Lycopene

Lycopene (chemical formula of C₄₀H₅₆) is a linear unsaturated hydrocarbon carotenoid, the major bright red pigment, a phytochemical found in fruits such as tomatoes and other red fruits such as papaya, pink grapefruit, apricots, red oranges, watermelon, rosehips and guavas ¹, ², ³, ⁴, ⁵. Human body cannot make lycopene on its own, so it needs to be replenished from food ⁶, ⁷. It has been estimated that 80% of the lycopene in the US diet comes from tomatoes and tomato products like tomato sauce, tomato paste, and ketchup ⁸, ⁹, ¹⁰, ¹¹, ¹². Tomatoes are also the cheapest source for lycopene production ¹³. The tomato-based products are a better source of Lycopene than raw tomatoes ¹⁰. In the United States, Lycopene consumption among men ranges from 6.6 to 10.5 mg/day and among women from 5.7 to 10.4 mg/day ¹⁴. In the European population, the average consumption of lycopene ranges from 5 to 7 mg/day ¹⁵. Eating food containing lycopene can improve body’s immune system, regulate blood fats, and prevent cardiovascular diseases ¹⁶. High intakes of lycopene-rich food or supplements may result in a deep orange discoloration of the skin known as lycopenodermia. Because lycopene is more intensely colored than the carotenes, deep orange discoloration of the skin (lycopenodermia) may occur at lower doses than carotenodermia (orange discoloration of the outermost skin layer due to excess of dietary carotenoids) ¹⁷.

Lycopene is not a provitamin A carotenoid because it cannot be converted to retinol. Lycopene is a natural pigment made by plants, lycopene helps to protect plants from light-induced stress and it also transfers light energy during photosynthesis ¹⁸. Lycopene is the most common carotenoid in the human body and is one of the most potent carotenoid antioxidants and scavenger of free radicals with antioxidant activity ranking of lycopene > alpha-carotene > beta-cryptoxanthin > zeaxanthin = beta carotene > lutein ¹⁹, ²⁰. Lycopene oxidation potential is 100 times that of vitamin E and is more than twice that of carotene ²¹, ²². Lycopene as antioxidant can neutralize reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyradicals, and nitrogen dioxide. As an antioxidant, lycopene is increasingly used in food, pharmaceuticals, and cosmetics ²³. Lycopene has also been shown to be a hypolipidemic agent to reduce lipid levels in the body which has potential for reducing cardiovascular disease, inhibitor of pro-inflammatory and pro-thrombotic factors, decreasing genetic damage, and inhibiting the occurrence and development of tumors ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹. Its name is derived from the tomato’s species classification, Solanum lycopersicum ³⁰.

In North America, 85% of dietary lycopene comes from tomato products such as tomato juice or paste. One cup (240 mL) of tomato juice provides about 23 mg of lycopene ³¹. Processing raw tomatoes using heat (in the making of tomato juice, tomato paste or ketchup, for example) actually changes the lycopene in the raw product into a form that is easier for the body to use. The lycopene in supplements is about as easy for the body to use as lycopene found in food.

• Lycopene’s absorption is improved with concurrent dietary fat intake, this is because lycopene is fat soluble and oil in tomato sauce, for example, makes it ideal for absorbing lycopene. There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing. Results of a randomized study published in 2005 demonstrated that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared with cooking tomatoes without olive oil. In another study, there was no difference in plasma lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.

Lycopene is the most abundant carotenoid in the human body, accounting for about 50% of the total carotenoid content ³². Lycopene is widely disseminated in various organs and tissues of the human body, mainly including blood, adrenal glands, testicles, and liver ³³. Generally, the content of lycopene in the serum is used to represent nutritional status of human lycopene ³⁴. Under normal conditions, the concentration of lycopene in human serum is in the range of 0.2 ∼ 1.0 µmol/L, accounting for 6.35% of total lycopene content ³⁵. It was noted that the lycopene in plants is mainly in the trans configuration, while the proportion of cis-isomer of lycopene in human body is higher ³⁴. Cis-isomer lycopene has stronger bioavailability and can be digested and absorbed more easily ³⁶. After the human body obtains lycopene from plants, lycopene enters the intestinal tract in packages of oil droplets, when are then transformed into mixed micelles ³⁷. Through digestion and absorption, the lycopene-containing chylomicrons produced by enzyme cleavage are circulated in the blood or are transported to various body organs via lipoproteins ³⁸.

Lycopene has been investigated for its role in chronic diseases, including cardiovascular disease and cancer ³⁹. Numerous epidemiological studies suggest that lycopene may help prevent cardiovascular disease by decreasing cholesterol synthesis and increasing the degradation of low-density lipoproteins (LDL or “bad” cholesterol) ⁴⁰, although some interventional studies have shown mixed results ²⁹.

A number of test tube and animal studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver ⁴¹, ³⁹. However, epidemiological studies have yielded inconsistent findings regarding lycopene’s potential in reducing cancer risk.

The few human intervention trials have been small and generally focused on intermediate endpoints and not response of clinically evident disease or overall survival and thus have limited translation to practice ¹⁸, ⁴². A Cochrane Review in 2011 concluded there is insufficient evidence to either support, or refute, the use of lycopene for the prevention of prostate cancer. Similarly, there is no robust evidence from randomized controlled trials to identify the impact of lycopene consumption upon the incidence of prostate cancer, prostate symptoms, PSA levels or adverse events ⁴².

On the basis of overall evidence, the association between tomato consumption and reduced risk of prostate cancer is limited ⁴³.

Figure 1. Lycopene chemical structure

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Figure 2. Lycopene isomers

Footnotes: Natural occurrence of lycopene shows that it exists mostly as a trans-isomer ⁴⁵, while in human tissues and plasma, it appears as a cis-isomer ⁴⁶. There are four common cis-isomers of lycopene, 15-cis, 13-cis, 9-cis, and 5-cis lycopene. All trans-lycopene predominates in tomato products, suggesting that all trans-lycopene is isomerised in the body or is less bioavailable. Cis-lycopene has stronger bioavailability and can be digested and absorbed more easily ³⁶. After the human body obtains lycopene from plants, lycopene enters the intestinal tract in packages of oil droplets, when are then transformed into mixed micelles ³⁷. Through digestion and absorption, the lycopene-containing chylomicrons produced by enzyme cleavage are circulated in the blood or are transported to various body organs via lipoproteins ³⁸.

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Lycopene Food Sources

Lycopene is widely distributed in a variety of plants, mainly in mature fruits (see Table 1 and 2) ⁴⁸. Lycopene mainly accumulates in the chromoplast of cells and usually forms complexes with proteins. Different from other carotenoids, lycopene exists in the plastids as a crystalline structure ⁴⁹. In addition to the familiar tomato and watermelon, lycopene is also available in guavas, grapefruit, mango, papaya, autumn olive, carrot root, citrus fruits, persimmon, rosehip ⁵⁰, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵, ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹. Scientists have also found numerous other plants that accumulate high levels of lycopene, such as autumn olive ⁵⁰, rose hip ⁵⁹ whose lycopene content can reach 540 and 352 mcg/g fresh weight (Table 1). For a more comprehensive list of foods containing lycopene, please go to the United States Department of Agriculture Food Composition Databases here: https://www.nal.usda.gov/sites/default/files/page-files/Lycopene.pdf

An acceptable daily intake (ADI) of 0.5 mg/kg body weight per day using a safety factor of 100 for lycopene from all sources has been established by the European Food Safety Authority (EFSA) panel on food additives, flavorings, processing aids and materials in contact with foods in 2008 ⁶². This guideline was concluded based on a one-year rat study, which established a no-observed adverse-effect level (NOAEL) of 50 mg/kg body weight per day and a non-reversible increase in alanine transaminase (ALT).

Lycopene in tomatoes consists of 94–96% all-trans, 3–5% 5-cis, 0.1% 9-cis, 1% 13-cis, and <1% other cis isomers ⁶³. Most lycopene in tomatoes can be found within the insoluble and fibrous parts, mainly tomato skin, which comprises 5 times more lycopene than the pulp ⁶⁴. Lycopene in tomato constitutes over 60% of the carotenoids, with other carotenoids found in tomatoes including δ-carotene (1–2%), γ-carotene (1–1.3%), neurosporene (7–9%), lutein (0.01–1.1%), phytoene (5.6–10%), phytofluene (2.5–3%), alpha-carotene (0.03%), and β-carotene (3–7%) ⁶⁵. Tomatoes also contain certain amounts of flavonoids (kaempferol, naringenin, quercetin, and hydrocinnamic acids), fibers (cellulose, pectins) and also a good source of vitamins and minerals including vitamin B6, C, E, biotin, folic acid, potassium and riboflavin ⁶³.

The amount of lycopene carotenoid is affected by various factors, such as the degree of maturity of the plant material, fruit variety, light, temperature, climate, irrigation, location of plantation, soil quality, processing, and conditions of storage ¹², ⁶⁶. When the temperature exceeds 35°C, the amount of lycopene decreases because it is converted to beta-carotene. The lycopene content can increase by about 36% when grown in soil containing the necessary microorganisms ¹¹. The amount of lycopene is higher in ripe fruits because they contain less chlorophyll ⁶⁶. Light and oxygen have the greatest impact on storage and processing. Lycopene synthesis in tomatoes is promoted via supplementation with red, far-red, and blue light ⁶⁷, ⁶⁸.

