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From the Townsend Letter
December 2016

Sniffing Out Pain
Part 2: The Multimodal Actions of Essential Oils on Pain Perception and Pain Relief
by Sarah A. LoBisco, ND
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Part 1 of this article

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Why Integrative Pain Management Right Under Our Noses
Olfactory processing is associated with the limbic system and has an effect on memory, emotions, and physiology. The emotional effect of odors and their relationship to pain perception are neurologically connected by the amygdala. This brain structure is intricately involved in pain processing through its associated CRF receptors and its role in the stress response. These connections make aroma alone impactful in effecting pain processing.1
In a previous article, I discussed these complex interactions between odors modulating psychological and physiological responses. Now, I will discuss how aromatic compounds, which contain secondary metabolites, can provide multimodal effects on pain more profoundly than odor alone. Specifically, I will show how combining pleasant aromatic associations and powerful secondary metabolites can entice a physiological relaxation response as they modify pain perception on a molecular level.
What Are Essential Oils?
 Essential oils are aromatic secondary metabolitesproduced by plants in order to modulate immune function and stimulate various molecular pathways.1-8 As a result, they enhance cellular and biochemical responses and provide defense against stressors that could interfere with optimal development.1-14
ProTheraIn humans, essential oils favorably affect all levels of health, biochemical, physiological, and psychological. This is due to the fact that these plant compounds not only exert modulation of molecular pathways and cellular receptor interaction but also provide a profound impact on emotions through their aromatic quality.1-14 Essential oils are absorbed easily into our system through skin application, inhalation, or ingestion and excreted quickly, mostly through the kidneys. They have a low toxicity profile, when used in their proper, pure form.8,10
Essential oils are a truly holistic and mind-body medicine tool with a vast array of applications. For example, with one bottle of an essential oil, biochemistry could be altered through the presence of secondary metabolites that: inhibit unwanted microbial growth, defend against oxidative stress, modulate hormonal pathways, and balance inflammation.2-6,8,10,13 Furthermore, the aroma of essential oils could also produce a calming effect, affecting memory and focus, and affecting physiology through the olfactory response.1,11-12 In fact, the connection between aromatherapy and mitigating negative physiological stress patterns has an infinite amount of positive benefits and synergistically adds to all of their listed beneficial effects.1
Essential Oils: Physiological, Biochemical, and Psychological Effects on Pain
Probably one of the most recognized and validated applications for aromatherapy and essential oils is their ability to induce relaxation.11,12 However, the antimicrobial action of high-phenol oils, without the negative consequences of microbiota devastation, are a close second.3,15-28
The impact of essential oils on physiology, biochemistry, and psychology can be examined from two vantage points. The first is a more microscopic view, which examines an oil's individual constituents and evaluates the biochemical and molecular pathways affected by them. The second is a macroscopic interpretation. This wider viewpoint encompasses the integrative and synergistic actions of the odor itself, along with the biological constituents' effects on the mind and body. We will explore both and then connect these effects to pain response.
All the Tiny Wonders Inside a Bottle: The Microscopic View of Essential Oils
At the microscopic level the constituents present in essential oils are vast, and their classifications can be complex.2,10,29 These secondary metabolites can be grouped on the basis of their chemical structure composition, their solubility in various solvents, or their synthesis (e.g., phenylpropanoid, which produces tannins). For example, a common way to classify the volatile components is to organize them as either terpenoids or phenylpropanoids, or alternatively, into hydrocarbons and oxygenated compounds.10
Categorizing active constituents in essential oils based on their chemical structures can be exemplified as follows:

  • terpenes (hydrocarbons resulting from several isoprene units, C5H8, synthesized in the cytoplasm of plant cells)
  • terpenoids (terpenes that undergo enzymatic biochemical modification through incorporation of oxygen molecules and manipulating methyl groups)
  • phenylpropenes (a subfamily of various groups of phenylpropanoids, they are synthesized from the amino acid precursor phenylalanines)
  • "different degradation products originating from unsaturated fatty acids, lactones, terpenes, glycosides, and compounds that contain either sulfur or nitrogen"29

As stated in the introduction, it has been demonstrated that odor itself can have physiological effects, including the modulation of skin conduction, heart rate, blood pressure, respiratory rate, and regional cerebral blood flow.30-34 Furthermore, the psychological and memory-enhanced associations with odor can impact physiological processes and emotional state.35-40
Essential oils go further with the addition of these active constituents that modulate cellular signaling, biochemical responses, and neurotransmitter signaling independently of emotional arousal. In The Therapeutic Benefits of Essential Oils, Nutrition, Well-Being, and Health, the authors explain the three comprehensive actions of essential oils as a result of their synergistic constituents and properties. These include:

1.  Biochemical (pharmacological): essential oils' constituents interact with cellular receptors for hormones and enzymes, modulating their effects.
2.  Physiological: essential oils impact specific biological functions through their various constituents that modulate molecular pathways.
3.  Psychological: the "olfactory area of the brain (limbic system) undergoes an action triggered by the essential oil molecules and then, chemical and neurotransmitter messengers provide changes in the mental and emotional behavior of the person. …"10

