The Unique Synergies Of Caffeine

Ashwagandha is a herb that belongs to the night shade family of plants. The nightshade family of plants is a very interesting one and includes a lot of vegetables that make up large parts of many diets. Notable nightshade members are potatoes, tomatoes, chili peppers, goji berries and even tobacco! Another name for the nightshade family is Solanaceae. This is where Ashwagandha gets its Latin name from; Withania somnifera. Ashwagandha is a short perennial shrub, with a large root system that develops small deep orange fruits. The fruits resemble a small cherry and the leaves look frosty due to the many tiny hairs that are on them. This one of the reasons why Ashwagandha is also referred to as ‘winter cherry’. Traditionally, the Ashwagandha root is used, however new research has found high concentrations of key components in the leaves too. Various manufacturers have taken notice of this. One of the most notable being Natreon who produce a specialized extract of Ashwagandha called Sensoril. Sensoril is made from the leaves of Ashwagandha, giving it a unique chemical composition, which produces noticeable calming effects.

Clearly, caffeine serves a very important role for these flowering plants, and thus it is no surprise that caffeine is found in numerous different species of plants. However, humans aren’t buzzing around slurping down caffeinated nectar, so how did humans first come into contact with this energizing compound?

This is where things get tricky, and there are lots of different theories as to how humans first came into contact with caffeine. One common theory is that once humans discovered fire, and were able to heat up water, they started making water infusions of various leaves. This makes quite a lot of sense, a cup of tea is wonderful, but chewing on tea leaves is not a very pleasant experience. Additionally, caffeine is highly water soluble in the context of hot water. Caffeine is found in the leaves of lots of different plant species, which are found throughout the world. For example, Camelia sinensis (Asia), Ilex paraguariensis (South America), Ilex vomitoria (North America) and Coffea arabica (Middle East & Africa) leaves all contain caffeine and all seem to have a long established history of the leaves being used to brew infusions with.

More than likely however, the first uses of caffeine containing plants likely were spiritual/ceremonial. These beverages would have acquired tastes, and would not be nutritious while demanding quite a bit of effort to make. However, caffeine, especially in ancient times would have had mind blowing effects on the consumers of these mystical leaf infusions. This would especially be the case for leaves that are especially rich in caffeine, such as the Ilex species. In fact, Ilex vomitoria and Ilex cassine have historically been used ceremonially by various different Native American tribes, in a ceremonial beverage referred to as “black drink”.

Other caffeine containing plants certainly seem to have been utilized ceremonially too. Theobroma cacao for example comes to mind, having been a highly important botanical for the ancient Mayans. Tea and even coffee have traditionally also been used ritualistically. One thing that all of these caffeine containing plants however seem to have in common, is that more often than not, they are made into beverages using hot water to extract bioactive molecules, of which caffeine is one of the primary bioactives! Thus, there likely is something to the theory that our first encounters with caffeine were facilitated via the discovery of hot water!

We oftentimes don’t take a moment to think about just how complex coffee is, but from growing, processing, drying, shipping, roasting and brewing coffee, there is a lot of complexity involved.

Then the seeds have a coating of parchment on them, which needs to be removed. Now we have green coffee beans, which are shipped around the world to roasters. Roasters then take the processed coffee beans, and meticulously roast them, in a process where the coffee bean itself starts to function as a bioreactor that generates bioactive compounds. They then end up in the hands of homebrewers or professional baristas who need to precisely grind the beans to within exacting particle size standards. Then, grind sizes need to be dialed in, in order to make the perfect cup of coffee. Humans have certainly spent A LOT of time, money and effort into making that morning cup of coffee many of us drink.

Thus, it was quite incredible that one of the most famous poets at the time, Johann Wolfgang von Goethe had quite the affinity for both coffee and science. After seeing a demonstration from a young chemist called Friedlieb Ferdinand Runge, where Runge dilated the pupils of a cat with atropine he had isolated, Goethe was so impressed that he handed Runge a bag of coffee beans. Goethe’s intention with this transaction would be for Runge to isolate the, at the time, unknown compound from it, which gave coffee its unique properties. After tinkering with it for a few months, Runge was successfully able to isolate caffeine, which he at the time called “Kaffebase”.

