Many of the clinical uses of zinc supplements are for conditions thought to arise from a marginal zinc deficiency, but some indications are based on the concept that high-dose zinc supplements act as a therapeutic agent.
Traditionally, zinc supplementation has been used to treat deficiency or prevent deficiency in conditions such as acrodermatitis enteropathica, anorexia nervosa, malabsorption syndromes, conditions associated with chronic diarrhea, alcoholism, diabetes, HIV and AIDS, recurrent infections, severe burns, Wilson’s disease and sickle cell anaemia. Zinc supplements are also popular among athletes in order to counteract the zinc loss that occurs through perspiration.
Oral zinc supplements, lozenges and nasal sprays and gels have been investigated in the treatment of the common cold. It has been demonstrated that a transient increase in zinc concentrations in and around the nasal cavity prevents rhinovirus binding to cells and disrupts infection and/or modulates inflammatory cytokines that may exacerbate cold symptoms.
A randomised, double-blind placebo-controlled trial with 160 people tested the effects of a nasal spray of 0.12% zinc sulfate and found that it reduced the total symptom score, but had no effect on the duration of cold symptoms or the mean time to resolution. The effectiveness of intranasal zinc gluconate as a preventative agent against experimentally induced rhinovirus infection was tested in a study of 91 subjects. It was administered for 3 days prior to rhinovirus inoculation followed by 6 days of treatment. This regimen had no effect on total symptom score, rhinorrhea, nasal obstruction, or the proportion of infected volunteers who developed clinical colds. Two other trials using a dose of zinc in a nasal gel formulation showed that zinc treatment significantly reduced cold duration compared with placebo when used within 24-48 hours of symptom onset. The nasal gel spray contained either 33 mmol/L zinc gluconate or placebo and was administered as one dose per nostril four times daily until symptoms resolved or for a maximum of 10 days. Symptoms that responded included nasal drainage, hoarseness and sore throat.
Both positive and negative results have been obtained for different forms of oral zinc supplements and specialised preparations. A 2000 Cochrane review analysed the results from seven trials involving 754 cases and concluded that current evidence is inconclusive as to whether zinc lozenges are an effective treatment for symptoms of the common cold. This conclusion is considered conservative, as an intention-to-treat analysis at 7 days found a statistically significant RR of 0.69 and the numbers needed to treat for one person to benefit ranged from 4 to 8. The authors of the review were concerned about blinding of the studies and variation in doses used making a conclusive recommendation difficult.
Since then, several new studies have been published. McElroy and Miller (2002) showed that treatment with zinc gluconate glycine lozenges (Cold-Eeze) significantly decreased cold duration (7.5 vs 9.0 days for non use) and significantly reduced cold frequency and concomitant antibiotic use in school-aged subjects. A subsequent phase IV study by the same pair of researchers (2003) investigated the therapeutic and prophylactic effectiveness of Cold-Eeze for the common cold in a cohort of 134 subjects drawn from the previous study. Once again, zinc gluconate glycine lozenges shortened cold duration (6.9 vs 9.0 days) and the mean number of colds (1.7 vs 1.28), achieving a 25% reduction in cold incidence. Zinc lozenges were administered once daily during the cold season and four times daily as acute treatment. An adult study demonstrated that zinc gluconate (13.3 mg) or zinc acetate (5 or 11.5 mg) lozenges had no effect on duration or severity of cold symptoms. A recent double-blind, placebo controlled study found that frequent administration of zinc orotate lozenges (37 mg zinc each) and intranasal zinc gluconate spray had no effects on severity of cold symptoms or their duration.
It is not clear why some trials have produced positive results whereas others have not; however, it is suspected that the type of zinc and formulation used has an influence over effectiveness. A closer look at the evidence shows that zinc gluconate or zinc acetate are the forms generally associated with positive results whereas other forms are less effective. Additionally, lozenge additives such as sorbitol and citric acid are thought to decrease zinc ion release, which is necessary for zinc’s virucidal activity. It has been suggested that zinc lozenges be allowed to completely dissolve in the mouth without chewing and that citrus fruits or juices be avoided 30 minutes before or after dissolving each lozenge to avoid negating the therapeutic effects of zinc.
AGE-RELATED MACULAR DEGENERATION
Both dietary and supplemental zinc have been investigated in the prevention and/or progression of ARMD.
