If one leg of a table breaks then the whole structure may topple over. The same may be said of people dealing with mood, anxiety, stress or sleep problems (MASS). Typically, if a person is experiencing issues in one area, the other three are affected, and like the table that can no longer stay balanced, the person fails to function optimally. This is MASS, and when the four legs are affected, it becomes critical MASS.

Mood swings, anxiety, stress and sleeplessness are universal and non-discriminatory. When one becomes prominent, it affects the remaining three states.

Barring diagnosable mental diseases (e.g., unipolar depression, bipolar depression, and generalized anxiety disorder, GAD—all of which are characterized by neurochemical dysfunction) there are quite a few dietary ingredients that can help restore healthy balance.

Triggers & Tipping Points
Stress may be the trigger in most instances of low mood, anxiety and sleeplessness. Vladimir Badmeav, MD, PhD, CEO of American Medical Holdings, explained that stress is not a modern phenomenon; it has pervaded human lives throughout the evolutionary process. However, there is a growing number of diagnosed anxiety disorders, including social anxiety disorder, post-traumatic stress disorder, generalized anxiety disorder, panic disorder and obsessive-compulsive disorder. These conditions and the aging of the global population are factors responsible for the rapid increase in sales of anti-anxiety drugs and supplements.

“Health professionals and consumers are increasingly looking for novel drugs and supplements with proven safety and efficacy for the treatment of anxiety disorders,” Dr. Badmeav said. “The U.S. is the largest market for anxiety disorder therapeutics and supplements worldwide with the highest number of patients reporting anxiety disorders anywhere in the world. The yearly cost for managing anxiety disorders in the U.S. alone is $42 billion, which accounts for almost one-third of the overall cost for mental illnesses.”

About 27% of the European population suffers from affective disorders, with depression being the most prevalent health problem in several EU member states, he added. However, the fastest growing population with affective disorders resides in the Asia-Pacific region, registering a compound annual growth rate of more than 5% during 2009-2017. “Stress is one of the most significant health issues of the 21st century—it is now considered a global epidemic—and with it comes anxiety, depression/mood disorders and insomnia,” Dr. Badmeav noted.

Dr. T. P. Rao, assistant general manager, Taiyo Kagaku Co Ltd., Japan, explained that sleeplessness or insomnia is commonly associated with stress and anxiety. When someone has a stressful event or anxiety, the body’s stress-defense mechanism triggers the release of stress hormones such as norepinephrine, epinephrine and cortisol into the bloodstream, which may influence the onset and modulation of inhibitory neurotransmitters responsible for proper sleep. Typically, anxiolytic or sedative drugs are prescribed for the suppression of chronic stress and anxiety disorders. And each can have dramatic side effects, such as drowsiness.

“Most people think of stress as a feeling; and they will often make/post comments, emoticons, and hashtags on social media about how stressed out work, life, and the pursuit of balance is,” said Chase Hagerman, brand director, Chemi Nutra, Austin, TX. People want to avoid any stress, he added, but that is, of course, impossible as “stress is a necessary evil and our bodies need it for the fight-or-flight response.”

The human body produces cortisol as a stress-response, and Mr. Hagerman noted that a certain amount is actually necessary for the body to function normally. However, an abundance of cortisol from chronic stress results in heightened anxiety, sleeplessness, low mood, cognitive disruption, and even lowered physical performance.

Mr. Hagerman also acknowledged the external environment as a potential stressor (e.g., heat stress and exercise exhaustion) that can result in release of too much cortisol. Elevated cortisol is very destructive, as the potent catabolic stress hormone breaks down the body’s muscle protein into amino acids, which are then converted to glucose in the liver. Thus, in both diet and exercise, the induced physical stress results in the triggering of elevated levels of cortisol, which can remain elevated for several hours, resulting in a substantial period of cannibalization of hard-earned lean muscle mass, and can compromise rehabilitation and recovery. In addition, high levels of cortisol can lower the concentration and activities of many of the important immune cells that fight infection. Mr. Hagerman thus made a case for sports nutrition supplements that target the MASS interrelation.

Shaheen Majeed, marketing director, Sabinsa Corporation, East Windsor, NJ, likewise emphasized the stress-cortisol relationship as a cornerstone of MASS. The typical busy lifestyle naturally drains energy, both mental and physical. With the addition of constant high expectations both professionally and personally, these factors combine to decrease quality of life caused by chronic physical and mental overload; the sensation of feeling overwhelmed by life.

“This condition is known as metabolic stress and it affects the body in different ways,” Mr. Majeed said. “The body’s response to metabolic stress depends on the magnitude and duration of the stress, but can involve overeating, co-elevation of cortisol and insulin, and suppression of certain anabolic hormones, finally leading to a milieu of systemic inflammation and oxidative stress.”