Evidence suggests that the accumulation and biosynthesis of lycopene takes place in different plant organs. Previous studies evaluated the lycopene in distinct portions of tomato fruit: the skin, the water-insoluble fractions, fiber, and soluble solids. Interestingly, lycopene is found in higher concentrations and different chemical configurations in the tomato peel ⁶⁹. Ranveer et al. ⁷⁰ found that the outer part of the tomato pericarp contained more chromoplasts. This suggests that the peel and seeds of tomato, which have traditionally been discarded as production waste in many cases, could be a potential good source of lycopene ⁷¹. The content of lycopene in tomato puree shows the highest stability (with a total loss of 20%). It has high stability in comparison with other substances, such as ascorbic acid, kaempferol, and quercetin, and also after multiple sterilization and evaporation cycles. Its stability may be related to the presence of, e.g., ascorbic acid and phenolic compounds in tomatoes, and also to the influence of these compounds on the inhibition of the process of isomerization and autooxidation of lycopene. They ensure greater stability compared to pure lycopene ⁶⁶.

Table 1. Lycopene content in some fruits

Fruits name	Species	Organ	Lycopene content (mcg/g)
Autumn olive	Elaeagnus umbellata	Fruit	150 ∼ 540
Carrot	Daucus carota	Root	70
Guavas	Psidium guajava	Fruit	35.5
Grapefruits	Citrus paradisi	Fruit	6.1 (pulp) 0.32 (flavedo)
Mango	Mangifera indica	Fruit	0.53
Papaya	Carica papaya	Fruit	14.4 ∼ 33.9
Persimmon	Diospyros kaki	Fruit	270
Pummelo	Citrus grandis	Fruit	5.83
Rose hip	Rosa canina	Fruit	129 ∼ 352
Tomato	Lycopersicon esculentum	Fruit	26.2 ∼ 6290
Watermelon	Citrullus lanatus	Fruit	36.5 ∼ 69.2

Footnote: Lycopene content expressed as fresh weight except dry weight in persimmon

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Table 2. Lycopene content of selected foods

Food	Serving	Lycopene (mg)
Tomato paste, canned	1 cup	75.5
Tomato purée, canned	1 cup	54.5
Tomato juice, canned	1 cup	22
Vegetable juice cocktail, canned	1 cup	17.3
Tomato soup, canned, condensed	1 cup	16.1
Watermelon, raw	1 cup	6.9
Tomato, raw	1 medium	3.2
Ketchup (catsup)	1 tablespoon	2.1
Pink or red grapefruit, raw	½ grapefruit	1.8
Baked beans, canned	1 cup	1.3

[Source ⁷² ]

Lycopene Chemistry

Lycopene (ψ,ψ-carotene), one of more than 600 carotenoids synthesized by plants and photosynthetic microorganism, is a tetraterpene hydrocarbon containing 40 carbon atoms and 56 hydrogen atoms with a molecular mass of 536 s ⁷³, ⁷⁴. Lycopene molecule is a linear hydrocarbon with 2 non-conjugated and 11 conjugated double bonds ⁷⁵. These bonds may undergo isomerization under the influence of factors such as temperature, light, and chemical reactions ¹¹, ⁷⁶. The isomerization leads to structures such as 5-cis, 9-cis, 13-cis, and 15-cis Lycopene (Figure 2) ⁴⁷. With so many double bonds, it can theoretically exist in 1056 cis-trans configurations ⁷⁷. However, there are 72 isoforms found in nature ⁷⁸. Lycopene is sensitive to oxygen, light, heat, acids, metal ions, and catalysts ⁷⁹. The most stable form is 5-cis lycopene. The stability of the other isomers decreases in the following order: all-trans, 9-cis, 13-cis, 15-cis, 7-cis, and 11-cis Lycopene ⁷⁷. Lycopene isomerization affects its activity and bioavailability ⁸⁰. Lycopene isomers differ in their physical and chemical properties. They have a different melting point, polarization, color intensity, solubility, and ability to crystallize ⁸¹.

Lycopene of natural origin occurs as trans isomers ⁸². However, in the human body, Lycopene exists as cis isomers. Isomerization conversion occurs during the storage, processing, and transport of food products and during metabolic processes in the human body ¹². The heat treatment process of food increases the bioavailability of lycopene. This is related to the transformation of its trans form into the cis form ⁸³. These processes also help to release Lycopene from the plant matrix, which also improves its absorption ⁸⁴. The cis isomers have greater solubility in bile acids and are more readily absorbed in the colon ⁸⁵, ⁸³. They are also better absorbed into the bloodstream due to their smaller crystal sizes ⁸⁶.

The bioavailability of lycopene has been examined and demonstrated in several studies relating lycopene to prostate cancer and other diseases. The bioavailability of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than in raw tomatoes ⁸⁷. Lycopene bioavailability has been observed to be highly variable, which may lead to varying biological effects after lycopene consumption. Healthy males participated in a crossover design study that attempted to differentiate the effects of a tomato matrix from those of lycopene by using lycopene-rich red tomatoes, lycopene-free yellow tomatoes, and purified lycopene. Thirty healthy men aged 50 to 70 years were randomly assigned to two groups with each group consuming 200 g/d of yellow tomato paste (lycopene, 0 mg) and 200 g/d of red tomato paste (lycopene, 16 mg) as part of their regular diet for 1 week, separated by a 2-week washout period. Then, in a parallel design, the first group underwent supplementation with purified lycopene (16 mg/d) for 1 week, whereas the second group received a placebo. Sera samples collected before and after the interventions were incubated with lymph node cancer prostate cells to measure the expression of 45 target genes. In this placebo-controlled trial, circulating lycopene concentration increased only after consumption of red tomato paste and purified lycopene.

Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red and lipophilic. As a natural pigment made by plants, lycopene helps to protect plants from light-induced stress ⁸⁸ and it also transfers light energy during photosynthesis ⁸⁹. Lycopene is found in a number of fruits and vegetables, including apricots, guavas, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products ⁸⁸.

Unlike beta-carotene, lycopene lacks a beta-ionone ring and therefore has no pro-vitamin A activity ²⁸. However, the 11 conjugated and two non-conjugated double bonds in lycopene make it highly reactive towards oxygen and free radicals, and this anti-oxidant activity probably contributes to its efficacy as a chemoprevention agent ²⁸.

Lycopene uses

Lycopene extracted from tomatoes has a strong deep red color. Lycopene extracted from tomatoes is authorized for use as a food colorant in the USA (CDR 21 73.295), Australia, New Zealand (registered as 160d under Schedule 3 of Standard 1.3.1 in Australia New Zealand Food Standards Code), and the European Union (registered as E160d under EFSA; UK Food Standard Agency) ⁶³. In Japan, tomato color, defined as “a substance composed mainly of lycopene obtained from tomato fruits”, is permitted for use as a food additive under the Food Sanitation Law. Meanwhile, synthetic lycopene is currently not being approved as food coloring within the EU, but is considered as generally recognized as safe (GRAS) for use as a food ingredient by the FDA (GRAS notice No. GRN 000119) ⁶³. Synthetic lycopene is a highly purified product with 96% lycopene. Synthetic lycopene consists of all trans-lycopene (>70%) and approximately 3.5% other cis isomers. Three different formulations of commercial lycopene preparations are lycopene 10%, lycopene 10 cold-water dispersible in dark red powder form, and lycopene dispersion 20%. These synthetic lycopenes offer an alternative to the food industry to replace the extraction of lycopene from tomatoes, which have been widely used in breakfast cereals, bakery, convenience food, dairy, sauces, and sweets ⁹⁰.

Non-synthetic lycopene commonly referred to as “lycopene juice” is used as colorant in food preparations, dairy products, non-alcoholic flavored drinks, cereal products, fish and meat products, and spreads to increase the visual appeal of food products ⁶³. Synthetic lycopene is also added to some food and beverages as dietary supplement, infant formula, breakfast cereals, instant soup, low-fat dressing, nutrient bars and meal replacements, yogurt, meatless meat products, crackers, salty snacks, and drinks (i.e., juice drinks, dairy fruit drinks, and energy drinks) ⁹¹. Safety evaluation of natural tomato oleoresin extract derived from food-processing tomatoes reported that the 50% lethal dose (LD50), derived from the acute oral toxicity study was greater than 5000 mg/kg body weight ⁹².

Lycopene Health Benefits

Lycopene inhibits androgen receptor expression in prostate cancer cells in vitro and along with some of its metabolites, reduces prostate cancer cell proliferation and may modulate cell-cycle progression ⁹³.

Lycopene may also affect the insulin-like growth factor (IGF) intracellular pathway in prostate cancer cells.

Results from several in vitro and animal studies have indicated that lycopene may have chemopreventive effects for cancers of the prostate, skin, breast, lung, and liver; however, human trials have been inconsistent in their findings.

The recommended intake is at least 10mg of lycopene per day—from food. And tomato-based products do, give you the most bang for your buck.

Clinical trials utilizing lycopene in prostate cancer patients with various different clinical presentations (e.g., early stage, prostate-specific antigen (PSA) relapse, advanced disease) have yielded inconsistent results.

The U.S. Food and Drug Administration (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of Generally Recognized as Safe (GRAS). In clinical trials involving prostate cancer patients, doses ranging from 10 to 120 mg/d have been well tolerated, with only occasional mild-to-moderate gastrointestinal toxicities.

Lycopene Possibly Ineffective for:

• Bladder cancer. Research suggests that there is no link between lycopene consumption in the diet or lycopene blood levels and the risk for bladder cancer.

• Diabetes. Research suggests that increased lycopene consumption in the diet does not decrease the risk of developing diabetes.

Insufficient evidence to rate effectiveness lycopene for:

• Age-related eye disease (age-related maculopathy). Research on the effect of lycopene in age-related eye disease is inconsistent. Some evidence suggests that people with low lycopene levels are almost twice as likely to develop age-related eye disease compared to people with high levels. However, other research suggests that there is no link between lycopene levels or lycopene intake and the risk of age-related eye disease.

• Asthma. Research on the effects of lycopene in people with asthma is inconsistent. Taking lycopene does not seem to reduce asthma symptoms in adults with stable asthma. However, in people with a history of exercise-induced asthma, taking a specific lycopene product (LycoMato, LycoRed Corp., Orange, NJ) seems to improve lung function after exercise.