A 2002 Cochrane review assessed the effects of antioxidant vitamin and/or mineral supplementation on the progression of ARMD and found that evidence of effectiveness is currently dominated by one large trial that showed modest benefit in people with moderate to severe signs of the disease who were administered antioxidant vitamins and zinc together. More recently, results of the Age-Related Eye Disease Study were published (AREDS 2001), which showed that high-dose vitamins C and E, beta-carotene, and zinc supplementation delayed the progression from intermediate to advanced disease by 25% over 5 years. The 11 centre, double-blind, prospective study involved 3640 volunteers aged between 55 and 80 years who were randomly divided into four treatment groups, receiving either antioxidant supplements (500 mg vitamin C, 400 international units (IU) vitamin E, and 15 mg beta carotene daily), zinc oxide and cupric oxide (80 mg elemental zinc, 2 mg elemental copper daily), antioxidants plus zinc, or placebo. The contribution of zinc to this result is unknown (see Lutein monograph for more information about ARMD).
Overall, the current available data are insufficient to conclusively state that zinc supplementation used as stand-alone treatment should be taken during the early signs of disease; however, when taken in combination with antioxidant vitamins the evidence is more supportive for its use in intermediate ARMD.
In terms of primary prevention, a 2005 study found that high dietary intake of zinc, beta-carotene and vitamins C and E was associated with a 35% reduced risk of ARMD in elderly persons.
Zinc supplementation is sometimes used in diabetes in order to avoid deficiency, a state associated with both type 1 and 2 diabetes in numerous studies. It is still unknown whether restoring zinc status to normal levels or using high-dose zinc to induce other effects will be beneficial in the clinical management of diabetes, its complications or its prevention, as current data from both animal and human studies have produced varied results.
A prospective, double-blind, clinical interventional study of 56 obese women with normal glucose tolerance who were randomised to treatment with zinc, 30 mg/day, or placebo for 4 weeks found that zinc treatment decreased insulin resistance from 5.8 to 4.3 and insulin decreased from 28.8 to 21.2 mU/mL in the zinc group, but was unchanged in the placebo group. These results are particularly noteworthy because the women were not zinc deficient, suggesting a therapeutic role for zinc.
Clinical note — Zinc deficiency and diabetes
Diabetes affects zinc homeostasis in many ways and is associated with increased urinary loss, decreased absorption and decreased total body zinc. The role of zinc and zinc deficiency in diabetes and its complications or prevention is currently unclear. It has been suggested that deficiency may exacerbate destruction of islet cells in type 1 diabetes and may adversely affect synthesis, storage and secretion of insulin, a process that requires zinc. Furthermore, evidence indicates that patients with type 1 diabetes mellitus have a higher concentration of free radicals than healthy controls, which is due to increased oxidant production and/or decreased efficiency of endogenous antioxidant systems. It is suspected that deficiency of key micronutrients (i.e. zinc, copper, manganese and selenium), which are integral components of important antioxidant systems, may be partly responsible.
IMPROVES WOUND HEALING
Zinc is an essential cofactor in wound healing and immune function. Therefore, zinc deficiency retards both fibroplasia and epithelialisation, and results in delayed wound healing. Zinc supplements are used to restore zinc status in cases of wound healing associated with malnutrition and deficiency. Additionally, zinc administered orally or topically to wounds can promote healing and reduce infection, according to one major review.
In 2001, a randomised study demonstrated that oral zinc sulfate significantly improved healing of cutaneous leishmaniasis. Results showed that the cure rate for a dose of 2.5 mg/kg was 83.9%, for 5 mg/kg it was 93.1% and for 10 mg/kg it was 96.9%, whereas no lesions showed any sign of healing in the control group.
Topical zinc oxide promotes cleansing and re-epithelialisation of ulcers and reduces the risk of infection and deterioration of ulcers compared with placebo, according to one double-blind trial of leg ulcer patients with low serum zinc levels. Evidence from animal and in vitro research suggests that topically applied zinc solution is more effective when combined with iron than when used alone, and can effectively enhance healing in acute partial-thickness and second-degree burn wounds.
ARTERIAL AND VENOUS LEG ULCERS
A 2000 Cochrane review assessed six placebo-controlled trials of zinc sulfate supplementation in arterial and venous leg ulcers and concluded that overall there is no evidence of a beneficial effect on the number of ulcers healed. However, there is some evidence that oral zinc might improve healing of venous ulcers in people with low-serum zinc levels.
Double-blind studies producing encouraging results have used oral zinc (600 mg/day) combined with topical treatment and compression bandages.
ACNE AND OTHER SKIN CONDITIONS
Over the past 2-3 decades, tetracyclines and macrolide antibiotics have been widely prescribed for the treatment of acne; however, resistance has been reported, especially to erythromycin and clindamycin with cross-resistance being widespread among strains of Propionibactenum acnes. As a result, non-antibiotic treatments such as topical and oral zinc preparations have been investigated as both alternatives and adjuncts to these treatments.
