Formulating strategies to address the booming stress category

Magnesium, vitamin D3 and L-theanine are among the ingredients to consider in a supplement formulated to target acute stress.

Maja Orešnik, Science and research director

December 16, 2020

7 Min Read
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Even before the pandemic, mood/relaxing supplements were a booming category that grew at a compound annual growth rate (CAGR) of 5.7% from 2014 to 2019, reaching 1.3 billion euros in 2019, according to proprietary Euromonitor data.

COVID-19 has been a far-reaching health crisis, as its negative impacts go beyond the physical health of those who contract the virus and affect the emotional well-being of many people. Concerns about mental well-being grew from 36% of global consumers in April 2020 to 43% in May 2020, according to FMCG Gurus

It is thus no surprise that IQVIA (“the human data science company”) reported the calming/sleep/mood over-the-counter (OTC) category to grow 25% in European pharmacy retail sell-out figures in March and that proprietary Euromonitor data forecasts mood/relaxing supplements to be one of the top five fastest-growing categories globally in 2020.

Formulating strategies

When formulating a supplement to address this market opportunity, it’s important to keep some specifics in mind to create a product concept that will not only ride the current wave of interest but ensure stable sales in the future.

When formulating our newly launched supplement products addressing stress, PharmaLinea’s research and development (R&D) team followed two main strategies. The first was to formulate a clinically supported product. The market is currently dominated by low-quality supplements formulated using repetitive commodity herbals, such as melissa, lavender and chamomile, with questionable safety and no direct clinical proof of effects. While these products might fit certain brands, we see a growing demand for clinical substantiation, coming from both increasingly educated consumers and increasing numbers of pharmaceutical companies entering the supplement field. To ensure more stable returns in the long term, we believe this trend cannot be overlooked. Additionally, burnout and stress are increasingly recognized by health institutions (e.g., World Health Organization [WHO]), opening the stress supplement market to brands based on promotion through medical detailing—and for this, clinically supported products are necessary.

The second strategy we applied was formulating for a specific positioning and with specific mechanisms of that positioning in mind. General herbal anti-stress products might be a fit for a certain segment of the market and at a certain stage of a category’s development. As the stress supplement category grows increasingly developed and mature, products should follow in the level of complexity and specificity. Taking the example of our launch this year, we developed two products—a capsule geared to chronic stress and a sachet aimed at acute stress—specifically targeting the underlying biological mechanisms of either acute exposure to short periods of intense stress or prolonged, chronic exposure to stress.

Acute vs. chronic formulating specifics

When formulating for these two specific positionings, one needs a complete understanding of the complex effects of stress. Increasing numbers of clinically studied, often adaptogenic ingredients show positive results against stress symptoms. Such ingredients can be the basis, but the more secondary physiological consequences should also be considered.

Chronic stress, for instance, has been linked to several negative health conditions including high blood pressure, high cholesterol, atherosclerosis, coronary heart disease, diabetes, sleep problems, decreased immunity, burnout and neuropsychiatric disorders like anxiety and depression. In our view, ingredients with proven cardiovascular benefits should be given high priority. Folate is also an important nutrient, with a function of maintaining normal homocysteine plasma concentrations1 and consequently lowering the risk for cardiovascular disease (CVD),2 impaired cognition3 and mood4 disorders. Vitamins B6 and B12 are involved in a wide range of physiological processes and play an essential role in the normal functioning of the central nervous system.5,6,7 It is beneficial to include B group vitamins in a formulation, as supplementation may aid the reduction of stress6 and fatigue.7

When formulating for acute stress, adapting dosages to those studied for immediately evident effects should be considered. One can focus the product on stress symptom relief, stress response improvement, and support of the nervous system during short periods of intense stress.

Acute stress is associated with increased magnesium in plasma, playing a protective role to diminish the adverse effects of stress. Supplementation with this mineral can help reduce stress and anxiety by balancing out cortisol levels8 and relaxing nerve activity to allow for better sleep.9 Magnesium is especially effective in alleviating severe stress in adults, especially when paired with another important brain nutrient, vitamin B6.10

Vitamin D3 is important for regulation of several stress response proteins in the small intestine11 and modulation of inflammation.12 It is crucial for the normal functioning of the innate and adaptive immune system, which is paramount for successful adaptation during intense stress periods.13

Adding L-theanine to the formulation, a highly studied amino acid proven to reduce stress and anxiolytic effects,14 offers a high probability for immediate results, as the effects are usually observed within an hour after intake.15

Listing all the potential ingredients brings us closer to a product concept. However, with this step, the process of product development hardly even begins. Consistent market success can only be achieved once a company arrives at a finished product with proven stability of ingredients at the end of shelf life, as well as a pleasant user experience.

