The Vitaceae or grape family includes about 900 species in 15 genera. About 70 interfertile (capable of interbreeding) species compose the genus Vitis. Of these, V. vinifera is the best known, as well as the most culturally and economically important.1 Vitis vinifera originated in central Asia, but it now occurs in many regions of the world as a result of extensive cultivation and escape.2 It is a perennial liana (woody, climbing vine) that climbs with coiled tendrils. Grapes were among the first fruits to be domesticated thousands of years ago, and there are currently an estimated 10,000 cultivars of this single species. The domesticated subspecies V. vinifera subsp. vinifera (syn. V. vinifera subsp. sativa, or V. sativa) is monoecious (hermaphroditic), having both male and female reproductive organs in a single individual. It descended from a wild ancestor V. vinifera subsp. sylvestris (syn. V. sylvestris), which is dioecious — having male and female reproductive organs in separate individuals. The subspecies sylvestris now occurs in the wild from the Atlantic coast of southwestern Europe to Tajikistan and the western Himalayas in central and southern Asia.3 More than 90% of the world production of grapes is from V. vinifera.4 However, other Vitis species, including V. berlandieri, V. riparia, and V. rupestris, are used as germplasm resources to breed rootstock for improved resistance against fungal diseases.5 Other Vitis species used for wine production, in particular V. labrusca, also provide seed material for the production of grape seed extract (GSE*).6
GSEs typically are produced from dried or fresh grape seeds that are obtained as a byproduct of the juice and wine industries. First, the grape seeds are extracted using a solvent (e.g., water, or mixtures of water with ethanol or acetone) and then filtered and subjected to further processing in order to produce GSE that contains anywhere from 50% to 90% phenolic compounds.7 There is also a pharmacopeial GSE called “Grape Seeds Oligomeric Proanthocyanidins,” defined in the United States Pharmacopeia (USP) as the fraction of an extract of the ripe seeds of V. vinifera containing not less than 75.0% oligomeric proanthocyanidins (OPCs).8
HISTORY AND CULTURAL SIGNIFICANCE
The Latin genus name Vitis means “grape vine,” while the species name vinifera means “produces wine” or “wine bearing’” and is related to the Latin terms vinum (“wine”) and vinea (“vineyard”).9 The words “wine,” vin (French), and Wein (German) stem from the ancient Greek term οίνος (oinos) and the Latin term vinum.10
Swedish botanist Carl Linnaeus (1707-1778) included Vitis vinifera in his 1749 work Materia Medica and described its occurrence as “orbis totus temperatus” (global, temperate). For therapeutic use, he did not describe the seed but rather the leaf (as Vitis Folia), stating that it was used to treat stranguria (slow, painful urination) and tussis (cough).11
Grape is considered a “cultural keystone species” and is associated with divinities and rituals, evidenced by representations on artifacts of ancient cultures of the Mediterranean.12 Archaeobotanical evidence of Vitis species is mainly in the form of waterlogged, mineralized, and charred seeds. It is difficult to determine whether these seeds originated from wild or cultivated plants13 because the seeds of V. vinifera subsp. sylvestris (wild) and V. vinifera subsp. vinifera (cultivated), for example, are morphologically very similar.14 Domestication of the cultivated grape reportedly took place between the seventh and the fourth millennia BCE in the Caucasus region (between the Black Sea and the Caspian Sea) in present-day Georgia, Armenia, and Azerbaijan,5,15 where the crop exhibits high genetic diversity. From the Caucasus, cultivation is believed to have spread to Mesopotamia and Egypt and then throughout the Mediterranean16 and beyond. Approximately 9,000-year-old grape pips (seeds) found in the southern Caucasus provide the earliest known archaeological evidence of grape cultivation.17 Based on botanical, ampelographic (the science concerned with identification and classification of grape vines), archaeological, paleontological, historical, ethnographical, and linguistic studies, Georgia is recognized as one of the earliest sites of grape domestication.18 Today, the most widely cultivated species in Georgia are V. vinifera and V. labrusca and their varieties, including V. labrusca var. izabella (purple), V. vinifera var. Rkatsiteli (white), and V. vinifera var. Saperavi (red). The fermented grape seed residue byproduct of these species are being studied in Georgia as potential source materials for commercial production of GSE.6
