How I Circumvented Coffee's Negative Effects on Brain Function

how coffee affects the brain I drink a lot of coffee. Three cups a day on most days.

The health benefits of coffee have received a lot of attention in the last decade. And for good reason. Coffee does seem to reduce the risk of later developing Parkinson’s disease 2 and other neurological conditions. Coffee also delivers a potent blend of hundreds of antioxidants, which has a neuroprotective effect on the brain.

As an example, here’s the phenolic content of coffee:

Table 1. Antioxidant Composition of Coffee

mean contentminmaxSDnNnumber of references
Phenolic acids
Hydroxycinnamic acids3,4-Dicaffeoylquinic acid2.66 mg/100 ml2.662.660111
3,5-Dicaffeoylquinic acid1.55 mg/100 ml1.551.550111
3-Caffeoylquinic acid51.80 mg/100 ml4063.616.69222
3-Feruloylquinic acid4.17 mg/100 ml4.174.170111
4,5-Dicaffeoylquinic acid2.05 mg/100 ml2.052.050111
4-Caffeoylquinic acid59.60 mg/100 ml5366.219.34222
4-Feruloylquinic acid8.57 mg/100 ml8.578.570111
5-Caffeoylquinic acid70.03 mg/100 ml47.899625.76444
5-Feruloylquinic acid11.69 mg/100 ml11.6911.690111
Caffeic acid0.03 mg/100 ml00.130.06444
Other polyphenols
Alkylmethoxyphenols4-Ethylguaiacol0.64 mg/100 ml0.640.640111
4-Vinylguaiacol0.46 mg/100 ml0.460.460111
Alkylphenols3-Methylcatechol0.10 mg/100 ml0.080.110.02331
4-Ethylcatechol0.13 mg/100 ml0.090.160.04331
4-Methylcatechol0.04 mg/100 ml0.020.050.02331
MethoxyphenolsGuaiacol0.16 mg/100 ml0.160.160111
Other polyphenolsCatechol0.41 mg/100 ml0.040.70.28442
Phenol0.12 mg/100 ml0.120.120111
Pyrogallol0.54 mg/100 ml0.390.780.21331

But most people don’t address coffee’s downsides. Believe it or not, coffee has some under-recognized negative effects on brain function.

In this post, I’ll discuss the two key drawbacks of regular coffee consumption. I’ll also provide some actionable tips to mitigate the downsides of coffee. Warning: this post gets fairly neuroscience-heavy by the end, so I’ll try to keep things light in the beginning.

I should also quickly mention that there are a few disadvantages to coffee consumption that I never address. These omitted negatives are coffee’s mild hypertensive effect and the fact that it can interfere with good sleep quality.

Downside #1: Coffee Markedly Suppresses Cerebral Blood Flow

It’s no secret that coffee tends to impair blood flow in the brain 3. Researchers have been investigating this phenomena for decades.

In order to function optimally, your brain needs to be well-perfused. There’s no way around it. Severely restricted blood flow leads to ischemia. Blood carries hemoglobin, which carries oxygen into nervous tissues.

The brain is highly metabolically active. It’s constantly using energy, even while you’re sleeping or engaged with nothing in particular. (The brain’s activity at rest is called the ‘default mode network’).

That’s why evolutionary biologists like to think of the brain as being energetically expensive. Being smart must be really important from an evolutionary standpoint to justify such insane energy expenditure.

Here’s a relevant abstract, about the vasoconstrictive effect of caffeine. Vasoconstriction is just narrowing of blood vessels, which increases blood pressure.

Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. We investigated the effects of caffeine on cerebral blood flow (CBF) in increasing levels of chronic caffeine use. Low (mean = 45 mg/day), moderate (mean = 405 mg/day), and high (mean = 950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state, there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. Our results suggest a limited ability of the cerebrovascular adenosine system to compensate for high amounts of daily caffeine use.

Cerebral vasoconstriction refers to the reversible narrowing of blood vessels in the brain. Stimulants are well known to be vasoconstrictive, and the worst offender is amphetamine.

To summarize the above study, the authors reported that caffeine reduced cerebral blood flow by 27%.

