Aromatherapy, Essential oils/quality and safety, Liver/essential oils, Drug-medication interactions, Synergy

Exploring the Complexities and Caveats of Safe Internal Use of Essential Oils for Pain: Highlighting Intestinal Discomfort, Part 1

By Sarah A. LoBisco, ND, IFMCP

An Overview

Last year, I had the privilege to write a two-part article series for Townsend Letter, “Sniffing Out Pain.”^1-2 In Part I, “Olfaction’s Complex Connections of Emotions, Memory, and Pain Perception,” I explained how the sense of smell can induce powerful affective experiences due to the intricate neuroanatomy of olfaction.^3-4 Unlike other senses, smell has reciprocal axonal connections with the primary emotion areas: the amygdala, hippocampus, and orbitofrontal cortex (OFC). This means olfactory stimulation can bypass the primary olfactory cortex and directly activate the amygdala at the secondary olfactory cortex.^3-4

How the brain determines and translates odors is individualized and extremely complex. The exact mechanisms of this still have not been fully elucidated.¹ As a result, an aroma can alter emotional response, perception, and pain sensation based on an individual’s past experiences of it.^1-4 In fact, there is even evidence of epigenetic behavioral imprinting and physiological transmissions of emotions triggered by an odor based on an offspring’s mother’s prenatal association with it.¹

In Part II, “The Multimodal Actions of Essential Oils on Pain Perception and Pain Relief,” I provided evidence that essential oils’ pleasant aromas are combined with their powerful secondary metabolites to entice a simultaneous physiological and psychological relaxation response as they modify pain perception. They have been shown in clinical trials to alter pain acuity by modulating one’s emotional response and nervous system tone. Furthermore, in vivo and clinical trials have reported specific actions of certain essential oils and their constituents on cellular receptors for nociception. Due to their biochemical profile, and the influence of manufacturing practices on the presence and integrity of these delicate constituents, it is imperative to use quality, therapeutic essential oils for these desired therapeutic outcomes.²

I have been requested to write a follow up to these articles on the “nitty gritty” of putting this knowledge of essential oils to clinical use. With any medical intervention, physicians in training must first build on basic principles and understand contradictions, precautions, and side effects to be competent in prescribing and avoid harm.

Due to the complexity and caveats that exist about essential oils, I have divided the present article into segments and have narrowed my focus to their internal application for intestinal pain. This is because ingestion is the most controversial and misunderstood topic within aromatherapy and gastrointestinal concerns are common in integrative medicine practices, even if not the chief complaint. This also has been the area I see rapid, consistent results in my GI clients over the past eleven years.

First, I provide an overview of essential oils, including modes of application; details on liver biotransformation, metabolism, and excretion throughout the body; medication interactions; and the controversies and inconsistencies regarding various subtopics in aromatherapy.

Next, I review all the considerations for oral administration of selected essential oils for intestinal discomfort. In this portion, I discuss what the research states about their mechanisms of actions (including their effects on the microbiome) and dosages reported in clinical trials, if available.

I have also included a table that can be used as a dilution guide and for conversions of measurements to accurately dose essential oils. It is applicable for all modes of administration. Finally, I provide insight on how I use them with my clients.

After understanding all the complexities of prescribing essential oils using this example, doctors can apply this knowledge and find information for selecting specific essential oils for other areas of pain relief within Part II of my first series.

The Art and Science of Aromatherapy- Considerations, Caveats, and Controversies

Precise dosages, applications, and safe use of essential oils are unfamiliar to many practitioners. To complicate matters, they are also controversial among aromatherapists trained in different schools of applications. This is due to differences in training and licensing requirements for aromatherapy certifications. ^5-9

Currently, there is no international standardization for aromatherapists. The National Association for Holistic Aromatherapy and Alliance of International Aromatherapists are two well-known professional organizations.^5-8

To compound matters of confusion, there have been several misleading headlines in the media on the actions of essential oils.^10-13 These have often been based on extrapolations from in vitro or in vivo studies that assess only one or two constituents that are found within them. These same experiments also often dose at much higher levels than would be administered therapeutically of an essential oil.^10-26

This has led many busy physicians and intelligent scientists to falsely equate the same mechanism of action of an essential oil’s isolated compounds to the oil itself. Unfortunately, these assumptions have resulted in physicians believing that some essential oils are risky and unsafe for their patients.^10-14 The most recent flashy lead story, “Will Essential Oils Like Lavender and Tea Tree Make Your Breasts Larger?” is an example of this hype.¹¹

Below are evidence-based reasons why one should remove these biases and not make this error of comparison. Rather, one should consider the synergistic effects of an essential oil, which is comprised of hundreds of different compounds and their total effect in humans,^15-26 not a single component’s effect in petri dishes or rats.

