JPED Journal

Symptoms

To our knowledge, only 3 studies have looked specifically at the effects of Pycnogenol® on ADHD clinical symptoms. In 2006, Trebatická et al. studied the effect of Pycnogenol® on a series of cognitive and clinical variables [180]. Compared with placebo, they found a reduction in hyperactivity and inattention symptoms, and an improvement of cognitive function such as visuomotor coordination and concentration. No significant effects were observed in the placebo group. The authors also measured the effects of treatment on symptoms over time: 1 month after stopping treatment, they observed a relapse of symptoms at the initial level, suggesting that Pycnogenol® has effects on symptoms without fundamentally altering the processes underlying the disorder. Except for the visuo-motor coordination and concentration cognitive tests, which exhibited sustained enhancement in performance even 1 month after stopping treatment. However, the authors attribute this improvement to a learning effect.

Another recent study (2022), controlled not only by placebo but also by MPH, showed a significative improvement on hyperactivity and impulsivity symptoms after 10 weeks of administration, both for MPH and Pycnogenol®, which is an extremely promising result. Regarding attentional aspects, an improvement with both products was shown, but significant only for MPH [125]. It should also be noted that the effects of MPH were already visible after 5 weeks, whereas for Pycnogenol® it took 10 weeks to observe significant effects. This result was expected by the authors, given the slower mechanisms of action known from natural food supplements. What’s more, the study revealed a virtual absence of side effects in patients treated with Pycnogenol®, compared with a significant increase in side effects reported in patients treated with MPH, after 5 and 10 weeks. These very promising results concerning side effects will be discussed in greater detail later in this review.

With regard to effects on ADHD symptomatology, we can also cite Hsu et al. (2021) [189], who studied the effects of polyphenolic compounds in pine bark extract (Oligopin®) (same composition as Pycnogenol®: including of 67%–75% oligomeric procyanidins, 4%–10% catechin, 4%–10% ferrulate glucoside, 3%–8% taxifoliol glucoside, 1%–5% ferulic acid) on symptoms of inattention and impulsivity and attentional performance in children with ADHD. The dose administered to patients was similar to studies conducted to date with Pycnogenol®. The polyphenol treatment was compared with placebo. Results revealed a notable decrease in inattention and impulsivity performance assessed through CPT-III, as well as a reduction in hyperactivity/impulsivity and inattention symptoms evaluated by the SNAP-IV, among children with ADHD after four weeks of treatment. Conversely, in line with their expectations, the placebo group did not show any discernible effect. Through the examination of blood samples, the study also revealed a decrease in oxidative stress, but failed to show that this correlated with symptomatic improvement, suggesting the need for future investigations into this link.

Pycnogenol® is characterized by a lack of side effects, compared with MPH. In the study by Weyns et al. (2022) [125], and in line with existing literature [122,180], participants reported up to 5 times more side effects with MPH than with Pycnogenol®. It has been highlighted that in 70 clinical studies conducted on healthy and patient subjects (5723 subjects : children and adults), the overall frequency of adverse reactions to Pycnogenol® is very low (1.8%) and these are mild and unrelated to dose or duration of treatment [122,70]. The gastrointestinal discomfort is the most frequently occurring side effect which can be countered if Pycnogenol® is taken during or after meals [122,180,70]. Dizziness, headaches, and nausea are among the most commonly reported side effects. Moreover, since its introduction on the European market, no severe adverse effects have been reported [161]. Consequently, the administration of Pycnogenol® in children and adolescents could be a very promising alternative to MPH, effective, natural, safe and reassuring for patients and their parents who fear the side effects of existing drugs. Pycnogenol®’s virtual absence of side effects could, in the long term, be accompanied by improved therapeutic compliance.

