Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in adults and children, often treated with methylphenidate (Ritalin®). However, approximately 30% of patients do not respond to psychostimulants or experience limiting adverse effects1 hence the interest in alternative or complementary therapies.
We evaluated an innovative nutraceutical formula, composed (per capsule) of saffron (20 mg), Bacopa monnieri (175 mg), choline bitartrate (160 mg), a vitamin B complex (B6 6 mg, B9 0.460 mg and B12 0.150 mg), vitamin D3 10 mg (1000 IU), magnesium (450 mg), zinc (3 mg) and a probiotic/prebiotic blend (10^10 CFU each of Lactobacillus rhamnosus GG, Bifidobacterium longum 1714, L. helveticus R0052 + B. longum R0175, B. breve CCFM1025, plus prebiotic fibers acacia gum, FOS and inulin).
A natural multimodal approach, acting on neurotransmitters, micronutritional status and the intestinal microbiota, can significantly reduce ADHD symptoms in children.
The tested formula could represent a promising alternative or complement to methylphenidate, particularly in patients intolerant to stimulants or wishing to reduce the dosage, subject to confirmation by larger-scale trials.
In the UK, ADHD affects approximately 5-7% of school-aged children and 3-4% of adults, manifesting most commonly as high levels of inattention, impulsivity, and hyperactivity. First-line treatment often involves psychostimulants such as methylphenidate (Ritalin®), which target dopaminergic and noradrenergic neurotransmission.
These medications significantly reduce symptoms in approximately 70% of patients 2.
However, they are associated with frequent side effects (loss of appetite, sleep disturbances, growth retardation, etc.) and approximately one third of children cannot tolerate them or do not respond sufficiently to them1 & 3.
This has led to the search for alternative, more natural therapeutic strategies aimed either at replacing stimulants or reducing their necessary doses.
A better understanding of the pathophysiology of ADHD suggests that beyond prefrontal dopamine/norepinephrine deficiency, other biological pathways may be involved: oxidative stress and neuronal inflammation, nutritional imbalances, dysregulation of the gut microbiota and the gut-brain axis, etc 4 & 5.
Furthermore, several nutrients and plant extracts have individually shown beneficial effects on ADHD symptoms or cognitive functions in clinical studies.
The formula encompasses three components of complementary active ingredients to target different ADHD mechanisms. Each has been selected on the basis of preclinical or clinical data suggesting an interest in ADHD or attentional functions;
Saffron (Crocus sativus), for example, has been shown in a controlled trial to improve ADHD symptoms as effectively as methylphenidate over 6 weeks, with favourable tolerability and a positive effect on sleep and anxiety 1.
Children given 20-30 mg/d of saffron had a reduction in their inattention/hyperactivity score equivalent to that observed on Ritalin, with no significant difference according to parent and teacher assessments.
Saffron, traditionally known for its sedative and antidepressant properties, acts in particular via its active compounds (safranal, crocin), which modulate serotonergic transmission and cerebral oxidative stress.
Studies highlight its positive effects on mood, concentration, and behaviour, without the side effects of psychostimulants22 & 23</sup.
A randomised, double-blind, placebo-controlled study showed that saffron extract supplementation (30 mg/day for 8 weeks) significantly improved emotional well-being in healthy adults with subclinical signs of stress, anxiety, or low mood. The study also revealed a decrease in depression scores and an improvement in social relationships at the end of the protocol, suggesting a beneficial effect of saffron on mild depressive symptoms in undiagnosed individuals24.
Bacopa monnieri is an Ayurvedic nootropic reputed to improve memory and attention. An open study in children aged 6-12 showed that standardized Bacopa extract (225 mg/d for 6 months) significantly reduced hyperactivity, inattention and impulsivity in 85-93% of participants 2.
Parents reported a reduction in restlessness symptoms in 93% of cases, and improved self-control in 89%2.
Bacopa exerts neuroprotective and anti-inflammatory effects and may increase cholinergic neurotransmission, supporting its use to support cognitive function in ADHD.
