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By Liz Wallis for Turmeric Life

Many people "know" that it's a good idea to have black pepper along with turmeric. "Know" is in quotes because it's one of those things everybody says but practically no one can give you a reason for. The most frequent explanation is that it somehow improves absorption. All kinds of figures are published for that, but most websites claim 2000%. Sometimes you even see "2000 times as much" with many exclamation points appended.

Um, no. 2000% is 20 times as much, not 2000 times as much. And while the piperine in black pepper can help indirectly with absorption, it isn't the magic bullet for absorption that it's made out to be.

So what does it do?

In a few words, it slows the metabolism of the curcumin in turmeric. The term ‘metabolism’ is used very loosely these days. People say “I have a fast metabolism (or a slow one).” That’s very vague usage that refers to all the bodily processes that turn food into energy. When we talk about the metabolism of curcumin, or any other single food item or food extract, we mean the process that converts it to other forms that can be used in the body, or that the body is able to eliminate. The new forms are referred to as metabolites.

For some drugs, one or more of the metabolites is actually the active form of the drug. This is not the case for all drugs, though, and not for curcumin, either. Its primary metabolite, tetrahydrocurcumin, does have some antioxidant activity. In fact, some research suggests that it is a better antioxidant than curcumin itself. However, it lacks most of the other beneficial mechanisms of whole curcumin [1]. So it’s desirable to slow down the conversion of curcumin to tetrahydrocurmin and the other metabolites, if possible.

Until the late 20th century, scientists assumed that almost all metabolism took place in the liver. But it became obvious that hepatic (liver-related) metabolism could not account for the speed with which some drugs appeared to be eliminated from the bloodstream. Tests that looked at a drug’s bloodstream levels found them to be far less than expected. Some other mechanism had to be at work, and it was eventually found. Now we know that metabolism of many food and drug compounds takes place in two (sometimes three) distinct phases, and that the first phase takes place in the intestines, before the compound ever gets into the bloodstream [2].

The mechanism for most of these metabolic changes is the cytochrome P450 family of proteins. ‘P450’ refers to the fact that the frequency of its absorption peak is 450nm (nanometers). CYP450 (the common abbreviation for cytochrome P450) gets mentioned a lot without much understanding of what it refers to. For example, you often see statements such as “black pepper slows down CYP450.” No, the cytochrome P450 family of proteins is not a single entity. It’s a superfamily of over 50,000 unique proteins in over 18 sub-families (18 in humans, many more in some other organisms). Each of the sub-families may be broken down into multiples as well. So bear that in mind when you see the terminology being tossed around online. Incorrect usage probably suggests that the author doesn’t really understand what they’re saying, which might also suggest second thoughts about the claims they’re making (and the product they promoting).

Back to pepper.

The piperine in black pepper inhibits the chemical changes brought about by a specific P450 protein, CYP3A4. These processes are sometimes referred to as metabolic pathways. And as it happens, CYP3A4 enables the primary metabolic pathway for the conversion of curcumin to tetrahydrocurcumin. So reducing the effect of CYP3A4 allows curcumin to stay in its original state in the intestines for longer, so that more of it can be absorbed before it’s converted to the less effective metabolites.

One interesting point is that curcumin itself is a potent inhibitor of CYP3A4, as well as being a substrate of it (“substrate” means the pathway for that compound’s metabolism). It’s not at all uncommon, in fact, for a compound to also be an inhibitor or an inducer of the same CYP450 family that participates in its metabolism.

CYP3A4 also acts in the liver after curcumin reaches the bloodstream. But its most important effect is on curcumin while it’s still in the small intestine. The more curcumin that can get into your bloodstream (and from there to your tissues), the more benefit you’ll have from it. Black pepper slows down the metabolism of curcumin and allows it to stay in that form for a longer period of time so that more of it can be absorbed if a fat or oil is present to permit absorption at all.

So yes, black pepper helps indirectly with absorption, because it provides a longer interval for curcumin to be absorbed while it’s still in a free curcumin state, before it’s converted to its metabolites (tetrahydrocurcumin is the primary one but there are others as well).

Does pepper help in any other way with absorption?

Yes, one additional thing pepper does is to expand the brush border of the cells lining the small intestine. These cells (called epithelial cells) are long thin projections from the base of the intestinal lining, and are covered with a border of extremely tiny cells called microvillii. The microvillii are so small, in fact, that they can be seen only with an electron microscope. This graphic illustrates in a very simple form how the ‘fingers’ of microvillii extend out from the epithelial cells.
Intesstinal brush border
The combination of epithelial cells and their covering of microvillii allows the intestinal lining to absorb the nutrients from our foodstuffs. Black pepper changes the membrane characteristics of the microvillii, causing them to grow larger both in length and diameter, thereby increasing the surface area available for absorption even more. This is what is meant by expanding the brush border.

