Originally published in All About Spices, reprinted by permission
1. Basic information
2. Pepper and metabolism
3. Pepper as an anti-inflammatory
4. Cannabinoids in pepper
5. Pepper in wine
6. Pepper and Vitiligo
7. Black pepper and the pancreas
8. Black pepper and Epilepsy
9. Non-dietary uses for black pepper (including its essential oil)
A glossary is provided at the end, rather than trying to explain all the scientific and medical terms within the text itself.
Black pepper, from either piper nigrum or piper longa, is a small fruit with a single hollow seed. It grows on a long woody vine that climbs up whatever support it can find, and eventually trails over the top and grows back down. Pepper is a tropical plant, available to plant outdoors in tropical areas of the US, and as a house plant in temperature climates. Logee's, a tropical plant supplier in the US, sells pepper seedlings, as do several other companies..
The fruit itself is in several very thin layers (called the exocarp, the mesocarp and the endocarp) over the seed. The entire fruit and seed contain piperine, the active ingredient most often discussed.
Black pepper is made by picking the fruit when it's nearly ripe, and then allowing it to dry in the sun. The outer layers of the fruit ferment, oxidize and turn black as they dry up. White pepper starts out as unripe green peppercorns. They are soaked in water until the outer layers of the fruit begin to slough off (a process called retting). Then the seeds are polished to remove any remaining bits of the fruit. Thus white pepper consists only of the seed portion of the original fruit. For that reason, it also has more piperine per volume than either black or green peppercorns. Green peppercorns are picked and sold unripe with little additional processing. They are subject to mold and other contamination because of the moisture content. So they are often sold pickled or freeze-dried. Mature red peppercorns are also sometimes sold in pepper mixtures. However, the pink ‘peppercorns’ in many mixtures are not pepper, but the fruit of another plant and do not contain piperine.
Black pepper is one of the oldest of the commercially traded spices, with a documented history going back thousands of years. It originated in India, and is still widely grown there. But other countries, primarily Vietnam, have entered the world market and now dominate it. Our organic pepper comes from India. Malabar is the most widely sold variety of piper nigrum. A distinction is made by some writers between Malabar and Tellicherry pepper. Tellicherry is not a separate variety, nor is it Malabar pepper grown on the slopes of Mt. Tellicherry, or any of the other fanciful claims made across the internet. Tellicherry is pepper that has been selected out of a harvest for the largest fruits. There are fewer of these large fruits in any given lot of harvested pepper, and Tellicherry pepper therefore costs more. That is the only difference. The variety is still Malabar.
Black pepper has as long a medical history as a culinary one. Early medical practitioners valued it to treat indigestion, constipation, joint pain, liver problems, and even sexual dysfunction-it was thought to be an aphrodaisiac. Now we know that many of those beliefs were valid (well, maybe not the aphrodaisiac!).
One of pepper's properties is its ability to affect the metabolism of other substances, both foods and drugs. This can have both good and bad consequences. Piperine, the primary active part of black pepper, slows down the metabolism of curcumin, one of the active constituents of turmeric, and allows it to remain effective in the body for much longer than it would without the pepper. On the other hand, piperine also slows down the metabolism of opioids, most antidepressants and antipsychotics, and many other drugs whose dosage depends on the rate of clearance. Having pepper along with those drugs can result in too high a level in the bloodstream
Before you panic and throw away the pepper on your dinner table, the use of pepper to flavor foods at the table is usually not a problem. The pepper sold pre-ground for use in pepper shakers will have lost most of its piperine before it's consumed. But if you're in the habit of grinding fresh pepper all over your plate at every meal, even as much as 1 gram (approximately 1/2 tsp) has been found to inhibit metabolism of some classes of drugs. 
