Chocolate vs. CFS: flavanols and beyond

There have now been several preliminary studies testing the effects of phytochemical-rich plants in ME/CFS, some of which show benefit (discussed later). Of these, I find the 2010 trial with chocolate particularly intriguing ¹.

This was a very small pilot trial (UK, n=10 CFS, Fukuda criteria + severe fatigue; no mood disorders, no drugs) to test the effect of polyphenol-rich chocolate for 8 weeks on symptoms. It had a double-blind, placebo-controlled, crossover design (8–2–8), with several subjective outcomes; and high methodological quality in a recent systematic review ². The active treatment arm had an improvement in fatigue, anxiety, depression and disability (pre–post effect: –35%, –37%, –45% and +31%, respectively); anecdotally, 2 people with short illness duration even returned to work ¹. For reference, this is a greater reduction in fatigue, depression and anxiety than over a year of CBT or GET in the large PACE trial (UK, n=641 CFS, multiple criteria), which used some of the same outcome measures ³.

Despite all this, the cocoa trial has barely been cited in CFS research, let alone replicated, suggesting a general lack of interest. It was obviously very small in size and measures, being a preliminary study. Perhaps participant age and BMI also tend toward the higher end, but they seem within range of epidemiological studies ^4–6. Caveats and scepticism aside, I’m interested in how it might work.

Mechanisms?

Chemically, cocoa is rich in various things, including minerals (e.g. magnesium and iron), xanthine alkaloids (e.g. theobromine and caffeine) and flavanol polyphenols (e.g. catechins and procyanidins). The CFS trial specifically used a chocolate supplied by Nestlé with a high polyphenol content, especially epicatechin. The active arm consumed 45g/day chocolate (68% cocoa liquor), containing 55.35mg epicatechin (45x 1.23mg/g) ¹. Assuming similar analysis, this might be equivalent to that in about 97g of commercial dark chocolate (Lindt 85%) ⁷ or 38g of pure non-alkalised cacao ⁸.

Symptom improvements in the trial suggest general effects on mood and function, which could be connected to changes in any specific areas (e.g. brain, muscle, immune, autonomic, etc.). The absence of biomarkers precludes evidence of specific pathways, while the authors speculated on modulation of neurotransmitters and oxidative stress, by cocoa cannabinoids and flavonoids respectively ¹.

In the general research literature, many studies on cocoa are now available. In vitro, cocoa has antioxidant, antimicrobial ⁸ and antiviral activity ⁹, while in vivo, cocoa has effects on many systems/organs—below are some brief examples of human trials which seem relevant.

• Blood. In healthy humans, cocoa has acute antioxidant ¹⁰ and anti-inflammatory activity ¹¹, while boosting nitric oxide and circulation ^12,13. Systematic reviews and meta-analyses of RCTs with cocoa products (~50–100mg EC) support improvements to blood flow (FMD), blood pressure, lipid profiles, insulin sensitivity and inflammation ^14,15. Further, in trials on healthy adults, 4 weeks of flavanol-rich cocoa capsules (23, 46 and 92mg EC) had dose-dependent effects on other redox and lipid markers (incl. GSH, OxLDL and AA/EPA ratio) ¹⁶; and 3 weeks cocoa consumption increased (post-vaccination) NK cell activity ⁹.
• Brain. Several recent trials suggest cocoa may benefit brain function (for review see ¹⁷). For instance, trials in healthy adults have shown that acute or chronic consumption of flavanol-rich cocoa (89–185mg EC) improves cerebral blood flow ¹⁸, mood and cognition ¹⁹, in relation to dentate gyrus function ²⁰, insulin sensitivity ²¹ and BDNF ²². Note, in a trial on older adults, cognitive improvements were equivalent to about 3 decades of life (press release) ²⁰.
• Muscle. A recent systematic review of 13 trials concluded that cocoa flavanol supplementation improves vascular function, lowers exercise-induced oxidative stress and alters metabolism, but not performance in athletes ²³. However, further notable effects have been reported in some subpopulations. In people with heart failure and type-2 diabetes, 3 months epicatechin-rich cocoa (100mg EC) normalised skeletal muscle redox and mitochondrial markers ^24,25. Similarly, in normal sedentary subjects, dark chocolate (26mg EC) improved skeletal muscle markers and exercise performance ²⁶.

