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Sleep, Perchance to Dream

Once Again Nut Butter
Sleep & Relaxation Sleep & Relaxation

People are losing sleep and fretting over it. Here’s why and how you can formulate products that help dreams happen.

Non-GMO Project

Tossing and turning at night could never be an Olympic sport. Too many people are really good at it. Delayed sleep onset, insomnia and half sleep/half flip-flopping are affecting more people than ever. The vicious cycle shows itself when sleep-deprived people need energy to power their daily lives, then need to full-body-and-mind relax so that they can fall and stay asleep.

If you don’t have a formula, food or beverage geared toward providing relaxation and inducing sleep, you may want to consider one. Old-school melatonin may not be suitable for everyone, as it can cause intense dreaming.

“With societal demands increasing worldwide—whether it be at school, home or in the workplace, individuals are starting to resort to supplements or other modes of anxiolytics to reduce levels of stress (i.e. meditation, yoga, podcasts),” observed Mariko Hill, product development executive, Gencor, Hong Kong. “Due to increasing stressors of today, individuals are having troubles relaxing and sleeping, thus exogenous supplementation may be key to relieving their nerves.“

And it’s more than just sleep, as inability to sleep well is not an isolated well-being issue. Brian Appell, marketing manager, New Jersey-based OmniActive Health Technologies noted that consumers aren’t necessarily taking supplements for stress, “but rather, supplementing to combat the constellation of issues brought on by stress, such as the inability to focus for sustained time, inability to relax, lack of energy and poor cognitive function, to name a few. These will continue to be strong categories and I suspect they will become even bigger, as science and media continue to tout the effects of chronic stress and lack of sleep.”

In agreement is Golan Raz, head of global health division of New Jersey-based Lycored, who asserted that current lifestyles are a recipe for stress. Working hours in front of screens (computer and smartphone) prohibits the ability to achieve balance of mental, emotional and physical systems and to calm them. Exacerbating this condition is, of course, less-than-optimal diets.

“Over the past decades, it has become clear that worldwide there is a significant increase in the amount of people experiencing problems with increased anxiety and stress leading to a problematic sleeping pattern,” said Marguerite Gerritsen, managing director, Pharmactive Biotech Products, Madrid, Spain. She lays blame on modern 24/7 lifestyles with the need to be always available and on call, blurring the boundaries between work and private life. A growing factor exacerbating emotional stress and anxiety that impacts sleep, she pointed out, is the pressure many feel from social media and its string of influencers that are painting the perfect lifestyle image to strive for. This constant comparison and feeling that one is falling short often generates a vicious circle of anxiety leading to less sleep causing in turn more stress and anxiety. Furthermore, the link between sleep and depressive symptoms is evident and can be both the cause or the consequence of depressive symptoms and mood disorder. Some researchers have observed that people with insomnia have a tenfold risk of developing depression compared with those who sleep well.

“Facing this situation, many people are looking for more natural remedies to ease their condition without having undesired side effects or risk of dependency. Considering this is a growth market it makes a lot of sense to launch new formulations featuring ingredients with a proven impact on balancing mood and a reduction of anxiety, leading to overall better sleep quality,” she commented.

There are subsets of consumers who are also seeking products to relax and achieve sleep that do not include pharmaceuticals. For example, according to Maria Dolores Garcia, product manager Frutarom Health, a division of International Flavors & Fragrances Inc., there is a growing geriatric population who are experiencing age-related insomnia and who are more inclined to take a natural product instead of a drug to help ease them into a state of relaxation and sleep.

There are also the nocturnal workers—and this is a hefty population that works against the biological circadian rhythm. Think night-shift first responders, hospital workers, police; professionals that work several nights in a row and are off for several more to catch up on their sleep and lives. They often experience problems obtaining quality sleep.

“Formulating products to relax and induce a healthier sleep makes tremendous sense for supplement/nutrafood formulators, as consumers are willing to improve their quality of sleep,” she said.

According to Marketdata LLC, the two main regions for the sleep and relaxation market, U.S. and Europe, have had an approximate combined sales of $40 billion, with an average CAGR of 5 percent.

Ingredient Solutions

The market of ingredients for inducement of sleep and relaxation without side effects or dependency has greatly advanced in recent years.

Gencor has developed an ingredient that is relevant for millions of people who cannot achieve a sound sleep due to pain and discomfort—a natural alternative to “pm” formulas. Levagen, Gencor’s branded palmitoylethanolamide (PEA), has potent anti-inflammatory, anti-anxiolytic and analgesic properties, Hill reported. PEA is an endogenous fatty acid amide that is produced in the body in response so stress, inflammation and pain. It can also be found in an abundance of foods such as peanuts, egg yolk and soy.

