How do you like your coffee — espresso or enema?

Caffeine as a gateway drug, part two

Some prefer the rectal route Photo by Jon Butterworth on Unsplash

This is part two of the Caffeine as a Gateway Drug series exploring how drugs work, based on an exploration of caffeine.

Part one provides the introduction. Another article Bodily logistics provides some of the basic physiology relating to how substances move around and out of the body.

What coffee can teach you about how drugs work

Bodily logistics

This is a pretty long read, so you might want to prepare yourself by getting a cup of coffee and taking advantage of it’s drug like effects before you jump in…

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Have you ever had one of those days where you’re ransacking the house looking for whatever chocolate you can find?

One particular afternoon I found myself dangerously close to settling for the compound cooking chocolate when I stumbled across a mystery bag of dark chocolate balls tied up nicely in a little cellophane bag.

Jackpot.

I bit down on one of the chocolate morsels, expecting the sweetness of a sultana, only to find the grit of a coffee bean.

Now, in some circumstances this might’ve led me to stop eating. But not that day. I would push on and pretend to enjoy them.

I don’t want to admit how many were left in the bag at the end of this session, let’s just say that I’ve since realised my storm eating tendencies do not serve me well.

All was unremarkable for around an hour or so.

Then…ping!

Ok, that may be a bit of an exaggeration- we’re not talking Requiem of a Dream type effects, it was just coffee after all. But why did it take around an hour for the caffeine effects to hit me when my morning espresso gets my brain activated and stomach moving in a solid 15? (Sorry if that’s too much information)

This is what we’ll explore in this article, where we get to talk about three important interrelated concepts: formulation, route of administration, and absorption.

Let’s get physical

Chocolate covered coffee beans, iced coffee and a shot of espresso are all examples of different formulations of caffeine.

A formulation has specific physical properties. There are two key things to look at when it comes to the formulation — the physical state of substance, and the concentration of drug it contains.

This might not be considered the most technically accurate terminology for the purists, but on a practical level there are four physical states that are important when it comes to drugs — solid, liquid, gas, and semisolid.

I’ve surprised myself here, and discovered there are actually formulations of caffeine that provide examples of each of these different states — great for these articles, but perhaps not so good for public health. There are so many products, that I’ve got to use a bulleted list (and I’m sure there are more that I missed):

• Solids — chocolate covered coffee beans, chews, gum, melts, mints, lozenges, wafers, oral strips, dispersible tablets, capsules*, tablets*, gummies, suppositories*, oral powder, patches, nasal powder

• Liquids — coffee, tea, yerba mate, coca cola, red bull and other energy drinks, lotion, enemas, tincture, injection*, eye drops, nose spray, effervescents (once dissolved in water)

• Semisolids — caffeine creams, gels, coffee flavoured ice cream, gelati and yoghurt

• There aren’t really any examples of a caffeine gas although there are vapour inhalers which are aerosols.

* caffeine is sometimes used as a medicine for treatment of migraine and anaemia of prematurity in neonates.

Whole coffee beans, crushed coffee beans and coffee are all different formulations of caffeine Photo by Sina Asgari on Unsplash

To relate this to medicines, the caffeine is what we call the active ingredient or generic name while the various formulations represent different products or brands.

Each formulation has different physical properties that influence how the drug works. One of these is the amount of active ingredient contained within a particular unit size of the product.

For the chocolate coated coffee beans and other solid formulations, the amount is usually stated as the weight of active ingredient per bean (or tablet, or capsule etc). For most drugs, this amount is in milligrams (mg). You might occasionally get up to 2000mg/2g for something like fish oil, but not much bigger as few people are keen to swallow big giant tablets or capsules.

The amount of drug contained in a liquid, semi-solid or gas formulation is expressed as concentration — the amount of active ingredient contained within a specified volume of product. Some solid drugs like powders can also be expressed in terms of concentration.

So how much caffeine is actually in commonly consumed products?

