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The Way to My Heart? Through My Stomach…

Heart health, gut microbiota and diet are closely linked in ways we are just beginning to understand. It is well-known that diet can alter microflora balance and tip the scales toward a pro-inflammatory status affecting heart health, but new research has uncovered other interesting links between gut and heart health. A 2015 study published in Metabolism found women with and without metabolic syndrome who produced equol, a gut bacteria metabolite resulting from soy consumption, enjoyed cardiovascular benefits from consuming soy nuts.1 However, non-equol producers experienced no improvement. This suggests the possibility that in order to enjoy the cardiovascular benefits from soy, a certain balance or type of gut bacteria is required.

Many nutritional interventions appear to work regardless of gut microbiota. A 2015 randomized, controlled clinical trial published in the journal Hypertension by a university group in London, found the primary active constituents of beet root are the nitrates like betain.2 In this study, 250 ml of beet root juice (compared to a placebo of nitrate-free beet juice) reliably lowered blood pressure in hypertensive patients, as well as improved endothelial function by 20 percent (p<0.001). Remarked the authors, “This is the first evidence of durable BP reduction with dietary nitrate supplementation in a relevant patient group.”

But juicers might want to keep the fiber. A study in the American Journal of Clinical Nutrition following 7,216 men and women for eight years found baseline consumption of fruits and fiber was associated with a significantly lower death rate, and those consuming the highest level of fruits (>210 g/d) had a 41-percent lower risk of mortality, which was mainly associated with cardiovascular disease.3

The questions around cardioprotective effects of whole grains continues. The Dietary Guidelines for Americans recommends at least half of our grain consumption come from whole grains, but study findings tend to be inconsistent. In a well-designed controlled crossover study in the Journal of Nutrition, which was co-authored by researchers from Nestlé and General Mills, an increase of 140 g/d in whole grain consumption did not result in significant effects in blood pressure, fecal measurements or gut microbiology.4

Studies like this one lead to more questions than answers, such as whether the “gold standard” randomized controlled trial is adequate to measure effects of interventions such as whole grains, especially when it is difficult to control every possible mitigating factor (such as the elimination of whole grains from subjects’ diet during the washout period). Perhaps the type of whole grain was a factor as well, but some also suggest that a lack of effect also illustrates why simply eating a balanced diet according to prevailing nutrition recommendations may not be sufficient to impact health, especially as we age.

Lest we forget that diet does not exist in a vacuum, there are a number of psychological and social factors that impact nutrition and cardiovascular outcomes. In the Cardiovascular Risk in Young Finns Study published in Circulation, 1,089 children were followed for 27 years, which resulted in a fantastic dataset.5 Higher ratings of emotional, parental health and self-control behavior patterns in children resulted in a significantly better cardiovascular risk rating as adults. Although the study did not focus on specific nutritional aspects, it may be worth our time as an industry to consider ways to integrate dietary interventions with lifelong behaviors that optimize health outcomes.

Reams of evidence suggest polyphenols support cardiovascular health. A recent six-week controlled clinical trial in Portugal was published in the American Journal of Clinical Nutrition, which compared the effects of two olive oils containing different levels of polyphenols on proteomic biomarker scores related to coronary artery disease.6 The findings were surprising: the olive oil lower in polyphenols was slightly more effective than the enriched olive oil. Could there be other compounds in olive oil other than polyphenols responsible for its well-known health benefits?

Regardless, the research on polyphenols continues, with berries as the main focus. Ongoing trials on polyphenols from colored berries and flowers, based on a search of, include the following: a study on a hibiscus extract beverage on cardiovascular and endothelial health, which completed in February 2015; another study on a chokeberry extract in former smokers, to complete in May; and another study on cranberry extract in obese, insulin-resistant humans at Pennington Biomedical Research Center, anticipated to complete in July.

On berries, a study published in Italy in April 2015 found that a formulation of white mulberry leaf extract, berberine and red yeast rice both lowered low-density lipoprotein (LDL) and raised high-density lipoprotein (HDL) cholesterol in humans with high cholesterol not already on statins.7 This formulation was compared to a similar one without mulberry, but with astaxanthin, folic acid, policosanol and CoQ10. Based on the complexity of the formulations, it is difficult to conclude much about the contributions of each ingredient; however, the authors suggested that the mulberry extract might have made the difference for the high-performing formulation.

Future research is expected to add to our increasing knowledge of how to reach the heart through the gut.


1.       Acharjee S et al. “Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status.” Metabolism. 2015 Feb;64(2):236-43. DOI: 10.1016/j.metabol.2014.09.005.

2.       Kapil V et al. “Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study.” Hypertension. 2015 Feb;65(2):320-7. DOI: 10.1161/HYPERTENSIONAHA.114.04675.

