Skip to main content

Advertisement

SpringerLink
Log in

Resveratrol adjunct to methylphenidate improves symptoms of attention-deficit/hyperactivity disorder: a randomized, double-blinded, placebo-controlled clinical trial

  • Original Contribution
  • Published:
European Child & Adolescent Psychiatry Aims and scope Submit manuscript

Abstract

Current pharmacological approaches have failed to provide complete remission for patients with Attention-Deficit/Hyperactivity Disorder (ADHD). This study aimed to evaluate the efficacy and tolerability of resveratrol (that have been shown to have antioxidative, anti-inflammatory, and anti-apoptotic effects) as an adjunct to methylphenidate in pharmacologic treatment of ADHD. This 8-week, double-blinded, placebo-controlled trial randomized 66 participants to receive either 500 mg/day resveratrol or matched placebo in addition to methylphenidate. ADHD symptoms were evaluated in the patients using the Parent and Teacher versions of ADHD-Rating Scale (ADHD-RS) at three measurement points with time intervals of 4 weeks. Furthermore, the tolerability of the treatment strategies was systematically compared. Repeated measures analysis demonstrated a significant effect for time–treatment interaction on all three subscales of the Parent ADHD-RS during the trial period (total: p = 0.015; inattention: p = 0.032; hyperactivity/impulsivity: p = 0.036). Nevertheless, the effect for time–treatment interaction was not significant for the Teacher version of ADHD-RS (total: F = 0.81, df = 1.33, p = 0.401; inattention: F = 0.57, df = 1.37, p = 0.507; hyperactivity/impulsivity: F = 0.65, df = 1.34, p = 0.466). The frequencies of complications in the treatment groups were similar. Resveratrol administration for a duration of 8 weeks improved characteristic symptoms in patients with ADHD according to their parents. Further investigations containing larger sample sizes, longer supplementation periods, and dose–response evaluations are required to replicate these findings in ADHD children more confidently.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dehbozorghi S, Bagheri S, Moradi K, Shokraee K, Mohammadi MR, Akhondzadeh S (2019) Efficacy and safety of tipepidine as adjunctive therapy in children with attention-deficit/hyperactivity disorder: randomized, double-blind, placebo-controlled clinical trial. Psychiatry Clin Neurosci 73:690–696. https://doi.org/10.1111/pcn.12913

    Article  CAS  PubMed  Google Scholar 

  2. Rowland AS, Skipper BJ, Umbach DM, Rabiner DL, Campbell RA, Naftel AJ, Sandler DP (2015) The prevalence of ADHD in a population-based sample. J Atten Disord 19:741–754. https://doi.org/10.1177/1087054713513799

    Article  PubMed  Google Scholar 

  3. Castells X, Blanco-Silvente L, Cunill R (2018) Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev 8:Cd007813. https://doi.org/10.1002/14651858.CD007813.pub3

    Article  PubMed  Google Scholar 

  4. Curatolo P, Paloscia C, D'Agati E, Moavero R, Pasini A (2009) The neurobiology of attention deficit/hyperactivity disorder. Eur J Paediatr Neurol 13:299–304. https://doi.org/10.1016/j.ejpn.2008.06.003

    Article  PubMed  Google Scholar 

  5. Sharma A, Couture J (2014) A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother 48:209–225. https://doi.org/10.1177/1060028013510699

    Article  PubMed  Google Scholar 

  6. Steele M, Jensen PS, Quinn DM (2006) Remission versus response as the goal of therapy in ADHD: a new standard for the field? Clin Ther 28:1892–1908. https://doi.org/10.1016/j.clinthera.2006.11.006

    Article  CAS  PubMed  Google Scholar 

  7. Ghajar A, Aghajan-Nashtaei F, Afarideh M, Mohammadi MR, Akhondzadeh S (2018) l-Carnosine as adjunctive therapy in children and adolescents with attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled clinical trial. J Child Adolesc Psychopharmacol 28:331–338. https://doi.org/10.1089/cap.2017.0157

