Chocolate: My Favorite Vegetable

Beatrice A. Golomb, MD, PhDwith

Eric Brown

"Nine out of ten people like chocolate…

"The tenth person always lies." - John Q. Tullius

Till recently, popular

perceptions negative –

taking your life in your hands

The Rap• High in saturated fat - Bad for cholesterol

• High in sugar - Bad for insulin/ diabetes

• High in calories - Makes you fat

• Which makes you slothful

• Plus, it gives you cavities

• These should hurt heart health

• And overall health

• Flip side: good for your mood

• Makes you happier and therefore nicer

Obesity / “BMI”

Slothful

Blood Sugar…

People ate chocolate despite presumed health effects

My therapist told me the way to achieve true inner peace is to finish what I start. So far today, I have finished 2 bags of M&M’s and a chocolate cake. I feel better already.

– Dave Barry

But mindful of putative benefits to mood

"Chocolate makes everyone smile - even bankers." ~ Chocolatier Benneville Strohecker

Emerging Alternative View: Chocolate provides any number of important

dietary elements

Principles• Prefer outcomes that balance risks &

benefits -- to the patient (e.g. all-cause mortality; not single cause or class)

• Prefer long-term follow-up. (Shortterm can be opp. to longterm effects)• RCT best: 2nd is prospective longitudinal.• Require Data: but Think Physiologically!• Beware: Not all chocolate is alike!• Accompaniments differ, and carry their own

health ramifications: Nuts; dairy; sugar amount; trans fats; etc.

Chocolate “Types”

Cocoa Butter

+ -

+ Dark

Chocolate*

Cocoa

- White chocolate

White

baking bar*Add milk-> milk chocolate

(or, chocolate milk)

**Add cream -> mousse!

CHOCOLATE is a vegetable Antioxidant via phytonutrients1,2 BP3-5 Insulin resistance3-5, • Improve cholesterol profile6

Inflammation (women)6

Coronary artery diameter7 (on angio)• Supply many interesting compounds1.Vinson 2006 J Agric Food Chem 54:8071 2. Spadafranca 2010 BrJNutr 103:1008 3.Grassi 2005 AmJClinNutr 81:611

4. Grassi 2005 Hypertension 46:398 5.Grassi 2008 J Nutr 138:16716. Hamed 2008 SouthMedJ 101:1203 7 *Flammer 2007

Circulation116:23768. Nogueira 2011 J Physiol 589: 4615

Blood pressure: RCTDesign: Meta-analysis of RCTsSs: 173 (from 5 studies)Exposure: Cocoa productsControl: Cocoa-free controlsDuration: Median 2 weeksOutcome: Blood pressureResult:(mean pooled) SBP: -4.7 mm Hg* (95%CI -7.6 to -1.8 mmHg) DBP: -2.8 mm Hg* (95%CI -4.8 to -0.8 mmHg) Taubert 2007 Arch Intern Med 1657:626 "Effect of cocoa and tea intake on blood pressure: a

meta-analysis"

Blood sugar/ insulin Design: Double-blind RCTSs: 118 (59/group) diabetic (Type-2) post-menopausal women

(on statin plus glucose-lowering drug)Exposure: High-Flavonol chocolate*, 27g/d splitControl: Callebaut regular chocolate, 27g/d splitDuration: 1 yearOutcomes: 1. Insulin. 2. Insulin resistance: HOMA (homeostatic assessment of IR)3. Insulin sensitivity (QUICK-IS: quant IS index)Result: Insulin: -0.8 ± 0.5 mU/L P=0.02 HOMA-IR: -0.9 ± 0.2 P=0.004 QUICK-IS: +0.003 ± 0.00 P=0.04*27 g/day (split dose) flavonoid-enriched chocolate (with 850 mg flavan-3-

ols [90mg epicatechin] & 100mg isoflavones [aglycone equivalents)]/d)

Curtis 2012 Diabetes Care 35: 226 (Flavonol enriched chocolate…)

CholesterolDesign: Double-blind RCTSs: 118 (59/group). Post-menopausal women w/ type 2

diabetes, on statin plus glucose-lowering drugExposure: Hi-Flavonol chocolate*, 27g/d splitControl: Callebaut regular chocolate, 27g/d splitDuration: 1 yearOutcomes: Ratio of Total chol (TC):HDL; LDL-cholesterol.

