Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Class
Qualifying studies
Minimum requirements
A
Systematic review or meta-analysis of human trials
 
B
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
C
RDBPC human trials
1 study

In 2007, the global prevalence of children with hyperactivity and difficulties focusing was estimated to be 5.29%. (21) More recent estimates suggest an increased prevalence of 7.9%. (26) Children with concerns of inattention or hyperactivity may present with lower levels of certain nutrients, such as zinc, vitamin D, and omega-3 fatty acids. (2)(3)(17)

Inflammation and oxidative stress have also been associated with an increased risk of cognitive or behavioral difficulties.  For these reasons, interventions aimed at correcting nutrient inadequacies, decreasing inflammatory markers such as CRP, IL-6, IL-12, and TNF-α, or improving antioxidative capacity may be helpful, particularly if corrections are associated with improved attention or behavior scores. (1)(15)(16)

The ingredients presented in the protocol below may help address concerns and mechanisms of decreased inattention and hyperactivity in children or adults.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

500-1000 mg EPA and 200-650 mg DHA, once per day, for a minimum of 8-16 weeks (5)(6)(7)(15)

  • Improved parent ratings (using the Conners Parent Rating Scale (CPRS)) of children’s inattention, hyperactivity, and impulsivity in children with ADHD (25)
  • Improved behavior ratings, utilizing scales such as the Conners Rating Scale, in children diagnosed with ADHD (23)
  • Improved oxidative stress by increasing glutathione reductase and superoxide dismutase activity; improved plasma inflammatory markers by decreasing levels of CRP and IL-6 in children with ADHD when compared to baseline levels (15)
  • Increased erythrocyte cellular EPA and DHA and improved working memory in children with ADHD (29)
  • Systematic review and meta-analysis found n-3 PUFA effective in improving cognitive performance in adolescents with ADHD and/or n-3 PUFA deficiency (7)
  • Systematic review and meta-analysis of 10 studies found n-3 PUFA improved emotional lability such as oppositional behavior and conduct problems in children with ADHD (9)
EPA and DHA in the Fullscript catalog

Zinc

10-15 mg as elemental zinc (from zinc sulfate or zinc oxide), 1-2 times per day, for a minimum of 5-13 weeks (4)(11)(28)(30)

  • Increased attention was observed in children with ADHD when concomitantly administered with methylphenidate compared with methylphenidate alone (19)
  • Increased serum zinc concentrations correlated to improvements in symptoms of anxiety, depression, and social skills in children with low zinc levels and/or at risk for zinc deficiency (11)
  • Reduced required dose of amphetamine by 37% when given 30 mg zinc per day in children with ADHD (4) 
  • Overall prevalence of clinically significant attention deficit and hyperactivity decreased as well as CPRS scores for attention deficit, hyperactivity, oppositional behavior, and conduct disorder; additionally, behavioral improvements were amplified in children with mothers of low education (28)
Zinc in the Fullscript catalog

Vitamin D

2000 IU per day, for a minimum of 8-12 weeks, or 50,000 IU per week, for a minimum of 6 weeks as vitamin D3 (cholecalciferol) (10)(18)(24)

  • Improved all subscales of symptoms in children with ADHD with a notable improvement in inattention when used as an adjunct to methylphenidate (10)
  • Systematic review and meta-analysis of four randomized controlled trials found vitamin D reduced ADHD total scores, inattention scores, hyperactivity scores, and behavior scores, and raised serum vitamin D levels, which were typically lower in children with ADHD than controls (14)
  • Vitamin D supplementation at 2000 IU daily for 12 weeks associated with increased serum dopamine levels in children with ADHD when compared with both baseline and placebo (24)
  • Improved evening symptom scores according to the Weekly Parent Ratings of Evening and Morning Behavior (WPREMB) in children with ADHD when concomitantly administered with methylphenidate (18)
Vitamin D in the Fullscript catalog

Pycnogenol

1 mg per kilogram of body weight, once per day, for a minimum of 4 weeks (12)(13)(8)(27)

  • Associated with normalized total antioxidant status (TAS), improved glutathione to oxidized glutathione ratio and total anti-oxidative capacity in children with ADHD (13)
  • Children with ADHD experienced improvements in attention, visual-motoric coordination, and concentration as well as decreased hyperactivity; notably, symptoms relapsed one month after ceasing supplementation (27)
  • Improved hyperactivity and glutathione to oxidized glutathione ratio in children with ADHD; additionally, catecholamine concentration normalized demonstrated by decreased adrenaline and noradrenaline (12)
  • Improved attention in children with ADHD; additionally oxidative damage decreased as shown by improved TAS and decreased DNA damage (8)
Pycnogenol in the Fullscript catalog

