Peptides are often touted in beauty products. That’s because they’ve been shown to increase collagen production in research studies, which, in turn, will give people smoother and firmer skin over time.

There are a few particular peptides that are the best: Palmitoyl pentapeptide-3, Acetyl hexapeptide-3, Palmitoyl oligopeptide, and Matrixyl-3000.

[Read More: What Are the Best Peptides?]

The Controversy

These and most other peptides used in skin care exceed the 500 Dalton Rule, meaning they should not be able to penetrate the skin.

So, if studies say they work, but the rules say they shouldn’t be able to, how exactly are peptides working effectively in skin care?

What the 500 Dalton Rule and Dr. Leslie Baumann Say about Peptides

Anything under 500 Daltons can almost certainly penetrate the skin. But over that, it seems topical products often aren’t effective.

The general rule is that almost nothing larger than 500 Daltons can pass through the skin barrier (Experimental Dermatology). This is based off of a few things:

1. Nearly all of the contact allergens that we know of are small than 500 Daltons.

2. The most common pharmaceutical ingredients applied topically are under 500 Daltons.

3. Effective drugs that contain a transdermal delivery system are under 500 Daltons.

While there are some exceptions relevant to skin care— allergies to latex (over 50,000 Daltons) and the successful use of tacrolimus (822 Daltons) to treat certain skin conditions, for example — overall, the 500 Dalton rule appears to be a good general rule of thumb. This is because we know that something under 500 Daltons will be able to cross the skin barrier effectively. We have not yet discovered the method that allows anything over 500 Daltons to cross the skin barrier.

[Read More: What Exactly is the 500 Dalton Rule?]

By this rule, peptides should not be absorbed in your skin and, subsequently, should not be effective.

Dermatologists are split on this issue: some say they work; others disagree. One of our favorite dermatologists at FutureDerm, Dr. Leslie Baumann, M.D., does not condone their use as an anti-aging ingredient:

“Many active ingredients that are used as “buzz words” in skin care cannot penetrate the skin, leaving them useless, for instance: oxygen, stem cells, hyaluronic acid, and peptides,” Dr. Baumann said.

[Read More: FutureDerm’s Exclusive Interview with Dr. Leslie Baumann, M.D.]

What Studies Say About Peptides

Studies show that peptides are effective at increasing collagen production. How can this be?

Despite the fact that peptides are greater than 500 Daltons, there are several studies that suggest peptides are helpful when applied topically. This presents a certain problem because if it works, then it brings the 500 Dalton rule into question.

For example, double-blind study with a control group that had participants apply different things to each side of their face found that palmitoyl pentapeptide-3 effectively increase the production of collagen and of extracellular matrix proteins (International Journal of Cosmetic Science).

Another study found that when palmitoyl oligopeptide stimulates collagen production in skin fibroblasts when used twice a day for six months (Dermatologic Therapy). And palmitoyl olgiopeptide has been shown to down-regulate elastin expression.

Given these studies, as well as many others, it’s hard to understand how peptides could be considered ineffective as ingredients. After all, if several studies have demonstrated peptides ability to cross the skin barrier, doesn’t that mean they work?

Why Are Some Peptides Considered Penetration Enhancers?

When paired with the T2 peptide, Biotin can penetrate the skin.

As it turns out, some peptides have been found to be penetration enhancers. But keep in mind that these aren’t the ones you know and love in your cosmetics.

In a study on murine skin, biotin was not absorbed when applied alone, but it was absorbed when it had been formulated with arginine oligomers (Nature Medicine). However, as the study points out, researchers are not entirely certain how these molecules move along the cells membranes and tissue barriers. Nonetheless, the study found that arginine oligomers were an effective topical delivery system for drugs.

Other studies have demonstrated that other peptides work for this process as well. For example, a T2 peptide known as LVGVFH was also found to help increase the delivery of drugs in porcine skin (Molecular Pharmaceutics). Researchers tested the skin to see if this worked because it disrupted the skin barrier, since this is how penetration enhancers like sodium lauryl sulfate function. They found that the T2 peptide did not do damage to skin, meaning it didn’t disrupt the skin barrier.

So how did it work? The researchers found that the T2 peptide changed the lipid layer, but did not damage it! By enhancing penetration, they help other ingredients get through the skin barrier, making those ingredients more effective.

So How Do Peptides Work in Skin Care Products?

One way peptides might work without penetrating skin is by sending signals to cells.

The short answer is that we’re not exactly sure. Based on the rules that we’re now using, peptides should not work. Yet, a number of studies show they can be very effective in skin care. As it turns out, there are a few ways that they might still work.

One is through signaling. This is when the peptide sends a chemical message that mimics the ones cells send to one another to cause them to behave a certain way. Mimicking could make these changes without actually having to penetrate the skin, which means that even though peptides don’t go through the skin barrier, they still work effectively.

The other way they could work is by being broken down by the skin. In the Experimental Dermatology article on the 500 Dalton rule, the researchers consider that latex allergies might exist because when latex comes into contact with skin, it is broken down into smaller peptides that can penetrate skin. It’s possible that larger peptides also behave in this way and are broken down by the skin to a size that can cross the skin barrier.

Bottom Line

Given our current level of understanding, it seems impossible that peptides should be able to cross the skin barrier. In particular, we’re talking about peptides like palmitoyl tetrapeptide-4 and palmitoyl tetrapeptide-7, and some small peptides are actually penetration enhancers. And, if we just go by their Dalton size, then it’s true that they should not be effective ingredients.

But studies have shown that they work, which contradicts scientific knowledge about penetration and size.

There may actually be ways that peptides can benefit you skin even though they’re too large to be absorbed as is. One is by signaling, which would allow them to send chemical messages to cells without even having to penetrate the skin at all. The other is by being broken down by skin into small units that can be absorbed.

So here is our stance on peptides: until more research is done proving how they work in spite of their large size, proceed with caution. Given that it takes a few months to stimulate collagen production significantly enough to notice a difference, peptides are best as a long- term supplement to your skin care regime anyway – not a heavy-hitting treatment like alpha hydroxy acids or retinoids.

What do you think about peptides? Let us know!