By Jake Towner
Life is truly a blessing, especially when you consider how lucky humans are to have an entire planet and all its flora to enjoy. In this article I’m going to discuss the pharmacokinetics of terpenes; how terpenes are absorbed, moved through the body, distributed, metabolized, and finally excreted. This is an enormous task simply because there are over 20,000 terpenes that can be found in animals, plants, bacteria, fungi, and archaea(1). You will remember from my previous articles in past issues of Kurple that I discussed terpenes, terpenoids, and their structure, nomenclature, and synthesis. Even though over 20,000 terpenes exist in nature, they all share something in common. All 20,000 terpenes are based on a subunit called isoprene. At the end of this article you will see a reference and a link for Sigma-Aldrich that will take you to a page named “Terpenoid Metabolism.” It is highly advanced science but understanding the mevalonate pathway, an essential cellular metabolic pathway, will greatly help you understand the reasons why terpenes have such a profound effect on human metabolic functions. More on that later. For now, we’re going to dive into some more of my favorite terpenes and then we’ll get deeper into details about the metabolism of terpenes in humans. Keep in mind this is just a very brief introduction. Otherwise, we would have to investigate over 20,000 chemical pathways and Kurple is not an encyclopedia. Let’s get to it.
There are three terpenes of interest in this article: cineol, anethole and menthol. We will start with cineol, which is also called eucalyptol. Sound familiar? Eucalyptol also gives the eucalyptus plant its distinct aroma. The lethal dose in mice for ingested pure 1,8-cineol is 3,849 mg/kg(2). This means, to kill a mouse, you need about 4 grams of oil for every kilogram that the mouse weighs. Even this is quite a lot for a mouse considering their small size. Obviously, cineol is highly powerful in very small amounts when ingested, but much less toxic when inhaled. When inhaled, the amount of cineol in cannabis is nowhere near the overdose threshold, even if you were to smoke an entire ounce in one sitting. The toxicity of cineol is something you would only have to consider when you’re thinking about ingesting cannabis. When was the last time you ate a pound of marijuana? Yeah, it’s been a while for me, too.
Let’s get into the cool stuff. How can cineol protect the brain from Alzheimer’s disease? It turns out that cineol affects memory and learning. Cineol is a small molecule that passes the blood-brain barrier with ease. Once past this barrier, it has protective effects on neurotransmission that have shown to prevent Alzheimer’s. Cineol also has been shown to have antibacterial, antifungal, antioxidant, anti-inflammatory, and anticancer properties as well as the ability to improve asthma therapy and pain management. This terpene also can be used as a natural insecticide. In addition to cannabis, cineol is naturally found in bay leaves, camphor laurel, tea trees, mugwort, sweet basil, wormwood, rosemary, sage, and other aromatic plants. By the way, I’ve seen cineol spelled both as cineol and as cineole so there seems to be some confusion about that.
The next terpene in line is anethole. It is found naturally in anise, star anise, anise myrtle, fennel, liquorice, camphor, and magnolia blossoms. It is a unique molecule that is responsible for the ouzo effect; a property due to its slight solubility in water and great solubility in ethanol. When liquor containing anethole is diluted with water it spontaneously forms a micro-emulsion. Anethole also tastes very sweet and in fact is 13 times sweeter than sugar. Much like cineol, anethole has antimicrobial and antifungal properties, in addition to being an effective insecticide.
The final terpene is menthol. I will briefly discuss menthol since it is so well known. Historically, it was used to treat a variety of gastrointestinal ailments. Menthol is a carminative, meaning it prevents gas build up in the colon. Menthol’s ability to activate TRPM8 receptors creates the cool feeling on skin. It activates kappa opioid receptors and blocks certain sodium channels thus reducing neural activity that may stimulate muscles.
Before we wrap things up, I want to talk to you about terpene metabolism in general. There is only limited data available about terpene metabolism and its terpene specific as well. That is why I attached the following image to persuade you this point. Terpene metabolism is intimately inter-twined with the same biochemical pathways that also synthesize steroids, carotenoids, ubiquinone, among other compounds. It follows then that terpenes are going to impact the systems in the body that are responsible for detoxifying itself, repairing itself, and producing energy for itself. The mevalonate pathway, as the image shows, gives rise to a wide range of compounds, which also means this variety of compounds coexist with each other. This implication of the mevalonate pathways has even further implications. Maybe Michael Phelps was on to something(3).
In addition to the chemicals that build up to terpenes, I want to investigate the chemicals that terpenes break down. This is where the terpene specific data comes into play. One terpene that would demonstrate this best would be limonene. It breaks down into cis- and trans-carveol, perillyl alcohol, perillic acid, limonene-1,2-diol and limonene-8,9-diol. Complete elimination of limonene occurs within a 24-hour period. These compounds have additional effects but each of them are beneficial in other ways. For example, carveol has been found to prevent breast cancer. This means that terpene metabolism is extremely complex. Staying mindful of your strain’s terpene profile and how it works may not be an easy task, but it is well worth it.
A final consideration after you have determined how much of a certain terpene your sample contains, is how much your body absorbs when it is inhaled. Not all of the terpenes will reach your blood when inhaled. In particular, 54-76% of terpenes Alpha pinene, camphor, and menthol are absorbed through pulmonary routes(4).
(1)Terpene Metabolism. Sigma-Aldrich. https://www.sigmaaldrich.com/life-science/cell-biology/cell-biology-products.html?TablePage=104559348
(2)J. Xu. Z. Hu. C. Wang. Z. Yin. Q. Wei. L. Zhou. L. Li. Y. Du. R. Jia. M. Li. Q. Fan. X. Liang. C. He. L. Yin. (2014) Acute and subacute toxicity study of 1,8-cineole in mice. Int J Clin Pathol. 7(4)1495-1501 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014229/
(3)Terpenoid backbone biosynthesis. https://www.genome.jp/kegg-bin/show_pathway?org_name=map&mapno=00900&mapscale=&show_description=hide
(4)C. Kohlert. I. Van Rensen. R. Marz. G. Schindler. E.U. Graefe. M. Veit. (2000) Bioavailability and Pharmacokinetics of Natural Volatile Terpenes. Planta Medica. 66(6):495-505. https//:doi.org/10.1055/s-2000-8616
