Monday, July 1, 2013

Mad Science of Menthol

Menthol, billed as a "Cough Suppressant/Oral Anesthetic"
Because I've been battling a cold the past few days, complete with a sore throat and cough, I've been sucking on quite a few cherry menthol cough drops.  They particularly helped me get through a 6 hour drive without coughing my germs all over the car.  This had me thinking a bit about menthol.  Menthol is in a lot of products, including pain-relief gels, toothpastes and mouthwashes, cold medications like Vick's Vaporub, cigarettes, foods like candy and chewing gum, and my favorite cherry menthol cough drops.  For mild over-the-counter relief from a sore throat or other cold symptoms, menthol is hard to beat.

But what is menthol?  Why does it make your throat feel cool?  How does it work?  Let's take a quick look at an ancient medicine that we have only recently begun to understand.  Read on....

        
Mint
Menthol is one of our most ancient medicines

Menthol has been used for hundreds of years as a treatment for rhinitis (runny nose), congestion, and cough.  Menthol has also been used for centuries in folk medicine to relieve pain and itching.  It is most commonly found in plants of the Lamiaceae (mint) family, specifically the Mentha genus that contains peppermint (Mentha piperita), spearmint (Mentha spicata), and corn mint (Mentha arvensis; a major source of industrial menthol production), among others.  It is thought that peppermint has been grown and used for medicinal purposes in Japan for at least 2000 years.   

Purified menthol was first isolated from oil of  peppermint plants (species Mentha piperita) in 1771 by the German-born physician and chemist Hieronymus David Gaubius, who called it camphora europaea menthae piperitidis.  By the end of the 1700s, world-wide consumption of mint oils was estimated to be only about one thousand kilograms per year.  By the end of the 1800s, that number jumped to 175 thousand kilograms.  Today, we consume about 26 million kilograms of peppermint oils annually.  The actual amount of menthol consumed is thought to be about 6 million kilograms(7000 tons), an amount valued at more than $300 million that is then sold in many types of products that generate billions of dollars of further revenue.  With all of the cold, flu, and pain-relief products that contain menthol, menthol production is big business.    

Structure of menthol
Molecular mechanisms of menthol

Menthol is a cyclic terpene alcohol that is a solid at room temperature but melts into a liquid at slightly higher temperatures, making it a perfect ingredient for things like cough drops, lip balms, and topical creams that need to be solid or semi-solid at room temperature.  

Many people find relief in the pleasant "cool" sensation that menthol stimulates, but menthol doesn't actually cool anything.  It took well over 200 years from Gaubius's isolation of menthol to our understanding of how it actually works.  Menthol doesn't actually lower the temperature.  It just has the unique property of making you feel "cool" the same way that capsaicin in chili peppers makes you feel "hot."  It effectively tricks you senses.  In 1886, a scientist named Goldscheider presented some of his studies on menthol at a meeting of the Physiological Society of Berlin.  At the time, many people thought that the cooling effect of menthol on the skin had something to do with its evaporation (we previously discussed evaporative cooling here).  Goldscheider found that menthol application did not decrease surface temperature, and he attributed the cooling sensation of menthol to the activation "thermoreceptors" in "special nerves of temperature."  It wasn't until 1978 that it was more clearly shown that menthol indeed activates sensory nerves.  Through this activation of sensory nerves, menthol has been proposed to exerts affects on breathing, thirst, and alertness.      

Menthol as an active ingredient in a topical rub.
Menthol activates sensory nerves by acting on a protein found in nerve cells called TRPM8, a member of the TRP family of ion channels that are involved in various functions, including the sensation and transmission of mechanical, chemical, and thermal stimuli.  There are approximately 28 TRP channel family members; seven are activated by heat while two are activated by cool temperatures.  The gene for TRPM8 was discovered in 2001, and TRPM8 is sometimes called the "cold receptor," though it is clear now that it isn't the only cold receptor that exists.  Mice genetically engineered to lack TRPM8 have reduced pain and cold sensitivity, but still have some remaining sensitivity. 

TRMP8 is a temperature-regulated ion channel that is activated along a temperature range from cool (26° C [79 °F]) to cold (less than 15° C [56 °F]).  An ion channel is a protein in the membrane of a cell (we discussed a bit about biological membranes here) that allows the passage of charged atoms or molecules (ions).  Ion channels are almost always regulated; that is, the cell can control whether they are predominately open or closed.  Stimulation of TRPM8 opens the ion channel and allows influx of calcium ions (an important ion in cell signaling) into the nerve cell, resulting in nerve depolarization and stimulation of an electrical signal (called an action potential) that transmits sensory signals to the brain.  In addition to temperature, TRPM8 is also activated directly by the menthol found in oils from plants like peppermint, corn mint, and eucalyptus.  By activating TRPM8, menthol "tricks" your sensory nerves into thinking that they've gotten "cooler."  

TRPM8 activation can be either analgesic (pain relieving) or pro-algesic (pain causing).  Some people with chronic pain and some chemotherapy patients can develop a hypersensitivity to cold (called "cold allodynia"), and TRPM8 blockers (antagonists) may have important therapeutic potential.  This is an area of active research, as both Bayer Healthcare and Janssen Pharmaceuticals have developed, patented, and published on TRPM8 antagonists (patents WO2006040103 and US20100160337, respectively).

