Fruit Acids

Common Name(s): Alpha hydroxy acids, Citric acid, Fruit acids, Gluconolactone, Glycolic acid, Lactic acid, Malic acid, Tartaric acid

Medically reviewed by Drugs.com. Last updated on Jul 3, 2025.

Clinical Overview

Use

Fruit acids have been used to treat a range of dermatological conditions, including acne, photoaging, dry skin, psoriasis, actinic keratosis, and melasma. Additionally, they have been investigated as a treatment for fibromyalgia, dental scaling, and dry mouth, and for prevention and treatment of urinary tract stones. However, apart from topical application, clinical trials are lacking to support any additional indications.

Dosing

Chemical peels: Dosing for chemical peels involving glycolic acid may depend on a variety of factors, including the condition being treated, patient expectations, patient age, cumulative sun exposure, skin type, area being treated, peeling agent used, concentration of peel agent, frequency of application, quantity applied, and length of time applied. Typically, on the first visit, glycolic acid is applied for approximately 2 to 3 minutes to determine sensitivity and provide guidance for future length of exposure. Intervals between peels are generally 2 to 4 weeks; 6 to 8 peels are required for most patients.

Dry skin disorders: Alpha hydroxy acid 8% to 10% cream or lotion applied 2 to 3 times daily to affected area(s). If dry skin persists after 2 weeks, the concentration can be increased by 2% to 4%. Once the skin appears healthy, the frequency can be reduced to every 2 to 3 days.

Fibromyalgia: 3 Super Malic tablets (each containing malic acid 200 mg) twice daily.

Contraindications

Hypersensitive individuals and those with irritated skin should use alpha hydroxy acids cautiously. Patients who have undergone recent cosmetic surgeries, have open wounds, or have used isotretinoin therapy within the last 6 to 12 months should not receive alpha hydroxy acid peels. In patients with a history of recurrent or active herpes simplex lesions, treatment with an oral antiviral agent should occur before undergoing chemical peels.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

See Drug Interactions section.

Adverse Reactions

Dryness, scaling, burning, erythema, and similar effects may occur in sensitive individuals or with prolonged use.

Toxicology

No data.

Source

Acidic organic compounds are derived primarily from fruit and other natural sources.Rubin 1994 Specifically, malic acid is derived from apples, glycolic acid (the smallest alpha hydroxy acid) is derived from sugar cane, lactic acid is derived from sour milk, tartaric acid is derived from grapes, and citric acid is derived from citrus fruits.Green 2009, Kneedler 1998, Rubin 1994, Van Scott 1996 Other sources may be used for commercial production of these acids (eg, starch, glucose, other sugars).

History

Organic acids, such as lactic acid, have long been used in dermatologic preparations as humectants to improve moisturization of the outer skin layers. In ancient Egypt, it was believed that Cleopatra bathed in spoiled milk, which contains lactic acid.Kneedler 1998 Organic acids have also been used to remove hair from and to tan animal hides.Windholz 1983 In 1974, alpha hydroxy acids were first used in dermatology for their topical efficacy against severe hyperkeratosis of ichthyosis.Yu 2004

Most organic acids can be caustic in sufficiently high concentrations. As agents that modify the keratinization process (see Pharmacology), alpha hydroxy acids may be useful for the treatment of acne and other skin disorders.Van Scott 1974 Because they help debride dead cells from the skin, they have been added to a variety of skin cleansers. People with all types of skin are typically able to tolerate alpha hydroxy acid products, including those with sensitive or darker skin.Briden 2004 Glycolic acid is commonly used for skin peel procedures.Sharad 2013

A number of cosmetic companies market products that contain alpha hydroxy acids for their antiaging effects on the skin. Removal of top skin layers may enhance the appearance of the skin.

Chemistry

Fruit acids are a group of organic acids that share a common chemical structure consisting of a hydroxyl group positioned at the alpha-carbon position. Consequently, these compounds are often referred to as alpha hydroxy acids.Kaminsky 2003 Common fruit acids include lactic, citric, and malic acids. Because of the structural configuration of these acids, they are optically active. Alpha hydroxy acids typically are water-soluble compounds.Kneedler 1998 However, some alpha hydroxy acids, such as mandelic acid and benzylic acid, are more lipophilic, making them more suitable for treating conditions such as oily skin.Green 2009 Gluconolactone, a polyhydroxy acid, contains a ring structure that is hydrolyzed to gluconic acid, which is an alpha hydroxy acid and poly-alpha hydroxy acid. This gives the molecule keratolytic and moisturizing capabilities. The lactone structure masks the acidity of the molecule, and the compound is suitable for patients with sensitive skin.Rona 2004 Unlike glycolic acid, gluconolactone pretreatment does not cause an increase in sunburn cells following ultraviolet B (UVB) irradiation.Green 2009