Exact amounts in coffee and other brewed drinks vary based on preparation, but the following list is based on the information from Food Standards Australia and New Zealand so should provide a reasonable indication:

• A coffee containing a single shot of espresso - 145mg per serve (i.e. adding milk will dilute the concentration but if you drink the full serve the amount of caffeine will be the same)

• Energy drinks - 80mg per 250ml

• A cup of instant coffee made with just one teaspoon of coffee – 80mg per serve

• Black tea – 50mg per serve

• Cola drink – 25mg per 250ml

• Milk chocolate - 10mg per 50g bar

They don’t mention dark chocolate coated coffee beans, but according to the USDA, a serving of 28g (1oz) milk chocolate coated coffee beans contains 227mg of caffeine. Most standards recommend adults shouldn’t consume more than 200mg of caffeine in one go, with a daily limit of 400mg in total.

The question is, how many chocolate coated coffee beans would I have dared to eat it one sitting? In other words, what dose of caffeine did I consume?

I’d say it was entirely feasible I ate a handful, or around 28g of beans. That means my dose would’ve been at least 227mg of caffeine- about one and a half times my usual dose of 145mg. (It’s also higher than the recommended dose of 200mg in a single serving-oops!)

We’re going to cover the relationship between dose to effect in the next article. Right now though, it’s important to note that the dose I administered doesn’t necessarily mean that’s the amount of active drug that made it into my bloodstream. More about that later.

The physical properties of a formulation will be part of what determines the way you get it into the body, known as the route of administration.

What’s route got to do with it?

There’s not many ways of talking about route of administration without getting bogged down in technical terms, so I’m going to try out an analogy. Let’s take a moment to consider the structure of an office building.

Photo by Mathias Reding on Unsplash

I should warn you, most of what I know about the structure of office buildings comes from watching Die Hard, so there may be some flaws in this analogy, but let’s go with it and see where it takes us.

All office buildings have external surfaces that you can see from the outside– windows, walls, doors, roof, maybe a helicopter pad and other things. Day in day out, these surfaces have to withstand a battering. Wind, rain, the heat of summer, the cold of winter, birds that don’t see the glass and smash into the windows, birds that do see the glass and poo all over it. The external surfaces are exposed to the elements and get pretty dirty at times, but they’re critical to keeping the inside well maintained.

Zoom in to the internal parts of the building. Each floor looks kind of like an independent entity when viewed on its own but remains connected to the overall building through things like the electrical and communications systems, elevators, and stairwells. Just off the elevator there’s likely to be a small reception area to greet any visitors, beyond which are corridors connecting the different spaces enabling people to move around to get their jobs done and stay reasonably healthy at work, go to the toilet etc. The indoor areas of the office building are kept clean and maintained at a comfortable temperature. If a bird were flying around in here pooping on the furniture and artwork it would not be good.

Now think about the bits of the office building that make contact with the outside, but sit on the inside of the building. Things like the lobby, air conditioning ducts, pipes and other types of spaces that John McClane would make use of if faced with a hostage situation. These parts of the building let the people and deliveries in, maintain the air flow, allow the waste products to be removed. It’s not unusual for a bird to fly into the lobby every now and then, but it’s dealt with before it gets too far. It would be unusual, however, for a bird to swim in through the wastewater pipes.

So what’s a building got to do with route of administration?

Imagine the drug is a delivery of office supplies. The way that you of get this delivery of office supplies into the building is like the route of administration.

One approach is to use the external surfaces and stick the box of supplies up on the roof. That’s great if the roof is where the supplies are needed, but not so great if the problem is inside. Also not great if the supplies are needed for window repair. It’s pretty hard to stick a box to a vertical surface, you’ll need a different package better suited to this use.

If you want to get the delivery of office supplies inside the building, you’ve got three choices. The first option is to use something that’s able to leach through the window or other external surface (that doesn’t really work with the office supply analogy unless there’s a Die Hard set in a science fiction universe where McClane’s able to morph through walls like in the Matrix).

Second option is to create an entry point by breaking through the external surface. A Die Hard inspired approach would be to bust through the window dangling from the roof suspended in the air by a fire hose- but that wouldn’t get you very far within the building. A more sophisticated Batman inspired approach would be laser cutting a small opening in the window, shooting through a cable attached to a grappling hook and sliding the supplies along the cable line to their destination.L

Third and final option to get the package inside the building is to make use of the inside spaces that interact with the outside. Entering the inside of a building through the lobby is pretty standard practice, and should be smooth sailing once you get past security. Getting a delivery through the ducts or pipes would probably require some more specialised equipment, but where there’s an opening, there’s a way.