Unfortunately, there seem to be scarce trials on conditions often comorbid with ME/CFS (e.g. fibromyalgia, IBS and mood disorders) ^5,6. However, ME/CFS has been compared to MS, where there have been a couple. The first was a small randomised trial (n=12 MS) finding improved fatigue in the hours after a dark cocoa drink ²⁷. A subsequent larger placebo-controlled trial (n=40 RRMS) with cocoa for 6 weeks had a small effect on fatigue, but moderate effect on fatigability (walk test) and redox biomarkers (GSH?) ²⁸. Note, these trials used commercial products (i.e. G&B and Aduna, respectively), likely with lower flavanol content than many above.

Flavanols

How does cocoa produce these effects? In some trials, the nutrient content of cocoa is tightly controlled so as to only vary flavanol levels, suggesting they mediated improvements to gut microbiota ²⁹, blood markers ^21,22,29, brain function ^18–22 and MS fatigue ²⁸. Other studies have specifically identified epicatechin as a mediator of vascular effects in humans ^12,13, and improvements to muscle redox, mitochondria and fatigue resistance in animal models ^24,30,31.

Flavonoids come in many shapes and sizes with divergent metabolism. Cocoa flavanols consist of monomers (e.g. catechin and epicatechin) and oligomers (e.g. procyanidin B and C). Generally, monomers are partially absorbed in the small intestine ³² and responsible for acute effects ^12,13, while unabsorbed flavanols (esp. polymerisation >2) are metabolised by the gut microbiome to γ-valerolactones, which can then be absorbed and exert bioactivity ^33–36. Consequently, flavanols also modulate the gut microbiome. For instance, a 4 week trial showed cocoa flavanols have prebiotic effects, by increasing beneficial bacteria (Lactobacilli and Bifidobacteria) and suppressing others (Clostridium histolyticum) ²⁹. Further, the increased Lactobacilli correlated a drop in CRP, supporting a link with systemic anti-inflammatory activity ²⁹. Therefore, the effects of flavanols may largely occur via their metabolites and the microbiome ^32–36.

Regarding metabolic effects, 2 animal studies with metabolomics revealed induction of NAD synthesis. In the first, dietary proanthocyanidins (incl. catechins and procyanidins) dose-dependently boosted de novo NAD synthesis and SIRT1 activity in the liver ³⁷. In the second, dietary epicatechin reversed age-related declines in gene expression, including NAD metabolism in blood and muscle ³⁸. Preclinical studies show that NAD⁺/SIRT positively regulates many facets of health (e.g. mitochondria, redox, inflammation, insulin sensitivity, endothelial function, BDNF ³⁹, etc.) and retards ageing ⁴⁰. Cocoa flavanols may also promote redox homeostasis via stimulation of the Nrf2 pathway (e.g. in vitro ^41,42 and vivo ^30,43), which regulates over 250 genes (incl. glutathione and mitochondria ⁴⁴) and declines during ageing ⁴⁵. Note, in trials on older people, precursor repletion normalises glutathione and several aspects of ageing (e.g. redox, mitochondria, lipids, insulin sensitivity, inflammation and body composition) ^46–48. On the other hand, in a recent trial on young adults, high-dose pure epicatechin (200mg/day) inhibited aerobic adaptations to cycling exercise ⁴⁹. This seems similar to some other trials with high-dose antioxidants and may be due to the excessive dose or isolation ^49,50.

Finally, while flavanols seem responsible for many beneficial effects of cocoa, other components may also contribute. For instance, cocoa is also rich in the methylxanthine theobromine and to a lesser extent caffeine, which have stimulatory effects. At some level theobromine may start to modulate heart rate, vascular function, cognition ⁵¹ and immunity ⁵². Methylxanthines also appear to enhance flavanol absorption and vascular effects ⁵³.

Beyond cocoa…

Cocoa is remarkable for being among foods with the highest antioxidant and polyphenol content ⁵⁴, and the richest source of several flavanols. However, flavanol content varies in relation to cacao bean and processing (e.g. alkalisation); note, most trials above used high-flavanol cocoas provided for research (e.g. Mars/Cocoapro ^{12,13,18–22,29,53} and others ^{10,11,16,24,25} vs commercial ^9,26–28). Excessive consumption of cocoa methylxanthines could also produce undesirable stimulatory effects. Therefore it may be useful to consider a broader dietary context.