How does black pepper accomplish this feat? By way of two mechanisms. Black pepper inhibits a family of enzymes known as cytochrome P450 3A, usually abbreviated "CYP3A." There are multiple variants in this family, and pepper inhibits two of them (CYP3A4 and CYP3A5). These enzymes are expressed both in the liver and the small intestine (though the amount of CYP3A5 is very small). They participate in the metabolism of a very wide range of commonly prescribed medications, and many foods as well. Some of these are listed in this Wikipedia article
. Other inhibitors and inducers of CYP3A4 are listed in the second and third columns of the table. Piperine is noted under the 'Unspecified Potency' section of the inhibitors. Other sources and research have reported it to be a moderate inhibitor.
Piperine also inhibits the drug transporter P-glycoprotein. P-gp is a protein that resides in cell membranes, and moves toxins or unwanted metabolites out of cells. In the liver, P-glycoprotein pumps them into the bile ducts. In the blood-brain barrier, it pumps them back into the capillaries. Inhibiting this function might sound like a bad thing to do, and in some cases, it is. Keeping P-gp from doing its job can result in undesirable levels of drugs or toxins in the body. On the other hand, some tumors produce large amounts of P-gp, which allows them to expel the cancer drugs used to kill them. In that case, inhibiting its mechanism is good, and pepper is being investigated for its possible role in combating cancer. It's known that pepper can enhance the mechanisms of some anti-cancer drugs, because it prevents the tumor cells from getting rid of the drugs.
Doctors have known for years that some groups of people seem to metabolize drugs differently than others, and it appears now that dietary pepper may play a part in that difference. "First-pass" metabolism (the ability to metabolize a food or drug in the liver and small intestine, before it ever reaches the bloodstream), is a problem for many drugs. Pepper's ability to inhibit this intestinal metabolism may allow drug combinations that avoid being prematurely metabolized. It may also allow doctors to prescribe smaller amounts of some drugs, if they can be combined with the piperine from pepper 
What should you be aware of if you're on prescription medications and you also like to have a lot of pepper? The first thing, as mentioned above, is that if you're using pre-ground pepper in a pepper shaker, you're unlikely to have any problems. If you're adding substantial amounts of freshly ground pepper to your food, keep it under one gram (approximately 1/2 teaspoonful total) a day). That's still quite a lot of pepper. And of course, talk to your doctor if you have any concern about your medication interacting with pepper.
Please note that you do not need to worry about bell peppers. They're in the capsicum family and do not contain piperine. However, hot peppers (chili peppers) do contain capsaicin, which has the same inhibitory effect on the CYP3A family as piperine. It is much less potent, though, and not typically a problem unless you consume large amounts.
Black pepper as an anti-inflammatory
Black pepper is anti-inflammatory, thus helping with many kinds of inflammation-related pain. One study looked at the effect of piperine on human chondrocytes. They were pre-treated with piperine at three different concentrations, and then exposed to IL-1ß, a known component of the inflammatory reponse. The treated cells showed a far lower expression of the COX-2 enzymes and other markers for inflammation 
Another study looked at the typical damage caused by rheumatoid arthritis. There are two types of specialized cells in the joints, one of which is called 'fibroplast-like synoviocytes.' These cells line the synovium and secrete chemicals that help to lubricate the joint. But when inflammatory processes begin, as in rheumatoid arthritis, they lose the properties that inhibit their proliferation and begin to reproduce far beyond their normal numbers. They also start to produce inflammatory chemicals such as interleukin-6, interleukin-8 and prostaglandins. In a study with artificially induced rheumatoid arthritis in rats, piperine was found to inhibit the growth of fibroplast-like synoviocytes and to reduce the expression of IL-6, IL-8 and prostaglandins. 