Mouthwash label showing menthol as an active ingredient.
Menthol also has many other effects beyond TRPM8 activation.  Menthol can inhibit voltage-gated sodium and calcium channels found in pain-sensitive (nociceptive) nerves; inhibiting these channels could reduce the transmission of pain signals.  Menthol is also a weak activator of certain types of opiod receptors (kappa-opiod receptors) that can alter perception of pain.  Menthol also has direct antibacterial and antifungal activity.  This is important for the use of menthol in antiseptic mouthwashes, but the mechanisms of this is not yet as well-understood as the mechanism of its cooling effects.  We still have a lot to learn about the many pharmacological effects of menthol. 

Lots of cold products contain menthol.
Menthol for congestion and cough

While menthol is ubiquitously used in cough drops and syrups as well as nasal sprays to relieve congestion and nasal irritation, recent studies have actually shown that menthol does not significantly increase nasal air flow.  Some studies have shown that menthol actually increases congestion.   Instead, the feeling of cold in the nose may provide a false sense of improved breathing that nonetheless may still be important by providing a sense of symptom relief.       

Menthol has also long been used for its antitussive (cough-suppressing) effects, and recent scientific studies show that it does indeed suppress coughing.  Coughing is a protective reflex that protects your airways by forcefully expelling excess mucus or harmful vapors or irritants from the lungs.  Millions of dollars are spent yearly on over-the-counter cough suppressants, though many have been shown to be no better than honey or other sugary syrups, which alone can suppress coughing.   Menthol and sucrose (sugar) are two of the only things that have been legitimately shown to suppress the cough reflex, but we don't yet fully understand how either of these actually work.  However, that means the time-honored cough remedies like menthol cough drops and hot tea with sugar or honey are just as valid therapeutics as more expensive cough syrups.             

The dark side of menthol

Not all the uses of cool minty menthol are beneficial, though.  Menthol has been added to cigarettes since the late 1920s.  This resulted from an accidental creation of the first mentholated cigarettes by an Ohio man named Lloyd "Spud" Hughes in 1924.  He stored some cigarettes in a tin container of menthol crystals.  When he smoked them, he was pleasantly surprised, and in 1927, the Axton-Fisher Tobacco Company started producing "Spud Menthol Cooled Cigarettes," which were the fifth most popular cigarette brand by 1932.  Many other companies followed suite and began producing their own brands of menthol cigarettes.   

Cigarette smoke contains irritants that are masked by menthol.
Many researchers and physicians have shown that menthol in cigarettes can relieve some of the irritation caused by cigarette smoke and promote smoking, particularly by making cigarettes seem less unpleasant to first-time smokers through masking the effects of irritants.  Research has suggested that menthol cigarette brands are very successful at attracting adolescent smokers.  Menthol may also prolong the use of cigarettes in smokers by masking the signs of respiratory diseases caused by smoking.  Cigarettes containing menthol don't necessarily need to be labeled "menthol.  In fact, while only about 27% of cigarettes made in the USA are marketed as "menthol,"  it is believed that menthol is an additive in 90% of US cigarettes.  Even imperceptible amounts of methanol may have have a reinforcing effect on cigarette addictiveness through pharmacological interactions with nicotine, making it an additive that is very much in the tobacco companies' best interests to use. 

In March of 2011, the US FDA's Tobacco Products Scientific Advisory Committee (TPSAC) concluded that "removal of menthol cigarettes would benefit public health in the United States," though the committee did not overtly recommend a ban or recommend any plan to reduce menthol cigarette use.  While candy-flavored cigarette additives are banned by the FDA, menthol continues to be used.  Some groups, including law enforcement groups, feel that the popularity of menthol cigarettes is so high that banning them could create a "black market" for smuggling or making mentholated cigarettes and actually do more harm than good.  However, in June of 2013, the European Union officially agreed to ban mentholated cigarettes to specifically prevent young people from becoming addicted to tobacco.  Whether the US ever follows suite and proposes a similar ban remains to be seen.  It is clearly a complicated issue, and the pros and cons of such a ban must be considered.     

A final note
                        
While menthol is generally considered to be safe by the FDA, high concentrations of menthol can cause acute localized allergic reactions like rash or more systemic allergic reactions like respiratory difficulty and asthmatic reactions.  It is thought that over-activation of TRPM8 can also least to symptoms of asthma, causing airway constriction and mucus production.  If you are going to use a product containing menthol, please use it only in line with the manufacturer's instructions and consult with your doctor first.  Nothing that you read on the internet (including TheMadScienceBlog) is ever a good substitute for real professional medical advice. 

Text © 2013 TheMadScienceBlog;  Images are public domain.  


Sources and further reading:
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3 comments:

  1. Good Post.. I'm 10 year smoker, already knew Mint but I was searching more deeply now about Mint properties and its mechanical/physical beaver and the info here helped me understanding more ;) nice blog

    TRPM8's channel and its mechanism is quiet interesting

    Cheers ;)

    ReplyDelete
  2. Thank you for the great post,It is really a big help.thanks for sharing nice blog. cigarette tubes

    ReplyDelete
  3. Do you think that menthol cigarette are any better then any of the rest? This brand might be worse as it is said that smoking these will crystallize your lungs. Abitsaving,com

    ReplyDelete