Uses and Pharmacology

Acne

Hyperkeratinization appears to play a role in the development of acne and is often the result of decreases in the rate of skin cell sloughing, which itself is due to an increase in the cohesion of cells known as corneocytes.(Hunt 1992) Alpha hydroxy acids may decrease the cohesiveness of corneocytes by weakening intercellular bonding,(Van Scott 1984) freeing skin cells, and permitting more efficient cell removal and skin cleansing.(Van Scott 1989) The American Academy of Dermatology/American Academy of Dermatology Association guidelines of care for the management of acne vulgaris (2016) state that gluconolactone has been reported to have value in the treatment of acne (grade B recommendation, level II evidence).(Zaenglein 2016)

Clinical data

One fruit acid component, gluconolactone, is as effective as benzoyl peroxide in the treatment of acne. In a double-blind trial of 150 patients, a solution of gluconolactone 14% was compared with benzoyl peroxide 5% lotion and a placebo vehicle. Both active treatments reduced the number of inflamed lesions (compared with baseline) during the 12-week study. While there was no difference between active treatments during the first 4 weeks, benzoyl peroxide was better at reducing the number of inflamed lesions by weeks 8 and 12 than the alpha hydroxy acid gluconolactone. Both groups were similarly effective in reducing the total number of inflamed and noninflamed lesions, but dryness was reported by more patients treated with benzoyl peroxide. Overall, 50% of benzoyl peroxide–treated patients reported adverse events compared with 24% of those treated with gluconolactone and 10% of the placebo-treated patients. Dryness, scaling, and burning were the most commonly reported events.(Hunt 1992)

In a multicenter, open-label study, the effects of an alpha hydroxy acid cream (Hyseac AHA) on mild to moderate acne in combination with other agents and as monotherapy were assessed in 248 patients. All participants used Hyseac AHA cream (containing arginine glycolate, malic acid, esterified malic acid, sebomes [sebum reducing agents], phytosfingosine, and piroctone olamine) twice daily for 60 days. Approximately half of patients used the product as monotherapy and the other half in combination with other pharmacological agents (ie, antibiotics, retinoids, benzoyl peroxide). The overall efficacy rate was 64.2% for all patients, with no differences noted between treatment groups (64.8% with combination therapy vs 63.3% with monotherapy). There were also no differences in efficacy based on type of acne.(Baldo 2010)

In a clinical study, 22 patients with acne applied aqueous lactate 5% lotion over the entire face twice daily for 1 year. Antibiotic use was permissible during times of acute flare-ups. Efficacy was assessed by counting the number of lesions, comedones, and cysts. Maximal effects on inflammatory lesions were noted between 8 and 24 weeks of therapy, and for comedones, maximal effects were noted between 8 and 30 weeks. Adverse effects included temporary prickling sensations occurring on the lesions, irritation, and facial oiliness, which disappeared after the first several days of treatment. Findings demonstrate safe and effective use of lactate lotion for the prevention of acne lesions.(Garg 2002)

The efficacy of alpha and beta hydroxy acid peels were compared in a split-face, double-blind, randomized study of 20 patients with mild to moderate facial acne. Patients applied a glycolic acid 30% peel to 1 side of the face and a salicylic acid 30% peel to the other side of the face. Participants completed 6 treatments, administered every 2 weeks. Both treatments produced significant reductions in acne lesions by the second treatment (P<0.05). At the 1-month follow-up visit, a 43% reduction in acne lesions occurred on the glycolic acid side compared with 47% on the salicylic acid side. Following 2 months of treatment, 75% of the sides treated with glycolic acid experienced good or fair improvement compared with 81% on the sides treated with salicylic acid. Though not statistically significant, more acne lesions were noted at the 2-month follow-up visit on the glycolic acid sides compared with the salicylic acid sides. Also, the salicylic acid sides had fewer acne lesions at the 2-month follow-up visit compared with baseline (P<0.01).(Kessler 2008)

In another study, lactic acid peels were found to improve skin texture, pigmentation, and appearance after use for 3 months in 7 Indian patients with scarring due to acne.(Sachdeva 2010)