• Hardening of the arteries (atherosclerosis). There is some evidence showing that higher lycopene blood levels is associated with a reduced risk of hardening of the arteries. There is also early evidence that higher lycopene blood levels can reduce the risk of heart disease associated with hardening of the arteries. However, there does not appear to be a link between lycopene levels and stroke risk.

• Enlarged prostate (benign prostatic hypertrophy). Early research shows that taking lycopene can slow the progression of prostate enlargement and can improve symptoms in people with this condition. However, other research found no link between lycopene intake in the diet and the development of an enlarged prostate.

• Breast cancer. Research about how lycopene affects breast cancer risk is inconsistent. Some evidence suggests that having higher lycopene blood levels is associated with a lower risk of breast cancer. However, other research shows that neither lycopene intake nor lycopene blood levels are linked to breast cancer risk.

• Heart disease. Some research shows that women with higher levels of lycopene in their blood have a lower risk of developing heart disease. However, other research shows no link between lycopene intake and the risk of heart attack or stroke in women. Also, increasing dietary lycopene does not seem to prevent heart attacks in men at low risk for heart disease.

• Cataracts. One study suggests that higher lycopene blood levels are associated with a lower risk of developing cataracts. However, other studies have found no link between lycopene intake or lycopene blood levels and the risk of developing cataracts.

• Cervical cancer. Research about how lycopene affects the risk of cervical cancer is inconsistent. Some evidence suggests that higher lycopene blood levels or higher lycopene intake in the diet is linked to a lower risk of cervical cancer. Other studies have not found this link.

• Colorectal cancer. Research about how lycopene affects the risk of colorectal cancer is inconsistent. Some research suggests that people with high lycopene intake in the diet are less likely to develop colorectal cancer than those with low intake. However, other research shows no link between lycopene intake and the risk of colorectal cancer.

• Gingivitis. Early research shows that taking a specific lycopene supplement by mouth (LycoRed, Jagsonpal Pharmaceuticals) for 2 weeks or receiving a single injection of lycopene gel into the gums reduces gingivitis.

• Brain tumor (giloma). Early research shows that taking lycopene by mouth for 3 months does not improve the response to radiotherapy and chemotherapy in people with brain tumors.

• Ulcers caused by H. pylori infection. Early research shows that taking lycopene by along with antibiotics does not help treat H. pylori infection compared to taking antibiotics alone.

• Human papilloma virus (HPV) infection. Women with higher levels of lycopene in their blood seem to recover from cancer-associated HPV infection faster than women with lower lycopene blood levels.

• High cholesterol. Early research shows that taking a specific lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) by mouth daily for 6 months lowers total cholesterol and low-density lipoprotein (LDL or “bad” cholesterol), and increases high-density lipoprotein (HDL or “good” cholesterol). However, other evidence suggests that lycopene does not affect cholesterol levels in healthy adults or in those with heart disease.

• High blood pressure. Early research shows that taking a specific lycopene product (LycoMato, LycoRed Corp., Organge, NJ) daily for 8 weeks lowers blood pressure in people with high blood pressure. However, other research suggests that there is no link between lycopene blood levels and the risk of developing high blood pressure.

• Lung cancer. Research about how lycopene affects the risk of lung cancer is inconsistent. Some research shows that lower lycopene intake in the diet is linked to an increased risk of lung cancer. However, other research suggests that there is no link between lycopene consumption in the diet or lycopene blood levels and lung cancer risk.

• Male fertility problems. Early research shows that taking lycopene by mouth daily for 3 months improves sperm quality in some men with fertility problems due to unknown causes.

• Menopausal symptoms. Early research shows that taking a specific product containing lycopene, calcium, vitamin D3, astaxanthin, and citrus bioflavonoids daily for 8 weeks reduces menopausal symptoms including hot flashes, joint pain, anxiety, and depression.

• White pre-cancerous patches in the mouth (oral leukoplakia). Early research shows that taking a specific lycopene supplement by mouth twice daily improves white pre-cancerous patches in the mouth.

• Ulcers and swelling in the mouth (oral mucositis). Early research shows that taking lycopene by mouth daily for 2 months improves ulcerations in the mouth in people with oral mucositis.

• Ovarian cancer. There is inconsistent evidence about the effect of lycopene on ovarian cancer risk. Some research shows that a diet rich in carotenoids, including lycopene, seems to help prevent ovarian cancer in young (premenopausal) women. However, other research shows that the risk of developing ovarian cancer is not linked to lycopene blood levels.

• Pancreatic cancer. Some early research shows that a diet high in lycopene, primarily from tomatoes, seems to lower the risk of developing pancreatic cancer.

• High blood pressure during pregnancy. Research on the effect of lycopene for preventing high blood pressure during pregnancy is unclear. Some research shows that taking a specific lycopene supplement twice daily starting between weeks 16 and 20 of pregnancy and continuing until delivery lowers blood pressure and reduces associated complications. However, other research suggests that lycopene does not affect blood pressure during pregnancy.

• Prostate cancer. Research on the effects of lycopene for preventing or treating prostate cancer is inconsistent. Some research suggests that increasing lycopene consumption in the diet, or higher lycopene blood levels, is linked with a lower risk of developing prostate cancer. However, other research shows no link between lycopene intake or blood levels and prostate cancer risk. In addition, early research in men with precancerous changes in their prostate shows that taking lycopene supplements might delay or prevent the progression to prostate cancer. However, in other research, taking lycopene daily for up to one year did not seem to help treat prostate cancer.

• Prostate swelling and pelvic pain. Early research shows that taking a specific combination of lycopene, selenium, and saw palmetto by mouth for 8 weeks reduces pain in men with prostate swelling and pelvic pain compared to saw palmetto alone.

• Kidney cancer (renal cell carcinoma). Early research shows no link between lycopene consumption in the diet and the risk of developing kidney cancer.

• Sunburn. Early research shows that taking lycopene by mouth, alone or together with other ingredients, might protect against sunburn.
• Other conditions.

More evidence is needed to rate lycopene for these uses.

Antioxidant effects

Lycopene has the ability to reduce reactive oxygen species (ROS) and eliminate singlet oxygen, nitrogen dioxide, hydroxyl radicals, and hydrogen peroxide ⁹⁴, ⁹⁵, ¹⁰. Lycopene’s effect on reactive oxygen species (ROS) includes radical attachment, electron transfer, and allylic hydrogen abstraction ⁹⁴. Lycopene can react with free radicals in more than one way ⁹⁴, ⁹⁶. Lycopene quenches singlet oxygen twice as much as beta-carotene and 10 times as vitamin E (alpha-tocopherol) ⁹⁷. Among all the lycopene isomers, the greatest antioxidant properties are shown by the 5-cis form, followed by 9-cis, 7-cis, 13-cis, 11-cis and all-trans ⁷⁷. This is probably related to the better solubility and lower self-aggregation in the polar environment by cis forms ⁹⁸. The antioxidant activity of lycopene is greater in the case of tomato extracts than in the case of pure lycopene. This is due to its synergistic effect with other compounds such as beta-carotene, phytofluene, and phytoene ⁹⁴.

Cardiovascular diseases

Due to the role of oxidative stress in cardiovascular diseases, the use of antioxidants may bring health benefits ⁹⁹. Several randomized controlled trials have examined whether supplementation with lycopene, tomato products, or tomato extracts might benefit cardiovascular health by improving blood pressure, lipid profiles, or function of the vascular endothelium. Scientific evidence confirms that lycopene plays a beneficial role in the prevention of cardiovascular disease ¹⁰⁰, ¹⁰¹. Numerous test tube and animal studies indicate that lycopene may be potentially beneficial in the treatment of cardiovascular disease, due to its antioxidant effects as well as other mechanisms, including its ability to inhibit inflammatory reactions. Unfortunately, there are few human clinical trials on lycopene in the literature on the effects of lycopene in the treatment of atherosclerosis and other cardiovascular diseases ¹⁰², ¹⁰³.

In a recent 2020 meta-analysis, higher lycopene intake — from food and/or lycopene supplements — was not associated with improvements in blood pressure or concentrations of blood fats; the included studies were heterogeneous with respect to lycopene delivery (i.e., as a supplement or as food, varying tomato-containing products or extracts) and dose, characteristics of participants (healthy or with disease), and study duration ¹⁰⁴. The share of lycopene in the diet of the respondents depending on the form of its administration (supplements with or without food, based on tomato juice/paste /raw product or in combination with olive oil) was quite diverse and its daily dose ranged from 1.44 to 75 mg. In 11 out of 43 studies, lycopene did not reduce risk factors for cardiovascular disease ¹⁰⁴. It is believed that in addition to the strong antioxidant activity with potential health-promoting properties of lycopene, the cardiovascular system is also influenced by its anti-inflammatory, anti-atherosclerotic, and anti-platelet effects. Moreover, it also improves endothelial function (EF; blood flow and nitric oxide [NO] bioavailability). Lycopene can bind to plasma low-density lipoprotein (LDL or “bad” cholesterol) and by this mechanism, it provides protection against atherosclerosis by suppressing lipid peroxidation.

Tierney et al ¹⁰⁴ meta-analysis of eight trials found no effect of supplemental lycopene on systolic or diastolic blood pressure; no benefits were found in healthy subjects or in subjects with high blood pressure. The meta-analysis also showed no effect of lycopene supplementation on total cholesterol (10 trials), low-density lipoprotein (LDL or “bad” cholesterol) (11 trials), or HDL (11 trials) cholesterol ¹⁰⁴. Moreover, some, but not all short-term trials ¹⁰⁵, ¹⁰⁶ have indicated supplemental lycopene might improve function of the vascular endothelium in healthy subjects ¹⁰⁷, ¹⁰⁸. However, large, long-term placebo-controlled studies are needed.

