I hate to break it to you, but you have been drinking an insecticide all along…

Early morning. You just woke up and you are trying to get in touch with reality. Somebody is talking to you, but you just hear a distant undefined noise and refuse to listen until you have your first cup of coffee. If you could see yourself in this description, you are in good company! A large portion of the world population is consuming this famous drink to start the day. Well, many do not drink it only in the morning. If you are like me, coffee is getting you through the entire day. It is a very complex hot drink, a mixture of different chemicals, caffeine being the most characteristic one. And it is exactly with this chemical that we inaugurate the section of the blog called “Natural product of the month”.

Caffeine belongs to the class of alkaloids (purine alkaloids to be more precise)^a and it is found in various plant species, above all of course in the shrub that gives us coffee bean, Coffea arabica.^b Discovered two centuries ago, it is the world’s most widely consumed psychoactive drug (1), and it is not only present in coffee, but also in several different beverages and food. Drinks containing it, especially, are consumed to relieve or prevent sleepiness or to improve cognitive performance. You might now wonder what the connection between caffeine and insecticides is: very simple caffeine is an insecticide. Curious? Continue reading to find out more.

Caffeine in plant defence

We often see plants as passive. After all, what can they do if they are attacked by an animal that aims to eat them? They cannot run away. They are stuck there. No hope (apparently). Yet, they did not succumb during evolution. How is that possible? Well, plants are not that helpless as they might seem. They have different defence lines. Some defences are anatomical traits, others are chemical compounds that may kill the herbivore (or act in many other ways). Sometimes plants produce and store defensive chemicals, while in other cases these are produced and accumulated only when the plant is attacked. Caffeine is the kind of compound that is produced and accumulated, but its amount in the plant also increases when needed upon attack.

Some plant species use caffeine to protect themselves against herbivore insects (2). Indeed, this compound is toxic to many different insect species, although some of them have developed ways to detoxify or to protect themselves from its action. When the herbivore attacks a plant that accumulates caffeine, while feeding, it ingests a certain amount of this alkaloid that is easily absorbed, and acts by paralyzing the insect (2). The action is exerted at the nervous system level, where caffein inhibits an enzyme called phosphodiesterase devoted at breaking down an intracellular compound, cyclic AMP. This latter compound activates specific cellular processes, but its concentration is normally highly regulated. Upon the inhibition of the phosphodiesterase, cyclic AMP is accumulated in the neurons, impairing their function, and leading to the paralysis.
Furthermore, caffeine seems to also have a different mode of action, by interfering with the calcium signalling and homeostasis (3), leading to the deregulation of numerous cellular processes. However, some insects might be able to cope with low amounts of the compound. Bees collecting pollen on citrus flowers (which also contain the alkaloid) seem to be able to metabolize caffeine, which at low concentration also increases their alertness and improves their memory (4).^c

It is amazing how caffeine can help plants to protect themselves and this action is not limited to the fight with herbivores. Being part of complex ecosystems, they need to interact also with other plants with which sometimes they need to compete for space and resources. Once again this can happen in different ways, and one of them is a phenomenon known as allelopathy, by which a plant species produces chemicals that affect growth and performance of other plants. In case of caffeine, it seems that the activity is not only against other species, but also against Coffea arabica itself (5). Basically, coffee plants are doing some kind of population control, by inhibiting the germination of seeds of their own species if they are too close to the parent plant. Indeed, too many shrubs, even if from the same species, would be withdrawing resources that at the end would be not enough for all the individuals. The autotoxicity of caffein released by fallen leaves and seed coats contributes to regulate the population density of the plants, and it has been shown also in the field. Although this phenomenon can be a problem in coffee plantations,^d it is very useful to the plant in order to avoid overcrowding.

