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In 3 Days Loss Your Weight Super Fast _ NO DIET NO EXERCISE #weightloss #weightlosstransformation #losefattips #burnfat #fatlosstips #homemade #beforeandafter #healthyrecipes #foryou #fypage 

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@myhealthhacks
In 3 Days Loss Your Weight Super Fast _ NO DIET NO EXERCISE #weightloss #weightlosstransformation #losefattips #burnfat #fatlosstips #homemade #beforeandafter #healthyrecipes #foryou #fypage
♬ Explosive Phonk - VEL94EV

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When Healthy Eating Becomes an Obsession w/ Christy Harrison - Food Heaven Made Easy

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Is it possible to be too obsessed with healthy eating? Today we talk with non-diet dietitian Christy Harrison about a condition known as orthorexia, which is an unhealthy preoccupation with healthy eating. Christy is the perfect person to talk to about this condition because she’s both a registered dietitian nutritionist and certified intuitive eating counselor. She’s […]

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🍫 Chocolate Cheatsheet    👉 Who already knew that white chocolate isn’t actually chocolate?  PS. If you consume a lot of dark chocolate or maybe you are pregnant and you are concerned about cadmium or lead, you can try for options such as Mast, Taza and Ghirardelli that have lower amounts.

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@healthwithcory
🍫 Chocolate Cheatsheet 👉 Who already knew that white chocolate isn’t actually chocolate? PS. If you consume a lot of dark chocolate or maybe you are pregnant and you are concerned about cadmium or lead, you can try for options such as Mast, Taza and Ghirardelli that have lower amounts.
♬ original sound - Cory Rodriguez

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This is an attention grabber-type ad found on Tik Tok to showcase a 'quick fix' way to lose weight. It highlights using hot water and a large amount of ground clove. It's targeted to overweight persons who are desperate to lose weight and have probably failed at lifestyle change. I don't think there are any diversity or inclusivity considerations with this ad; to me it appears neutral in that way. While I think that using clove as an herbal medicine may have some uses for some people, supplements such as this one should be managed by a health professional. Based on the information about clove below, there are possibly some uses for it as a health supplement.

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Generic Name: clove (KLOVE)
Brand Name:

Medically reviewed by Drugs.com on February 22, 2021. Written by Cerner Multum.

What is clove?

Clove is an herb also known as Bourgeon Floral de Clou de Girofle, Bouton Floral de Clou de Girofle, Caryophylli Flos, Clavo de Olor, Clous de Girolfe, Ding Xiang, Feuille de Clou de Girofle, Fleur de Clou de Girofle, Flores Caryophylli, Gewurznelken Nagelein, Girofle, Giroflier, Huile de Clou de Girofle, Kreteks, Lavang, Lavanga, or Tige de Clou de Girofle.

Clove is a common flavoring agent in foods and beverages, and is used as a flavoring or fragrance in other products such as toothpaste, soaps, and cosmetics. When used as a food product, clove is not likely to produce health benefits or side effects. When used as a medicinal product, clove may produce both desired and unwanted effects on the body.

Clove has been used in alternative medicine as a possibly effective aid in treating premature ejaculation, when it is combined with other ingredients and applied to the outer skin of the penis before sexual intercourse. Clove may have been combined with other plants or extracts in a specific preparation to treat this condition.

Other uses not proven with research have included tooth pain, "dry socket" after oral surgery, mouth or throat irritation, cough, upset stomach, vomiting, diarrhea, and other conditions.

It is not certain whether clove is effective in treating any medical condition. Medicinal use of this product has not been approved by the FDA. Clove should not be used in place of medication prescribed for you by your doctor.

Clove is often sold as an herbal supplement. There are no regulated manufacturing standards in place for many herbal compounds and some marketed supplements have been found to be contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Clove may also be used for purposes not listed in this product guide.

Warnings

Follow all directions on the product label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

Before taking this medicine

You should not use this product if you are allergic to clove.

Ask a doctor, pharmacist, or other healthcare provider if it is safe for you to take clove by mouth or use it on the skin if you have:

The use of clove as a flavoring agent in foods is considered safe during pregnancy. However, it is not known whether clove used as medicine will harm an unborn baby. Do not use this product without medical advice if you are pregnant.

It is not known whether clove passes into breast milk or if it could harm a nursing baby. Do not use this product without medical advice if you are breast-feeding a baby.

Do not give any herbal/health supplement to a child without medical advice. Clove oil taken by mouth can cause liver damage, seizure (convulsions), or other serious side effects in children.

How should I use clove?

When considering the use of herbal supplements, seek the advice of your doctor. You may also consider consulting a practitioner who is trained in the use of herbal/health supplements.

If you choose to use clove, use it as directed on the package or as directed by your doctor, pharmacist, or other healthcare provider. Do not use more of this product than is recommended on the label.

If you use a product containing clove to prevent premature ejaculation, apply it only to the outer skin of the tip of your penis. People who have used clove for this purpose have applied the product 1 hour before sexual activity, and washed it off just before intercourse.

Do not use different forms (tablets, liquid, tincture, teas, etc) of clove at the same time without medical advice. Using different formulations together increases the risk of an overdose.

Do not take topical (for the skin) clove by mouth. Topical forms of this product are for use only on the skin.

Call your doctor if the condition you are treating with clove does not improve, or if it gets worse while using this product.

Clove can affect blood-clotting and may increase your risk of bleeding. If you need surgery, dental work, or a medical procedure, stop taking clove at least 2 weeks ahead of time.

Store at room temperature away from moisture, heat, and light.

What happens if I miss a dose?

Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra clove to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while using clove?

Avoid continued use of topical clove if you or your sexual partner have severe genital irritation during or after sexual intercourse.

Avoid using clove together with other herbal/health supplements that can also affect blood-clotting. This includes angelica ( dong quai), capsicum, danshen, garlic, ginger, ginkgo, horse chestnut, panax ginseng, poplar, red clover, turmeric, and willow.

Clove side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using clove and call your healthcare provider at once if you have severe burning, redness, pain, or swelling after use on the skin.

Also call your doctor at once if you have taken oral clove and you have:

lactic acidosis--muscle pain or weakness, numbness or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired;

liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

signs of infection--fever, chills, sore throat, mouth sores, cold or flu symptoms, cough, trouble breathing.

Common side effects of topically applied clove may include:

trouble having an orgasm (delayed ejaculation);

itching, rash;

mild skin irritation; or

sore gums, mouth irritation, bleeding or swollen gums, or tooth changes after using clove inside the mouth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect clove?

It is not likely that other drugs you take orally or inject will have an effect on topically applied clove. But other drugs may interact with clove taken by mouth. Tell your healthcare provider about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your healthcare provider.

More about clove

Professional resources

Related treatment guides

Further information

Consult with a licensed healthcare professional before using any herbal/health supplement. Whether you are treated by a medical doctor or a practitioner trained in the use of natural medicines/supplements, make sure all your healthcare providers know about all of your medical conditions and treatments.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.
Medical Disclaimer

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Clove Uses, Side Effects & Warnings - Drugs.com

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Generic Name: clove (KLOVE) Brand Name: Medically reviewed by Drugs.com on February 22, 2021. Written by Cerner Multum. Clove is an herb also known as Bourgeon Floral de Clou de Girofle, Bouton Floral de Clou de Girofle, Caryophylli Flos, Clavo de Olor, Clous de Girolfe, Ding Xiang, Feuille de Clou de Girofle, Fleur de Clou de Girofle, Flores Caryophylli, Gewurznelken Nagelein, Girofle, Giroflier, Huile de Clou de Girofle, Kreteks, Lavang, Lavanga, or Tige de Clou de Girofle.

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This reel's target audience is wide. I think this influencer is hoping to reach mostly women of all ages and varying degrees of health and health awareness. There is no indication that the influencer is backing up the information he is sharing; he is relying on you trusting what he says. When I looked into who he was, I couldn't find any actual credentials of Cory's. I could easily find that he is a health and fitness influencer with a particular interest in brain health, and a former body builder.

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This podcast was found using a general search on nutrition podcasts. I think the target audience is fairly educated young-to-middle aged women who are seeking a healthy lifestyle. This specific episode discusses a type of eating disorder called 'orthorexia' which is an obsession with healthy eating. What I like about this podcast is the two women who created and host the show are registered dieticians and actively remind their listeners to be aware of the information they consume on social media regarding health. These RDs are licensed and have to meet continuing education requirements. I think the topics they discuss have an impact on the decision-making of their listeners. One thing I didn't see online were links to any evidence-based research or scholarly sources, which would lend them additional credibility.

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Are There Health Benefits to Drinking Red Wine?

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Find out what the research says about red wine, who should avoid it, and how it may affect your health.

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This article was found in a very broad search of 'is wine good for me?' This is the type of question that I'd bet the internet gets thousands of times per day. As always, WebMD did not disappoint. I don't think the article targets a particular gender, race, ethnicity, or background, but I do think it targets existing drinkers--and I'll tell you why. It highlights the positives of wine drinking, and in some ways downplays the negatives. I even found some contradictory and confusing information: on the positive side, the article mentions drinking red wine in moderation can reduce inflammation and possibly prevent some cancers, including colon. A few paragraphs down, it states that one drawback of drinking wine is there is evidence that it is linked to some cancers, including colon. What?! As a nurse, that's confusing. The article states at the top that it has been 'medically reviewed' and lists the name of an MD. I think this gives the reader a false sense of security that the information within is legitimate. However, I saw no links to scholarly articles showing evidence-based research, for either stance. WebMD could be the death of us all!

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Joe Leech, Dietitian (MSc Nutrition & Dietetics)

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17 Diet and Nutrition Memes to Share With Your Fact-Denying Friends | Diet vs Disease

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Many of us identify ourselves with what we eat or don’t eat. But the majority of diets, nutrition “cures” and “dangers” on social media are wrong (& stupid)

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This article is a collection of health and nutrition memes and either the debunking or endorsement of the information within. They are commented on by a dietician who has an MSc (Master of Science in Nutrition and Dietetics). I think the article is aimed at younger people of both genders who rely on social media to get their information. Some of these memes can be harmful because they give no context or are outright lies, and the dietician who wrote the article debunks or explains each meme in easy language. He links a few sources, although not scholarly, and links to his 'about' page to lend him a bit of credibility.

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Artificial Sweetener vs. Sugar: Which Is Better?

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Artificial Sweetener vs. Sugar: Which Is Better?

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3 Protein Powder SCAMS To Avoid (WATCH OUT!)

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While clove has anti-obesity properties as supported in this scholarly article, the outlandish claims in the Tik Tok ad that fat will melt away are extreme and not evidence-based.

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Culinary Spices in Food and Medicine: An Overview of Syzygium aromaticum (L.) Merr. and L. M. Perry [Myrtaceae]

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Spices-dried aromatic parts of plants (leaves, seeds, bark, roots, rhizomes, buds, etc) used to enhance flavour, taste and colour (sensory quality) of foods, are increasingly finding other useful roles in healthcare beyond their primary use as culinary…

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This article supports the notion that certain regimens (like meal commercial diets) have been associated with weight loss, but there is nothing substantial. The commercial doesn't offer the consumer any solid facts to back up their program.

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Weight loss maintenance: A review on dietary related strategies

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Weight regain after weight loss is a common problem for all those obese or overweight who have had a recent weight loss. Different cures such as diet therapy, behavioral therapy, exercise or a mixture of them have been advised as solutions. The purpose…

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Based on this article, there is not an abundance of research on Orthorexia, but there is some. The research that is referenced in this article is pretty accurately discussed in the podcast, including the discussion regarding comorbidities and quality of life. Overall, the podcast aligns with the evidence in the article.