3.       Buil-Cosiales P et al. “Fiber intake and all-cause mortality in the Prevención con Dieta Mediterránea (PREDIMED) study.” Am J Clin Nutr. 2014 Dec;100(6):1498-507. DOI: 10.3945/ajcn.114.093757.

4.       Ampatzoglou A et al. “Increased whole grain consumption does not affect blood biochemistry, body composition, or gut microbiology in healthy, low-habitual whole grain consumers.” J Nutr. 2015 Feb;145(2):215-21. DOI: 10.3945/jn.114.202176.

5.       Pulkki-Råback L et al. “Cumulative effect of psychosocial factors in youth on ideal cardiovascular health in adulthood: the Cardiovascular Risk in Young Finns Study.” Circulation. 2015 Jan 20;131(3):245-53. DOI: 10.1161/CIRCULATIONAHA.113.007104.

6.       Silva S et al. “Impact of a 6-wk olive oil supplementation in healthy adults on urinary proteomic biomarkers of coronary artery disease, chronic kidney disease, and diabetes (types 1 and 2): a randomized, parallel, controlled, double-blind study.” Am J Clin Nutr. 2015 Jan;101(1):44-54. DOI: 10.3945/ajcn.114.094219.

7.       Trimarco V et al. “Effects of a New Combination of Nutraceuticals with Morus alba on Lipid Profile, Insulin Sensitivity and Endotelial Function in Dyslipidemic Subjects. A Cross-Over, Randomized, Double-Blind Trial.” High Blood Press Cardiovasc Prev. 2015 Apr 14.

By: Blake Ebersole

This article was first published in Natural Products Insider in June 2015

Extracts: More Than a Cup of Tea

Why extract when you can just consume the whole plant? Extracts concentrate the bioactive part of plants into a manageable dose, while removing the inert parts such as cellulose. And since a lot of botanicals that support health don’t taste very good, we would prefer to be able to consume them as one or two capsules—not 10 or 20.

On a basic level, making a botanical extract is like making a cup of tea: Just soak some plant material in some hot water and enjoy.

Yet, as many tea connoisseurs know, making tea is both an art and a science. The quality of the cup of tea is predicated on a number of variables that include raw material composition, the solvent (such as water or alcohol), the amount of tea to water, the water’s temperature and steeping time. Changes in these variables necessarily results in differences in the end product that are detectable by the human palate.

Let’s say you want to make a powdered extract from this cup of tea. The temperature, time and method of removing the water all impact the quality of the end product. To standardize the extract to a certain specification, including potency, color, powder size and impurities, requires another additional set of controls and experience.

Lastly, maintaining consistency from batch to batch is an additional challenge with natural products prone to variations in climate, geography and harvest methods.

The choice of solvent is a key variable that, along with raw material selection, has the most impact on the final extract. Different solvents will extract different classes of bioactive compounds, so it is important to know what you are trying to extract.

Historically, extraction facilities often selected solvents that provided the best yield, with little regard for safety or regulatory acceptance. As regulators and consumers have become more discerning, so have the processing methods. Today, “green” extraction methods offer a lot of the positives consumers demand—but not without some key tradeoffs.

Like dissolves like, so water will dissolve similarly polar compounds such as flavonoids. Water as a solvent is often preferred by consumers because of its “clean” image; however, it is also a challenge to work with as a master oxidizing agent and a great medium for microbial growth.

Due to its low vapor pressure, water is also among the most difficult solvents to remove during drying, resulting in extra heat and time that can further degrade the native composition of the original plant. Powdered extracts made with water are often hygroscopic, meaning they attract moisture from the air readily, which can lead to clumping and microbial growth in what was once a perfectly clean and flowable extract.

Ethanol is often preferred as a solvent, because it does not present many of the challenges of water. Many generations of physicians have produced liquid extracts known as tinctures—herbs steeped typically in ethanol at established concentrations.

Ethanol is good to dissolve diverse types of compounds, but for many fat-soluble molecules, saturation is reached at a low concentration, resulting in poor extraction efficiency. Thus, extracts using ethanol only often demand a premium price, and may not reach the level of potency offered by other non-polar solvents.

Supercritical extracts using solvents such as carbon dioxide (CO2) have become popular, and for good reason. This method of extraction can be performed at moderate temperatures, and CO2 is one of the cleanest and lowest cost solvents around. Supercritical COis often used to remove caffeine from tea, and extract essential oils from spices and herbs.

The main disadvantages of supercritical extraction include high capital and operating costs, poor selectivity of compounds without optimization, and the time and expertise required to perfect or optimize a process. Often, to achieve a standardized product, a supercritical extraction may have to be paired with other processing methods, which can add to cost.

Standard methods of extraction can be complemented with emerging technologies to achieve a superior product.

