How Terpenes Work.

If you’re reading this, you most likely heard of Terpenes.

But have you ever wondered how Terpenes work? How they can affect both the body and the mind, and are there different mechanisms at work? Is it important to understand how they work in the first place?

That depends, of course, on how you’re involved in natural healing. Understanding the principles of how Terpenes work can undoubtedly give you a more in-depth perspective on the ways you can use them.

Throughout the major part of its history, Natural healing has been based on the traditional use of aromatic plants. In the second half of the 19th century, empirical research on essential oils took place. Their chemistry and biological properties began to be studied more systematically. In the 1890s, pinene, limonene and terpinolene were among the first chemically characterised terpenes (Kubeczka 2016).

By the time René-Maurice Gattefossé entered the scene, major constituents were known – Gattefossé mentions over 40 in his book Aromatherapy (1937/1993) – along with their structure, or at least molecular formula. Knowledge of the biological properties of Terpenes in that time was a mix of herbal medicine, individual case reports and early experiments.

In subsequent decades, more sophisticated experimental methods were developed: various in vitro assays and animal models for testing biological effects in vivo. However, despite the accumulating knowledge what Terpenes do, nothing was known about how they work.

It was not until the late 1980s when pharmacodynamic research on the constituents of Terpenes started to emerge, focussing on molecular mechanisms. Of those early studies, some of the more salient were elucidation of the mechanism for the spasmolytic activity of menthol and peppermint oil (Hawthorn et al 1988) and the finding of a connection between linalool and glutamatergic system (Elisabetsky et al 1995), which explains an integral part of how lavender or other linalool-rich oils exert their generally calming effect.

Indeed, it took roughly a century from the early days of elucidating the molecular structure of the first constituents to the beginnings of unravelling the mysteries of their biological activity.

Currently, in times when the discovery of new synthetic drugs has been declining, we’re witnessing an explosion of natural products research, of which plant volatiles and Terpenes play a significant role.

Terpenes research

So, how do Terpenes work? It has become widely accepted that they can act via pharmacological and psychological mechanisms. These are the two fundamental mechanisms, as they are mediated respectively by the body and the mind. We’ll look separately into each, although in practice they often overlap and interact (which is a good thing!), and it may be difficult to distinguish between them. Note that this is not a “this oil does this and that oil does that” type of article but more like a bird’s eye overview.

PHARMACOLOGICAL MECHANISM

Effects of Terpenes on the body are usually termed pharmacological because they are subject to pharmacokinetic parameters of absorption, distribution, metabolism and elimination. Pharmacokinetic parameters determine bioavailability and affect the toxicity of constituents.

Bioavailability is the crucial pharmacological parameter, and it must be sufficient to produce observable pharmacological effects. If you take a few whiffs of Terpenes from the bottle, the concentration of bioactive constituents in your blood will be too low to reach pharmacologically relevant levels. However, the issue of bioavailability is complex, and it will be addressed in another post. Here, we’re only concerned with the general principles.

If there’s one thing you should know to understand the difference between pharmacological and psychological mechanism, it’s substance specificity. Pharmacological effects are substance-specific, which means that a given constituent will cause similar effects (yet not necessarily to the same degree) across the different subjects, by acting on the same molecular targets in a dose-dependent manner.

After entering the body via inhalation, topical application or internally, the constituents can bind to various proteins, such as ion channels, receptors, enzymes, carrier proteins, and proteins involved in signalling pathways. Due to their lipophilic nature, most can readily dissolve in cell membranes, where they can disrupt communication of the cell with its surrounding. Many antimicrobial constituents work by disrupting the cell membranes of microbial pathogens. The same thing happens in the cell membranes of our own tissues, which is why potent antimicrobial oils are also potential irritants.

Terpene constituents typically exert their pharmacological effects by inhibiting the function of the proteins they bind to, and therefore inhibit or slow down associated biological processes. That is how lavender can induce calming and sedative effects in the brain, or how anti-inflammatory and spasmolytic effects are mediated.

how essential oils work, essential oil pharmacology

Approximate size comparison between (A) cyclic monoterpene, (B) mid-sized protein and (C) phospholipid bilayer of a cell membrane. It seems quite hard to imagine how a tiny molecule 500th or 1000th the mass of a protein can modify its functional properties, right?

In some cases, the constituents activate specific receptors and consequently enable or speed up associated processes. That is how many anxiolytics work, or why peppermint oil feels cold, or how we’re able to sense the smell of essential oils.