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Orthorexia Nervosa: An Obsession With Healthy Eating

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Despite a focus on eating, orthorexia nervosa may lead to malnourishment, loss of relationships, and poor quality of life.

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This article does mention something that Cory talks about in his video: flavonoids, which lends him some credibility. However, this article does not discuss the inferiority of the health benefits of milk or white chocolate, although what Cory says makes sense. The research also stresses dark cocoa/chocolate in moderation is beneficial, but too much could be harmful.

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Abstract

Cocoa contains more phenolic antioxidants than most foods. Flavonoids, including catechin, epicatechin, and procyanidins predominate in antioxidant activity. The tricyclic structure of the flavonoids determines antioxidant effects that scavenge reactive oxygen species, chelate Fe2+ and Cu+, inhibit enzymes, and upregulate antioxidant defenses. The epicatechin content of cocoa is primarily responsible for its favorable impact on vascular endothelium via its effect on both acute and chronic upregulation of nitric oxide production. Other cardiovascular effects are mediated through anti-inflammatory effects of cocoa polyphenols, and modulated through the activity of NF-κB. Antioxidant effects of cocoa may directly influence insulin resistance and, in turn, reduce risk for diabetes. Further, cocoa consumption may stimulate changes in redox-sensitive signaling pathways involved in gene expression and the immune response. Cocoa can protect nerves from injury and inflammation, protect the skin from oxidative damage from UV radiation in topical preparations, and have beneficial effects on satiety, cognitive function, and mood. As cocoa is predominantly consumed as energy-dense chocolate, potential detrimental effects of overconsumption exist, including increased risk of weight gain. Overall, research to date suggests that the benefits of moderate cocoa or dark chocolate consumption likely outweigh the risks. Antioxid. Redox Signal. 15, 2779-2811.

I. Introduction

A. History

Chocolate is best known as an indulgent confection, but historically it has also been consumed for its purported healing properties ( 60). Foods and beverages made from beans from the Theobroma cacao tree (cocoa, cacao) have been consumed by humans since at least as early as 460 AD ( 224). The medicinal uses of cacao or chocolate either as a primary remedy or as a vehicle to deliver other medicines originated in Mesoamerica, where it was consumed by indigenous peoples, and diffused to Europe in the mid-1500s. Between the 16th and 20th centuries, well over 100 uses for cacao or chocolate, as a medical treatment, have been documented ( 60). Among these, three applications are most common: (i) to induce weight gain in emaciated patients; (ii) to stimulate the nervous system; and (iii) to improve digestion and elimination ( 60).

The Kuna Indians of the San Blas islands of Panama consume an average of three 10-ounce cups of cocoa beverage daily, ingesting approximately 1880 mg of procyanidins ( 39, 162). The prevalence of hypertension among the Kuna islanders is very low (2.2%) and blood pressure (BP) does not increase with age ( 104). The population also experiences lower rates of diabetes mellitus, myocardial infarction, stroke, and cancer than mainland Panamanians ( 103). Among Kuna who have migrated to urban areas on mainland Panama, the prevalence of hypertension is higher (10.7%) and reaches 45% among those over age 60 () ( 104). McCullough et al. have hypothesized that the high intake of a traditional cocoa beverage may be partly responsible for the low incidence of cardiovascular disease among the Kuna islanders ( 162). Compared to Kuna living in a suburb of Panama City, those still living on the remote islands consume twice as much fruit, four times as much fish, and 10 times as much cocoa ( 162).

The majority of research on chocolate and cocoa has taken place over the last decade ( 41) and has primarily focused on the relationship between cocoa consumption and cardiovascular risk. More recent research has provided insights to the possible benefits of cocoa consumption on other organ systems. This review will discuss the reported physiologic effects of cocoa consumption and possible mechanisms by which they might occur.

B. Economic data

Worldwide, chocolate consumption ranges from 0.12 kg per person per year in China to 11.85 kg in Ireland. The United States falls somewhere in the middle of this range, with per capita annual consumption of 5.18 kg ( 33). Developed countries account for 64% of worldwide consumption ( 75a). The largest cocoa bean producing country in the world is Côte d'Ivoire, which produced 1.2 million tons of cocoa in 2006-2007 ( 113a).

C. Components of cocoa

Cocoa, or cacao, is the dried and fully fermented fatty seed of the fruit of the cocoa tree, Theobroma cacao ( 163). Cocoa liquor is the paste made from ground, roasted, shelled, and fermented cocoa beans, called nibs. It contains both nonfat cocoa solids and cocoa butter. Cocoa liquor is what is referred to as "percent cacao" on food packaging. Cocoa powder is made by removing some of the cocoa butter from the liquor. Chocolate is a solid food made by combining cocoa liquor with cocoa butter and sugar. The proportion of cocoa liquor in the final product determines how dark the chocolate is. Milk chocolate is made with the addition of condensed or powdered milk to the chocolate mixture ( 281). The type of chocolate consumed most in the United States is milk chocolate, which typically contains 10%-12% cocoa liquor ( 18). Semisweet or bittersweet chocolate is often referred to as dark chocolate and must contain no less than 35% by weight of cocoa liquor. White chocolate contains only cocoa butter (at least 20% by weight) combined with sweeteners and dairy ingredients ( 258).

Cocoa liquor is a complex food and contains many bioactive compounds. Cocoa butter contains significant amounts of fatty acids, whereas the nonfat cocoa solids contain vitamins, minerals, fiber, and polyphenols.

II. Epidemiology: Chocolate and Health Outcomes

The majority of research on cocoa and health has been in the form of clinical trials on surrogate markers. However, a few prospective cohort studies are notable. An early ecological study investigated coronary mortality in relation to consumption of coffee, tea, cocoa, alcohol, and tobacco in 20 countries, but found no significant associations ( 28). Later studies have mostly supported a protective association between cocoa or chocolate consumption and a variety of health indicators. These include total and cardiovascular mortality, serum C-reactive protein, psychological well-being, and risk of diabetes, myocardial infarction, and/or stroke ( 30, 59, 116, 189, 236).

The first cohort study of cocoa intake and cardiovascular outcomes was published in 2006 ( 29). The study population included 470 Dutch men free of cardiovascular disease and diabetes from the Zutphen Elderly Study cohort. Systolic and diastolic BPs were inversely associated with cocoa intake after adjustment for a wide range of possible confounders. This relationship was statistically significant for diastolic BP ( p=0.03) and near significant for systolic BP ( p=0.06). Cocoa consumption was associated with significantly lower cardiovascular and all-cause mortality. Those in the highest tertile of cocoa intake compared with those in the lowest tertile had 50% lower rates of all-cause mortality and cardiovascular disease. Individuals in the highest tertile consumed more than 2.30 g of cocoa daily, whereas those in the lowest tertile consumed less than 0.36 g/day. Consumption of other food groups, including confectionary, was not associated with mortality.

In 2009, a study in Stockholm, Sweden assessed cardiac mortality in a particularly high-risk group: nondiabetic patients hospitalized with a first myocardial infarction ( 116). After a mean 8.6 years of follow-up, patients who reported eating chocolate twice or more per week were 66% less likely to suffer a cardiac death compared to those who reported never eating chocolate. After adjustment for demographic and socioeconomic variables, coffee consumption, and intake of sweets, there was a significant, linear, inverse relationship between frequency of chocolate consumption and cardiac mortality ( p=0.01). Total mortality, however, was not associated with chocolate consumption.

Other observational studies have identified a number of positive health outcomes associated with cocoa or chocolate consumption. In a Japanese study, risk of being found to have diabetes was reduced 35% among men who consumed "chocolate snack pieces" once per week or more compared with those who never or almost never ate chocolate ( 189). A similar but nonsignificant reduction in risk was observed for women ( 189). In another study, a J-shaped relationship was observed between dark chocolate consumption and serum C-reactive protein (CRP) levels in Italian men and women ( 59). Individuals consuming a 20-g serving of dark chocolate daily had the lowest CRP concentrations. A 2009 study suggested a relationship between psychological health and chocolate preference in which elderly men preferring chocolate reported feeling less lonely and depressed and happier than men preferring other types of candy ( 251).

A cross-sectional analysis of data from 2217 participants in the NHLBI Family Heart Study identified an inverse relationship between chocolate consumption and calcified atherosclerotic plaque in the coronary arteries ( 61). Individuals who reported consuming (any type of) chocolate two or more times per week were 32% less likely to have prevalent coronary artery calcification compared with those who never ate chocolate. The odds ratios decreased with increasing frequency of chocolate consumption and were adjusted for age, sex, energy intake, waist-to-hip ratio, education, smoking, alcohol consumption, total cholesterol:HDL ratio, nonchocolate candy intake, and diabetes mellitus.

In 2010, Buijsse and colleagues released results from the first cohort study to demonstrate a reduced risk of myocardial infarction and stroke associated with chocolate consumption ( 30). The study followed 19,357 men and women in Germany over a mean of 8 years. Compared with the bottom quartile of chocolate consumption, those in the highest quartile had a 39% reduced risk of myocardial infarction or stroke ( p=0.014). The highest quartile reported a mean chocolate intake of 7.5 g/day. The food frequency questionnaire used in this study did not distinguish between white, milk, and dark chocolate. However, a more detailed analysis of intake among a subset of participants found that milk chocolate was the type most often consumed (57%), followed by dark chocolate (24%) and white chocolate (2%).

Another 2010 study partially supports the findings of Buijsse et al. In this study, Mostofsky and colleagues assessed the relationship between chocolate consumption and heart failure in 31,823 middle-aged and elderly women over 9 years of follow-up ( 175). They found that women consuming 1-3 servings per month or 1-2 servings per week of chocolate had significantly lower rates of heart failure hospitalization or heart failure death compared with those consuming no chocolate (OR, 0.74; 0.68, respectively). However, the odds of heart failure outcomes were slightly, but not significantly, higher among women who reported consuming 3-6 servings per week (OR, 1.09; 95% CI, 0.74-1.62) or one or more servings per day (OR, 1.23; 95% CI, 0.73-2.08).

III. Effects on Cardiovascular Disease

A. Pathogenesis

Cardiovascular disease is the leading cause of death and disability-adjusted life years globally and is associated with risk factors, including hypertension, smoking, hyperlipidemia, and diabetes mellitus ( 286). The vast majority (80%) of cardiovascular disease burden is now experienced in low- and middle-income countries ( 286). Atherosclerosis is the result of a series of inflammatory responses at the cellular and molecular level that leads to the development of lesions in medium-sized arteries. Chronic inflammation is responsible for the progression of atherosclerotic lesions through advancing stages. It has been proposed that endothelial dysfunction initiates the process of atherosclerosis. There are many possible etiological factors for endothelial dysfunction, including elevated LDL or homocysteine in the blood, infectious microorganisms, genetics, and oxidative stress. The injury caused by these varied agents initiates an inflammatory response that may continue indefinitely ( 209). The resulting chronic inflammatory state is characterized by increasing numbers of macrophages and lymphocytes and proliferation of smooth muscle cells. Unabated inflammation will further increase the concentration of macrophages and lymphocytes that promote the formation of fibrous tissue in the lesion through the release of hydrolytic enzymes, cytokines, chemokines, and growth factors. The resulting complicated lesion has the potential to narrow the lumen of the artery and block blood flow ( 209). Advanced plaques high in lipid content are particularly vulnerable to disruption, which can lead to the occlusive thrombosis that characterizes acute coronary syndromes ( 43).

Diet has been established as one of the most important lifestyle factors that can strongly influence the incidence of cardiovascular disease ( 51, 76, 125). Dietary flavonoids may decrease cardiovascular risk by protecting lipids, proteins, and nucleic acids from oxidative damage, as well as reducing inflammation and regulating vascular homeostasis ( 205). Flavonoid intake has been inversely associated with coronary artery disease (CAD) incidence and mortality ( 98).