Ion-exchange chromatography is one of the best ways to purify natural products, although the higher concentrations of actives achieved are offset by lower yields and higher processing costs. Ultrasound and microwave-assisted extraction are newer ways to achieve better yields during standard solvent extraction, as they act to break the plant cells and release active components better than simple heat or static mixing.

Today’s botanical extraction toolbox offers endless possibilities to achieve desired purity while retaining the natural composition of the botanical.


By: Blake Ebersole

This article was first published in Natural Products Insider in February 2015

How To Create Natural Product Intellectual Property

The longtime policy of the US Patent and Trademark Office (USPTO) to prohibit patenting of natural products is controversial because it has strong arguments both for and against. Now, the patentability of natural products has come under new scrutiny recently, as the USPTO recently offered a new guidance document regarding how natural products patent applications should be examined in response to recent Supreme Court decisions addressing the patentability of genes.

On one side, the lack of patentability for natural products allows for greater access to natural products in the form of foods and dietary supplements. The flip side is that the significant investments needed to adequately research and develop many natural products into what the medical establishment considers “evidence-based” therapeutic products are not protected without strong patents. The consumer choice could be viewed as either a completely high-quality bottle of plant extract with fantastic clinical research and validation costing hundreds of dollars and available only by prescription—or the model that we have for most natural products today: accessible and generally high quality, but not quite at the level of pharma.

This dichotomy has led to the pharma and supplement/food industries existing, in a sense, on different planets. And since patents are the critical requirement for large R&D investments, natural products often get left in the dust. Although natural product molecules form the underlying structural skeleton for the overwhelming majority of drugs, adding even a seemingly innocuous carbon group to a natural compound creates something that would never be found in nature, and could never be considered a food or supplement—but is fully patentable.

How can we bridge the gap between “evidence-based” therapies and high-quality, accessible products from natural sources? This remains as the billion-dollar question, one whose answer will hopefully be addressed by future innovations resulting from the new patent law.

According to the new USPTO guidance, patentable inventions based on natural products are those that are “significantly different” from natural products, principles and phenomena.  How to interpret “significantly different” gets very complicated and is outside the scope of this post, but is described in some detail in the guidance. Here are some key examples given:

  • Composition of multiple natural products that leads to a synergistic or unexpected effect.
  • A process to create a composition containing two or more natural products.
  • A process applying an abstract idea (such as a law of nature) to create a new practical application for a natural product.

While the USPTO guidance is still in a public comment period, there are many on the natural products drug discovery side who believe that the new rules will hurt development efforts.  But there are others who believe that the new guidance will force inventors to be truly innovative and apply new technologies and processes to creating natural products, while continuing to allow Americans access to our trusted herbs at a reasonable price.  This onion has yet to be fully peeled, but it will be interesting to see how this story develops due to its potential impact on our access to effective healthcare.

By: Blake Ebersole

This article was originally published in Natural Products Insider in March 2015.

Why Spices are Special

The human pursuit of spices has helped to create the world (and America) as we know it today. Hundreds of years ago, merchants from Europe traveled by land and sea to transport exotic and expensive plants such as cinnamon, rosemary, nutmeg and turmeric from Asia. But when the Ottoman Empire restricted Europe’s spice routes to Asia in the 1400s, explorers such as Christopher Columbus looked for alternate routes to India and instead stumbled on our glorious land. It’s not a far stretch to thank cinnamon for our providence.spices-1327344

Spices hold a special place in human existence that we are just starting to understand. Sure, they are prized to provide bold and unique flavors, aromas and colors to otherwise bland foods. But many don’t know the hidden story: before the invention of refrigeration, spices’ underlying bioactivity, in the form of potent and diverse antioxidant and antimicrobial food-preserving properties, helped to prevent sickness and contagion caused by food spoilage. Thus, spices carried a magical aura for those who demanded them, and at the same time, they provided a livelihood for many generations of farmers, harvesters and suppliers.

Today, our interest in spices has shifted to the scientific study of their health benefits, to see if they can help us live healthier lives. On a molecular level, the chemical properties that make spices great flavorings, colorings and food preservatives are closely linked to the properties which help to promote human health. Polyphenols, carotenoids and terpenoids are all highly bioactive and health-supporting classes of compounds common to many spices, and are the focus of thousands of medical research studies.

Consuming enough of these active compounds to make a difference in our health can be tough through food alone. The mantra of many is that a diet with a diversity of spices can help us live longer, but no one is suggesting that fried chicken made with 14 of them is a health food (yet!). And while variety may be the “spice of life,” research suggests a variety of spices added to food can lead to a tendency to overeat.1 Likewise, consumer health media recommendations to sprinkle some cinnamon on toast or add a pinch of turmeric powder to curry may be naïve to some key underlying practical and scientific caveats such as compliance, dose response and opposing effects.