Shen et al. ¹⁰⁹ studied the effect of lycopene on oxidative stress induced by di-(2-ethylhexyl) phthalate in the heart of SPF-grade ICR mice. Researchers observed that lycopene caused an increase in cardiac GSH-Px activity and an increase in cardiac GSH levels. There was also a decrease in the level of cardiac myeloperoxidase (MPO), cardiac H2O2, and a decrease in cardiac glutathione S transferase (GSH-ST) activity. The study showed that lycopene can inhibit oxidative stress caused by di-(2-ethylhexyl) phthalate ¹⁰⁹. Ferreira-Santos et al. ¹¹⁰ proved that a diet enriched with lycopene prevents hypertension caused by angiotensin 2. It also helps to improve the remodeling of the cardiovascular system. Lycopene had an antioxidant effect by increasing the activity of GSH-Px and SOD in the liver ¹¹⁰.

In 2017, Alvi et al. ¹¹¹ showed that lycopene can lower hypercholesterolemia by targeting the expression of the liver genes PCSK-9 and HMGR, and by reducing the affinity of PCSK-9 to form a complex with EGF-A-like LDL-R repeats, leading to an increase in LDL-Receptor activity and the subsequent elimination of LDL (low density lipoprotein or “bad” cholesterol) from the body. Observations obtained indicate that supplementation with lycopene in this form may be particularly beneficial for patients intolerant to statins. To emphasize, lycopene, unlike these and other synthetic drugs, is a natural product. In addition, it has the advantage that even despite high doses, it is not toxic, completely safe, not harmful to the environment, and cheap. Therefore, it is highly effective in inhibiting hypercholesterolemia and thus reducing maybe the occurrence of atherosclerotic cardiovascular disease (ASCVD) ¹¹², ¹¹³.

In another study, researchers tested lycopene in myocardial inflammation caused by palmitate in Wistar rats. Lycopene had a beneficial effect on the lipid profile and reduced oxidative stress. It lowered cardiac MDA and cardiac H2O2 levels and cardiac MPO activity and increased cardiac SOD activity and cardiac GSH levels. Lycopene had an anti-inflammatory effect by reducing the expression of NF-κB mRNA in the heart. It decreased the level of IL-1β and IL-6 and increased the level of anti-inflammatory IL-10 in the heart ¹¹⁴. Zeng et al. ¹¹⁵ showed in test tube studies using neonatal cardiomyocytes and in 57/BL6J mice studies that lycopene can inhibit myocardial hypertrophy by reducing oxidative stress. Reactive oxygen species (ROS) generation increased during the hypertrophy process; however, lycopene reversed this trend and inhibited the activation of the ROS-dependent pro-hypertrophic mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling pathways. Lycopene also activated the expression of antioxidant genes induced by the antioxidant response element ¹¹⁵.

He et al. ¹¹⁶ studied the activity of lycopene on a mouse model representing the state after heart attack. The model was created via ligation of the left anterior descending coronary artery. Researchers observed a decrease in the expression of IL-1β and TNF-α and inhibition of the NF-κB pathway in the ischemic myocardium. The study proved that lycopene reduces inflammation and apoptosis of cardiomyocytes after a heart attack ¹¹⁶. Another study proved the protective effect of lycopene in atrazine-induced Kunming mice heart inflammation. Researchers observed a decrease in the levels of pro-inflammatory mediators in heart: COX-2, TNF-α, IL-6, and IL-1β and an increase in the anti-inflammatory cardiac TGF-β1. Serum TNF-α levels were also lowered. Lycopene blocked the activation of the TRAF6-NF-κB pathway. It also reduced NO levels in heart and cardiac NOS activity ¹¹⁷.

Table 3. Cardioprotective effect of lycopene on humans in clinical trials

Study Authors/Country	Area of Interest	Study Design	Age and Health Condition	Dose and Treatment Period of Lycopene	Main Findings
Misra et al., 2006 (India) 118	Lipid profile	Parallel, RCT	41 healthy postmenopausal women at the age of 46	Two capsules of lycopene (LycoRed) 2 mg per day (n = 20 women), for 6 months; Control (n = 21) hormone replacement therapy (HRT) estradiol valerate 2 mg and norethisterone acetate 1 mg	LycoRed showed beneficial effects on serum lipids and markers of oxidative stress that were comparable to HRT. LycoRed: ↓TC(24.2%); ↓LDL(14.9%); ↑HDL (26.1%), ↓MDA, ↑GSH
Paran et al., 2009 (Israel) 119	Blood pressure	Crossover, RCT	50 hypertensive patients with hypertension between 46 and 66 years old; SBP 140–159 mmHg DBP 90–99 mmHg	Encapsulated tomato extract (Lyc-O-Mato®) 250 mg, containing 15 mg per day (n = 26 men; n = 24 women) for 6 weeks; Control (26 men; n = 24 women) placebo capsule with soya oil and normal diet for 6 weeks	Tomato extract containing 15 mg of lycopene favorable reduction of SBP from 145.8 to 132.2 mmHg and 140.4 to 128.7 mmHg and DBP 82.1 to 77.9 mmHg. Serum lycopene content increased from 0.30 μmol/L
Kim et al., 2011 (Korea) 120	Endothelial function	Parallel, RCT, double-blind	126 healthy men aged 22–57 years	Lycopene in the form (Lyc-O-Mato®) 6 mg per day (n = 41 men); 15 mg per day (n = 37 men) for 8 weeks; Control placebo capsule with soya oil and normal diet for 8 weeks	Supplementation with lycopene in the amount of 15 mg/day for 8 weeks in the group of tested men had a positive effect on endothelial function. Increased the RH-PAT index by 23%. Decreased oxidative DNA damage and increased plasma SOD activity. Moreover, it lowered SBP and the level of: hs-CRP, sICAM-1 and sVCAM-1.
Burton-Freeman et al., 2012 (USA) 121	Oxidative stress	RCT, Crossover	25 healthy patients age 27 ± 8 years	Randomly selected patients received (n = 12 men and n = 13 women): I: 85 g tomato paste/day, II: a diet without the participation of tomatoes (control) by 360 min	Lycopene significantly attenuated high-fat meal ↓LDL oxidation and ↓interleukin-6 a proinflammatory cytokine and a proinflammatory cytokine and inflammation marker
Xaplanteris et al., 2012 (Greece) 122	Endothelial function	RCT, Crossover	19 healthy patients age 39 ± 13 years	Patients (n = 8 men, n = 11 women) received: I: 70 g of tomato paste containing 33.3 mg of lycopene in their diet, II: diet without tomato paste: control for two weeks every day	Tomato paste supplementation increased FMD compared with the control period. It improves the functions of the endothelium. Moreover, it lowers plasma lipid peroxides (TOS)
Abete et al., 2013 (Spain) 123	Oxidative stress markers	RCT, Double-blind, Crossover	30 healthy patients aged 39 ± 6 years	Randomly selected patients received (n = 9 men, n = 21 women): I: tomato sauces 160 g/day containing (27.2 mg lycopene/day), II: commercial tomato sauce 160 g/day with a reduced content of lycopene (12.3 mg lycopene/day) for 10 weeks	The consumption of tomato sauce with a higher concentration of lycopene (27 mg/day) caused a decrease in oxidized LDL-cholesterol levels
Grajendragadkar et al., 2014 (UK) 124	Vascular function	Parallel, RCT, double-blind	72 patients, including 36 with cardiovascular disease and 36 healthy volunteers aged 30–80 years	Lycopene 7 mg per day patients healthy (n = 23 men, n = 1 women) for 2 months; Control (n = 10 men, n = 2 women) placebo capsule CVD patients (n = 15 men, n = 9 women): 7 mg per day lycopene, Control (n = 10 men, n = 2 women) placebo capsule by 8 weeks	Lycopene supplementation in CVD patients improved endothelium-dependent vasodilatation (EDV) by 53%. EDV values were close to the baseline values of healthy patients, indicating an improvement in endothelial function by lycopene. It also caused a slight reduction in SB pressure in patients with CVD by 2.9 mmHg
Tsitsimpikou et al., 2014 (Greece) 125	Metabolic syndrome Endothelial function Lipid profile	Parallel, RCT	27 patients with metabolic syndrome aged 53 ± 10 years	Randomly selected patients received: I: tomato juice 100 mL 4 times a week over a period of two months (n = 13 men, n = 2 women), II: water: control group (n = 11 men, n = 1 women)	Tomato juice: ↓LDL, ↑HDL. In addition, it lowered the markers of inflammation TNF-α and IL-6. Endothelial function and insulin resistance improved also improved as a result of consuming tomato juice
Ghavipour et al., 2015 (Iran) 126	Oxidative stress	RCT	64 overweight and obese female patients (BMI ¼ 25 kg/m2 or higher) aged between 20 and 30 years	Female students received: I: tomato juice 330 mL/day containing (37.0 mg/day lycopene) (n = 32), II: control: water (n = 28) for 20 days	Tomato juice consumption significantly: ↑TAC, ↑erythrocyte SOD, ↑CAT and ↑GPx of plasma and ↓MDA of serum compared with the control group after 20 days
Deplanque et al., 2016 (France) 127	Lipid profile	Parallel, RTC	145 healthy patients aged 17–70 years	Patients divided into two groups, the first (75 patients) taking CRTE capsules containing 15 mg/day lycopene and the second (70 patients) taking placebo capsules without lycopene for 2 weeks	Supplementation of CRTE (tomato extract containing 15 mg of lycopene) for 2 weeks increased the plasma level of lycopene and improved the response of oxidized LDL to a high-fat meal in healthy, normal-weight patients. It also had a positive effect on blood glucose, insulin and TG levels
Valderas-Martinez et al., 2016 (Spain) 128	Atherosclerosis	RCT, Crossover	40 healthy patients aged 28 ± 11 years	Randomly selected patients received (n = 19 men, n = 21 women): I: Raw Tomato (RT): 7 g of tomato/kg of body weight, II: tomato sauce (TS): 3.5 g of tomato sauce/kg of body weight; III: tomato sauce with olive oil (TSOO): 3.5 g of tomato sauce with refined olive oil/kg of BW; IV: control: 0.25 g of sugar dissolved in water/kg of BW for 14 weeks	The three groups of products used: RT, TS and TSOO among the examined patients resulted in: ↓TC, ↓LDL, ↑HDL↓. In the assessment of inflammatory markers, the products (TR, TS, TSOO) caused: ↓MCP-1. Whereas, TR and TOOO: ↓IL18 and TOOO: ↓IL6, ↓VCAM-1
Colmán Martínez et al., 2017 (Spain) 129	Inflammatory biomarkers Atherosclerosis	RCT, Crossover	28 patients (men) at high risk of cardiovascular disease age 69 ± 3 years	The patients randomly drank in the studies: I: 200 mL (low dose) tomato juice, II: 400 mL (high dose) tomato juice, III: control: water for 4 weeks every day	The use of alternating doses of juices resulted in: ↓ICAM-1, ↓VCAM-1, ↓IL8. A reduction was observed after the consumption of tomato juice (low dose): chemokine CXCL10, CRP, and IFN. However, these changes were not noticed after consuming the juice at a higher dose
Petyaev et al. 2018 (Russia) 130	Lipid profile	RCT	142 patients with coronary artery disease aged 45 to 73 years	Patients divided into two groups. One group took lacto-lycopene (Nestle Inc.) (n = 68), the other group took microencapsulated GA lycopene (Lycotec Ltd.) (n = 74 patients) at 7 mg/day (1 capsule) for 4 weeks	The Ga lycopene (lycosome) supplement caused an increase in serum lycopene concentration in patients compared to lacto-lycopene. At the end of the study, it also lowered the oxidized LDL levels by five times. Such an effect was not observed in patients treated with lacto-lycopene. Ga lycopen also caused an increase in tissue oxygenation and flow-mediated dilation by the end of the observational period
Wolak et al., 2019 (Israel) 131	Blood pressure	Parallel, RCT	61 hypertensive patients aged 35–60 years	Patients divided into 5 groups: I receiving the tomato nutrient complex, (TNC) containing 5 mg of lycopene (n = 12 patients), II receiving TNC containing 15 mg of lycopene (n = 12 patients), III receiving TNC containing 30 mg of lycopene (n = 13 patients), IV taking synthetic lycopene in the amount of 15 mg (n = 12 patients), V taking a placebo—lycopene-free capsules (soybean oil) (n = 12 patients) administered once daily for 8 weeks	Supplementation with TNC containing lycopene 15 (from 137.4 mmHg to 127.2 mmHg) and 30 mg (from 136.4 mmHg to 130 mmHg) caused a decrease in SBP. On the other hand, TNC (lycopene 5 mg) and synthetic lycopene 15 mg had no effect on the decrease of SBP. In the case of diastolic blood pressure (DBP), a TNC containing 15 mg of lycopene had a beneficial effect on its reduction (from 83.8 to 78.6)

