Beta-carotene is the most active precursor of vitamin A (Wang et al 1998). It is a naturally occurring carotenoid pigment found in fresh fruits and green and yellow vegetables. Beta-carotene is converted to vitamin A in vivo. The best dietary sources of beta-carotene include carrots, dark green leafy vegetables such as spinach, green leafy lettuce, sweet potatoes, broccoli, cantaloupe, and winter squash. Ordinary cooking does not destroy beta-carotene (USP DI 2004).
Beta-carotene is often used in complementary clinical settings. It is useful in diminishing the photosensitivity reactions that occur in patients with erythropoietic protoporphyria. Much controversy surrounds the clinical utility of beta-carotene in the prevention and treatment of cancer. Still, it remains a frequently used supplement in many individuals.
Actions & Pharmacology
Beta-carotene is a natural precursor of vitamin A that has antioxidant and pro-oxidant properties, and may also have photoprotective effects in erythropoietic protoporphyria.
Beta-carotene can function as both an antioxidant and a pro-oxidant. Beta-carotene shows radical-scavenging activity under physiologic oxygen partial pressures (less than 100 mm Hg). When exposed to hyperoxic partial pressures (greater than 150 mm Hg) beta-carotene shows pro-oxidant properties with a loss of its antioxidant capacity (Powers et al 1999).
Another study concluded there was no antioxidant effect. An in vitro experiment conducted in cells loaded with beta-carotene and then exposed to peroxyl radicals concluded that beta-carotene did not provide any antioxidant protection to live cells under normobaric oxygen tension (Day et al 1998). Experimental data show beta-carotene acts as an antioxidant in vitro, but in vivo data are less convincing. Pro-oxidant data are based on high oxygen tension levels, giving little support that beta-carotene acts as a pro-oxidant in the body (Krinsky 1998).
Beta-carotene exerted a protective effect against exercise-induced asthma (EIA) in a randomized, double-blind, placebo-controlled trial of 38 subjects aged 8 to 33 with proven EIA. Beta-carotene 64 mg daily or placebo was given for 1 week and pulmonary function was tested. This protocol was completed twice with a 4-week washout period. Postexercise forced expiratory volume in 1 second (FEV-1) was reduced by more than 15% in all participants taking placebo. In the beta-carotene treated group, 53% showed a postexercise FEV-1 reduction of less than 15%. Strenuous exercise may promote increased free-radical production resulting in lipid peroxidation and tissue damage. It is believed the antioxidant properties associated with beta-carotene may protect against some of this damage (Neuman et al 1999).
Heavy use of multivitamins, including beta-carotene, may increase the risk of advanced and fatal prostate cancer, according to an article in the Journal of the National Cancer Institute. Investigators involved in the National Institutes of Health–AARP Diet and Health Study screened men (n=295,344) at entry for self-reported multivitamin use and followed them for 5 years; 47% of subjects reported taking beta-carotene supplements more than 7 times per week, compared with 20% who reported never taking beta-carotene. By study end, an association was found between the frequent use of beta-carotene supplements in combination with either selenium or zinc and an increased risk of advanced and fatal prostate cancers. However, a similar pattern for localized prostate cancer was not observed (Lawson et al 2007).
Conversely, supplementation with beta-carotene in individuals having low plasma levels of the antioxidant may confer protection against less advanced forms of the disease. In one study, the effects of intakes of vitamin E, beta-carotene, and vitamin C on risk of prostate cancer were examined in 29,361 men followed for 8 years (average follow-up was 4.2 years); of these, 42% reported taking beta-carotene supplements. Those men with low dietary intakes of beta-carotene who took the supplement form of the antioxidant (calculated at about 2000 mg/day) had a decreased risk of prostate cancer. By study end, just 1,338 men had been diagnosed with prostate cancer (38.9% with the advanced form of the disease). However, no association was found between supplementation with beta-carotene and risk of prostate cancer in men with normal baseline plasma levels of the antioxidant (Kirsh et al 2006). This finding parallels that of the Physician's Health Study, which showed that although beta-carotene supplementation did significantly reduce the risk of prostate cancer in men with low baseline plasma levels of the antioxidant, it had no effect on men with higher baseline plasma levels (Cook et al 1999). No association was found between supplementation with beta-carotene and prostate cancer risk in the β-Carotene and Retinol Efficacy Trial (CARET; Omenn et al 1996).