While there are well-documented traditional medicinal uses of other plant parts of V. vinifera — for example, the dried leaf (pharmacopeial name: Vitis viniferae folium),19 the dried fruit or raisin (Uvae passae or Vitis viniferae fructus), and processed forms such as wine (Vinum)20 — extraction of the seed for functional, nutritional, or therapeutic uses is a relatively new innovation. Development of GSE traces back to research begun in the late 1940s, although commercial products did not appear until the 1970s. In 1947, French scientist Jack Arthur Masquelier (1922-2009) extracted a colorless fraction from peanut (Arachis hypogaea, Fabaceae) skin, proposing that its major components were oligomers of flavan-3-ol units (e.g., (+)-catechin or (-)-epicatechin), which today are classified as oligomeric flavan-3-ols. Over the decades, this led to research into other potential sources of the compounds, including pine (Pinus spp., Pinaceae) bark and grape seed. By 1970, Masquelier had isolated these flavanols from grape seeds21 and applied for a patent for his extraction process, which was granted to his company, Société Civile d’Investigations Pharmacologiques d’Aquitaine (SCIPA), in 1972 by the French National Institute of Industrial Property (INPI).22 Today, GSE is used as a component of dietary supplement products and natural health products for venous insufficiency (in which veins have problems sending blood from the legs back to the heart), to promote wound healing, and to reduce inflammation.23 It is also used as a functional food additive and cosmetic ingredient.
In 2003, San Joaquin Valley Concentrates (Fresno, California) submitted a Generally Recognized as Safe (GRAS) notice to the US Food and Drug Administration (FDA) for a GSE to be used as an antioxidant or emulsifier component of food products at levels ranging from 0.01% to 0.08%. The FDA responded that it had no questions regarding San Joaquin’s conclusion that GSE is GRAS under the intended conditions of use.24 In the same year, Polyphenolics, Inc. (Madera, California) submitted a GRAS notice for GSE and grape pomace extract (GPE) for use as antioxidants in certain fruit beverages at a concentration of up to 210 parts per million (alone or in combination with other ingredients). Again, the FDA had no questions regarding Polyphenolics’ conclusion that GSE and GPE are GRAS under the intended conditions of use.25 Subsequently, in 2007, Polyphenolics, Inc. requested and received an independent GRAS extension expert opinion that justified increasing the concentration in beverages to up to 845 mg/L (200 mg/8 oz). Enovita, a GSE from Indena (Milan, Italy), is also GRAS as per an independent GRAS assessment and conclusion (G. Ris email to T. Smith, June 18, 2018).
In 2008, a new dietary supplement quality standards monograph titled “Grape Seeds Oligomeric Proanthocyanidins” was proposed for entry into the USP. A draft monograph was published in the Pharmacopeial Forum for public comment,26 after which the final monograph became official in the 33rd revision of the USP in 2010.27