A study of plants used in indigenous cultures in Asia found that piper longa, a close relative of the more common piper nigrum, inhibited paw swelling in rats by suppressing the intracellular adhesion stimulated by TNF-a 
In a Chinese study, mice were injected with staphylococcus aureus, a bacterium responsible for many instances of severe, even fatal, infections. One group of mice had been pre-treated with varying doses of piperine. The trial found that all but one inflammatory indicator was reduced by the piperine. It's important to note that a study where mice are injected intra-peritoneally can't be directly compared to a human ingesting pepper orally. But in vitro tissue studies showed similar results 
Black pepper contains a cannabinoid
You may have read recently that several varieties of black pepper contain the sesquiterpine ßcaryophyllene, a cannabinoid. No, you can't get high on pepper-it affects only the CB2 cannbinoid receptors. The CB1 receptors are the ones responsible for psychoactive reactions to cannabinoids. CB2 receptor agonists reduce pain 
, inhibit inflammation 
, may help with osteoporosis and may stimulate the immune system 
. The extent to which pepper can be utilized in pharmaceuticals remains to be seen, but you can add freshly ground pepper to your food right now to take advantage of the ßcaryophyllene in it. In fact, this is another reason to use pepper in its original forma as a whole food, rather than just a piperine extract.
Black pepper and wine
Wine, you say? No, you don't put black pepper in wine. But some wines do have a distinct black pepper aroma and tang. Syrah from the northern Rhône valley of France, and Shiraz from Australia are two of the better known, but there are others as well, including the ever popular Zinfandel. It turns out that rotundone, a sesquiterpene found in black pepper, is also present in the skins of some wine grape varieties. Rotundone is one of the volatile compounds in some well known herbs as well, including thyme, marjoram and rosemary.
Pepper and Vitiligo
Coumponds in black pepper have been found to increase the presence of melanocytes. While investigating folk remedies for vitiligo, researchers found that a hot water extract of black pepper was used successfully to treat the condition. They determined that this extract promoted growth of the pigment cells in vitro. An extract of piperine was successful as well in people. The traditional Ayurveda preparation known as Trikatu (which combines piper nigrum, piper longa and ginger) has been widely used for skin conditions in India, including vitiligo. One trial found that a chloroform extract of P. nigrum (which included other compounds besides piperine) stimulated more melanocyte production than piperine alone, indicating that other compounds in the pepper, besides just piperine, contributed to the activity 
Black pepper and the pancreas
Another important mechanism of black pepper is to increase the secretion of pancreatic enzymes. These enzymes exist in "pre-cursor" form in tiny organelles in the pancreas. Elaborate protocols exist in the pancreas, liver and small intestine to activate these pre-cursors in the correct places (in other words, NOT in the pancreas, to prevent the pancreas from trying to digest itself). The activation of these pre-cursors is managed by a tightly controlled cascade of events that takes place in both the pancreas and the small intestine. For example, chymotrypsinogen is converted into chymotrypsin only in the duodenum, not in the pancreas itself. Another pre-cursor, pepsinogen, should be activated only when it encounters hydrochloric acid in gastric secretions, where it's converted in several steps into pepsin. If the secretion duct from the pancreas to the small intestine is blocked by a gallstone, this activation can take place in the pancreas itself.
The causes of idiopathic chronic pancreatitis are not well understood. But one thought is that a decrease in the secretion of pancreatic juices (particularly trypsinogen and chymotrypsinogen) may be a factor. When this happens, the organelles carrying these pre-cursors may fuse with another type of organelle called lysosomes, resulting in early conversion (within the pancreas, in other words) of trypsinogen into trypsin. Trypsin itself converts more trypsinogen into trypsin, and also converts chymotrypsinogen into chymotrypsin. The resulting damage to the pancreas causes bleeding from increased capillary permeability, inflammation and impaired lipid (fat) digestion. The inflammation provokes a systemic immune response that results in an increase in white blood cell and cytokine production. This is classic pancreatitis. Since the piperine in black pepper increases the secretion of the pancreatic enzymes, it may help to reduce the incidence of idiopathic pancreatitis.
In a 2000 study conducted on female Wistar rats, piperine was found to increase all four of the major enzymes: lipase, amylase, trypsin and chymotrypsin 
. It's worth mentioning that a single dose of piperine did not change the enzyme levels.