What’s The Workaround?

cacao nibs how coffee affects the brain

Cacao nibs oppose caffeine-induced suppression of cerebral blood flow. I take cacao with my coffee to restore blood flow to the brain.

My view is that the effects of coffee on brain function are net positive.

But coffee’s tendency to impair cerebral blood flow seriously detracts from the beneficial effects.

I’ve found a great way to circumvent this deleterious effect of caffeine. The answer is consuming cacao nibs (or cocoa extract) along with coffee.

Cacao is a nootropic in its own right. Cacao also markedly enhances cerebral blood flow in healthy volunteers1. By what mechanism?

Cacao’s antihypertensive effect is via induction of nitric oxide synthase (NOS).  As its name implies, NOS synthesizes nitric oxide, which is a gasotransmitter and vasodilator. Nitric oxide is a natural (endogenous) vasodilator, meaning that it lowers blood pressure and opposes other molecules like norepinephrine that constrict blood vessels.

You might find this abstract interesting (I certainly do):

The effect of flavonol-rich cocoa on the fMRI response to a cognitive task in healthy young people (2006)

Flavonols are the main flavonoids found in cocoa and chocolate, and can be especially abundant in certain cocoas. Research over the past decade has identified flavonols as showing diverse beneficial physiologic and antioxidant effects, particularly in context of vascular function. The present study employed functional magnetic resonance imaging based on blood oxygenation level-dependent (BOLD) contrast to explore the effect of flavonols on the human brain. Magnetic resonance imaging was used to measure BOLD responses to a cognitive task in 16 healthy young subjects. The data presented show an increase in the BOLD signal intensity in response to a cognitive task following ingestion of flavonol-rich cocoa (5 days of 150 mg of cocoa flavonols). This may arise either as a result of altered neuronal activity, or a change in vascular responsiveness, or both–the net effect then being dependent on which of the two effects is dominant. No significant effects were evident in behavioral reaction times, switch cost, and heart rate after consumption of this moderate dose of cocoa flavonols. A pilot study evaluated the relationship between cerebral blood flow and a single acute dose (450 mg flavonols) of flavonol-rich cocoa and showed that flavonol-rich cocoa can increase the cerebral blood flow to gray matter, suggesting the potential of cocoa flavonols for treatment of vascular impairment, including dementia and strokes, and thus for maintaining cardiovascular health.

So, the idea is that taking cacao along with coffee can offset some of the cerebral vasoconstriction/impaired blood flow that caffeine causes.

Downside #2: Caffeine May Hinder BDNF

This is where things get a little neuroscience-heavy. The take home message is that because caffeine is an adenosine receptor blocker, it may hinder the beneficial effects of brain-derived neurotrophic factor (BDNF) on cognitive function. At this stage, it’s unclear whether this interaction is clinically significant or mere speculation.

Brain-Derived Neurotrophic Factor (BDNF) can be crudely understood as fertilizer for the brain. In keeping with this view, we expect BDNF to both promote long-term potentiation (LTP) and concomitantly suppress long-term depression (LTD). LTP is the Hebbian activity-dependent strengthening of synapses.

Tiago M. Rodrigues et al. found that BDNF-related suppression of LTD requires Adenosine(A2) receptor activity. Put differently, BDNF failed to activate its endogenous receptor Trk B and suppress LTD in the presence of an adenosine antagonist or when adenosine was depleted by treatment with the enzyme adenosine deaminase. These results raise intriguing questions about whether the most widely-used psychoactive drug caffeine might interfere with the neurotrophic fate of BDNF, since caffeine is an antagonist at all adenosine receptor subtypes. Moreover, we may speculate that because adenosine accumulates during wakefulness and is a natural sleep promoting substance, the antidepressant effect of acute sleep deprivation may be in part dependent on adenosine boosting the synaptic effects of BDNF – a neuropeptide with well-characterized antidepressant properties.