Footnote: ↑, increase; ↓, decrease.

Abbreviations: RCT = Randomised controlled trial; TC = Total cholesterol; LDL = Low density lipoprotein; HDL = High density lipoprotein; MDA = Malondialdehyde; GSH = Glutathione; SBP = Systolic blood pressure; DBP = Diastolic blood pressure; RH-PAT = Reactive hyperemia peripheral arterial tonometry; SOD = Superoxide dismutase, hs-CRP = high-sensitivity C-reactive protein; sICAM-1 = Soluble inter-cellular adhesion molecule-1; sVCAM-1 = Soluble vascular-cellular Adhesion Molecule-1; FMD = Flow-mediated dilatation; CVD = cardiovascular diseases; BMI = Body mass index; TAC = Total antioxidant capacity; CAT = Catalase; GPx = Glutathione peroxidase; CRTE = Carotenoid-rich tomato extract; TG = Triglyceride; TSOO = Tomato sauce with refined olive oil; BW = Body weight; CRP = C-reactive protein; IFN = Interferon.

Anti-inflammatory effects

Lycopene is great in inhibiting the inflammatory response, and its anti-inflammatory activity is mainly related to the suppression of its basic mediators, such as reactive oxygen species (ROS). Moreover, Lycopene inhibits the synthesis and release of pro-inflammatory cytokines, including IL-1,, IL-1β, IL-6, IL-8, IL-12,  and TNF-α, thereby preventing the promotion of inflammation ¹³², ¹³³, ¹³⁴, ¹³⁵. Lycopene’s anti-inflammatory activity is thought to be mediated at multiple levels, primarily through inhibition of the nuclear factor κB (NF-κB), regulation of mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS), and the inhibition of enzymes involved in the metabolism of arachidonic acid—cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) ¹³⁶.

According to the research of Hung et al. ¹³⁷, lycopene has the ability to suppress TNF-alpha-induced activation of NF-kappa B, reduce the expression of intracellular adhesion molecule-1 (ICAM-1) and interactions between monocytes and endothelial cells, thus emphasizing its high vascular efficacy. Whereas, the studies by He et al. ¹³⁸ carried out in 2016, show that lycopene reduces the risk of graft vasculopathy. The effect of this is its high activity in the suppression of intimal hypertrophy and smooth muscle cell proliferation and diminution of inflammation in the vessels of the allograft ¹³⁸. According to these authors, lycopene appears to be of potential importance in the suppression of allograft atherosclerosis by lowering Rho-coupled kinases and regulating the expression of key factors via the NO/cGMP pathways ¹³⁸.

An increased inflammatory response and cardiomyocyte apoptosis characterized by inflammation, apoptosis, infarction, and fibrosis are key processes in ventricular remodeling after a heart attack. On the other hand, the administration of lycopene in the amount of 10 mg/kg body weight in mice resulted in inhibition of the NF-κB signaling pathway. The result was a reduction in the expression of fibrosis mRNA (TGF-β1, collagen I, collagen III), inflammatory markers (TNF-α, IL-1β), and markers of apoptosis (caspase-3, -8 and -9), which, consequently, reduced the inflammatory response and cardiomyocyte apoptosis after a heart attack ¹³⁹. In contrast, the studies by Le et al. ¹⁴⁰ showed that the use of lycopene in the diet for 21 days in the amount of 5 mg/kg enhances the expression of transforming growth factor beta 1 (TGF-β1), which results in protection against changes caused by atrazine (ATR—synthetic herbicide) and inflammation of the heart. The above studies showed that the effectiveness of lycopene was also associated with the reduction of the amount of nitric oxide (NO) increased by atrazine and the activity of NOS. In addition, lycopene suppressed atrazine-induced levels of the proinflammatory cytokines TNF-α, IL-6, IL-1β, and COX-2 and the activation of NF-κB, as confirmed by its anti-inflammatory effect in the protection of the myocardial. In the case of studies on the effect of lycopene on changes induced by myocardial infarction (heart attack) in a rat model, it was noticed that it suppressed the increase in MMP-9 and type I collagen expression, and inhibited p38 activation and decreased collagen levels in the periinfarct zone ¹⁴¹.

In the studies of Ferreira-Santoset et al. ¹⁴², the use of 10 mg/kg of lycopene inhibited the angiotensin 2-induced changes in the cardiovascular system. Lycopene at this level reduced myocardial hypertrophy and its fibrosis and showed a beneficial effect in reducing arterial hypertension. In 2017, Yang et al. ¹⁴³ showed that lycopene inhibits TNFα-induced adhesion of monocytes to EC (endothelial cells) by reducing ICAM-1 expression. The studies also confirmed that lycopene suppresses activation of the inflammatory transcription factor NF-κB by blocking the degradation of IκBα. The transcription factor NF-κB is believed to be responsible for a number of inflammatory diseases in the human body, including atherosclerosis, and its activation by TNFα is required for transcriptional activation of EC adhesion molecules ¹⁴⁴. This confirms that lycopene inhibits the expression of adhesion molecules by blocking NF-κB activation. Pretreatment with lycopene for 3 hour, according to studies by Yang et al. ¹⁴³, suppresses TNFα-induced IκBα degradation. Blocking NF-κB activity by lycopene is assumed to be mediated by modulation of upstream targets in the NF-κB pathway. Moreover, a short incubation with lycopene for 3 h only partially inhibited the appearance of NF-κB in EC nuclei. On the other hand, extending it to 12 h increased the effect of lycopene on p65 translocation ¹⁴³. The research carried out in 2015 by Sung et al. ¹⁴⁵, showed that lycopene can enhance the activation of the phosphoinositide 3-kinase/Akt pathway, and then the induction of Nrf2 nuclear translocation in the EC. According to Yang et al. ¹⁴³, lycopene also induces the expression of the phase II enzyme GCL and HO-1, and Nrf2 translocates to the nucleus and binds to ARE to activate transcription. The anti-inflammatory effect of lycopene is mediated by inhibition of IκBα degradation, and ICAM-1 expression is reduced by siRNA transfection of HO-1 ¹⁴³. Increased expression of HO-1 in atherosclerotic plaques with the participation of lycopene suppresses the progression of atherosclerotic disease, which confirms its protective role. In addition, the anti-inflammatory effect of lycopene-induced HO-1 was investigated by Sahin et al. ¹⁴⁶.