1. Petri dish studies have been inconclusive in outcomes^-16 and have questionable validity due to the use of plasticizers, which can interfere with the test results.^{15-16, 20-21}

2. Toxicology reports are often based on in vivo studies using isolated compounds and nonapplicable methods of administration for humans (e.g., gastric lavage). Furthermore, rodents’ metabolism of various substances differs from people. ^17-19,23

3. The property of synergism of essential oils modulates the actions of all the compounds present and may impact a human’s metabolome in individualized ways.^24-26

It is imperative that one understands these points when considering the use of essential oils to real world applications.

Factors Related to Safe Use of Essential Oils

The three most common and routine routes of administration include the following:

1. Inhalation, including direct inhalation, palm inhalation, diffusion, steam inhalation, and spritzers;

2. Topical application, including massage, body oil, lotions, creams, baths, and use in dressings; and

3. Ingestion (oral).^{5, 7-9}

Other applications, rectal and intravenous, have been reported in the literature. These are not often used or recommended by most schools of aromatherapy.^27-28

Whichever method used, safety is always the first consideration. This is based on several factors. According to the National Association for Holistic Aromatherapy (NAHA), these are quality, quantity, chemical composition of the oil, integrity of the skin, and age of the individual.²⁹

I believe that the safe application method and dosage of essential oils should also be based on the user’s knowledge, experience, preference, and comfort level. It is also important to consider the essential oil being prescribed and the synergistic, epigenetic, and biotransformation properties of both the essential oil and the individual. Therefore, my additions to the list of safety factors include (1) understanding essential oil mechanisms of actions and their metabolism and (2) medication and lifestyle factors (epigenetics) that influence essential oils’ effects.

Integrity of the skin and age of the individual are self-explanatory and should already be familiar with the practitioner. Although a full review of all these other factors is beyond the scope of the article, I will briefly touch upon them.

Quality and Standards

In discussing quality and standards of essential oils, it is important to denote the difference between them and risk association. For example, although the FDA regulates prescription drugs’ standards and quality, even correct dosage can lead to medical errors, side effects, and various toxicities.^30-35

For essential oils, the agencies of ISO (International Organization for Standardization) and the Association Française de Normalisation (AFNOR) are recognized by most aromatherapists for regulation, setting standards, and certifications. As with their standards across the market, those for essential oils are based on consensus and this means they have caveats and biases.^38-41

ISO standards exist for approximately 50 essential oils.^39,41 As noted on the ISO website: “ISO is an independent, non-governmental international organization with a membership of 161 national standards bodies. Through its members, it brings together experts to share knowledge and develop voluntary, consensus-based, market relevant International Standards that support innovation and provide solutions to global challenges.”³⁸

AFNOR is a member of ISO and develops their international standardization activities, information provision, certification, and training through a network of members of its own association.^39-41 AFNOR also does not claim to seek to ensure quality in their recommendations.^*asterisk (refers to footnote at the end)

In an email exchange between myself and a chemist from a well-known essential oil company, it was explained to me that the ISO standards for essential oils were created, in most cases, because an AFNOR standard existed. He stated that if an ISO/AFNOR standard is met, it will probably be a high-quality oil; however, this is not always the case.^*asterisk

These standards of essential oils are related to the relative percentage of certain constituents found within the essential oils that are deemed to be the most relevant for its effects. The values are usually determined from an analysis using a Gas Chromatology/Mass Spectrometry (GC/MS).^36-44 This method does not distinguish between natural or synthetic constituents; therefore, it cannot determine if there has been “spiking” of these substances with manipulated compounds or adulterants to reach accepted standardized levels.^42-44

The Caveats to Consider when Using GC/MS and Certificates of Analyses (CAs) to Verify Quality

Essential oil marketers may claim superiority of their essential oils based on GC/MC analysis and their verifications of analysis (CAs) that match ISO/AFNOR standards. Not being aware of the factors regarding GC/MS with essential oils, practitioners may make the false assumption that a CA for an essential oil provides a similar assurance of quality as their favorite brand of nutraceuticals.

Below is a summary of considerations regarding CAs of essential oils that highlights why relying on them to determine quality is incomplete.

• Not all essential oil manufactures agree on the standardized percentage of active constituents to achieve therapeutic benefits. Therefore, a physician must be aware of the effects they wish to deem from the selected essential oil and its chemotype. These various populations within the same species produce differing plant secondary metabolites with distinct effects.²

Oftentimes the genus and species will be labeled on the bottle and its “active” compounds are revealed in the product description. Otherwise, the chemotype is labeled as “ct” followed by the predominant constituent.

• As previously discussed, if a constituent is present on the CA, it does not ensure that it hasn’t been adulterated or synthetically spiked to achieve the standardized level.

Other companies will different constituents present on a CA could still be producing high quality essential oils. I will review some verification testing that companies may use to determine quality in the next section.** note at the end of text

• Plants will produce different percentages of compounds based on external pressures, their environment, the season, temperature, and climate. This means that there will be natural variations of components within the same chemotypes of essential oils. These cyclical changes in amounts of constituents on CAs does not necessarily indicate manipulation and adulteration of essential components.^45-47 Conversely, they are often a welcome pattern.

