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4+ Potential Benefits of Limonene + Side Effects

Written by Puya Yazdi, MD | Last updated:
Evguenia Alechine
Jonathan Ritter
Medically reviewed by
Evguenia Alechine, PhD (Biochemistry), Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Puya Yazdi, MD | Last updated:

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Limonene

Limonene is a compound naturally found in all citrus fruits. It has been used to dissolve gallstones, while limited evidence suggests it may relieve pain and heartburn. How strong is the evidence? Read on to find out.

What is Limonene?

Limonene is found in the oils of many citrus fruits, including lemon, orange, mandarin, lime, and grapefruit [1].

Limonene is added to numerous foods, drinks, perfumes, soaps, and chewing gum as a flavor and fragrance enhancer [1].

Mechanisms of Action

Researchers have investigated the biochemical mechanism of limonene in animal and cell studies. This is a summary of their findings. In laboratory settings, limonene:

  • Prevented the growth of cancer cells by inhibiting G proteins that are involved in cell signaling pathways that induce cell growth, such as p21ras. Limonene inhibits post-translational addition of hydrophobic groups to the G protein peptide precursor, which is necessary for the proteins to mature and function properly [2].
  • Suppressed the expression of genes that produce MMPs, proteins that break down the extracellular matrix. Limonene also increased antioxidant, inducible iNOS, COX‑2, and ERK expression levels in rats, contributing to its antioxidant and anti-inflammatory effects [3].
  • Increased the ability of docetaxel to induce apoptosis in prostate cancer cells. More reactive oxygen species are produced in the cancer cells, while the amount of glutathione, an antioxidant that inhibits tumor growth, is significantly reduced. The activity of caspase, an enzyme involved in triggering apoptosis, is also increased [4].
  • Reduced TNF-α and inhibits TNF-α-induced NF-κB translocation, reducing inflammation [5, 6].
  • Along with the product of its breakdown, perillyl alcohol (POH), helped prevent the HPA axis from being overstimulated, which reduced stress [7].
  • Reduced breast cancer growth by inhibiting the expression of cyclin D1 and IL-6. Cyclin D1 speeds up the progression of a cell through the cell cycle, allowing cancer cells to proliferate faster. Since cyclin D1 is overexpressed in many breast cancers, the ability of limonene to reduce the expression of cyclin D1 suggests that limonene could help slow down breast cancer growth [8].
  • In stomach cancer cells, decreased BCL2 and increased p53, inhibiting the spread of cancer [9].

The essential oil of Citrus aurantium exhibited anti-anxiety activity through interaction with serotonin receptors. Limonene interacted with 5-HT1A receptors to reduce anxiety, but the exact mechanism is still unknown [10].

Potential Health Benefits of Limonene

Limonene supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

Possibly Effective For

1) Gallstones

In a study of 200 patients, 20 – 30 mL of a 97% limonene solution injected into the biliary system dissolved gallstones completely in almost half of the patients, with partial dissolution in another 14.5%. The researchers noted that the procedure was safe, without adverse events [11, 1].

Limonene, given every other day as a biliary injection, dissolved the remaining gallstones after surgical gallstone removal in a pilot trial of three patients. In a fourth patient, limonene was given instead of performing surgery, but this was not successful [12].

It is unknown whether limonene has any effect on gallstones when taken as a supplement. The biliary injection of limonene is experimental—don’t try this at home.

Insufficient Evidence For

The following purported benefits are only supported by limited, low-quality clinical studies. There is insufficient evidence to support the use of limonene for any of the below listed uses. Remember to speak with a doctor before taking limonene supplements, and never use them in place of something your doctor recommends or prescribes.

2) Pain

In rats, limonene reduced pain (induced by physical stresses) and sensitivity to pain [13].

Limonene reduced widespread pain in the bones and muscles of mice, likely by acting on nerves [14].

Inhaling limonene reduced pain severity in 63 women (out of 126 women in labor with similar levels of pain) [15].

Limonene as an aromatherapy agent reduced nausea, vomiting, and pain during the first stage of labor in a study (DB-RCT) of 100 pregnant women [16].

3) Heartburn

In a study of 19 people taking heartburn medications, 17 had no heartburn symptoms after taking only limonene daily for two weeks [1].

Another study (DB-RCT) of 13 participants found that, after two weeks, limonene relieved heartburn symptoms in all but one of the patients [1].

4) Bowel Movements

In a very small study of 5 healthy adults, limonene increases bowel movements, which can promote regularity in people who struggle with regular bowel habits [17].

Animal Research (Lacking Evidence)

No clinical evidence supports the use of limonene for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

5) Immune System

Healthy mice treated with limonene produced significantly more antibodies when exposed to foreign antigens and stimulated immune cells in the pancreas and intestines [18].

In mice with lymphoma, limonene improved survival, increased their ability to fight bacterial infections, and reduced hypersensitivity to foreign compounds, which can ultimately reduce allergic reactions [19].

Limonene increased the activity of macrophages (white blood cells that engulf foreign particles) in the lungs of rats in a dose-dependent manner [20].

6) Stress, Anxiety, and Depression

Limonene exerts a significant anti-stress action on animals in addition to its anti-inflammatory effects. Limonene decreased stress in rats under environmental stress [7].

Basil essential oil, which contains limonene, showed anti-anxiety and sedative effects in mice. However, due to the presence of other compounds in the oil, these effects may not be due to limonene alone [21].

While bitter orange essential oil (also contains limonene) has anti-anxiety and sedative effects, limonene extract failed to show the same effects. This may be due to the interaction of limonene with other compounds [10].

Another study showed that essential oil of Brazilian Peppertree (S. terebinthifolius) and compounds present in this oil, including limonene and α-phellandrene, decreased sensitivity to pain and depression [13].