Result:Cholesterol Effect of Enriched vs Regular Chocolate TC:HDL -0.2 ± 0.1 P = 0.01 LDL -3.9 +/- 3.9mg/dL P = 0.04

*27 g/day (split dose) flavonoid-enriched chocolate (with 850 mg flavan-3-

Curtis 2012 Diabetes Care 35: 226 (Flavonol enriched chocolate…)

Obesity / “BMI”• Comes with fat and sugar • Indulgence

CHOCOLATE vs BMIHypothesis: Frequent modest chocolate is

calorie neutral: extend to BMI the metS benefits of chocolate

Ss: 1018 adults (694 men, 324 women) w/o DM or CAD, from San Diego

Design: Cross-sectional Exposure: Chocolate times/weekOutcome: BMI (measured weight & ht)Covariates: Age, sex, calories, activity, sat fat,

moodResult: More frequent chocolate eaters: more

calories, no more exercise BUT weigh less!Golomb et al 2012. "Association Between More Frequent Chocolate

Consumption & Lower Body Mass Index." Arch Intern Med 172: 519-21

Finding: Better than wt neutral. Might Chocolate Make you Thinner?Chocolate Frequency

Association to BMI Adjustment Modelβ p

-0.14 0.01 Unadjusted

-0.13 0.02 Age-sex adjusted

-0.13 0.01 Age-sex-activity

-0.15 0.01 (Age-sex-activity-calories)

-0.19 0.001 Age-sex-activity-sat.fat

-0.20 0.001 Age-sex-activity-sat.fat-CESDGolomb et al 2012. Arch Intern Med 172: 519-21

CHOCOLATE vs BMICan't presume causality BUT:-- Rationale guided conduct of study-- No identified "confounders" to explain-- Rodent studies concordant-- In humans, benefit to other metabolic

parameters-- Emailed after study was published by a

researcher who did an RCT of chocolate, and unexpectedly found sev lbs wt loss in the chocolate vs control group, among overwt but not normal wt subjects

SO: there are prospects for causality.

“What you see before you is the result of a lifetime of chocolate” -Katherine Hepburn

Exercise?

Cocoa derived epicatechin in mice: Lean muscle mass, Fat mass, "Mitochondrial Biogenesis" Muscle "Vascularity"

Exercise mimetic?

Nogueira 2011 J Physiol 589: 4615-31 "(-)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle"

Villarreal 2010 "Chocolate: an exercise mimetic?" Southwest Chapter American College of Sports Medicine 2010 Annual Meeting, Oct 22, San Diego.

If chocolate is an exercise mimetic, putting chocolate in your mouth might

actually work in lieu of exercise

Chocolate Milk & EnduranceDesign: Crossover RCTSubjects: 9 trained male cyclistsChocolate "intervention": "chocolate milk" CM: Chocolate milk = Mars Refuel, 459± 53mL, 62.9±7.2g, FR: Fluid replacement = Gatorade, 526.3±60.4 mL, 30.7±3.5g CR: carb replacement:Endurox R4, 526.3±60.4 mL, 72.5±8.3gOutcome: Cycle duration. (3 trials of glyogen depleting, 4hr recovery, cycle to exhaustion. Intervention @ 0&2hr recoveryResult: CM: 32 ± 11 min FR: 23 ± 8 min, p = 0.01 CR: 21 ± 8 min, p = 0.01 CM -> cycled 43% and 51% longer than w/ FR & CR

Thomas 2009 "Improved endurance capacity following chocolate milk consumption compared with 2 commercially available sport drinks" Appl Physiol Nutr Metab 34: 78-82

Exercise?"The divine drink which builds up resistance and fights fatigue. A cup of this precious drink permits a man to walk for a whole day without food." – Hernando Cortés, 1519

Heart HealthDesign: Prosp Cohort (Zutphen

Elderly Study) 1

Ss: 470 elderly menF/U: 15 yrsExposure: Top vs bottom third of

Cocoa consumption (estimated fm cocoa-containing foods)

Result: Cardiovascular death:

RR: 0.50 (0.32-0.78) P = .004

1 Buijsse 2006 Arch Intern Med; 166:411.Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study

Heart HealthDesign: Prosp Cohort 1

Ss: 1169 Swedes 45-70 w/ 1st-MI, no DMF/U: 8 yrsExposure: chocolate in prior 12mo. Never, <1/mo, 1/wk, 2+/wkOutcome: cardiac deathResult: Dose Heart Deaths (compared to no choc.) 0 1.0 <1/mo 0.73 (.3-1.3) 1/wk 0.56 (.32-.99) 2+/wk 0.34 (.17-.70)

1 Janszky 2009 J Intern Med 266: 248-57. "Chocolate consumption and mortality following a first acute myocardial infarction: the Stockholm Heart Epidemiology Program."