Anti- cancer effects

A total of 15 articles involving the clinical trials on the anti-cancer effect of lycopene were reviewed and it was reported that 11 out of these 15 studies reported positive outcomes and four of them reported that lycopene had no effect upon reducing the risk of cancer. The first related cohort study came in 1995 whereby 47,894 human subjects who were initially free of diagnosed cancer were recruited in 1986 and given validated semiquantitative food-frequency questionnaire as a mean of dietary assessment. Follow-up questionnaires were given in 1988, 1990 and 1992 and the data collected were analyzed. Data analysis pointed out that only lycopene was found to be able to reduce the risk of prostate cancer. Four food items which were known for their high lycopene content such as tomatoes, tomato juices, tomato sauces and pizza were also able to reduce risk of prostate cancer. The combined intake of these four items managed to establish an inverse association with risk of prostate cancer ¹⁴⁷. The author then suggested that lycopene or tomato-based food might be beneficial for prostate cancer and this became the first evidence of anti-cancer property of lycopene among humans. A similar outcome had been reported in another cohort study comprised of 47,365 participants who were given dietary questionnaire for dietary assessment in 1986, 1990 and 1994. The pooled analysis showed that lycopene was able to reduce the risk of prostate cancer but the association was considered moderate after controlling for fruits and vegetable consumption and olive oil consumption (marker for Mediterranean diet) ¹⁴⁸. In terms of plasma lycopene, a case–control study nested within a prospective Health Professionals Follow-up Study with 450 incident prostate cancer cases reported that higher plasma lycopene could reduce risk of prostate cancer but such association was only restricted to older participants without family history ¹⁴⁹.

Results from cohort studies had been conflicting whereby reports from studies with large sample sizes inclined towards a direction whereby lycopene was not able to reduce risk of cancer or lycopene could only have moderate effect on cancer risk reduction ¹⁴⁷, ¹⁴⁸, ¹⁵⁰, ¹⁵¹, ¹⁵². The outcome from meta-analysis of cohort and case–control studies was positive whereby it was reported that lycopene could reduce risk of prostate cancer, lung cancer and breast cancer, especially at low plasma lycopene concentration ¹⁵³, ¹⁵⁴, ¹⁵⁵, ¹⁵⁶. High level of evidence from randomized controlled trials suggested that lycopene could be beneficial for cancer as seen in increment in apoptotic index among hyperplastic and neoplastic cells and suppression of PSA in prostate cancer patients ¹⁵⁷, ¹⁵⁸, ¹⁵⁹. However, in randomized controlled trials, lycopene failed to cause any significant change towards Bax protein and IGF-1, as opposed to what had been shown in cell culture and animal studies ¹⁵⁷, ¹⁶⁰. Although with the new perspectives towards the anti-cancer activity of lycopene, it is still insufficient for scientists to gauge the anti-cancer potential of lycopene in cancer prevention in human ¹⁶¹.

Lycopene has been investigated to treat established prostate cancer in several phase 1 and 2 pilot studies and in patients with biochemical relapse, metastatic prostate cancer or castration‐resistant prostate cancer ¹⁶², ¹⁶³, ¹⁵⁹, ¹⁶⁴, ¹⁶⁵. These small studies did not support the use of lycopene as a single agent for the treatment of prostate cancer. Consumption of tomato products and lycopene supplements remains widespread among prostate cancer patients, including those undergoing docetaxel‐based chemotherapy ¹⁶⁶.

Prostate cancer

Several early prospective cohort studies suggested that lycopene-rich diets were associated with significant reductions in the risk of prostate cancer, particularly more aggressive forms ¹⁶⁷.
A prospective cohort study is study that follows over time groups of individuals who are alike in many ways but differ by a certain characteristic (for example, female nurses who smoke and those who do not smoke) and compares them for a particular outcome (such as lung cancer). Several pooled data analyses of observational studies that examined potential links between dietary intakes and/or circulating concentrations of lycopene and risk of prostate cancer have been completed. A 2015 meta-analysis of observational studies ¹⁶⁸, ¹⁶⁹ found no association of prostate cancer risk with dietary lycopene intakes (10 case-cohort and two prospective cohort studies) but an inverse association with blood lycopene concentrations (two case-control, nine nested case-control, and one cohort studies). Additionally, a meta-analysis of 15 nested case-control studies ¹⁷⁰ conducted by the Endogenous Hormones, Nutritional Biomarkers, and Prostate Cancer Collaborative Group showed an inverse association between circulating lycopene concentrations and risk of advanced stage and/or aggressive prostate cancer, while no association was found with risk of non-aggressive or localized disease. A 2017 meta-analysis of observational studies ¹⁷¹ found inverse associations between both dietary (6 cohort/case-cohort and 15 case-control studies) and circulating (1 cohort study, 4 case-control studies, and 12 nested case-control studies) lycopene and prostate cancer risk; risk reductions were 12% in both analyses. However, this meta-analysis found no associations between dietary lycopene (5 studies) or circulating lycopene (6 studies) and advanced prostate cancer ¹⁷¹.

While there is considerable scientific interest in the potential for lycopene to help prevent prostate cancer, it is not yet clear whether the prostate cancer risk reduction observed in some observational studies is related to lycopene itself, other compounds in tomatoes, or other factors associated with lycopene-rich diets ¹⁷². Experimental studies in rats suggest that lycopene is protective against prostate cancer but not the only protective compound found in tomatoes ¹⁷³. The 2014 World Cancer Research Fund International report on Diet, Nutrition, Physical Activity, and Prostate Cancer suggested the need for better designed studies to establish whether consumption of lycopene-containing foods could be linked to a lower risk of prostate cancer ¹⁷⁴.

To date, a few short-term, dietary intervention studies using lycopene in patients with precancerous prostate lesions (high grade prostatic intraepithelial neoplasia) or prostate cancer have been completed. Specifically, two small randomized controlled studies examined the effect of lycopene supplement for up to six months in men with high grade prostatic intraepithelial neoplasia ¹⁷⁵, ¹⁷⁶. The consumption of 30 to 35 mg/day of lycopene supplement in the form of tomato extract ¹⁷⁵ or together with selenium (55 mg/day) and green tea catechins (600 mg/day) ¹⁷⁶, showed no benefit on the rate of progression to prostate cancer at six-month and 37-month follow-ups ¹⁷⁵, ¹⁷⁶. Earlier small trials in men with high grade prostatic intraepithelial neoplasia led to similar conclusions ¹⁷⁷. Additionally, a randomized controlled trial in men with localized prostate cancer found that supplementation with 15, 30, or 45 mg of lycopene until prostatectomy (surgical removal of all or part of the prostate gland) did not significantly increase plasma lycopene concentration, modify the ratio of steroid hormones in blood, or reduce the concentration of markers of prostate cancer proliferation (i.e., prostate-specific antigen [PSA] and Ki-67) compared to placebo ¹⁶². In another trial, 54 patients with metastatic prostate cancer were randomized to orchidectomy (a surgical procedure to remove one or both testicles) alone or orchidectomy plus 4 mg/day of lycopene ¹⁷⁸. The proportion of complete clinical response to treatment assessed by serum PSA and/or bone scan returning to normal and patient survival rate were found to be significantly higher in patients supplemented with lycopene ¹⁷⁸. Moreover, a meta-analysis of six randomized controlled trials in patients with non-metastatic prostate cancer found that supplemental lycopene (15-30 mg/day for 3 to 24 weeks) had no effect on circulating PSA concentrations ¹⁷⁹. Yet, a subgroup analysis revealed a benefit of PSA reduction in patients with higher concentrations at baseline (PSA ≥6.5 µg/L) ¹⁷⁹.

Large-scale, controlled clinical trials are needed to further examine the safety and efficacy of long-term use of lycopene supplements for prostate cancer prevention or treatment.

Other types of cancer

In a meta-analysis of 12 prospective cohort studies, no association was found between total and individual carotenoid intake and risk of breast cancer, except with beta-carotene for which a 5% reduction in breast cancer risk was estimated for every 5 mg/day increment in consumption ¹⁸⁰. In a pooled analysis of 14 nested case-control studies and one follow-up study of a clinical trial, reductions in breast cancer risk were found to be associated with blood concentrations of total carotenoids (-26%), aplha-carotene (-20%), and lutein (-30%) ¹⁸⁰. Another study that recalibrated data for consistency across eight large prospective cohorts before pooled analysis found reduced breast cancer risk to be associated with the highest versus lowest quintile of blood concentrations of total carotenoids (-21%), β-carotene (-17%), and lycopene (-22%) ¹⁸¹. Further analyses found an inverse association between the blood concentrations of β-carotene and α-carotene and risk of estrogen receptor-negative (ER-), but not estrogen receptor-positive (ER+), breast tumors ¹⁸¹. A similar result was reported in a case-control study nested within the multicenter, large, European Prospective Investigation into Cancer and Nutrition (EPIC) study ¹⁸². In a nested case-control study of the Nurses’ Health Studies (NHS and NHSII), a 20% reduction in risk of breast cancer was seen in those with the highest total plasma carotenoids (≥142.1 µg/dL) compared to the lowest (<84.6 µg/dL), and this association was strongest in those presumed to be at higher risk of breast cancer ¹⁸³. Protective associations were observed for higher circulating levels of the carotenoids, α-carotene (-20%), β-carotene (-18%), as well as lutein and zeaxanthin (-17%) ¹⁸³. In contrast to the abovementioned pooled analysis ¹⁸¹, this study ¹⁸³ found a protective association between higher circulating carotenoids and estrogen receptor positive (ER+) , but not estrogen receptor negative (ER-) , breast tumors.

A case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study found a 31% lower risk of colorectal cancer with the highest versus lowest quartile of beta-carotene intake, while no associations were shown with blood concentrations of other carotenoids or total carotenoids ¹⁸⁴. The nested case-control study was included in a meta-analysis of 22 observational studies that failed to find associations between carotenoid intakes and colorectal cancer ¹⁸⁵. A meta-analysis of 15 observational studies (11 case-control and 4 prospective cohort studies) reported no association between lycopene intake and colorectal cancer ¹⁸⁶.

Pooled data also suggested that higher intakes of individual carotenoids, especially beta-cryptoxanthin and lycopene, might be associated with a reduced risk of cancers of the mouth, pharynx, and larynx ¹⁸⁷, but most of the data come from case-control control studies ¹⁸⁸. A case-control study is a type of observational study commonly used to look at factors associated with diseases or outcomes ¹⁸⁹. The investigator measures the exposure and outcome in study participants, and studies their association ¹⁹⁰. The results of case-control studies are more likely to be distorted by bias than results of prospective cohort studies.