Lower levels of flavanols are present in many foods (Phenol-Explorer), which would contribute to overall intake. For instance, other sources of monomeric catechins include cider apple (EC), broad beans (EC) and green tea (EGCG); and oligomeric procyanidins include peach (B1), apples (B2), quince jelly (B3) and broad bean (B4). Moreover, flavanols are a type of flavonoid within the larger class of polyphenol, which contains many other molecules capable of favourably modulating the microbiome ^33,35,36 and metabolism (e.g. NAD/SIRT ^55,56). Accordingly, in 2 controlled trials, 1 with increasing high-flavonoid (>15mg/100g) fruit and veg consumption (n=154 adults, CVD risk), and another high-flavanol cocoa (n=40 older adults), both increased blood BDNF and improved global cognitive function ²².

It’s also worth noting that other foods can affect the activity of polyphenols. For instance, carbohydrates can increase bioavailability and bioactivity ^57,58, whereas in some studies milk/dairy was obstructive (e.g. cocoa ^10,11,59, tea ⁶⁰, coffee ⁶¹ and blueberry ⁶²). Note, several cocoa studies not finding effects of milk used very high doses of flavanols, beyond typical dietary levels ⁵⁹.

Ultimately, several broad classes of phytochemicals (e.g. terpenoids, phenolics and glucosinolates) contain many molecules with overlapping and beneficial effects on health. These are generally plant secondary metabolites with protective functions, which may transfer when eaten, as suggested by evolutionary theories of xeno- ⁶³ and para-hormesis ^64,65. In particular, phytochemicals may help protect against environmental stress, disease and ageing by supporting homeostasis, for instance via favourable modulation of microbiome and metabolic pathways discussed above. This seems highly relevant to the aetiology and pathology of ME/CFS, which can involve prolonged infection, dysbiosis, immune activation, oxidative stress and general dysregulation.

ME/CFS studies

Could other phytochemicals be beneficial in ME/CFS? Interestingly, this has been explored in many animal models. These studies show that various stressors (e.g. chronic activity and immune stimulation) can induce CFS-like behaviours (representing fatigue and pain) and related pathology (e.g. inflammation and oxidative stress), which can all be prevented by various phytochemical extracts (e.g. olive extract ⁶⁶, curcumin ⁶⁷, naringin ⁶⁸ and EGCG ⁶⁹). Further, some studies show delayed treatment can reverse CFS-like behaviours and restore biomarkers (e.g. BDNF, SIRT1, Nrf2 and redox) ^70–72. So generally these studies support the idea that many phytochemicals (incl. polyphenols and ginsenosides) can ameliorate chronic stressor-induced dysfunction and disease (in rodent models).

However, human ME, CFS or ME/CFS is complex, contains varied aetiology, symptoms and comorbidity ⁵, and there are few trials. These include placebo-controlled (pollen extract ⁷³ and cocoa ¹), controlled (Robuvit ^74,75) and uncontrolled trials (curcumin ⁷⁶), all of which seemed to improve symptoms. With regard to biomarkers, the relatively larger trials with Robuvit lowered symptoms and oxidative stress (d-ROMs) within 3 months ⁷⁴ and 4 weeks ⁷⁵. Robuvit (French oak extract) contains 20% roburins, a type of ellagitannin polyphenol. Ellagitannins and ellagic acids are present in several foods (e.g. some berries, nuts and pomegranate) and metabolised by the gut microbiota to urolithins, which can be absorbed and persist in blood for days, where they may exert systemic effects (e.g. anti-inflammatory, antioxidant, autophagy, etc.) ^36,77.

So all considered, perhaps there is at least some preliminary indication that various phytochemicals (esp. polyphenols) might be able to improve some aspects of ME/CFS, and perhaps via similar biological effects and pathways as cocoa discussed earlier? Moreover, since these pathways are involved in many chronic diseases and ageing, perhaps there is potential for more general benefit to comorbidities and healthspan?

Resources

• Phenol-Explorer (top 100 sources)
• List of phytochemicals in food

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