Friederike Ostermeyer

November 19, 2025, 3:05 pm | Read time: 5 minutes

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Several large observational studies report a 20 to 25 percent lower risk of depression with regular coffee consumption.¹ That’s good news for fans of the black pick-me-up. Yet, the insidious disease can strike anyone. Medications often alleviate symptoms, but it takes weeks for them to work. Sometimes, standard antidepressants don’t work at all. In such cases, ketamine or electroconvulsive therapy (ECT) can bring improvement within hours. To the researchers’ surprise, both methods have the opposite effect on the brain compared to coffee. How can this be? A new study from China² has addressed this question and discovered something surprising.

This is what the researchers wanted to find out

The central question was: How can ketamine and electroconvulsive therapy work so quickly, while patients need a lot of patience with traditional medications? Is there a common “switch” that triggers the rapid antidepressant effect? What exactly happens in the brain? And this is where coffee comes into play. The researchers discovered a system in their study that frequently consumed caffeine also affects, but in a completely different way. Researchers Julio Licinio and Ma-Li Wong found this so-called coffee paradox so remarkable that they wrote a scientific commentary³ about it.

Also interesting: Drinking coffee late can significantly disrupt sleep

The power of adenosine receptors

Back to the actual study. For a long time, it was unclear what mechanism was behind the methods with ketamine and ECT. Therefore, they administered a therapeutic dose of ketamine to mice and conducted an ECT-like electrical stimulation. Through precise real-time measurements in their brains, they observed a rapidly rising adenosine level in brain areas associated with depression. This important messenger signals our need to sleep so that the body and brain can recover. It also has a calming effect on nerve cells and reduces stress. Causality checks, where the receptors were removed or blocked, showed that this adenosine surge is necessary for the effect. Subsequently, the researchers developed variants that triggered even stronger signals with fewer side effects. Another important finding: Ketamine increases adenosine through changes in energy metabolism, not by making the receptors fire more. This is an important approach for new, effective therapies.

Also interesting: What’s in coffee and how does the hot beverage affect health?

What does coffee have to do with depression in this case?

Coffee or caffeine, one of the most commonly consumed psychoactive substances, has the property of blocking adenosine receptors. This prevents fatigue signals from getting through, keeping us awake and alert. However, this also means that coffee weakens or even prevents the effects of ketamine and ECT. Yet, regular coffee consumption is known to have a protective effect. Or is it just the one cup right before or after therapy that’s problematic? The researchers explored this question in the aforementioned commentary on the study.

More on the topic

Caffeine and Its Effects Drinking coffee late at night can significantly disrupt your sleep.

Study on Mice Can an Ingredient in Tomatoes Alleviate Depression?

What distinguishes the “coffee brain” from others

It is further stated that coffee enthusiasts have permanently upregulated adenosine receptors. This means their density is higher and they are generally more active. They also have more “spare receptors.” This could at least explain the protective effect of coffee regarding depression. However, when a dose of caffeine is added, the desired effect for the coffee drinker also occurs. Blocked receptors mean more alertness, and the calming effect is absent. Here, the researchers suspect the resolution of the paradox: Caffeine only negates the protective effect while it is active, that is, for three to twelve hours. Otherwise, it helps the brain and its receptors be better equipped against depression. The researchers describe the mentioned 20 to 25 percent as “remarkable.” Therefore, the commentators’ advice so far is that coffee drinkers affected by depression should refrain from the hot beverage 24 hours before and after therapy.

Also interesting: Coffee can do much more than just wake you up

And yet many questions remain unanswered

First of all, mouse brains are not human brains. Human depression is an extremely complex field, and everyone reacts differently to substances. A possible transfer to humans is plausible but not yet clinically proven. New study designs would first need to be developed. At the same time, adenosine is a multifunctional molecule that works not only in the brain but throughout the body.
Coffee was not directly tested on the mice but served merely as a prompt for the accompanying commentary. The quite logical considerations remain theoretical for now. And last but not least, the brain itself is one of the greatest unsolved mysteries of the universe. The study wonderfully illustrates how to get as close as possible to certain answers. In this case, the researchers uncovered an important key mechanism that could improve the success rates in treating depression. And finally, it shows once again that certain substances can be both “friend” and “foe.” Sometimes, timing is everything.