Piperine

Piperine is the chemical that gives black pepper its spice. In addition to this, piperine prevents inflammation and oxidative stress and has shown promise in treating numerous diseases such as diabetes, epilepsy, white spot disease and Parkinson's disease. It may also stimulate metabolism, accelerate weight loss, improve cholesterol levels and brain function, and relieve pain.

What is black pepper?

Black pepper is the most widely used spice in the world. Long before scientific research could explain how black pepper works, it was used in folk medicine to treat numerous ailments including rheumatism, flu, muscle aches, chills, fever, migraines and digestive problems. In addition to this, black pepper has been used to stimulate circulation and appetite (1). Piperine is the active ingredient in black pepper and is responsible for many of the effects of this spice. Piperine is what gives black pepper its characteristic pungent flavor (2, 3). In its pure form, piperine is a white or slightly yellowish powder. It tastes similar to pepper and accounts for 98% of the alkaloids found in black pepper (4, 3). Piperine is classified as a cinnamamide. This group of chemicals has sedative, antispasmodic and antidepressant effects (5). Piperine has numerous potential health benefits. It may protect against inflammation, improve cognitive function, mood, cholesterol levels and blood pressure, and alleviate allergies.

In addition to this, piperine acts as an antioxidant and can increase the bioavailability of other drugs and supplements, meaning that the body can utilize these active ingredients more effectively.

Mechanisms of action of piperine

Piperine has many potential effects on the body. These include, but are not limited to:

A reduction in inflammation: Piperine can reduce the levels of certain cytokines that promote inflammation (IL-1b, TNF-α and PGE2), as well as increase the levels of cytokines that reduce inflammation (IL-10) (6).
An increase in the bioavailability of many drugs and supplements: By inhibiting the detoxifying enzymes that break down drug compounds (such as CYP3A4) and increasing the absorption of drugs/supplements in the digestive tract, piperine can increase the body's ability to utilize these compounds (7).
An antioxidant effect: piperine acts directly as a hydroxyl and superoxide free radical scavenger (8).
Inhibition of prostaglandins (hormone-like fats): This can help with diarrhea (9).
An increase in dopamine and serotonin levels in the brain: This can help to improve mood and cognitive function, as well as prevent neurodegenerative diseases (10, 11).
An increase in the rate of muscle metabolism through an increase in ATPase activity. This could increase energy utilization by the muscles and support weight loss (12).

Potential health benefits of piperine

Many of the human studies cited below were conducted using a combination of curcumin with piperine. However, many in vivo or animal studies have shown that piperine alone has the same effects.

Piperine can increase the bioavailability of drugs and supplements

Piperine was identified in 1979 as the very first substance to increase the bioavailability of other substances (13, 7). In other words, piperine increases the body's ability to utilize nutrients and drugs (14).

This means that lower or less frequent doses of a drug can be used to achieve the same effect. This is very useful when it comes to drugs that have unwanted side effects.

Piperine does this via the following mechanisms (7):

Piperine prevents the body from breaking down some drugs by blocking drug-metabolizing enzymes (such as CYP3A4, CYP2E1, CYP1B1, and CYP1B2) in the liver.
Piperine increases the amount of active drug ingredients and nutrients absorbed through the digestive tract by stimulating the transport systems in the digestive tract. For example, piperine can increase the bioavailability of curcumin - a compound found in turmeric - by 154% in rats and 2000% in humans (15).

Piperine also increased blood concentrations and lifespan of the anticonvulsant drug carbamazepine in 2 studies of 32 people, possibly by blocking the enzyme CPY3A4, which breaks down this drug. Similarly, in another study, piperine increased the bioavailability of the muscle relaxant chlorzoxazone by blocking the enzyme CYP2E1 (16, 17, 18).

All herbal extracts that combine piperine and curcumin increased the bioavailability of the sedative midazolam, the anti-inflammatory flurbiprofen and the painkiller Tylenol in a study involving 8 healthy volunteers (19).

A drug delivery system composed of piperine lisopherene increased the bioavailability of THC and CBD compared to the prescription spray Sativex in a small study of 9 healthy volunteers (20).

Overall, evidence suggests that piperine increases the bioavailability of many substances. This may mean that the amount of medication needs to be adjusted in consultation with the treating physician.