Antiaging/Photoaging/Actinic keratosis

Alpha hydroxy acids exert a thinning effect on the stratum corneum, increase the thickness of the epidermis by increasing glycosaminoglycans and collagen fibers, and increase dermal volume. Specifically, the acids cause an "ungluing" of cells, causing them to shed instead of maintain their "stickiness." The thinning effect of the stratum corneum can be noted up to 14 days after treatment discontinuation.(Prestes 2013, Rubin 1994, Van Scott 1996) Additionally, alpha hydroxy acids stimulate the synthesis of collagen in the dermis. The overall effect is improvement in wrinkles, elasticity, and skin tone.(Rona 2004, Rubin 1994) Chemical peels with alpha hydroxy acids can be used to treat a variety of dermatological conditions, including acne, rosacea, age spots, melasma, scarring, and wrinkles.(Briden 2004) However, alpha hydroxy acids may increase ultraviolet (UV) sensitivity and associated postinflammatory hyperpigmentation, so use of sunscreen is important.(Prestes 2013) These peels cause an increase in dermal perfusion, as noted by marked erythema and vasodilation occurring after treatment.(Kneedler 1998) It may take as long as 6 months before patients achieve noticeable results with alpha hydroxy acid peels. Patients typically require 4 to 6 peels over a 4- to 6-month time period; however, the success of these peels is dependent on the severity of the condition being treated.

Animal data

In a murine model, the effects of glycolic acid and lactic acid were assessed in hairless mice randomized to receive either glycolic acid 5% or lactic acid 5% applied daily to the right side of the back with placebo applied to the left side of the back for 14 days. No differences were noted between the alpha hydroxy acid and placebo application sites with regard to transepidermal water loss and capacitance (a measure of hydration). Additionally, no difference in epidermal thickness was noted for alpha hydroxy acid–treated skin, placebo-treated skin, or untreated skin. Electron microscopy suggested the stratum corneum was decreased in areas treated with glycolic and lactic acids compared with the areas receiving placebo. An increase in the number and secretion of lamellar bodies was noted in the areas treated with alpha hydroxy acids.(Kim 2001)

Clinical data

In 11 healthy subjects, 4 alpha hydroxy acids applied to the volar forearms and arms were evaluated to determine their effects on the stratum corneum and their potential to prevent skin irritation. There were no differences among the 4 alpha hydroxy acids with regard to transepidermal water loss and erythema following 4 weeks of twice-daily application. Following a challenge with sodium lauryl sulfate, all sites experienced an increase in transepidermal water loss; however, lower transepidermal water loss occurred at sites treated with alpha hydroxy acids than at sites treated with placebo or those left untreated. Gluconolactone and tartaric acid yielded the lowest transepidermal water loss values.(Berardesca 1997) Topical application of glycolic acid 10% emulsion was used to explore the effects of alpha hydroxy acids on the pH of the stratum corneum and skin surface. Following a 10-minute application, the pH of the stratum corneum and skin surface were reduced and the latter was maintained for at least 3 hours, demonstrating both deep penetration as well as long-lasting effects.(Schreml 2012)

In a clinical study, the efficacy of alpha hydroxy acids on photoaging was assessed in 17 subjects with moderate to severe photoaged skin. Subjects were assigned a 25% concentration of a lotion containing lactic acid, glycolic acid, or citric acid, with instructions to apply to 1 forearm twice daily and a placebo lotion to apply to the other forearm. After treatment for an average of 6 months (range, 4 to 8 months), forearm thickness on the side treated with alpha hydroxy acids increased from 11.5±1.1 mm at baseline to 14.3±1.1 mm (25% increase). The forearm thickness on the placebo side decreased from 12.2±0.9 mm to 11.9±0.9 mm, a 2% decrease from baseline. The difference between the treated and placebo forearms was statistically significant (P<0.0001) and was discernible by pinching the skin. Histologically, the mean epidermal thickness and papillary dermal thickness were greater on the forearms treated with alpha hydroxy acids compared with the forearms treated with placebo. Regarding ultrastructural findings, forearms treated with alpha hydroxy acids had an epidermal base layer with more uniform basal keratinocyte nuclei, reduced clumping of tonofilaments in the cytoplasm, increased perinuclear localization of the tonofilaments, and formation of microvilli. Transient burning and/or itching were reported with initial treatment with alpha hydroxy acid lotion but improved or disappeared with continued use.(Ditre 1996) A multi-ingredient topical formulation containing glycolic acid (10%) and antioxidants was applied twice daily for 8 weeks in combination with sunscreen to the hands of 33 adult females (40 to 75 years of age) to determine the effects on moderate to severe photodamage. Both the investigator- and participant-graded assessments reflected significant improvements by week 8 and some as early as week 4. Compared with baseline, Investigator Global Assessment scores showed significant improvements at weeks 4 and 8 in age spots, freckles, and discoloration (P<0.05 each for paired t-test). More than 50% of participant-graded reports noted improvements in skin firmness, tightness, and elasticity, and more than 70% reported improved age spots, freckles, discoloration, softness, smoothness, radiance, tone, overall skin health, and appearance.(Gold 2013)

