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About the author: FutureDerm.com is proud to introduce John Su on our staff as a Contributing Writer. John is an established skin care expert and aspiring dermatologist. He also runs a blog, The Triple Helix Liaison, dedicated to providing unbiased, meaningful, and insightful information about skin care. For his full bio, please visit our About page.
Two weeks ago I mentioned that menthol, a peppermint oil-derived cyclic alcohol known for giving “tingling” and “cooling” sensations, was ranked 99 in a study that examined how well 102 selected compounds enhanced penetration (1).
In that study, menthol’s rank of 99 was determined by its low ER/IP ratio (11.22/58.8). As previously discussed, the Enhancement Ratio (ER) is determined by quantifying stratum corneum (SC) disruption. Specifically, the changes in lipid contents, which indicated whether the various chemical penetration enhancers (CPEs) like menthol, were categorized as fluidizers, extractors, or hybrids.
Studies indicate that menthol is more of an “extractor,” meaning that it enhances penetration by extracting SC lipid bilayers rather than partitioning into them, which is what “fluidizers” do (2). This can lead to significant water loss in the skin as the SC lipid bilayers are essential in maintaining correct levels of SC water permeability (3). The Irritation Potential (IP) is determined by cell viability via the methyl thiazol tetrazolium (MTT) assay mentioned in the last post; the assay measures enzyme activity.
Or more appropriately, the LACK of activity since CPEs initiate competitive hydrogen bonding, which leads to SC protein (remember enzymes are proteins) denaturation (unfolding). Broken enzymes = dead cells. This ability to enhance penetration may be at least partially responsibility for any irritant contact dermatitis (4), which with chronic use, may lead to allergic contact dermatitis (5).
MENTHOL AS A TREATMENT
Itch can be caused by several factors, such as bug bites, cytokines, substance P, but most importantly by histamine. Histamine is released from mast cells and induces itch by exciting a subset of unmyelinated C-fibers (6), which mediate itch responses. Unlike antihistamines which directly antagonize the histamine receptor subtype I (H1R), menthol reduces histamine-induced itch by acting as a cold stimuli (7). Menthol does this by activating a member of the transient receptor potential (ion channel) family, TRPM8, which will result in feelings of cold via alterations in the calcium ion levels. While the exact mechanism by which menthol reduces itch has yet to be completely elucidated, studies suggest that its antipruritic (anti-itch) property, like its analgesic property (anti-pain), comes partly from the suppression of A-delta fiber activation (8).
Pain is caused by… well a lot of stuff. Menthol, having counterirritant properties, acts by stimulating pain receptors in the skin and causing inflammation in order to bring relief to other parts of the body (9). As explained above, it does this by agonistically binding to the TRPM8 channel, resulting in the conduction and inhibition of both the A-delta fibers and Group C nerve fiber nociceptors, which are needed to express pain (10). But wait, menthol is just a completely ironic compound (no it doesn’t contain Fe…) because at high concentrations and with chronic use, it has actually caused the opposite of pain relief: cold allodynia and hyperalgesia (11), which are forms of moderate and extreme sensitivity to cold pain. Ouch! That’s a double whammy! You don’t see that with morphine. Though there are the withdrawal symptoms…
Yes I know, the last two paragraphs were very informative and surprising right? Okay, maybe not. Regardless, it all comes down to relevancy. For the average consumer who does not have chronic itch or pain, does menthol matter? What can you take away from all this?
- Menthol is a CPE that has been used to enhance multiple pharmaceutical drugs and consequently has the same effects in topical cosmetics.
- Consequently, as an “extractor” it can lead to increased dryness due to TEWL.
- Like anything, it can trigger an allergic reaction.
- Despite being a counterirritant, the “inflammation” that occurs from menthol is not the same as what you’d see for example, with a pimple. Inflammation involves vast and varying mediators and indicators, and the ones seen with topical menthol application do not directly increase the stereotypical inflammatory response of an acne papule or pustule (think red and swollen skin). In fact, studies indicate that menthol may even be anti-inflammatory in that regard. In vitro, it has been shown to inhibit the production of inflammatory prostaglandins (both lipooxygenase and cyclooxygenase pathways) and interleukin-1 cytokines (12). So despite what some people want you to believe, menthol won’t cause “collagen breakdown” or whatever.
Ultimately, menthol is just another ingredient that cosmetic manufacturers like to use in an attempt to trick the consumers into believing the misguided notion that, “If it’s burning/stinging/tingling, it must be working.” Fortunately, it does also act as a very effective penetration enhancer. While it has proven benefits (and risks) for those in chronic pain and/or itch and has been widely recommended by dermatologists, for the average consumer, it’s really a matter of personal choice. It’s all about achieving maximal penetration and minimal irritation. I personally, benefit from it. But again, this will vary from person to person! I’d love to hear your opinions down below or on my blog!