In a recent dose-response meta-analysis of observational studies, higher blood concentrations of several carotenoids, including alpha-carotene (3 studies), beta-carotene (4 studies), as well as combined lutein and zeaxanthin (3 studies), were linked to a lower risk of developing bladder cancer ¹⁹¹.

Type 2 diabetes

The lycopene status of type 2 diabetes patients from different populations has been studied extensively by previous researchers. In a cross-sectional surveillance study, the lycopene level of 24,377 Korean adults (19–74 years) was assessed using 24-hour dietary recall. The result showed the dietary lycopene intake was significantly higher in non-type 2 diabetes men compared to type 2 diabetes men ¹⁹², ¹⁹³. In a case-control study ¹⁹⁴, lycopene intake in type 2 diabetes patients was significantly lower compared to age-matched healthy controls. The study further explicated that subjects with proliferative diabetic retinopathy had significantly lower lycopene levels than subjects without diabetic retinopathy or with non-proliferative diabetes ¹⁹⁵. This result is in accordance with a community-based cross-sectional study in Australia, which demonstrated a significantly lower level of lycopene in the type 2 diabetes-retinopathy group ¹⁹⁶, ¹⁹⁷. Moreover, Ford et al. ¹⁹⁸ reported that the United States population with newly diagnosed type 2 diabetes had a significantly lower level of lycopene compared to the US adults with good blood sugar control. Another study investigating the lycopene status among type 2 diabetes patients in Germany revealed the plasma concentration of lycopene was significantly lower in very old type 2 diabetes patients (mean age 75.7 ± 0.8 years) as compared to healthy controls ¹⁹⁹. Also, a significant inverse correlation between age and the level of lycopene was reported in the study ¹⁹⁹.

In 2010, Li et al. ¹⁹⁵ demonstrated that HbA1c was negatively correlated with lycopene. Coyne et al. ²⁰⁰ reported a significant reduction in plasma glucose and fasting insulin concentrations with increased serum lycopene in type 2 diabetes patients. However, She et al. ²⁰¹ did not find a significant association between HbA1c and lycopene level in a sample of 40 type 2 diabetes participants. Bose and Agrawal ²⁰² observed no significant changes in fasting blood glucose and HbA1c levels for type 2 diabetes patients following a 30-day supplementation of ripe cooked tomatoes (200 g tomatoes/day). Similarly, Upritchard et al. ²⁰³ supplemented type 2 diabetes patients with 500 mL of tomato juice along with Vitamin E and C for 4 weeks, and reported that lycopene supplementation did not affect plasma glucose concentration. Very recently, HbA1c and fasting blood glucose levels were found to decrease significantly with the higher lycopene intake ²⁰⁴.

Some studies reported no effect of lycopene on type 2 diabetes. For example, a prospective study in Korea failed to show a correlation between dietary lycopene and the incidence of type 2 diabetes, even though lycopene intake was significantly higher in non-diabetic subjects than in diabetic patients ¹⁹³. In a European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort study (n = 37,846), Sluijs et al. ²⁰⁵ demonstrated that lycopene intake was not associated with a reduced risk of type 2 diabetes. A similar result was depicted in a nested case-control study ²⁰⁶. After 10 years of follow-up, the study showed no prospective association between baseline plasma lycopene, as assessed by using FFQ, with the risk of type 2 diabetes in middle-aged and older women from the United States. Another prospective study demonstrated that dietary lycopene did not reduce the risk of type 2 diabetes in a Finnish cohort of men and women ²⁰⁷. In Asia, a cross-sectional study of the Chinese urban population also reported that lycopene has no protective role on type 2 diabetes ²⁰¹.

In summary, epidemiological observations and large-scale population studies using human models have revealed a mixed association between lycopene intake and type 2 diabetes. Therefore, properly designed clinical studies are warranted to clarify and validate the potential of lycopene in managing diabetic conditions.

Osteoporosis

Recently, the effect of lycopene on bone health has received additional attention from researchers ²⁰⁸. The beneficial effects of lycopene on bone health have been studied using animal models, cell cultures, and epidemiological/clinical studies in the context of postmenopausal osteoporosis. Human epidemiological studies have investigated the specific effects of tomato/lycopene on bone health, and the majority have shown a positive correlation between tomato/lycopene consumption and the prevention of bone loss ²⁰⁹.

The Framingham Osteoporosis study evaluated associations between total and isolated carotenoids with bone mineral density (BMD) in older adults (~75 years old) ²¹⁰. An inverse relationship between lycopene levels and four-year bone loss in the lumbar spine in older women (~75 years old) was observed ²¹⁰ and a follow-up study reported a protective effect of lycopene against hip fractures ²¹¹. Mackinnon et al. ²¹² reported a notable increase in a clinically relevant bone resorption marker, the crosslinked N-telopeptide of type 1 bone biomarker (NTx), as well as oxidative stress markers in postmenopausal women after one-month restriction of lycopene in the diet. This also led to a drastic reduction in serum lycopene along with other carotenoids such as α-carotene, β-carotene, lutein, and zeaxanthin ²¹². Similarly, 30 mg/d lycopene supplementation in postmenopausal women in either juice or capsule form for four months decreased serum NTx level ²¹³. An epidemiological study in premenopausal women, which evaluated the effect of dietary carotenoids on bone mineral status, showed a positive correlation between lycopene intake and total body bone mineral density (BMD) and bone mineral content (BMC) ²¹⁴. Another study revealed lower levels of serum lycopene in postmenopausal women with osteoporosis compared to non-osteoporotic women ²¹⁵.

The epidemiological and clinical studies discussed above have demonstrated that lycopene intake (≥30 mg/day) is effective in reducing bone resorption markers in postmenopausal women ²¹², ²¹³.

Lycopene Health Benefits for Men

Past research, has shown that a diet rich in lycopene-containing foods may help lower the risk of prostate and other cancers. Now, in a report just published in the journal Neurology, a team of Finnish researchers has linked lycopene levels in the blood to stroke protection ²¹⁶. They made this connection after following more than a thousand middle-aged men for 12 years. Men with the greatest amounts of lycopene in their blood had a 55% lower chance of having any kind of stroke. The lycopene connection was even stronger (59%) when it came to protecting against strokes due to blood clots (the most common kind) ²¹⁶. The researchers suggested that lycopene, in addition to its ability to attack free radicals, may also reduce inflammation and cholesterol, improve immune function, and prevent blood from clotting. All of these may help reduce ischemic strokes, which are caused by clot-caused blockages in blood flow to the brain. How the added that larger studies are needed to confirm the findings and to figure out if the stroke protection is due to lycopene or healthy lifestyle habits, because a high lycopene consumer is likely to eat more vegetables and not be a smoker ²¹⁶.

For cancers, as pointed by the FDA (see below), “there was no credible evidence to support qualified health claims for tomatoes or tomato-based foods and a reduced risk for lung, colorectal, breast, cervical, or endometrial cancer. FDA further concluded that there was no credible evidence to support qualified health claims for lycopene, as a food ingredient, component of food, or as a dietary supplement, and a reduced risk of any of these cancers. Thus, FDA denied these claims. FDA concluded that there was very limited credible evidence for qualified health claims for tomatoes and/or tomato sauce and a reduced risk for prostate, gastric, ovarian, and pancreatic cancers provided that the qualified health claims were appropriately worded so as to not mislead consumers” ²¹⁷.

Lycopene, Cancers and U.S. Food and Drug Administration (FDA) Conclusion

In 2004, FDA received two petitions for qualified health claims regarding tomatoes and/or lycopene and cancer risk reduction from The Lycopene Health Claim Coalition (consisting of H. J. Heinz Company, LycoRed Natural Products Industries, Ltd, The Morningstar Company, and The Prostate Cancer Foundation) and American Longevity, Inc. Both petitioners requested that FDA evaluate the relationship between tomato and/or lycopene consumption and prostate cancer risk. One petitioner also requested that FDA review the relationship between tomato and/or lycopene consumption and the risks of other forms of cancer, including lung, colorectal, gastric, breast, cervical, ovarian, endometrial, and pancreatic cancers. In response to these petitions, FDA evaluated evidence for associations between lycopene (a food component) and tomatoes (a food) separately and each form of cancer.

Based on the scientific evidence, FDA concludes that there is no credible evidence to support a qualified health claim for tomato lycopene; tomatoes and tomato products, which contain lycopene; lycopene in tomatoes and tomato products; lycopene in fruits and vegetables, including tomatoes and tomato products, and lycopene as a food ingredient, a component of food, or as a dietary supplement and reduced risk of prostate cancer ²¹⁸.

The FDA found no credible evidence to support an association between lycopene intake and a reduced risk of prostate, lung, colorectal, gastric, breast, ovarian, endometrial, or pancreatic cancer ²¹⁹. The FDA also found no credible evidence for an association between tomato consumption and a reduced risk of lung, colorectal, breast, cervical, or endometrial cancer. The FDA found very limited evidence to support an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers ²¹⁹.

On November 8, 2005, FDA issued letters of enforcement discretion for these qualified health claims ²¹⁷.

Prostate Cancer

“Very limited and preliminary scientific research suggests that eating one-half to one cup of tomatoes and/or tomato sauce a week may reduce the risk of prostate cancer. FDA concludes that there is little scientific evidence supporting this claim” ²¹⁸.

Gastric Cancer

“Four studies did not show that tomato intake reduces the risk of gastric cancer, but three studies suggest that tomato intake may reduce this risk. Based on these studies, FDA concludes that it is unlikely that tomatoes reduce the risk of gastric cancer.”

Ovarian Cancer

The qualified health claim for ovarian cancer was “One study suggests that consumption of tomato sauce two times per week may reduce the risk of ovarian cancer; while this same study shows that consumption of tomatoes or tomato juice had no effect on ovarian cancer risk. FDA concludes that it is highly uncertain that tomato sauce reduces the risk of ovarian cancer.”

