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Tuesday, September 22, 2015

Something about Terpenes

When most people think about marijuana, they think about the psychoactive effects of 9-delta-Tetrahydrocannabinol and the newly touted health benefits of Cannabidiol. Unfortunately, there are many other chemicals that are overlooked that have medical benefits and give marijuana it's flavor profile.

This class of chemicals is known as terpenes, which are hydrocarbons most often associated with conifers. While cannabinoid research has moved at a sluggish pace, medical research involving terpenes has been moving at a blistering pace. Still it is important to remember that marijuana alone has 200 terpenes, so you can imagine how long it will take to design experiments for each and every known terpene in the floral kingdom.

Pinene

When people talk about “rolling up a heap of pine,” they are referring to marijuana that is rich in Pinene. In many strains of marijuana, the two isomers of pinene (alpha-pinene and beta-pinene) make up more than 50% of all terpene mass. Pinene is the second most abundant terpene in marijuana.

Since this is the most abundant terpene in most conifers, and given that conifers are the main producers of natural terpenes, Pinene makes up the bulk of all terpenes on planet earth. This is far from a bad thing since pinene has several known medical and industrial applications.

In an experiment testing the anti-microbial effects of both Pinene isomers, researchers found that both have anti-bacterial activity. In particular researchers were using these isomers in tandem with other medicines to determine if they improved the effectiveness of killing methicillin-resistant Staphylococcus aureus (MRSA.) Both chemicals were found to drastically improve results and are seen as broad-spectrum antibiotics [1].

Pinene is not just good at killing bad cells, the laundry list of health benefits includes; bronchodilation, which could be used to aid asthma patients; anti-inflammation; and an increase in memory function due to the inhibition of acetylcholinesterase[2]. Pinene works in concert with other terpenes to effectively reverse some of the negative side effects of THC use.

Myrcene

Myrcene is well understood to be the most common terpene in cannabis but is not always the most dominant terpene. It's fragrance seems to defy description, but comparisons to fruit and cloves are common, which is likely why it is so commonly used in the fragrance industry.

Within the human body, myrcene acts as an analgesic, antibacterial, anti-diabetic, anti-inflammatory, anti-insomnia, anti-proliferative/anti-mutagenic, antipsychotic (tranquilizing effect as opposed regulating dopamine concentrations) and an antispasmodic. Myrcene appears to be in a league of its own in terms of potential uses, but it does beg the question if this is because it has been more thoroughly studied.
Commonly found in Hops, mangoes, lemongrass, thyme, and its namesake Myrcia, myrcene for a long time has been used medicinally. The analgesic effect of lemongrass tea is thought to be a result of this terpene. In higher than normal concentrations this can be used as a tranquilizer which causes a barbiturate-induced sleep [3].

It was more recently found that myrcene interacts with the adrenergic system to create a release of natural opioids[4]. This suggests myrcene is one of the main reasons why marijuana is so good for pain relief. It's important not to forget that these terpenes often work together to achieve their goals. Many studies on essential oils find stronger results in pain relief, or fighting bad bacteria for the oils themselves as opposed to each of their constituents tested alone.

Limonene

Despite its name, Limonene is actually named after the lemon. This cyclic terpene, commonly found in the rinds of citrus fruits, sees wide use industrially. From cosmetics and perfume, to solvents for medical studies, cleaners, 3D printers and a host of other applications, limonene is commonly used.

Since the 1970's it has been known that limonene and other monoterpenes can help in the fight breast cancer. The study of limonene naturally extended to it's metabolites, where it was found that perillyl alcohol is much more effective at fighting cancer. In some strains of cancer perillyl alcohol and other monoterpenes like limonene change the gene expression of carcinomas thereby blocking progression and promotion. In some successful trials, tumors were completely regressed.

Limonene has also been used as an indicator of liver disease since the liver is the first step in metabolizing limonene[5]. A study in the same vein found in cases of alcohol-induced liver disease, limonene can help prevent a build up of damaging, excess iron[6]. A similar study found that limonene causes temporary damage to the liver and a raised number of immune cells in the liver, suggesting some of the metabolites might be toxic to internal cellular structures, but the damage is not permanent.