Piperine acts as an antioxidant

Piperine can protect against oxidative stress by neutralizing free radicals (8). In a small study of 20 people with pancreatitis, a combination of 500 mg curcumin and 5 mg piperine improved the antioxidant status of the subjects (lower fat peroxidation and MDA and higher glutathione levels). Combinations with the same ratio of curcumin and piperine also improved antioxidant status in 3 other studies involving over 100 subjects with metabolic syndrome, nearly 100 subjects with chronic lung disease, and 40 subjects with osteoarthritis (21, 22, 23, 24).

Together with everyday risk factors such as pollution and radiation, a high-fat diet can increase the production of free radicals. When rats fed a high-fat diet were given piperine, their free radical levels decreased. Piperine also increased the levels of enzymes that neutralize free radicals (SOD, CAT, GPx and GST) (25, 26). In a cell study, low doses of piperine reduced free radical levels. However, very low doses can stimulate the production of free radicals (8).

Piperine has anti-inflammatory properties.

In a clinical study of over 100 subjects with type 2 diabetes or metabolic syndrome, a combination of curcumin and piperine had anti-inflammatory effects (as measured by lower CRP levels). However, this mix contained 100 times more curcumin than piperine (22). A similar mix also reduced inflammation (reduced levels of IL4, IL6 and CRP) in a clinical study of 40 subjects with osteoarthritis (27). In rats, piperine alone reduced short- and long-term symptoms of inflammation (28). In rats with arthritis, piperine reduced pain and size of swelling areas at the joints (and reduced pro-inflammatory molecules such as IL-6, MMP13 and PGE) (29). In rats with gum disease (periodontitis), piperine reduced gum inflammation and bone resorption. It also reduced the production of the pro-inflammatory molecules IL-1β, MMP-8 and MMP-13 (30).

In addition, piperine reduced inflammation of the uterus (endometriosis) in mice (31).

Piperine can improve cholesterol levels

In 2 clinical trials involving over 200 people with type 2 diabetes or metabolic syndrome, a combination of 1,000 mg curcumin and 10 mg piperine per day lowered total cholesterol levels, LDL and VLDL cholesterol levels, while increasing levels of good HDL cholesterol (32) In another study, rats with high fat and cholesterol levels in their blood were fed piperine for three weeks. Without changing their diet, there was a reduction in total cholesterol, LDL and VLDL cholesterol levels, while at the same time the levels of good HDL cholesterol increased (33).

Piperine could be useful in metabolic syndrome

As mentioned above, a combination of 1,000 mg curcumin and 10 mg piperine per day improved oxidative status, inflammatory status and blood lipid levels in two clinical trials involving over 200 subjects (22, 34). In rats with metabolic syndrome, piperine was able to lower blood pressure, improve glucose tolerance, reduce markers of oxidative stress and inflammation, prevent tissue damage and inflammation of the liver (fibrosis) and improve liver function (35).

Piperine can lower blood sugar levels

In a clinical study involving 100 subjects with type 2 diabetes, a combination of 500 mg curcumin and 5 mg piperine lowered blood glucose levels and reduced liver damage (36). In diabetic rats, a low dose of piperine reduced blood glucose levels. In contrast, higher doses increased blood glucose levels (37).

Piperine could help with white spot disease

White spot disease is a condition in which areas of the skin lose their pigmentation over time. In a clinical study of 63 subjects suffering from this condition, a combination therapy of piperine and UV-B radiation promoted skin repigmentation (38).

Piperine can improve cognitive function

Several studies conducted with animals suggest that piperine can improve brain function (39, 40).

For example, rats fed piperine learned faster and remembered longer (41). It also improved brain function in rats with Alzheimer's disease. Rats fed piperine showed increased memory function compared to rats in the control group (39, 40). Piperine protected the hippocampus and cerebrospinal fluid from free radicals. It also stimulated the growth of brain cells in the hippocampus - an area of the brain that is heavily involved in memory (39, 40).

Piperine could alleviate depression

In mice exposed to chronic stress, piperine had antidepressant effects. These were associated with increased production of new brain cells and increased BDNF levels in the hippocampus (42).

Another study showed that a two-week administration of piperine alleviated depression in mice. It also increased serotonin levels in the hippocampus and hypothalamus (43).

Depression is common in epilepsy. In rats with epilepsy, piperine reduced symptoms of depression and increased serotonin levels (11).