Pancreatic Cancer

The qualified health claim for pancreatic cancer was “One study suggests that consuming tomatoes does not reduce the risk of pancreatic cancer, but one weaker, more limited study suggests that consuming tomatoes may reduce this risk. Based on these studies, FDA concludes that it is highly unlikely that tomatoes reduce the risk of pancreatic cancer.”

Lung Cancer

The evidence for a relationship between tomato or tomato-based foods intake and a reduced risk of lung cancer is from one cohort study, one sub-cohort study and one nested case-control study. None of these 3 studies supported a relationship between tomato or tomato-based food intake and lung cancer risk reduction. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between tomato or tomato-based food consumption and lung cancer.

Breast Cancer

The evidence for a relationship between tomato intake and reduced risk of breast cancer is based on two case control studies. Neither of the studies found a relationship between tomato or tomato-based food intake and breast cancer risk. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between tomato or tomato-based food consumption and breast cancer.

Colorectal Cancer

The evidence for a relationship between tomato or tomato-based food consumption and reduced risk of colorectal cancer is based on two case-control studies from the United States and Italy. Neither case-control study found a relationship between tomato or pizza consumption and colorectal cancer risk reduction. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between tomato or tomato-based food consumption and colorectal cancer.

Endometrial Cancer

There were no studies that evaluated the relationship of tomatoes or tomato-based foods and endometrial cancer risk. Based on the above, FDA concludes that there is no credible evidence supporting a relationship between tomato or tomato-based food consumption and endometrial cancer.

Cervical Cancer

There was one observational study that showed that the consumption of tomatoes was not significantly different between control and cervical cancer cases and no studies showing a relationship between tomatoes or tomato-based foods and risk of cervical cancer. Therefore, FDA concludes that there is no credible evidence to support a relationship between the consumption of tomatoes or tomato-based foods and cervical cancer risk.

Lycopene supplement

Man-made lycopene and lycopene from natural sources, mainly tomatoes, are available as lycopene supplements containing up to 15 mg of lycopene per softgel capsule ²²⁰. Many studies suggest that eating lycopene-rich foods or having high lycopene levels in the body may be linked to reduced risk of cancer, heart disease, and age-related eye disorders. However, measures of lycopene intake have been based on eating tomatoes, not on the use of lycopene supplements.

Lycopene Supplements may give you a purified form of lycopene, but you’re not sure you’re getting what you get from food. Since tomatoes also contain other nutrients, such as vitamin C and potassium, the potential benefits of lycopene alone are still unclear. Furthermore, you may be getting the wrong form of lycopene in a supplement. There are also a lot of compounds in food that aren’t lycopene but that are similar, and some of those molecules may be part of what makes lycopene so beneficial ²²¹.

• Lycopene deficiency is not considered a medical condition. There is a lack of evidence on whether increasing low lycopene levels may benefit health.

The appropriate dose of lycopene depends on several factors such as the user’s age, health, and several other conditions. At this time there is not enough scientific information to determine an appropriate range of doses for lycopene. Keep in mind that natural products are not always necessarily safe and dosages can be important. Be sure to follow relevant directions on product labels and consult your pharmacist or physician or other healthcare professional before using.

Lycopene is likely safe when taken by mouth in appropriate amounts. Daily supplements containing up to 120 mg of lycopene have been used safely for up to one year.

Doses of lycopene ranging between 8 mg and 45 mg administered over a period ranging from 3 weeks to 2 years have been reported to be safe in randomized clinical trials targeting the prostate. When adverse effects occurred, they tended to present as gastrointestinal symptoms and, in one study, the symptoms resolved when lycopene was taken with meals. Another study reported that one participant withdrew because of diarrhea.

As an antioxidant, lycopene has been taken by mouth in doses of 6.5, 15, and 30 milligrams daily for eight weeks. Lyc-O-Mato® capsules (each containing up to 15 milligrams) have been taken by mouth once daily for eight weeks and 26 days, or twice daily for four months. Two capsules of LycoRed® (each containing 15 milligrams of lycopene) have been taken by mouth once daily for 21 days ²²².

To treat asthma caused by exercise, 30 milligrams of lycopene in the form of Lyc-O-Mato® has been taken by mouth daily for one week ²²².

To treat coronary artery disease, 1.24 grams of six-percent lycopene oleoresin capsules (LycoRed®) has been taken by mouth daily for one week. Two LycoRed® softules (each containing 2,000 micrograms of lycopene) have been taken by mouth daily for six months. Lycopene has been taken by mouth in the form of tomato products, capsules, and Lyc-O-Mato® in doses of 39.2-80 milligrams for 1-12 weeks ²²².

To treat enlarged prostate, 15 milligrams of lycopene (LycoVit®) has been taken by mouth daily for six months ²²².

To treat brain tumors, eight milligrams of lycopene has been taken by mouth daily for three months ²²².

To treat heart disease, lycopene has been taken by mouth in the form of tomato products, capsules, and Lyc-O-Mato® in doses of 39.2-80 milligram doses daily for 1-12 weeks ²²².

To treat gum disease, LycoRed® (providing eight milligrams of lycopene) has been taken by mouth daily in divided doses for two weeks ²²².

To treat high blood pressure, lycopene has been taken by mouth in 4-44-milligram doses daily for up to six months. Lyc-O-Mato®, containing 15 milligrams of lycopene, has been taken by mouth daily for six weeks and eight weeks. A dose of 250 milligrams of Lyc-O-Mato® has been taken by mouth for eight weeks ²²².

To treat infertility, 2,000 micrograms of lycopene has been taken by mouth twice daily for three months ²²².

To lower lipid levels, lycopene has been taken by mouth in 4-44-milligram doses daily for up to six months. Two LycoRed® softules (each containing 2,000 micrograms of lycopene) have been taken by mouth daily for six months ²²².

To treat mouth sores, LycoRed®, containing 4-8 milligrams of lycopene, has been taken by mouth daily for three months in two divided doses ²²².

To treat inflammation of the mouth, 16 milligrams of lycopene has been taken by mouth daily in two divided doses for two months ²²².

To prevent ovarian cancer, 4,000 micrograms of lycopene has been taken by mouth daily ²²².

To treat high blood pressure associated with pregnancy, LycoRed® (containing two milligrams of lycopene per capsule) has been taken once or twice daily until delivery ²²².

• Pregnancy and breast-feeding: Lycopene is likely safe during pregnancy and breast-feeding when taken in amounts commonly found in foods ³¹. However, lycopene is POSSIBLY UNSAFE when taken as a supplement during pregnancy. A study using a specific lycopene supplement (LycoRed, Jagsonpal Pharmaceuticals) found that taking 2 mg daily, starting between weeks 12 and 20 of pregnancy and continuing until delivery, increased the rate of premature births and low-birth-weight babies. Not enough is known about the safety of lycopene supplements during breast-feeding ³¹. If you are pregnant or breast-feeding, avoid using lycopene in amounts greater than those typically found in foods.

To prevent or treat prostate cancer, two milligrams of lycopene has been taken by mouth twice daily, and four milligrams of lycopene has been taken by mouth twice daily for one year. Lyc-O-Mato®, containing up to 120 milligrams of lycopene, has also been taken by mouth in divided doses twice daily for periods of up to one year. LycoRed® softules, providing a total daily dose of 10 milligrams of lycopene, have been taken daily for three months.

• Prostate cancer: Developing laboratory research suggests lycopene might worsen established prostate cancer by increasing the spread of cancer without having any effect on cancer cell growth. Until more is known, avoid lycopene if you have a prostate cancer diagnosis ³¹.

To protect skin from sun damage, 55 grams of tomato paste in olive oil (providing 16 milligrams of lycopene) has been taken by mouth daily for 12 weeks ²²².

Children (younger than 18 years) : There is no proven safe or effective dose for lycopene in children ²²².

Lycopene side effects

High intakes of lycopene-rich food or supplements may result in a deep orange discoloration of the skin known as lycopenodermia. Lycopenemia is a clinical condition characterized by pigmentation of the skin color from yellow to orange. Lycopenemia is caused by the accumulation of lycopene due to excess consumption of lycopene resources taken from the diet. Lycopene deposits take place in the stratum corneum, which has high lipid content and affinity against lycopene. Often, the diagnosis of lycopenemia is determined by a history of diet. With the changes in diet, the symptoms are eliminated ²²³.

Pregnancy

The consumption of lycopene in foods taken through diet during pregnancy and breastfeeding is generally safe ²²⁴. However, lycopene supplements taken in addition to food lycopene taken during pregnancy are probably not safe (Khan UM, Sevindik M, Zarrabi A, Nami M, Ozdemir B, Kaplan DN, Selamoglu Z, Hasan M, Kumar M, Alshehri MM, Sharifi-Rad J. Lycopene: Food Sources, Biological Activities, and Human Health Benefits. Oxid Med Cell Longev. 2021 Nov 19;2021:2713511. doi: 10.1155/2021/2713511)). In a study, 2 mg of lycopene was used daily as a supplement starting from 12 to 20 weeks of pregnancy until birth. As a result, the proportion of preterm and low birth weight infants increased ²²⁵. However, in a different study using lycopene supplements, these problems were not seen. There is not enough information about the reliability of lycopene supplementation during breastfeeding. Consequently, it is recommended to avoid supplementing lycopene in addition to food-borne lycopene during pregnancy and lactation ²²⁶.

In a study conducted on pregnant women, lycopene and vitamin C levels were found to be significantly lower in preeclamptic pregnant women compared to healthy pregnant women. Also, there was an increase in oxidative stress markers (glutathione peroxidase, superoxide dismutase, and malondialdehyde). As a result, it was thought that additional dietary antioxidants (lycopene and vitamin C) might be beneficial in the prevention of preeclampsia (high blood pressure that can occur during pregnancy) ²²⁷.

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