internal and external mechanisms causes cellular damage; finally, dysregulated immune function, oftentimes downstream of the other intertwined systems, is a direct link to the inflammatory response at the PSU. A recent review by Del Rosso et al71 discusses the current clinical data supporting these as the systemic patient-centric approach to AV.
Natural compounds and dietary supplements, including nutraceuticals used in complementary and alternative medicine, are a growing trend in wellness and beauty and may offer an expanded approach to the treatment and management of AV beyond conventional medicines addressing the pathophysiology only at the PSU.2,4 For example, vitamin A was one of the first vitamins to be recommended for its role in treating acne and is now the basis for the development of tretinoin and isotretinoin, which are powerful AV treatments.7 We can also see that treating the systemic drivers of hair thinning has found success, as supplements that provide whole-body support for daily stressors from metabolism, lifestyle, hormones, and others have repeatedly been shown to improve hair thinning over time in different populations.8-11
But, while supplements are regulated by the US Food and Drug Administration, they are not subjected to the same standards as drugs, and oftentimes, there is limited data from well-designed clinical studies. Very recently, a systematic review in JAMA Dermatology looking for evidence for oral nutraceuticals in the treatment of AV identified 2582 abstracts of which only 42 met their criteria (a total of 3346 participants).12 Still, the review presented several studies showing encouraging data for the safety and effectiveness of oral nutraceuticals for treating AV and noted vitamin D, green tea extract, probiotics, and several others as having fair- to good-quality studies in this space.12 Furthermore, fish oil, probiotics, and oral zinc have been studied for their role in treating AV, yet convincing data regarding the safety and efficacy of these agents is still too limited to be recommended in the AAD Guidelines of Care for Management of Acne.4 Because of this, their use and recommendation for addressing AV is limited.
In this article, we review clinical evidence for various botanicals, vitamins, and minerals to address the systemic root causes of AV (stress, diet and metabolism, hormones, skin and gut microbiome dysbiosis, oxidative stress, and immune response). Although the severity of AV in these studies is not always noted, the type of acne is reported when available. We also present the promising results of a 12-week clinical study using a supplement containing 20 botanicals, vitamins, and minerals supported by evidence to address non-cystic acne or improve skin health. Broadening the scope of therapeutics to include a systemic approach using standardized, effective ingredients could offer a more comprehensive approach to AV management. To continue pushing the field of dermatology forward, we need to bridge the gap between the clinical evidence suggesting systemic drivers of AV and the clinical effectiveness of dietary supplements and botanicals to address those targets. When we do that, we may be able to improve clinical outcomes of AV patients, whether that is used in conjunction with conventional treatments, decreasing the dose or treatment time, or offering more natural solutions for patients who prefer so.
Addressing the Stress Response in the Skin
Clinically, higher reported stress levels have been associated with an increased acne grade in adult women.13,14 While these data confirm the anecdotal reports of the impact of systemic stress on acne in adult females, there is a lack of therapeutics available to address psycho-emotional stress in the acne patient. Oftentimes suggestions to decrease stress can focus on a lifestyle change, for example, meditation, yoga, and exercise can be recommended to reduce stress that contributes to adult acne.15
Alternative medicinal practices have characterized a few botanicals that have been used to manage stress with purported physiological mechanisms. Ashwagandha, a shrub found in Asia and Africa, has now become popular as an "adaptogen," and may prevent the detrimental fluctuations of cortisol and other stress hormones released during a generalized stress response.16 The natural ayurvedic Holy Basil (Ocimum tenuiflorum) has also been used in traditional medicine to combat stress.17 In a double-blind, placebo-controlled study, adult participants who received Holy Basil showed a significant decrease in the self-reported perceived stress scale as well as a decrease in salivary and hair cortisol levels.17,18 On a mechanistic level, pre-clinical and clinical studies also indicate additional potential benefits including its antioxidant, analgesic, and anti-inflammatory properties.19,20 Its medicinal properties are attributed to its biochemically active components such as eugenol, carvacol, and rosmarinic acid.17 In a recent systematic review, Holy Basil was found to be therapeutically associated with improving psychological, physiological, metabolic, and immunological impacts of lifestyle-related chronic disease.20 The improvement across these domains is attributed to Holy Basil's anti-inflammatory effects, making it a candidate that may also be useful in targeting the underlying stress-induced inflammation reported in patients with AV.20
Diet and Metabolism
Sugar consumption and insulin fluctuation have been directly implicated in the development of AV.4,21 As such, AV management also includes recommendations for consuming a low glycemic diet and maintaining balanced blood insulin levels. Studies suggest that the anti-diabetic medication metformin that targets gluconeogenesis improves AV in women with PCOS purportedly by reducing hyperinsulinism and the resulting ovarian hyperandrogenism.22 It has also been suggested that men with metabolic