To date, only one study has shown no significant positive effect of Pycnogenol® on ADHD symptoms [191]. But this study also showed that there was no significant effect of MPH compared with placebo. The three treatments did not differ significantly from each other, which is quite unusual and surprising in the literature, as even MPH showed no effect. They therefore do not fundamentally contradict the 3 studies cited above [54]. The absence of results can probably be explained by the fact that the treatment duration was too short to observe any real effects: 3 weeks. In addition, it would appear that the study lacked power [180]. Today, studies on Pycnogenol® suggest that a treatment duration of at least 10 weeks is considered long enough to observe clear effects while minimizing patient burden and maximizing compliance [180,131,153,125].

In summary, studies investigating the effects of Pycnogenol® on ADHD symptomatology, after a sufficiently long course of treatment, consistently show an improvement in attention and a reduction in impulsive and hyperactive behavior. Combined with a virtual absence of side-effects, these highly promising results suggest that Pycnogenol® could be a fully-fledged, natural therapeutic alternative with no side-effects. However, at this moment, we still lack sufficient evidence since the studies, which are too limited in number, vary in methodology and demand a genuine, rigorous commitment to scientific inquiry.

To date, the effects of Pycnogenol® on ADHD symptoms have been studied exclusively through clinical questionnaires completed by parents and/or teachers, and the 3 studies cited above, while methodologically divergent, each point to differences in results and sensitivity between parent and teacher scales, which has already been discussed and demonstrated in the existing literature [192,193]. Indeed, Weyns et al. (2022) [125] show that the positive effects of ADHD symptoms were found only with teacher ratings and not with parent ratings. Similarly, Trebatická et al. (2006) [180] found a clear improvement with teacher ratings, but a weaker and less obvious improvement with parent ratings. This loss of sensitivity by parent scales was also noted by Hsu et al. (2021) [189] showing improvement with Placebo and this phenomenon could be explained by the fact that children’s classroom behaviors are more strictly controlled and visible than behaviors at home [194]. Also that teachers are probably more objective and sensitive to behavioral changes as they compare the child to other children in the class and are less emotionally involved in the task. In contrast, parents may be more stressed and focused on their child, which could affect their sensitivity and reduce the possibility of noticing symptomatic improvements in their child [195,125]. And as Weyns et al. [125] point out, this phenomenon could be all the more important with Pycnogenol® given its slower and more subtle effects, compared with MPH. In addition, it is important to note that MPH acts during school hours and children see their effects fade by the time they go home, while Pycnogenol® seems to offer a prolonged action that should be perceptible both at school and at home, but in a more discreet way.

These results raise question about the use of clinical questionnaires that are highly subjective and sensitive to biases related to the respondent and the conditions of observation. It is highly probable that the evaluation of cognitive and symptomatological repercussions, using behavioral scales alone, is insufficient to specifically and, above all, more objectively identify the impact of the product on cognitive functions. Even more so given the cognitive deficits (executive and attentional) found in ADHD, widely documented in existing scientific literature, and at the heart of its symptomatology [17]. Given also the pro-cognitive effects of Pycnogenol® demonstrated in healthy subjects and in neurodegenerative diseases [185,181,178,182,186,179,183]. At present, therefore, it seems essential to be able to objectivize the response to Pycnogenol® treatment with appropriate and measurable neuropsychological tests, enabling its probable effects on the brain to be explored more directly. Despite these very encouraging initial investigations, this field of research is still in its infancy and requires more in-depth explorations aimed at measuring the impact of taking Pycnogenol® on the cognitive performances shown to be impaired in ADHD and constituting the core of its symptomatology, such as divided attention, selective attention, inhibition, flexibility, working memory, vigilance, delay aversion and reaction time variability [13,14,17,196,16].