In a 12-week, controlled clinical study, 57 subjects with visible signs of photoaging were randomized to receive a polyhydroxy acid preparation containing gluconolactone 4% for application once in the morning and a gluconolactone 10% cream to be applied in the evening, or an alpha hydroxy acid preparation consisting of a glycolic acid 8% cream to be applied in the morning and a glycolic acid 8% night cream to be applied each evening. Patients were instructed to apply the creams twice daily for 12 weeks. Both polyhydroxy acid and alpha hydroxy acid preparations produced improvements in the skin after approximately 6 and 12 weeks of treatment. All photoaging parameters had improved at the 6-week follow-up visit (except for wrinkles) compared with baseline. Following 12 weeks of treatment, statistically significant improvement in all parameters was noted in both treatment groups. Alpha hydroxy acid treatment resulted in significantly better improvements in sallowness after 12 weeks of treatment compared with polyhydroxy acid treatment (17% vs 12%, respectively; P<0.05). Additionally, alpha hydroxy acid therapy was associated with a greater improvement in pinch recoil after 12 weeks of treatment compared with polyhydroxy acid treatment (P<0.05).(Edison 2004) In a prospective, randomized study, 18 patients with actinic keratosis were randomized to apply glycolic acid 70% in combination with a fluorouracil 5% peel to one half of the face and a glycolic acid peel to the other half of the face once weekly for 8 doses. After 6 months, 92% of actinic keratosis lesions were cleared with the combination compared with 20% on the side treated with glycolic acid monotherapy.(Marrero 1998)

Glycolic acid (70%) and lactic acid (85%) "superficial" chemical peel formulations (defined as destruction occurring in the epidermis) were compared in a randomized, open-label controlled study in 27 women to determine their effects on fine wrinkles around the lateral portion of the eyes. The formulations were applied for 3 minutes once every 30 days for a total of 3 months; sunscreen was applied every 3 hours to reduce risk of UV-induced postinflammatory hyperpigmentation. The control group (sunscreen only) did not experience any significant changes in fine wrinkles, while significant improvements in fine wrinkles were noted with both glycolic acid and lactic acid (P<0.05). It was noted that the time required for improvements were nonuniform between the left eyes and right eyes, which is likely due to varied types of wrinkles resulting from various daily habits (ie, increased UV exposure to one side of the face, sleeping positions). Overall, the formulations were well tolerated. Transient redness and burning were reported but no hypo- or hyperpigmentation occurred.(Prestes 2013)

A 12-week open-label, nonblind, interindividual trial also compared glycolic acid and lactic acid peels with topical vitamin C; however, the primary outcome was efficacy in reducing periorbital melanosis in adults in India (n=90). The glycolic acid 20% peels and the lactic acid 15% peels were applied every 3 weeks for 12 weeks, whereas those in the vitamin C group applied topical vitamin C 20% nightly. All patients were to apply sunscreen, wear sunglasses, and avoid direct sunlight. Both glycolic acid and lactic acid peels were significantly more effective than vitamin C from 6 weeks onward (P=0.007 and P=0.034, respectively). At 12 weeks, the glycolic acid peel was observed to be significantly more effective than the lactic acid peel (P=0.035); results were supported by physician global assessments. Transient erythema, burning, irritation, itching, and dryness were the most common adverse effects reported, with the incidence in groups paralleling efficacy: 33% with glycolic acid, 20% with lactic acid, and 10% with topical vitamin C.(Dayal 2016)

Contact dermatitis

Clinical data

In a randomized, single-blind study, the ability of fruit acids (ie, malic, citric, lactic) to induce contact dermatitis was assessed in 20 healthy volunteers without skin diseases. Fifteen areas on the back were stenciled, and each area was randomized to receive morning and afternoon application (3 hours apart) of the following: malic acid 2% (pH 2 and 4), citric acid 5% (pH 2 and 4), or lactic acid 20% (pH 2.5 and 4) alone or in combination (alternating) with sodium lauryl sulfate (SLS) 0.5%; SLS either alone (positive control) or alternating with distilled water; or distilled water alone (negative control). Application of the test solutions occurred for 4 consecutive days. Application of malic or citric acid twice daily did not cause any irritant effects. However, application of lactic acid pH 2.5 twice daily caused erythema and marked clinical reaction (visual score), but this was not noted with the pH 4 solution. An irritant effect was noted when alternating exposure to one of the fruit acids with SLS. However, the irritant effect was not as pronounced as it was following alternating exposure to distilled water and SLS, suggesting fruit acids may confer some protection against exposure to SLS.(Schliemann-Willers 2005)

Dry skin and ichthyosis

Lactic acid (in concentrations of approximately 1% to 2% in creams or lotions) has been reported to be an effective, naturally derived skin humectant having beneficial effects on dry skin and also in severe hyperkeratotic conditions.