Other studies have found similar results in both rats and human pancreatic tissue. The message, of course, is that a single dose of black pepper (or any of the other spices in the trial) doesn't provide any benefit. You need to adopt a pattern of good eating in order to see results.
Black pepper has also been found to reduce the inflammation and damage caused by deliberately induced pancreatitis in mice.
…piperine pretreatment reduced the production of tumor necrosis factor (TNF)-a, interleukin (IL)-1ß, and IL-6 during cerulein-induced AP [Acute Pancreatitis]. In accordance with in vivo results, piperine reduced cell death, amylase and lipase activity, and cytokine production in isolated cerulein-treated pancreatic acinar cells. In addition, piperine inhibited the activation of mitogen-activated protein kinases (MAPKs). These findings suggest that the anti-inflammatory effect of piperine in cerulein-induced AP is mediated by inhibiting the activation of MAPKs.
Thus, piperine may have a protective effect against AP .
Black pepper and epilepsy
Acting on reports of traditional African medications, researchers tested extracts from a specific variety of black pepper, Piper guineense L., against tonic/clonic seizures in mice. This may be of academic interest only in most parts of the world Piper guineense is not easily available everywhere. But the results suggest that additional studies might prove to be useful 
Non-dietary uses for black pepper
Black pepper is used in many parts of the world as an insecticide. With all the recent talk of the Zika virus, it's pertinent to note that an extract of piper nigrum was found effective against the larvae of Aedes aegypti, one of the mosquitos that carry Zika 
Black pepper essential oil is widely used in the perfume industry. In fact, until the popularity of turmeric spurred interest in black pepper as well, perfumery was the primary market for the use of black pepper essential oil 
Can you use black pepper essential oil in Golden Paste instead of black pepper itself?
At the current time, the answer to that is no. Piperine is present in both the fruit and the seed, but the process of making the EO leaves it behind. A representative of one company that manufacturers black pepper essential oil told us specifically that no attempt is made to add it to back in to their products, and that no other manufacturer he knew of did so either.
Agonist: a chemical that binds to a cell receptor and activates the receptor to produce a specific response.
Cannabinoid: one of a class of compounds that acts on the cannabinoid receptors in certain kinds of cells.
Cytokines: proteins that participate in cell signalling.
Drug Transporter: drug transporters are proteins which move substances in and out of specific cells, in order that those substances may be used by the cells, or to remove toxins or unwanted substances from the cells.
Duodenum: the first and shortest segment of the small intestine, the part that connects to the stomach.
In vitro: processes that take place in test tubes or culture dishes rather than in a living body. Often the first step in research that may lead to in vivo (in a living body) work later.
Idiopathic: of unknown origin.
Interleukin: A group of signalling proteins that participate in almost all immune system functions. While they are vital to proper immune responses, an over-abundance can contribute to inflammatory processes.
Melanocytes: skin cells that produce the pigment melanin.
Metabolism: the processes by which anything ingested by an organism is converted and/or broken down in preparation for being used or excreted.
Oleoresin: a resin in solution in an oil.
Piperine: the primary active constituent of piper nigrum and the other black pepper varieties.
Prostaglandins: A group of compounds that exhibit hormone-like activity. One particular class of these is involved with inflammation through the production of COX-1 and COX-2 enzymes.
Retting: to soak in water or expose to moisture, to remove unwanted woody or fibrous material.
Sesquiterpine: One of the class of terpenes, hydrocarbon molecules in a specific ring formation. Terpenes are found in the essential oils and resins of plants such as conifers. Turpentine is one well know terpene.
Synoviocytes: A specialized type of cell that lines the interior of joint synovia (the fluid filled capsule that protects the bones in a joint from contacting each other).
TNF-a: sometimes written TNF-alpha, it's short for Tumor Necrosis Factor-alpha. TNF is an important signalling protein in immune system processes.
Vitiligo: a skin condition caused by the destruction of melanocytes, the cells that product the skin pigment. Vitiligo may appear in small patches or in much larger areas of the skin.
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