Read on:

Hippocampal Long-Term Potentiation (LTP) is orchestrated by Brain-Derived Neurotrophic Factor (BDNF) through activation of tropomyosin-related kinase B (TrkB) receptors. Emerging evidence highlights the importance of the BDNF / Trk B signal transduction pathway in the formation of long-term memory, synaptic plasticity, regulation of neurogenesis and trophic support for neurons. Mice genetically engineered to lack BDNF suffer developmental defects in the central and peripheral nervous systems, suggesting BDNF plays a critical role in neural development.

trk bTrk B is the endogenous receptor for BDNF, and ligand binding with BDNF triggers autophosphorylation. Activation of the dopamine receptor D5 and the excitatory N-methyl-D-aspartate receptor (NMDAR) are the two most important neural events in promoting the expression of BDNF in cortical neurons. Although antidepressants are a heterogeneous class of medications, their mechanism of action converges on BDNF-associated autophosphorylation of Trk B, as does the antidepressant effect of exercise. Moreover, both the tricyclic antidepressant imipramine and the natural flavonoid 7,8-dihydroxyflavone are direct agonists at the Trk B receptor. Finally, genetic abnormalities in BDNF, like the Val66Met single-nucleotide polymorphism (SNP) have been linked to vulnerability to stress-related mental illnesses like PTSD and major depressive disorder.

Tiago M. Rodrigues' group reported that the influence of BDNF on TrkB receptors is under strict control of adenosine via A(2A) receptors. Adenosine is an endogenous metabolite of adenosine triphosphate (ATP), the molecular unit of intracellular currency. Astrocytes form a so-called “tripartite synapse” with three components: the presynaptic terminal, postsynaptic terminal and the astrocyte. During gliotransmisison, the astrocytes release extracellular ATP which is hydrolyzed to ADP and finally adenosine; hence astrocytes constitute the largest source of extracellular adenosine.

tripartite synapse

Adenosine plays an important role in sleep homeostasis or how the brain “keeps track” of prior sleep debt. Sleep is increasingly being understood as a local (i.e., occurring at the level of individual neural networks), use-dependent process whereby extracellular adenosine accumulates as a byproduct of normal neural activity (gliotransmission).

The accumulation of adenosine during daytime activity corresponds to the increase in sleep pressure (fatigue) that culminates in the evening, triggering the biphasic sleep/wake switch. (Adenosine is a sleep promoting substance, so levels are highest before bed and lowest in the morning, when sleep pressure has been dissipated). Put simply, adenosine levels may be one way that the CNS tabulates how much sleep debt must be “payed back.” The local, use-dependent nature of sleep protects neurons from being worked to death and raises questions about whether specific neural subpopulations or circuits might “sleep” while the entire organism is awake.

Now let’s return to the role of adenosine in Trk B signaling. Under physiologic conditions, BDNF promotes synaptic strengthening by inhibiting long-term depression (LTD). Rodrigues’ group induced LTD using Low-Frequency Stimulation (LFS, 900 pulses, 1 Hz) in the CA1 area of rat hippocampal slices, and as expected, found that LTD was significantly attenuated when these slices were treated with BDNF (60-100 ng/mL).

caffeine Next, Rodrigues’ group showed that the effect of BDNF on LTD was prevented by K252a, a potent inhibitor of Trk B autophosphorylation, suggesting that the effect of BDNF on LTD requires activation of Trk B. Finally, BDNF lacked an inhibitory effect on LTD under selective A(2AR) blockade and in an adenosine depleted background with adenosine deaminase. Taken together, these results suggest that A(2A)R activation is required for BDNF dependent suppression of LTD, and raise questions about what effects ubiquitous adenosine receptor-modulating substances like caffeine may have on BDNF / Trk B signaling.

  1. Francis ST, Head K, Morris PG, Macdonald IA. The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol. 2006;47 Suppl 2:S215-20.

  2. Derkinderen P, Shannon KM, Brundin P. Gut feelings about smoking and coffee in Parkinson’s disease. Mov Disord. 2014;29(8):976-9.

  3. Addicott MA, Yang LL, Peiffer AM, et al. The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?. Hum Brain Mapp. 2009;30(10):3102-14.

comments powered by Disqus



Subscribe to BrainProTips

Get the latest posts delivered right to your inbox.

or subscribe via RSS with Feedly!