When Runge isolated caffeine from coffee beans, he only discovered part of why coffee is stimulating. Over the years, we have discovered that coffee contains a plethora of psychoactive compounds. For example, it contains other methylxanthines which are related to caffeine and have similar effects, such as theophylline and paraxanthine, albeit in very small quantities. More interestingly though, coffee beans contain beta-carbolines which block monoamine oxidase (MAO) enzymes, which can enhance the stimulant properties of caffeine. Coffee beans also contain the unique compound trigonelline, which appears to have significant mood promoting effects.

If we look at other caffeine-containing beverages, we also quickly discover that caffeine is oftentimes found in the presence of lots of different bioactive compounds. Take green tea for example, which contains caffeine in addition to small amounts of L-theanine, and catechins like EGCG and epicatechin. Yerba mate oftentimes contains a broad spectrum of methylxanthines in high concentrations such as theophylline and theobromine, in addition to of course caffeine itself. Yerba mate also contains a wide array of polyphenols and flavonoids, like rutin and quercetin, which can also modify the effects of caffeine. Theobroma cacao is also a very interesting example, it contains high amounts of theobromine in addition to caffeine, while also containing endocannabinoid compounds such as anandamide.

It’s quite clear then, that caffeine is never naturally consumed in total isolation, as it is always contained within plants that contain a wide array of other bioactive compounds which modulate the activity of caffeine. It was only until Runge isolated caffeine from coffee beans, that we really started to focus on caffeine in total isolation. This became especially prominent once pure caffeine was easily obtainable through total synthesis, which was first performed in 1895 by Hermann Emil Fischer. It of course took a long time before pure synthetic caffeine was commercialized, but once it was, it started to pop up everywhere! Synthetic caffeine is very cheap and abundant, so it’s easy to make pure caffeine products. However, subjectively, pure caffeine in total isolation feels quite lackluster when it is compared to traditional caffeine sources, such as coffee, yerba mate, or tea. Thus, it is no surprise that most commercial energy drinks (which usually utilize synthetic caffeine or pure isolated caffeine) often contain a plethora of other bioactive compounds such as taurine and B-vitamins.

Subjectively speaking I (Emiel, Nootropics Depots product specialist) have noticed huge differences in effects between pure isolated caffeine, and my favorite caffeine delivery systems, coffee and yerba mate. In fact, I’ve even noticed stark differences in effects between different cultivars of coffee, and even coffees from different origins. For example, coffee beans from Ethiopia tend to feel smoothly stimulating with a prominent mood brightening effect. On the flipside, coffee beans from Columbia tend to have a much zippier and focusing effect for me. I recently brought this up on a reddit thread, and discovered others had experienced these differences too. I’ve even noticed that the type of coffee extraction makes a big difference too. For example, a shot of espresso often feels more “full bodied”, stronger, motivating and mood boosting to me, whereas a simple filter coffee can oftentimes feel more cleanly stimulating and focusing. This is somewhat independent of caffeine content, because contrary to popular belief, espresso actually contains less caffeine than filter coffee! This was recently brilliantly demonstrated in this great video by James Hoffman:

This clearly demonstrates that caffeine appears to be highly modifiable by other compounds. For example, the high pressure of an espresso extraction may be extracting other non-caffeine bioactive compounds from ground coffee beans, such as the beta-carbolines, more efficiently than percolation. There is still a lot we have yet to discover on this front, but one thing is clear, caffeine makes a fantastic base compound for designing nootropic stacks around. So let’s jump outside of the plants caffeine is contained in, and let’s look at some novel caffeine based combinations we can make utilizing pure isolated caffeine!

As we discussed in our recent sabroxy podcast, sabroxy contains a unique flavone called Oroxylin A. Oroxylin A acts as a dopamine reuptake inhibitor and in our experience produces a very smooth stimulating effect when combined with caffeine. Not only is the dopamine reuptake inhibitor effect at play here though, oroxylin A also activates adenosine A2A receptors, which is one of the few adenosine receptors that caffeine blocks in order to produce its stimulant effects. However, blockade of adenosine A2A appears to produce some jittery effects, so filtering it out to some degree with sabroxy helps smooth out the effects of caffeine, while enhancing the dopaminergic effects of caffeine. Overall, this results in a very uplifting and motivating effects profile!

We’ll stop this blog here, because we could keep going on and on about various different combinations we can make with caffeine, and we don’t want this to turn into an E-Book! However, we hope this blog has provided you with some insight that will help you develop many different caffeine stacks. As has become abundantly clear throughout this blog, caffeine stacks well with just about anything and can thus be a very flexible part of many different nootropic stacks!