    Article  CAS  PubMed  Google Scholar 

  8. Liu DY, Shen XM, Yuan FF, Guo OY, Zhong Y, Chen JG, Zhu LQ, Wu J (2015) The physiology of BDNF and its relationship with ADHD. Mol Neurobiol 52:1467–1476. https://doi.org/10.1007/s12035-014-8956-6

    Article  CAS  PubMed  Google Scholar 

  9. Lopresti AL (2015) Oxidative and nitrosative stress in ADHD: possible causes and the potential of antioxidant-targeted therapies. Atten Defic Hyperact Disord 7:237–247. https://doi.org/10.1007/s12402-015-0170-5

    Article  PubMed  Google Scholar 

  10. Ikonomidou C, Kaindl AM (2011) Neuronal death and oxidative stress in the developing brain. Antioxid Redox Signal 14:1535–1550. https://doi.org/10.1089/ars.2010.3581

    Article  CAS  PubMed  Google Scholar 

  11. Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, Fokou PVT, Martins N, Sharifi-Rad J (2018) Resveratrol: a double-edged sword in health benefits. Biomedicines 6:91. https://doi.org/10.3390/biomedicines6030091

    Article  CAS  PubMed Central  Google Scholar 

  12. Kanthasamy K, Gordon R, Jin H, Anantharam V, Ali S, Kanthasamy AG, Kanthasamy A (2011) Neuroprotective effect of resveratrol against methamphetamine-induced dopaminergic apoptotic cell death in a cell culture model of neurotoxicity. Curr Neuropharmacol 9:49–53. https://doi.org/10.2174/157015911795017353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pacheco M, Frozza R, Bernardi A (2018) Anti-inflammatory effects of resveratrol: mechanistic insights. Int J Mol Sci 2018:19

    Google Scholar 

  14. Bastianetto S, Ménard C, Quirion R (2015) Neuroprotective action of resveratrol. Biochim Biophys Acta (BBA) Mol Basis Dis 1852:1195–1201. https://doi.org/10.1016/j.bbadis.2014.09.011

    Article  CAS  Google Scholar 

  15. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L (2015) Roles of resveratrol and other grape-derived polyphenols in Alzheimer's disease prevention and treatment. Biochem Biophys Acta 1852:1202–1208. https://doi.org/10.1016/j.bbadis.2014.10.006

    Article  CAS  PubMed  Google Scholar 

  16. Rege SD, Kumar S, Wilson DN, Tamura L, Geetha T, Mathews ST, Huggins KW, Broderick TL, Babu JR (2013) Resveratrol protects the brain of obese mice from oxidative damage. Oxid Med Cell Longev 2013:419092. https://doi.org/10.1155/2013/419092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L (2015) Roles of resveratrol and other grape-derived polyphenols in Alzheimer's disease prevention and treatment. Biochim Biophys Acta 1852:1202–1208. https://doi.org/10.1016/j.bbadis.2014.10.006

    Article  CAS  PubMed  Google Scholar 

  18. Moore A, Beidler J, Hong MY (2018) Resveratrol and depression in animal models: a systematic review of the biological mechanisms. Molecules. https://doi.org/10.3390/molecules23092197

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wightman EL, Haskell-Ramsay CF, Reay JL, Williamson G, Dew T, Zhang W, Kennedy DO (2015) The effects of chronic trans-resveratrol supplementation on aspects of cognitive function, mood, sleep, health and cerebral blood flow in healthy, young humans. Br J Nutr 114:1427–1437. https://doi.org/10.1017/s0007114515003037

    Article  CAS  PubMed  Google Scholar 

  20. Ge JF, Xu YY, Qin G, Cheng JQ, Chen FH (2016) Resveratrol ameliorates the anxiety- and depression-like behavior of subclinical hypothyroidism rat: possible involvement of the HPT axis, HPA axis, and Wnt/beta-catenin pathway. Front Endocrinol (Lausanne) 7:44. https://doi.org/10.3389/fendo.2016.00044