Moreover, he continued, anxiety is the psychophysiological signal that the stress response has been initiated. Anxiety has undesirable effects on performance and it also results in increased irritability and “nerves,” that in turn lead to poor or distressed mood.

“Stress and anxiety can imbalance the mind and body, making tasks as simple as remembering where you put your keys more difficult,” he noted. “Day-to-day stress can lead to a cascade of reactions such as anxiety, poor mood and sleeplessness, not to mention the detrimental effects stress can have on one’s health. Metabolic disorders that include obesity, hypercholesterolemia and diabetes may also be off-shoots of stress.”

Bruce Abedon, PhD, director of scientific affairs, NutraGenesis LLC, Brattleboro, VT, explained that cortisol overload from stress triggers feelings of anxiety and poor mood. High levels of circulating cortisol also make sleep onset more difficult to achieve as it interferes with the ability of melatonin to induce sleep. “That is why people who are stressed often have more difficulty sleeping. This also can create a vicious circle where stress and anxiety lead to less sleep and lack of sleep, in turn, stresses the body and can further dampen mood,” he said.

There is also a cognitive factor that should not be ignored, according to Karen Todd, RD, CSCS, HFS, senior director of global brand marketing, Kyowa Hakko USA, Inc., New York, NY. “Our research has shown that folks who have issues with concentration or focus usually have issues with depression and insomnia; these issues go hand-in-hand,” she said. “Stress, anxiety, mood and lack of sleep are all tied together and without disentangling them they will continue to have an unraveling effect and spiral a person out of control.”

Interestingly, the supplement industry often separates mood from brain/cognitive support, according to Barbara Davis, PhD, vice president, medical and scientific affairs, PLT Health Solutions, Morristown, NJ. However, several ingredients targeted for brain and cognitive support also positively address mood, as well as anxiety and sleep.

“Support for stress and, hence, mood in today’s complex world is an important cognitive health trend,” she said. Currently in the U.S., more than 75 million people experience stress with negative consequences for their physical and mental health, quality of life and economic activity. “There is no doubt the ingredients that will be most successful will have an experiential effect on consumers. This produces positive reinforcement and better compliance on an on-going basis.”

Overall, according to Steve Siegel, vice president, Ecuadorian Rainforest, LLC, Belleville, NJ, “all of these maladies are intertwined, so one may cause others to appear.”

For example, someone who is stressed or anxious will have difficulty falling asleep. Sleeplessness, especially over several nights, often also causes mood swings, and more anxiety, exacerbating stress. “It’s a painful cycle and one that many consumers are having a difficult time breaking,” he said.

MASS Formula Ingredients
There are quite a few compelling ingredients that can address mood instability, anxiety, stress and sleeplessness.

Lactium, from Pharmachem Laboratories Inc., Kearny, NJ, is a milk protein hydrolysate that contains a bioactive peptide with anti-stress properties. In total, five studies were conducted on 190 healthy subjects, which confirmed the anti-stress efficacy of Lactium. A recent study showed Lactium, at a dose of 167 mg/day, was particularly efficient for subjects who demonstrated the highest initial intensity of symptoms. This was true after a 15- and 30-day treatment. Extensive clinical research showed no side effects and no toxicity. Lactium is a patented, Generally Recognized As Safe (GRAS) dietary ingredient ideal for functional foods and beverages.

In a recent study published in the Journal of International Medical Research, a consumer product called Target 1—a formula featuring Lactium (milk casein)—helped significantly decrease symptoms of burnout. The randomized, double-blind, placebo-controlled clinical trial evaluated the effects of the formula on participants with burnout syndrome using different evaluation instruments over the 12-week study period.

SerinAid phosphatidylserine (PS), from Chemi Nutra is “ideal for stress reduction,” according to Mr. Hagerman. A number of research studies, involving both exercising and non-exercising subjects, have shown that PS suppresses the release of cortisol under conditions where its release would have otherwise increased. PS also aids in recovery by reducing muscle damage and providing the physiological machinery for faster muscle repair.

Nutragenesis’ Sensoril is a multi-patented, full-spectrum, standardized root and leaf extract of ashwagandha (Withania somnifera), a renowned Ayurvedic, adaptogenic botanical grown in India that has been used for its ability to balance, energize, rejuvenate and revitalize, according to Dr. Abedon. “Sensoril possesses superior bioactivity because it is standardized to the highest levels of ashwagandha bioactives in the industry (≥10% health-enhancing glycowithanolides),” he said. “Sensoril can be used in a wide range of delivery systems including capsules, tablets, stick packs, gummies, bars and other foods, confectioneries, as well as liquid formulations such as ready-to-drink beverages and shots.”