• Unavailability of CAs of competitor brands of essential oils does not necessarily mean that they are “hiding something.” Rather, they may be “protecting something.” Legalities regarding propriety blends and differing quality standards of several popular essential oil companies is making it more difficult to obtain some CAs.

Verification Testing for Quality Essential Oils

Companies that produce quality essential oils ensure impeccable sourcing of raw materials, optimal distillation techniques, verification of active compounds, testing for contaminants, efficient manufacturing procedures, and prioritizing sustainability. It is important to do your research on companies and find a supplier you trust for obtaining essential oils. I have made the effort to visit one company’s farms and witness their harvesting, sourcing, verification tests, manufacturing, and distribution to validate their integrity and authenticity.

Due to the complexity of essential oils, your company should use more than one verification test. As I’ve made evident, an online GC/MS of CAs will only get you so far. Make sure you understand and can verify which quality control methods a manufacturer uses. Below is an example of testing methods used, based on a popular essential oil brand:⁴⁸

• Densitometry

• Viscometry

• Refractometry

• Polarimetry

• Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

• Inductively Coupled Plasma-Atomic Optical Emission Spectrometry (ICP-OES)

• Gas Chromatography (GC)

• High Performance Liquid Chromatography (HPLC)

• Fourier Transform Infrared Spectroscopy

• Automated Micro-Enumeration

• Disintegration

• pH

• Microscopy

• Combustibility

• Flash Point

• Gas Chromatography Mass Spectrometry (GC/MS)

• Chiral Chromatography

• Isotope Ratio Mass Spectrometry (IRMS)⁴⁸

Quantity and Dosage Considerations for Essential Oils

Most health care provides have the “five rights” for the administration of drugs drilled into their heads from medical training. These are the right patient, the right drug, the right time, the right dose, and the right route.^49-51 This checklist may appear to make the administration of treatment less comprehensive and detailed than it truly is.^52-54 Within these parameters, most practitioners will consider the following influences more thoroughly:^52-59

• Mechanisms of action of the drug(s) and/or substance(s),

• Weight of the individual,

• Kidney and liver health,

• Most effective route,

• Allergies,

• The patient’s age,^52-54

• Relevant polymorphisms in biotransformation pathways,⁵³

• The patient’s current health conditions,⁵⁶ and

• Nutrient-drug and other interactions.^{53, 57-58}

Metabolism and Biotransformation of Essential Oils: Taking a Walk Down CYP450 Lane

We now have an awareness that quality and factors of quantity, including consideration of biochemical individuality and drug metabolism, is important for prescribing the safest dose of any medicine, natural or otherwise.

I will now focus on the liver biotransformation of some common essential oils and their metabolites indicated for pain and digestion. I will also further explain synergism and how this needs to be considered for essential oils’ metabolism and potential interactions. These aspects will help to guide the practitioner in deciphering how essential oils will be processed in each unique patient and their potential interactions with current supplements, nutraceuticals, and/or medications.

Chamomile Compounds

German chamomile (Matricaria recutita L.) herb and essential oil are both indicated for anxiety, irritation, inflammation, intestinal spasm/colic, and sedation.^60-63 According to Alternative Medicine Review,⁶¹ and verified in several sources:^60,62-63

German chamomile flowers contain 0.24- to 2.0-percent volatile oil that is blue in color. The two key constituents, (-)-alpha-bisabolol and chamazulene, account for 50-65 percent of total volatile oil content. Other components of the oil include (-)-alpha-bisabolol oxide A and B, (-)-alpha-bisabolone oxide A, spiroethers (cis- and trans- en-yn-dicycloether), sesquiterpenes (anthecotulid), cadinene, farnesene, furfural, spathulenol, and proazulene (matricarin and matricin). Chamazulene is formed from matricin during steam distillation of the oil. Yield varies depending on the origin and age of the flowers. European Pharmacopoeia recommends chamomile contain no less than 4 mL/kg of blue essential oil.⁶¹

It is important to know the species and chemotype of German chamomile oil when using it in clinical practice. Although similar, it cannot be blindly interchanged for Roman chamomile essential oil due to their different biochemical makeup. Notably, for those on anticoagulants, there are levels of coumarins in Roman chamomile oil. As stated in one review:

Roman chamomile contains up to 0.6% of sesquiterpene lactones of the germacranolide type, mainly nobilin and 3-epinobilin. Both α-bisabolol, bisabolol oxides A and B and chamazulene or azulenesse, farnesene and spiro-ether quiterpene lactones, glycosides, hydroxycoumarins, flavanoids (apigenin, luteolin, patuletin, and quercetin), coumarins (herniarin and umbelliferone), terpenoids, and mucilage are considered to be the major bio-active ingredients.⁶²

The evidence for interactions with liver enzymes is not conclusive. One in vitro study of German chamomile tested its effects on four selected human cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2D6 and CYP3A4). The researchers’ conclusions were based on increasing concentrations of major constituents incubated with recombinant CYP isoforms. They reported the following:

1. CYP1A2 was most inhibited by chamazulene (IC50 = 4.41 microM), cis-spiroether (IC50 = 2.01 microM) and trans-spiroether (IC50 = 0.47 microM) and active towards CYP3A4.

