Actives Pairings With Clinical Testing Behind Them

*Updated as of 5/17/2022

When you start dabbling in actives, you’ll easily fall into the rabbit hole of what you can and can’t layer. One of the complicated aspects of trying to figure out actives layering and why brands may not even be able to give clear answers is simply the fact it hasn’t gone through enough testing to truly know. Not to mention, the formulas these actives sit in can add another layer of complexity.

The good thing is there are some active combinations that have been looked at for their benefits. Some have even been found to have a synergistic effect.  Synergistic benefits, in chemist speak - essentially means 1 + 1 = 3 or 4 or 5! get our drift.

So here’s a running list of tested active combinations. We’ll continue to populate as we continue to go down more skincare science rabbit holes. We try to choose ingredients you can readily find on the shelves. If there’s any combo you’re curious about, leave us a comment!

Vitamin C (Ascorbic Acid) + Madecassoside

A French lab tested a combination of 5% ascorbic acid and 0.1% madecassoside (one of the acitve components in centella asiatica extract or “cica” products) in a double-blinded study looking at photoaged skin of 20 female subjects. After a whopping 6 months of treatment, they found significant improvements in clinical scores for both superficial and deep wrinkles, suppleness, firmness, roughness, and skin hydration. These results were further supported by instrumental measurements for skin elasticity and histological assessment of the papillary dermis (this means that they looked at changes in the deep layers of skin with a microscope).

State of the Evidence: More data needed. 6 months is impressive, but ultimately it’s a small study and we haven’t seen another one on this particular combination.

Reference Study:

Adapalene + BPO

Adapalene + BPO is the latest and greatest acne treatment duo simply for its significantly less irritating use experience without too much of a compromise in efficacy. 

One review paper looked at data pooled from 3 randomized controlled studies. They looked at Epiduo (0.1% adapalene + 2.5% BPO), 0.1% adapalene alone, 2.5% BPO alone, AND just a placebo gel with no active ingredients. The exciting thing is that there are over 900 subjects per group!

Unsurprisingly, the combination was much more effective at reducing lesion counts by the end of week 12. Another takeaway that we sort of knew is that cocktails become especially helpful for more severe breakouts. This combo has even been tested for postmarks and scarring.

State of the Evidence: Robust!

Reference Study:

*There are many others looking at this combination.

Sodium Ascorbyl Phosphate (SAP) + Retinol

A lab in Thailand looked at 5% SAP (sodium ascorbyl phosphate) with 0.2% retinol. There were 3 test groups with 10 subjects each, one group used SAP only, one retinol only, and one with the combination. The study was 8 weeks long. Retinol was used once daily while SAP was used morning & night.

All three groups saw acne lesion reduction. Retinol & SAP alone both had ~50% reduction by 8 weeks, while the combo group had 63% reduction. Even though each group was small, we appreciated that they looked at each combination separately. We see a lot of "combo" studies with no comparison with the individual actives so it's hard to gauge whether or not the combo adds anything synergistically. While this study alone doesn't mean you should replace your current acne regimen with this specific combination, we really want to highlight the benefit of tackling acne from a few different angles!

State of Evidence: Promising!

Reference Study:

Niacinamide + Hexylresorcinol

Unilever looked at a 0.4% 4-hexylresorcinol and 3% niacinamide in a 12 week clinical study. 44 subjects of Chinese origin, between the ages of 35-60 years old with at least 3 hyperpigmentation spots applied two products half face. 1 product only had 3% niacinamide while the other had the combo of 3% niacinamide and 0.4% hexylresorcinol. The combination showed significant improvements in hyperpigmentation, fine lines, crows feet, and skin firmness.

State of Evidence: Promising!

Reference Study:

*More to come!


Sorry-not-sorry-but-sorry for all of the questions! I’m clearly a noob!

What about sodium ascorbyl phosphate (SAP) at the same time as tretinoin as an acne treatment?

Ophira June 29, 2023

Do you have any insights as to how some of the antioxidants you’ve promoted in the past might work together in the same routine? I currently own bottles of Timeless VitC (therefore, L-AA in water) and The Ordinary’s EUK-134 and Resveratrol. According to DECIEM, I can get away with using EUK-134 and Resveratrol at night on alternating days. I’m guessing that VitaminC doesn’t play well with the other anti-oxidants, at least not at the exact same time, because of their differing pH needs (VitC needing less than 3.5 and EUK-134 and resveratrol operating at a higher pH). I also know that EUK-134 is self-regenerative, but I don’t know what that means in practice (like if I use VitC 12 hours later does it destroy the molecule?). One of the studies that I read has a chart that indicated. that EUK-134 has the greatest efficacy in the first 6-14 hours… in a bottle combined with sqOOH, where they were monitoring the sqOOH levels over time.* If you had to form a hypothesis, do you think I could get away with using all of them in the same routine? What’s the underlying scientific reason that mixing EUK-134 and resveratrol is unadvisable (aren’t anti-oxidants also supposed to stabilize each other? and if I’m only using like a drop of resveratrol…).

I’m also wondering about the peptides Matrixyl and Argireline by The Ordinary, combined with L-AA. I’m hoping to use both to heal my skin matrix on a deeper level so that the texture and elasticity improve over time. I live in a dry climate and I let myself get pretty dehydrated and it’s starting to become a vicious cycle. I’m not sure, but acids lessen the integrity of the peptides, right? How do the peptides work? Do they remain active even 12 hours later for example, so the L-AA might still have an effect on them? What if I had the time to just wait a couple of hours to apply the peptides after the L-AA? Your Matrixyl article says that Sederma’s study on humans looked at a 3% use twice a day, so I was vaguely thinking of applying L-AA first thing in the morning when I wake up and then once I’ve had a couple of coffees and a morning nap, I could apply the peptides (along with EUK-134 and/or a drop of resveratrol) and then do them again in the evening with my tretinoin prescription. Does that make hypothetical sense to you?

Hahahahhaa these are not easy questions and the truth may be that we just don’t know. Thank you for really getting my brain juices flowing!

*Figure 8 in “Use of the synthetic superoxide dismutase/catalase mimetic EUK-134 to compensate for seasonal antioxidant deficiency by reducing pre-existing lipid peroxides at the human skin surface” in International Journal of Cosmetic Science 26(1), 2004 (it has been forever since I’ve cited a journal don’t make fun of my formatting!)

O June 29, 2023

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