So now we’re across the different ways of getting those supplies into the building let’s put it back in bodily terms and introduce some more terminology.

Drugs applied to the external surfaces

Applying a drug to an external surface of the body is called topical administration. These surfaces include the skin, the conjunctiva of the eye and eye lids, the outer ear, the lips, fingernails, external genitalia and the outside of the anus. Most drugs applied to these areas stay put and don’t make it into the inside of the body, like the box of office supplies placed on the roof.

Unlike the building analogy that fell down when it came to a delivery being able to leach through a window, there are drugs that can pass through the skin into the general bloodstream. Sometimes this happens as a side effect when a drug is applied topically to an area where the skin is thinner with good blood flow, like the genitals, lips, anus, underarms and eye lids. Other times it’s because the drug has been specifically formulated into a patch that gradually releases drug into the blood over time. This is referred to as transdermal administration.

Creams are an example of topical administration Photo by Ana Essentiels on Unsplash

Drugs injected into an internal compartment

Breaking through an external surface to get to the inside of the building is like what happens when you get an injection or an implant. A needle breaks through the skin and any other tissue the needle makes contact with, the drug is then transported through the needle or other device and ends up deposited in the desired location. The collective term for these injected or implanted routes of administration is parenteral administration.

Drugs that are put straight into the bloodstream through a vein are given by the intravenous (IV) route. The special thing about this route of administration is that it delivers the drug right into the transport network of the body, so it’s able to get moving around the body straight away. The building analogy doesn’t really work here unless you go sci fi mode and imagine robots that roam around the corridors, up and down the lifts to each floor in a defined circuit of movement.

Drugs that are injected into other parts of the body don’t move around to other parts of the body unless they make it into the general bloodstream. How easily they move into the blood is determined by the physical properties of the drug and its formulation. Insulin is self-injected into the layer of fat under the skin (subcutaneous) and moves into the bloodstream fast or more slowly depending on the product used. Semaglutide (ozempic) is also self-injected subcutaneously, and moves slowly into the bloodstream over a number of days. Adrenaline (epinephrine) can be self-injected into the muscle (intramuscular) using an EpiPen to treat anaphylaxis. This moves into the bloodstream rapidly to get things under control quickly.

Vaccines are often given by intramuscular injection Photo by Ed Us on Unsplash

Drugs delivered via the outside-inside spaces

The last way of getting deliveries into the building is via the inside spaces that have contact with the outside environment. Within the body, you can think of these spaces as any orifice within the body that you could insert, drop, spray or flush something into. This includes: the inside of your nose and sinus passages, your vagina and uterus (if you have one/both), your urethra and bladder, your lungs, and your gut all the way from mouth to rectum.

These surfaces are what’s called your mucous membranes. Unlike the fully external surfaces that are built to keep all foreign material out of the body by default, the mucosa are a bit more discerning to allow the inward passage of things the body needs, and outward passage of things the body needs to get rid of. Except the bladder and urethra- that’s purely for moving things out of the body, not in (a bit like the building’s wastewater pipes).

Photo by Aleksander Saks on Unsplash

Drugs administered into the stomach and intestines

The most commonly used of these types of spaces to put a drug into is the gastrointestinal tract. This is the standard pathway for getting substances into the body, like the delivery of office supplies coming through the front door into the lobby, past security and up the elevator to the destination.

Now, while the gastrointestinal tract does include everything from lips to anus, there are some special attributes that apply specifically to drugs that are administered into the stomach and intestines. That means any drug that is swallowed by mouth (oral), inserted into the rectum (rectal) or injected via an enteral feeding tube (e.g. nasogastric). These routes of administration all fall under the collective term enteral administration.

As explained in Bodily logistics, drugs that are swallowed have a number of steps they have to go through before they are able to move from the gut to the bloodstream. Solid formulations must first be broken down into smaller particles in order to pass into the blood, which is known as the process of absorption.