2. CYP2C9 and CYP2D6 were less inhibited, only chamazulene (IC50 = 1.06 microM) and alpha-bisabolol (IC50 = 2.18 microM) revealed a significant inhibition by the latter.⁶⁴

There are several caveats with these conclusions that were discussed above. It is biased to base effects on isolated compounds in petri dishes to actions of the essential oil in humans.

Natural Medicines rates German chamomile’s evidence for inhibition of liver enzymes as “D” level, an anecdotal and minor interaction. It does report a potential moderate interaction in combination with two medication classes, sedatives and oral contraceptives. Although this is also based on anecdotal evidence, it is rated “moderate” because the effect can result in a more severe impact.⁶³

Regarding safety, German chamomile herb is generally regarded as non-toxic ^60-63 and has evidence of beneficial use in human trials.⁶³ Natural Medicines reported the following for German chamomile essential oil: “Six drops of oil infused with German chamomile flower has been safely applied nightly for up to 6 weeks in children 6-18 years-old (98621).”

There is one report of a woman who was on warfarin and after taking chamomile herb concurrently experienced hemorrhaging. A review on this plant states that the small amounts of coumarin content present in German chamomile likely would not have contributed to this.⁶¹ This holds for the essential oil of Roman chamomile as well.⁶¹ It could be that that the tea was Roman chamomile, which as previously stated does contain coumarins. This is not verifiable by the review.

A contraindication of using German chamomile is that those with allergies to the Asteraceae/Compositae family (ragweed, chrysanthemum, marigold, daisy, etc.) may experience cross-over hypersensitivity reactions to chamomile ^60-64 and the essential oil.

Citrus Oils Constituents – First the Furanocoumarins

Citrus oils are common essential oils and have a high percentage of limonene content,⁶⁵ a compound often used for relief of heartburn, dissolving cholesterol-containing gallstones, and as a chemopreventive.⁶⁶ Components in the essential oil differ from citrus fruits, pulps, or juices. The volatiles make up 85-99% of total weight. These include limonene (a monoterpene), terpenoids, aldehyde, alcohols, esters, acids, and trace levels of sulfur and nitrogen compounds. Non-volatiles (PMF, furanocoumarin) make up the remaining amount of the essential oil.⁶⁵

Due to the small amount of furanocoumarin present in the essential oil of citrus oils, the well-known interaction between grapefruit juice and the CYP34A enzyme is unlikely and less of a concern. ^65-68 I will still always suggest monitoring by the prescribing physician with any new intervention. I personally am especially vigilant if clients are of the “sensitive type,” on several medications, herbs, and/or supplements, and/or has clinically relevant genetic variances.

Citrus Oils Constituents and Biotransformation

A thesis to determine the extent of inhibition of nine citrus essential oils on three CYP450 enzymes is often referenced to provide “evidence” of citrus oils impacting liver biotransformation. Although the author proved that limonene alone, the most abundant constituent did not have an influence on biotransformation, different citrus oils tested had differing outcomes in this in vitro study. The author concludes:

The results for CYP2E1 concluded that Citrus tangerine, tangerine, was the most potent inhibitor and inhibited through competitive inhibition. The results for CYP3A6 concluded that none of the nine citrus essential oils inhibited the activity of CYP3A6 at a good quality concentration. Lastly, the results for CYP2A6 concluded that both Citrus bergamia, bergamot, and Citrus aurantifolia, lime, were strong potent competitive inhibitors at low concentrations with a KI of 0.878 µg/mL and a KI of 0.045 µg/mL. The inhibition of CYP 2A6 has recently been identified as a possible therapeutic approach to smoking cessation, therefore giving significant importance to bergamot and lime oils and the compounds found in them.⁶⁹

It’s important to note that this thesis was done on rat liver microbiomes and the assays themselves may have altered the constituents in the essential oils.⁶⁹ This petri dish study once again makes the accuracy in findings to essential oils and human metabolism very questionable.