In 2012, the company Nutrilinks Sarl (Lausanne, Switzerland) submitted an application to the European Food Safety Authority (EFSA) for an opinion on scientific substantiation of its proposed health claim for GSE related to maintenance of normal venous blood flow. The subject of its application was a dry extract obtained by extraction of grape seeds with ethanol and ethyl acetate, and subsequent evaporation, filtration, concentration, and spray-drying, standardized to total polyphenol content (minimum 35% of gallic acid, catechins, and epicatechins, and minimum 7% of procyanidin dimers B1, B2, B3, and B4). The EFSA concluded that the data did not establish a cause-and-effect relationship between the consumption of this GSE and maintenance of normal venous blood flow.28 Another application by the same company was submitted to the EFSA in 2012 for an opinion on scientific substantiation of a health claim for its GSE related to the elimination of excess water in the body. The EFSA panel concluded that the applicant’s proposed claim statement (“helps to drain the body in case of water accumulation”) in the context of “normal venous circulation in the legs” refers to the maintenance of normal venous blood flow, and that a claim for GSE and maintenance of normal venous blood flow had already been assessed and rejected.29
CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND MEDICINES
In the United States, GSE is classified as GRAS for certain limited food uses and appears on the FDA’s list of “Substances Added to Food” (formerly “Everything Added to Food in the United States,” or EAFUS).30 GSE may also be used as a component of dietary supplement products, which require FDA notification within 30 days of marketing if a structure-function claim is made and product manufacturing that adheres to current Good Manufacturing Practices (cGMPs).31 In Canada, GSE standardized to 80-85% OPCs is regulated as an active ingredient of licensed natural health products (NHPs), which require pre-marketing authorization from the Natural and Non-prescription Health Products Directorate (NNHPD). Depending on the dosage and strength, labels of licensed GSE NHPs may carry one or both of the following claim statements: “Source of antioxidants for the maintenance of good health” and “Helps to relieve symptoms related to non-complicated chronic venous insufficiency (CVI), such as sensation of swelling, heaviness and tingling of the legs.”32
In the European Union, different types of GSE are listed as components of cosmetic products and are used for various functions (e.g., antidandruff, antimicrobial, antioxidant, oral care, skin-protecting, and UV-absorbing functions). “Oleoyl GSE” (obtained by the reaction of oleoyl chloride with GSE), “Propyl Oleoyl GSE” (obtained by the reaction of oleoyl chloride with the propyl ether of GSE), and “Undecylenoyl GSE” (obtained by the reaction of GSE with undecylenoyl chloride) are all used for antioxidant function; “Palmitoyl GSE” (GSE reaction products with hexadecanoyl chloride) is used for skin-conditioning function; and “Sodium GSE Phosphate” (sodium salt of a complex mixture of esters of phosphoric acid and GSE) is used for antioxidant and skin-conditioning functions.33
Proanthocyanidins (PACs) are the major chemical compounds in GSEs. The PAC content of GSEs typically comprises 5-30% monomers (including catechins, epicatechins, and other flavan-3-ol monomers), 17-63% oligomers,† and 11-39% polymers (and their gallic acid esters). GSEs contain primarily B-type PACs (flavan-3-ol polymers where the units are linked by a single bond). The large number of grape varieties used to make GSEs accounts for the varied concentrations of bioactive chemical compounds in the seeds.7,34
There are a number of clinical studies on various GSEs for numerous conditions and functions, such as atherosclerosis prevention,35,36 chronic periodontitis,37 climacteric syndrome,35 estrogen levels,38 hyperlipidemia,36,39,40 hypertension,41,42 idiopathic male infertility,43 leg swelling during prolonged sitting,44 liver function,45 oxidative stress and reperfusion injury caused by cardiopulmonary bypass surgery,46 postprandial oxidative stress and inflammation in persons with metabolic syndrome,47 postprandial blood glucose,48 renal failure in chronic kidney disease,49 antioxidant capacity and lipid peroxidation in type 2 diabetes mellitus,50 and skin protection from UV radiation.51 Most of these studies are of varying degrees of quality and, while they all show some positive outcomes, they are either preliminary studies; were not randomized, double-blind, and placebo-controlled (RDBPC); did not explain randomization, blinding, or withdrawals; and/or had a very small study population.