Linalool

Linalool is most commonly associated with lavender, but also found in mugwort, basil, bay leaves, hops and of course Cannabis sativa. Like the other terpenes, it has been touted for it's therapeutic effects and has its roots buried deep in herbal medicine. It seems increasingly that we find evidence to support the merits of herbal medicine, instead of disproving it as mumbo jumbo.

Classically lavender scents have been seen as relaxing. This is likely because when we inhale the lavender scents, we are also inhaling linalool. This chemical was shown in 2009 to exhibit stress relief, reduce aggressive behavior and enhance social activity. Strains of marijuana with linalool could help reduce stress and promote social activity [7].

In a 2015 study, Linalool and Beta-pinene both produce an anti-depressant effect through their interaction with the monoaminergic system [8]. This is in line with classical methods of fighting depression since most anti-depressants are used to increase the production of Serotonin, norepinephrine or dopamine. All three of these neurotransmitters are considered monoamines.

Further studies will be needed to prove exactly how linalool interacts with the monoaminergic system before any marketable medicines can be produced. Still though the research gives credence to the use of aromatherapy to help with moods. Perhaps those who stop to smell the roses really do see the world differently?

Beta-Caryophyllene

Although beta-caryophyllene is the most abundant sesquiterpene found in marijuana, it is also a known agonist of Cannabinoid Receptor type 2 (CBR2). Since the psychoactive effects are caused by agonism Cannabinoid Receptor Type 1, one cannot get high from smoking beta-caryophyllene. None the less beta-caryophyllene one of the most interesting found in marijuana.

The CBR2 receptor has been linked to neuropathic pain in several different studies. Since beta-caryophyllene is a selective CBR2 agonist, it was seen as a prime candidate for investigation. Of the three types of pain, beta-caryophyllene proved effective at fighting both inflammatory and neuropathic pain [9]. Acute short-term pain seemed unaffected.

Unlike the cannabinoid receptor 1, which is largely localized in the Central Nervous System, Cannabinoid receptor type 2 proteins are mostly found in the immune system, the Gastrointestinal system, and the peripheral nervous system. This means CB2 ligands are attractive in fighting autoimmune diseases and potentially Crohn's disease[10].

One of the most recent revelations was that CBR2 are found within the germ cells of the testes and could potentially be used as a male contraceptive [11]. In mice long-term treatment with beta-caryophyllene, there were no morphological changes to the testes and the total number of sperm created were not effective. The treatment is promising because it only decreased the viability of sperm already available by blocking the final stage of sperm production, spermiogenesis.

1, 8 Cineole aka Eucalyptol

Eucalyptus is a plant whose therapeutic abilities cannot be understated. For centuries, this chemical has been included in medicines that treat everything from the common cold, to pain and ADHD. Unsurprisingly, the main terpene in Eucalyptus is eucalyptol, which is also responsible for many of the therapeutic properties of the plant.

Eucalyptol is primarily found in cannabis Sativa, bringing with it an energetic and focused mood. Likely this is a result of acetylcholinesterase inhibition, which is seen in other cyclic monoterpenes [12].

A 2013 experiment showed that 1,8-Cineole can also limit the amount of fat that infiltrates the liver [13]. The thought is that it might be developed into a drug that helps those suffering from either too much or too little cholesterol. A separate 2015 study found that in mice with a condition called non-alcoholic steatohepatitis (NASH) there was also a reduction in liver cell fat accumulation, suggesting it is a candidate for medicinal use [14].

Like other chemicals in this class, eucalyptol has been shown to be an effective cancer treatment option. In 2013, an experiment showed that 1,8-Cineole forced colorectal cancer cells to undergo apoptosis, or programmed cell death [15]. They said it “would be an effective strategy to treat colorectal cancer.”

Pulegone

In the early days of terpene research, Pulegone was among some of the more promising candidates for being used as a medicine. Initial research suggested it could be used as a sedative, and had antipyretic (fever reducing) activity.

Like limonene, and 1, 8 cineole, Pulegone was shown to aid in short-term memory consolidation by inhibiting the enzyme that destroys acetylcholine (ACh.) Reduced levels of ACh in the hippocampus has been linked to memory problems associated with both smoking pot and Alzheimer's [16]. However pulegone was not very good at that, nor were its other potential properties found to be overwhelming.