Caffeine and human health

Caffeine-containing products have been consumed by humankind for hundreds of years because of their flavour and of their stimulating effect.
Upon ingestion, caffeine is rapidly and almost completely absorbed in the stomach and small intestine and distributed to all tissues, including the brain (where it easily crosses the blood–brain barrier), and it exerts its stimulatory effect as antagonist of the adenosine receptors (6). These receptors are cellular structures that are so called because they bind adenosine, an endogenous chemical, which slows down neural activity. Caffeine receptor antagonism attenuates these inhibitory effects, resulting in wake-promoting effects (7). Furthermore, caffein acts on phosphodiesterase activity, and as explained before for insects, this induces increased intracellular level of cyclic AMP, leading to the release of adrenaline and to the prolongation of its effect.^e Ultimately, caffein increases alertness and cognitive abilities (1). The stimulatory effects begin around 15 minutes after consumption and may last up to 5/6 hours. Caffeine is metabolized by the liver and its products are excreted with urines.
Since the adenosine receptors are located not only in the central and peripheral nervous systems, but also in various other organs, caffeine has a plethora of different effects (1, 6). It induces an increase of blood pressure and body temperature, promotes vasoconstriction or vasodilatation depending on the organ or tissue, increases metabolic rate, etc. It seems to have a positive effect on neurological disorders, especially in women. If associated with some pain relievers, it improves their effectiveness. It also affects cardiovascular function, with positive effects on healthy individuals, being instead harmful for cardiac patients. The implication in other phenomena are not studied enough (like its influence on cancer) or are not completely understood, due to contrasting evidences (like its diuretic effect).
Short-term side effects deriving from caffeine intake include palpitations, gastrointestinal disturbances, anxiety, tremor, increased blood pressure and insomnia. The influence of caffeine on human sleep has been extensively studied, and it was shown that it reduces total sleep time, efficiency and perceived quality. It seems that the lighter sleep stages prevail at the expense of deeper stages, which occur less frequently and have a shorter duration (6). However, you might have realized that different people respond differently to caffeine and indeed it became recently clear that the effects depend on complex genetic and environmental factors, besides age, sex and general health conditions.
Studies have shown that caffeine dependence and tolerance can develop and, as with other drugs, people who abruptly stop drinking it after prolonged use may suffer from withdrawal symptoms. However, these aspects are still highly debated, since there are many things that are not clear yet, as, for example, if its use activates the reward system (8).
Finally, special care should be taken by pregnant and breast-feeding women since caffeine can penetrate the placental barrier and it is also passes in breast milk. During gestation it can affect the foetus and increase the chances of miscarriages.

Sources of caffein

The most common caffeine sources are coffee, tea,^f mate, guaraná and cocoa (therefore it is found also in chocolate). It was recently found also in the flowers of citrus species (especially in the pollen) and it is produced by some fungi, as well. Caffeine is added to many soft and energy drinks, in some cases because plant containing it are an ingredient (like cola), in other instances because synthetic caffeine is added to them. Caffeine concentrations in these beverages can be quite variable. In case of coffee, for example, the amount of caffein can vary depending on the coffee species and variety used, on the processing of the coffee beans, but also on the way coffee is prepared. An espresso contains 20-100  (most often 40-60) mg of caffeine, a cup of coffee (250 mL) around 60-120 mg, decaffeinated coffee around 2-4 mg, a cup of tea 10-100 mg, a cup of cocoa 2-50 mg, a glass of cola based drinks 25-100 mg.^g The daily intake should never exceed 1 g, while the lethal dose is 5-10 g.^h
Finally, the bioavailability (i.e. how much compound we truly take up) depends a lot on the matrix, since other compounds can interfere with absorption, but also with metabolism. Due to its many effects on human health, caffeine is a constituent of many nutraceuticals, over-the-counter pain relievers and prescription drugs.

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Despite its long use, there is still a lot to know about caffeine. Many of the effects on human health are still debated and every now and then there is new data increasing our knowledge on the topic. However, this compound is a nice example of a plant derived chemical that is very important to the plants producing it, as it acts as a defence system, and of course for humakind as well.

Notes
a. Alkaloids are a specific class of natural products.
b. The genus Coffea, belonging to the Rubiaceae family, comprises more than 100 species, among which Coffea arabica, Coffea canephora (C. robusta) and Coffea liberica are three species used to make coffee beverage.
c. This effect is similar to that observed in humans.
d. Interestingly, some plant species like sage, thyme and rosemary may diminish toxic accumulation of the allelochemical in old coffee plantations (by taking caffeine up and accumulating it in their roots), and increase coffee production.
e. Don’t worry, we are too big to suffer the same fate of insects with the doses of caffeine that we normally use.
f. Did you also hear about teine, mateine, and guaranine? Just forget about them cause these molecules simply do not exist, or, better, they are just caffeine.
g. These amounts are purely indicative and can vary depending on several variables.
h. Depending on the weight of the individual. Never forget: “Dosis sola facit, ut venenum non fit” (i.e. the dose makes the poison).