Mice that inhaled limonene showed significantly reduced anxiety levels. Limonene is also highly volatile, which means that it easily evaporates into a gas, making it ideal for inhaled aromatherapy [22].

7) Metabolic Syndrome and Obesity

Metabolic syndrome increases the risk of heart disease, strokes, and type 2 diabetes. This syndrome involves high blood sugar, fat, and cholesterol, insulin resistance, and high blood pressure [23].

In mice fed a high-fat diet, limonene reduced blood pressure, heart rate, and blood sugar and increased levels of antioxidants, lowering the risk of developing nonalcoholic fatty liver disease due to large amounts of fat in the liver [24].

When high blood pressure was artificially induced in rats, limonene reversed the changes in the liver and pancreas caused by oxidative stress, overwork, high blood sugar, and insulin [24].

Limonene decreased the size of fat cells, reduced glucose and fat levels in the blood, and decreased the accumulation of fat in the liver of mice fed high-fat diets [25].

In obese mice, limonene lowered blood sugar levels, reduced the amount of low-density lipoprotein (LDL) cholesterol, and raised the level of high-density lipoprotein (HDL) cholesterol in the blood [25].

Limonene also reduced overall appetite and increased breakdown of fat cells, leading to weight loss in rats [26].

8) Inflammation in the Gut

Limonene protected the gut lining and was a more effective anti-inflammatory agent than ibuprofen in rats with inflammation in the colon [6].

In a cell-based study, limonene reduced reactive oxygen species and inflammatory cytokines in human leukemia cells [27].

In rats with intestinal inflammation, limonene slowed down inflammatory bowel disease (IBD) and prevented further damage to the lining of the large intestine [3].

9) Wound Healing and Skin Repair

Due to its anti-inflammatory effects, limonene applied to the skin of mice reduced damage, inflammation, and rashes [28].

Limonene also increased the production of new cells and blood vessels and improved skin healing after an injury in mice [28].

The blood vessels of diabetics tend to be narrower and harder with poorer circulation than those of non-diabetics, which prolongs wound healing time and inflammation. Limonene applied to the skin of diabetic mice reduced inflammation and wound size and formed new skin, speeding up wound healing [29].

10) May Protect the Eyes

Oxidative stress is caused by free radicals, which damage cells. Due to its antioxidant properties, limonene protected human eye cells from damage by hydrogen peroxide, which is a natural byproduct of human metabolism [30].

Cancer Research

Human Trials

In a pilot trial in patients with advanced cancer, limonene reduced the size of lymph nodes in a female breast cancer patient [1].

In another study of 43 women with breast cancer, limonene administered before surgery decreased cyclin D1, a protein that stimulates the growth of cancer cells [8].

In a study of 32 cancer patients, one patient with breast cancer and three with colorectal cancer were given limonene, which slowed tumor growth. However, side effects like nausea, vomiting, and diarrhea prevented them from taking high doses of limonene [31].

Despite these early results, it is extremely important to talk to your doctor before supplementing with limonene if you have cancer. Each patient—and each cancer—is different, and your doctor is best positioned to determine whether limonene might be a helpful supplement to try as a complement to your therapy.

Animal & Cell Trials

Many substances have anti-cancer effects in cells, including downright toxic chemicals like bleach. This doesn’t mean that they have any medical value. On the contrary, most substances (natural or synthetic) that are researched in cancer cells fail to pass further animal studies or clinical trials due to a lack of safety or efficacy.

Limonene has antioxidant properties, allowing it to counteract the effects of free radicals, which damage DNA and lead to cancer [3, 32]. As an antioxidant, limonene can prevent cell damage and reduce the risk of cancer.

Limonene increased the effectiveness of an anti-cancer treatment with docetaxel (Taxotere) against prostate cancer cells without harming healthy cells [4].

In an animal study, orange oil with limonene reduced the growth of liver tumors, while it increased the growth of, and new connections between, normal cells [33].

Limonene also caused dose-dependent cell death in human stomach cancer cells [9].

Moreover, lemon extract prevented pancreatic and intestinal damage in mice caused by the chemotherapy drug cyclophosphamide (Cytoxan) [34].

Side Effects

While limonene is not toxic in animals even after multiple doses, it caused skin irritation and sensitivity in some cosmetics and scented household products [35].

14 people in a study developed dermatitis (skin inflammation and rashes) after using detergents, hand cleansers, and dish-washing liquids containing limonene. Three individuals exhibited this allergic reaction after using cosmetics with limonene [36]. However, these results cannot be attributed to the effect of limonene alone.

Skin patches containing limonene and linalool were worn by 4,731 individuals, and 422 (8.9%) participants developed an allergic reaction on their skin [37].

While limonene caused kidney cancer in rats, this should not affect humans since the protein involved in this particular pathway is not present in humans [35].

In a study of 32 patients with various forms of cancer, limonene caused nausea, vomiting, and diarrhea at high doses [31].

Based on various studies, limonene is safe in humans as long as it is taken in moderate amounts and for up to a year. Longer studies (2 years) were conducted with mammalian cells and rats with no negative effects [31].

Supplementation

Forms

Limonene is naturally found in the rinds of citrus fruits such as grapefruit, lemon, lime, and oranges.

Limonene can be supplemented as an oil, usually in soft gel capsules. The oil can also be used as aromatherapy or applied externally to the skin.

User Reviews

Some users stated that limonene relieved their heartburn, some even more than traditional heartburn medications, such as Nexium and Prilosec. The only reported side effect of limonene was orange-flavored burps.

Most of the reviews reported that limonene was effective in relieving heartburn, but some said that it caused nausea. In some cases, limonene helped users suffering from bloating, flatulence, and stomach pain, even though it took two weeks of use.

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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