As Pycnogenol® is composed exclusively of polyphenols, known for their antioxidant and immunomodulatory properties, Darzi et al. (2022) [187] set out to study the relationship between a polyphenolrich diet and the risk of developing ADHD in kindergarten and primary school children aged 4 to 12. Impressively, the authors were able to confirm their hypotheses, showing that increased dietary intake of polyphenols, calculated by a questionnaire evaluating the level of polyphenols ingested in their daily diet, is associated with a lower risk of developing ADHD. The authors call for prospective studies to confirm these observations and explore a causal link. Their results are therefore consistent with the idea that polyphenols (contained in a large number of plant foods) could have a protective effect against ADHD, but how exactly do they act in ADHD?

Mechanism of action of Pycnogenol®

The NO pathway and the brain

In its link with the brain, Pycnogenol® is supposed to acts via the nitric oxide (NO) production pathway. The active metabolites of Pycnogenol® (flavonoids, phenolic acids, catechin, taxifolin and procyanidins) that accumulate in endothelial cells have been shown to cross the blood-brain barrier [197]. Indeed, its mechanism of action is based on its ability to enhance endothelial vasodilation by increasing NO production [173,198]. NO influences a range of physiological functions, including neurotransmission, development, plasticity, and neuronal apoptosis [199-200]. Numerous reports have also demonstrated that NO might be involved in memory [160], and learning [201,202], and may be associated with ADHD [75,203]. Since the latter has beneficial effects on cerebral function by vascular smooth muscle relaxation, NO leads to increased blood flow and ensures a sufficient supply of oxygen to neuronal cells, regulating noradrenaline and dopamine release and intake [204-206,197,131]. NO inhibits the activity of monoamine transporters, thus influencing the levels of dopamine and noradrenaline in the extracellular space [206]. This parallels the action of MPH, however, NO, being a gaseous neurotransmitter, operates differently by acting through cell membranes. Furthermore, NOS1 a crucial enzyme responsible for generating the signaling molecule NO in neurons, plays a role in promoting the growth of neurites, indicating a potential impact on early brain development [207]. Simpson et al. (2019) [159] explain the beneficial effects of Pycnogenol® on cognition in their review as follows: “it acts as a regulator and protects cells from oxidative stress 1) by being a powerful free radical scavenger; 2) by protecting DNA from damage; 3) by increasing the synthesis of antioxidant enzymes; and 4) by protecting other endogenous antioxidants (vitamin C, vitamin E and glutathione) from oxidative damage” [160,161,159].

In animal models, research shows a beneficial effect of Pycnogenol® on the brain. Specifically, studies have shown that Pycnogenol® has neuroprotective properties following traumatic brain injury in rats. This effect appears to be achieved by reducing oxidative brain damage, levels of pro-inflammatory cytokines and loss of synaptic proteins, thereby preserving synaptic function [208,110,209,131]. Moreover, in models of neurodegeneration associated with oxidative stress, Pycnogenol® demonstrates positive effects by enhancing choline acetyltransferase activity (ChAT; an enzyme found in the nervous system that catalyzes the synthesis of the neurotransmitter acetylcholine (ACh), a vital neurotransmitter involved in various physiological functions, including regulation of heart rate and transmission of nerve impulses in the brain) in the hippocampus, increasing Glutathion (GSH) levels (a marker of oxidative stress, considered a relevant clinical marker in disorders in which stress plays a role), and reducing protein carbonyl levels (a marker of oxidative damage to proteins and is commonly used as a measure of oxidative stress in biological systems) [210,131].

In human studies, Pycnogenol® is also believed to exhibit neuroprotective properties through its antioxidant pathway, by preventing B-amyloid-induced neuronal cell death in Alzheimer’s disease [211,179]. Belcaro et al. (2014) demonstrated in a study involving healthy adults that Pycnogenol® not only enhanced cognitive function but also reduced anxiety levels by significantly lowering oxidative stress compared to the control group, which maintained elevated levels of oxidative stress [185]. These findings imply that Pycnogenol® could serve as a therapeutic option for individuals experiencing high oxidative stress levels, potentially benefiting cognition and anxiety.