Within the Physician's Health Study—a large, randomized, placebo-controlled trial with 12 years of follow-up—a nested case-control study was conducted to examine the effects of supplemental beta-carotene on the risk of developing nonmelanoma skin cancer (NMSC) in subjects with low baseline plasma levels of the antioxidant. Beta-carotene 50-mg was administered on alternate days to 1,338 men, most of whom subsequently developed NMSC over the 12-year follow-up, specifically, basal cell carcinoma (BCC, n=1156) and squamous cell carcinoma (SCC, n=166). An age- and smoking-matched control group (n=1338) remained free of NMSC at the time of diagnosis of the case, and both groups had similar mean baseline levels of beta-carotene. Following conclusion of the 12-year study, no positive effects of supplementation with beta-carotene on the risk of NMSC, BCC and SCC were observed among subjects. No association between plasma levels of beta-carotene and risk of NMSC was found (Schaumberg et al 2004).
Earlier trials yielded similar results, including 2 that showed no statistically significant benefit of supplemental beta-carotene for basal or squamous cell skin cancers (Frieling et al 2000, Green et al 1999). The Skin Cancer Prevention Study followed men who had received treatment for an earlier skin cancer, and interceded with beta-carotene supplementation (50 mg/day) to observe the effect of supplementation on the development of subsequent NMSC. After 5 years, a 10-fold increase of plasma levels of beta-carotene were noted in the men; however, there was no effect on skin cancer (Greenberg et al 1990).
No statistically significant benefit associated with beta-carotene supplementation has been found for the following cancers: colorectal (Bjelakovic et al 2006, Albanes et al 2000, Cook et al 2000); gastric (Plummer et al 2007); lung (Cook et al 2000, Omenn et al 1996); pancreatic (Rautalahti et al 1999); renal cell (Virtamo et al 2000); or urothelial cell (Virtamo et al 2000). Several large studies of beta-carotene supplementation show no beneficial effect on the prevention of malignant neoplasms (Hennekens et al 1996).
Beta-carotene supplementation appeared to increase the risk of lung cancer among smokers in one study (Albanes et al 1996). The CARET trial reported that male smokers receiving a combination of supplemental beta-carotene and retinyl palmitate (vitamin A) had a 39% greater incidence of lung cancer (CARET; Omenn et al 1996). In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, male smokers aged 50-69 years (n=29,133) were randomly assigned to treatment with 1 of 4 regimens. Those receiving supplementation with beta-carotene (20 mg) had a 16% greater incidence of lung cancer (Heinonen et al 1994). Taking beta-carotene supplements did not appear to have a direct effect on precancerous conditions such as cervical dysplasia and HPV infection (Romney et al 1997).
Evidence suggests that serum beta-carotene levels may be reduced in diabetic patients. A case-controlled study assessed the effects of diabetes on vitamin A, beta-carotene, alpha-tocopherol, and retinol binding protein (RPB). Patients with type 2 diabetes (n=107) and a control group (n=143) received a dietary assessment, fasting blood levels, and a 10-hour urinalysis. Serum beta-carotene was significantly higher in the control group (p=0.002). The diabetic group had a significantly higher serum and urine RPB concentration (p=0.0001). Diabetic patients with renal impairment had a significantly higher urinary excretion of RPB (p=0.0001). Serum retinol concentrations in patients with diabetes were normal. There was a negative correlation between fasting blood glucose and serum beta-carotene (p=0.008) (Abahusain et al 1999).
In another study, beta-carotene supplementation was ineffective in reducing the risk of developing type 2 diabetes in a 12-year, randomized, double-blind, placebo-controlled study. The incidence of type 2 diabetes was not significantly different: 396 men in the beta-carotene group and 402 men in the placebo group developed type 2 diabetes. The two groups were comparable in terms of age, body mass index, smoking status, alcohol intake, physical activity, and other variables (Liu et al 1999).