A number of pro-inflammatory enzyme systems are involved in the pathogenesis of atherosclerosis, including xanthine oxidase and NADH/NADPH oxidase ( 159) that produce reactive oxygen species (ROS), which can cause endothelial dysfunction ( 265). Flavanols, particularly epicatechin ( 222), in cocoa have anti-inflammatory properties that inhibit the production of ROS, and have antihypertensive and vasoprotective effects ( 42).

Cocoa polyphenols modulate the activity of NF-κB ( 141), a protein complex involved in DNA transcription that is a pivotal factor in a number of inflammatory processes () ( 226). NF-κB activation in leukocytes (as well as in endothelial cells and macrophages) results in leukocyte adhesion to the endothelium, tissue invasion, and the secretion of mediating factors leading to tissue injury. Cocoa polyphenols can reduce the activity of NF-κB, downregulating leukocyte activation and attenuating the production of inflammatory mediators and ROS ( 226, 229). Further, polyphenols act synergistically with other nutrients, such as vitamin C and selenium, to increase endogenous antioxidant capacity ( 229).

Cocoa flavanols can affect oxidant enzymes such as lipoxygenases, involved in arachidonic acid metabolism and the biosynthesis of leukotrienes. High-procyanidin chocolate was found to increase plasma prostacyclin and decrease plasma leukotrienes ( 220, 233), reflecting anti-inflammatory and vasoprotective properties ( 233).

B. Effects on endothelial function

Endothelial function is recognized as an important measure of cardiac risk, as impaired endothelial function has been found to predict both recurring and incident cardiovascular events ( 7, 34, 52, 57, 68, 209, 215, 253, 284, 285) ().

Endothelial function refers to arterial vasomotor responses mediated predominantly by the release of NO (vasodilating), and endothelin (vasoconstricting) from the vascular endothelium ( 145, 266), and plays an important role in the pathogenesis of atherosclerosis, hypertension, and cardiovascular disease ( 266). Endothelial dysfunction has been shown in the coronary and peripheral circulations before the development of atherosclerotic plaque ( 284, 285). Individuals with cardiac risk factors develop endothelial dysfunction via decreased NO production, abnormal signaling, and increased oxidative stress ( 266). Endothelial dysfunction has been shown to reverse in response to cardiac risk modification efforts ( 266). NO also has an anti-inflammatory effect, counteracting leukocyte recruitment and platelet aggregation at the site of inflammation ( 225) though other substances play important roles in modulating vascular tone, fibrinolysis, coagulation, and inflammation ( 274).

Human trials have demonstrated vasoprotective effects mediated by NO ( 92, 225, 256). A 2008 meta-analysis of randomized, controlled trials of flavonoid-containing foods concluded that cocoa was the only food to show significant effects acutely and chronically on flow-mediated dilatation (FMD) of the brachial artery, a noninvasive method to measure endothelial function ( 107). Data from two long-term studies and six acute studies indicated that chocolate or cocoa significantly increased FMD by 1.45% and 3.99%, respectively ( 107). Corti et al. reviewed 11 human trials of cocoa and endothelial function and found that all demonstrated significant improvement in FMD after cocoa consumption ( 42). Acute studies were 2 h in duration, whereas longer-term studies were 2 weeks long, with the exception of one 4-week study ( 17) and a 5-day study ( 73). Four of the trials were conducted on healthy individuals ( 65, 73, 222, 231) and two on smokers ( 95, 97). Other study populations included diabetic patients ( 17); hypertensives ( 85); hypertensives with impaired glucose tolerance ( 84); patients with at least one cardiovascular risk factor ( 92); and heart transplant recipients ( 75). In five of the studies, a cocoa beverage was administered ( 17, 73, 92, 95, 222); the other six used dark chocolate ( 65, 75, 84, 85, 97, 231).

C. Effects on platelets

When the endothelium is damaged and the underlying fibrous matrix exposed, as it is when atherosclerotic plaque ruptures, platelets can adhere to the matrix and become activated ( 9). Once activated, platelets can recruit leukocytes and endothelial progenitor cells, and interact with these cells to induce inflammatory responses and promote thrombus formation ( 88, 158).

Dietary flavonoids, and flavanols in particular, have been associated with decreased platelet reactivity. Although the specific mechanisms responsible for this association have not yet been identified, it has been theorized that flavanols may affect the activity of platelets by inducing changes in membrane fluidity, ligand-receptor affinity, and intracellular signaling pathways ( 105). It has also been suggested that platelet-derived nitric oxide may be a target of flavanols ( 204). Although many plant foods contain flavanols, cocoa is an especially concentrated source ( 150), and has been recognized as having significant effects on platelets in humans. A systematic review of 25 intervention studies of polyphenol-rich diets and platelet function noted cocoa's platelet-inhibiting effects as the only consistent finding among the trials ( 194). In 2007, Bordeaux and colleagues found that, among healthy participants in a platelet function study, those who had consumed chocolate before testing ( n=141) had reduced platelet activity compared to nonconsumers ( 23). A small study of 30 healthy subjects found that platelet activation decreased 2 and 6 h after cocoa consumption ( 205). In another trial, cocoa consumption inhibited platelets in vivo, whereas dealcoholized red wine consumption did not ( 204). Hamed and colleagues demonstrated that these short-term effects could also be seen after 1 week of solid dark chocolate consumption (containing 700 mg of flavonoids per day) in 28 healthy subjects ( 89). Flammer and colleagues found that dark chocolate consumption decreased platelet adhesion 2 h after consumption in 22 heart transplant patients ( 75). A study by Heptinstall et al. evaluated the effects of cocoa beverage consumption on platelets and leukocytes in vitro and ex vivo supporting previous findings of platelet inhibition, and identifying a potential role for cocoa flavanols in suppressing leukocyte activation ( 96).

Existing evidence strongly supports a beneficial effect of cocoa consumption on platelet activation, an important contributor to the inflammation and thrombosis that leads to advanced cardiovascular disease. The effects are likely due mostly to the actions of flavanols, though the minerals (potassium, magnesium, and calcium) in cocoa or stearic acid present in in chocolate may also play a role ( 196).

D. Effects on lipids

Cocoa's effects on serum lipids are not as clear as its effects on endothelial function and platelet activity. Evidence for a lipid-lowering effect is limited and inconclusive.

Numerous studies have investigated the effects of cocoa consumption on the lipid profile, with conflicting results. In one trial in patients with hypertension, daily consumption of 100 g flavonoid-rich chocolate over 2 weeks significantly reduced serum total cholesterol by 7% and LDL by 12% ( 85). Consumption of cocoa and dark chocolate increased HDL by 4% in one study ( 267).

Mellor et al. found that HDL increased in subjects consuming a high-polyphenol chocolate, but not in persons consuming a low-polyphenol chocolate over the course of 16 weeks ( 166).

In contrast, Engler et al. found no difference in serum lipids between subjects consuming 46 g of high-flavonoid dark chocolate and those consuming low-flavonoid chocolate daily for 2 weeks ( 65). Almoosawi et al. also did not observe significant changes in total cholesterol among overweight and obese subjects after 2 weeks of daily consumption of dark chocolate containing either 500 mg or 1000 mg polyphenols ( 6).

Feeding studies of cocoa beverages containing only cocoa powder have also had mixed results. Wang-Polagruto and colleagues studied the effects of consuming a high flavanol (446 mg total flavanols) cocoa beverage relative to a low flavanol (43 mg) cocoa beverage daily for 6 weeks in hypercholesterolemic postmenopausal women ( 269). In this study, HDL levels increased 6.6% in the high flavanol group, whereas HDL decreased 9.6% in the low flavanol group ( p<0.05). Another study investigated the effects of consuming a cocoa beverage containing four different levels of polyphenols (0 g, 13 g, 19.5 g, or 26 g) daily for 4 weeks on the lipid panel in normocholesterolemic and mildly hypercholesterolemic individuals ( 14). Although none of the polyphenol-containing cocoa treatments differed significantly from the placebo cocoa, all three significantly improved LDL and HDL levels from baseline in subjects with high LDL at the start of the study. However, these improvements were small. Baba et al. observed a greater increase in HDL (24%) after daily ingestion of 12 g sugar plus 26 g cocoa powder for 12 weeks. This increase was significantly different than the small increase (5%) observed in the control group, which only received 12 g sugar daily ( 15). At least three studies found no effect of cocoa beverage consumption on blood lipids ( 45, 178, 188), including one which tested a combination of liquid cocoa and solid dark chocolate ( 45).

Because of their high flavonoid content, the cocoa solids present in chocolate are typically hypothesized to affect measures of cardiovascular health, whereas other components of chocolate products ( e.g., cocoa butter) are thought to have little or no effect. Given this reasonable assumption, the results of a study by Kris-Etherton et al. are surprising ( 135). In their study, consumption of milk chocolate as a substitute for a high-carbohydrate snack bar improved levels of serum HDL and triglycerides. This improvement occurred despite the fact that the milk chocolate bar increased the total fat and saturated fat in the diet. Because milk chocolate contains a relatively small proportion of cocoa solids, this finding might suggest that a component in chocolate other than flavonoids (possibly stearic acid) was responsible. However, in another trial, HDL increased by 11.4% and 13.7% when subjects consumed dark chocolate and polyphenol-enriched dark chocolate, respectively, but not when they consumed white chocolate ( 181). One possible explanation for the results of Kris-Etherton et al. is that the chocolate bar's displacement of a high-carbohydrate snack, rather than some active compound in the chocolate bar itself, led to the change in lipid levels.

A 2010 meta-analysis of eight trials summarized the short-term impact of cocoa consumption on blood lipids ( 119). The data from these trials indicate that cocoa may significantly reduce LDL cholesterol, and may also reduce total cholesterol when consumed in low doses by individuals with cardiovascular risk factors. This meta-analysis supports a lipid-lowering effect of cocoa, but it is limited by the small total sample ( n=215), the paucity of well-designed trials, and the heterogeneity of the studies included. Whether cocoa products substantially improve lipid levels in the blood remains unclear. There is, however, convincing evidence that consumption of chocolate in most forms has at worst, a neutral effect on the lipid profile. This evidence should allay fears that the high saturated fat content of chocolate would negate the effects of its other health-promoting compounds. Further, although cocoa may not appreciably change the quantity of lipids in the blood, it may change their quality, that is, their ability to cause blood vessel damage.

Lipids, n-6 fatty acids in particular, are susceptible to peroxidation by reactive oxygen species (ROS) produced as a result of normal metabolic processes or pathological events. To a certain extent, cells can compensate for the activity of ROS with endogenous antioxidant defenses, but when pro-oxidants exceed antioxidants, cells experience oxidative stress ( 287). Exogenous antioxidants from food sources are therefore important in maintaining a favorable balance between ROS and the antioxidants that can inactivate them ( 287).

Levels of oxidized LDL in the blood have been shown to predict CAD better than total cholesterol, triglycerides, HDL, and LDL ( 63, 110). In general, intervention studies suggest that cocoa can inhibit LDL oxidation. Decreased levels of plasma-oxidized LDL have been observed in subjects after long-term daily consumption of cocoa powder ( 14, 15) and dark chocolate ( 267). These effects might be attributed to epicatechin, which attenuates LDL oxidation and protects the endothelium from the actions of oxidized LDL ( 246). However, some studies suggest that consumption of chocolate low in flavonoids may also be beneficial. In two studies, milk chocolate ( 135) and white chocolate ( 181) inhibited LDL oxidation. In the latter study, a marker of lipid peroxidation decreased 11.9% after consumption of white chocolate, dark chocolate, or dark chocolate enriched with polyphenols ( 181). These results indicate that the fatty acids in chocolate may play an important role in LDL oxidation.