For instance, a clinically significant effective dose of cinnamon powder often recommended for managing blood sugar is a teaspoon or more—quite a “cinnamon challenge” for the palate and the stomach. Impurities that can be found in cinnamon powder, such as added sulfites and naturally occurring coumarin can tip the opposing-effects equation in the wrong direction, especially when doses are in baking measurements. On the other hand, science has validated the efficacy of concentrated, purified extracts, both from Chinese cinnamon (cassia) as well as “true” cinnamon (Cinnamomum verum syn. zeylanicum). Both the “whole food” and the scientific approaches have merits, but the second seems to garner increasingly more credibility among top medical experts.

In another example, four-week supplementation with the amount of straight turmeric powder contained in a strong curry (2.8 g) did not improve oxidative stress, inflammation or global metabolic profile in overweight women.2 But in another study just published on a purified, brain-optimized form of curcumin, just 80 mg of the potent turmeric active consumed daily for four weeks led to significant improvements in measures of short-term memory, attention and mental energy.

On the other side of getting enough of the active compound absorbed to make a difference is the argument for moderation. Again, we seek to know what the relationship is between the amount of dose and the health benefit observed, and no two natural compounds are exactly alike in this way. The scientific results can be hard to predict. For example, in cell culture experiments where one biological mechanism is isolated, it is common and desirable to see the response increase as the dose increases. But for human trials, more does not always mean better. In one example, daily low dose (750 mg) of rosemary marginally improved cognitive function in elderly adults, but the higher 6-gram dose did not.4

For some spices, their aroma and impact on the brain through our nose is the main source of impact on health. A fair number of well-designed studies have shown positive results with herb and spice aromatherapy on various cognitive-related measures. One study found lavender or rosemary aromatherapy improved relaxation and test scores in nervous nursing students.5 However, rosemary consumed in a capsule form—while wearing a nose clip to block effects of the aroma—did not induce consistent short-term improvements in cognitive function in young adults.6

Topical applications of spices have been used in traditional medicine like Ayurveda for hundreds of years, with turmeric being well proven and used by allopathic physicians for its wound-healing capabilities. The bioactivities of spices that preserve food also promote health in ways that are well known mechanistically, but in a clinical-sense are just now emerging. For example, in a 2014 study, an ointment containing cinnamon was effective at reducing pain after childbirth.7 In another study, a topical application of black pepper essential oil improved vein visibility for IV insertion better than the standard of care.8 This study did not measure whether sneezing increased, although the essential oil used in the study would probably have improved dinner too.

The potential of spices in human health and wellness is vast, and with sound science, more is learned every day about how and why spices can be beneficial.


1.       Jones JB et al. “A randomized trial on the effects of flavorings on the health benefits of daily peanut consumption.” Am J Clin Nutr. 2014 Mar;99(3):490-6. DOI: 10.3945/ajcn.113.069401.

2.       Nieman DC et al. “Influence of red pepper spice and turmeric on inflammation and oxidative stress biomarkers in overweight females: a metabolomics approach.” Plant Foods Hum Nutr. 2012 Dec;67(4):415-21. DOI: 10.1007/s11130-012-0325-x.

3.       Cox KH, Pipingas A, Scholey AB. “Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population.” J Psychopharmacol. 2014 Oct 2. PII: 0269881114552744.

4.       Pengelly A et al. “Short-term study on the effects of rosemary on cognitive function in an elderly population.” J Med Food. 2012 Jan;15(1):10-7. DOI: 10.1089/jmf.2011.0005..

5.       McCaffrey R, Thomas DJ, Kinzelman AO. “The effects of lavender and rosemary essential oils on test-taking anxiety among graduate nursing students.” Holist Nurs Pract. 2009 Mar-Apr;23(2):88-93. DOI: 10.1097/HNP.0b013e3181a110aa.

6.       Lindheimer JB, Loy BD, O’Connor PJ. “Short-term effects of black pepper (Piper nigrum) and rosemary (Rosmarinus officinalis and Rosmarinus eriocalyx) on sustained attention and on energy and fatigue mood states in young adults with low energy.” J Med Food. 2013 Aug;16(8):765-71. DOI: 10.1089/jmf.2012.0216.

7.       Mohammadi A et al. “Effects of cinnamon on perineal pain and healing of episiotomy: a randomized placebo-controlled trial.” J Integr Med. 2014 Jul;12(4):359-66. DOI: 10.1016/S2095-4964(14)60025-X.

8.       Kristiniak S et al. “Black pepper essential oil to enhance intravenous catheter insertion in patients with poor vein visibility: a controlled study.” J Altern Complement Med. 2012 Nov;18(11):1003-7. DOI: 10.1089/acm.2012.0106.

By: Blake Ebersole

This article was first published in Natural Products Insider, December 2014