Studies of beta-carotene's effects on immune function have yielded conflicting results. In one placebo-controlled crossover study (n=25), supplementation with beta-carotene 15 mg daily for 26 days resulted in an elevated expression of peripheral blood monocyte surface molecules involved in initiating immune responses and an increased secretion of tumor necrosis factor alpha. All participants were nonsmokers (Hughes et al 1997).
However, other short- and long-term trials show that beta-carotene supplementation has no effect on T-cell mediated immunity. Twenty-five healthy elderly women were given placebo or beta-carotene 90 mg daily for 23 days. Beta-carotene supplementation had no effect on delayed-type hypersensitivity, in vitro lymphocyte proliferation, production of interleukin 2, or production of prostaglandin E2. In a long-term (12-year) randomized, placebo-controlled trial from a subset (n=54) of the Physician's Health Study, men receiving beta-carotene 50 mg every other day showed no differences from the placebo group in the profile of lymphocyte subsets or in percentages of natural killer cells and activated lymphocytes (Santos et al 1997).
A study conducted to assess the effects of carotenes on night vision showed no effects. Subjects in the Blue Mountain Eye Study (n=3,654) were interviewed for nutrient and food intake by questionnaire. Self-reported poor night vision in women was associated with higher intakes of beta-carotene (p=0.03) and total vitamin A (p=0.048). There was no association between night vision and beta-carotene or vitamin A intake in men. The study concluded that perceived poor night vision caused an increase in carrot consumption in women (Smith et al 1999).
Oral carotenoids (25 mg daily) or carotenoids plus vitamin E (500 IU daily) reduced ultraviolet light (UV)-induced erythema in 17 healthy volunteers with skin type I or II. After 12 weeks of supplementation, approximate sun protection factors (SPF) of 2.4 and 3.0 were estimated for carotenoids alone and for carotenoids plus vitamin E, respectively (Stahl et al 2000).
Beta-carotene alone or in combination with canthaxanthin was administered to 36 patients with erythropoietic protoporphyria. Daily doses of 50 mg to 200 mg were given during the summer months. Eighteen patients reported being symptom-free, 16 patients improved, and two patients improved only slightly. Carotenemia was the only side effect reported (Thomsen et al 1979).
One recent meta-analysis suggests that supplementation with beta-carotene may increase overall mortality (Bjelakovic et al 2007). Data was extracted from 385 publications involving 68 randomized trials with a total of 232,606 subjects. Using statistical analysis and other methodology to review the medical literature, the authors concluded that supplementation with beta-carotene, either alone or in combination with other antioxidants, was significantly associated with increased all-cause mortality (dose range=1.2 mg to 50 mg in studies examined). Further studies are warranted to examine whether a correlation exists between supplementation with beta-carotene and increased risk of death. Distinctions should be made between the clinical utility of supplementation in persons with a deficiency of beta-carotene, and its possible deleterious effects in persons with adequate plasma levels of the antioxidant.
Vitamin A or beta-carotene supplementation of Nepalese women of childbearing age significantly reduced mortality during pregnancy and through 12 weeks postpartum. Of more than 44,000 women who were given weekly vitamin A supplements of 23,300 IU (7,000 mcg retinol equivalents, as retinyl palmitate), or trans-beta-carotene (7,000 mcg retinol equivalents, assuming a conversion ratio to retinol of 6 to 1 after uptake), or placebo, more than 7,000 women per treatment group became pregnant. Mortality per 100,000 pregnancies was 426 in the vitamin A group, 361 in the beta-carotene group, and 704 in the placebo, yielding relative risks of 0.60 (p=0.04) and 0.51 (p=0.01) for vitamin A and beta-carotene. Mortality among women in the vitamin A group was not different from that among women in the beta-carotene group. This suggests that the risk of maternal death among women who are deficient in vitamin A can be substantially reduced by modest increases in vitamin A or beta-carotene intake (West et al 1999).
