The mystery of caffeine

Here’s a good riddle for you:

Many epidemiological studies have suggested that coffee/caffeine consumption reduces one’s risk of developing Parkinson’s. Study after study has suggested that drinking coffee is beneficial.

Recently, however, Japanese researchers have discovered something really curious: people with Parkinson’s have reduced levels of caffeine in their blood compared to healthy controls… even when they have consumed the same amount of coffee. (???)

In today’s post we will look at what coffee is, review the results of this study, and try to understand what is going on.


Kaldi the goat herder. Source: CoffeeCrossroads

Legend has it that in 800AD, a young Ethiopian goat herder named Kaldi noticed that his animals were “dancing”.

They had been eating some berries from a tree that Kaldi did not recognise, but being a plucky young fellow – and being fascinated by the merry behaviour of his four-legged friends – Kaldi naturally decided to eat some of the berries for himself.

The result: He became “the happiest herder in happy Arabia” (Source).

This amusing encounter was apparently how humans discovered coffee. It is most likely a fiction as the earliest credible accounts of coffee-consumption emerge from the 15th century in the Sufi shrines of Yemen, but since then coffee has gone on to become one of the most popular drinks in the world.

Silly question, but what exactly is coffee?

For a person who doesn’t drink coffee (like myself), this is actually a really interesting question. Coffee is a beverage made from ground up roasted beans, which are the seeds of berries from the Coffea plant.

These are the berries:


Coffea berries. Source:

These are the beans (unroasted) from inside the berries:


Unroasted Coffee beans. Source: Kopiholic

And these are the coffee beans after roasting:

Roasted Coffee beans. Source: Guatefriends

Coffee production makes for fascinating reading (Click here for more) and why we roast the beans is equally interesting (Click here for that), but those matters are taking us off message here.

There are basically two types of coffee beans: Arabica and Robusta.

Approximately 70 percent of the coffee beans we use are Arabica. Surprisingly, the less popular Robusta actually has twice as much caffeine as Arabica. And caffeine is the stimulant that rewards people for drinking this beverage.

And what exactly is caffeine?

Caffeine is the world’s most widely consumed psychoactive drug. And we consume a lot of it.

The UK currently consumes 165 million cups of tea daily (that is 60.2 billion per year). Each cup contains 40mg of caffeine, but more if the tea is left to brew longer. They also consume 70 million cups of coffee per day. About 70 per cent of this is instant coffee containing around 60mg of caffeine per cup (Source). Collectively, that’s a lot of caffeine per day.

The Red Bull energy drink contains 31.98mg of caffeine per 100 ml of liquid (thus one 250 ml can of Red Bull Energy Drink contains approximately 80mg of caffeine).

Red bull (Not paid advertising). Source: Redbull

More specifically, caffeine is a methylxanthine-class stimulant.

What does that mean?

Methylxanthines are a unique class of drug that are derived from the purine base xanthine. Xanthine is a compound that is naturally produced by both plants and animals.

The stimulant Theobromine (present in chocolate) is also a methylxanthine. Caffeine penetrates the blood-brain barrier (the protective membrane surrounding the brain) more readily than theobromine. Curiously though, theobromine is a more potent cardiac stimulant than caffeine (you would have thought this would be the other way around, huh?).

The most prominent role of caffeine is as a nonselective competitive blockade of adenosine A1 and A2A receptors. Consequently blocking these receptors prevents the onset of drowsiness induced by adenosine – hence the reason people feel more awake after drinking caffeinated coffee.

Source: Slideplayer

But be warned, you can have too much of a good thing: Consumption of 1–1.5 grams per day is associated with a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after caffeine use.

Having said that, a bit of caffeine each day has been shown to have positive effects on Parkinson’s.


Fancy a cuppa? Source: Science-All

What do we know about caffeine and Parkinson’s?

We have previously discussed the enormous contribution that the Honolulu Heart Study has made to our understanding of Parkinson’s (click here to read that post). Many of the earliest associations with the condition were found in that large epidemiological study. And one of those findings was that the consumption of coffee reduced one’s risk of developing Parkinson’s.


Title: Association of coffee and caffeine intake with the risk of Parkinson disease.
Authors: Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR.
Journal: JAMA. 2000 May 24-31;283(20):2674-9.
PMID: 10819950               (This article is OPEN ACCESS if you would like to read it)

The researchers behind this article analysed the data from the Honolulu Heart Study – an epidemiological study of 8,006 “non-institutionalized men of Japanese ancestry, born 1900-1919, resident on the island of Oahu” – and found that the age-adjusted incidence of Parkinson’s declined consistently with increased amounts of coffee intake (from 10.4 per 10,000 person-years in men who drank no coffee to 1.9 per 10,000 person-years in men who drank at least 28 oz/d). This and other findings in their analysis indicated that higher coffee (and caffeine) intake is associated with a significantly lower incidence of Parkinson’s.

Subsequent studies have replicated this association, and several have demonstrated the neuroprotective effects of caffeine (click here for a review on this topic).

Has caffeine ever been clinically tested on Parkinson’s?

Yes, it has:

Title: Caffeine for treatment of Parkinson disease: a randomized controlled trial.
Authors: Postuma RB, Lang AE, Munhoz RP, Charland K, Pelletier A, Moscovich M, Filla L, Zanatta D, Rios Romenets S, Altman R, Chuang R, Shah B.
Journal: Neurology. 2012 Aug 14;79(7):651-8.
PMID: 22855866               (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators conducted a six-week randomised, controlled trial of caffeine in Parkinson’s. Specifically, they wanted to assess effect of caffeine upon :

  • daytime somnolence
  • motor severity
  • non-motor features

The participants (with daytime somnolence as determined by Epworth Sleepiness Scale score of >10) were given 100 mg of caffeine twice daily for three weeks, then 200 mg twice daily three weeks, or a matching placebo treatment. 61 people with Parkinson’s were recruited to the study. 31 of them were randomly assigned to the placebo treatment, while the other 30 went on to be part of the caffeine group.