In ADHD

So, as mentioned, Pycnogenol® is supposed to act on the brain via the NO production pathway. Is this the mechanism by which Pycnogenol® could improve symptoms and cognitive function in individuals with ADHD ? Indeed several studies suggest that ADHD may be associated with altered NO signaling pathways [212,203]. NO levels, associated with the oxidant-antioxidant and immune imbalance highlighted in ADHD, modulating stress levels in the brain and affecting neurotransmission, appear to influence behavior and cognitive functioning in several areas: impulsivity, aggression, anxiety, depressive symptoms and cognitive performance [213,214]. More precisely, NOS1 is associated with a range of neurodegenerative and psychiatric disorder, such as ADHD and other impulsivity disorders [213,215-217,84]. This gene variant was one of the prominent discoveries in an ADHD GWAS study as well [39]. Studies have revealed that 28% of adult ADHD patients possess a particular genetic variation in the NOS1 promoter region (termed ex1f-VNTR) leading to reduced NOS1 expression. This variation is closely linked to alterations in the functioning of brain regions such as the prefrontal cortex and ventral striatum, both implicated in the impulsive and aggressive behaviors frequently associated with ADHD [212,218,84]. On the neurobiological level, NO may play a role in the development and brain organization of white matter [85]. Additionally, the NOS1ex1f gene has been linked to the severity of ADHD symptoms [39, 219, 85]. Depending on the study, this connection was age-dependent (only in adult) [219] and/or gender-dependent (only in girls) [84,86], and was also specifically associated with the impulsive/hyperactive and combined types of ADHD, not inattention type only [84-86]. These findings indicate that the NOS1 gene, which produces the gaseous neurotransmitter NO and is linked to ADHD symptoms, is a potential candidate gene for ADHD [86].

Extended to an animal model, researchers support the hypothesis of the involvement of NO in ADHD, suggesting that NOS dysfunction could lead to ADHD-like symptoms, particularly inattentive phenotype [220,212,214,221,84]. Additionally, authors demonstrated that administering MPH increased NOS expression and that giving mice a NOS inhibitory drug altered their response to MPH [220,222]. Hayman & Fernandez (2018) [223] conducted a human genetic analysis identifying 14 interconnected genes enriched with pathways related to NO and alpha-1 adrenergic synthesis in ADHD. These genes were found in the cerebellum early in life, transitioning to the cortex during childhood and adolescence. To date, the data leads to the hypothesis that a genetic variation and dysregulation in prefrontal NOS1 contribute to cognitive deficits and a downregulation of striatal NOS1 is associated with impulsive phenotypes [213]. These investigations provide understanding into the genetic and neurodevelopmental dimensions of ADHD while also emphasizing the promise of natural therapeutic interventions that target this pathway, such as Pycnogenol®.

At present, the biochemical antioxidant and immunomodulatory effects of Pycnogenol® are not fully elucidated and require further investigation [81]. Nevertheless, several promising results have been demonstrated in ADHD. It has been shown that the concentration of catecholamines (stress hormones) is positively correlated with hyperactivity in children with ADHD [188]. Authors have shown that taking Pycnogenol® for 1 month improves ADHD symptoms, and that this is the result of a reduction in dopamine levels and a tendency to lower adrenaline and noradrenaline levels in the urine. Studies by Chovanová et al. (2006) et Dvořáková et al. (2006) [184,155] concur with these findings, also showing that after 1 month’s treatment with Pycnogenol®, there was a normalization of stress hormone (catecholamine) levels, including adrenaline, noradrenaline and dopamine, in children with ADHD, associated with a reduction in hyperactivity/impulsivity symptoms [184]. In addition, they showed that oxidative stress and incidents of DNA damage were significantly reduced (by 6.3% and 35.4% respectively). In addition, Pycnogenol® increases the reduced glutathione (GSH)/ oxidized glutathione (GSSG) ratio (a marker of oxidative stress, considered a relevant clinical marker in disorders in which stress plays a role), accompanied by an increase in the level of the total antioxidant status (TAS), in favor of an antioxidant effect [188,189]. After treatment with Pycnogenol®, there was a negative correlation between the GSH/GSSG ratio and dopamine concentration, suggesting an improvement in redox homeostasis and dopamine neurotransmission [188,189,54]. These results demonstrate the antioxidant effect of treatment with Pycnogenol® [189], suggesting that the immune and oxidant-antioxidant imbalance track offers potential for dietary supplements composed of polyphenols [54,70]. 