By the way, you sometimes see the claim that this action of black pepper somehow “irritates” the intestinal lining, usually along with a sales pitch for a turmeric product that does not contain pepper. The piperine in black pepper is not the only compound that has this property--both the capsaicin in chili peppers and a compound in ginger do the same thing. Capsaicin is also a CYP3A4 inhibitor, though a much less potent one than piperine. Chilli peppers are a major part of Indian cuisine and perform the same function in curcumin metabolism as the piperine in black pepper. None of them cause any kind of “irritation” of the intestinal lining, however.

So why did we say at the beginning that black pepper is not a magic bullet for absorption? Because curcumin is a lipophilic molecule. That means it is not soluble in water, but in fat. It isn’t carried through the epithelial lining via the same processes that water-soluble compounds use. It must be carried by any fat that’s present in the small intestine (that is a large oversimplification, but the point is that a fat is required). If insufficient fat is present, only small amounts of curcumin will get through the epithelial lining into the lymph system and from there into the bloodstream. This fact is almost certainly what explains the details behind the claim of 2000% better absorption.

Just out of curiosity, I went back to the 1997 trial that originally reported a 2000% better absorption of curcumin when piperine was administered along with curcumin.

I’ve taken the liberty of using the graph from the study without getting permission, because I couldn’t find any way to get in touch with the people who published the study. And I found to my amazement that the study has apparently never been duplicated in the 22 years now since it first appeared. The 2000% increase just keeps getting repeated and passed around with no verification of the original claim.
Serum concentration of curcumin with and without the addition of piperine
But even if that figure is valid, and we’ll assume that it is, let’s look at a couple of points.

The serum concentration of curcumin at 45 minutes, when piperine is included with the curcumin, is indeed just about 20 times as much as without the piperine. But note that the concentration drops off very steeply. A quick glance at this figure makes it look as though there is a huge increase over a large amount of time, and that is simply not the case. In fact, the time frame for that 2000% increase is so brief that it can’t even be depicted at the scale used by the study authors. Notice that it is just a straight vertical line with no time parameter. No doubt if the measurements had been taken at more frequent intervals, there would be an upward slope, a peak and a downward slope, like the other lines in the graph. But  with the measurement intervals used in the study, the absorption peaked and declined so rapidly that it wasn’t possible to depict anything more than a vertical line.
Here is another view of that image with a grid superimposed on it to better illustrate how the concentration changed with increments of time.
As you can see, even with piperine added, the concentration of curcumin dropped off to half of the peak amount within the next 6-7 minutes. In another 6-7 minutes, it had dropped to about .025µg/ml, a very small amount. It slowly dropped from there to zero over the next two hours. When you take a good look at the graph, it’s obvious that the 2000% claim is valid for only a very brief moment in time, too small to even say how long. Yet the claims for most curcumin extracts give the impression that their product has 2000% better absorption over some carefully unspecified, but much longer, period of time.
It is clear that the piperine did provide some benefit here. Why so short a time frame, though, if black pepper really is all that helpful for absorption? The answer is that without the presence of a lipid (fat), very little curcumin was absorbed even with the piperine added. When you start with a level very close to zero, multiplying it by 20 still doesn’t give you very much. Another possibility for this specific trial is the small amount of curcumin ingested by the human volunteers. Other trials have used much larger amounts and found much higher serum concentrations even without the addition of piperine.

For example, in a study carried out in 2001, participants were given varying amounts of curcumin, between one and eight grams. To quote the study authors “The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of curcumin and gradually declined within 12 hours” [3]. Piperine was not included in this trial, yet the absorption of curcumin was significantly higher than the 1997 trial.

Another possible reason for the results of the 1997 study is that the participants fasted for at least 12 hours before consuming the curcumin and they were allowed only 150ml of water (slightly more than five ounces) along with the curcumin. The study did not specify how long afterward they were prevented from eating. But since blood was drawn at intervals out to six hours, it’s probably reasonable to assume that they did not eat during that time frame. In other trials where patients consumed their normal diets, absorption was almost certainly affected by the typical fat content of their meals.

So black pepper does affect the absorption of curcumin into the bloodstream. But it does so indirectly, by slowing the metabolism of curcumin to less effective forms such as tetrahydrocurumin and the other metabolites, so that more curcumin is available to be absorbed over a longer period of time. Black pepper also acts to expand the brush border of the epithelial cells lining the small intestine, allowing a greater surface area for absorption.

However—and this is what all the debate about absorption boils down to--if no fat is present to convey the fat-soluble curcumin across that border, the amount that’s absorbed will still be small. While black pepper (or some other source of CYP3A4 inhibition) is an important point in curcumin bioavailability, it is the presence of a lipid that allows absorption through the intestinal lining into the lymph system and from there to the bloodstream.

References
1. Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses
https://www.ncbi.nlm.nih.gov/pubmed/25547723

2. Intestinal drug metabolism and antitransport processes: A potential paradigm shift in oral drug delivery
https://www.sciencedirect.com/science/article/pii/0168365995001476

3. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.
https://www.ncbi.nlm.nih.gov/pubmed/11712783