The ability of piperine to enhance the effects of other compounds may also be helpful when it comes to depression. Resveratrol is a compound that can alleviate depression, and this antidepressant works better in mice when combined with piperine (44).

Piperine could be helpful for Parkinson's

In mice with Parkinson's disease, piperine improved motor control. It also improved brain function and learning (45).

Increasing dopamine levels is the most widely used method to treat Parkinson's disease. Piperine inhibits MAO-A and MAO-B - the enzymes that break down dopamine - which may increase dopamine levels in the brain (10).

Piperine also prevented the death of dopamine neurons in mice. It protects the neurons as it has antioxidant and anti-inflammatory properties and prevents programmed cell death (45).

Piperine could alleviate allergies

Piperine reduces inflammation and suppresses excessive immune system responses, making it a good candidate for the prevention and treatment of allergies (46, 47). In mice, piperine reduced sneezing, nasal itching and other symptoms of allergies. It dose-dependently reduced levels of histamines, nitric oxide, IgE and pro-inflammatory cytokines such as IL-6 and IL1b (46).

Piperine can relieve pain

Just 5 mg of piperine per kilogram of body weight reduced pain in rats and mice. In humans, the equivalent dose is 1/6 teaspoon (48). Another study showed that higher doses in the range of 30 to 70 mg per kilogram of body weight had a similar effect to the painkiller indomethacin (49).

Piperine could support weight loss

Rats with high blood lipid levels and cholesterol lost weight when piperine was added to their diet (33).

In addition, piperine increased the number of calories burned in isolated muscle from rabbits. This increase in metabolic rate could be another explanation for piperine supporting weight loss in animals (12). In addition, piperine prevented and slowed the production of fat cells (50).

Piperine could lower blood pressure

Piperine caused a significant drop in average blood pressure in rats (51). In another study with rats, piperine was able to partially prevent an increase in blood pressure caused by a drug (a NOS inhibitor) (52). High blood pressure can cause stiffening of the arterial walls, which is one of the predictors of heart disease and stroke. In rats, piperine prevented hardening of the arterial walls and kept the arteries young and flexible (52).

Piperine could prevent gallstones

Gallstones form when cholesterol crystallizes in the gallbladder. Piperine prevented the formation of cholesterol gallstones in mice by reducing the size of cholesterol crystals and reducing the transport of cholesterol from the liver into the gallbladder (53).

Piperine could increase nutrient absorption in the digestive tract

Preliminary research suggests that piperine allows the body to absorb more nutrients by facilitating the passage of nutrients through the intestinal membrane. Piperine may also increase the surface area of the intestine that can absorb nutrients from food, further increasing the efficiency of the intestine (54).

Piperine could relieve diarrhea

Piperine prevented diarrhea in mice. In rabbits and pigs, it worked as well as loperamide - a drug used to treat diarrhea - but without causing the side effects characteristic of loperamide (9, 55).

It also has antispasmodic effects, which can reduce spasms in the digestive tract (55).

Piperine could prevent stomach ulcers

Piperine prevented the formation of gastric ulcers in rats and mice. It was effective against stomach ulcers caused by stress, stomach acid and the painkiller indomethacin (57). Heliobacter pylori is a bacterium that can cause chronic gastritis, stomach ulcers and, in rare cases, stomach cancer. Piperine inhibited the growth of the bacterium and inhibited its adhesion to cells, reducing the risk of infection (58).

Piperine could prevent seizures

In many (but not all) rodent models of epilepsy, piperine reduced the number of seizures and deaths due to seizures at doses in the range of 10 mg per kilogram of body weight (59, 60).

Piperine may have anti-cancer effects

The following studies are preliminary and are still in the cell or animal stage. Further research is needed to determine whether piperine can be used for therapeutic purposes. Under no circumstances should piperine be used as a substitute for existing cancer therapy. In skin cancer, piperine prevented the spread of tumor cells to other parts of the body (metastases), resulting in a significantly higher survival rate in mice (61). It also reduced tumor growth and metastasis in mice with breast cancer (62). In addition, piperine prevented breast cancer and reduced cancer growth in rats with an efficiency of 80 to 90% (63). It also slowed the growth of colon, prostate and breast cancer cells (64, 65, 62).