Although one study failed to find an effect of either flavonoid-rich dark chocolate or low-flavonoid chocolate on LDL oxidation ( 65), most available evidence supports the hypothesis that consumption of cocoa or chocolate protects lipids from oxidation.

E. Effects on BP

A relationship between cocoa consumption and reduced BP was first observed in the Zutphen Elderly Study ( 29). Subsequent randomized, controlled trials have confirmed the association. A meta-analysis of five such trials found that cocoa consumption was associated with significant reductions in systolic and diastolic BPs of 4.7 and 2.0 mm Hg, respectively. Other intervention studies have had similar findings ( 6, 66, 84) but a few have found no effect of cocoa on BP ( 45, 65, 178, 180). A 2010 study found that a daily dose of 1052 mg cocoa flavanols was required to reduce 24-h ambulatory BP. There was no effect on seated BP or on either measure at lower doses of flavanols ( 48). Another study found that a dark chocolate bar containing 500 mg polyphenols lowered BP as effectively as a bar containing 1000 mg ( 6). Crews et al. did not observe any change in BP among healthy men and women over the age of 60 who consumed both a cocoa beverage and dark chocolate daily for 6 weeks (providing a total of 754.71 mg proanthocyanins), relative to those consuming low-flavanol control products ( 45). However, Berry and colleagues demonstrated that consumption of a high-flavanol (701 mg) cocoa beverage could significantly improve BP response to exercise compared to a low-flavanol (22 mg) beverage ( 21).

Although some studies have not observed significant changes in BP associated with consumption of cocoa products containing average levels of flavanols, the majority of the research conducted in this area indicates that regular cocoa/chocolate ingestion can reduce BP. A meta-analysis of 10 trials published in 2010 confirmed the findings of the previous 2007 meta-analysis. Mean change in systolic and diastolic BP across the trials was −4.5±1.35 and −2.5±1.36 mm Hg, respectively. There was a wide range of flavanol intake across these trials, with epicatechin intake as low as 5 mg/day or as high as 174 mg/day ( 56). Of note, in the trial reporting the lowest level of flavanols, subjects, nevertheless, experienced significant improvement in BP ( 256). Similar to the trials of flow-mediated dilatation, Hooper and colleagues' meta-analysis of flavonoid-rich food trials highlighted cocoa as the sole food capable of significantly reducing BP in human studies ( 107). In addition to a reduction in risk for MI and stroke, Buijsse et al. reported significantly lower systolic ( p=0.0008) and diastolic ( p<0.0001) BPs among individuals consuming higher amounts of chocolate ( 30).

A number of mechanisms have been proposed to explain cocoa's effects on BP ( 83). Because of their importance in BP maintenance, the improvements in nitric oxide availability and endothelial function associated with cocoa consumption may explain much, if not all, of its antihypertensive effects ( 183). However, there is some evidence that flavanols and flavanol-rich foods, including cocoa, can inhibit angiotensin-converting enzyme (ACE) activity in vitro ( 2, 3). Angiotensin-converting enzyme regulates the renin-angiotensin system; it cleaves angiotensin-I into angiotensin-II, which stimulates the release of vasopressin or aldosterone and antidiuretic hormone, increasing sodium and water retention. It also inactivates vasodilators bradykinin and kallidin ( 138). Whether ACE inhibition mediates the antihypertensive activity of cocoa flavanols in humans is not yet known.

F. Cardiovascular effects: conclusion

Rimbach et al. noted that beneficial effects on BP, FMD, and platelet aggregation have not been found in all human trials ( 67, 73). Further, improvements are often small when they are observed ( 165, 256). The authors also raise the concern about chocolate's caloric density and its potential to contribute to weight gain, which may counteract any small benefits of cocoa's polyphenol content. This is a legitimate concern, as evidenced by a study by Taubert et al., in which daily dark chocolate consumption providing an additional 480 kcal per day decreased systolic BP by 5 mm Hg ( 255). However, in a subsequent study, Taubert and colleagues found that a mere 30 kcal per day of dark chocolate for 18 weeks reduced systolic BP by 2.9 mm Hg ( 256). Their argument also ignores the fact that the bioactive components of cocoa ( i.e., flavanols) are found in the nonfat portion of the cocoa bean and can be readily isolated in a low-energy-dense form, that is, cocoa powder. For example, in their study in CAD patients, Heiss et al. used an active treatment that provided a substantial daily dose of 375 mg flavanols but only 50 kcal ( 94).

Rimbach et al. also questioned the rigor of cocoa feeding trials, noting their small sample sizes and acknowledging the need for randomized, placebo-controlled, and cross-over studies. However, the majority of the endothelial function studies discussed in this review, including those from our lab, are randomized and placebo-controlled, and many are cross-over designs and/or double-blinded. It is true that most cocoa and chocolate studies have used small sample sizes, increasing variance and risk of type 2 error, biasing toward the null. Nevertheless, when they detect significant differences in cardiovascular measures that favor treatment, this is a testament to the strength of the observed effect. summarizes results from these human trials investigating cardiovascular effects of cocoa or chocolate.

IV. Effects on Insulin Resistance

There is reason to believe that the flavanols in cocoa may ameliorate insulin resistance by reducing oxidative stress, improving endothelial function, and/or altering glucose metabolism. Ceriello and Motz have proposed that oxidative stress is the underlying mechanism for both insulin resistance and cardiovascular disease ( 35). This hypothesis is supported by the observation that many antidiabetic drugs and drugs used to treat cardiovascular disease demonstrate antioxidant effects. This effect may be direct-as in the case of calcium channel blockers, statins, ACE inhibitors, and AT-1 receptor antagonists-or indirect-as in acarbose and glinides, which prevent oxidative stress caused by postprandial hyperglycemia ( 35). If this hypothesis is correct, the demonstrated antioxidant activity of cocoa flavanols ( 170) could theoretically also protect against insulin resistance. However, better evidence exists for an insulin-sensitizing effect mediated by changes in endothelial function and/or glucose metabolism.

Many polyphenols, including catechin and epicatechin, have been found to alter glucose metabolism in animal and in vitro studies ( 90). In studies, catechin has inhibited alpha-glucosidase activity ( 114) and inhibited absorption of glucose from the intestine ( 121, 273). Studies in diabetic rats support an insulin-sensitizing effect of cocoa. In two such studies, epicatechin regenerated pancreatic β-cells ( 37) and increased insulin secretion ( 37, 100). In a 2005 study, supplementation of diabetic rats with cocoa extract for 4 weeks was dose-dependently associated with reduced serum glucose and LDL, and increased HDL ( 213). A similar study by Jalil and colleagues found that cocoa extract reduced postprandial hyperglycemia, plasma free fatty acids, and 8-isoprostane, a biomarker of oxidative stress ( 115). However, no change was observed in fasting glucose or insulin.

The well-documented effects of cocoa on endothelial function also point to a possible effect on insulin sensitivity. The relationship between endothelial function and insulin resistance is a reciprocal one. Increased insulin sensitivity improves endothelial function; conversely, improvement in endothelial function can increase insulin sensitivity ( 131). In healthy individuals, insulin increases blood flow to skeletal muscles and glucose uptake by muscle cells through vasodilation. In contrast, in insulin-resistant individuals, insulin-mediated vasodilation is impaired and glucose disposal is inhibited. Insulin resistance has been associated with reduced activity of endothelium-derived NO synthase and with increased plasma levels of asymmetric dimethylarginine, an endogenous NOS inhibitor ( 254). Thus, the availability of NO likely plays a role in mediating cells' response to insulin. Because of cocoa's ability to increase bioavailability of NO, the possible relationship between cocoa consumption and insulin resistance has been investigated.

Although low rates of hypertension may be the most striking of the Kuna population's unique characteristics ( 102), their comparatively low rates of diabetes are also intriguing ( 103). Grassi and colleagues reported that ingestion of 100 g of flavonoid-rich dark chocolate for 15 days was associated with not only reduced BP and improved endothelial function, but also improved insulin sensitivity in hypertensive patients ( 84). These results have also been observed in healthy individuals and in hypertensives with impaired glucose tolerance ( 84). In the former study, subjects received oral glucose tolerance tests (OGTT) after consuming either dark chocolate or white chocolate for 15 days. Compared with white chocolate, ingestion of dark chocolate was associated with higher homeostasis model insulin resistance (HOMA-IR) values, and lower quantitative insulin-sensitivity check index values. In the latter study, hypertensive, glucose-intolerant subjects also received OGTT after 15 days of daily consumption of either flavanol-rich dark chocolate or white chocolate. Dark chocolate decreased HOMA-IR, increased insulin sensitivity, and increased β-cell function compared to white chocolate.

Insulin sensitivity improved significantly in overweight and obese adults consuming high-flavanol cocoa (902 mg flavanols) for 12 weeks compared to low-flavanol cocoa ( 49). Cocoa's effects on insulin resistance may be dependent on its continual consumption over a long period of time. In one study, daily cocoa (900 mg flavanols) ingestion for 2 weeks was not sufficient to improve measures of insulin resistance, though it did improve insulin-mediated vasodilation ( 178). Almoosawi et al. found in their study, that fasting capillary whole blood glucose was significantly reduced after 2 weeks of daily dark chocolate (500 or 1000 mg polyphenols) consumption ( 6).

The evidence from these studies suggests that cocoa may be useful in ameliorating insulin resistance in metabolic syndrome and slowing the progression to type 2 diabetes. Results from other studies indicate that cocoa may also have therapeutic potential in preventing cardiovascular complications in diabetic patients. In one such study, flavanol-rich cocoa consumption three times daily for 30 days increased flow-mediated dilatation by 30% in medicated diabetics. Further, acute improvement in FMD after a single dose of cocoa was found to be dose-dependent ( 17). Although studies in humans with diabetes are lacking, a number of animal studies support beneficial effects of cocoa on glucose control ( 115, 213). Additional studies to confirm these effects in humans are needed, though there is biologic plausibility and preliminary evidence for an insulin-sensitizing effect of cocoa.

In summary, there are plausible mechanisms for the antioxidant effects of cocoa polyphenols to directly influence insulin resistance and, in turn, reduce risk for diabetes. Cocoa may induce pancreatic β-cell regeneration and stimulate insulin secretion, have a hypoglycemic effect, and improve glucose tolerance. The vasodilatory effects of cocoa can also improve insulin sensitivity mediated by endothelial function. Sustained consumption of cocoa over long periods may affect insulin resistance to a greater degree than single doses of cocoa products.

V. Effects on Immune Function and Carcinogenesis

There are no clinical trials documenting immune effects of cocoa or cocoa extracts in humans. However, preclinical evidence in mice and rats demonstrates that cocoa may exhibit some immunomodulatory effects. Ramiro-Puig et al. ( 202) demonstrated that a diet consisting of 10% cocoa can enhance antioxidant defenses in the thymus and influences differentiation of thymocytes. Other studies have found that 3 weeks of a 10% cocoa diet increases the percentage of B cells and decreases the percentage of T-helper cells in the spleen of young rats ( 200, 201). Further, gut-associated lymphoid tissue is also affected by cocoa intake-specifically, Peyer's patches and mesenteric lymph nodes that show changes in lymphocyte composition and T-helper cell percentages. It is believed that flavonoids most likely represent the active ingredients responsible for immunomodulatory effects ( 127).