So far that might not sound very fascinating. But that’s how all pharmacologically active substances work, regardless of whether they’re of natural or synthetic origin. They either activate some process in the body or deactivate it. They don’t remove the cause for the condition but help the body to better cope with an out-of-balance situation, and – ideally – heal on its own.

There’s no magic panacea like the ancient Mithridatium that could protect us from every disease. I know no-one wants to hear this, but the paradox of life is that organisms inevitably sentence themselves to death by the very source they’re crucially dependent on: oxygen. All higher life forms need oxygen to be able to maintain their highly efficient metabolism. But that same efficient metabolism produces free radicals from the oxygen, which slowly, but inevitably cause our cells and bodies to ‘rust’ over the years. This is the fundamental cause for ageing, and there’s no way around it – despite the ingenious biochemical mechanisms that have evolved to slow it down, and all the antioxidants and healthy lifestyles.

Unfortunately, no medicine can provide some utterly new functionality to the body that previously wasn’t there; what they can do is help re-establish the balance to physiological processes that for whatever reason went out of ‘focus’.

Terpenes AND THE IMMUNE SYSTEM

Take the immune system. A healthy immune system is precisely tuned to distinguish between pathogenic substances and the body’s healthy tissue. When this balance is lost, an overactive immune system starts invading its own body, which can result in chronic inflammation and autoimmune diseases. When the immune system is weak on the other hand, we succumb to microbial infections.

essentail oil immunostimulation, essential oil immune boostImmunostimulation works on the immune system and antimicrobial activity directly inhibits the growth of microorganisms, hence these are two different biological activities.

These are the two sides of the same coin, as common molecular mechanisms are involved. Anti-inflammatory substances suppress the immune system and damage repair system, and immunostimulants act pro-inflammatory, they stimulate inflammation.

The immune system is undoubtedly susceptible to poor diet, for example to deficiencies of protein, zinc or vitamin D, and can be improved accordingly. But evidence that small organic compounds of plant origin can specifically fortify a normally functioning immune system is weak (Gertsch et al. 2011, Anastasiou and Buchbauer 2017).

MIXTURE MAKES THE DRUG: SYNERGY AND NETWORK PHARMACOLOGY

Nonetheless, there are more exciting things about Terpenes. As small and highly diffusive molecules, Terpenes seem to be almost designed to reach maximum diversity and number of potential targets. That’s beneficial for the multi-purpose defence and communication systems of plants.

Not only can a single constituent bind to a variety of proteins, but mixtures of constituents can affect multiple networks of molecular processes, if sufficiently bioavailable.

network pharmacology, systems pharmacology, polypharmacology, essential oil synergy

Biological processes can be thought of as interrelated networks. Affecting multiple nodes at the same time can have a more robust effect on the system as a whole.

Thinking in terms of network and systems pharmacology opens up a vast space for the potential synergistic effects. By targeting networks instead of single molecules, synergistic interactions can affect pharmacokinetics (increasing bioavailability), or increase the robustness of pharmacological effects. By utilising mixtures of constituents, a similar effect can be achieved with pharmacologically less potent substances, reducing potential side effects encountered with conventional medicines that are based on highly potent monosubstances (Gertsch 2011).

Network effects and synergistic interactions can theoretically occur in a variety of possible ways. However, they should be applied in a therapeutic context very carefully as more parameters come into play that need to be taken into account. We are only beginning to probe this immensely complex space. But as Jürg Gertsch (2011) remarks, to achieve such level of depth in pharmacognosy, the molecular mechanisms need to be understood first. And I may add, we seem to be well under way.

The mechanism of action of phytochemicals is not clearly understood but may depend upon the composition of the active ingredients in the product being used.

The beneficial effects of phytochemicals are attributed to their antimicrobial and antioxidant properties. In addition, the inclusion of phytochemicals in the diets alters and stabilizes the intestinal microbiota and reduces microbial toxic metabolites in the gut, owing to their direct antimicrobial properties on various pathogenic bacteria, which results in relief from intestinal challenge and immune stress, thus improving performance.

Another important beneficial effect of dietary inclusion of phytochemicals is reduction in oxidative stress and increase in antioxidant activity in various tissues, and thus, improved health. Phytochemicals also exert their action through immunomodulatory effects such as increased proliferation of immune cells, modulation of cytokines, and increased antibody titers