There can be hundreds of various constituents found in one essential oil.6,8,10,29 This synergism of molecules affects and balances physiology in a more complex way than a single synthetic compound. For example, several in vitro studies have demonstrated that oils deemed estrogenic have additional components that have antitumoral properties. Furthermore, the same "estrogenic" compound exhibits other cellular responses beyond hormonal modulation.41-43
For example, one in vivo study using a methanolic extract of fennel seeds (FSME) demonstrated anticancer potential against a breast cancer cell line (MCF7) and a liver cancer cell line (Hepg-2). According to the study, FSME modulated various antioxidant activities and glutathione content. The authors concluded that it had the potential to "reduce oxidative stress and protect mouse cells from damage caused by reactive oxygen species. … FSME also exhibited an antitumor effect by modulating lipid peroxidation and augmenting the antioxidant defense system in EAC-bearing mice with or without exposure to radiation. Furthermore, it appears the concentration and dosage of essential oils may modulate estrogenic activity as well as the cellular environment."41 When testing for active constituents of the extract, several constituents found in the volatile oil were present, which could account for creating these synergistic effects.
As stated above, the effect of a constituent can have a balancing effect of the biochemistry based on the "estrogen environment" present. Another study examined estrogenic effects of several components considered to have estrogen activity (e.g., limonene, citral [geranial and neral], geraniol, nerol, trans-anethole, and eugenol). The study consisted of testing these constituents on estrogen sensitive yeast cells expressing the human estrogen receptor, in the estrogen-responsive human cell line Ishikawa Var I, and in vivo in ovariectomized mice. Although the authors found some evidence of certain constituents showing in vitro estrogenic effects in yeast cells, there was a failure to replicate the results in the human cell line and rodents in nontoxic doses. They concluded:

At high concentrations, estrogenic activity was detected for citral (geranial and neral), geraniol, nerol and trans-anethole, while eugenol showed anti-estrogenic activity. Molecular graphics studies were undertaken to identify the possible mechanisms for the interaction of geranial, neral, geraniol, nerol and eugenol … but none of these compounds showed estrogenic or anti-estrogenic activity in the estrogen-responsive human cell line Ishikawa Var I at levels below their cytotoxic concentrations, and none showed activity in a yeast screen for androgenic and anti-androgenic activity. The potential in-vivo estrogenic effects of citral and geraniol were examined in ovariectomized mice, but neither compound showed any ability to stimulate the characteristic estrogenic responses of uterine hypertrophy or acute increase in uterine vascular permeability. These results show that very high concentrations of some commonly used essential oil constituents appear to have the potential to interact with estrogen receptors, although the biological significance of this is uncertain.43

These studies demonstrate that on the cellular level essential oils and their constituents have complex actions. The "unknown effects" discussed in the previous study could be related to these compounds acting as phytoestrogens that modulate estrogen beta, an antiproliferative receptor, verses estrogen alpha.45,35 The fascinating complexity of these natural compounds displays an "innate intelligence" that supports a truly individualized approach to balancing biochemistry through the modality itself.
Authenticity of Constituents for Different Effects
There is evidence that the chirality of the odorants found in essential oils exert an influence on their mode of action. This indicates that the composition of authentic essential oils may produce different effects than altered compounds with synthetic additives or isolated constituents.
One study examined the effects of chiral fragrances (enantiomers of limonene and carvone) on the autonomic nervous system (ANS) and on self-evaluation in 20 healthy subjects. The researchers measured skin temperature and conductance, breathing rate, pulse rate, blood oxygenation saturation, and blood pressure. Visual analog scales measuring mood, calmness, and alertness assessed for subjective experience of the fragrances, as well as a rating for pleasantness, intensity and stimulating properties. Each subject was tested at baseline, a control of continuous air, and with administration of a fragrance enantiomer. The results indicated that while inhalation of (+)−limonene and (−)−limonene increased systolic blood pressure, only (+)−limonene impacted subjective alertness and restlessness. (−)−Carvone caused increases in pulse rate, diastolic blood pressure, and subjective restlessness; whereas (+)−carvone increased both systolic and diastolic blood pressure.46,47
In another study, the authors tested how the chirality of linalool, a component in lavender, could be attributed to differing nervous system effects in 24 subjects. The effects of both R−(−) and S−(+) linalool enantiomers on various physiological parameters, which included heart rate, blood pressure, electrodermal activity, and salivary cortisol, were measured. The authors reported that although both forms were found to be relaxing, the R−(−) linalool proved to demonstrate stress-relieving effects, whereas, the S−(+) linalool acted on electrodermal activity, a measurement of sympathetic activity of the nervous system.

The study clearly indicated that odorants can modulate salivary cortisol levels, with both linalool enantiomers exerting relaxing effects. Concerning blood pressure and heart rate, S-(+)-linalool acted as an activating agent in contrast to electrodermal activity. R-(-)-linalool proved to be stress-relieving as determined by heart rate. In conclusion, the results revealed that (1) chirality crucially influences the physiological effects of odorants and that (2) odorants may act differently on certain physiological parameters.47

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