Some drugs absorb more readily than others. This means the amount of drug that ends up in the blood stream is usually smaller than the dose that was administered, sometimes considerably so. The proportion of drug absorbed from the gut is referred to by the term bioavailability. Higher bioavailability means a greater proportion of the dose ends up in the blood.

After a drug has been absorbed from the stomach or intestines (including the upper part of the rectum), it gets taken straight to the liver via the portal circulation. Here, some drugs undergo a process called first pass metabolism which can further reduce the amount of drug that ends up in the general circulation. This is why for some drugs, the oral dose is quite a bit higher than if the same drug was given by another route.

Putting a drug onto the tongue will likely end up in the stomach and undergo first pass metabolism, while under the tongue or in the cheek will absorb into the general circulation Photo by Alex Guillaume on Unsplash

Drugs administered to the other mucous membranes

If oral administration is like supplies being delivered through the lobby, then administration via the other mucous membranes is like any other way into the building that bypasses the security screening of the liver without having to break through an external surface.

The reason I was so pedantic earlier about specifying drugs that were swallowed by mouth into the stomach is because drugs that are administered inside the mouth can take a different journey, depending on where they are placed. If drugs are administered under the tongue (sublingual) or inside the cheek cavity (buccal) they are absorbed directly into the general circulation and avoid first pass metabolism. If a drug is placed on top of the tongue (e.g. an oral strip) it’s likely that a large proportion of the dose will mix with saliva and be swallowed, so it will still undergo first pass metabolism.

Drugs administered via the other mucous membranes can also be absorbed directly into the general circulation, depending on the physical properties and formulation of the drug. This includes drugs administered via the nose (nasal), vagina (vaginal) and lungs (pulmonary).

Drugs administered into the bladder (intravesical) are not absorbed and are for local effect only.

Photo by Lukas Blazek on Unsplash

So why did the coffee beans take longer to work than the espresso?

Back to the story that started this — the chocolate coated coffee beans vs the espresso. Why did the effect of the beans take longer to hit me than the espresso?

Let’s work through looking at some of the concepts we’ve covered so far.

We have two different formulations of caffeine, both given by the oral route but using different doses.

The espresso is a liquid formulation containing around 145mg of caffeine. I didn’t mention this earlier, but I tend to have my coffee first thing in the morning with breakfast. So while it’s not on an empty stomach, there’s probably not much else in the stomach getting in the way of the caffeine being absorbed.

Caffeine is the kind of drug that is perfectly built for absorption with a bioavailability of 99%. Not only that, it starts moving into the bloodstream from the moment it hits the stomach, and by the time it’s through the small intestine nearly the entire dose has been absorbed. Because it moves through cell membranes like Neo in the Matrix morphs through walls, first pass metabolism isn’t really an issue. All this to say that you can start feeling the effects of an espresso within around 15 minutes of taking your first sip.

The chocolate coated coffee beans however, well they’re quite literally a bit more of a grind. Here we’re dealing with a solid formulation containing around 227mg of caffeine- so right off the bat it’s not surprising that the effect will be greater once it kicks in.

Unlike the espresso which hits the stomach ready to move straight away, the digestive system has its work cut out for it with the coffee beans. It basically has to act as the grinder to get the beans down to a small particle size, then act as the coffee machine to get the caffeine into solution. This takes time.

After about 45 minutes or so the caffeine will start moving across to the bloodstream toward the liver, just as it does with the liquid formulation. Only in this case there’ll be 1.5 times the amount of drug.

This concept of delayed time to effect is really important to understand if you ever find yourself in a position of using a drug given orally “to effect” or “as needed”. A classic example of this is edible cannabis, but it’s equally relevant to the use of opioids for breakthrough relief of pain, like in palliative care. If your body hasn’t provided feedback that the desired effect is starting to come within 30 minutes it’s easy to assume the drug isn’t working for you and that you need to take more. Then, an hour later you find yourself in all sorts of problems. To avoid this, for anything given orally as required the safest thing to do is wait at least an hour to see how it’s affecting you before you take anything else.

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That brings part two to a close. We’ve covered a lot of ground, but there’s still plenty left to explore. In part three we’ll look at the ways drugs get around the body, the relationship between dose and effect, and debunk some myths – like why it’s not scientifically possible for a caffeine product to make you alert with zero side effects.