    Article  Google Scholar 

  21. Ghanizadeh A, Mohammadi MR, Yazdanshenas A (2006) Psychometric properties of the Farsi translation of the kiddie schedule for affective disorders and schizophrenia-present and lifetime version. BMC Psychiatry 6:10. https://doi.org/10.1186/1471-244x-6-10

    Article  PubMed  PubMed Central  Google Scholar 

  22. Akhondzadeh S, Mohammadi MR, Khademi M (2004) Zinc sulfate as an adjunct to methylphenidate for the treatment of attention deficit hyperactivity disorder in children: a double blind and randomized trial [ISRCTN64132371]. BMC Psychiatry 4:9. https://doi.org/10.1186/1471-244x-4-9

    Article  PubMed  PubMed Central  Google Scholar 

  23. Farokhnia M, Shafiee Sabet M, Iranpour N, Gougol A, Yekehtaz H, Alimardani R, Farsad F, Kamalipour M, Akhondzadeh S (2014) Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer's disease: a double-blind randomized clinical trial. Hum Psychopharmacol 29(4):351–359. https://doi.org/10.1002/hup.2412

    Article  CAS  PubMed  Google Scholar 

  24. Kashani L, Omidvar T, Farazmand B, Modabbernia A, Ramzanzadeh F, Tehraninejad ES, Ashrafi M, Tabrizi M, Akhondzadeh S (2013) Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression. Psychoneuroendocrinology 38(6):767–776. https://doi.org/10.1016/j.psyneuen.2012.08.010

    Article  CAS  PubMed  Google Scholar 

  25. Malek M, Ashraf-Ganjouei A, Moradi K, Bagheri S, Mohammadi M-R, Akhondzadeh S (2020) Prednisolone as adjunctive treatment to risperidone in children with regressive type of autism spectrum disorder: a randomized, placebo-controlled trial. Clin Neuropharmacol 43:39–45

    Article  CAS  Google Scholar 

  26. Seidman LJ, Valera EM, Makris N (2005) Structural brain imaging of attention-deficit/hyperactivity disorder. Biol Psychiat 57:1263–1272

    Article  Google Scholar 

  27. Castle L, Aubert RE, Verbrugge RR, Khalid M, Epstein RS (2007) Trends in medication treatment for ADHD. J Attent Disord 10:335–342

    Article  Google Scholar 

  28. Huang Y-S, Tsai M-H (2011) Long-term outcomes with medications for attention-deficit hyperactivity disorder. CNS Drugs 25:539–554

    Article  Google Scholar 

  29. Santosh PJ, Sattar S, Canagaratnam M (2011) Efficacy and tolerability of pharmacotherapies for attention-deficit hyperactivity disorder in adults. CNS Drugs 25:737–763

    Article  CAS  Google Scholar 

  30. Palta P, Samuel LJ, Miller ER III, Szanton SL (2014) Depression and oxidative stress: results from a meta-analysis of observational studies. Psychosom Med 76:12

    Article  CAS  Google Scholar 

  31. Brown NC, Andreazza AC, Young LT (2014) An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Res 218:61–68

    Article  CAS  Google Scholar 

  32. Joseph N, Zhang-James Y, Perl A, Faraone SV (2015) Oxidative stress and ADHD: a meta-analysis. J Attent Disord 19:915–924

    Article  Google Scholar 

  33. Hawkey E, Nigg JT (2014) Omega-3 fatty acid and ADHD: Blood level analysis and meta-analytic extension of supplementation trials. Clin Psychol Rev 34:496–505

    Article  Google Scholar 

  34. Frémont L (2000) Biological effects of resveratrol. Life Sci 66:663–673

    Article  Google Scholar 

  35. Dasgupta B, Milbrandt J (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci 104:7217–7222

    Article  CAS  Google Scholar 

  36. Chung S, Yao H, Caito S, Hwang J-w, Arunachalam G, Rahman I (2010) Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 501:79–90

