More than just simply feeling blue, mood disorders such as anxiety and depression can have a complex and profound impact on a person’s quality of life and well-being.

According to the American Psychological Association, mood disorders are estimated to cost more than $50 billion per year in lost productivity in the U.S. Depending on the diagnosis or the severity of the condition, prescription medications are often a necessary solution; however, they also bring with them fear of side effects like weight gain and drowsiness.

Dietary supplements designed to support mood health have come a long way in recent years. A variety of ingredients not only target those suffering from a range of mood-related health concerns, they are also increasingly supported by clinical research affirming their benefits.

“As we’ve seen over the past 10-15 years, more and more people are turning to natural alternatives,” said Deanne Dolnick, vice president, Next Pharmaceuticals, Salinas, CA. “They feel more comfortable taking a product derived from a plant source rather than manufactured in a lab.”

One factor supporting the increased interest in natural mood support is the stigma associated with mental disorders. “Depression affects one in 10 Americans, according to recent Centers for Disease Control and Prevention (CDC) findings, yet 80% of those suffering from depression are not treated,” said Rick Kaiser, vice president of sales and marketing, Natreon Inc., New Brunswick, NJ. “There remains significant stigma in society to individuals with mental health issues, making diagnosis even harder. Because of the reluctance of consumers to reveal their struggles with depression to their physicians, many are seeking alternative therapies in the natural products channel.”

Botanically Derived Ingredients
Historically, St. John’s wort has been the go-to botanical for treating mild depression. Kava, valerian and passionflower have also been quite popular for relaxation and sleep improvement. Suppliers have continued to broaden their offerings of plant-origin, mood support ingredients, and are lending greater credibility to the segment with products that are supported by strong clinical science.

“Consumers are increasingly turning to natural solutions, and particularly to the use of plants,” said Amandine Moco De Sa, business manager, Naturex, Avignon, France. “Among the plants most used for stress conditions, such as passionflower, St John’s wort, hops and lavender, Naturex is particularly interested in lemon balm due to its long history of use. Its leaves have been used since antiquity for their comforting properties.”

To that end, Naturex developed its Cyracos ingredient from a specific variety of lemon balm leaves that have been substantiated for efficacy through clinical studies. “The manufacturing process for Cyracos is traditional and maintains the full spectrum of actives from the plant,” Ms. Moco De Sa said. She added that clinical studies conducted on the ingredient confirmed its efficacy. “Results demonstrated that 600 mg of Cyracos per day during a period of only two weeks significantly reduces stress-associated symptoms without any side effects, such as drowsiness.”

Next Pharmaceuticals’ key ingredient for mood health, Relora, is a blend of plants used in Traditional Chinese Medicine that hinges on two ingredients: Magnolia officinalis bark extract and Phellodendron amurense bark extract. Previous studies have confirmed Relora’s ability to help “quiet the part of the brain that responds to stress” (the hypothalamic-pituitary-adrenal axis; however, a study published in August in the Journal of the International Society of Sports Nutrition cemented the ingredient’s unique calming effect as it relates to cortisol levels. Cortisol is a biochemical hormone released during times of stress. An excessive amount of circulating cortisol is a primary cause of feelings of anxiety and stress.

The double-blind, placebo-controlled trial followed 56 subjects for four weeks as they were exposed to normal daily stressors. “Those who took Relora for four weeks as compared to those taking placebo experienced the following results: anger reduced by 42%, fatigue reduced by 31%, confusion reduced by 27%, depression reduced by 20%, cortisol reduced by 18%, tension reduced by 18%, overall stress reduced by 11% and global mood state increased by 18%,” said Next Pharmaceuticals’ Ms. Dolnick. “These results indicate daily use of Relora reduces cortisol exposure and perceived stress while improving a variety of mood parameters, suggesting an effective natural approach to controlling the detrimental health effects of chronic stress without the tranquilizing side effects of pharmaceutical agents.”

Natreon recently licensed its patented Sensoril ashwagandha-based ingredient for stress to NutraGenesis, Brattleboro, VT—a company with which Natreon has partnered for nearly a decade. Sensoril is harvested in India and extracted with a solvent-free aqueous process. The product is currently the subject of eight in-process human clinical trials that Natreon’s Mr. Kaiser said were scheduled to be published in peer-reviewed journals within the next 12 months. 

“Sensoril ashwagandha is being researched for a number of health related conditions associated with depression,” he said.

“We’ve completed studies in diabetics with cardiovascular issues, bipolar subjects at the University of Pittsburgh, and build on our previousl clinical research published in JANA (Journal of the American Nutraceutical Association).”

