How Caffeine and Cannabinoids Interact in the Human Body

Millions of people around the world love coffee. In fact, many would say they depend on it, which isn’t surprising considering coffee is the world’s most popular legal psychoactive substance—far surpassing alcohol and tobacco in global popularity. Since at least the early 20th century, coffee has been one of the leading agricultural commodities, with its production, sale, and consumption playing a crucial role in the economies of many developing and developed countries.

The popularity of coffee is largely due to its main active ingredient: caffeine, a powerful neurostimulant that gives the drink its characteristic energizing effect. Besides coffee, caffeine is also found in many soft drinks, energy drinks, and tea—the second most popular legal neurostimulant after coffee.

Unlike cannabis, which can have either sedative or stimulating effects depending on its composition and concentration, caffeine is exclusively a stimulant. Cannabis also has more pronounced psychoactive effects, noticeably altering perception when consumed in large amounts, while caffeine’s effects are limited to increased alertness and, in high doses, nervousness and tension. Additionally, cannabis effects can be modulated by factors like the user’s mindset and environment (“set and setting”), whereas caffeine’s effects are straightforward and not easily modulated. Despite these differences, many people use both substances together to combine their effects.

Scientists continue to study the paradoxical yet clearly synergistic interaction between caffeine and cannabinoids. The main mechanisms of how these substances affect the body’s receptors—and each other—are already well understood. This article explores how coffee and cannabinoids interact, examining the physiological and psychological mechanisms behind their combined effects.

The Effects of Caffeine on the Human Body

Like cannabis, caffeine affects several types of neural receptors in the human body. Physiologically, this results in increased adrenaline production, which creates the familiar physical and psychological stimulation: a faster heart rate, higher blood pressure, and quicker transmission of nerve impulses in the brain.

In addition to stimulating adrenaline, caffeine also causes a spike in dopamine—the so-called “pleasure” or “motivation” hormone. However, unlike adrenaline, caffeine doesn’t increase dopamine production; instead, it slows the body’s ability to metabolize naturally occurring dopamine, leading to a longer-lasting sense of pleasure and increased focus.

Despite the important roles of these hormones, the main substance responsible for caffeine’s stimulating effect is adenosine. Adenosine is a natural hormone that regulates sleep and wake cycles. During wakefulness, adenosine gradually accumulates in certain brain regions, and when it reaches a critical level, it causes fatigue and drowsiness, pushing the body toward sleep for recovery.

Adenosine molecules bind to specific brain receptors (A1 receptors), gradually reducing neural activity and causing “mental fatigue.” The more adenosine accumulates, the more receptors are activated, leading to deeper fatigue.

Adenosine, Caffeine, and Dopamine

Adenosine and caffeine have similar physical structures, allowing caffeine to effectively “replace” adenosine at A1 receptors.

However, despite their structural similarity, the two substances have opposite effects: adenosine activates (stimulates) A1 receptors, while caffeine blocks them. Dopamine also interacts with these receptors, but only partially, producing feelings of pleasure, motivation, and focus.

If adenosine occupies the receptors, dopamine cannot bind, resulting in worsened mood and well-being—a possible natural mechanism to encourage sleep.

However, if caffeine binds to the receptor first, it blocks adenosine’s effects and allows dopamine to bind as well:

• Caffeine occupies the adenosine site, blocking the receptor and its effects.
• Unlike adenosine, caffeine does not prevent dopamine from binding, allowing for both stimulation and increased pleasure and motivation.

This simple mechanism explains why coffee produces its characteristic stimulating effect, as well as feelings of pleasure and motivation.

The Combined Effect of Cannabis and Caffeine on A1 Receptors

While caffeine’s ability to block adenosine and interact with dopamine leads to a more pronounced psychoactive effect, this also underlies a common issue with cannabis use: short-term memory loss. This effect is naturally present with cannabis use, but studies show that combining cannabinoids with coffee significantly amplifies this negative effect.

Both substances affect clusters of CB1 and A1 receptors in the hippocampus—the brain region responsible for learning, memory formation, and emotional processing. Laboratory studies with animal brain tissue and live subjects show that when A1 receptors are activated by adenosine, the sensitivity of CB1 receptors to cannabinoids drops by about a third. When A1 receptors are blocked by caffeine, CB1 receptor sensitivity increases, intensifying both dopamine effects and the ability of cannabinoids like THC to impair short-term memory.

In other words, while cannabis or THC alone may slightly disrupt short-term memory, combining it with coffee can significantly block memory formation mechanisms in the hippocampus, greatly increasing “memory lapses.”

This mechanism also explains why using cannabis in the evening or at night has less impact on short-term memory: higher adenosine levels at these times help protect memory formation from cannabinoid interference.

Additionally, since the combination of coffee and cannabis amplifies dopamine’s effects, it’s not surprising that using both substances together produces a stronger and longer-lasting euphoria, while also increasing the risk of psychological dependence.

Technically, caffeine binds to A1 receptors, replacing adenosine, while THC slows the metabolism of dopamine, allowing more dopamine to bind to the same receptors and producing a cumulative effect of pleasure from both substances.

Additional Research and Observations

These findings are supported by other independent studies. For example, a 2014 study examined the combined psychoactive effects of THC and MSX-3, a caffeine-like stimulant that also blocks A1 receptors. The subjects—squirrel monkeys accustomed to recreational THC use—consumed lower doses of THC when given low doses of MSX-3, but increased their THC intake with higher MSX-3 doses, indicating that blocking A1 receptors amplified the euphoria from cannabinoids by increasing dopamine levels in the brain.

Some critics suggested that low doses of MSX-3 enhanced the effects of small amounts of THC, while higher doses required more THC for the same effect. However, current knowledge about A1 and CB1 receptor mechanisms indicates that increasing stimulant doses simply raises overall dopamine levels and the perceived “high” from combining these substances.

Other studies, such as a 2012 animal study, show that combining caffeine or similar stimulants with cannabinoids has a stronger negative impact on short-term memory formation than high doses of cannabinoids alone. Specifically, the combination of a typical cup of coffee’s caffeine content with a small dose of THC had a greater effect on memory in test rats than high doses of THC alone.

Paranoia and Aggression with High Doses of Caffeine and THC

It’s also important to note that, in addition to effects on memory and euphoria, combining coffee and cannabinoids can significantly intensify the psychoactive effects of both substances. A large dose of caffeine before using THC can greatly amplify the subjective strength of the cannabinoid’s effects, potentially leading to negative experiences such as paranoia, anxiety, aggression, and fear—even with small amounts of THC.

This phenomenon was observed in the 2014 study mentioned earlier, where monkeys given higher doses of MSX-3 consumed more THC but also experienced discomfort, panic, or increased aggression due to the excessive stimulation of brain receptors by high levels of unprocessed dopamine. Despite these negative experiences, the monkeys still preferred to consume larger amounts of THC with the stimulant, confirming that the effect was due to overstimulation of brain receptors.