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

Nervous tension is one of the most prevalent mental health symptoms and may lead to significant impairment in both emotional and physical health. (15) It not only impacts the quality of life of the patient, but evidence shows that it may also increase the risk of all-cause mortality. (15)

The development of nervous tension can be multifactorial and may include commonly known factors such as traumatic experiences, as well as the involvement of inflammatory cytokines, genetic susceptibility, and nutrient deficiencies (1)(8)(15) Addressing the various causes as well as modulating physiological responses to stress may assist in decreasing nervous tension.

The protocol presented below represents research on ingredients showing efficacy in supporting symptoms of nervous tension.

L-theanine

200-400 mg, once per day, minimum 4 weeks (6)(18)(19)

  • Supplementation with L-theanine increased alpha brain wave activity, indicating a potential mechanism for its ability to induce a relaxed but alert state, when compared to placebo and/or caffeine; additionally, L-theanine has been shown to reduce stress-induced blood pressure elevation (19)
  • L-theanine supplementation improved self-rated anxiety scores, using the State-Trait Anxiety Inventory (STAI) in participants with no major psychiatric illness, suggesting potential efficacy in the general population (6)
  • Systematic review of 9 studies found doses ranging from 200 to 400 mg per day decreased stress and anxiety when people were exposed to stressful conditions (18)
  • When administering L-theanine in conjunction with current medications, anxiety improved as shown by decreases in Hamilton Depression Rating Scale (HAMD-21), Pittsburgh Sleep Quality Index (PSQI), and STAI anxiety scores, as well as improved cognitive function in patients with major depressive disorder (7)
L-theanine in the Fullscript catalog

Magnesium

300 mg, once per day, minimum 8 weeks (14)

  • Systematic review of 18 studies found subjective anxiety to improve from magnesium supplementation; stress exposure has been shown to increase renal excretion of magnesium, and magnesium may act as a modulator for the HPA axis by reducing adrenocorticotropic hormone (ACTH) and cortisol (1)
  • In participants with both anxiety and low serum magnesium, supplementation led to a reduction in scores on the Depression Anxiety Stress Scales (DASS-42) after four weeks (14)
  • Depression and anxiety improved, as demonstrated by a net decrease of 6 points on PHQ-9 and 4.5 points on GAD-7 scores (16)
Magnesium in the Fullscript catalog

Vitamin D

1000-10,000 IU daily (13)

Note: Additional evidence below supports dosing 50,000 IU vitamin D3, once per one or two weeks, minimum 12 weeks (4)(5)

  • An increase in serum serotonin levels and a decrease in serum neopterin levels were shown in the study group treated with vitamin D (50,000 IU once per week for three months), in addition to standard of care (SOC), compared to a group receiving only SOC; additionally, the vitamin D treated participants also saw a decrease in Generalized Anxiety Disorder (GAD) scores, while no changes were seen in the SOC group (4)
  • In women with type 2 diabetes, vitamin D supplementation (50,000 IU every two weeks for 16 weeks) decreased anxiety levels from moderate to mild on the Depression, Anxiety and Stress Scales (DASS- 21) questionnaire; additionally, supplementation was shown to reduce hs-CRP levels and increase IL-10 concentrations (5)
  • Supplementation was found to improve anxiety and depression scores in all doses, while high dose (10,000 IU daily) improved serum vitamin D, and decreased clinical relapse in patients with Crohn’s disease with remission (13)
Vitamin D in the Fullscript catalog

Ashwagandha (Withania somnifera) 

240-600 mg, total per day of standardized extract containing between 35% and 1.5% of withanolides, respectively, for a minimum 8 weeks (2)(3)(11)