Citrus Oils and Limonene Metabolism

Although biases do exist on isolated constituents’ actions being extrapolated to an essential oil’s effects, the mechanisms for metabolism of citrus oils in human trials are lacking. Therefore, it may be somewhat appropriate to consider how limonene undergoes biotransformation and is metabolized, given that citrus oils are mostly limonene by weight. The popularity of the limonene supplement has made the study of this in vivo and in human trials more readily accessible.^{66, 70-76} According to a review in Examine:

Limonene is rapidly and almost wholly absorbed in the GI tract after ingestion, and then gets divided to various body tissues after first pass metabolism in the liver where it may be subject to metabolism into carveol metabolites or perillyl metabolites by CYP2C enzymes of which inter-species differences exist.⁷¹

After a 1.6g dose, between 52-83% of the dose is excreted in 48 hours and no build up of the compound is seen 21 days after cessation. The half-life of D-limonene in humans is estimated to be between 12 and 24 hours.

The primary metabolites of limonene in humans are perillic acid, dihydroperillic acid, and limonene-1,2-diol. These metabolites are glucuronidated by the liver and excreted via the urine.⁷¹

The supplement is generally considered safe in humans, though reports of toxicity exist in vitro and in vivo.^66,70-71 The IARC monograph on limonene reports that rodents’ metabolic processing of this compound are unlikely to be correlated to human effects:

Limonene is metabolized in humans and experimental animals to a variety of metabolites, including perillic acid and d-limonene-1,2-diol. Although deemed nephrotoxic in rats, this monograph reviewed in detail the difference between the metabolites interaction with proteins formed in rats versus with human urine protein content.⁷⁰

The Alternative Medicine Review validated these conclusions and further expanded on its distribution and safety profile.⁶⁶ Limonene is reported to be rapidly distributed to tissues in the body, and its metabolites are detectible in the blood, liver, lung, kidney, with the highest amount found in fatty tissue. No accumulation of the metabolites was found in 21 days of repetitive dosing in one study.^66,70

In summary, the safety of limonene has been validated; however, it is important to note that it is metabolized by CYP2C enzymes and is glucuronidated. This could impact other medications.^70-71 Natural Medicines reports the evidence for inhibition as “D” level evidence, anecdotal and preliminary.⁷⁶

How Synergy in Essential Oils Impacts Their Effects

Now that we understand the complexity of determining the exact mechanisms of essential oil biotransformation in studies based on single constituents, I want to further discuss the topic of synergism and essential oils. As already stated, extrapolation of mechanisms from their isolates is just that, an assumption based on the trend of behavior of one compound. These actions will likely not correlate or fully represent how unaltered essential oils behave as a synergistic symphony within humans’ complex systems.

Although essential oils contain different constituents at a higher potency than extracts and herbals, The School for Aromatic Studies provides a wonderful definition of this concept of synergy used herbal medicine:

Many herbalists acknowledge that one of the main differences between whole herbs and traditional extracts on the one hand, versus individual vitamins, minerals, isolated phytochemicals, or conventional single – molecule drugs on the other hand, is the principle of synergy.

Synergy can be defined in a number of ways, but the underlying idea is that complex interactions among the many constituents of an herb give rise to its unique characteristics, personality, and healing properties. To borrow a concept from physics, the very complexity of a living plant – which contains perhaps thousands of interacting chemicals – gives rise to emergent behavior: activities and effects which could not have been predicted from what is known about the individual components of the system. In other words, the whole herb is far more than the sum of its constituents.

– Lisa Ganora ‘Herbal Constituents’⁷⁷

A 2014 article titled, “Essential Oils, A New Horizon in Combating Bacterial Antibiotic Resistance,” discusses how synergism is related to essential oils’ actions in combination with antibiotics. The researchers noted that essential oils have multifactorial effects based on these complex molecular properties in combination with their aromatic influences. Furthermore, they are lipid soluble, which improves their bioavailability. ⁷⁸ This should be noted when comparing an essential oil compound found in a capsule or tablet to ingesting the unaltered essential oil. The authors stated:

It is likely that several components in essential oils play a role in characterizing the fragrance, the density, the texture, the color, ability in cell penetration, lipophilicity, fixation on cell walls, and most importantly the bioavailability. Considering that a vast range of different groups of chemical compounds are present in one essential oil, it is most likely that antibacterial activities cannot be attributed to one specific mechanism or component; and hence, there may be several targets in a cell which result in the potentiating influence. Thus, it is more meaningful and rational to study the whole essential oil rather than some of its components as whether concept of synergism truly exists between the components in essential oils.⁷⁸

The Isolates vs. the Oil – Metabolism and Medications

To contrast studies on their isolates, Examine compiled a synthesis of research on the essential oils of lavender and peppermint. Silexan, a proprietary lavender essential oil preparation that is standardized for 20-45% linalool and 25-46% linalyl acetate was reported to have no significant effect on CYP450 enzymes:

Oral ingestion of Lavender oil at 160mg (as the brand name product Silexan) in otherwise healthy persons over 11 days had no significant effect on CYP1A2, CYP2C9, CYP2D6, and CYP3A4 as assessed by drug pharmacokinetics relative to placebo, while the influence on CYP2C19 appeared to be affected but was not deemed to be clinically relevant.⁷⁹

In the review of peppermint, Examine reported that menthol may effect CYP2D6 due to its inhibition of coumarin 7-hydroxylation, which may account for how peppermint tea was reported to affect drug levels of nicotine. However, compared to its isolate on CYP3A4, peppermint oil had a different dosage level of interaction and a reversable effect. The website states:⁸⁰

Menthol has been confirmed to inhibit coumarin 7-hydroxylation (CYP2D6 mediated) with an IC₅₀ of 70.49μM (the (-)-menthol isomer) or 37.77μM (the (+)-menthol isomer) which is thought to underlie the increased ratio of nicotine to cotinine seen with coingestion of peppermint tea with nicotine, as nicotine is converted to cotinine by two enzymes (one of which is CYP2D6^[29]).

