a victim of its reliance on "just-in-time manufacturing” and highly concentrated sourcing. Because over 30% of APIs for the US market are produced in just one or two facilities globally, the system isn't just inefficient; it’s brittle. We are, in a sense, trapped in a system that prioritizes cost-reduction over the resilience required for public health.
The researchers suggest several policy shifts to prevent a repeat of this supply chain failure:
The ADHD medication shortage wasn't a failure of clinical oversight or a sudden surge in "TikTok-driven diagnoses”, as many have suggested. It was a failure of logistics. It reminds us that the path from a lab in Germany to a patient's hand in the US is far more precarious than we realized.
ADHD is a neurodevelopmental condition rooted in delayed or atypical maturation of the prefrontal cortex (the brain region that governs self-regulation). This maturational lag underlies the hallmark difficulties with attention, hyperactivity, and impulsivity, and also impairs what researchers call executive function: the cognitive toolkit we rely on for working memory, impulse control, mental flexibility, emotional regulation, and the ability to tolerate delays in reward.
The Background:
Standard treatments work through two main routes. Stimulant and non-stimulant medications are considered very safe and effective treatments, but are not without risk of side effects and are not appropriate for every ADHD patient. Behavioral and psychosocial interventions can improve self-regulation and social functioning, but they require sustained effort and produce variable results. These limitations have kept the search for better alternatives active.
One candidate that has drawn growing attention is transcranial direct current stimulation (tDCS). The technique is appealingly simple: a weak electrical current is applied to the scalp through small electrodes, modulating the excitability of neurons in the underlying cortex without requiring surgery, anesthesia, or significant discomfort. Its safety profile and ease of use have made it attractive to researchers.
The Study:
A newly published meta-analysis set out to give the technique its most rigorous test yet, pooling results from randomized controlled trials, including crossover designs, that compared active tDCS against sham stimulation in people with ADHD across all age groups.
The Results:
The findings were consistently null. Across seven trials enrolling 303 participants, tDCS produced no significant reduction in overall ADHD symptom severity compared with sham. Breaking symptoms into their components made no difference: neither hyperactivity/impulsivity nor inattention improved. Turning to executive function, 18 studies with 872 participants found no meaningful gain in inhibitory control, and 12 studies with 506 participants found the same for working memory. Smaller bodies of evidence, including three studies on cognitive flexibility (122 participants) and two on hot executive function, the motivational and emotional dimension of self-regulation (86 participants), similarly came up empty. Variation in outcomes across studies was small to moderate, and there was no evidence of publication bias skewing the picture.
The authors’ conclusion was succinct: tDCS was well tolerated but “did not demonstrate significant overall efficacy for core ADHD symptoms or executive functions.”
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