Choline (choline bitartrate, 40 mg providing 16 mg choline) is a precursor of acetylcholine, a neurotransmitter involved in attention and memory processes. Studies have shown that an intake of citicoline (CDP-choline form) improves psychomotor speed, selective attention and reduces impulsivity in adolescents, even without ADHD6.
In a double-blind study, boys taking 250-500 mg/d of citicoline for 28 days performed better on cognitive tests (Ruff 2&7, CPT-II) compared to placebo 6.
The addition of choline to the formula therefore aims to support acetylcholine synthesis and cognitive function, which could contribute to concentration and working memory in children with ADHD.
Carefully selected vitamins and minerals have been incorporated to optimise brain metabolism and compensate for potential deficiencies often reported in children with ADHD.
Magnesium (450 mg in highly bioavailable form, bisglycinate or citrate) is an essential cofactor involved in over 300 enzymatic reactions, including those of neurotransmission (it regulates NMDA receptors and neurotransmitter release). Studies have found that many children with ADHD have suboptimal magnesium status, particularly low intraerythrocyte magnesium3.
A French study showed that combined magnesium-vitamin B6 supplementation (6 mg/kg Mg and 0.6 mg/kg B6 for 8 weeks) significantly improved hyperactivity, aggression and academic attention in 40 ADHD children3.
Symptoms improved (decreased hyperactivity and improved attention) in parallel with an increase in intraerythrocyte Mg, and recurred when treatment was stopped3. This result suggests that magnesium intake (supported by vitamin B6 which promotes its cellular entry) can reduce neuromuscular and central hyperexcitability in these patients3.
In this formula, vitamin B6 is provided in moderate doses (6 mg in active form pyridoxal-5-phosphate) in synergy with magnesium, to support the synthesis of neurotransmitters such as serotonin, dopamine and GABA whose production depends on B6.
Vitamin B9 and B12 are included to ensure adequate folate and cobalamin status, which are essential for monoamine metabolism via the methylation cycle.
Insufficient folate/B12 levels can lead to elevated homocysteine and neurodevelopmental dysfunction.
Although no studies have shown that B9/B12 supplementation alone improves ADHD, it is rational to correct any deficiency to optimise overall brain function.
Vitamin D plays a neurosteroidal role, influencing synaptic plasticity and the production of neurotransmitters such as dopamine8.
Furthermore, it has been found that the majority of children with ADHD have insufficient Vitamin D levels, correlated with the severity of comorbid disorders (anxiety, sleep disorders)9.
A 2019 meta-analysis showed that Vitamin D supplementation in ADHD children treated with Ritalin provided a small additional benefit on symptoms7.
Four controlled trials (n=256) reported that adding 1000–2000 IU/d of vitamin D3 for 8–12 weeks modestly reduced total ADHD and hyperactivity scores compared with placebo7. The mean difference, although statistically significant, was small in magnitude, reflecting a small but real clinical improvement without notable adverse effects.
Therefore, we included 1000 IU of Vitamin D3 to normalise levels, which could indirectly promote better behavioural and sleep regulation.
Zinc is a trace element crucial for numerous brain enzymes, the modulation of NMDA and GABA receptors, and dopamine metabolism.
A meta-analysis confirmed that children with ADHD tend to have lower serum zinc levels than controls, suggesting that marginal zinc deficiency may contribute to symptoms10.
Clinical trials, particularly in the Middle East where zinc deficiency is more common, have indicated that zinc supplementation can improve ADHD symptoms. For example, a double-blind trial in 44 children showed that zinc sulfate monotherapy (150 mg/day) for 12 weeks significantly reduced hyperactivity, impulsivity, and irritability compared to placebo11.
More recently, a systematic review of 6 RCTs (489 children) concluded that zinc supplementation provides a moderate overall benefit on total ADHD symptoms, pooled SMD = –0.62, p = 0.04 vs. placebo)12.