Peppermint also appears to inhibit CYP3A4 in a reversible manner, which was thought to be due to the menthol content; peppermint oil had a K_i of 35.9+/-3.3µg/mL and menthol a K_i of 87.0+/-7.0nM/mL. This was confirmed to increase the AUC of felodipine by 140%, which underperformed relative to grapefruit juice as a reference (173%).⁸⁰

I cross-referenced the cited reference in the above excerpt and found it was a two-part study. The first part was an in vitro experiment using human liver microsome cells to assess this inhibitory effect on CYP enzymes. The second part of the experiment was a randomized four-way crossover study on oral pharmacodynamics in 12 volunteers. The interventions consisted of administration of 10-mg ER felodipine tablet in combination with either grapefruit juice (300 mL), peppermint oil (600 mg), ascorbyl palmitate (500 mg), or water.^80-81

The conclusions were more nuanced in the referenced study. The authors reported that peppermint oil was a moderately potent reversible inhibitor of in vitro CYP34A activity and the results of the human trial were inconclusive:⁸¹

Peppermint oil, menthol, menthyl acetate, and ascorbyl palmitate were moderately potent reversible inhibitors of in vitro CYP3A4 activity. Grapefruit juice increased the oral bioavailability of felodipine by inhibition of CYP3A4-mediated presystemic drug metabolism. Peppermint oil may also have acted by this mechanism. However, this requires further investigation. Ascorbyl palmitate did not inhibit CYP3A4 activity in vivo.⁸¹

Liver’s Darling Defense and Essential Oils – Glutathione and Phase II Metabolism

Another contention between essential oil users, aromatherapists, researchers, and the media is the topic of liver damage. Some claim they harm this precious organ while others deem they protect it.^81-82 There are several aspects to consider with this, and the most pertinent is its link to phase II metabolism and glutathione.

First, due to the need to be metabolized, any external foreign compound at the right dosage could potentially damage the liver. This is related to the production of excess electrophiles. The liver is usually able to neutralize these “free radicals” through a multiplicity of glutathione enzymes and by a nonenzymic conjugation with glutathione (GSH). However, when these systems are overwhelmed, damage can ensue.^81-87

It’s important to realize that essential oils act synergistically; and along with compounds that may modulate biotransformation, many are antioxidants.^{82, 88-96} In fact, some constituents and essential oils (e.g., lemongrass and rare citral containing oils,⁸⁸ black cumin,⁹³ cumin, fennel, and clove ⁹⁴) have been found to increase glutathione in vitro and in vivo.^{88, 93-95} For example, fennel and thyme oil have protected against damage to the liver from carbon tetrachloride.⁸² Therefore, a blanket statement of an essential oil causing liver damage is radically unfounded.

Glucuronidation and Essential Oils

Oils that contain phenols, such as carvacrol found in oregano, methyl salicylate in wintergreen, eugenol in clove, and thymol in thyme, go through glucuronidation. This is something to consider if one has a single nucleotide polymorphism (SNP) in this enzyme or using medications that are cleared by this pathway. Drugs to be aware of when using these essential oils include aspirin, propofol, acetaminophen, and carprofen. Those with a phenol sulfur-transferase (PST) SNP may also want to be cautious of oils high in phenols.^97-99

A little note for animal lovers and their cats on this topic. Unlike humans, kitties lack the phenol UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6 and UGT1A9; therefore, one may want to be cautious with these oils around their furry friends as well.¹⁰⁰

The Medication-Essential Oil Interaction Effect Summary for the Clinician

Although experimental and clinical trials can be helpful in determining general responses for a single intervention in an overall population, it is important to remember that due to epigenetic factors, individual responses to any modality will differ. As integrative medicine practitioners, we often get the “outliers,” with whom unexpected outcomes from common interventions occur. This consideration is not only important in deciding which essential oils to choose, but how to use them with other health modalities.

As with any new intervention to err on the side of caution is warranted. I always start with one essential oil at a time until I know the client’s response. I will also monitor responses and dosages throughout use. I only introduce additional therapies sequentially, as needed, after the half-life of the modality and the body has time to respond.