    Article  CAS  Google Scholar 

  37. Pasinetti GM, Wang J, Ho L, Zhao W, Dubner L (2015) Roles of resveratrol and other grape-derived polyphenols in Alzheimer's disease prevention and treatment. Biochim Biophys Acta (BBA)-Mol Basis Dis 1852:1202–1208

    Article  CAS  Google Scholar 

  38. Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS (2015) A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85:1383–1391

    Article  CAS  Google Scholar 

  39. Kou X, Chen N (2017) Resveratrol as a natural autophagy regulator for prevention and treatment of Alzheimer’s disease. Nutrients 9:927

    Article  Google Scholar 

  40. Leal G, Afonso PM, Salazar IL, Duarte CB (2015) Regulation of hippocampal synaptic plasticity by BDNF. Brain Res 1621:82–101

    Article  CAS  Google Scholar 

  41. Jain S, Banerjee BD, Ahmed RS, Arora VK, Mediratta PK (2013) Possible role of oxidative stress and brain derived neurotrophic factor in triazophos induced cognitive impairment in rats. Neurochem Res 38:2136–2147

    Article  CAS  Google Scholar 

  42. Wang X, Xie Y, Zhang T, Bo S, Bai X, Liu H, Li T, Liu S, Zhou Y, Cong X (2016) Resveratrol reverses chronic restraint stress-induced depression-like behaviour: involvement of BDNF level, ERK phosphorylation and expression of Bcl-2 and Bax in rats. Brain Res Bull 125:134–143

    Article  CAS  Google Scholar 

  43. Swanson JM, Flodman P, Kennedy J, Spence MA, Moyzis R, Schuck S, Murias M, Moriarity J, Barr C, Smith M (2000) Dopamine genes and ADHD. Neurosci Biobehav Rev 24:21–25

    Article  CAS  Google Scholar 

  44. Avshalumov MV, Chen BT, Koós T, Tepper JM, Rice ME (2005) Endogenous hydrogen peroxide regulates the excitability of midbrain dopamine neurons via ATP-sensitive potassium channels. J Neurosci 25:4222–4231

    Article  CAS  Google Scholar 

  45. Tsang AH, Chung KK (2009) Oxidative and nitrosative stress in Parkinson's disease. Biochim Biophysica Acta (BBA)-Mol Basis Dis 1792:643–650

    Article  CAS  Google Scholar 

  46. Sankhwar ML, Yadav RS, Shukla RK, Singh D, Ansari RW, Pant AB, Parmar D, Khanna VK (2016) Monocrotophos induced oxidative stress and alterations in brain dopamine and serotonin receptors in young rats. Toxicol Ind Health 32:422–436

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was the postgraduate thesis of Dr Maryam Rafeiy-Torghabeh under the supervision of Prof. Shahin Akhondzadeh for the Iranian Board of Psychiatry. This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (Grant no. 38897). The funding organization had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the article and the decision to submit the article for publication.

Author information

Author notes

  1. Maryam Rafeiy-Torghabeh and Amir Ashraf-Ganjouei contributed equally in to this study.

Authors and Affiliations

  1. Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Street, 13337, Tehran, Iran

    Maryam Rafeiy-Torghabeh, Amir Ashraf-Ganjouei, Kamyar Moradi, Sayna Bagheri, Mohammad-Reza Mohammadi & Shahin Akhondzadeh

Authors
  1. Maryam Rafeiy-Torghabeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amir Ashraf-Ganjouei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kamyar Moradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sayna Bagheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad-Reza Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shahin Akhondzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shahin Akhondzadeh.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to disclose.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rafeiy-Torghabeh, M., Ashraf-Ganjouei, A., Moradi, K. et al. Resveratrol adjunct to methylphenidate improves symptoms of attention-deficit/hyperactivity disorder: a randomized, double-blinded, placebo-controlled clinical trial. Eur Child Adolesc Psychiatry 30, 799–807 (2021). https://doi.org/10.1007/s00787-020-01562-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00787-020-01562-z

Keywords

Search

Navigation