How Does Caffeine Wake People Up?

For many people, morning is impossible to navigate without at least one cup of coffee. Amidst its many compounds that give this brew its unique taste, coffee contains caffeine, which helps push away the morning grogginess and perk a person up.

Many articles attribute caffeine’s effects to its ability to block adenosine from its receptors in the brain. Since adenosine promotes sleep, inhibiting it prevents people from feeling tired. But this is not the whole story.

“There’s not a single mechanism for caffeine to wake us up or for keeping us awake,” said Giancarlo Vanini, a neuroscientist at the University of Michigan. Instead, he said that caffeine acts in several ways across the brain to fend off fatigue. Additionally, Vanini’s team found that this tiny molecule may also decrease pain associated with poor sleep.

Caffeine Turns Off Sleep Neurons Across the Brain

Normally, adenosine builds up in the brain and binds adenosine receptors (ARs) on neurons.¹ In a region of the brain responsible for processing reward and motivations, adenosine binds to ARs on inhibitory neurons; this activates these neurons, which in turn shut off neurons in the hypothalamus that promote wakefulness. Alternatively, adenosine can directly activate sleep-promoting neurons in the hypothalamus.² Lastly, adenosine decreases the release of acetylcholine in the prefrontal cortex, which leads a person to feel less awake.³

Vanini explained that caffeine possesses a similar structure to adenosine and, as a result, it can bind to two ARs and block adenosine from its active site. With caffeine bound to the ARs across these three pathways, the inhibitory neurons are not activated and more acetylcholine is released. ^4-6 As a result, a person feels more awake. While Vanini said that there were many other mechanisms that caffeine is suspected to work through, these three pathways are probably the most well-studied.

Vanini added that a person’s susceptibility to caffeine will depend on their genetics. Indeed, previous studies showed that some individuals who rated themselves as insensitive to caffeine had a distinct alteration in a gene for one AR.⁷ Vanini added that these effects will also be influenced by the amount and frequency with which a person consumes caffeine.

Caffeine Intercepts Pain Signals Mediated by Adenosine

Vanini and his team recently wondered if caffeine could also influence a different sleep-related effect. They had seen that sleep-deprived animals responded worse to a subsequent injury compared to well-rested animals, so they thought about the way that many people respond after a poor night’s sleep: with a cup of coffee. “What if we could treat the side effect—A.K.A. the increasing pain caused by sleep deprivation—in the same way, by using caffeine?”

In a study with rats, they showed that caffeine prevented the increased pain response and decreased its duration in sleep-deprived animals.⁸ Thinking back to the mechanisms of caffeine in the brain, Vanini and his team focused on the hypothalamus because, in addition to housing sleep machinery, it contains neurons involved in regulating pain. Using a more selective adenosine antagonist that bound a specific AR, they showed that adenosine signaling increased the pain responses following disrupted sleep and that caffeine impeded this pathway as well.⁸

Although they did not see an effect of caffeine on post-surgical pain in a small clinical trial, Vanini said that they did see a reduction in post-operative delirium.^9,10 Considering the relevance of dose and other factors, Vanini is hoping to repeat the study to determine if caffeine, and by extent adenosine, also regulates pain in humans.