Clinical data

Twenty patients with a range of dry skin complications, including xerosis, epidermolytic hyperkeratosis, and ichthyosis, applied either regular or extra-strength alpha hydroxy acid–containing cream to a test site, and a non–alpha hydroxy acid moisturizer to another site for a period of 4 weeks. After 2 weeks of treatment with alpha hydroxy acid–containing creams, symptoms were reduced and cosmetic appearance improved; further improvement occurred with continued treatment. The improvements were significant compared with baseline and with the sites treated with non–alpha hydroxy acid moisturizer.(Kempers 1998)

Fibromyalgia

It has been hypothesized that patients with fibromyalgia experience muscle pain due to abnormal muscle energy metabolism. Malic acid is involved in generating adenosine triphosphate (ATP) and has been investigated for its use in the management of fibromyalgia in combination with magnesium, which is also believed to play a role in ATP production.(Leventhal 1999, Russell 1995)

Clinical data

In a randomized, double-blind, placebo-controlled crossover study, 24 patients with fibromyalgia were randomized to receive 3 Super Malic (malic acid 200 mg and magnesium hydroxide 50 mg per tablet) or 3 placebo tablets twice daily for 4 weeks, followed by a 2-week washout period, after which patients switched to the other treatment group for an additional 4 weeks. Following this crossover study, 18 patients continued into an open-label study in which the dose of Super Malic was increased every 3 to 5 days until benefit was achieved or a treatment-related adverse effect occurred. After 2 months in the open-label trial, patients could reintroduce any medication they used prior to study entry. There were no statistically significant differences between the treatment and placebo periods with regard to 3 primary pain/tenderness measurements. However, dose-titrated Super Malic given for a longer duration in the open-label portion of the study resulted in improvements in pain/tenderness measurements.(Russell 1995)

Hand sanitizer

Clinical data

A double-blind, randomized controlled trial (N=212) investigated the effectiveness of a hand disinfectant containing ethanol 62% plus citric acid 2% and malic acid 2% for prevention of rhinovirus and associated common cold illnesses in healthy adults. Addition of fruit acids to the sanitizer was previously shown to extend the antiviral activity for up to 4 hours after application. Although no treatment effect on rhinovirus infection or rhinovirus-associated illnesses was observed, the number of common cold illnesses in the intention-to-treat analysis was significantly reduced with the intervention compared with controls (48% vs 75%, respectively; P=0.01). The ethanol plus fruit acid hand sanitizer was associated with hand irritation that led to at least 9% withdrawal rate, whereas no hand irritation occurred in controls.(Turner 2012)

Hyperglycemia

Clinical data

Healthy adults were enrolled in a series of 3 randomized, controlled crossover studies (double-blinded when possible) to study the effect of pomegranate juice, pomegranate polyphenol extract, and pomegranate-equivalent fruit acid solution of malic and citric acids on postprandial glycemia. The pomegranate juice significantly reduced the glucose area under the curve (P=0.000005) by a third as well as the peak glucose concentration (P=0.0004) after a test meal compared to controls. However, neither the polyphenol-rich extract nor the fruit acid solution had that effect, which indicated that the postprandial hypoglycemic effect of pomegranate juice was likely not related to the polyphenols or the fruit acids.(Kerimi 2017)

Hyperpigmentation

Clinical data

Areas of excessive pigmentation can develop after skin inflammation, which can be especially problematic in darker-skinned patients. The addition of glycolic acid peels to a standard topical regimen of hydroquinone, tretinoin, and hydrocortisone was evaluated in 30 patients with Fitzpatrick skin types III/V. The glycolic acid peel group had a statistically significant (P=0.004) improvement in Hyperpigmentation Area and Severity Index score after 21 weeks.(Sarkar 2017)

Melasma

Glycolic acid has been investigated for its use in the treatment of melasma. Specifically, glycolic acid reduces the stratum corneum and is able to augment the effect of hydroquinone, the most commonly used treatment for melasma.(Garcia 1996)