Heart FailureDesign: Prospective CohortSs: 31,823 women 48-83 (Sweden) -- No hx diabetes, heart failure, MIF/U: 9 yearsChocolate: Consumption by quartilesOutcome: Heart failureAnalysis: "Survival analysis"Result: 379 hospitalized + 40 died, of HF 1-2 "servings" per week = optimal HR: 0.68 (95%CI 0.50-0.93) More than daily: nothing (trend unfavorable)1 Mostofsky 2010 Circ Heart Fail 3: 612-6 Chocolate intake and incidence of heart failure: a population-based prospective study of middle-aged and elderly women

StrokeDesign: Prospective Cohort (mammography cohort)

Subjects: 33,372 Swedish women age 49-83.

Follow-up: 10.4yrs ave.

Chocolate: FFQ 1997, chocolate on ave over prior year. Quartiles to group chocolate.

Lowest <8.9g/wk. Highest >45g/wk (mean 66.5)

Outcome: Strokes over 1 yr (1998): Covariates: Many Age, education, smoking, BMI, activity, aspirin

use, hx HTN, dx atrial fibrillation, FH premature heart disease, alcohol, coffee, tea, total calories, fresh red & processed red meat, fruit, vegetables,

Larsson 2011 JACC 58 1828-9. Chocolate consumption & risk of stroke in women

StrokeStroke Type Risk, hi vs low chocolate quartile

Only hi quartile benefit: All 0.8 (0.66-0.99) p =0.01 (for trend) Infarction 0.83 (0.66-1.04) p =0.04 Hemorrhagic 0.58 (0.34-1.00) p =0.04Comment: >45g/wkvs <9. Only hi quartile benefited median

66.5 g/week (chocolate equivalent to ~15 “kisses”)Comment: Same result RR for stroke= 0.8, in 2012 meta-analysis of prospective

studies, men & women, >100,000 people†

Larsson 2011 JACC 58 1828-9. "Chocolate consumption and risk of stroke in women."

†Larsson 2012 Neurology 79:1223-9. "Chocolate consumption and risk of stroke: A prospective cohort of men and meta-analysis."

Brain - MoodPopular perception that when people need a pick-me-up,

they pick up chocolate.

~No evidence, hitherto.

Denise Mann 2010 "Study: Chocolate and depression go hand in hand", CNN Health.com Apr 26 http://www.cnn.com/2010/HEALTH/04/26/chocolate.depression/index.html

Brain - MoodDesign: Cross-Sectional

Subjects: 1018 adult men and women 20-85 years

Chocolate measure:

Times/wk (SSQ). Time/mo (FFQ). Servings/mo (FFQ)

Outcome: Center for Epidemiological studies – Depression Scale. Cutoff at 16 = used as a screening cutpoint for depression.

Result:

Higher chocolate linked higher depression

Rose N, Koperski S, Golomb B 2010. "Mood Food: Chocolate and Depressive Symptoms in a Cross-sectional Analysis." Arch Intern Med 170(8) : 699-703

Mood • BG add here from choc chapter

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CES-D <16

CES-D 16-21

CES-D ≥22

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CES-D Men CES-D Women

All Men WomenWithin Panels: Times/wk, Times/mo (FFQ), Servings/mo

MoodCESD <16 CESD 16 Rel. Diff

(%)P

Chocolate (g) 5.4 (8.8) 8.4 (15) 56. .004

Fat (g) 68 (40) 75 (46) 9.5 .17

KCalories 1681 (791) 1785 (958) 6.2 .24

C'hyde (g) 187 (91) 198 (109) 5.9 .28

Caffeine (mg) 148 (147) 158 (155) 1.1 .70

Rose, Koperski, Golomb 2010 Arch Intern Med 170(8) : 699-703

CHICKEN OR EGG?