Its mechanism of action has been shown in several studies, Hill noted. Levagen’s anti-inflammatory and analgesic actions stems from its direct and indirect actions on PPAR-a receptors and CB1/2 receptors, respectively. By binding on to PPAR-a receptors on mast cells, as well as those found on macrophages and nerve endings, PEA can inhibit secretion of pro-inflammatory compounds and stops pain signals from reaching the central nervous system. Further, she added, Levagen can inhibit fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide, an endocannabinoid that binds on to CB1 and CB2 receptors, thus reducing levels of pain. By inhibiting FAAH, PEA may indirectly influence these receptors; this is called the “entourage effect.”

Hill pointed to a recent study that has shown PEA to be capable of improving sleep patterns in patients with disturbed sleep due to pain, bolstering its potential use in a PM type of product. The systematic review suggested Levagen may also have interactions with sleep/wake cycles in humans. “PEA is proposed to facilitate better sleep due to its well-described anti-inflammatory and pain-relieving properties,” she explained. “Furthermore, a lack of sleep has been strongly associated with increased signaling molecules (cytokines) released from inflammation.” An imbalance of pro- and anti-inflammatory signals may cause people to be more susceptible to interrupted, insufficient sleep. The beneficial effect of PEA on sleep may be caused by acting through TRPV1 agonist that are known to facilitate sleep (vasorelaxation effect). “Thus, PEA may be an effective solution for those with troubles sleeping, increased stress or nerves to reduce inflammation and restore the sleep/wake cycle.”

Another use for this ingredient can be for athletes, such as rugby or football players who get banged up during games, the pain from which often interferes with healthy sleep. Gencor, Hill reported, has worked with elite sports teams (mainly professional rugby—a high-contact sport where levels of pain and inflammation influence sleep and concussion rates) in the areas of sleep, pain management and recovery. “Feedback has been tremendous over the past two seasons of use, as practitioners have reported a reduction of NSAIDS (nonsteroidal anti-inflammatory drugs), better quality of sleep and faster return to play of players after using Levagen+ in their recovery protocols, she related.”

Researched heavily since the 1950s, L-theanine, an amino acid found in green tea leaves, is known to directly stimulate the production of alpha brain waves, which creates a sense of physiological calm, relaxation and mental alertness, according to Maryn Capote, sales director for California-based Ethical Naturals Inc. (ENI). L-theanine has been found to significantly reduce stress, tension and anxiety, which positively impacts mood, focus and cognition. L-Theanine does not cause drowsiness, she added, a key attribute sought by more sleep-deprived people globally.

According to Capote, studies found that L-theanine can cross the blood-brain barrier, and clinical trials confirmed L-theanine has relaxing properties. Research on human volunteers has demonstrated that L-theanine creates a sense of relaxation via at least two different mechanisms. First, she explained, it directly stimulates the production of alpha brain waves, which are responsible for creating a state of deep relaxation and mental alertness similar to what is achieved through meditation. Second, L-theanine supports formation of GABA (gamma amino butyric acid, the inhibitory neurotransmitter), which influences the levels of two other neurotransmitters, dopamine and serotonin, also producing significant relaxing effects. Additionally, L-theanine has been shown to reduce mental and physical stress, as well as improves cognition and mood in a synergistic manner with caffeine.

Capote reported that ENI’s AlphaWave L-theanine was the subject of a completed clinical trial at the Wellington Sleep Investigation Centre in New Zealand. In the study, 200 mg AlphaWave showed positive effect on tonic alpha power, decreased anxiety and tension and reduced fatigue. In addition, AlphaWave significantly reduced the heart rate compared with placebo.

Frutarom Health, said Garcia, manufactures botanical-sourced ingredients based on different monographies of plants that support their efficacy with traditional use for centuries. The supplier offers five botanicals known for inducing relaxation, and Capote explained why each is suitable for sleep/relaxation formulas.

1. Chamomile (Chamomilla recutita) is commonly regarded as a mild tranquilizer or sleep inducer. Its calming effects may be attributed to an antioxidant called apigenin, which it contains in abundance.

2. Hops (Humulus lupulus) has a long history of being used to help improve sleep. Scientific research shows that their natural sedative effects can increase sleep duration.

3. Lemon balm (Melissa officinalis) is a plant native to the Mediterranean. It has been reported to have calming effects, and is used to reduce anxiety, sleep problems and restlessness.

4. Passionflower (Passiflora incarnata) is a common component of herbal sleep aid formulations. It has long been used by Native Americans for its sedative and anxiolytic effects and is approved by the German Kommission E monograph to treat nervousness and insomnia.

5. Valerian (Valeriana officinalis) is the best known “natural tranquilizer, sleep aid and stress reducer in Western herbal medicine.”