I have covered a lot of details, therefore, my key points to remember for potential interactions of essential oils with drugs and for any intervention are listed below. These are based on my experience with clients and from my review of the literature above.

1. Natural does not mean inert. Any supplement, herb, essential oil, nutraceutical, or drug will impact the organs of elimination and excretion because they all need to be processed by the body. Interactions with them can occur with nutrients, foods, and between modalities.

2. Everyone is different, with different detoxification capacities and abilities to metabolize drugs, supplements, and nutrients. This can result in “unusual” effects for some people. Therefore, it is often helpful to check clinically relevant detoxification SNPs in sensitive patients and to not dismiss them as “head cases” when they report strange responses to any intervention.

3. For those on medications that must be dosed and kept within narrow ranges of blood values, allow at least 2-3 hours between taking them and using essential oils. Monitor responses more frequently and during the introduction of the essential oil or additional intervention.

If one is on anticoagulants, such as heparin or warfarin, and/or antiplatelet drugs, such as aspirin, only introduce the use of essential oils if “clotting time” is being monitored. This includes prothrombin time (PT) and international normalized ratio (INR). Some essential oils that may present with the highest risk with these medications include:

• Birch (Sweet) (Betula lenta)

• Garlic (Allium sativum)

• Oregano (Origanum onites as well as the following synonyms Origanum smyrnaeum, Origanum vulgare, Origanum compactum, Origanum hurtum, Thymbra capitata, Thymus capitatus,Coridothymus capitatus, Satureja capitate)

• Tarragon (Artemisia dracunculus)

• Wintergreen (Gaultheria fragrantissima)^43,101

4. According to Therapeutic Benefits of Essential Oils, Nutrition, Well-Being and Health, most components of essential oils are taken in then metabolized by limited phase I, followed by glucuronidation and sulfation through the kidneys as polar compounds or exhaled through the lungs as CO2.¹⁰¹

This means that if a person has reported drug and supplement effects in alignment with “sensitive” types, SNPs in phase II metabolism should be considered. Those with compromised kidney health and lung capacity should also be monitored closely. The practitioner should evaluate kidney and lung function in these patients, as they would any intervention.

Overall, there is small risk for accumulation due to their short half-life and fast metabolism.^{82, 101}

5. Most studies that have reported liver toxicity with essential oils involve ingesting more than 5ml of essential oils at a time.^{19, 102-106} Considering the appropriate dosage should be one to two drops, these reports are not really “toxicity” issues, rather they are overdosages. Furthermore, trials in vitro and in vivo have provided evidence that some essential oils can induce glutathione and act as antioxidants, protecting the liver.

6. After over eleven years of using essential oils with my clients and seventeen years of personal use, I have found that some of the earliest signs of inappropriate dosage of essential oils can be complaints of headaches and/or frequent urination.

I have noticed that headaches are usually a result of their aroma, causing overstimulation of easily excitable neurons at a low threshold. This usually occurs in “sensitive patients” that note they commonly react to smell and generally have a high body burden of toxicants. Usually, after supporting their biotransformation pathways with nutrients and herbals and/or supporting functional neurology factors (e.g., oxygenation, blood sugar, mitochondrial and neurological stimulation through exercise), these clients can then introduce essential oils into their protocol. This most often occurs with inhalation methods versus ingestion.

If one is using excessively high dosages, it can overwhelm a compromised metabolic pathway in the liver and kidneys. Due to the fact the kidney is responsible for glucuronidation and sulfation of some essential oils constituents, urination may increase as the body tries to metabolize them. Therefore, be extra cautious with proper dosage and use in those with liver and kidney compromise and/ or with multiple sensitivities.

7. Children and those on many medications should use three-quarters to half potency when using essential oils topically and internally. Infants should not use topical or oral routes for essential oils, unless caregivers are well-versed in diluting essential oils. (Specific dosage charts exist for pediatrics and are available online.) I have found many adult clients need less medication, and some even discontinue medications with time, if their prescribing physician works with us and is open-minded and integrative.

8. Within the literature, aromatherapy is deemed overall safe and beneficial when used properly and safely.^105-108

If you’d like additional details on essential oils, medication interactions, and safety on my essential oils, please visit my essential oils database under the category “children and safety” found at http://dr-lobisco.com/essential-oils-database/.

Internal Usage of Essential Oils: Controversy, Scare Tactics, and Bad Science

Now that we have knowledge of the basic overview of application of essentials and have safety information regarding their biotransformation and metabolism, it is time to discuss how to use them orally. First, let’s consider the hesitancy that may be present in a practitioner.

As stated above, this is the most debated method of aromatherapists in the United States. However, this is not the case in France and Germany.^{5-8, 109} The National Cancer Institute states:

Although essential oils are given orally or internally by aromatherapists in France and Germany, use is generally limited to inhalation or topical application in the United Kingdom and United States. Nonmedical use of essential oils is common in the flavoring and fragrance industries. Most essential oils have been classified as GRAS (generally recognized as safe), at specified concentration limits, by the U.S. Food and Drug Administration (FDA). (Refer to the International Federation of Aromatherapists website [www.ifaroma.org/] for a list of international aromatherapy programs.)

