When a familiar ingredient takes on a new role: why menthol?

In dermatology and skincare practice, menthol has long occupied a narrow, well-defined niche: it is the classic cooling ingredient, a modulator of sensory perception in toners, creams for tired legs, and anti-itch products. It is seen as a sensory trigger that stimulates thermoreceptors, and rarely as a serious biological regulator of regeneration. All the more unexpected, then, is researchers' turn toward terpene compounds in tackling one of medicine's hardest problems — treating diabetic wounds.

Chronic hyperglycemia turns healing into a prolonged dead end: microcirculation suffers from endothelial dysfunction, the local immune response gets stuck in relentless inflammation, and excess free radicals damage young cells and break down the extracellular matrix [1]. The wound cannot move on to full proliferation and epithelialization.

Seeking accessible molecules that could break this vicious circle, the research team turned to menthol—a cyclic monoterpene from peppermint essential oil—building on earlier animal experiments in animals with normal metabolism [2]. This time they raised the bar: they modeled severe diabetes to see whether a menthol cream could cope with metabolically compromised tissue [1].

Study design: how the 0.5% cream was tested

To reproduce metabolic failure, type 1 diabetes was induced in male Wistar rats with streptozotocin (50 mg/kg) [1]. Only animals with persistent hyperglycemia — 250 mg/dL and above, which stayed above 400 mg/dL throughout the study — were included. One week after the diabetic state was established, a standardized skin wound was created on the animals' backs with a 2 cm biopsy punch.

The animals were divided into three groups of 10: the first received a placebo — a neutral Lanette cream base; the second received an insulin cream (0.5 IU/g) as an active comparator; and the third received the experimental 0.5% menthol cream [1]. The formulations were applied daily for 14 days, with regular planimetry of the wounds; at the end of the period, the researchers assessed histology, the inflammatory cytokine profile, antioxidant status, and angiogenesis markers.

The results were striking. By day 6, wounds in the menthol and insulin groups were closing noticeably faster than under the plain base. By day 14, wound area in the control group had decreased by 88%, compared with 93% for the insulin cream and 94% for menthol (p < 0.01 vs. the base) [1].

Histology supported the visual dynamics: in the menthol group, the authors documented a continuous epidermal layer and more mature organization of collagen bundles in the dermis, whereas epithelialization in the control group remained incomplete.

Three lines of action: how the proposed mechanism works

What makes this work interesting is the authors' attempt to decipher which molecular pathways allow a simple terpene compound to influence repair. The data support a coherent hypothesis built around three key mechanisms: damping the inflammatory cascade, mobilizing antioxidant defenses, and stimulating factors of cellular renewal.

The first mechanism is an anti-inflammatory shift. In wound tissue, menthol application produced a statistically significant drop in mRNA expression of Nfkb, the gene encoding the key pro-inflammatory transcription factor NF-κB, along with lower levels of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) [1]. At the same time, the authors noted a rise in the anti-inflammatory interleukin-10 (IL-10) and a decline in myeloperoxidase (MPO) activity — an enzymatic marker of excessive neutrophil infiltration. In other words, menthol does not switch off local immunity; it helps the wound escape chronic inflammatory stagnation and paves the way for granulation.

The second mechanism is an antioxidant shield. Oxidative stress in diabetes depletes the cells' endogenous reserves and hampers the migration of fibroblasts and keratinocytes. In the menthol group, the researchers recorded a significant increase in reduced glutathione (GSH) and higher activity of first-line defense enzymes — superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) [1]. Strengthening this enzymatic arm helps neutralize toxic reactive oxygen species right at the site of injury.

The third mechanism is vascular tone and cell growth. Regenerating tissue showed higher levels of endothelial nitric oxide synthase (eNOS) protein and a parallel increase in stable nitric oxide metabolites (nitrites) in plasma [1]. Nitric oxide (NO) is a fundamental regulator of endothelial function: it boosts local perfusion and drives angiogenesis, without which granulation tissue cannot mature [3]. Together with increased expression of the proliferation marker Ki67, this points to active division of basal layer cells and fibroblasts, accelerating wound closure.

The limits of the evidence and what it means in practice

Impressive as the wound-area numbers are, the practicing specialist needs to keep clinical skepticism intact and to distinguish a preclinical model from real therapeutic practice.

First, this is an experiment in rodents with an acute model wound created against artificially induced diabetes. That is fundamentally different from a long-standing diabetic ulcer in a patient with comorbidities, burdened by pronounced peripheral neuropathy, critical limb ischemia, and resistant microbial biofilm. None of these coexisting factors were reproduced in the experiment.

Second, the authors studied a narrow protocol: male rats only, a single concentration (0.5%), and a short two-week observation window. The paper contains no pharmacokinetic data and no assessment of systemic toxicity risk or local sensitization of damaged skin. Moreover, the antioxidant assays contain an obvious methodological inconsistency: the methods section describes analysis of liver tissue, while the figure captions attribute the numbers to wound biopsy samples.

So what does this mean for the dermatologist and the skincare specialist? This publication is not a call to action, and it is no reason to apply pharmacy or cosmetic menthol formulations to damaged skin, open erosions after ablative procedures, or diabetic feet. High menthol concentrations on a compromised epidermal barrier can cause contact dermatitis and irritation. The deeper practical lesson is this: the study shows that the potential of long-studied natural monoterpenes extends far beyond sensory effects. If further standardized research confirms the safety and controllability of these molecular mechanisms in humans, we may see the arrival of genuinely new targeted topical products for stimulating repair.

References

1. Vieira A.J., Beserra F.P., Prata G.B. et al. Menthol-based cream as a novel therapy for diabetic skin wounds. Pharmaceutics 2026; 18(1): 125.
2. Rozza A.L., Beserra F.P., Vieira A.J. et al. The use of menthol in skin wound healing—anti-inflammatory potential, antioxidant defense system stimulation and increased epithelialization. Pharmaceutics 2021; 13(11): 1902.
3. Malone-Povolny M.J., Maloney S.E., Schoenfisch M.H. Nitric oxide therapy for diabetic wound healing. Adv Healthc Mater 2019; 8(12): e1801210.