Overall, studies have yielded conflicting results, possibly due to considerable placebo effects, with better effects generally seen on inflammatory lesions than other lesion types. This is most likely due to the fact that zinc has a marked anti-inflammatory effect, which was first observed with zinc sulfate and later with zinc gluconate, which is a better tolerated form.
Numerous studies have been conducted investigating the effects of zinc supplementation in acne vulgaris. Doses between 90 mg and 200 mg (30 mg elemental zinc) daily taken over 6-12 weeks have been associated with generally positive results, whereas larger doses tend to be poorly tolerated. More recently, an open study involving 30 subjects with inflammatory acne found that a lower dose of oral zinc gluconate (30 mg) taken daily reduced the number of inflammatory lesions after 2 months regardless of whether P. acnes was present.
Two double-blind studies have compared the effects of oral zinc supplementation with two antibiotic medicines, minocycline or oxytetracycline, over 3 months. Zinc sulfate (135 mg) was as effective as oxytetracycline after 12 weeks’ use, decreasing acne scores by 65% in one study, whereas the same dose was not as effective as minocycline (500 mg) in the second study.
Zinc has also been investigated as an adjunct to antibiotic therapy under laboratory conditions. When administered in combination with erythromycin, it inhibits erythromycin-resistant propionibacteria according to two in vitro studies.
A number of studies have investigated the effects of a topical erythromycin-zinc acetate formulation.
Statistically significant effects have been observed within the first 12 weeks of treatment for acne severity grades, and for papule, pustule and comedo counts, with the effect of the combination superior to preparations containing erythromycin alone. Human studies have identified antibacterial activity against Propionibactenum spp. in short-term treatment, which is mostly attributed to zinc and sebosuppressive effects.
REDUCED MALE FERTILITY
Zinc deficiency leads to several clinical signs, such as decreased spermatogenesis and impaired male fertility. When zinc deficiency is not present, a 2002 survey found no statistically significant relationship between zinc in seminal plasma or serum and semen quality or local antisperm antibody of the IgG or IgA class. Furthermore, zinc levels did not influence sperm capacity to penetrate cervical mucus in vitro or in vivo, and did not affect subsequent fertility.
In men, zinc deficiency may lead to impaired testosterone synthesis, resulting in hypogonadism and impotency. One placebo-controlled study has investigated whether oral zinc supplementation improves erectile dysfunction. The study involved 20 uraemic haemodialysis patients and showed that 6 months treatment with oral zinc acetate (25 mg elemental zinc) taken twice daily 1-2 hours before meals resulted in greater libido, improved potency and more frequent intercourse compared to placebo. Active treatment also resulted in significant increases in plasma zinc, serum testosterone, and sperm count and decreases in serum levels of LH and FSH.
ATTENTION-DEFICIT HYPERACTIVITY DISORDER
In 1990, Arnold et al observed that boys aged 6-12 years with ADHD with a higher baseline hair zinc level had better responses to amphetamine therapy than children with mild zinc deficiency. At the time it was suggested that children responding poorly to drug therapy and presenting with mild zinc deficiency would require zinc supplementation instead of amphetamine treatment to address the condition. Since then, numerous controlled studies have identified that children with ADHD have lower zinc tissue levels (serum, red cells, hair, urine, nails) than normal children. It is not certain why this occurs, but may result from not sitting at the kitchen table long enough to consume a balanced diet, picky eating, stimulant-related appetite suppression, malabsorption or biochemical changes.
Two double-blind studies have investigated whether oral zinc supplementation has a beneficial effect in ADHD, producing promising results. One randomised study involving 400 Turkish children with a mean age of 9.6 years found that treatment with 150 mg zinc sulfate (equivalent to 40 mg of elemental zinc) daily for 12 weeks resulted in significant reductions in hyperactive, impulsive and impaired socialisation symptoms, but not in reducing attention deficiency symptoms, as assessed by the ADHD Scale. A significant difference between zinc and placebo were already evident by week 4 (P = 0.01). Older children with low zinc and free fatty acid levels and high BMI responded best to treatment. A second placebo-controlled trial used a combination of 55 mg zinc sulfate (equivalent to 15 mg elemental zinc) and methylphenidate (1 mg/kg) daily for 6 weeks in Iranian children aged 5-11 years and reported significant benefits with the combination.
It is important to note that both studies were conducted with children from countries with suspected zinc deficiency and further investigation is required to determine whether the same beneficial results will occur in children living in Western countries.