Clinical data

The efficacy of glycolic acid in combination with either hydroquinone or kojic acid for the treatment of melasma was assessed in a clinical study. Thirty-nine patients with melasma applied the 2 formulas to the right and left sides of the face twice daily for 3 months. Patients began to notice benefit with treatment after 4 weeks of application. Fifty-one percent of patients experienced equal reductions in hyperpigmentation with both hydroquinone and kojic acid in combination with glycolic acid. A larger reduction with hydroquinone occurred in 21% of patients, and a larger reduction occurred with kojic acid in 28% of patients. No differences occurred with regard to pigmentation between the 2 treatment groups.(Garcia 1996)

In another trial of azelaic acid in 60 patients with melasma, a glycolic acid peel every 3 weeks for 24 weeks was added to daily azelaic acid 20% cream and was compared to azelaic acid cream alone. Improvements in a severity index and quality of life were observed in the combination group compared to the cream only group without significant adverse effects.(Dayal 2017)

Propionic academia

Clinical data

Propionic academia, an autosomal recessive inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase, is characterized by metabolic decompensation, including severe metabolic acidosis with risk of relapsing, life-threatening episodes and multiorgan failure. Oral citric acid (potassium-sodium-hydrogen citrate 1,200 mg 3 times daily for 7 days) was administered as compassionate therapy to a 6.5-year-old girl during a life-threatening episode of severe lactic acidosis. Treatment dramatically improved her clinical condition, with a return of consciousness and baseline condition within 2 days. Oral citric acid remained a mainstay of therapy whenever she showed signs of metabolic impairment, preventing recurrent episodes during the 3-year follow-up.(Siekmeyer 2013)

Psoriasis

Clinical data

In a double-blind, split-face clinical study, 20 patients with scalp psoriasis and seborrheic psoriasis applied the following formulations to each half side of the face or body twice daily for 8 weeks: a 10% (w/w) glycolic/lactic acid scalp lotion either as monotherapy or in combination with a 0.1% (w/w) betamethasone scalp application, betamethasone in combination with a placebo lotion, or a placebo lotion alone. Areas treated with alpha hydroxy acid scalp lotion as monotherapy resulted in improvements in all cases. However, when betamethasone was combined with the alpha hydroxy acid lotion, most of the affected sites were healed, resulting in an approximately 50% reduction in the duration of treatment needed compared with alpha hydroxy acid lotion or betamethasone application treatment applied as monotherapy.(Kosterelos 2000)

Upper GI symptoms of chronic kidney disease

Clinical data

A double-blind, randomized, controlled interventional study conducted in 42 patients with upper GI symptoms of chronic kidney disease investigated the use of citric acid and other mouth rinses to improve upper GI uremic symptoms. Upper GI symptoms experienced by subjects included anorexia (100%), taste changes (93%), nausea (88%), and dry retching (66%). Patients were to trial each solution in a blinded manner for up to 18 hours by regularly sipping and rinsing their mouth. Citric acid solution (1 g per 500 mL) was the only solution tested that did not relieve symptoms in the majority of patients. Sodium bicarbonate (5 g per 500 mL), salt (5 g per 500 mL), and deionized water (500 mL) were all more effective than citric acid in most patients; however, the small study population and high individual variation prevented results from reaching statistical significance. Citric acid solution improved symptoms (eg, dry mouth, taste changes) in 35% of patients, but 57% were intolerant and reported increased nausea and dry retching.(Manley 2017)

Urolithiasis

Clinical data

A systematic review of herbal medicines for urinary stone treatment identified 16 randomized controlled trials (N=928), 3 of which (N=151) investigated the use of oral citrate (potassium citrate) as a single agent compared with various herbs. The pooled data revealed a significant reduction in mean stone size (P<0.0001) and decrease in urinary excretion of urate (P=0.0003) after 3 months of therapy with citrate compared with phytotherapy. The quality of data was graded as low to very low. While no adverse events occurred with the herbal agents, adverse effects reported with use of potassium citrate included fatigue and loss of appetite in 1 study (26%) and GI disturbance in another (13.3%).(Monti 2016)