New perspectives: Gut microbiota

Finally, studies have also shown that polyphenols and their metabolites have a prebiotic effect on the gut microbiota by stimulating its growth [224]. Polyphenols increase the families of good bacteria and reduce the number of pathogenic bacteria in the gut, thereby improving gut permeability [225,226]. This has been studied in human and animal diets, in vitro and in vivo. Studies are converging to show that polyphenols, with their antioxidant and anti-inflammatory properties, can also be used to modulate the gut microbiota [227-234,224,153]. As gut microbiota is thought to be altered in ADHD due to oxidative and immune imbalance [77], Pycnogenol® could act on the latter through its antioxidant and anti-inflammatory effects [102] and would be favorable to the composition of the gut microbiota. Thus, a rebalancing of the gut microbiota could be involved in the effect of Pycnogenol® on ADHD symptomatology and possibly cognitive functioning. Research into the microbiota and ADHD is totally new, and the exploration of this type of data presents a major challenge for the prevention and treatment of this disorder. In view of the existing literature on the gut-brain axis, the study of the association between gut microbiota and cognitive performance remains unexplored in ADHD and nebulous in neurotypical subjects. As gut microbiota and bioinformatics analyses become increasingly advanced, conducting a study in this field would be highly valuable. This research could enhance our understanding of ADHD’s etiopathogenesis and aid in developing prevention and treatment strategies that directly target the gut microbiota through diet or dietary supplements, such as, most likely, Pycnogenol®.

Conclusion 

In conclusion, ADHD, the most prevalent neurodevelopmental disorder is considered to be multifactorial with complex determinism, but to date, neither genetic nor specific environmental factors have been clearly identified. More recently, studies have suggested the existence of immune, oxidant-antioxidant imbalances and a neuroinflammatory state that may contribute to ADHD symptomatology, in line with the promising new wave of research addressing the potential role of the gut microbiota in the expression of the disorder. This latest research highlights the importance of environmental factors in the etiopathogenesis of ADHD, and more specifically the importance of nutrients ingested through food or dietary supplements.

Pycnogenol®, essentially composed of polyphenols, is recognized for its antioxidant, immunomodulating and anti-inflammatory properties on the human body. Thanks to these virtues, the beneficial effects of taking Pycnogenol® as treatment of prevention of ADHD, seems to be a very promising option. In ADHD, the few studies carried out to date have consistently demonstrated that treatment with Pycnogenol® for a minimum of 4 to 10 weeks leads to an improvement in attention span and a reduction in impulsive and hyperactivity behaviors. Combined with almost no side effects, these highly promising results, suggest that Pycnogenol® could constitute a fully-fledged therapeutic alternative to MPH, natural and without side effects. Polyphenols and their metabolites also have a probiotic effect on the gut microbiota, which is thought to be altered in ADHD. Pycnogenol® offers a new avenue of treatment that could improve ADHD symptoms by reducing neuroinflammation state, oxidative stress, improving neurotransmission and rebalancing the gut microbiota. These lines of research are totally innovative, and the exploration of this type of data presents a major challenge for the prevention and treatment of ADHD, requiring future investigations.

Acknowledgments

B.L. was supported by a grant of the Belgian Kids’ Fund for Pediatric Research.

Conflict of interest

The authors state that their research was carried out without any commercial or financial ties that could be seen as a possible conflict of interest.

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