Maja Orešnik is the science and research director at PharmaLinea Ltd.


1 Ambrosino P et al. “Cyclic supplementation of 5-MTHF is effective for the correction of hyperhomocysteinemia.” Nutr Res. 2015;35(6):489-495.

2 Mazza A et al. “Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial.” J Biol Regul Homeost Agents. 2016;30(3):921-927.

3 “Scientific Opinion on the substantiation of health claims related to folate and contribution to normal psychological functions (ID 81, 85, 86, 88), maintenance of normal vision (ID 83, 87), reduction of tiredness and fatigue (ID 84), cell division (ID 195, 2881) and contribution to normal amino acid synthesis (ID 195, 2881) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.” EFSA J. 2010;8(10):1760.

4 Lewis SJ et al. “Folic acid supplementation during pregnancy may protect against depression 21 months after pregnancy, an effect modified by MTHFR C677T genotype.” Eur J Clinical Nutr. 2012;66:97-103.

5 “Scientific Opinion on the substantiation of health claims related to vitamin B6 and protein and glycogen metabolism (ID 65, 70, 71), function of the nervous system (ID 66), red blood cell formation (ID 67, 72, 186), function of the immune system (ID 68), regulation of hormonal activity (ID 69) and mental performance (ID 185) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.” EFSA J. 2009;7(10):1225.

6 “Scientific Opinion on the substantiation of health claims related to vitamin B6 and contribution to normal homocysteine metabolism (ID 73, 76, 199), maintenance of normal bone (ID 74), maintenance of normal teeth (ID 74), maintenance of normal hair (ID 74), maintenance of normal skin (ID 74), maintenance of normal nails (ID 74), contribution to normal energy-yielding metabolism (ID 75, 214), contribution to normal psychological functions (ID 77), reduction of tiredness and fatigue (ID 78), and contribution to normal cysteine synthesis (ID 4283) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.” EFSA J. 2010;8(10):1759.

7 “Scientific Opinion on the substantiation of health claims related to vitamin B12 and contribution to normal neurological and psychological functions (ID 95, 97, 98, 100, 102, 109), contribution to normal homocysteine metabolism (ID 96, 103, 106), maintenance of normal bone (ID 104), maintenance of normal teeth (ID 104), maintenance of normal hair (ID 104), maintenance of normal skin (ID 104), maintenance of normal nails (ID 104), reduction of tiredness and fatigue (ID 108), and cell division (ID 212) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.” EFSA J. 2010;8(10):1756.

8 Golf SW et al. “Plasma Aldosterone, Cortisol and Electrolyte Concentrations in Physical Exercise after Magnesium Supplementation.” Clin Chem Lab Med. 1984;22(11):717-721.

9 Held K et al. “Oral Mg2+ supplementation reverses age-related neuroendocrine and sleep EEG changes in humans.” Pharmacopsychiatry. 2002;35(4):135-143.

10 Pouteau E et al. “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. 2018;13(12):e0208454.

11 Kühne H et al. “Vitamin D receptor regulates intestinal proteins involved in cell proliferation, migration and stress response.” Lipids Health Dis. 2014;13:51.

12 “Scientific Opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.” EFSA J. 2010;8(2):1468.

13 Aranow C. “Vitamin D and the Immune System.” J Investig Med. 2011,59(6):881-886.

14 Kimura K et al. “L-Theanine reduces psychological and physiological stress responses.” Biol Psychol. 2007;74(1):39-45.

15 White DJ et al. “Anti-Stress, Behavioural and Magnetoencephalography Effects of an L-Theanine-Based Nutrient Drink: A Randomised, Double-Blind, Placebo-Controlled, Crossover Trial.” Nutrients. 2016;8(1):53.

About the Author(s)

Maja Orešnik

Science and research director, PharmaLinea Ltd.

Maja Orešnik is the science and research director at PharmaLinea Ltd.

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