The American College of Physicians (ACP) clinical practice guidelines on dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults (2014) recommends monotherapy with citrate as an option to prevent recurrent nephrolithiasis, primarily calcium stones, in patients with active disease when increased fluid intake fails to reduce stone formation (weak recommendation, moderate-quality evidence).(Qaseem 2014) The Italian CLU Working Group guidelines for dietary treatment of urinary risk factors for renal stone formation (2015) recommend a calcium-rich diet (1,200 mg/day) with a higher content of potassium, magnesium, and citrate to reduce risk of stone formation in elderly renal stone patients with high disease activity, and to use citrate salts as an option when dietary changes have not been effective. They note that although natural sources of dietary citrate (ie, lemons, oranges, grapefruit, lime, melon) have the potential to increase urine citrate levels, quality clinical trial data are lacking to support this approach for hypocitraturia. No high- or fair-level recommendations for dietary therapy in pediatric patients could be provided due to a lack of data.(Prezioso 2015)

Xerostomia, drug-induced

Clinical data

Fruit acids have been used successfully in clinical trials to improve drug-induced xerostomia.(Famiano 2011, Gómez-Moreno 2013, Gómez-Moreno 2013, Gómez-Moreno 2014) In 3 separate 2-week, double-blind, randomized, controlled trials (N=156), investigators assessed the efficacy of a commercial spray containing malic acid 1% plus xylitol and fluoride in patients with drug-induced dry mouth; mean ages of participants in the 3 studies ranged from 48 to 78 years. The most common medications used by participants and causing dry mouth were antihypertensives and antidepressants. Compared with control (xylitol and fluoride spray), dry mouth severity scores improved significantly with the malic acid intervention in all studies (P<0.05), and unstimulated as well as stimulated salivary flow also improved significantly (P<0.05). In contrast to controls, the majority of patients in the treatment group experienced some clinical recovery (14% to 15% vs 80% to 92%, respectively).(Gómez-Moreno 2013, Gómez-Moreno 2013, Gómez-Moreno 2014) Additionally, the need for use of the spray was observed to be approximately 50% less in the malic acid group than in the control group.(Gómez-Moreno 2013) Similarly, a randomized, single-blind, controlled trial (N=54) evaluated use of citric acid as a natural sialogogue for controlling drug-induced xerostomia compared with salivary substitutes in adults taking a minimum of 2 medications known to cause dry mouth. Citric acid mouthwash (3%) was compared with artificial saliva and control (distilled water); 5 mL of the assigned solution was retained in the mouth for 30 seconds 1 hour after meals and brushing teeth and repeated 4 times daily for 30 days. One hour after treatment, both citric acid 3% and artificial saliva solutions improved dry mouth significantly more than control; however, citric acid provided significantly longer lasting relief than saliva substitutes (P=0.0047) without affecting resting salivary flow rate.(Famiano 2011)

Dosing

Dry skin disorders: Alpha hydroxy acid 8% to 10% cream or lotion applied 2 to 3 times daily to the affected area(s). If dry skin persists after 2 weeks, the concentration can be increased by 2% to 4%. Once the skin appears healthy, the application frequency can be reduced to every 2 to 3 days.(Rubin 1994)

Fibromyalgia: 3 Super Malic tablets (each containing malic acid 200 mg) administered twice daily.(Russell 1995)

Chemical peels: Dosing for chemical peels involving glycolic acid may depend on factors such as the condition being treated, patient expectations, patient age, cumulative sun exposure, skin type, area(s) being treated, peeling agent(s) used, concentration(s) of peel agent(s), frequency of application, quantity applied, length of time applied, and desired result. Typically, on the first visit, glycolic acid is applied for approximately 2 to 3 minutes to determine sensitivity and provide guidance for future length of exposure. Intervals between peels are generally 2 to 4 weeks, and 6 to 8 peels are required for most patients.(Prestes 2013, Tung 2000, Van Scott 1996)

Skin cleanser: A facial cleansing formula with tamarind fruit pulp extract containing tartaric acid (2%) was nonirritating when 0.2 g was applied for 30 minutes for 5 days to the arms of healthy Thai female volunteers.(Maenthaisong 2007)

Drug-induced dry mouth: In clinical trials, commercially available sprays and mouthwash formulations containing malic acid 1% for 2 weeks (administered on demand for a maximum of 8 doses/day) or citric acid 3% 4 times daily for 30 days have been effective in reducing xerostomia induced by antihypertensives and antipsychotics.(Famiano 2011, Gómez-Moreno 2013, Gómez-Moreno 2013, Gómez-Moreno 2014)

Proprionic academia: Oral citric acid (potassium-sodium-hydrogen citrate 1,200 mg) 3 times daily for 7 days was administered in a case report of a 6.5-year-old girl with propionic academia experiencing an episode of metabolic decompensation. Over the next 3 years, oral citric acid therapy was administered whenever the girl showed signs of metabolic impairment to prevent another severe, life-threatening decompensation episode.(Siekmeyer 2013)

