Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2017

Open Access 01-12-2017 | Study protocol

Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial

Authors: Annelies A. J. Verlaet, Berten Ceulemans, Helene Verhelst, Dirk Van West, Tess De Bruyne, Luc Pieters, Huub F. J. Savelkoul, Nina Hermans

Published in: Trials | Issue 1/2017

Login to get access

Abstract

Background

Methylphenidate (MPH), the first choice medication for attention-deficit hyperactivity disorder (ADHD), is associated with serious adverse effects like arrhythmia. Evidence on the association of ADHD with immune and oxidant-antioxidant imbalances offers potential for antioxidant and/or immunomodulatory nutritional supplements as ADHD therapy. One small randomised trial in ADHD suggests, despite various limitations, therapeutic benefit from Pycnogenol®, a herbal, polyphenol-rich extract.

Methods

This phase III trial is a 10-week, randomised, double-blind, placebo and active treatment controlled multicentre trial with three parallel treatment arms to compare the effect of Pycnogenol® to MPH and placebo on the behaviour of 144 paediatric ADHD and attention-deficit disorder (ADD) patients. Evaluations of behaviour (measured by the ADHD-Rating Scale (primary endpoint) and the Social-emotional Questionnaire (SEQ)), immunity (plasma cytokine and antibody levels, white blood cell counts and faecal microbial composition), oxidative stress (erythrocyte glutathione, plasma lipid-soluble vitamins and malondialdehyde and urinary 8-OHdG levels, as well as antioxidant enzyme activity and gene expression), serum zinc and neuropeptide Y level, urinary catecholamines and physical complaints (Physical Complaints Questionnaire) will be performed in week 10 and compared to baseline. Acceptability evaluations will be based on adherence, dropouts and reports of adverse events. Dietary habits will be taken into account.

Discussion

This trial takes into account comorbid behavioural and physical symptoms, as well as a broad range of innovative immune and oxidative biomarkers, expected to provide fundamental knowledge on ADHD aetiology and therapy. Research on microbiota in ADHD is novel. Moreover, the active control arm is rather unseen in research on nutritional supplements, but of great importance, as patients and parents are often concerned with the side effects of MPH.