Indications & Usage
Beta-carotene supplementation can be used for prophylaxis of vitamin A deficiency, although dietary improvement is preferable. For treatment of documented vitamin A deficiency, vitamin A supplements are preferred. Beta-carotene is also used for photosensitivity reactions in erythropoietic protoporphyria (prophylaxis and treatment) and severe polymorphous light eruption (prophylaxis and treatment) (USP DI 2004).
Although research is ongoing, supplemental beta-carotene has also been used for the following: angina, asthma, cancer prevention, cardiovascular disease, cataract prevention, diabetes, free-radical reduction during bone marrow transplantation, immunostimulation, night vision, and oral leukoplakia.
Precautions & Adverse Reactions
Beta-carotene supplements are not recommended for patients with lung cancer or asbestosis (Albanes et al 1996; Chuwers et al 1997). Caution is also advised in patients with impaired renal function, impaired liver function, hypervitaminosis A, and anorexia (USP DI 2004).
Beta-carotene may cause yellow skin discoloration due to carotenodermia (USP DI 2004; Product Info: Solatene 1996). This condition may be differentiated from jaundice by the lack of pigmentation in the sclera and represents a therapeutic response to the drug. The protective response from the drug will not be seen until the carotenemic effect becomes apparent. It is usually first seen as yellowness of the palms and soles (Product Info: Solatene 1996). Hypervitaminosis A does not result from the carotenemic condition (Gilman et al 1980; Mathews-Roth et al 1974).
Slight diarrhea or loose stools could occur during beta-carotene therapy but may not require drug withdrawal (Product Info: Solatene 1996; Mathews-Roth et al 1974). Although rare, the manufacturer has reported the occurrence of ecchymoses and arthralgia during beta-carotene administration (USP DI 2004; Product Info: Solatene 1996).
FDA-rated as Pregnancy Category C. Beta-carotene crosses the placenta. No problems with pregnancy have been documented in women taking up to 30 mg (5,000 retinol equivalents) of beta-carotene daily (USP DI 2004).
Beta-carotene is safe in normal dietary amounts.
Concurrent use of orlistat and beta carotene may result in decreased beta carotene efficacy. Clinical Management: Patients should be instructed to space the administration of orlistat and beta carotene by at least two hours.
Cholestyramine, Colestipol, Mineral Oil, and Neomycin
Concurrent use may interfere with the absorption of beta-carotene or vitamin A (USP DI 200 4). Clinical Management: Vitamin A requirements may be increased; monitor for deficiency.
Vitamin A toxicity has been reported in a 20-year-old Japanese woman whose diet included an excessive amount of beta-carotene-rich foods. Her symptoms included low-grade fever, cheilitis, dry skin, limb edema, and headache. It is unclear whether the toxicity symptoms were due to beta-carotene or vitamin A consumption (Nagai et al 1999).
Mode of Administration
Tablets, capsules, liquid
The preferred way of designating vitamin A activity is in retinol equivalents (RE); 6 mcg of beta-carotene is equivalent to 1 RE and 10 units of vitamin A activity (USP DI 2004).
Erythropoietic Protoporphyria – Adults: 30 to 300 mg daily in single or divided doses. Children under 14 years old: 30 to 150 mg daily.
Extended therapy (2 to 6 weeks) is needed to accumulate enough beta-carotene in the skin to exert a protective effect. If an adult dose of 180 mg daily for 3 months (serum level at 800 mcg/100 mL) does not provide a clinical response, then it may be concluded that beta-carotene supplementation will be of no benefit. Patients who develop carotenodermia should be instructed to increase exposure to sunlight gradually until individual exposure limits are established (Product Info: Solatene 1996).
Vitamin A Deficiency (prophylaxis) – Adults and adolescents: 1,000 to 2,500 RE (the equivalent of 10,000 to 25,000 units of vitamin A activity) or 6 to 15 mg of beta-carotene daily.
Children: 500 to 1,000 RE (the equivalent of 5,000 to 10,000 units of vitamin A activity) or 3 to 6 mg of beta-carotene per day (USP DI 2004).