Short term – mood benefits*

*Macht 2007 Appetite 49: 667

Mood Mechanisms:Factoid: Chocolate has substances that bind

“cannabinoid receptors” in the brain* I suggest it is the “chocolate receptor;” The intended ligand is chocolate, & regular

binding is essential for good neurochemical health. Some of us see no need for"special" brownies

. *di Tomaso 1996. Brain cannabinoids in chocolate. Nature; 382:677-8.

Cannabinoids

"Researchers have discovered that chocolate produces some of the same reactions in the brain as marijuana.

“The researchers also discovered other similarities between the two, but can't remember what they are."

--Matt Lauer

. *

Mood Mechanisms (MM)Anandamine, N-oleoylethanolamine N-

linoleoylethanolamine*Polyphenols (antioxidation)Altered copper balance: Copper FungicidesMethylxanthines (boost mood; anxiogenic in excess)

Theobromine Caffeine (also: Sleep Effects)Withdrawal: amines, methylxanthinesTetrahydro-beta carbolines: potential neuroalkaloidsMicroflora contamination Magnesium repletion.Biogenic amines Phenylethylamine Ethylamine Synephrine Serotonin Histamine Isobutylamine Tyramine Normetanephrine Octopamine Tryptamine• Millen MM, Golomb BA 2012 "Chocolate: Mood" Chapter 30 in Nutrition and

Health Springer Science+Business Media, LLC• *Fatty acid cannabinoid agonists

Biogenic Amines?

AggressionDesign: Cross-sectionalSubjects: 1018 adults (San Diego), 20-85Exposure: Chocolate times/weekOutcome: 1. Overt Aggression Scale (a): behavioral aggression

against others, self, or objects in the last week. 2. Road rage: tally of increasingly severe behaviors

engaged in (last 2 weeks) (0-10, max seen=7) 3. Impatience (self-rated, 0-10)Covariates: age, sex, smoking, alcohol

Golomb et al 2011. "Chocolate consumption is linked to aggression." Circulation suppl 173 P53

AggressionChocolate Effect,

per time/week

βSEP

OASMa +0.180.06 0.005

Impatience +0.090.03 0.004

Road Rage +0.110.03 <0.001

Ordinal Logistic Regression:

Adj. for age sex smoking alcohol

β = regression coefficient. SE = standard error

P = probability effect could occur by chance

Golomb et al 2011. "Chocolate consumption is linked to aggression." Circulation suppl 173 P53

Aggression

MemoryDesign: Cross-sectional (="slice in time")Subjects: 1018 men + women (age20-85)Chocolate: Times/week. Mean 2±2.5 (0-20) Memory: Word recall test (number correct). Mean 86±8.Analysis: RegressionAge-interaction effect: P<0.001 (I.e. relation of chocolate to memory differs w age)Covariates: Age, sex, exercise, calories Trans-fats, LDL-chol, depression (CES-D)Result: if age< 50, chocolate memoryGolomb et al 2012: Circulation 126:A16156 More Frequent Chocolate Consumption is Linked to Better Word Memory

Chocolate-MemoryImprovement per chocolatex/wk

(SE) P

Unadjusted 0.64 (.17) <0.001

Age, sex 0.66 (.18) <0.001

Age, sex, exercise 0.67 (.18) <0.001

Age, sex, exercise, calories 0.78 (.22) 0.001

All Above+transfat, LDL 0.83 (.22) <0.001

All above+CES-D* (depression) 0.89 (.24) <0.001

NO tested covariate approached similar significance as a predictor"Food for Thought"?Golomb et al 2012: Circulation 126:A16156 More Frequent Chocolate Consumption is Linked to Better Word Memory

Cognitive RCTDesign: Double-blind RCT (1:1:1 randomization)Subjects: 90 Alzheimer's Unit patients w/ MCI mild cognitive impairment (Petersen criteria). (Exclude statin users)Chocolate "intervention": Hi, med, low flavanol chocolate. High and Med used Cocoapro processed cocoa powder. Low used highly processed alkalinized cocoa. HF: 990 mg flavanols MF: 520mg LF: 45mgDuration: 8 weeksOutcomes: 1 Trails A/B 2.Fluency words/timeResults (HF vs LF chocolate): Trails A+B time: 38±11 vs 53±18 seconds p<0.05 Verbal fluency: 28 vs 22 words/min p<0.05Desideri, 2012 "Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment: The Cocoa, Cognition, and Aging (CoCoA) Study" Hypertension 60: 794-802

Pre-Carious? Or the opposite?Cavities form when specific cavity-promoting

bacteria feed on carbohydrates & produce a slime layer of water-insoluble "glucan" by which they adhere firmly to the tooth, & produce acid that leads to local demineralization of the tooth

Cocoa polyphenols significantly biofilm (slime) formation & acid production by cavity-forming bacteria (Streptococcus mutans & S. sanguinis).