  • A statistically significant reduction in Hamilton-Anxiety Rating Scale (HAM-A) scores and morning cortisol levels was demonstrated with the use of ashwagandha (11)
  • One proposed mechanism of action was the moderating effect of ashwagandha on the hypothalamic-pituitary-adrenal axis (HPA axis) response to stressors; however, further investigation was suggested (11)
  • One study assessed the intervention of psychotherapy treatment (PT) alone versus  naturopathic treatments (including the use of ashwagandha as well as dietary counseling, breathing techniques for relaxation, and a multivitamin); symptoms, including anxiety as rated with the Beck Anxiety Inventory, social functioning, overall quality of life, fatigue, and concentration showed further improvement in the naturopathic treatment group compared to the group receiving only psychotherapy (3)
  • Ashwagandha was shown to reduce serum cortisol levels from baseline levels which was correlated with a reduction in scores on stress assessment scales in patients with a history of chronic stress (2)
Ashwagandha in the Fullscript catalog

Probiotics

10 billion CFU daily (e.g., Lactobacillus plantarum P8, although other strains may be effective as well) for a minimum of 4 weeks (9)

  • Meta-analysis and systematic review of 34 controlled clinical trials found probiotics to significantly improve depression and anxiety (10)
  • Stressed adults experienced reduced pro-inflammatory cytokine levels (IFN-γ and TNF-α) and stress/anxiety scores when supplemented with Lactobacillus plantarum P8 in a dose of 10 log CFU per day (9)
  • Improved overall anxiety (panic anxiety, neurophysiological anxiety, negative affect, and worry) and negative mood regulation in healthy young adults; additionally, dose (CFU) was found to positively impact outcomes more than species (17)
  • Systematic review and meta-analysis of 7 studies found probiotic supplementation improved psychological symptoms including depression, anxiety, and perceived stress in healthy volunteers (12)
Probiotics 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. Boyle, N. B., Lawton, C., & Dye, L. (2017). The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients, 9(5). https://pubmed.ncbi.nlm.nih.gov/28445426/ (A)
  2. Chandrasekhar, K., Kapoor, J., & Anishetty, S. (2012). A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian Journal of Psychological Medicine, 34(3), 255–262. https://pubmed.ncbi.nlm.nih.gov/23439798/ (B)
  3. Cooley, K., Szczurko, O., Perri, D., Mills, E. J., Bernhardt, B., Zhou, Q., & Seely, D. (2009). Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PloS One, 4(8), e6628. https://pubmed.ncbi.nlm.nih.gov/19718255/ (C)
  4. Eid, A., Khoja, S., AlGhamdi, S., Alsufiani, H., Alzeben, F., Alhejaili, N., Tayeb, H. O., & Tarazi, F. I. (2019). Vitamin D supplementation ameliorates severity of generalized anxiety disorder (GAD). Metabolic Brain Disease, 34(6), 1781–1786. https://pubmed.ncbi.nlm.nih.gov/31478182/ (C)
  5. Fazelian, S., Amani, R., Paknahad, Z., Kheiri, S., & Khajehali, L. (2019). Effect of Vitamin D Supplement on Mood Status and Inflammation in Vitamin D Deficient Type 2 Diabetic Women with Anxiety: A Randomized Clinical Trial. International Journal of Preventive Medicine, 10, 17. https://pubmed.ncbi.nlm.nih.gov/30820304/ (C)
  6. Hidese, S., Ogawa, S., Ota, M., Ishida, I., Yasukawa, Z., Ozeki, M., & Kunugi, H. (2019). Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial. Nutrients, 11(10). https://pubmed.ncbi.nlm.nih.gov/31623400/ (C)
  7. Hidese, S., Ota, M., Wakabayashi, C., Noda, T., Ozawa, H., Okubo, T., & Kunugi, H. (2017). Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study. Acta Neuropsychiatrica, 29(2), 72–79. https://pubmed.ncbi.nlm.nih.gov/27396868/ (C)
  8. Kiecolt-Glaser, J. K., Belury, M. A., Andridge, R., Malarkey, W. B., & Glaser, R. (2011). Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain, Behavior, and Immunity, 25(8), 1725–1734. https://pubmed.ncbi.nlm.nih.gov/21784145/ (B)
  9. Lew, L.-C., Hor, Y.-Y., Yusoff, N. A. A., Choi, S.-B., Yusoff, M. S. B., Roslan, N. S., Ahmad, A., Mohammad, J. A. M., Abdullah, M. F. I. L., Zakaria, N., Wahid, N., Sun, Z., Kwok, L.-Y., Zhang, H., & Liong, M.-T. (2019). Probiotic Lactobacillus plantarum P8 alleviated stress and anxiety while enhancing memory and cognition in stressed adults: A randomised, double-blind, placebo-controlled study. Clinical Nutrition , 38(5), 2053–2064. https://pubmed.ncbi.nlm.nih.gov/30266270/ (B)
  10. Liu, R. T., Walsh, R. F. L., & Sheehan, A. E. (2019). Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials. Neuroscience and Biobehavioral Reviews, 102, 13–23. https://pubmed.ncbi.nlm.nih.gov/31004628/ (A)
  11. Lopresti, A. L., Smith, S. J., Malvi, H., & Kodgule, R. (2019). An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study. Medicine, 98(37), e17186. https://pubmed.ncbi.nlm.nih.gov/31517876/ (B)
  12. McKean, J., Naug, H., Nikbakht, E., Amiet, B., & Colson, N. (2017). Probiotics and Subclinical Psychological Symptoms in Healthy Participants: A Systematic Review and Meta-Analysis. Journal of Alternative and Complementary Medicine , 23(4), 249–258. https://pubmed.ncbi.nlm.nih.gov/27841940/ (A)
    1. https://pubmed.ncbi.nlm.nih.gov/27841940/ (A)