In vitro, cocoa has been found to reduce secretion of TNF-α, monocyte chemoattractant protein-1, and NO by lipopolysaccharide-stimulated macrophages ( 127), with differential effects, based on fraction size, on IL-5 secretion in peripheral blood mononuclear cells ( 152). Cocoa procyanidins have also been shown to affect signaling pathways of polymorphonuclear cells, white blood cells involved in inflammation and injury ( 127). Kenny et al. demonstrated that flavanol fractions can enhance secretion of the cytokines TNF-α, IL-1, IL-6, and IL-10 from stimulated human peripheral blood mononuclear cells ( 126). Cocoa procyanidins decrease IL-2 at the transcriptional level. Ramiro et al. demonstrated that IL-4 release can be enhanced in the presence of cocoa flavonoids, thus downregulating T-lymphocyte activation and the acquired immune response ( 199).

Chronic inflammation and oxidative stress are significant contributing factors to carcinogenesis. Reactive oxygen (ROI) and nitrogen intermediates (RNI) can damage DNA or interfere with DNA repair, leading to mutations necessary for cells to avoid controls on growth and replication. Inflammation increases the production of ROI and RNI stimulated by cytokines and chemokines, and angiogenesis ( 69). Cocoa constituents, such as procyanidins and catechins, influence immune responses by modulating activation of the transcription factor NF-kB, involved in inflammatory responses, cellular proliferation, cell adhesion, and regulating cytokine production ( 149).

The antioxidant activity of cocoa flavanols is of particular interest for its potential influence on the initiation stage of carcinogenesis. In a study examining the radical scavenging capacity of 10 beverages containing antioxidants, cocoa mix ranked fifth, behind coffee, prune juice, and green tea, but ahead of grape juice and other types of tea ( 137). In another study, dark chocolate consumption significantly improved DNA resistance to oxidative stress in the short-term. In this study, Spadafranca et al. ( 239) assigned 10 healthy subjects to consume 45 g of dark chocolate or white chocolate for 14 days. Oxidative damage to DNA was reduced in the dark chocolate group 2 h after consumption; 22 h later the effects were not seen ( 239).

It has been suggested that foods containing antioxidant polyphenols, including cocoa, may have anticancer properties ( 271). In particular, the polyphenols epicatechin gallate and EGCG in green tea appear to have significant anticancer effects ( 38, 197, 283). Intake of soy, an important source of the isoflavone genistein, has been associated with up to 49% reduced risk of endometrial and ovarian cancers in women ( 182). Epidemiologic studies of cocoa intake and cancer risk are few, and those assessing overall mortality provide only weak support for a benefit of cocoa. However, human intervention trials indicate that cocoa favorably affects intermediary factors in cancer progression-specifically, markers of antioxidant status ( 155). In vitro and ex vivo studies support an anti-inflammatory effect of cocoa flavanols, but these effects have not been universally replicated in vivo ( 225). One study, a cross-over feeding trial in men and women at high risk for atherosclerosis, found that cocoa consumption was associated with reduced expression of the adhesion molecules VLA-4, CD40, and CD36 on monocyte surfaces and reduced circulating levels of the inflammatory markers soluble P-selectin and ICAM-1. However, other biomarkers of inflammation, including IL-6 and high sensitivity-CRP, were unaffected ( 172). The observed decrease in adhesion molecules is consistent with a previous cocoa study in postmenopausal hypercholesterolemic women ( 269).

Cocoa polyphenols have also been found to inhibit the mutagenic activity of heterocyclic amines in vitro and ex vivo ( 157). Kim et al. found that a cocoa polyphenol extract inhibited TNF-α (a pro-inflammatory cytokine involved in the pathogenesis of cancer) as well as VEGF expression in JB6 mouse epidermal cells. This extract reduced TNF-α-induced upregulation of VEGF by directly inhibiting phosphoinositide 3-kinase and mitogen-activated protein kinase kinase-1 activities ( 132).

There is growing evidence that polyphenols may play a role in regulating apoptosis ( 203). Apoptosis may be triggered intrinsically, through the mitochondrial pathway ( 118) or extrinsically by death ligands and receptors ( 99). It is the external pathway that may potentially be modulated by bioactive food components. Numerous dietary agents have been found to induce apoptosis in cancer cells in vitro; they include compounds in green tea, cruciferous vegetables, red pepper, grapes, and many other fruits, vegetables, herbs, and spices ( 130). Flavanols found in cocoa have also exhibited pro-apoptotic effects. Proanthocyanadins inhibited growth of human lung cancer cells in vitro and in vivo ( 230), and epicatechin synergistically enhanced apoptosis in lung cancer cells treated with EGCG ( 252). Phenol-rich cocoa extracts were found to prevent apoptosis in MLP29 liver cells induced by Celecoxib, suggesting that upstream components of the apoptotic pathway (such as the Bax gene) are targets of cocoa phytochemicals ( 11).

In summary, cocoa exhibits regulatory effects on immune cells involved in innate and acquired immunity. Cocoa is a rich source of flavonoid antioxidants, which might promote changes in redox-sensitive signaling pathways involved in the expression of many genes and consequently in several cell functions, such as the immune response. Procyanidins and catechins may prevent inflammatory and oxidative damage to DNA and thus affect carcinogenesis. No human trials demonstrate benefit in cancer treatment, though cocoa has consistently demonstrated an ability to increase serum antioxidant status, and enhance apoptosis of cancer cells, thus theoretically reducing cancer risk.

VI. Effects on the Central Nervous System

Flavonoids in cocoa have demonstrated a variety of effects in central nervous processes, and there is promising preliminary evidence for protection from neurodegradation, increased perfusion, decreased neuroinflammation, and modulation of neuronal function through interaction with a number of signaling pathways.

The pathogenesis of Parkinson's disease involves the death of neurons in the substantia nigra. This process is believed to be mediated by the formation of the endogenous neurotoxin 5- S-cysteinyl-dopamine (5- S-cys-DA) and its oxidation product, dihydrobenzothiazine, that may be produced through a mechanism involving ROS ( 242). Neuronal injury by 5- S-cys-DA is attenuated by a number of derivatives of catechin and epicatechin, including quercetin, hesperetin, and caffeic acid ( 242).

Neuroinflammation is involved in the pathogenesis of Parkinson's disease, Alzheimer's disease, and neuronal injury associated with stroke ( 111). Chronic responses in glial cells, occupying the majority of brain volume ( 133), can lead to progressive neuronal degeneration ( 5). Flavonoids may modulate this response; quercetin structurally resembles a number of kinase inhibitors that have anti-inflammatory effects in glial cells ( 240). Further, flavonoids interact with a variety of neuronal protein kinase and lipid kinase signaling cascades ( 240), and can possibly prevent excitotoxic death in neurons ( 122).

The consumption of flavonoid-enriched cocoa affects cerebral blood flow; functional magnetic resonance imaging studies demonstrate increased blood flow to gray matter 3 h after consuming cocoa as well as other changes to regional blood flow ( 77). Increased blood flow to the cerebral gray matter induces angiogenesis and new nerve cell growth in the hippocampus, a key region involved in the processing of memory ( 242). Increased blood flow velocity in the middle cerebral artery has been demonstrated, providing insights to possible protective effects against dementia and stroke ( 238).

Epicatechin induces both extracellular signal regulated kinase and cyclic AMP response element binding protein (CREB) activation in cortical neurons increasing CREB-regulated gene expression ( 221) involved in the formation of long-term memory ( 24). Flavonoids and their metabolites may interact within MAPK signaling pathways involved in mitogenesis, differentiation, apoptosis, and various forms of cellular plasticity ( 241), as well as, serine/threonine kinase, one of the key downstream effectors of phosphatidylinositol-3 kinase involved in neuronal survival ( 243).

In summation, the antioxidant properties of catechin and epicatechin derivatives can protect from neuronal injury and neuroinflammation implicated in the pathogenesis a number of neurological conditions. Cocoa can also increase cerebral blood flow, which can be neuroprotective. Further, epicatechin is involved in the processes of formation of long-term memory. These results are preliminary; clinical trials are necessary to confirm cocoa's neuroprotective effects in humans.

VII. Effects on Skin

Cocoa butter is a common ingredient in skin moisturizers, but cocoa's beneficial effects on skin may extend beyond its use as a topical agent. A number of studies have identified a role of cocoa flavanols in protecting skin from damage from UV light, believed to be mediated through factors, such as generation of ROS and inflammatory markers such as prostagladins, NO, leukotrienes, and histamine ( 276). Twelve weeks of high-flavanol cocoa consumption decreased erythema induced by UV light by 25% in one study ( 91) and specially produced high-flavanol chocolate (>600 mg flavanols and >10 000 ORAC units per 20 g portion) more than doubled the dose of UV light necessary to produce erythema in another. However, commercially available chocolate did not have this effect ( 276). The antioxidant actions of cocoa flavanols are one possible mechanism by which skin protection could be conferred. There is also some evidence that their vasodilatory effects may be important in nutrient delivery, and thermoregulation is dependent on cutaneous microcirculation ( 22). In support of this hypothesis is a study that found that consumption of high-flavanol cocoa for 12 weeks increased dermal blood flow and oxygen saturation by 70% and 80%, respectively ( 187). Though the volume of research in this area is limited, there is reason to believe that skin protection may be another possible health benefit of cocoa.

VIII. Effects on Obesity

Although chocolate may be perceived as an indulgent and fattening food because of its energy density, randomized trials have not found an increase in weight after sustained consumption of small amounts of cocoa ( 17, 49) or dark chocolate ( 256). In one study, a daily dose of 25 g (125 kcal) of dark chocolate slightly increased body weight after 3 months, but a 6 g dose (30 kcal) was not associated with any weight change. In both doses, the 24-h mean ambulatory BP decreased ( 55).

Nitric oxide (NO) has been shown to increase uptake of glucose, increase oxidation of fatty acids and glucose, inhibit fat synthesis, and enhance lipolysis in adipose tissue ( 120). Cocoa has been found to decrease visceral adipose tissue in rats, possibly by changing the expression of genes for enzymes and transport molecules involved in fatty acid synthesis and thermogenesis in liver and white adipose tissue ( 157).

Massolt and colleagues ( 156) demonstrated that the smell of chocolate could suppress appetite in humans. In their study, 12 females were given chocolate to eat and then randomized to either smell chocolate or to serve as a control (no eating or smelling). At the start of these sessions, insulin, glucagon-like peptide-1 (GLP-1), and cholecystokinin (CCK), but not glucose, were found to correlate with appetite levels. They also found that ghrelin levels correlated inversely with appetite. Chocolate eating and smelling both resulted in appetite suppression with no relationship seen between appetite levels and insulin, GLP-1, or CCK levels. Of note, the smell of dark chocolate (85% cocoa) resulted in a satiation response that was inversely correlated with ghrelin levels. As higher levels of ghrelin increase food intake and increase fat mass ( 257), these provocative findings suggest that regular cocoa and chocolate consumption may reduce appetite and possibly weight gain.

Although research to date has not specifically addressed whether cocoa may actually reduce adiposity, there is reason to believe that cocoa consumption may induce favorable metabolic changes through its effects on NO availability or lipid metabolism. The olfactory properties of cocoa may increase satiety and thus reduce appetite. Given the potential beneficial effects of cocoa on conditions frequently associated with obesity and the negligible risk of weight gain associated with effective doses of chocolate, moderate chocolate consumption appears to have a favorable risk/benefit profile for obese individuals.