Trial registration

Clinicaltrials.gov number: NCT02700685. Registered on 18 January 2016. EudraCT 2016-000215-32. Registered on 4 October 2016.
Appendix
Available only for authorised users
Literature
1.
Pelham WE, Foster EM, Robb JA. The economic impact of attention-deficit/hyperactivity disorder in children and adolescents. J Pediatr Psychol. 2007;32(6):711–27.CrossRefPubMed
2.
Polanczyk GV, et al. ADHD prevalence estimates across three decades: an updated systematic review and meta-regression analysis. Int J Epidemiol. 2014;43(2):434–42.CrossRefPubMedPubMedCentral
3.
4.
5.
Claes S, et al. Het toenemend gebruik van psychofarmaca. Visietekst werkgroep Metaforum Leuven, Katholieke Universiteit Leuven. 2010.
6.
Schachter HM, et al. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis CMAJ. 2011;165(11):1475–88.
7.
8.
Storebø OJ, et al. Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials. BMJ. 2015;351:h5203.CrossRefPubMedPubMedCentral
9.
Ceylan M, et al. Changes in oxidative stress and cellular immunity serum markers in attention-deficit/hyperactivity disorder. Psychiatry Clin Neurosci. 2012;66:220–6.CrossRefPubMed
10.
Pelsser LMJ, Buitelaar JK, Savelkoul HFJ. ADHD as a (non) allergic hypersensitivity disorder: a hypothesis. Pediatr Allergy Immunol. 2009;20(2):107–12.CrossRefPubMed
11.
Ceylan M, et al. Oxidative imbalance in child and adolescent patients with attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(8):1491–4.CrossRefPubMed
12.
El Adham EK, Hassan AI, El Aziz El-Mahdy AA. Nutritional and metabolic disturbances in attention deficit hyperactivity disease. Res J Med Med Sci. 2011;6(1):10–6.
13.
Ross BM, et al. Increased levels of ethane, a non-invasive marker of n-3 fatty acid oxidation, in breath of children with attention deficit hyperactivity disorder. Nutr Neurosci. 2003;6(5):277–81.CrossRefPubMed
14.
Kawatani M, Tsukahara H, Mayumi M. Evaluation of oxidative stress status in children with pervasive developmental disorder and attention deficit hyperactivity disorder using urinary-specific biomarkers. Redox Rep. 2011;16(1):45–6.CrossRefPubMed
15.
Güngör S, et al. The frequency of celiac disease in attention-deficit hyperactivity disorder. J Pediatr Gastroenterol Nutr. 2013;56(2):211–4.CrossRefPubMed
16.
Minter K, et al. Early childhood otitis media in relation to children’s attention-related behavior in the first six years of life. Pediatrics. 2001;107:1037–42.CrossRefPubMed
17.
Schmitt J, Buske-Kirschbaum A, Roessner V. Is atopic disease a risk factor for attention-deficit/hyperactivity disorder? A systematic review. Allergy. 2010;65(12):1506–24.CrossRefPubMed
18.
Tsai SJ. Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: a speculative hypothesis. Med Hypoth. 2006;67(6):1341–3.CrossRef
19.
Furlano R, et al. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr. 2001;138(3):366–72.CrossRefPubMed
20.
Noriega DB, Savelkoul HFJ. Immune dysregulation in autism spectrum disorder. Eur J Ped. 2014;173(1):33–43.CrossRef
21.
Verlaet AAJ, et al. Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. Eur Child Adolesc Psychiatry. 2014;23(7):519–29.CrossRefPubMed
22.
Trebatická J, et al. Treatment of ADHD with French maritime pine bark extract. Pycnogenol Eur Child Adolesc Psychiatry. 2006;15:329–35.CrossRefPubMed
23.
D’Andrea G. Pycnogenol: a blend of procyanidins with multifaceted therapeutic applications? Fitoterapia. 2010;81:724–36.CrossRefPubMed
24.
Wilson D, et al. A randomized, double-blind, placebo-controlled exploratory study to evaluate the potential of Pycnogenol for improving allergic rhinitis symptoms. Phytother Res. 2010;24(8):1115–9.PubMed
25.
Chovanová Z, et al. Effect of polyphenolic extract, Pycnogenol, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder. Free Radical Res. 2006;40:1003–10.CrossRef
26.
Dvořáková M, et al. The effect of polyphenolic extract from pine bark, Pycnogenol, on the level of glutathione in children suffering from attention deficit hyperactivity disorder (ADHD). Redox Rep. 2006;11:163–72.CrossRefPubMed
27.
Tenenbaum S, et al. An experimental comparison of Pycnogenol and methylphenidate in adults with attention-deficit/hyperactivity disorder (ADHD). J Atten Disord. 2002;6:49–60.CrossRefPubMed
28.
Greenblatt J. Nutritional supplements in ADHD. J Am Acad Child Adolesc Psychiatry. 1999;38:1209–10.CrossRefPubMed
29.
30.
Jennings CG, et al. Does offering an incentive payment improve recruitment to clinical trials and increase the proportion of socially deprived and elderly participants? Trials. 2015;16:80.CrossRefPubMedPubMedCentral
31.
32.
Buitelaar JK, Montgomery SA, van Zwieten-Boot BJ. Attention deficit hyperactivity disorder: guidelines for investigating efficacy of pharmacological intervention. Eur Neuropsychopharmacol. 2003;13:297–304.CrossRefPubMed
33.
34.
Pelsser LMJ, Buitelaar JK. Favourable effect of a standard elimination diet on the behaviour of young children with attention deficit-hyperactivity disorder (ADHD), a pilot study. Ned Tijdschr Geneesk. 2002;46(52):2543–7.
35.
Pastore A, et al. Analysis of glutathione: implication in redox and detoxification. Clin Chim Acta. 2003;333(1):19–39.CrossRefPubMed
36.
Conaway HH, Henning P, Lerner UH. Vitamin a metabolism, action, and role in skeletal homeostasis. Endocr Rev. 2013;34:766–97.CrossRefPubMed
37.
Naguib Y, et al. Antioxidant activities of natural vitamin E formulations. J Nutr Sci Vitaminol. 2003;49:217–20.CrossRefPubMed
38.