Zembrin is an ingredient for “calm focus” from PL Thomas & Co Inc., Morristown, NJ. A standardized, characterized and patented botanical extract from the Sceletium tortuosum herb, Zembrin’s unique composition is based on more than 300 years of documented indigenous use and has been developed for modern use in conjunction with recognized representatives of the indigenous knowledge-holders, the South African San Council, said PL Thomas’ Barbara Davis, PhD, RD, director of medical and scientific affairs.

“In addition to research on traditional use, pre-clinical and mechanistic studies have also been conducted,” she said. “Zembrin has a patented dual mechanism of action involving phosphodiesterase-4 (PDE4) and serotonin (5-HT) re-uptake inhibition.”

The ingredient is also supported by a robust clinical research program. Dr. Davis said Zembrin has been the subject of three randomized, double-blind, placebo-controlled clinical trials that documented its safety and efficacy. “The first clinical study confirmed safety and tolerability, and also demonstrated positive effects on stress, mood, coping and quality of sleep as spontaneously self-reported in diaries of subjects consuming Zembrin but not placebo (The Journal of Alternative and Complementary Medicine, 2012, 18:1-7),” she said. “A second randomized, double-blind, placebo-controlled trial demonstrated enhanced cognitive function as well as positive changes in mood and sleep (Chiu et al, submitted).”

The third study (Neuropsychopharmacology, August 21, 2013) was a functional magnetic resonance imaging (fMRI) study. “Results from this trial showed that a single dose of Zembrin acts on areas of the brain that recognize and respond to threat, confirming the calming effect of this botanical extract,” Dr. Davis said. “This unique ‘alert-serenity’ signature is useful for dealing with the stresses of everyday life.” 

Combating Anxiety & Stress
Fight or flight is an essential instinct for survival, but when the biological triggers that prompt the body’s response to fear fall out of alignment, anxiety and phobias can result. If left unchecked and/or untreated, anxieties and phobias can become debilitating.

Anxiety afflicts millions of U.S. adults. “According to the National Institute of Mental Health, 18.1% of U.S. adults have an anxiety disorder; of these, 22.8% are classified as severe,” said Kathy Lund, vice president of business development and marketing, AIDP Inc., City of Industry, CA. “Anxiety disorders, such as phobias and post-traumatic stress disorder (PTSD), are among the most common mental disorders. Though fear-memories are important for survival, the lack of control over such memories increases the risk for affective and anxiety disorders.”

Ms. Lund said cognitive therapy helps in treating these disorders; however, the rate of relapse or resistance to therapy justifies the search for novel cognitive enhancers that could control anxiety disorders more effectively. “Studies suggest that enhancement of plasticity in certain brain regions such as the prefrontal cortex (PFC) and/or hippocampus might enhance the efficacy of cognitive therapy,” she said. “Researchers have known for some time that magnesium is essential for proper brain function. Yet because most oral magnesium forms do not sufficiently raise brain magnesium levels, magnesium supplements have been of little use for enhancing cognitive function.”

AIDP developed Magtein, a novel magnesium compound, with that in mind. The high-bioavailability magnesium ingredient was previously shown to increase brain synaptic density in the hippocampus and to facilitate short- and long-term memory. More recently, the ingredient was the subject of four independent published animal studies that found it significantly improved brain functions by elevating brain levels of magnesium. 

“In the October 2011 issue of The Journal of Neuroscience, top neuroscientists at Tsinghua University in Beijing, University of Texas and University of Toronto revealed that by increasing the extracellular magnesium concentration in the brain with Magtein, the cognitive ability—an essential faculty that controls the fear and anxiety—is enhanced,” Ms. Lund explained. “This development becomes extremely significant considering anxiety disorders are the most common mental illness in America, affecting 18% of the population.”

A newly published independent study (Pharmacology Biochemistry Behavior, March 6, 2013) also demonstrated that Magtein led to the consolidation and retention of conditioned taste aversion (CTA) in rats. According to Jennifer Gu, PhD, AIPD’s vice president of research and development, this study verified previously published functions of Magtein in a different behavior system that had been known to use the same brain signaling pathways. “Magtein helps maintain the health of the neuron cells and increases neural plasticity,” Ms. Lund said. “The test reaffirms that continued Magtein supplementation can help to control stress or anxiety, plus increase memory and cognitive functions by elevating the brain’s magnesium levels.”

Magnesium is an essential cofactor for more than 300 enzymes involved in biosynthesis processes and energy metabolism. It plays an important role in many of the brain’s functions; however, most magnesium compounds have low brain bioavailability and severe gastrointestinal side effects. Ms. Lund said Magtein is the only magnesium compound that has been proven to raise the brain’s magnesium levels by increasing the brain’s synaptic density—the connections between brain cells that allow them to communicate with each other.