Another botanical gaining interest in this arena is saffron, a prized culinary herb that is found in the stigmas of the Crocus sativa flower. According to Alberto Espinel, PhD, director of R&D, for Madrid, Spain-based Pharmactive Biotech Products, SL, saffron exerts several pharmacological actions and has traditionally been used as an analgesic and sedative, among other uses. “Our ingredient, Affron is an aqueous extract of saffron stigmas and contains concentrated amounts of active molecules, namely crocins and safranal. Affron has a proprietary mechanism of action described in the patent EP3446678 based in an HPLC method.

Different mechanisms of actions have been proposed to explain the functional properties of saffron extracts, chiefly, as an anti-depressant, which helps induce sound sleep. Its MOA (method of action) here is to inhibit reuptake of serotonin and dopamine, and as an antioxidant, saffron may reduce oxidative stress. As an antidepressant agent, saffron extracts at minimal intake dosages have shown to be more effective than placebo and as efficient as the antidepressants fluoxetine, imipramine and citalopram for the treatment of mild-to-moderate depression,” he said, adding that the antidepressant efficacy of saffron has been confirmed in several meta-analyses.

Pharmactive’s Affron is supported by proprietary research. According to Espinel, in a 2018 randomized, controlled clinical trial healthy adults who consumed 18 mg Affron extract for one month experienced an improvement in sleep quality (lower scores in the Pittsburgh Sleep Quality Index, PSQI) and, additionally better daytime performance in those with a poorer sleep quality at the baseline.

Carotenoids also have suitability for relaxation and sleep formulas. For example, science on OmniActives’ Lutemax 2020 shows that this one ingredient can help with multiple issues related to stress, according to Appell. In one study, Lutemax 2020 supplementation improved sleep quality in subjects during long-duration exposure to digital screens and other sources of high-energy blue light.

Lycopene in tomato products has long been known to confer multiple benefits, including for the prostate. When the prostate enlarges, causing men to get out of bed to urinate, they tend to lose sleep. “Some men experience challenges in falling asleep and in maintaining sufficient quality of sleep, because of an enlarged prostate,” said Raz. “When an enlarged prostate is causing urinary dysfunction and sleeping disorders, multiple studies have shown that Lycomato may help with prostate-related symptoms and help improve the overall quality of life.”

Formulation Concepts

Sure, tablets and capsules remain very easy for many people to take. But the reality is that pill fatigue is hitting more people. In the sleep/relaxation product market, “Nowadays we find, for example, shots to support a fast and good sleep, apart from the well-known food supplements in tablets, capsules, or even teas,” observed Garcia. Another new delivery form she noted is “infusionable” tablets that can be taken both in oral form or solved in liquid, depending on preference. “Other ways to add these ingredients to a formulation can be in jelly-sweets, caramels, honey, dairy products, chocolate … adding functionality to consumers’ diets.”

Affron, according to Espinel, is also versatile. “Thanks to its low daily dosage and pleasant organoleptic profile, multiple galenic forms are possible with Affron such as lollipops, chewing gums, cereals, chocolate/nutrition bars, sticks and more.”

While eating a tomato (or two or three) will provide some lycopene for men who are experiencing poor sleep due to prostate issues, Lycored’s LycoComfort, which recently showed in a clinical trial to improve the quality of life and specifically prostate related symptoms, can be formulated in a beverage, shot, soft-gel and other delivery systems, according to Raz. It can be also combined successfully with other ingredients like omega-3 EFAs, vitamins, minerals as well as other botanical extracts.

Generic PEA is a lipophilic compound, said Hill, and therefore the ability for formulators to use beyond standard capsules and tablets are limited. Additionally, its lipid nature makes it more difficult to be absorbed in the GI (gastrointestinal) tract.

“Gencor’s Levagen+ has overcome these limitations by utilizing LipiSperse delivery technology, increasing functionality and bioavailability of PEA,” said Hill. Levagen+ can therefore be used in various formats such as effervescents, RTD (ready-to-drink) shots, powders etc., “providing endless opportunities for formulators to innovate a finished product. And because of its unique MOA compared to any other anxiolytics/nootropics in the market, formulators could also do combination products to target various pathways to induce relaxation and sleep (e.g. with ashwaghanda, lavender oil, chamomile etc.),” she emphasized.

According to research from the University of Pennsylvania’s Perelman School of Medicine, approximately 25 percent of Americans experience acute insomnia each year, but 75 percent of them tend to recover without developing more alarming sleep deprivation, such as chronic insomnia. These stats show that there is a huge market for sleep and relaxation products—because nobody has time to be tired except when they want to sleep! NIE

For More Information:

Ethical Naturals Inc., www.ethicalnaturals.com
Frutarom Health, www.frutarom.com
Gencor Pacific, www.gencorpacific.com
Lycored, www.lycored.com
OmniActive Health Technologies, www.omniactives.com
Pharmactive Biotech Products, http://pharmactive.eu/en/home-en

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