One recent RDBPC study investigated the effects of GSE supplementation on oxidative stress and metabolic profiles of female volleyball players. Forty healthy volunteers (14-24 years old) were randomly assigned to take 300 mg GSE (formulated by Barij Essence Pharmaceutical Co.; Kashan, Iran; no additional information provided) or placebo twice a day, with lunch and dinner, for eight weeks. Participants kept dietary records on one weekend day and two weekdays, and physical activity records on weeks two, four, and six of the study. Fasting blood samples were obtained before and after the intervention and centrifuged, and the total antioxidant capacity (TAC), total glutathione (GSH, an antioxidant), malondialdehyde (MDA, a marker of oxidative stress), nitrous oxide (NO), creatine phosphokinase (CPK), fasting plasma glucose (FPG), serum triglycerides, serum insulin, and very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol levels were measured. The GSE group experienced a significant increase in GSH compared to placebo, and a significant decrease in MDA compared to placebo. Additionally, GSE supplementation resulted in decreased serum insulin concentrations, decreased scores on the homeostasis model assessment for insulin resistance index, and increased scores on the quantitative insulin sensitivity check index compared to placebo, all of which are considered beneficial effects on insulin metabolism. There were no significant changes in CPK, TAC, NO, FPG, or serum lipid concentrations compared to placebo.52
Two meta-analyses have reported on clinical studies investigating the effects of GSE on cardiovascular risk markers. The first, conducted in 2011, included nine randomized, controlled trials published between 2000 and 2009 (N = 390) that focused on at least one of the following: systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, triglycerides, C-reactive protein (CRP), or total, LDL-, or HDL-cholesterol. This meta-analysis concluded that GSE supplementation was associated with significantly lowered SBP and heart rate with no significant effects on DBP, CRP, or serum lipid levels. While the reduction in SBP was modest compared to that seen with prescription antihypertensive drugs, it may still be meaningful since it is estimated that “every 3 mm Hg reduction in SBP could reduce the risk of all-cause mortality by 4%, mortality after stroke by 8%, and mortality after coronary artery disease by 5%.” The authors opined that GSE might have cardioprotective effects beyond SBP and heart rate reductions, and that larger studies should be done evaluating different dosages of GSE with longer follow-up durations.53
A more recent meta-analysis from 2016 included 12 articles (16 randomized trials, N = 810) that analyzed the effects of GSE on blood pressure over at least two weeks. Of the 16 clinical trials, four studied GSE’s effects in patients with prehypertension and stage 1 hypertension, four included healthy subjects, three in patients with metabolic syndrome, two in patients with hypertension, two in women with at least one menopausal symptom, and one in patients with above-average vascular risk. Overall, GSE was associated with significant changes in SBP and DBP. Significant decreases in SBP and DBP occurred more often in subjects under 50 years of age, while significant decreases in SBP alone occurred in obese subjects and patients with metabolic syndrome. Additionally, the authors identified study design, randomization, and baseline blood pressure as possible causes of heterogeneity (variability between the studies). Therefore, they recommend confirmation of their findings through a “large-scale, long-term, multiple-dose randomized controlled trial, especially among hypertensive patients.”54
At least seven clinical trials have studied GSE in combination with other ingredients for a variety of uses. Five of these addressed skin conditions. One found that skin radiance (e.g., for pink and olive skin tones) was significantly improved with six weeks of oral treatment with 150 mg per day of SkinAx2 (a product containing GSE, superoxide dismutase-rich melon [Cucumis melo var. cantalupensis, Cucurbitaceae] concentrate, vitamin C, and zinc; Activ’Inside; Libourne, France).55 Another oral supplement with 27.5 mg GSE, 210 mg biomarine complex, 54 mg vitamin C, 4 mg zinc, and 28.76 mg tomato (Solanum lycopersicum, Solanaceae) extract (Imedeen Man.Age.Ment; Ferrosan Laboratórios S/A; Copenhagen, Denmark) taken twice a day for 30 days improved skin hydration, dermal ultrasound density, reduction of skin pH, and overall signs of skin aging in men.56 Likewise, an oral supplement (Imedeen Time Perfection; Ferrosan S/A; Copenhagen, Denmark) with 105 mg BioMarine Complex, 14.8 mg LycoPhence GS (lycopene and GSE), and 30 mg acerola (Malpighia spp., Malpighiaceae) taken for 120 days was associated with improvements in skin hydration and pH, ultrasound density, and a histological increment of collagen and elastic fibers.57 An SPF 30 sunscreen containing GSE, vitamins E and C, and ubiquinone (Dr. Peter Hansen R&D; Stada; Bad Vilbel, Germany) effectively protected the subjects’ skin against infrared A radiation.58 Finally, a nonsteroidal topical cream (MD2011001; no other information provided) containing GSE, vitamin E, and epigallocatechin gallate (EGCG) provided a faster and statistically significant improvement in atopic dermatitis in patients who used it for 28 days, compared to placebo.59