The anti-cancer effect of piperine could be based on the following mechanisms:

Piperine stimulates the formation of free radicals in cancer cells - the same thing it protects the rest of the body's cells from as an antioxidant (63, 65).
It reduces the levels of cyclin B1 - a protein that is responsible for cell division (66).
It causes programmed cell death (apoptosis) of cancer cells by increasing the activity of capsase 3 (65, 66).

In addition, piperine increased the bioavailability of tumor-fighting drugs in animal models, thereby enhancing their effect (67).

Piperine could slow down the passage of food through the digestive tract

One study looked at the movement of food and fluids through the digestive tract of mice and rats. Low doses of piperine (1 to 1.3 mg per kilogram of body weight) increased the time it took for solid food to pass through the digestive tract. No change was observed in liquid gliders (68).

Another study showed that doses as low as 0.5 mg per kilogram of body weight slowed the passage of food through the digestive tract (69). Slowing the passage of food through the digestive tract reduces hunger, which is why piperine could potentially reduce hunger and weight (70).

Side effects and precautions

It should be kept in mind that due to the lack of high-quality studies, relatively little is known about the safety profile of piperine. In general, however, piperine is non-toxic and has relatively few side effects.

One human study reported that piperine had minor adverse side effects (15). Some humans reported nausea and stomach upset after using piperine. In rats, even a dosage equivalent to 250 times the human dose was not toxic (2).

It was once thought that piperine might be carcinogenic because its structure was similar to that of some carcinogenic chemicals. However, recent preliminary study results suggest that piperine may actually protect against cancer (71, 72). Piperine could lower thyroid hormone levels. In mice, 2.5 mg of piperine per day could lower thyroid hormone levels as much as a thyroid hormone-lowering drug (79).

Piperine could influence the function of the immune system. In some studies, piperine was able to reduce the number of T and B cells of the immune system and their activity in mice. In addition, it reduced the production of molecules that increase immune function (IFN-gamma, IL-2, IL-4, IgM, IgG2b, IgG3) (80, 81, 82). However, other studies indicate that piperine improves immune function in mice (83).

In addition, piperine could reduce fertility. In mice, it caused damage to sperm and reduced egg fertilization by 50% in female mice (84, 85). Finally, piperine may increase the bioavailability of toxins in the same way that it increases the bioavailability of drugs and supplements. For example, rats given piperine accumulated larger amounts of the fungal toxin aflatoxin B1 - a toxin that can cause liver damage and cancer - in their tissues (86).

Interactions of piperine with medications

Piperine increases the bioavailability of many substances, which means that it helps the body to use these substances more effectively. For this reason, piperine can enhance the effects of some medications and supplements, even at lower doses (73).

Piperine can enhance the effects of many drugs (including those that are broken down by the enzymes CPY3A4 and CYP2E1):

Diclofenac (a non-steroidal anti-inflammatory drug)
Ibuprofen (a non-steroidal anti-inflammatory drug)
Fexofenadine (an allergy medication)
Carbamazepine (an antiepileptic drug)
Chlorzoxazone (a muscle relaxant)
Ampicillin trihydrate (a type of penicillin, an antibiotic)
Norfloxacin (an antibiotic)
Nevirapine (an HIV medication)
Domperidone (an anti-emetic)
Docetaxel (an anti-cancer drug)
Glimepiride (a diabetes medication)
Nateglinide (a diabetes medication)
Metformin (a diabetes medication)

Piperine can also enhance the effects of supplements such as beta-carotene, curcumin and resveratrol ( 74, 15, 75). However, it prevented the anti-diabetic effects of curcumin in rats (76).

Sources of piperine

Regular black pepper contains between 0.4 and 7% piperine (3). Slightly lower amounts are found in white pepper and other types of pepper. To consume 1 gram of piperine, you would need to consume more than 6 teaspoons of piperine.

In addition, piperine is available in the form of supplements.

Dosages

As piperine is not an approved drug, there are no official dosage recommendations. Recommendations for supplements are the result of trial and error.

In humans, a dose of 20 mg piperine per day can increase the bioavailability of curcumin (15).

There are only a few human studies that have been conducted with piperine. The following doses have been shown to be effective in mice and rats. However, these doses are not directly transferable to humans:

For pain relief: 30 - 70 mg per kilogram of body weight (49).
To improve brain function: 5 - 50 mg per kilogram of body weight (77).
To lower blood pressure: 10 mg per kilogram of body weight (51).
For antioxidant effects: 20 mg per kilogram of body weight (78).