Cocoa substances added to water powerfully cavity & plaque formation in rats. Ferrazzano 2009 Fitoterapia 80: 255-62 "Anti-cariogenic effects of polyphenols from Ooshima 2000 Arch Oral Biol 45: 639-45 Ito 2003 Biosci Biotechnol Biochem 67: 2567-73

Pre-Carious? Or the opposite?Although killjoy David Beighton (Professor at King's

College, London) stated "Good oral hygiene, rather than eating lots of chocolate, is the way to good healthy teeth" (Quoted in a BBC story on the cavity-fighting benefits of cocoa products.)

Author Ooshima thinks cocoa substances should be added to toothpaste,

mouthwash.

Ferrazzano 2009 Fitoterapia 80: 255-62: Ooshima 2000 Arch Oral Biol 45: 639-45Ito 2003 Biosci Biotechnol Biochem 67: 2567-73 BBC News Aug 24, 2000 Chocolate 'fights' tooth decay

CHOCOLATE & SKINDesign: Dbl blind placebo-controlledSubjects: 30 adults (22women)Interv: 15 high flavonol Belgian chocolate, chocolate droplets

(Acticoa method, preserves flavonols), 20g/d x 12 wksControl: 15 conventional chocolate droplets, 20g/d x 12 wksOutcome: MED=min erythema dose UVB(280-320nm)

Result: Double the min erythema dose w "HF" chocolate (p=0.005), not placebo (P= 0.5)

Williams 2009 J Cosmet Dermatol 8 : 169-73. "Eating chocolate can significantly protect the skin from UV light"

Survival

“I have this theory that chocolate slows down the aging process…It may not be true, but do I dare to take the chance?” --Unknown

CHOCOLATE & MORTALITYDesign: Prosp Cohort (Zutphen Elderly Study) 1

Ss: 470 elderly menF/U: 15 yrsExposure: Highest vs lowest tertile Cocoa

(estimated fm cocoa-containing foods)Outcome:All death (314)Result: All Deaths: 0.53 (0.39-0.72) P<.001

1 Buijsse 2006 Arch Intern Med; 166:411. "Cocoa intake, blood pressure, and cardiovascular mortality: the Zutphen Elderly Study"

Women and Chocolate

"After about 20 years of marriage, I'm finally starting to scratch the surface of what women want. And I think the answer lies somewhere between conversation and chocolate."

– Mel Gibson

But benefits extend to men. Rebranding?

Not Just for Women

CaveatsChocolate comes with

“stuff”

• Dairy (Milk chocolate)

• Nuts

• Coffee

• Cinnamon (Mexican chocolate)

• Trans fats

The Rap• Bad for cholesterol?

• Bad for blood sugar?

• Makes you fat?

• Hinders exercise?

• Causes cavities

• These should hurt heart health?

• And overall health and survival?

• Good for your mood?

The R(ec)ap:

• Mood & aggression: associations unfavorable• Good for blood pressure• Good for insulin sensitivity• Good for cholesterol• Maybe good for BMI (animal exp + human observ’l)• Not “pre-carious” (prevents cavities, apparently)• Good for physical function (exercise)• Good for brain function (e.g. memory) • Favorable link to heart disease & stroke• Associated with longevity The (almost) perfect vegetable

Concluding Remarks"The superiority of chocolate, both for

health and nourishment, will soon give it the same preference over tea and coffee in America which it has in Spain."

- Thomas Jefferson

"Chemically speaking, chocolate really is the world’s perfect food."

• – Michael Levine, nutrition researcher

Or, the Ideal Medicine?

This no longer seems entirely facetious

As Recognized by our Forebears

"Chocolate is a divine, celestial drink …, panacea and universal medicine."

-- Geronimo Piperni (1796; quoted by Spanish army surgeon)

ChocolateAn important food group.

Incorrect. This neglects one other important food,

My other favorite vegetable: Coffee

Thank You!• Thanks to Eric Brown, who contributed

substantially to this talk

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Conflict of Interest

The chocolate industry doesn't give us money; rather, vice versa.