Background & Aims
Many medicines for pain are derived from ancient natural remedies, with obvious examples including aspirin from willow bark (1), morphine from the poppy (1), and ergotamine from mushrooms. (2) Widespread use across the ages provides clues to their effectiveness in pain and general safety and tolerability in humans. Science is often playing catch-up with innovation: the remedies are identified before they are understood. When science does intervene, refinements follow for example, triptans were developed to target a more restricted range of receptors than ergotamine, retaining the therapeutic effects but avoiding some side-effects (3). Mint is another example of a natural product with a heritage in pain. Furthermore, with ground-breaking work in the understanding of TRP receptors, we now better understand its therapeutic targets, opening avenues for discovering new molecules to target these receptors in novel ways (4). Our aim is to chronicle the historical uses of mint in pain.
Methods
A literature search was conducted using PubMed, Embase, and Google Scholar to discuss the various uses of menthol from antiquity to modernity. The databases were queried using a robust set of search strings related to ‘menthol’, ‘antiquity’, ‘uses’, and ‘analgesia’. 102 hits were returned and screened for duplicates (n=46), leaving n=56 unique search hits. The subsequent unique articles were screened for relevance via title and abstract, and those pertaining to the research topic with were carried forward for analysis (n=6).
Results
Humans have had an awareness of the naturally occurring plant extract menthol for millennia (9), which is derived from several mint herbs (genus Mentha), e.g., peppermint, corn mint, etc. (6). The first mentions of mint appear as early as 1550 BC in the Ebers Papyrus, Egypt, where it was used as a remedy to relieve stomach ailments (5). This echoes its use in irritable bowel syndrome today. There are also claims that this plant extract was being cultivated in Japan over 2000 years ago (5,6,10) for medicinal use. Hippocrates (c.460 BC – 370 BC) even considered mint as a cooling agent for peripheral pain: in early Greek times, pharmacy was related to herbal products, and the ancient Greeks had acknowledged the importance of pain therapy and had invented remedies, including those based on mint. (8). In 1721 peppermint first appeared in the London Pharmacopoeia, with the first isolation of the menthol compound by the Dutch botanist, Gambius, in 1771 (5,6,10).
Conclusions
From the earliest scripts in ancient Egypt detailing medical practices through to ancient Greece and the earliest description of the cooling analgesic benefits of mint by Hippocrates, it is evident that throughout history the Mentha herb has been popularly used by various peoples and civilizations for a wide range of uses including pain relief. In modernity, when referring to menthol, usually the L-(-)menthol isomer is implied as this has become a prominent ingredient in a variety of products (6). With the advent of modern science, our understanding of menthol’s mode of action has deepened, revealing specific receptors, including TRPM8, as pharmacological targets responsible for the cooling analgesic effects (5,8-10). With the arrival of modern technologies aiding in the characterisation of menthol’s pharmacological action, a robust scientific understanding can help substantiate the analgesic benefits that many civilisations have experienced across the ages.
References
1)McCurdy, C.R., Scully, S.S. Analgesic substances derived from natural products (natureceuticals). Life Sciences. (2005), 78(5): 476-84.
2)Schiff Jr., P.L. Ergot and its alkaloids. American journal of pharmaceutical education. (2006), 70(5).
3)Humphrey, P.P. The discovery of a new drug class for the acute treatment of migraine. Headache: The Journal of Head and Face Pain. (2007), 47: S10-9.
4)Julius, D. TRP channels and pain. Annual review of cell and developmental biology. (2013), 29: 355-84.
5)Finch, P.M., Drummond, P.D. Topical treatment in pain medicine: From ancient remedies to modern usage. Pain manag. (2015), 5(5): 359-371.
6)Kamatou, G.P.P., Vermaak, I., Viljoen, A.M., et al. Menthol: A simple monoterpene with remarkable biological properties. Phytochemistry. (2013), 96: 15-25. DOI: https://dx.doi.org/10.1016/j.phytochem.2013.08.005.
7)Li, Z., Zhang, H., Wang, Y., et al. The distinctive role of menthol in pain and analgesia: Mechanisms, practices, and advances. Front. Mol. Neurosci. (2022), 15:1006908. DOI: 10.3389/fnmol.2022.1006908.
8)Mavrogenis, A.F., Saranteas, T., Markatos, K., et al. Pharmacies for pain and trauma in ancient Greece. International Orthopaedics (SICOT). (2019), 43: 1529-1536. DOI: https://doi.org/10.1007/s00264-018-4219-x.
9)Pergolizzi Jr., J.V., Taylor Jr., R., LeQuang, J.A., et al. The role and mechanism of action of menthol in topical analgesic products. J Clin Pharm Ther. (2018), 43: 313-319. DOI: 10.1111/jcpt.12679.
10)Patel, T., Ishiuji, Y., and Yosipovitch, G. Menthol: A refreshing look at this ancient compound. J Am Acad Dermatol. (2007), 57: 873-878. DOI: 10.1016/ j.jaad.2007.04.008.