Urolithiasis: The ACP clinical practice guidelines for the dietary and pharmacologic management to prevent recurrent nephrolithiasis in adults (2014) recommend monotherapy with citrate (eg, potassium citrate, potassium-magnesium citrate, potassium-sodium citrate) as an option to prevent recurrent nephrolithiasis, primarily calcium stones, in patients with active disease when increased fluid intake fails to reduce stone formation (weak recommendation, moderate-quality evidence).(Qaseem 2014)

Pregnancy / Lactation

Information regarding the safety and efficacy of alpha hydroxy acid use in pregnant and lactating women is lacking. In pregnant rats, doses of malic acid up to 350 mg/kg for 10 consecutive days did not appear to have any negative effects on the mother or the fetus. Similarly, in rabbits, doses of malic acid up to 300 mg/kg for 13 consecutive days did not produce negative effects on the mother or the fetus.Kessler 2008

Interactions

Antimetabolites and corticosteroids: Use of antimetabolites and corticosteroids may delay wound healing in patients using chemical peels.(Tung 2000)

Hormone replacement therapy and oral contraceptives: Hormone replacement therapy and oral contraceptives may cause postinflammatory hyperpigmentation in some patients using chemical peels.(Tung 2000)

Isotretinoin (systemic): Isotretinoin (systemic) may enhance the adverse/toxic effect of fruit acids. Consider therapy modification.(Gerber 2014, Tung 2000)

Tetracyclines and other photosensitizing agents: Following a chemical peel with glycolic acid, there may be an increased risk of photosensitivity in patients using photosensitizing agents.(Van Scott 1996)

Adverse Reactions

Depending on the concentrations used, alpha hydroxy acids can cause severe skin irritation, burning, and sloughing. Skin erythema may occur with topical application and is expected to occur with chemical peels. Hypersensitive individuals and those with irritated skin should use caution when using alpha hydroxy acids.Edison 2004, Fiume 2001, Tung 2000, Van Scott 1996 The tartaric acid excipient in the formulation of the direct thrombin inhibitor dabigatran has been reported as the likely cause of a case of esophageal irritation and ulceration, as well as higher rates of dyspepsia documented with dabigatran compared with warfarin.Wood 2015

A case of recurring metabolic acidosis was reported in a 49-year-old woman with renal disease and a 3-year history of dialysis; the patient's abnormal pH and anion gap normalized after each dialysis treatment. Vitamin C level on admission was 500 mg/L (normal, 4.6 to 14.9 mg/L). It was discovered that she consumed excessive amounts of tartaric acid and 1 tablespoon/day of vitamin C powder, which was the likely cause of her recurring metabolic and anion gap acidosis due to being unable to excrete the tartaric acid.Elitok 2010 However, tartaric acid as the source of her metabolic acidosis has been questioned based on calculations reflecting what would be relatively low predialysis tartrate peaks.Emmett 2011

In a murine model, rats were fed malic acid 500 parts, 5,000 parts, or 50,000 parts per million for 104 weeks. Reductions in body weight gains and feed consumption occurred in those fed the high dose of malic acid, particularly during the first year. The differences were not as distinct during year 2 of treatment. No differences were noted with hematological, blood, or urine parameters. In a similarly designed study in beagles, no differences were noted with regard to weight changes between beagles fed malic acid and those fed a control diet.Fiume 2001

Toxicology

Fatal metabolic acidosis occurred in a 40-year-old mentally disabled male 20 hours after consumption of approximately 100 mL of concentrated citric acid beverage containing an estimated 90 g of citric acid. The serum citric acid level was 80.6 mg/dL (40 to 80 times the normal range); postmortem cardiac citric acid level was 39.8 mg/mL.Ikeda 2015 Two cases of life-threatening hyperkalemia were reported in males 16 and 32 years of age following ingestion of 6 tablespoonsful of cream of tartar (potassium bitartrate) that had been dissolved in a soft drink and water, respectively. In each case, GI symptoms (ie, nausea, vomiting, diarrhea) occurred within 4 hours of ingestion. Electrocardiogram abnormalities were documented upon admission. The patients’ symptoms were treated successfully in the emergency department.Rusyniak 2013

Application of malic acid 500 mg caused moderate irritation of the skin of rabbits. When malic acid 750 mcg was applied to the conjunctival sac of rabbits, severe ocular irritation resulted. It was also determined to be a strong irritant in guinea pigs. In a clinical study, 1 M of malic acid 2 mg/cm² was applied to the nasal folds of subjects and found to be a skin irritant; however, skin irritation was reduced as the pH of the product increased.Fiume 2001

References

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