While it is easy to get caught up in all the positive news continuing to come out of terpene research, it is also important to remember that not all the news is good. In a high dose group, female rats showed the presence of urothelial tumors when regularly administered pulegone [17]. The 2012 study supports the idea that the cytotoxic properties of piperitenone, a secondary metabolite of Pulegone is likely the main culprit.

In a separate study from 2011 it was shown that Pulegone also reduces the strength of L-type calcium ion currents that are most commonly associated with muscle contraction [18]. This is likely part of the cause of immobility in mice and the sedative effect. Unfortunately, this also affects the heart and poses potential health risks. Pulegone is a perfect example of why these chemicals need to be investigated in depth before attempting to use them as medicine.

Borneol

Borneol is one of the lesser terpenes of marijuana in terms of overall mass, but it too has many practical applications. Naturally found in the mugwort plant, this terpene has been used in traditional eastern medicine for a couple thousand years. Called moxibustion or moxa, a maceration of herbs was placed on key meridians of the body to prevent and cure cancer and many other ailments.

Until recently there was little to no evidence to back up this claim. A 2013 study found that in conjunction Borneol significantly increased the absorption of a chemical called Selenocysteine which led to increased success of treatment [19]. Greatly increased success.

To be clear, Selenocysteine (SeC) is not a new medicine developed in a laboratory with diverse adverse effects. SeC is the 21st amino acid that naturally occurs in organisms in all kingdoms of life, including humans. Humans have 20 known proteins that contain SeC, most of which are involved with protecting cells from oxidative damage. Good sources of dietary selenium include Brazil nuts and, and all meats are a good source of selenocysteine.

Perhaps the interaction with borneol in mugwort and naturally occurring selenocysteine helped reduce cancer rates in the east and moxa is no hoax.

Nerolidol

Marijuana is not the only intoxicant known for its terpenes. Many scientists also study the terpenes of wine in order to more accurately identify its flavors and health benefits. Like marijuana, the terpenes of wine vary from batch to batch and plant to plant. For example, Nerolidol has primarily been identified in a few white Italian wines like Grillo, Inzolia and Cataratto [20].

Nerolidol has several medicinal uses, but most recently it is being used to help antimicrobial medicines be absorbed through the skin. Specifically a disorder call leishmaniasis caused by protozoan parasites aptly belonging to the genus leishmania, which cause lesions [21]. Mice treated with Nerolidol showed a reduction in lesions but the disease was not cured but nerolidol alone. Nerolidol also has proven antimalarial properties and a sedative effect.

A 2015 study introduced the gut flora, or the bloom of bacteria in our lower GI tract to an essential oil blend consisting primarily of nerolidol [22]. Certain pathogenic bacteria were specifically suppressed while the commensal or good bacteria were unharmed. The finding will likely lead to further research involving other essential oil blends on the gut flora and give insights into preventing if not curing certain lower GI disorders.

Geraniol

Geraniol smells like lavender, but with sweet fruit and rosey undertones. It is considered safe as a food additive. However, several deaths have been reported from the consumption of Citronella oil, which is 93% geraniol [23]. If it were not already obvious, It is not a good idea to drink the fuel in a citronella candle. The name comes from geranium, which are high in geraniol.

Studies as far back as 1995 show that geraniol fights cancer, but it was not known exactly how this happened. Since then geraniol has shown to be effective against 4 types of cancer, leukemia, hepatoma, melanoma and pancreatic[24].

Early in 2015 however, a study was published that showed that geraniol inhibits cancer cells from receiving blood vessels from the body. This results in less metastasis, smaller tumor sizes and less successful tumors overall [25]. Geraniol will likely find a place in human chemotherapy.

Taken together, the body of cancer research done on terpenes might present us with a broad spectrum cure for cancer that is as simple as adding a little oil to your pasta sauce. Trials with essential oils are often dismissed, including from this piece, when talking about cancer research. Which is appropriate, we need to understand how each of the constituents work within our bodies, but it would be a shame to miss the key point that our food might be the greatest preventative medicine we have.




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