What many may not realize is that ingesting essential oils has been practiced worldwide for years via their use as flavoring agents. Currently, many are listed under the Substances Generally Recognized As Safe (GRAS) by the FDA (available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=182.20.)

Furthermore, Germany has a history of their internal use and has guidelines issued by The Commission E for their indications.⁹ For example, fennel essential oil has been used for orally for a wide array of intestinal issues.^{9, 110-114} According to the Expanded German E Commission by the American Botanical Council, this essential oil has vast applications and specific dosages of administration:

The Commission E approved the internal use of fennel oil preparations for peptic discomforts, such as mild, spastic disorders of the gastrointestinal tract, feeling of fullness, and flatulence; and also for catarrhs of the upper respiratory tract. Fennel honey was recommended for catarrhs of the upper respiratory tract in children. ESCOP approves the use of fennel syrup or fennel honey for catarrh of the upper respiratory tract in children (ESCOP, 1997).

In Germany, fennel seed is licensed as a standard medicinal tea for dyspepsia. It is also used in cough syrups and honeys (antitussives and expectorants), and stomach and bowel remedies, especially in pediatrics, as aqueous infusion, water (Aqua Foeniculi), drage (lozenge), juice, and syrup. It is often used in combination with aniseed (Leung and Foster, 1996; Wichtl and Bisset, 1994). In the United States, it is also used as a component of galactagogue preparations. Indications for use of fennel oil are similar to those for fennel seed. In Germany and the United States, fennel oil is used as an expectorant component of cough remedies, and also as a carminative component of stomach and bowel remedies in dosage forms including honey and syrup. Traditionally, it is combined with laxative or purgative herbs to counteract or modify their harsh griping effects in the bowels (ESCOP, 1997; Leung and Foster, 1996; Nadkarni, 1976; Wichtl and Bisset, 1994). The Commission E limits the use of fennel seed and fennel oil for up to two weeks and then recommends consulting a physician.¹¹¹

Although the European Union is currently replacing the German E Monographs by EMA Community Monographs, they are still considered an authoritative reference, according to Mark Blumenthal, the founder and direction of the American Botanical Council (ABC).^115,116

I believe that this oil is a perfect example of scare tactics regarding ingestion of essential oils. Many proclaim that this essential oil is toxic, dismissing Germany’s history of use and its presence in the food supply. This is mostly based on toxicology studies of one of its isolated compounds, estragole, from in vivo and in vitro trials. These are unfounded extrapolations as a 2012 review published in Evidence-based Complementary and Alternative Medicine provides evidence for. The authors state the following reasons for this:

• Studies do not assess quality of the whole fennel oil.

• Metabolism and biotransformation differences in humans and rodents.

  • It was reported that human liver cells have a high level of an enzyme that provides protection against the harmful reactants resulting from estragole metabolization in rodents that produce negative effects. (Allylic epoxide hydrolase activity is seven to 10 times higher than that seen in rat liver).

• Synergy

  • The article states, “In humans estragole usually enters the body as a component of fennel tea, or as a food that has been seasoned with herb that contains many other substances like nevadensin, epigallocatechine, other flavonoids, and anethole [in essential oil], that have a protective role and so counterbalance to the possible effect of pure estragole.”¹⁹

The authors of this review conclude, “Consideration of these issues (dose, administration form, and differences in metabolism between species) raises doubts about the conclusion that fennel seed can be ‘reasonably anticipated to be a human carcinogen.’ It is clear that human and animal metabolism cannot be directly compared but we think data should deserve attention.”

These three main points of quality, differences in metabolism and biotransformation, and essential oil synergy should be kept in mind by practitioners when determining the safety and application of essential oils. Furthermore, one should always be cautious to not take at face value headlines and hype that are aimed to produce fear of natural substances.

References are posted with the online article.

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*Due to FDA regulations, my affiliations, and legalities, I am unable to make specific references or recommendations of brands.

**There is one branded essential oil company with approval for internal ingestion from the FDA. It is the only dietary supplement line of essential oils.

Table 1:

Essential Oils Conversion and Measurement Chart

1 oz. = 30 ml

1 oz. = 600 drops essential oils

1 oz. = 2 Tbsp. or 6 tsp.

Using these conversions:

6 drops of EO per oz. of carrier oil = 1% dilution (1% of 600 drops)

3 drops of EO per Tbsp or 3 tsp. = 1% dilution (1% of 300 drops)

1 drop of EO per tsp. = 1% dilution

1 drop of essential oil = approximately 0.02 to 0.03 grams = 20-30 milligrams = 20000 micrograms (µg).

30 mg = approximately 1 drop*

*Compiled from references 157-161