In a 60-day, randomized, double-blind, placebo-controlled human clinical trial involving 98 subjects with moderate levels of stress, participants took 125 mg of Sensoril once or twice daily (or matching placebo) and were evaluated for improvements in health based on both objective and subjective criteria. For both doses, consumption of Sensoril resulted in significant reductions in the stress hormone cortisol (average of 24.2%), stress and anxiety (average of 69.9%), as well as many stress-related factors, including fatigue, inability to concentrate, forgetfulness and sleep. Greater and faster benefits for the higher vs. lower Sensoril dose indicated a significant dose response. Metabolic dysfunction affected by stress also improved while levels of DHEA (an energizing, anti-aging hormone) increased. Consumption of Sensoril resulted in enhancement of mood as well.

Sabinsa also supplies ashwagandha extract, which Mr. Majeed explained has been shown to help rejuvenate the body on a cellular level and help increase stamina and endurance. “It helps improve the fighting capacity of the body against all kinds of stress,” he said.

In an in vivo study, an aqueous suspension of ashwagandha root was used at 100 mg/kg oral dosage. The results indicated a significant increase in the plasma corticosterone level, phagocytic index and avidity index in rats subjected to cold swimming stress. The results indicated that Withania somnifera used in the crude form is a potent anti-stress agent.

Tulsi (Indian holy basil), also from Sabinsa, is a standardized extract of Ocimum sanctum containing a minimum of 2% ursolic acid. It has been studied for Generalized Anxiety Disorder (GAD), a recognized neurochemical imbalance/mental illness that is a cardinal symptom of many psychiatric disorders and often a component of many medical conditions. Ocimum sanctum has been studied for its role in GAD in a hospital-based clinical set-up. Thirty-five subjects (21 male and 14 female; average age 38.4 years) were given a fixed dose (500 mg/capsule, twice daily). The researchers observed that O. sanctum significantly attenuated generalized anxiety disorders and also its correlated stress and depression. The study concluded that O. sanctum may be useful to address GAD and may be a promising anxiolytic agent.

Licorice (Glycyrrhiza glabra), containing a minimum of 20% glycyrrhizinic acid, is described in the British Herbal Pharmacopoeia 1983 as an adrenocorticotropic and is useful for stress-support formulas, said Mr. Majeed. “The adrenal cortex participates in the stress response through its production of glucocorticoids. Licorice may therefore support the adrenal cortex during prolonged stress and be a valuable support in recuperation after a particularly exhausting life phase or disease.”

Mr. Majeed described ActiCissus (Cissus quadrangularis), standardized for a minimum of 10% ketosterones, as “an effective cortisol reducer.” The anti-glucocorticoid properties of Cissus helps preserve muscle tissue during times of physical and emotional stress, he said.

Adaptrin, from American Medical Holdings, is a botanical and mineral formula whose origin lies in the principles of Tibetan medicine; Adaptrin is designed to support the cardiovascular and immune systems affected by stress, especially long-standing stress. “Adaptrin lowers stress levels, and sharpens memory, overall energy and alertness, and sleep patterns; and promotes an increased general subjective sense of well-being,” Dr. Badmaev noted. “Adaptrin employs bioprotectant properties—helping to regulate the integrity of living cells—and balancing the effects of stress on the body. The concept of Tibetan herbal formulation provides broad, safe and effective multi-component preparations in the form of ‘condensed food’ to supplement (i.e., to nourish) the body, organs and systems; and it is this combined mechanism of action that is key to their success.”

Cognizin is Kyowa-Hakko’s branded citicoline that is used for focus, attention and memory issues in both young and older adults. Yet, according to Ms. Todd, some key additional benefits are the increase of dopamine as well as enhanced mood and quality of sleep, both of which have been shown in research by Dr. Perry Renshaw at The Brain Institute at the University of Utah in his studies with substance abuse. 

“Citicoline is also known to help the brain produce more dopamine, a neurotransmitter involved with pleasure and happiness,” she said. “It makes sense that if you wake up in the morning and you feel good and you are refreshed from a good night’s sleep you are more likely to make better decisions and function at a much higher level.”

Zembrin, from PLT Health Solutions, is the first patented, standardized and clinically studied extract of a specific cultivar of Sceletium tortuosum. The San people of South Africa have used Sceletium for millennia for its stress-relieving and mood-enhancing effects, according to Dr. Davis. It is standardized to total alkaloid content and conforms to a defined alkaloid profile for four main actives: mesembrenone, mesembrenol, mesembranone and mesembrine.

“It is the unique ‘fingerprint’ of Zembrin that is the subject of clinical trials, an extensive safety portfolio and the current patent portfolio,” she said. “Zembrin is distinguished by its relatively low level of mesembrine and relatively high level of mesembrenone. A U.S. patent recently awarded to HG&H Pharmaceuticals protects the modulation of 5-HT and PDE4 and the application of mesembrenone as a PDE4 inhibitor.”

