The role of oral nutraceuticals as adjunctive therapy to reduce side effects from isotretinoin: A systematic review

To the editor:

Although isotretinoin is a highly efficacious acne treatment associated with durable remission, adverse events such as mucocutaneous side effects are common and can result in treatment discontinuation. Since patients may be interested in natural and complementary therapies to alleviate these side effects, this review sought to evaluate the evidence regarding the role of oral nutraceuticals as adjunctive therapy with isotretinoin.

The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.¹ It was exempt from institutional review board approval. The study was registered with PROSPERO (CRD42022353051). A health sciences librarian (C.H.) performed a search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science databases from inception through January 30, 2023.^2,3 We included randomized controlled trials (RCTs) investigating at least one oral nutraceutical in patients with acne on isotretinoin. Outcomes of interest were adverse events, skin biophysical parameters, and adherence to treatment. Abstract and full-text screening were conducted by two independent reviewers (A.S., S.L., P.M., B.W., Y.C., M.A.). For each of the included articles, study design, nutritional intervention, and outcomes were reviewed. Quality assessment of included trials was performed using the Cochrane Risk of Bias (RoB) Checklist Tool.⁴

Among 2420 abstracts, 93 full-text articles were assessed for eligibility, with 8 articles (5 fair quality; 3 poor quality) meeting the criteria for inclusion in the review (Figure 1, Table 1).

Figure 1:

PRISMA Flow Diagram of Selected Studies

Table 1:

Characteristics and Results of Included Studies

Nutraceutical	Dosage	Length of Intervention	Blinding	Outcome	Quality
Omega-3	1 mg/kg/day	12 weeks	Double-blind	Lower rates of cheilitis (32.4%, vs. 92.3% p < 0.01), lip dryness (41.2% vs. 73.1%, p = 0.013) and xerosis (32.4% vs. 76.9%, p < 0.001) in patients who received omega-3 along with isotretinoin compared to placebo.	Fair
Omega-3	1 g/day	16 weeks	Double-blind	Cheilitis (at weeks 4, 8 and 12), xerosis (all weeks), and dryness of nose (all weeks) were significantly (p < 0.05) less frequent in the group that received omega-3 in addition to their isotretinoin compared to the group that received isotretinoin alone.	Fair
Evening Primrose Oil (EPO)	1,350 mg/day	8 weeks	Single-blind	Proportion of patients presenting with xerotic cheilitis after 2 months of therapy was significantly lower in the group receiving EPO. The group receiving EPO had a significantly lower score for transepidermal water loss (TEWL) on the lower lip (52.18 vs. 70.49, p = 0.043).	Poor
Evening Primrose Oil (EPO)	2,040 mg/day	9 months	Double-blind	EPO group had a statistically significant increase in skin hydration compared to the isotretinoin only group (8.70 vs. - 10.5, p < 0.002) which helped to ameliorate the adverse effects of dryness, lip cracking and peeling skin.	Fair
Biotin	10 mg/day	9 months	Unblinded	Mean skin hydration decreased in both groups but was found to be significantly lower in the group that only took isotretinoin (p < 0.001). There was an increase in the TEWL values of both groups, but no significant difference.	Poor
Vitamin E	800 IU/day	20 weeks	Double-blind	Administration of vitamin E did not decrease the average severity, duration, or incidence rates of side effects produced by isotretinoin.	Fair
Multi-ingredient*	N/A	6 months	Unblinded	Significant difference between the two groups in the sebum rate (2.4 vs. 1.5 p < 0.0001), hydration (53.2 vs. 48.5, p < 0.0001), and erythema (237 vs. 255, p < 0.0001) in favor of the group taking the dietary supplement.	Poor
Zinc Sulphate	1 mg/kg/day	20 weeks	Single-blind	The frequency of all treatment-related side effects (20% vs. 76.7%, p < 0.001) and the frequency of cheilitis (6.7% vs. 43.3, p = 0.001) was significantly less in the group treated with zinc and low-dose isotretinoin compared to the group treated with standard-dose isotretinoin alone.	Fair

^*Multi-ingredient supplement containing gamma linolenic acid (omega-6), vitamin E, vitamin C, beta-carotene, coenzyme Q10, and “Vitis Vitifera”

Two RCTs found that Omega-3 fatty acids reduced the frequency of mucocutaneous side effects. In a double-blind trial (n=60), Zainab et al. discovered omega-3 (1 mg/kg/day) reduced rates of cheilitis (32.4%, vs. 92.3% p<0.01), lip dryness (41.2% vs. 73.1%, p=0.013) and xerosis (32.4% vs. 76.9%, p<0.001). In a double-blind trial (n=118), Mirnezami et al. found omega-3 (1g/day) reduced cheilitis, xerosis, and nasal dryness (all p<0.05).

Two blinded RCTs (n=40; n=50) evaluating evening primrose oil, which contains omega-6 fatty acids, found that it was associated with reduced transepidermal water loss (p=0.043) and improved skin hydration (p<0.002) as well as improvement in xerotic cheilitis (p=0.035).

A single-blind trial (n=60) demonstrated that zinc (1mg/kg/day) with low-dose isotretinoin (0.25mg/kg/day) had similar efficacy, but reduced overall treatment-related side effects (20% vs. 76.7%, p<0.001) and cheilitis (6.7% vs. 43.3, p=0.001) compared to isotretinoin alone (0.5mg/kg/day) during 20 weeks of treatment.

An unblinded RCT (n=48) found a dietary supplement based on gamma-linolenic acid, vitamins C and E, beta-carotene, coenzyme Q10, and Vitis vinifera (grape seed) improved sebum rate, hydration, and erythema scores (p<0.0001). RCTs evaluating vitamin E (n=140) and biotin (n=60), did not find benefit.

Although studies were small and of limited quality, this review highlights that supplements containing omega-3 fatty acids may be a useful adjunctive strategy to reduce mucocutaneous dryness associated with isotretinoin. Evening primrose oil may also be helpful. Given its potential efficacy for acne, zinc may allow for lower dose isotretinoin regimens and thus reduced side effects.⁵ Future studies are required to further evaluate the benefit of these nutraceuticals. Clinicians should be prepared to discuss the potential role of nutraceuticals as adjunctive options for patients being treated with isotretinoin.