Although the heterogeneity of the studies is high and the specific impact on inattention vs. hyperactivity remains to be clarified, this data supports the addition of zinc as an adjuvant in the management of ADHD12.
In this formula, 6 mg of zinc (the maximum limit set by the DGCCRF for children under 10 years of age) is sufficient to correct a mild deficiency without risking overload.
Finally, the Pre and Probiotics component of the formula aims to harness the microbiota-gut-brain axis in ADHD. Emerging studies suggest that the gut microbiota can influence behaviour and brain function via the production of neuroactive metabolites (short-chain fatty acids, neurotransmitters such as GABA, serotonin), the modulation of immunity and systemic inflammation, as well as via the vagus nerve.
In animals, faecal microbiota transplants from ADHD patients induce hyperactivity, suggesting a possible causal role of the dysbiotic microbiota.
Clinically, a landmark Finnish trial5 followed children given the probiotic Lactobacillus rhamnosus GG (LGG) during infancy: by age 13, none of the children in the probiotic group had developed ADHD, compared to 17% in the placebo group5.
This pioneering result raises the hypothesis that an early modulated microbiota could lower the risk of neurodevelopmental disorders.
Furthermore, a recent pilot study13 & 14 administering a mixture of probiotics to children already diagnosed did not observe a significant difference vs. placebo in the entire sample, but noted an improvement in hyperactivity/impulsivity in the youngest ADHD children receiving probiotics (effect size d = 0.69).
Similarly, quality of life improved further with probiotics in children with comorbid autism spectrum disorders. These exploratory results encourage further research into optimal probiotic strains for ADHD.
This formula includes specific probiotic strains that have shown psychotropic effects in previous studies on stress, anxiety, and sleep.
Lactobacillus rhamnosus GG, one of the most well-documented probiotic strains, improves the intestinal barrier and favourably modulates the immune response.
In addition to its potential preventative role mentioned above, LGG has demonstrated anxiolytic and antidepressant effects in rodents via the vagus nerve and GABA, although these effects remain to be confirmed in humans.
Bifidobacterium longum 1714 is considered a “psychobiotic” due to its observed effects on the brain. In healthy volunteers, consumption of Bifidobacterium longum 1714 for 4 weeks reduced perceived levels of stress and improved some measures of visuospatial memory15. ECG recordings suggest this strain may induce a brain state more resilient to social stress16.
Meanwhile, Bifidobacterium breve R0175 mixture was the subject of clinical trials in adults with subclinical stress or anxiety. Messaoudi et al17 reported that a 30-day course of this probiotic duo resulted in a significant decrease in anxiety and psychological distress scores (HADS) compared to placebo in healthy volunteers.
These participants also had a decrease in morning cortisol, suggesting a balancing effect on the hypothalamic-pituitary-adrenal (HPA) axis, which is often overactive under stress18.
Improved HPA axis regulation and reduced anxiety may be beneficial in children with ADHD, especially those with associated emotional or sleep disturbances.
Finally, Bifidobacterium breve CCFM1025 is an emerging strain initially studied in China for its effects on depression and insomnia. A 2023 randomized trial showed that B. breve CCFM1025 (5×10^9 CFU/day) for 4 weeks improved sleep quality (PSQI score reduction) in adults with stress-related insomnia, compared to placebo19.
Animal models suggest that this strain exerts an antidepressant effect by favourably modifying the composition of the microbiota and the metabolism of tryptophan to serotonin20 & 21.
In the context of ADHD, where insomnia and dysphoric mood are common comorbidities, B. breve CCFM1025 can be expected to contribute to better sleep and improved mood, thereby indirectly supporting symptom management.
The ADHD Relief BioProgramme is based on ingredients that have individually demonstrated benefits in the management of ADHD or its associated symptoms (attention, behaviour, anxiety, sleep).
The hypothesis is that by combining these synergistic active ingredients, clinically significant improvement in ADHD symptoms (potentially comparable to standard treatments) can be achieved while minimising adverse effects.