In 2012, Zembrin was studied in a randomized, double-blind, placebo-controlled, crossover study in 20 healthy adult subjects. The overall aim of the study was to examine whether 25 mg of Zembrin taken once a day enhances cognition in normal subjects.

Statistically significant improvement for the Zembrin group was seen in two cognitive domains: cognitive set flexibility and executive function including processing speed. Despite conducting the study on a healthy non-depressed population, researchers noted Zembrin’s positive effect on mood.

In 2014, PLT Health Solutions and HG&H Pharmaceuticals announced the publication of a clinical trial that used functional Magnetic Resonance Imaging (fMRI) technology to study the effects of acute (short-term) supplementation with Zembrin on the “threat circuitry” of the human brain. The double-blind, placebo-controlled crossover trial conducted with 16 healthy university students showed that 25 mg of Zembrin reduced anxiety-related activity of the amygdala and its associated anxiety circuitry within two hours of consumption. “These results provide the first evidence for the areas of the brain where Zembrin’s anti-anxiety activity acts, and confirmation of the potential for Zembrin to help in the management of stress,” Dr. Davis said.

Taiyos’ Suntheanine branded L-theanine is backed by several studies that confirm functionality and safety, according to Dr. Rao. “Suntheanine has been shown to increase dopamine, serotonin and the inhibitory neurotransmitter glycine in the brain. With intake of 50 mg of Suntheanine, the alpha-brain waves were raised within 40 minutes, reflecting a relaxed and alert state of mind. Acute stress was attenuated by controlling heart rate and salivary SIgA with the intake of 200 mg of Suntheanine. Also, the intake of 200 mg of Suntheanine 30 minutes before bed was shown to improve the quality of sleep in both adults and children.”

The improvement in sleep quality was attributed to “modulation of the autonomous nervous system by increasing the parasympathetic nerve activity, decreasing the sympathetic nerve activity, and WASO (waking time after onset of sleep) during the night,” he explained. Suntheanine is not a sedative, Dr. Rao emphasized, “but it provides the anxiolytic effects through relaxing and calming down of the body and mind to prepare the body to have a good night of sleep. During daytime hours, the same component is useful for relaxation and stress relief.”

Botanical solutions, according to Ecuadorian’s Mr. Siegel, are quite useful in supporting mood health. Ecuadorian Rainforest provides several relevant herbs for MASS formulations: valerian, chamomile and lemon balm. For example, valerian has been shown to help induce sleep onset. According to one study, valerian may increase the amount of gamma aminobutyric acid (GABA) in the synaptic cleft, which may create a sedative effect.

For anxiety, Mr. Siegel noted chamomile helps take the edge off. “In one study, chamomile showed promise in alleviating symptoms of general anxiety disorder. The study placed subjects in a double-blind trial for eight weeks, giving one group a chamomile extract and the other a placebo. The study suggested that chamomile had an anxiolytic effect on patients with mild to moderate GAD,” he said. 

Lemon balm may also help increase mood and calmness. In one study, researchers gave 18 subjects either a 300 mg standardized lemon balm extract, a 600 mg standardized lemon balm extract, or a placebo for seven days. At the end of the study, those who took the 600 mg lemon balm extract not only reported a much better mood but also felt calmer and more alert.

Another botanical option with relevance for reducing stress response is LJ100, from HP Ingredients. This proprietary, patented extraction of Eurycoma longifolia was studied in a group of 63 men and women who were screened for moderate stress, and supplemented with either LJ100, a standardized hot-water extract of E. longifolia, or placebo for four weeks. Significant improvements were found in the LJ100 group for tension (11%), anger (12%) and confusion (15%). Stress hormone profile (salivary cortisol and testosterone) was significantly improved by supplementation, with reduced cortisol exposure (16%) and increased testosterone status (37%).

The authors concluded that supplementing with E. longifolia “improves stress hormone profile and certain mood state parameters, suggesting that this ‘ancient’ remedy may be an effective approach to shielding the body from the detrimental effects of modern, chronic stress, which may include general day-to-day stress, as well as the stress of dieting, sleep deprivation, and exercise training.”

Final Thoughts
Sabinsa’s Mr. Majeed cited the 2007 Stress & Anxiety Disorders Survey conducted by the Anxiety Disorders Association of America (ADAA), which indicated seven out of 10 adults in the U.S. stated they experience stress or anxiety daily, and agreed that it interferes with their lives and daily activities. About one-third reported persistent stress or excessive anxiety or that they have had an anxiety or panic attack. Seventy percent also reported trouble sleeping.

“The marketing benefit to this category of health is the fact that the condition is so vast,” Chemi Nutra’s Mr. Hagerman said. “There are many niches and markets that can benefit from stress reduction—athletes, working professionals, students, etc.  There are even sub-markets inside those markets down to the sport (e.g., cyclists, rowers, golfers) or down to the demographic (e.g., high school students, college students). 

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