“Every day, we lose a stunning 10,000 brain cells, and with them, we lose synapses too,” she said. “The researchers studying Magtein discovered that it increased synaptic density, meaning it boosted the number of synapses in the brain.”

The effect of stress and anxiety on memory has been well publicized, but in anxiety disorders this reaction is enhanced so that the fear memory continues even when one is no longer in danger, affecting cognitive ability on a daily basis, she added.

Researchers found that increasing brain magnesium with Magtein enhanced not only the learning and memory ability, but also top-down inhibition of fear memory of rats. “When the cognitive ability is enhanced, fear responses such as anxiety-like and PTSD-like behaviors are controlled,” noted Dr. Guosong Liu, a principal researcher of the ingredient.

Dr. Liu said magnesium treatment induced a unique pattern of action on brain regions involved in and responsible for the body’s emotional processes. It heightens the function of the prefrontal cortex, a brain region involved in controlling fear responses, without affecting the function of the amygdala—the brain’s evolutionary conserved region involved in fear memory formation and storage. “By increasing brain magnesium through Magtein, cognitive ability goes up, fear memory remains unchanged and is better controlled,” Dr. Liu concluded.

A warm glass of milk has long been considered to be a safe and effective fix for mild bouts of insomnia, but for Pharmachem Laboratories Inc., Kearny, NJ, a milk protein hydrolysate has demonstrated promise for effective relaxation and, subsequently, mood support.

“Lactium is a milk protein hydrolysate that has sound research showing its positive effects on promoting mood stabilization, promoting healthy, restful sleep and promoting relaxation to keep anxiety at bay,” said Mitch Skop, the company’s senior director of new product development. “In total, five separate studies have been conducted in recent years on 90 healthy subjects, which confirmed the anti-stress efficacy of Lactium. Several studies have been conducted on Lactium, demonstrating clear efficacy in stress relief, which by natural extension improves mood.”

Mr. Skop pointed to one double-blind, crossover study that was conducted over a 30-day period on 63 female volunteers showing at least one stress symptom. “Those subjects receiving Lactium had a significantly greater improvement in stress symptoms (versus placebo) in the following areas: digestive, intellectual, social, cardiovascular and emotional health,” he said. “The effect of Lactium was greater in subjects having a high intensity score for a major symptom at the beginning of the study. The areas mentioned here are all equally indicative of and responsive to mood.”

Another study was conducted on 44 healthy men and women who had difficulty sleeping. The subjects were given Lactium for four weeks. “Results showed that Lactium improves sleep duration and efficiency, especially in subjects with a moderate anxiety or depression profile,” he said. “Lactium was also shown to reduce daytime sleepiness.”

He added that an in vivo study also demonstrated Lactium’s interesting ability to reduce cortisol levels. “It is important to know that individuals who can be helped to relax and reduce their symptoms of stress—such as Lactium has been proven to do—are generally happier, have sustained better moods and enjoy better quality of life on a daily basis,” he said. “Addressing stress relief and a deeper sense of relaxation is the key to helping to improve mood, outlook and overall quality of life.”

A Positive Outlook
Given the increasingly hectic pace of our 24/7, always-on-the-go lifestyles, the probability of our collective stresses magically disappearing is highly unlikely. In fact, industry insiders said they fully expected stress levels to continue tracking upward. Given the parallel trend of increasingly healthy-minded consumers, this bodes well for the natural products category.

“As the population continues to age and there is continued stress of today’s modern society, the mood improvement category is likely to increase,” said AIDP’s Ms. Lund. “Current drugs used for treating mood and anxiety generally [suppress or activate the] brain’s signaling pathways. These approaches may address some of the acute issues but generally have undesired side effects since they inevitably disturb natural balances of the brain signaling.”

Pharmachem’s Mr. Skop agreed. “Increasingly, we are a stressed-out society; so much to do in what seems [like] a very short day. Chronic, higher stress leads to sleep insufficiency, mood swings and even digestive insufficiency.”

He went on to point out the connection between poor sleep quality and the propensity for anxiety. “Sleep insufficiency lowers resistance to stress and increases potential for anxiety,” he said. “Anxiety depletes sleep and mood is negatively affected. Because stress, mood and sleep are so strongly related, it is an axis that needs to be addressed as a whole. This is where we see the future, instead of trying to target each independently.”

There is one vital component to future market success, according to Natreon’s Mr. Kaiser: sound science. “As long as companies reinvest in meaningful clinical research, the future of natural alternatives is bright,” he concluded.