One RDBPC study investigated the benefits of a nutritional supplement in low-income patients recently diagnosed with hyperlipidemia (N = 191; 18-65 years old). Subjects were randomly assigned to receive a placebo or a proprietary phytonutrient supplement (PreLipid; Preventions Meds, Inc.; Lebanon, NJ; no additional information provided) containing red yeast rice (a product of a yeast [Monascus purpureus, Elaphomycetaceae] grown on white rice [Oryza sativa, Poaceae]) powder, GS powder, niacin, folic acid, and black pepper (Piper nigrum, Piperaceae) powder. Subjects taking PreLipid experienced significant reductions in LDL-C and non-HDL-C at 12 weeks compared to placebo.60
Another RDBPC study investigated the effects of 150 mg GSE (MegaNatural BP; Polyphenolics; Madera, CA) in a fruit juice blend (provided by Coca-Cola) on blood pressure and metabolic indices in men and women with prehypertension (N = 28; 25-65 years old). Subjects were randomly assigned to take placebo or 300 mg GSE/juice blend per day in two doses for 12 weeks. By week six, the GSE group experienced significantly reduced SBP (5.6%) and DBP (4.7%) compared to placebo. The higher the subjects’ baseline BP, the greater the reduction they experienced; in some cases, subjects taking the GSE/juice blend experienced nearly double the SPB and DBP reduction of those in the placebo group. While not significant, fasting insulin and insulin sensitivity of subjects in the GSE/juice blend group tended to improve after six weeks.61
The International Union for Conservation of Nature (IUCN) assigns wild V. vinifera to the conservation category of Least Concern (LC), meaning that the species is not considered to be threatened.2 In any case, GSE is produced from seeds of the widely cultivated grape that is used for production of juices and wines worldwide. Nonetheless, long-term survival of crop wild relatives remains critical for preserving genetic diversity. Some wild grape species are becoming threatened in Europe due to habitat loss, competition with alien grape species, and intensive deforestation.62
Perhaps the biggest concern is economic adulteration of GSE, which has a direct impact on its safety and efficacy. In 2016, the American Botanical Council (ABC)-American Herbal Pharmacopoeia (AHP)-National Center for Natural Products Research (NCNPR) Botanical Adulterants Prevention Program published a Botanical Adulterants Bulletin on GSE, reporting that “adulteration of GSE in commercial products appears to be a significant problem.” In one of the studies cited in the bulletin, samples of several commercial GSE products contained no GSE at all and were composed primarily of peanut skin extract. Although peanut skin extracts should not exhibit allergenic potential comparable to that of peanuts themselves (due to no protein content), allergenicity could still be possible due to contact with the peanut protein. Besides the obvious matter of consumer fraud, persons with peanut allergies who unwittingly consume these products could experience adverse reactions. Other known adulterants of GSE include pine bark, green tea (Camellia sinensis, Theaceae) extract, and other PAC-rich (e.g., propelargonidin-containing) extracts from non-grape seed sources.7
While GSE is a relatively new item of commerce, evidence that supports its various beneficial uses as a functional component of cosmetic, food, dietary supplement, and natural health products continues to grow. To ensure the safety and efficacy of GSE for its intended uses, all finished product brands and marketers should specify the production and procurement of only well-characterized GSE for use in consumer products. For example, the USP quality standards monograph Grape Seeds Oligomeric Proanthocyanidins provides a useful basis for a company to establish a scientifically valid specification with suitable tests and methods for verifying identity, composition, strength, and purity.
—Gayle Engels and Josef Brinckmann
* The acronym GSE should not be confused with the acronym GFSE, which refers to grapefruit (Citrus paradisi, Rutaceae) seed extract, an entirely different material. In some original publications on GFSE adulteration, the authors use “GSE” to refer to grapefruit seed extract.
†The authors define oligomers as PACs that have 2-7 units.
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- Soleimani M, Masoumi N. The effect of grape seed extract on semen oxidative stress markers in men with idiopathic infertility: a cross-sectional before-after study. Nepho-Urology Monthly. 2017;9(5):e13837.
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- Safaei N, Babaei H, Azarfarin R, Jodati AR, Yaghoubi A, Sheikhalizadeh MA. Comparative effect of grape seed extract (Vitis vinifera) and ascorbic acid in oxidative stress induced by on-pump coronary artery bypass surgery. Ann Card Anaesth. 2017;20(1):45-51.
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