Twenty patients with unipolar depression had an improved response to antidepressant medication when taken with zinc aspartate supplements (equivalent to 25 mg elemental daily), according to a small, double-blind pilot study. Significantly greater reductions in Hamilton Depression Rating Scale scores were achieved with zinc treatment compared to placebo by the 6th week and maintained until the end of the 12-week study.
Although reduced zinc status has been associated with chronic diarrhea and Crohn’s disease, the results from a small open study demonstrated that oral zinc sulfate (110 mg three times daily) resolved intestinal permeability problems in people with increased permeability and decreases relapse rates.
Overall, application of zinc preparations greatly reduces or eliminates recurrence of genital herpes infections and resolves symptoms of herpes simplex infections. Zinc sulfate gel applied every 2 hours was a more effective treatment than placebo in herpex simplex labial is in a double-blind study of 80 subjects. Another study of 200 volunteers with herpes simplex found that 0.25% zinc sulfate solution started within 24 hours of lesion appearance and applied 8-10 times daily cleared lesions within 3-6 days. A randomised placebo-controlled study using a weak zinc solution (0.05% or 0.025% zinc sulfate) found no effects on frequency, duration or severity of herpes attacks, suggesting that stronger concentrations are required for effectiveness.
There is evidence that suggests zinc deficiency may be intimately involved with anorexia in humans, if not as an initiating cause, then as an accelerating or ‘sustaining’ factor for abnormal eating behaviours that may deepen the pathology of the anorexia. Zinc status is compromised in anorexia nervosa due to an inadequate zinc intake, with supplementation (50 mg elemental zinc/day) shown to decrease depression and anxiety, stop body weight loss and improve weight gain. According to one randomised, double-blind, placebo-controlled trial, 100 mg of zinc gluconate doubled the rate of subjects with anorexia nervosa increasing their BMI compared to placebo.
IMPROVES TASTE PERCEPTION
Dysfunctional taste perception, or dysgeusia, is a condition that can at the least affect QOL and occasionally can become life-threatening. Zinc supplementation using 140 mg of zinc gluconate (20 mg elemental) per day can improve dysgeusia.
In 1987, a report was published suggesting a link between reduced zinc status and intermittent head noises in people suffering with tinnitus. This has been further investigated in several studies; however, the poorly defined patient groups and use of serum zinc as the means of measuring zinc status makes interpretation of results difficult to assess.
In 1991 Paaske et al reported the results of a randomised, double-blind study of 48 patients with tinnitus that had failed to find a significant effect on symptoms with sustained-release zinc sulfate tablets. Of note, only one subject had low zinc serum levels. More recently, a study of 111 subjects aged 20-59 years found individuals with tinnitus who had normal hearing had significantly lower serum zinc levels than controls, whereas zinc levels were normal for those with accompanying hearing loss. In addition, a significant correlation between average hearing sensitivity and serum zinc level was observed. Yetiser et al (2002) investigated serum zinc levels and response to supplementation in 40 patients with severe tinnitus of various origins. Some relief in tinnitus symptoms was reported by 57.5% of all subjects who received 220 mg of zinc daily for 2 months; however, the effect was considered minor. When results were divided by age, a different finding emerged as 82% of people over 50 years of age experienced an improvement on the tinnitus scale compared to only 48% of younger subjects. There was no correlation between severity of tinnitus and serum zinc levels. Zinc supplementation (50 mg/day) was further studied in a randomised, placebo-controlled trial involving 41 Turkish patients with tinnitus of no known cause. Active treatment for 2 months produced clinically favourable progress in 46.4% of subjects; however, this result was not statistically significant.
Oral zinc sulfate (10 mg/kg) supplements administered in three divided doses per day (up to 600 mg/day) for 2 months completely cleared recalcitrant viral warts in 87% of patients, according to a single-blind, placebo-controlled trial of 80 volunteers with at least 15 viral warts that were resistant to other treatments. Warts were completed cleared in 61% of patients after 1 month of treatment, whereas none of the patients receiving placebo reported a successful response and some developed new warts. In both placebo and treatment groups the drop-out rates were high: 50% and 45% respectively. Interestingly, patients in the treatment group with low serum zinc baseline levels (mean 62.4 µg/100 ml_) exhibited no signs or symptoms of deficiency and zinc serum levels failed to rise in the patients who remained resistant to zinc therapy. Treatment with high-dose zinc supplements was accompanied by nausea and in some cases vomiting and mild epigastric pain, although these symptoms were described as mild and transient.