    Narula, N., Cooray, M., Anglin, R., Muqtadir, Z., Narula, A., & Marshall, J. K. (2017). Impact of High-Dose Vitamin D3 Supplementation in Patients with Crohn’s Disease in Remission: A Pilot Randomized Double-Blind Controlled Study. Digestive Diseases and Sciences, 62(2), 448–455. https://pubmed.ncbi.nlm.nih.gov/27975236/ (C)

  14. Pouteau, E., Kabir-Ahmadi, M., Noah, L., Mazur, A., Dye, L., Hellhammer, J., Pickering, G., & Dubray, C. (2018). Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial. PloS One, 13(12), e0208454. https://pubmed.ncbi.nlm.nih.gov/30562392/ (C)
  15. Su, K.-P., Tseng, P.-T., Lin, P.-Y., Okubo, R., Chen, T.-Y., Chen, Y.-W., & Matsuoka, Y. J. (2018). Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms: A Systematic Review and Meta-analysis. JAMA Network Open, 1(5), e182327. https://pubmed.ncbi.nlm.nih.gov/30646157/ (A)
  16. Tarleton, E. K., Littenberg, B., MacLean, C. D., Kennedy, A. G., & Daley, C. (2017). Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PloS One, 12(6), e0180067. https://pubmed.ncbi.nlm.nih.gov/28654669/ (C)
  17. Tran, N., Zhebrak, M., Yacoub, C., Pelletier, J., & Hawley, D. (2019). The gut-brain relationship: Investigating the effect of multispecies probiotics on anxiety in a randomized placebo-controlled trial of healthy young adults. Journal of Affective Disorders, 252, 271–277. https://pubmed.ncbi.nlm.nih.gov/30991255/ (B)
  18. Williams, J. L., Everett, J. M., D’Cunha, N. M., Sergi, D., Georgousopoulou, E. N., Keegan, R. J., McKune, A. J., Mellor, D. D., Anstice, N., & Naumovski, N. (2020). The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review. Plant Foods for Human Nutrition , 75(1), 12–23. https://pubmed.ncbi.nlm.nih.gov/31758301/ (A)
  19. Yoto, A., Motoki, M., Murao, S., & Yokogoshi, H. (2012). Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses. Journal of Physiological Anthropology, 31, 28. https://pubmed.ncbi.nlm.nih.gov/23107346/ (C)