IX. Psychoactive Effects

A. Chocolate craving

In addition to the wide range of somatic effects of cocoa, possible psychological effects on mood, cravings, and cognitive function have also been suggested. Much of the research on cocoa's effects on psychological variables has focused on explaining chocolate cravings, likely because chocolate is such a widely craved food. In one study, chocolate accounted for 49% of all food cravings reported by a sample of 25 healthy women ( 101). Greater chocolate craving has been reported among women than among men ( 193, 212, 289) particularly during the perimenstrual period ( 27, 212, 288), and a significant but small decline in cravings may occur after menopause ( 108). However, this association may be at least partially explained by cultural factors, as suggested by the work of Zellner et al. ( 288). They found a large and significant difference between the proportions of American and Spanish women reporting perimenstrual chocolate cravings when asked an open-ended question about timing of cravings (40% vs. 4%) or when asked directly if they experienced perimenstrual cravings (60% vs. 24%).

Cravings or increases in chocolate consumption also appear to be associated with negative mood ( 208). In a cross-sectional study, chocolate consumption was associated with higher depression scores (indicating more depressive symptoms), but whether the relationship is a causal one is still unclear ( 208). Further, individuals classified as "emotional eaters" have reported greater craving for and consumption of chocolate ( 148). Willner and colleagues investigated the relationship between depressed mood and chocolate craving in an experimental study ( 278). In this trial, 120 female college students who liked chocolate were randomly assigned to hear music intended to induce either elated or depressed mood. Before and after listening to the music, subjects completed questionnaires measuring mood and attitudes to chocolate. They were then given the opportunity to complete a computer task to earn reinforcers of chocolate or carob. Afterward, subjects completed the questionnaires once more. Subjects in the depressed condition rated their craving for chocolate significantly higher than those in the elated condition and provided significantly more responses in the computer task to receive more reinforcers when chocolate, but not carob was given. The results of this study suggest that depressed mood may increase craving for chocolate. However, the reason that chocolate cravings occur during times of emotional distress is still not clear ( 278).

Parker et al. reviewed the psychoactive properties and mood effects of cocoa in 2006, with some noteworthy conclusions ( 195). They contend that a psychoactive component of cocoa is not likely to be the cause of chocolate cravings because milk chocolate, which contains a lower proportion of cocoa solids than dark chocolate or cocoa powder, is typically preferred. Rather, the unique orosensory properties of chocolate, which are responsible for its pleasurable taste, are the most likely explanation ( 195).

The findings of Rozin and colleagues provide strong evidence that it is not the bioactive compounds in cocoa solids, but rather the particular taste and mouth-feel of solid chocolate products that satisfy chocolate cravings ( 167). In their 1993 study, a total of 34 individuals who reported experiencing chocolate cravings at least once per week were given six sequentially numbered opaque boxes and instructed to open one at each occasion of a craving, in order. The boxes contained the following treatments, in random order: (i) a 44 g milk chocolate bar; (ii) six opaque capsules containing 3.8 g cocoa powder; (iii) six opaque capsules containing 4.5g white flour; (iv) 42.7 g white chocolate; (v) 39.9 g white chocolate plus six cocoa-containing capsules; and (vi) nothing. The boxes also contained craving rating scales, which the subjects were asked to complete before, immediately after, and 90 min after consuming the given treatment. The doses of the treatments were varied according to reported usual quantity of chocolate intake. Subjects who reported typically eating one chocolate bar when they experienced a craving received the doses described above, and those who reported eating more than one chocolate bar to satisfy a craving received double the amounts for all treatments. Milk chocolate was associated with the greatest reduction in craving (61 points on the 70-point scale), whereas white chocolate and white chocolate plus cocoa capsules were associated with significantly smaller decreases (42 and 43 points, respectively). The cocoa capsules had only a minimal decrease (16 points), which was similar to the reductions observed after consumption of flour capsules and no treatment. The results of this study strongly suggest that sensory properties are responsible for the satiation of chocolate cravings.

B. Mood and cognitive function

Two studies by Macht have also supported the view that chocolate's psychoactive properties are solely taste-related ( 146, 147). These studies found that chocolate consumption can improve a negative mood state in the short-term, but that the improvement is likely attributable to chocolate's palatability ( 146, 147). In Macht's 2007 study, ingestion of a palatable chocolate improved mood significantly more than a nonpalatable chocolate, whose effects were not significantly different from the control condition (nothing eaten) ( 147). In a 2006 study, Macht found that a chocolate bar elevated mood and elicited joy to a greater extent than an apple, but these effects were most pronounced at 5 and 30 min after consumption. This suggests that the sensory experience of eating chocolate improved mood, rather than neurochemical effects, which would be expected to manifest later ( 146).

On the other hand, there is some evidence to support a psychoactive effect of flavanols or methylxanthine compounds in cocoa-effects that may extend beyond mood to cognitive function. Scholey and colleagues conducted a randomized, controlled, double-blind crossover trial in 30 healthy adults to investigate the effects of cocoa flavanol ingestion on cognitive performance, state anxiety, and mental fatigue ( 218). The three treatments tested were cocoa beverages containing 46 mg (control), 520 mg, and 994 mg of total flavanols. Both of the flavanol-rich preparations significantly increased cognitive performance and reduced mental fatigue relative to the control beverage. Smit et al. looked to cocoa's methylxanthine compounds, caffeine and theobromine, as potential mood-altering agents ( 236) in two studies. The first was designed to compare the effects on mood, alertness, and cognitive performance of encapsulated cocoa powder (CP) equivalent to a 50 g chocolate bar, isolated caffeine and theobromine (CA+TB) equivalent to a 50 g chocolate bar, and a placebo. In a second study, the treatments were 60 g portions of chocolate prepared to look identical, but contain differing amounts of methylxanthines (zero, low-, and high-methylxanthines [MX]). Cocoa powder and CA+TB both significantly decreased reaction time and increased energetic arousal compared to placebo. CA+TB also significantly increased scores on a rapid visual information processing (RVIP) task and increased hedonic tone (a measure of positive mood) compared to placebo, whereas CP was associated with a nonsignificant increase. The chocolate treatments of varying methylxanthine levels produced similar results. High MX chocolate significantly decreased reaction time, whereas both low and high MX chocolates increased RVIP scores relative to placebo. Both MX chocolates increased energetic arousal and hedonic tone more than placebo, but these differences were not significant. In a follow-up study, fondness for a novel drink increased over repeated exposures when paired with theobromine and caffeine, but not when paired with a placebo, suggesting that the methylxanthines in cocoa may also contribute to partiality for chocolate ( 235). In all three of these studies, the effect of chocolate's orosensory characteristics was controlled for.

In a randomized, double-blind, placebo-controlled trial that investigated the effects of cocoa and dark chocolate on BP, blood lipids, and C-reactive protein (all null), Crews and colleagues also assessed neuropsychological functioning in a healthy, older (≥60 years) population ( 45). Ninety participants completed the trial, which was 6 weeks in duration. During the intervention period, subjects consumed either a polyphenol-rich artificially sweetened cocoa beverage and a dark chocolate bar (754.71 mg total proanthocyanidins) or nutrient-matched placebo cocoa and chocolate daily. Eight neuropsychological tests were administered as was a self-report questionnaire to assess subjects' perceptions of changes in their cognitive functioning. There were no significant differences in any of the cognitive test measures between the intervention and placebo groups.

Martin et al. conducted a comprehensive assessment of the metabolic impact of dark chocolate consumption in 30 subjects who consumed 40 g of dark chocolate daily for 2 weeks ( 154). They found that dark chocolate had significant effects only in subjects who reported higher anxiety at the beginning of the study. In these individuals, chocolate consumption reduced urine cortisol and catecholamines and partially normalized other metabolic parameters associated with the high-anxiety trait.

More research is needed to make sense of the inconsistencies in the current literature on cocoa's psychoactive effects. Nevertheless, cocoa products are unique among potentially health-promoting foods, and they are generally considered pleasurable and may positively affect mood. Currently, research suggests that any mood improvement is likely short-lived and due to chocolate's palatability, rather than its flavanol content, concentration of methylxanthines, or other bioactive compound.

X. Bioavailability of Cocoa Polyphenols

A. Metabolism of cocoa polyphenols

Because little is known about the absorption and metabolism of polyphenols, there is increasing interest and much speculation in this area ( 46, 150, 234). Cocoa has a high concentration of proanthocyanidins, which is large relative to that of other polyphenols ( 150) and can be detected in serum 30 min after consumption of cocoa ( 106). A dose-response effect has been shown between cocoa intake and serum epicatechin levels where 100 mg catechins increased serum levels increased by 200 n M 2 h after consuming cocoa products ( 151). Wang et al. found a similar dose-response effect in plasma epicatechin associated with dose-response increases in plasma antioxidant capacity and decreases in plasma lipid oxidation products ( 268).

Some studies have indicated that oligomers larger than trimers may not be able to be absorbed in the small intestine ( 16, 54, 62). Although it is possible that procyanidin oligomers are broken down into monomers and dimers, which may be absorbed, this does not appear to occur in the stomach ( 207). Therefore, the effects of proanthocyanidins in cocoa on plasma concentrations are much lower than those of epicatechin, the predominant monomeric flavanol in cocoa ( 106). However, the antioxidant activity of proanthocyanidins may be beneficial in the colon ( 150).

Urpi-Sarda et al. found that epicatechin metabolites from cocoa accumulated in the thymus, testicles, liver, lymph nodes, and spleen in Wistar rats fed a high cocoa diet compared to control rats, suggesting that these sites are important sites of oxidation ( 264).

B. Effects of food processing on flavonoids

The caveat of consuming chocolate for its health benefits is the requirement that the chocolate or cocoa contains an effective dose of the active components. Flavonoid content varies by the proportion of cocoa liquor present in different types of chocolate (white, milk, and dark), but even within categories there may be significant variation due to differences in cocoa bean processing (). For example, cocoa liquor that has undergone more fermentation has higher concentrations of flavonoids ( 164). The extent to which cocoa beans are roasted also has a substantial impact on the antioxidant capacity of the cocoa's phenolic compounds; longer roasting time is associated with reduced antioxidant activity ( 191). However, radical-scavenging Maillard reaction products such as melanoidins are also produced during roasting, partially replacing the lost antioxidant activity of cocoa polyphenols ( 191).

Variation in antioxidant capacity can also be seen in cocoa powder ( 169). Cocoa powder is often treated with alkali to neutralize the natural acetic acid in cocoa in a process called "Dutching." This process substantially reduces the flavanol content of the cocoa. In one study of commercially available cocoa powders, the flavanol content of heavily alkalized cocoas was 78.5% lower than that of natural cocoas () ( 164, 169). With the exception of products that have undergone Dutching, most cocoa and chocolate products will contain amounts of polyphenols that are reflective of the proportion of nonfat cocoa solids present ( 170).

With the assurance that a particular cocoa product contains a biologically relevant dose of flavanols, concern about the bioavailability may remain. The addition of milk, sugar, and other substances to cocoa powder or cocoa liquor in the production of commercial cocoa drink mixes and chocolate candy may impact the bioavailability of cocoa flavanols if not their concentration. A number of studies have sought to determine whether milk affects flavanol metabolism, with somewhat mixed results ( 129, 176, 210, 211, 227). In 2003, Serafini and colleagues found that consumption of dark chocolate with 200 ml of milk attenuated the increase in plasma antioxidant capacity observed after consumption of dark chocolate alone ( 227). They hypothesized that proteins in the milk may bind to cocoa flavanols, reducing their absorption. This study was followed by a string of other studies, which found no effect of milk on the bioavailability of cocoa flavanols ( 129, 210, 211). In a 2009 study, however, consumption of 250 ml of commercial cocoa with milk was associated with reduced urinary epicatechin metabolites, though plasma metabolites were not substantially affected ( 176). Cooper et al. found that (−)-catechin is the most affected by manufacturing conditions and cocoa origin compared to other cocoa polyphenols ( 40). Belscak-Cvitanović et al. found that cocoa powder mixtures containing lower fat (10%-12%) had higher total polyphenol, total flavonoid, flavan-3-ol, and proanthocyanidin contents compared to cocoa prepared from higher fat content (16%-18%) cocoa powder ( 20).