Lactobacillus rhamnosus GG

10 billion CFU per day of Lactobacillus rhamnosus GG, for a minimum of 1-6 months (16)(20)

  • Improved overall quality of life (PedsQL Child Self-Report Total Score) in children and adolescents with ADHD; reduced IL-12 p70, TNF-α, and IL-10 compared to baseline in children and adolescents with ADHD (16)
  • Supplementation during the first six months of life decreased the risk of neuropsychiatric disorders such as ADHD and Asperger syndrome over a 13 year follow-up study (20)
  • Systematic review of seven studies showed supplementation reduced risk of developing ADHD or Asperger syndrome when given to mothers one month prior to delivery and six months postpartum while breastfeeding (22)
Lactobacillus rhamnosus GG in the Fullscript catalog

Disclaimer

The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

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References
  1. Abdullah, M., Jowett, B., Whittaker, P. J., & Patterson, L. (2019). The effectiveness of omega-3 supplementation in reducing ADHD associated symptoms in children as measured by the Conners’ rating scales: A systematic review of randomized controlled trials. Journal of Psychiatric Research, 110, 64–73. https://pubmed.ncbi.nlm.nih.gov/30594823/ (A)
  2. Agostoni, C., Nobile, M., Ciappolino, V., Delvecchio, G., Tesei, A., Turolo, S., Crippa, A., Mazzocchi, A., Altamura, C. A., & Brambilla, P. (2017). The Role of Omega-3 Fatty Acids in Developmental Psychopathology: A Systematic Review on Early Psychosis, Autism, and ADHD. International Journal of Molecular Sciences, 18(12). https://pubmed.ncbi.nlm.nih.gov/29207548/ (A)
  3. Alhraiwil, N. J., Ali, A., Househ, M. S., Al-Shehri, A. M., & El-Metwally, A. A. (2015). Systematic review of the epidemiology of attention deficit hyperactivity disorder in Arab countries. Neurosciences , 20(2), 137–144. https://pubmed.ncbi.nlm.nih.gov/25864066/ (A)
  4. Arnold, L. E., Disilvestro, R. A., Bozzolo, D., Bozzolo, H., Crowl, L., Fernandez, S., Ramadan, Y., Thompson, S., Mo, X., Abdel-Rasoul, M., & Joseph, E. (2011). Zinc for attention-deficit/hyperactivity disorder: placebo-controlled double-blind pilot trial alone and combined with amphetamine. Journal of Child and Adolescent Psychopharmacology, 21(1), 1–19. https://pubmed.ncbi.nlm.nih.gov/21309695/ (C)
  5. Bélanger, S. A., Vanasse, M., Spahis, S., Sylvestre, M.-P., Lippé, S., L’heureux, F., Ghadirian, P., Vanasse, C.-M., & Levy, E. (2009). Omega-3 fatty acid treatment of children with attention-deficit hyperactivity disorder: A randomized, double-blind, placebo-controlled study. Paediatrics & Child Health, 14(2), 89–98. https://pubmed.ncbi.nlm.nih.gov/19436468/ (B)
  6. Bos, D. J., Oranje, B., Veerhoek, E. S., Van Diepen, R. M., Weusten, J. M., Demmelmair, H., Koletzko, B., de Sain-van der Velden, M. G., Eilander, A., Hoeksma, M., & Durston, S. (2015). Reduced Symptoms of Inattention after Dietary Omega-3 Fatty Acid Supplementation in Boys with and without Attention Deficit/Hyperactivity Disorder. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 40(10), 2298–2306. https://pubmed.ncbi.nlm.nih.gov/25790022/ (B)
  7. Chang, J. P.-C., Su, K.-P., Mondelli, V., & Pariante, C. M. (2018). Omega-3 Polyunsaturated Fatty Acids in Youths with Attention Deficit Hyperactivity Disorder: a Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 43(3), 534–545. https://pubmed.ncbi.nlm.nih.gov/28741625/ (A) 
  8. Chovanová, Z., Muchová, J., Sivonová, M., Dvoráková, M., Zitnanová, I., Waczulíková, I., Trebatická, J., Skodácek, I., & Duracková, Z. (2006). Effect of polyphenolic extract, Pycnogenol, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder. Free Radical Research, 40(9), 1003–1010. https://pubmed.ncbi.nlm.nih.gov/17015282/ (B)
  9. Cooper, R. E., Tye, C., Kuntsi, J., Vassos, E., & Asherson, P. (2016). The effect of omega-3 polyunsaturated fatty acid supplementation on emotional dysregulation, oppositional behaviour and conduct problems in ADHD: A systematic review and meta-analysis. Journal of Affective Disorders, 190, 474–482. https://pubmed.ncbi.nlm.nih.gov/26551407/ (A)