Littarru GP, Tiano L. Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol Biotechnol. 2007;37:31–7.
39.
Molyneux SL, et al. Coenzyme Q10: is there a clinical role and a case for measurement? Clin Biochem Rev. 2008;29(2):71–82.PubMedPubMedCentral
40.
Sezen H, et al. Increased oxidative stress in children with attention deficit hyperactivity disorder. Redox Rep. 2016;21(6):248–53.CrossRefPubMed
41.
Franceschi C, et al. Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mech Ageing Dev. 2005;126(2):351–61.CrossRefPubMed
42.
Rahman I, Yang SR, Biswas SK. Current concepts of redox signaling in the lungs. Antioxid Redox Signal. 2006;8:681–9.CrossRefPubMed
43.
Whitehouse RC, et al. Zinc in plasma, neutrophils, lymphocytes, and erythrocytes as determined by flameless atomic absorption spectrophotometry. Clin Chem. 1982;28(3):475–80.PubMed
44.
Aruoma OI. Free radicals, oxidative stress, and antioxidants in human health and disease. JAOCS. 1998;75:199–212.
45.
Dalle-Donne I, et al. Biomarkers of oxidative damage in human disease. Clin Chem. 2006;52:601–23.CrossRefPubMed
46.
Furukawa T, Meydani SN, Blumberg JB. Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech Ageing Dev. 1987;38(2):107–17.CrossRefPubMed
47.
Grimm T, et al. Inhibition of NF-κB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol). J Inflam. 2006;3(1):1–6.
48.
Booijink CC, et al. High temporal and inter-individual variation detected in the human ileal microbiota. Environ Microbiol. 2010;12(12):3213–27.CrossRefPubMed
49.
González TJB, et al. Study of the aminoglycoside subsistence phenotype of bacteria residing in the gut of humans and zoo animals. Front Microbiol. 2015;6:1–7.
50.
Dvořáková M, et al. Urinary catecholamines in children with attention deficit hyperactivity disorder (ADHD): modulation by a polyphenolic extract from pine bark (Pycnogenol). Nutr Neurosci. 2007;10:151–7.CrossRefPubMed
51.
Ozcan O, et al. Plasma leptin, adiponectin, neuropeptide Y levels in drug naive children with ADHD. J Atten Disord. 2015 [Epub ahead of print].
52.
de Vriese S, et al. The Belgian food consumption survey: aims, design and methods. Archives Public Health. 2005;63:1–16.
53.
De Keyzer W, et al. Relative validity of a short qualitative food frequency questionnaire for use in food consumption surveys. Eur J Public Health. 2012;23(5):737–42.CrossRefPubMed
54.
Pelsser LMJ, et al. Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder (INCA study): a randomised controlled trial. Lancet. 2011;377:494–503.CrossRefPubMed
55.
Berek M, et al. Improved functionality, health related quality of life and decreased burden of disease in patients with ADHD treated with OROS® MPH: is treatment response different between children and adolescents? Child Adolesc Psych Ment Health. 2011;5(26):1–13.
56.
Christensen E. Methodology of superiority vs. equivalence trials and non-inferiority trials. J Hepatol. 2007;46:947–54.CrossRefPubMed
57.
Piaggio G, et al. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006;295:1152–60.CrossRefPubMed
58.
Power TJ, et al. The predictive validity of parent and teacher reports of ADHD symptoms. J Psychopathol Behav Assess. 1998;20(1):57–81.CrossRef
59.
Tripp G, Schaughency EA, Clarke B. Parent and teacher rating scales in the evaluation of attention-deficit hyperactivity disorder: contribution to diagnosis and differential diagnosis in clinically referred children. J Dev Behav Pediatr. 2006;27(3):209–18.CrossRefPubMed
60.
Rohdewald PJ. Pycnogenol, French maritime pine bark extract. In: Coates PM, Blackman MR, Cragg GM, Levine M, Moss J, White JD, editors. Encyclopedia of Dietary Supplements. New York, Marcel Dekker, Inc.; 2005;545–53.
61.
62.
Cardona F, et al. Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem. 2013;24(8):1415–22.CrossRefPubMed
63.
Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther. 2002;40(4):158–68.CrossRefPubMed
Metadata
Title
Effect of Pycnogenol® on attention-deficit hyperactivity disorder (ADHD): study protocol for a randomised controlled trial
Authors
Annelies A. J. Verlaet
Berten Ceulemans
Helene Verhelst
Dirk Van West
Tess De Bruyne
Luc Pieters
Huub F. J. Savelkoul
Nina Hermans
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Trials / Issue 1/2017
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-017-1879-6

Other articles of this Issue 1/2017

Trials 1/2017 Go to the issue

Study protocol

Evaluating effectiveness and cost-effectiveness of a group psychological intervention using cognitive behavioural strategies for women with common mental disorders in conflict-affected rural Pakistan: study protocol for a randomised controlled trial

Study protocol

Jail-to-community treatment continuum for adults with co-occurring substance use and mental disorders: study protocol for a pilot randomized controlled trial

Study protocol

Prevention of diabetes in overweight/obese children through a family based intervention program including supervised exercise (PREDIKID project): study protocol for a randomized controlled trial

Study protocol

COSUMO: study protocol for the development of a core outcome set for efficacy and effectiveness trials in posterior segment-involving uveitis

Study protocol

Effects of digital Cognitive Behavioural Therapy for Insomnia on cognitive function: study protocol for a randomised controlled trial

Study protocol

PORTAF – postoperative radiotherapy of non-small cell lung cancer: accelerated versus conventional fractionation – study protocol for a randomized controlled trial