The impact of sugar on the biological effects of cocoa has not been investigated to a great extent. Studies in humans ( 219) and rats ( 186) indicate that the consumption of cocoa with carbohydrates, including sugar, may actually increase the bioavailability of cocoa flavanols. Whether the potential negative effects of over-consumption of sugar-namely, endothelial dysfunction ( 140), insulin resistance, and weight gain ( 109)-negate any benefit of increased plasma flavanol concentrations is not yet understood. In one trial, a sugar-free cocoa beverage produced greater improvements in BP and endothelial function than a sugar-sweetened cocoa; however, the differences were not statistically significant ( 188). If artificially sweetened cocoa is determined to have greater benefit than cocoa with sugar, palatability of such products will be an important consideration. Interestingly, subjects in another study reported preferring the taste of cocoa mixtures sweetened with nonnutritive sweeteners (aspartame/acesulfame K and stevia extract) to those sweetened with sugar or glucose, suggesting that sugar-free cocoas are acceptable to consumers ( 20).

Concurrent milk consumption can affect the metabolism of phenolic acid constituents of cocoa. Urpi-Sarda and colleagues found that urinary excretion of vanillic acid and phenylacetic acid increased after milk and cocoa were consumed together, whereas urinary excretion of other components (3,4-dihydroxyphenylacetic acid, protocatechuic acid, 4-hydroxybenzoic acid, 4-hydroxyhippuric acid, and hippuric acid) was reduced ( 263).

Often cocoa products are not consumed as purchased, but rather used to make other foods, beverages, or confections. In one study, polyphenol content of cocoa powder was not substantially affected by preparation techniques used to make chocolate frosting, hot cocoa beverage, or chocolate cookies; however, after undergoing baking in a chocolate cake, natural cocoa powder retained only 5% of its epicatechin content and 54% of its antioxidant activity measured by ORAC. The reason for this is likely the increase in pH caused by the addition of baking soda ( 244).

XI. Detrimental Health Effects

Chocolate has been implicated in conditions, such as acne ( 47) and heart burn or gastroesophageal reflux disease (GERD) ( 179, 282). There is also a common perception that chocolate can be a trigger for migraines ( 279). As discussed elsewhere in this review, weight gain is also a concern when energy-dense solid chocolate is consumed regularly.

Some population-based studies suggest that dairy intake may be positively associated with acne, and clinical trials indicate that a high glycemic index or glycemic load diet may also play a role in acne severity and duration ( 25, 70). Currently, evidence does not support a link between chocolate or any other specific food and acne, though few well-designed studies have been undertaken ( 47).

The American College of Gastroenterology names chocolate as one of the foods that may contribute to GERD symptoms, though it acknowledges a lack of rigorous testing of this hypothesis ( 58). Chocolate has been found to reduce lower esophageal sphincter pressure ( 179, 282). Yet, no studies have investigated whether eliminating chocolate from the diet can improve symptoms. There is currently not sufficient evidence to suggest that dietary modifications of any kind can improve GERD symptoms or pathological measures ( 123). Interestingly, one study found that chocolate was the most often cited constipation-causing food among patients with constipation-predominant irritable bowel syndrome ( 177), but no other studies have investigated this reported effect.

It has been hypothesized that phenylethylamine, present in chocolate, could provoke a migraine ( 160, 161). The perceived association between chocolate and migraines appears to be a widely held misconception. In one study investigating trigger factors of migraines, the proportion of patients who reported having heard that chocolate could be a migraine trigger (61.7%) was significantly and substantially greater than the proportion who identified chocolate as a trigger based on their own experience (14.3%, p<0.001) ( 279). Although one small study in 1991 found that chocolate ingestion was nearly significantly associated with migraine compared with placebo ( p=0.051) ( 82), one trial conclusively found no association ( 153).

The majority of the research discussed in this review has discussed protective or health-promoting effects of cocoa or chocolate consumption. It is certainly biologically plausible for cocoa to cause detrimental effects on human health. Chocolate consumption may exacerbate symptoms of GERD or trigger migraine headaches in sensitive persons, though human trials establishing a causal relationship are scant and inconclusive. The real possibility of weight gain when overindulging in chocolate or cocoa-based foods is real, but certainly not attributable to the cocoa content.

XII. Conclusions and Implications

Cacao, the quintessential ingredient in all true chocolate and cocoa products, is a highly complex food source. As this review indicates, cacao imparts to chocolate a rich endowment of nutritional properties, from minerals, to antioxidants, to vasoactive, and even psychoactive compounds.

The tendency in Western science when a food appears to have specific health effects is to seek the active ingredient. Indeed, specific effects of chocolate may be attributable to specific constituents, such as flavonoids. However, just as the active ingredient making a food such as spinach or broccoli highly nutritious may be nothing less than spinach or broccoli, the same may be true of chocolate. The active ingredient in chocolate may be chocolate, or at least cacao, with overall health effects representing at least the sum of diverse parts.

There is, however, much interest in, and potential gain from, elucidating those parts and their mechanisms of action. begins to suggest an array of mechanistic pathways, enumerating various constituents of chocolate, and their actions at diverse sites. Numerous cytokines and enzyme systems are influenced by various polyphenols in chocolate. Some of these pathways clearly involve direct antioxidant effects, whereas others likely do not. Among the unknowns is which of the many polyphenolic compounds in chocolate exert specific effects, and this area invites further investigation.

Table 6.

Quercetin, hesperetin, and caffeic acid

↓ 5- S-cysteinyl-dopamine and its oxidation product, dihydrobenzothiazine

Endogenous neurotoxin

Cocoa polyphenols (unspecified)

↓ circulating levels of P-selectin

Inflammatory marker

Cocoa polyphenols (unspecified)

↓ circulating levels of ICAM-1

Inflammatory marker

The implications of this review-an indication of both how much is known, and how much is unknown about specific metabolic and molecular effects of chocolate-are apt to vary with professional orientation and perspective. For the public health nutritionist, the operative questions are: is there a benefit, of what kind, and for whom? There is a strong body of accumulating evidence pointing to a net health benefit from routine consumption of dark chocolate, but further epidemiologic study before such evidence is widely acknowledged as truly decisive.

For the clinician/nutritionist dealing with patients individually, the operative questions are apt to be: what dose do I prescribe, what frequency, and for whom? The notion that chocolate can serve, quite literally, as "medicine" has been espoused in the peer-reviewed literature ( 78). Before such an assertion can migrate from postulate to practice, however, the prescriptive details are required. Short-term intervention studies utilizing such outcomes as endothelial function as a proxy for likely effects on cardiovascular endpoints are eminently feasible, and needed to clarify how the potentially medicinal effects of dark chocolate might best be translated into clinical counseling.

For the nutritional biochemist, a likely focus is: what are the specific constituents of chocolate responsible for observed effects in vivo and in vitro? As suggested by , diverse constituents of chocolate are known to exert a wide array of metabolic effects of potential clinical importance. Among the compounds in chocolate with promising effects, epicatechin stands out to some degree. Although molecular, metabolic, and overall medical effects of chocolate may owe something more to the whole than to any given part, food science would, nonetheless, benefit from further study of specific parts, or compounds, both in isolation and in various combination. Insights generated might have implications for fortification and functional foods, and help food scientists answer the questions most germane to their efforts: what additions, deletions, and/or modifications enhance or attenuate favorable health effects of chocolate?

Finally, for molecular biologists, and perhaps the dedicated readers of this journal, the focus may be less on the active compounds in chocolate, than on their actions. Namely, a question of general interest is apt to be: what are the mechanistic pathways involving oxidation and reduction that mediate effects of chocolate? As noted (see pp. 9-11), the means by which chocolate ingestion results in even as well-studied an effect as enhanced endothelial function is far from certain. Polyphenols, and in particular epicatechin, are known to reduce levels of endothelin, and increase levels of nitric oxide. However, these compounds also influence gene expression, and may help preserve eNOS. Which of these effects predominates, and which has the most direct clinical significance is unknown. Molecular and genetic studies are required to elucidate further the mechanisms of chocolate's diverse metabolic effects.

In general, this review invites the question: is dark chocolate legitimately considered a "health food"? The weight of evidence reviewed here would seem to support a qualified "yes." The qualification relates both to what is known, and what is not. What is known is that chocolate, unlike spinach, carries with it the liabilities of processing, added ingredients (notably sugar), and energy density. In Western societies prone to obesity, a concentrated source of calories represents at least a potential health threat.

Thus, the benefits of chocolate consumption must be weighed against the at-least theoretical risk of weight gain. Little actual evidence of that harm exists, however, at least for dark chocolate per se.

What is not known is how best to make use of chocolate for purposes of health promotion per se. While specific quantities of fruits and vegetables may be recommended, and even alcohol prescribed with some degree of confidence, a health-enhancing dose of chocolate remains a matter of conjecture. How much of what kind of chocolate is ideal for overall health? What frequency is optimal? Are there populations in which chocolate is of particular benefit, and populations in which it is less so- or even detrimental? The differential effects of chocolate observed in those with and without established coronary disease is an area clearly warranting further examination. Perhaps constituents of chocolate can help forestall, but not treat, coronary atherosclerosis. This is as yet unknown.

What is known, however, is that apparent health benefits of chocolate consumption relate to diverse constituents of chocolate and pertain to a wide array of health outcomes. While the case is strongest for cardiovascular benefits, the immunomodulating effects of chocolate hint at potential benefits in both infectious disease and cancer. Metabolic and psychological benefits are also strongly suggested, and mechanistically plausible.

The voluminous literature addressing health effects of cocoa and chocolate, only a portion of which is represented here, is overall quite compelling. The probability of a net health benefit for most people from habitual intake of dark chocolate is high. The translation of this general theme in the literature into specific public health guidance would seem the next great challenge for the research community. The recommendations, of course, must consider the potential for weight gain and increased cardiovascular risk by consuming chocolate products containing high amounts of sugar, possibly countering some of the documented benefits of cocoa. If a dose range for alcohol intake can be established, doing so for chocolate would seem perfectly feasible. Food can be medicine, and chocolate may be a noteworthy example. However, potential in this area will not be fully realized until or unless parameters for prescription are established.

Abbreviations Used

Acknowledgments

The authors thank Lisa Rosenberger, ND, LAc, Aruna Kotla, MD, and Valentine Yanchou Njike, MD, MPH, for technical assistance. This publication was supported by Cooperative Agreement #U48 DP000053 from the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention.

References

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Cocoa and Chocolate in Human Health and Disease

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Cocoa contains more phenolic antioxidants than most foods. Flavonoids, including catechin, epicatechin, and procyanidins predominate in antioxidant activity. The tricyclic structure of the flavonoids determines antioxidant effects that scavenge reactive oxygen species, chelate Fe2+ and Cu+, inhibit enzymes, and upregulate antioxidant defenses.

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This article convinced me there is some evidence-based research that wine can have some positive health effects. In this research, both HDL and sleep quality improved in wine drinkers over the mineral water-drinkers.

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Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial - PubMed

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European Foundation for the Study of Diabetes.

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Since this post contained many memes, I chose one to focus on, which was Apple Cider Vinegar and weight loss. This linked article summarized a systematic literature search, which ultimately revealed that research is insufficient to conclude if Apple Cider Vinegar is effective for weight loss.