  10. Dehbokri, N., Noorazar, G., Ghaffari, A., Mehdizadeh, G., Sarbakhsh, P., & Ghaffary, S. (2019). Effect of vitamin D treatment in children with attention-deficit hyperactivity disorder. World Journal of Pediatrics: WJP, 15(1), 78–84. https://pubmed.ncbi.nlm.nih.gov/30456564/ (B)
  11. DiGirolamo, A. M., Ramirez-Zea, M., Wang, M., Flores-Ayala, R., Martorell, R., Neufeld, L. M., Ramakrishnan, U., Sellen, D., Black, M. M., & Stein, A. D. (2010). Randomized trial of the effect of zinc supplementation on the mental health of school-age children in Guatemala. The American Journal of Clinical Nutrition, 92(5), 1241–1250. https://pubmed.ncbi.nlm.nih.gov/20881069/ (B)
  12. Dvoráková, M., Jezová, D., Blazícek, P., Trebatická, J., Skodácek, I., Suba, J., Iveta, W., Rohdewald, P., & Duracková, Z. (2007). Urinary catecholamines in children with attention deficit hyperactivity disorder (ADHD): modulation by a polyphenolic extract from pine bark (pycnogenol). Nutritional Neuroscience, 10(3-4), 151–157. https://pubmed.ncbi.nlm.nih.gov/18019397/ (B)
  13. Dvoráková, M., Sivonová, M., Trebatická, J., Skodácek, I., Waczuliková, I., Muchová, J., & Duracková, Z. (2006). The effect of polyphenolic extract from pine bark, Pycnogenol on the level of glutathione in children suffering from attention deficit hyperactivity disorder (ADHD). Redox Report: Communications in Free Radical Research, 11(4), 163–172. https://pubmed.ncbi.nlm.nih.gov/16984739/ (B)
  14. Gan, J., Galer, P., Ma, D., Chen, C., & Xiong, T. (2019). The Effect of Vitamin D Supplementation on Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Child and Adolescent Psychopharmacology, 29(9), 670–687. https://pubmed.ncbi.nlm.nih.gov/31368773/ (A)
  15. Hariri, M., Djazayery, A., Djalali, M., Saedisomeolia, A., Rahimi, A., & Abdolahian, E. (2012). Effect of n-3 supplementation on hyperactivity, oxidative stress and inflammatory mediators in children with attention-deficit-hyperactivity disorder. Malaysian Journal of Nutrition, 18(3), 329–335. https://pubmed.ncbi.nlm.nih.gov/24568073/ (B)
  16. Kumperscak, H. G., Gricar, A., Ülen, I., & Micetic-Turk, D. (2020). A Pilot Randomized Control Trial With the Probiotic Strain Lactobacillus rhamnosus GG (LGG) in ADHD: Children and Adolescents Report Better Health-Related Quality of Life. Frontiers in Psychiatry / Frontiers Research Foundation, 11, 181. https://pubmed.ncbi.nlm.nih.gov/32256407/ (C)
  17. Mahmoud, M. M., El-Mazary, A.-A. M., Maher, R. M., & Saber, M. M. (2011). Zinc, ferritin, magnesium and copper in a group of Egyptian children with attention deficit hyperactivity disorder. Italian Journal of Pediatrics, 37, 60. https://pubmed.ncbi.nlm.nih.gov/22206662/ (C)
  18. Mohammadpour, N., Jazayeri, S., Tehrani-Doost, M., Djalali, M., Hosseini, M., Effatpanah, M., Davari-Ashtiani, R., & Karami, E. (2018). Effect of vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms: A randomized, double blind, placebo-controlled trial. Nutritional Neuroscience, 21(3), 202–209. https://pubmed.ncbi.nlm.nih.gov/27924679/ (B)
  19. Noorazar, S. G., Malek, A., Aghaei, S. M., Yasamineh, N., & Kalejahi, P. (2020). The efficacy of zinc augmentation in children with attention deficit hyperactivity disorder under treatment with methylphenidate: A randomized controlled trial. Asian Journal of Psychiatry, 48, 101868. https://pubmed.ncbi.nlm.nih.gov/31841818/ (B)
  20. Pärtty, A., Kalliomäki, M., Wacklin, P., Salminen, S., & Isolauri, E. (2015). A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatric Research, 77(6), 823–828. https://pubmed.ncbi.nlm.nih.gov/25760553/ (C)
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  23. Rodríguez, C., García, T., Areces, D., Fernández, E., García-Noriega, M., & Domingo, J. C. (2019). Supplementation with high-content docosahexaenoic acid triglyceride in attention-deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Neuropsychiatric Disease and Treatment, 15, 1193–1209. https://pubmed.ncbi.nlm.nih.gov/31190827/ (B)
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