After three weeks, the researchers found that the caffeine treated group had a nonsignificant reduction in their sleepiness score. They also reported that caffeine treatment resulted in significant changes in bradykinesia and rigidity, but it did not increase tremor. It also caused no significant difference in fluctuations or dyskinesia; nor did it have any effect on quality of life, depression, or sleep quality. The investigators concluded that the “potential motor benefits suggest that a larger long-term trial of caffeine is warranted”.

Interestingly, another open-label clinical study conducted at the same time reported very similar results (Click here to read more about that study). Another clinical study of caffeine in Parkinson’s found that while caffeine improved freezing of gait in some subjects, a tolerance developed to the beneficial effect. That is to say, the effect lost its strength over time. But the researchers reported that a 2-week caffeine withdrawal period could restore the effect of caffeine (Click here to read more about this).

Overall, the clinical studies have suggested that caffeine has a mild effect on Parkinson’s.

How can it reduce the risk of Parkinson’s, but then only have a mild effect once someone is diagnosed?

Well, recently a research report was published that could partly explain this:

Title: Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease.
Authors: Fujimaki M, Saiki S, Li Y, Kaga N, Taka H, Hatano T, Ishikawa KI, Oji Y, Mori A, Okuzumi A, Koinuma T, Ueno SI, Imamichi Y, Ueno T, Miura Y, Funayama M, Hattori N.
Journal: Neurology. 2018 Jan 30;90(5):e404-e411.
PMID: 29298852             (This article is OPEN ACCESS if you would like to read it)

In this study the researchers analysed levels of caffeine and 11 products that result from its metabolism (called metabolites) in the serum from 108 people with Parkinson’s and 31 age-matched healthy controls (using mass spectrometry). Serum is the component of blood that is neither a blood cell nor a clotting factor. If you spin a test tube sample of blood at high speed, the cells will sink to the bottom exposing the serum.

The separation of blood cells and serum. Source: Emaze

The researchers assessed caffeine consumption and determined concentrations as 60 mg per cup of coffee, 30 mg per cup of tea, and 20 mg per cup of green tea. They found no difference in caffeine consumption between the two groups of participants (115mg/day for the controls and 107mg/day for the PD group).

When the investigators took a closer look at the serum they collected, they found that levels of caffeine and 9 of the 11 metabolites were significantly decreased in the people with Parkinson’s. The caffeine level were an average of 79 picomoles per 10 microlitres for people without Parkinson’s, compared to 24 picomoles per 10 microlitres for people with the condition. One of the metabolites had such low levels in more than 50 per cent of the people with Parkinson’s that accurate measure could not be made. Regardless of their total caffeine intake, people with Parkinson’s had less caffeine in their serum. And this effect was also present in people who had recently been diagnosed.

Serum levels of the caffeine metabolite 1-methyluric acid did not differ between the two groups, but serum of another caffeine metabolite 1,3,7-trimethyluric acid levels were much higher in the Parkinson’s group than in the control group. One difference within the Parkinsonian population that they noticed was that caffeine concentrations in people who had motor complications were significantly decreased compared with those without motor complications.

The researchers found no significant genetic variations (in the CYP1A2 or CYP2E1 genes, which provide the instructions for enzymes primarily involved in the metabolising of caffeine in humans) in any of the individuals involved in the study. They also could not see a difference based on the ADORA2A gene (which provides the instructions for the adenosine 2A receptor). Caffeine inhibits adenosine 2A receptor activation (Source), and inhibition of the adenosine 2A receptor can have beneficial effects on motor symptoms. This all suggested that no fault in the metabolism of caffeine and no issues with the sensitivity of the adenosine 2A receptor could explain the mysterious reduction in caffeine levels in the serum of people with Parkinson’s. The investigators concluded that lower levels of caffeine (and caffeine metabolites) could be a promising diagnostic biomarker for early Parkinson’s.

What does it all mean?

I like mysteries.

And this is a REALLY good mystery.

Why do people with Parkinson’s have such low levels of caffeine in their blood… even when they drink the same amount of coffee as control subjects???

At present, we don’t know the answer.

Perhaps there is something happening in the gut? As the researchers suggest in the discussion of the study: Gastrointestinal issues (such as constipation) affects up to 80% of people with Parkinson’s. Caffeine is mainly absorbed in the small intestine, where bacterial overgrowth is associated with levodopa absorption issues in Parkinson’s which can lead to motor fluctuations – Source.

Thus it is possible that something is changing in the gut.

It will be interesting to see if other research groups around the world can replicate this finding, or if it is specific to certain populations of people. It will also be necessary to have another look at some of the ‘gut bacteria in Parkinson’s’ studies to see what if anything could be extracted from that data to help explain this strange result.

Ultimately, however, if the effect is independently replicated (which shouldn’t take too long), then this low level of caffeine in the serum of blood could represent a novel biomarker – perhaps even an early indicator of Parkinson’s. Only time will tell. Let’s see the result replicated first.

The banner for today’s post was sourced from Youtube



  1. Kevin McFarthing (@InnovationFixer)

    Hi Simon – here’s another RCT on caffeine, CafePD, reported last year as an MDS abstract – and in Neurology – . Dr Postuma is the first author, as in the reference from 2012 you quote above.

    It shows no difference in motor scores after 6 months, and a potential worsening of cognitive scores and dyskinesia.



  2. Pingback: Café ! | Carnet

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