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Safety and side effects of apple vinegar intake and its effect on metabolic parameters and body weight: a systematic review - PubMed

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Due to inadequate research of high quality, the evidence for the health effects of AV is insufficient. Therefore, more large-scale, long-term clinical studies with a low risk of bias are needed before definitive conclusions can be made.

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NCI's fact sheet on artificial sweeteners contains some useful information for consumers. It covers all of the artificial sweeteners that we are commonly encountering in the U.S. Focusing on sucralose to compare the article above, there is currently no clear and consistent evidence that it causes negative health consequences in the current recommended amounts. This fact sheet does not compare natural sugar to each artificial sweetener.

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What are artificial sweeteners?

Artificial sweeteners are chemically synthesized substances that are used instead of sucrose (table sugar) to sweeten foods and beverages.

Because artificial sweeteners are many times sweeter than table sugar, much smaller amounts (200 to 20,000 times less) are needed to create the same level of sweetness. The caloric content of sweeteners used in such tiny amounts is negligible, which is why they are sometimes described as nonnutritive.

Six artificial sweeteners are approved by the US Food and Drug Administration (FDA) as food additives: saccharin, aspartame, acesulfame potassium (acesulfame-K, or Ace-K), sucralose, neotame, and advantame. Before approving these sweeteners, the FDA reviewed numerous safety studies that were conducted on each sweetener to identify possible health harms. The results of these studies showed no evidence that these sweeteners cause cancer or other harms in people.

Do animal studies suggest a possible association between artificial sweeteners and cancer?

Concerns about artificial sweeteners and cancer initially arose when early studies linked the combination of cyclamate plus saccharin (and, to a lesser extent, cyclamate alone) with the development of bladder cancer in laboratory animals, particularly male rats.

Most studies of the other approved artificial sweeteners have provided no evidence that they cause cancer or other adverse health effects in lab animals.
Cyclamate
As a result of the findings of early studies of cyclamate, it was banned in the United States in 1969. Although subsequent reviews of those experimental data and evaluation of additional data led scientists to conclude that cyclamate does not cause cancer, it has not been reapproved in the United States (although it is approved in many other countries).
Saccharin
Laboratory studies have linked saccharin at high doses with the development of bladder cancer in rats, and, as a result, in 1981 saccharin was listed in the US National Toxicology Program's Report on Carcinogens as a substance reasonably anticipated to be a human carcinogen. However, mechanistic studies (studies that examine how a substance works in the body) have shown that the ways in which saccharin causes cancer in rats do not apply in humans, and in 2000 it was removed from the list. (For more information on the delisting of saccharin, see the Report on Carcinogens, Fifteenth Edition.)
Aspartame
In 2019, an international scientific advisory group gave aspartame a high priority for review by the International Agency for Research on Cancer (IARC) Monographs program during 2020-2024 ( 1). At a June 2023 meeting, an international expert working group classified aspartame as Group 2B, "possibly carcinogenic to humans." This category is used when there is limited, but not convincing, evidence for cancer in humans or convincing evidence for cancer in experimental animals, but not both. In the case of aspartame, IARC found "limited" evidence of an association with liver cancer in humans and "limited" evidence from animal studies and studies of a possible mechanism ( 2).

The Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA) also met in June 2023 to perform an independent risk assessment of aspartame to potentially update the findings of its 2016 evaluation. Based on the evidence from animal and human studies, JECFA concluded that aspartame has not been found to have adverse effects after ingestion and did not change its recommendations on acceptable daily intake. It noted that aspartame is broken down in the gastrointestinal tract into metabolites that are identical to those of common foods and that no mechanism has been identified by which oral exposure to aspartame could induce cancer, thus it concluded that a link between aspartame exposure in animals and cancer could not be established.

In response to the IARC categorization, the FDA noted that it had identified significant shortcomings in the studies on which IARC based its conclusions and that it disagreed with IARC's conclusion that the data support classifying aspartame as a possible carcinogen.

What have studies shown about possible associations between artificial sweeteners and cancer in people?

Epidemiologic studies (studies of patterns, causes, and control of diseases in groups of people) have examined possible associations between intakes of artificial sweeteners and risks of several cancers in people. Although studies of this type are essential in identifying exposures that are associated with cancer, they have limitations in establishing a causal relationship. For example, people who differ in their consumption of artificial sweeteners may also differ in other ways, and it could be these other differences that account for their different cancer risks. Evidence for a causal relationship is stronger when multiple studies have generally similar results and when there is evidence for a biological mechanism that accounts for the connection.
Artificial sweeteners overall
A variety of individual studies and meta-analyses have evaluated associations of artificially sweetened beverages with the risk of cancer overall and with the risk of individual cancer types.

The results of these studies have been inconsistent. For example, intake of artificially sweetened beverages was associated with an increased risk of kidney cancer in a US cohort of postmenopausal women ( 3) but not in a European cohort of healthy adults ( 4). An "umbrella review" (a review of systematic reviews or meta-analyses) that took into account the quality of the included studies found only weak evidence for an association between intake of artificially sweetened beverages and either development of or death from any cancer ( 5).

A cohort study conducted in France called the NutriNet-Santé Study looked at intake of artificial sweeteners from all dietary sources and found that persons who consumed the greatest amounts of artificial sweeteners were slightly more likely to develop cancer than those who did not consume artificial sweeteners ( 6).

Because some studies have suggested that artificial sweeteners are associated with obesity, and obesity is in turn linked to at least 13 types of cancer, the NutriNet-Santé investigators also looked for associations between artificial sweetener intake and obesity-related cancers as a group. The risk of obesity-related cancers was slightly higher in people who consumed higher amounts of all artificial sweeteners than in those who did not consume artificial sweeteners. By contrast, an Australian cohort study found no association between artificially sweetened beverage intake and the risk of obesity-related cancers ( 7).
Saccharin
No clear evidence for an association between saccharin use and bladder cancer incidence in humans has emerged from epidemiologic studies. The results of these human studies contributed to the delisting of saccharin from the Report on Carcinogens.
Aspartame
The 2023 IARC finding of a possible association of aspartame with liver cancer in humans relied on data from three studies of four cohorts that looked at associations with artificially sweetened beverages during time periods in which such beverages mainly contained aspartame ( 8- 10). One of the studies ( 8) found an association with liver cancer risk in the whole cohort, whereas a second ( 9) found an association among persons with diabetes. The third found no association with liver cancer ( 10). After the IARC expert panel met, a fourth study that examined artificially sweetened beverages and the risk of liver cancer also found no association ( 11).

Other large cohort studies have not shown a clear association of aspartame with risk of cancer. These include the NIH-AARP Diet and Health Study, in which higher consumption of aspartame-containing beverages was not associated with the development of lymphoma, leukemia, or brain cancer during more than 5 years of follow-up ( 12). A 2013 review of the epidemiologic evidence published between January 1990 and November 2012 also found no consistent association between the use of aspartame and cancer risk ( 13).

The NutriNet-Santé cohort study, which looked at aspartame intake from all dietary sources, found that adults who consumed higher amounts of aspartame were slightly more likely to develop cancer overall, breast cancer, and obesity-related cancers than those who did not consume aspartame ( 6).
Sucralose
A range of studies have found no evidence that sucralose causes cancer in humans ( 14). The NutriNet-Santé cohort study did not find an association between sucralose intake and risk of cancer ( 6).
Acesulfame potassium
The NutriNet-Santé cohort study reported that adults who consumed acesulfame-K had a slightly higher risk of cancer overall as those who did not consume acesulfame-K ( 6). No other studies have examined whether acesulfame-K is associated with cancer in people.
Neotame and advantame
Neotame and advantame are derived from aspartame. No studies have reported on human cancer risks associated with either of these artificial sweeteners.

Do artificial sweeteners contribute to/play a role in obesity?

People may use artificial sweeteners to reduce the total calories they consume in their diet as part of an effort to avoid overweight and obesity, conditions that have been linked to at least 13 types of cancer. Concerns have been raised that some artificial sweeteners might increase obesity, potentially having an indirect effect on cancer risk, although the findings are mixed ( 15). For example, in a small randomized clinical trial of adults with overweight or obesity, participants who drank beverages containing sucrose or saccharin had a significant increase in body weight whereas those who drank beverages containing aspartame, rebA (highly purified stevia, a natural plant-based sweetener), or sucralose did not ( 16). However, a systematic review and meta-analysis of 17 randomized controlled trials found that substituting low- and no-calorie sweetened beverages for sugar-sweetened beverages was associated with small improvements in body weight ( 17).

In May 2023, the World Health Organization recommended against the use of non-sugar sweeteners to control body weight, based on a systematic review of the evidence.

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A fact sheet that reviews research studies on the possible connection between artificial sweeteners and cancer.

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The forbes article gives some inforamtion regarding sweeteners and points out some comparisons with real sugar. The misspelled Chron's Disease (Crone's) doesn't do anything in the way of credibility, although references and sources at the bottom of the page are supplied and most appear to be scholarly.

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Where do I start? Marie Osmond, a celebrity American sweetheart, has been pushing the Nutrisystem program for years. This video found on YouTube is sad. Marie says, "I was overweight, and that is unacceptable!" The word unacceptable to label oneself due to obesity is unacceptable, but this isn't the time to get on that soapbox. The ad touts 'metabolism burning shakes' and 'craving crusher shakes' without telling you what they contain. This ad targets women in the Baby Boomer generation who want to lose weight fast without having to plan on their own or change the way they think about food and nutrition. I didn't see any scholarly references in the commercial to back up the claims being made.

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This publication outlines a randomized clinical trial that ultimately showed that protein powder was beneficial for healthy older men.

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A whey protein-based multi-ingredient nutritional supplement stimulates gains in lean body mass and strength in healthy older men: A randomized controlled trial | PLOS ONE

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Protein and other compounds can exert anabolic effects on skeletal muscle, particularly in conjunction with exercise. The objective of this study was to evaluate the efficacy of twice daily consumption of a protein-based, multi-ingredient nutritional supplement to increase strength and lean mass independent of, and in combination with, exercise in healthy older men. Forty-nine healthy older men (age: 73 ± 1 years [mean ± SEM]; BMI: 28.5 ± 1.5 kg/m2) were randomly allocated to 20 weeks of twice daily consumption of either a nutritional supplement (SUPP; n = 25; 30 g whey protein, 2.5 g creatine, 500 IU vitamin D, 400 mg calcium, and 1500 mg n-3 PUFA with 700 mg as eicosapentanoic acid and 445 mg as docosahexanoic acid); or a control (n = 24; CON; 22 g of maltodextrin). The study had two phases. Phase 1 was 6 weeks of SUPP or CON alone. Phase 2 was a 12 week continuation of the SUPP/CON but in combination with exercise: SUPP + EX or CON + EX. Isotonic strength (one repetition maximum [1RM]) and lean body mass (LBM) were the primary outcomes. In Phase 1 only the SUPP group gained strength (Σ1RM, SUPP: +14 ± 4 kg, CON: +3 ± 2 kg, P < 0.001) and lean mass (LBM, +1.2 ± 0.3 kg, CON: -0.1 ± 0.2 kg, P < 0.001). Although both groups gained strength during Phase 2, upon completion of the study upper body strength was greater in the SUPP group compared to the CON group (Σ upper body 1RM: 119 ± 4 vs. 109 ± 5 kg, P = 0.039). We conclude that twice daily consumption of a multi-ingredient nutritional supplement increased muscle strength and lean mass in older men. Increases in strength were enhanced further with exercise training.

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Although this influencer didn't verbally cite any sources, I felt like he was providing information that seemed reliable and at the very least could be fact checked. Unfortunately, at the end of the video, he promoted his own brand of protein powder, which gave the whole video an undertone of a sales pitch. He seems to be targeting anyone who will listen and potentially purchase his product.